Table Of Contents:

What’s included: Ready-to-study summaries on a broad range of pharmacological concepts and drug-classes,
presented in succinct, intuitive and richly illustrated downloadable PDF documents. Once downloaded, you may
choose to either print and bind them, or make annotations digitally on your ipad or tablet PC.

Please Note: This subject is intended to give a summarized overview of a wide variety of theoretical pharmacological
concepts and clinical therapeutic indications. It is not intended to be an exhaustive list of all known drugs, or a
guideline for management of actual patients. Please always refer to your local therapeutic guidelines prior to making
treatment decisions.

Pharmacology Notes:
• INTRODUCTION TO CLINICAL PHARMACOLOGY
• PHARMACOKINETICS
• PHARMACODYNAMICS
• ANTIMICROBIAL THERAPY & SELECTIVE TOXICITY
• ANTI-ARRHYTHMIC DRUGS
• COMMON DRUGS USED IN ISCHAEMIC HEART DISEASE
• COMMON DRUGS USED IN MANAGING CHOLESTEROL & LIPIDAEMIA
• COMMON DRUGS USED IN MANAGING HEART FAILURE
• TREATING DIABETES
• TREATING THYROID DISORDERS
• TREATING HYPERINFLAMMATORY DISORDERS
• MODIFYING SEX-HORMONE PROFILES
• GASTROINTESTINAL DRUGS
• GENERAL NERVOUS-SYSTEM DRUGS
• EPILEPSY & ANTI-EPILEPTIC DRUGS
• ANESTHESIA & ANALGESIA
• PSYCHOSIS & ANTI-PSYCHOTICS
• AFFECTIVE DISORDERS, ANTI-DEPRESSANTS AND MOOD-STABILISING DRUGS
• DRUGS FOR HEMOSTASIS
• DRUGS FOR FLUID & ELECTROLYTE BALANCE
• DRUGS USED IN HYPERTENSION
• DRUGS USED IN CHEMOTHERAPY
• INTRO TO TOXICOLOGY
INTRODUCTION TO CLINICAL PHARMACOLOGY:
INTRODUCTION TO CLINICAL PHARMACOLOGY:

General Advice For Studying Drugs as a Medical Student – (Compartmentalize Everything):

- 1: Focus on Drug Groups/Families first (not individual drugs); (Exception: Generic names for ‘stand-alone’
drugs that don’t have a group – eg: Anti-epileptics/Adenosine/Digoxin/Phenytoin/etc):
o Learn The Common Suffixes – (Eg: “-olol”, “-statin”, “-opril”, “-epam”, etc)

o Learn The Primary Uses – Selected Clinical Applications & Implications

o Learn Key Side-Effects – (Most side-effects are due to mechanism of action, so you shouldn’t have to
m em orise them – Except idiosyncratic side-effects)

- 2: Learn the Mechanism of Action of each drug Group/Family:

o @ The Cellular Level – Ie: Target on the cell & Effects on the cell
o @ The Physiology Level – Ie: How the Cellular Effects change the Body’s Physiology

Eg: Amlodipine = Calcium Channel Blocker (@ Cellular Level); Antihypertensive (@ Physiological Level)
Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO
- 3: Then you can assimilate individual drug names into each Drug Group:
o Eg: Benzodiazepine Family includes: Diazepam, Lorazepam, Clonazepam, Midazolam, etc
o Eg: Opioid Family includes: Codeine, Morphine, Buprenorphine, Oxycodone, Methadone, etc
- 4: Focus on General Therapeutic Principles for treating certain diseases (Rather than specific drugs):
o Eg: Heart Failure is treated with ACE-Inhibitors, Beta-Blockers, and Diuretics
o Eg: Asthma is treated with Bronchodilators (Adrenergic & Anti-cholinergic), Corticosteroids (inhaled)
& other Novel drugs (eg: Montelukast, etc)

(Example of the general therapeutic algorithm for asthma). Source: https://ginasthma.org/

- Save learning specific Clinical Therapeutic Guidelines for the workplace

o Why?
§ Therapeutic Guidelines are specific to your location/workplace/hospital/health-system
§ Therapeutic Guidelines change regularly and without warning
§ Likely, by the time you graduate, the specific drug/dose/guideline will have changed
§ When treating your patient, you’ll want to check the most up-to-date guidelines first
anyway, regardless of what convention you learned in medical school
o Instead, if you insist on learning the current Therapeutic Guidelines now, then do it more to aid
your own understanding of the treatment rationales, than for use in future clinical practice; Eg:
Definitions for Keywords:
- Drug:
o A Chemical substance of known structure, other than a nutrient or an essential dietary ingredient,
which, when administered to a living organism, produces a biological effect
- Chemical Name:
o Describes the chemical structure (Eg: N-(4-hydroxyphenyl)acetamide = Acetaminophen Aka:
Paracetamol )
- Generic Name:
o The generally-agreed upon official name for a drug (Eg: Acetaminophen / Paracetamol)
- Trade/Brand Name:
o The brand name/registered trademark (Eg: Tylenol / Panadol)
- Pharmacodynamics:
o Describes the drug’s effect on the body at the receptor level, including efficacy, potency, agonism
and antagonism
- Pharmacokinetics:
o The relationship between drug administration, time-course/rate of absorption & distribution,
concentration changes in the body, and the drug’s removal from the body
- Selective Toxicity:
o A useful feature of Chemotherapy & Antibiotic drugs – Ie: Drugs that are ‘Selectively Toxic’ to
Microbes/Tumours, while having minimal effects on the host
o Selective Toxicity depends on the ability to exploit Biochemical differences between
Microbes/Tumours & the Host
- Agonist:
o A drug capable of binding and activating a receptor, leading to a pharmacological response that may
mimic that of a naturally occurring substance. Can be classified as full, partial or inverse
- Antagonist:
o Does not produce a biological response on binding to a receptor but instead blocks or reduces the
effect of an agonist. It may be competitive or non-competitive.
- Allosteric modulator:
o A drug that binds to a receptor at a site distinct from the active site. A conformational change is
induced in the receptor, altering the affinity of the receptor for the endogenous ligand.
- Desensitization
o A loss of responsiveness which may be due to the continued presence of an agonist at a receptor or
repeated presentation of the agonist
- Efficacy
o Used to describe agonist responses in relation to receptor occupation. High efficacy agonists can
produce a maximal response whilst occupying a relatively low proportion of receptors.
- Half-life (t½)
o The metabolic half-life of a drug in vivo is the time taken for its concentration in plasma to decline to
half its original level
o Clearance and distribution of a drug from the plasma are important parameters for half-life
determination
- Potency:
o Measure of the effective concentration of a drug. It is a vague term and it is advisable to further
categorise the measurement
- Occupancy
o The proportion of receptors to which a drug is bound
Quality Use of Medicines – Ie: Choosing Between Drug Therapies:
- Beneficial Effects:
o Where does the drug sit on the wide spectrum of benefits?:

ß Low-level relief, but ↑Quality of Life → Prevent/Control Serious Symptoms → Prevent Death →

- Harmful Effects:
o Where does the drug sit on the wide spectrum of drawbacks?:

ß Low -level harm , but tolerable → Serious/Severe Effects → Potentially Fatal→

- Cost-Benefit Analysis – Important Considerations for Therapeutics:

o Risk of Treatment Vs Risks associated with Non-Treatment
o Financial cost of treatment vs Opportunity cost of that money elsewhere (eg: Public health)
o Personal toll of side effects Vs Personal benefit of treatment

- Reducing Risk – How?:

o Get a better Understanding of the Disease:
§ Gives insight into potential Drug Targets
§ Helps explain to patient Why Drug is Useful/Necessary → ↑Patient Compliance
§ Understand How the Drugs Work (Major Effects/Side-Effects)
o Improve the Pharmacokinetics – Eg: Deliver drug Specifically to the Site of Action
o Improve the Pharmacodynamics – Eg: Use drugs that are more Selective (to receptor subtypes)
o Ensure Informed, Careful & Responsible Prescription

- Evidence-Based Medicine:
o Ie: Not Playing the Odds (Eg: Test to eliminate all other possibilities)
o All western medicines undergo multiple phases of drug testing prior to mass adoption
o “The Integration of Clinical Expertise with the Best Evidence from Systematic Research”

4 Qualities of A Good Prescription:

- 1: Judicious use of Medicines:
o Consideration of non-medical alternatives (Eg: Exercise to ↓BP rather than Anti-hypertensives)
- 2: Appropriate Use:
o Is the medicine chosen The Most Appropriate, given all clinical factors? (Eg: A K+ wasting diuretic in
someone with an existing arrhythmia)
- 3: Safe Use:
o Minimise Misuse – Ie: Make sure the patient knows how/when to use the drug (Eg: Diabetic taking
too much insulin → DKA)
- 4: Efficacious Use:
o Drug MUST deliver beneficial outcomes that are GREATER than adverse outcomes
“Traditional” Medicine Vs Western Medicine:
- Generally, Western Medicine is objectively more effective because:
o Purity of the active compound
o Accurate Dosage & Concentration
o Knowledge of Toxicity
o Note: Many existing drugs are purified from natural sources:
§ Atropine:
• Source – ‘Deadly Nightshade’ plant;
• Competitive Antagonist for the Muscarinic ACh-Receptor (Ie: An Anticholinergic);
• Prevents the Inhibitory action of the Vagus Nerve on the Heart → ↑Firing of SA-
Node & ↑AV-Node Conduction
§ Digitalis:
• Source – ‘Foxglove’ Plant;
• Decreases Na/K-ATPase function in cardiac myocytes → Na+ Accumulation → ↓Rate
of Na/Ca-Exchanger → ↑Intracellular Ca+ → ↑Refractory Period → ↓HR
• Useful in treating Atrial Fibrillation & Sometimes Heart Failure
§ Botox (Botulinum Toxin):
• Source – Bacterium Clostridium Botulinum
• Blocks ACh-Release from Pre-Synaptic Neurons
• Used to treat muscle spasms
§ Warfarin:
• Source – Woodruff plant
• Anticoagulant → Used as Primary & Secondary Prophylaxis for Thrombosis
§ Penicillin:
• Source – Penicillium Fungi
• Inhibits formation of Peptidoglycan Cross-Links in bacteria cell wall → Weakens
B a c te ria l W a ll → K ills B a c te ria → A n tib io tic
- Why some people prefer Traditional Medicine:
o Some people believe that “Natural” = “Safer” = Good for you … (Although not necessarily the case;
all of the most potent toxins and venoms are ‘natural’)
o May be ‘cheaper’ than prescription medicines … (Although not necessarily the case when taking into
account the Cost:Efficacy ratio)
o May be easier to purchase OTC (Over the counter)
o Common Eg: St John’s Wort – a crude OTC ‘antidepressant’ (Weak NA/5HT Uptake Inhibitor – similar
mechanism to SSRIs) – Risk of Serious Drug Interactions

https://www.amcollege.edu/blog/western-and-eastern-medicine
Drug Administration
- Goals:
o 1: Get it into the Circulation – So it can access its target tissue
o 2: Make sure it is a “Free-Drug” by the time it reaches its target – So it can exert its effect

- Routes of Administration:
o There are numerous routes of Administration (eg: IV/Oral/Suppository/Mucosal-Absorption)
o Choice depends on drug properties, desired onset, duration of action, pH of entry environment, &
bioactivation requirements (eg: Prodrugs)

- Tissue Reservoirs:
o After absorption, some of the Free-Drug is lost to Tissue Reservoirs/Blood Proteins
o Often bound drugs are released from tissues/proteins as the Concentration Of Free Drug dwindles
(Bound Drug ↔ Free Drug → Used/Metabolised)
- Target of Action:
o Where are the target Receptors/Enzymes/Cells/Tissues?
o Will Free-Drug in the blood be able to access its target?
 - Biotransformation:
o The Liver plays an important role in:
§ Bio-Activation: Drug Precursor → Active Drug Metabolites
§ Bio-Inactivation: Active Drug → Water-Soluble, Inactive Drug Metabolites
§ Detox: Toxic Substance → Water-Soluble, Non-toxic Metabolites
§ Conjugating: Ie: Making H2O-Soluble → Aids Renal Excretion
o Q: Does the drug pass through the liver before its target? (Eg: Yes- if oral; No- if IV)
- Excretion:
o Typically via the Kidney
o Substance must be H2O-Soluble

Pharmacokinetics Vs Pharmacodynamics:
- The TWO Influences on Drug’s Ability to Interact with its Target:
o 1: Pharmacokinetics: Access of the drug to its target, & subsequent Elimination from the body
o 2: Pharmacodynamics: Ability of the drug to Bind & Exert an Effect on the Target
PHARMACOKINETICS:
PHARMACOKINETICS

W hat is Pharm acokinetics? – “W hat the Body Does to the Drug”:

- The relationship between drug administration, time-course/rate of absorption & distribution, concentration
changes in the body, and the drug’s removal from the body

What Determines a Drug’s Pharmacokinetics?:

- Characteristics of Biological Membranes (across which ALL drugs must pass):
o Bi-phospholipid layer
o Hydrophilic Exterior
o Lipophilic Interior
o Selectively Permeable – allows passage of some, but not all drugs
- Properties of the Drug (Physical/Chemical):
o *** Lipid Solubility (High Solubility = High Permeability)
o Degree of Ionisation (Ionised/Charged molecules = Impermeable)
§ Determined by pKa (The pH where the drug is 50% Ionised)
o Molecular Size (Smaller = More Permeable)
- Concentration Gradient (Simple Diffusion):
o Most drugs cross membranes via Simple Diffusion
o ‘Diffusion-Controlled Distribution’ = Drugs will move down Concentration Gradients until
Concentrations of the drugs are equal in all parts of the body

W hy Pharm acokinetics is Im portant:

- A Drug must reach its site of action to exert its pharmacological effect
- 4 Things that determine the Concentration Of the drug at its site of action:
o 1: Absorption
o 2: Distribution
o 3: Metabolism
o 4: Elimination

Source: https://toolbox.eupati.eu/glossary/pharmacokinetics/
1: Absorption:
- Definition:
o The movement of the drug from site of administration into the plasma
o The Rate of Absorption determines the Intensity and Duration of drug action
o Eg: IV drugs bypass the problem of absorption because they’re instantly available in plasma
- Mechanisms of Drug Absorption:
o Most drugs are absorbed by Simple Diffusion → Therefore the Rate depends on:
§ Solubility (Influenced by pH & drug’s pKa)
§ Tissue Permeability
§ Surface Area
§ Blood Supply
o Other mechanisms include active transport, facilitated diffusion, etc
- (F) - Bioavailability:
o The amount of active drug that reaches the systemic circulation
o Is expressed as a percentage of the dose (Eg: IV dose has 100% bioavailability)
o Low ‘F’-values for Bioavailability occur with:
§ 1: Poorly Absorbed drugs
§ 2: Drugs that undergo extensive ‘First Pass Metabolism’ in the liver
o High ‘F’-Values for Bioavailability occur with IV dosing
- The ‘First-Pass’ Effect:
o Where a drug is metabolised by the liver before it reaches systemic circulation
o Results in reduced Bioavailability (F)
o Eg: An Orally-administered drug is:
§ 1: Absorbed in the GIT
§ 2: Transported via the Portal Vein → Liver
§ 3: Liver metabolises drug (first pass metabolism)
§ 4: Then releases metabolites into the systemic circulation
o Eg: Lignocaine – local anaesthetic & treat arrhythmias
§ If administered Subcutaneously, it is instantly at the site of action
§ If orally administered, all is absorbed, but none is available because it passes through the
liver before reaching the site of action

https://www.cyprotex.com/useruploads/ADME-Guide/Fig3-1-Metabolism-Schematic.png
2: Distribution:
- Definition:
o Movement of drugs between different body compartments and to the site of action
o (Ie: Once the drug is in the circulation, How Well & How Much gets to the site of action)
- Major Body Fluid Compartments:
o Plasma
o Interstitial Fluid
o Intracellular Fluid
o Transcellular Fluid (eg: CSF, Peritoneal Fluid, Pleural Fluid)
o Fat
o Brain
- Depends on Drug’s Ability to Cross Membranes:
o Lipid Solubility:
§ Lipophilic drugs readily cross membranes
§ Hydrophilic drugs don’t cross membranes
o Blood pH & Drug pKa:
§ Charged drugs don’t cross membranes
o Protein Binding:
§ Limits amount of drug that is free to cross membranes
§ Note: Generally, only unbound drug can be distributed across membranes
§ Most acidic drugs (Including All antibiotics) bind to albumin
o Regional Blood Flow:
§ Determines the amount of drug that is ‘available’ to that tissue in a given time period
- Vd - (Volume of Distribution):
o The volume that an Amount/dose (A) of a drug Appears to be dispersed in, given the Blood-
Concentration (C)
Vd = A/C
o This concept exists due to the fact that certain drugs disperse into different tissues more readily than
other tissues
§ Eg: For a drug confined to plasma, Vd = Blood Volume
§ Eg: For a drug distributed equally through the body, Vd = Total Body Volume
§ Eg: For a drug concentrated in the tissues, Vd = More than Total Body Volume
o It is useful for calculating initial loading dose (DL) to achieve a target (Steady-state) concentration
(Css):
D L = V d x C ss

- Multicompartment model:
o Drug can move from Blood → Other Tissues (eg: Nitrogen saturation in scuba divers doesn’t
distribute evenly between bodily tissues – eg: Prefers adipose tissue) – This is the same for many
drugs
o Drugs can move from Other Tissues → Blood (As blood Concentration decreases)
o Note: Redistribution of an administered drug out of the blood to another compartment reduces
blood levels – Hence the need for the Vd - (Volume of Distribution)
- Plasma Protein Binding:
o Drug molecules in the blood exist as EITHER:
§ ‘Bound’ Drugs: Bound to plasma proteins (eg: Albumin & a1-acid Glycoprotein)
§ or ‘Unbound/Free’ Drugs: Readily leave the circulation to distribute into tissues
- Depots:
o Certain body compartments with higher drug affinity than other compartments may act as a ‘drug
depot’, which will effectively store the drug and release it slowly over a longer period of time
o Eg: Fat is a depot for lipid soluble drugs (eg: Diazepam)
- Barriers:
o Certain specialised body structures limit/prevent diffusion of drugs
o Eg: Placenta, blood brain barrier
3: Metabolism / ‘Biotransformation’:
- Definition:
o Chemical transformation of a drug within the body as a result of ‘Biotransformation’
- Sites of Biotransformation:
o Mainly Liver
o GI Tract
o Lung
o Plasma
o Kidney
- Biotransformation may result in:
o Pro-Drug Activation:
§ Pro-drug → Active (for some drugs the active form of the drug is unsuitable for
absorption/distribution, and hence has to be administered in an inactive form that gets
metabolised by the liver into an active form)
o Drug may be Changed to another Active Metabolite
§ Eg: Diazepam to Oxazepam
§ Eg: Codeine to Norcodeine & Morphine
o Drug may be Changed to a Toxic Metabolite
§ Eg: Meperidine to Normeperidine
o Drug may be Inactivated:
§ Active Drug → Inactive form
- Factors Influencing Biotransformation:
o Interactions Between Drugs:
§ Drug-induced alterations of liver-enzymes: (includes herbal medicines & natural remedies)
§ Competition for metabolic pathways
o Enzyme Inhibition:
§ Enzyme inhibition may lead to increased concentration/bioavailability of another drug
§ Eg: Erythromycin (a CYP3A4 inhibitor) can increase risk of simvastatin toxicity (which is
metabolised by CYP3A4)
o Enzyme Induction:
§ Some drugs can enhance gene transcription, increasing the activity of a metabolizing enzyme
§ Eg: Phenobarbital can induce the metabolism of oral contraceptives via the CYP system
o Genetics:
§ Some people vary in their expression of the Cytochrome-P450-Enzymes
§ May alter the effectiveness of a drug (may have no effect/may overdose)
• Eg: CYP2D6 is absent in 7% of Caucasians → no response
• CYP2D6 is hyperactive in 30% of East Africans → same dose = toxic
o Disease Status:
§ Compromised organs:
• Liver
• Kidney
• Heart
• Vasculature
§ Viral infections can alter enzyme activity
§ Bacterial infections can produce toxins → alter drug activity/metabolism
o Hormone Status:
§ Oestrogen can affect metabolic enzyme activity
o Age/Gender:
§ Enzyme expression & activity changes with age
§ Gender differences related to hormonal status
o Diet:
§ Enzyme activity is affected by certain foods, vitamins & alcohol
- Phase I Reactions:
o Functional Group of drug is Exposed or Added to
§ New functional groups
§ Interchange existing functional groups
§ Expose existing functional groups
o Types of Phase I Reactions:

o Note: Oxidation Reactions are the most common

o Note: Oxidation Enzymes: part of the Cytochrome P450 Mono-Oxygenase family:
§ Other Roles of Cytochrome P450 Mono-Oxygenases:
• Synthesis:
o Conversion of cholesterol → bile acid
o Hydroxylation of steroids & Vit-D
o Conversion of Alkanes → Fatty Acids
o Conversion of FA’s → eicosanoids
• Catabolism:
o -of Fatty Acids
o -of Steroids
o -of eicosanoids

Phase II Reactions (‘Conjugation’)

-
o Drug/ Drug Metabolite is conjugated
§ Ie: It is merged with an endogenous polar compound
§ Aim: to ensure H2O solubility → excretion through kidneys

Credit: Rang et al: Pharmacology 5E

Types of Phase II Reactions:

o
§ Glucuronide Conjugation – Most Common
§ Glutathione Conjugation
§ Amino Acid Conjugation
§ Sulphate Formation
§ Acetylation
§ Methylation
4 : E lim in a tio n :
- Definition:
o The removal of the drug from the body
- Multiple Possible Routes of Elimination:
o Urine (Most drugs) – Must be naturally Water Soluble or Conjugated
§ Glomerular filtration (Passive excretion of Free Drugs only)
§ Tubular Secretion (Active process of Protein-Bound & Free Drugs)
o Lungs (Anaesthetic agents / Alcohol)
o Bile (Antibiotics)
o Faeces
o Saliva
o Breast Milk
- Renal Excretion depends on:
o GFR
o Water Solubility
o Tubular Secretion
o Reabsorption
- T1/2 – (Half Life):
o An exponential process
o The time taken for the drug concentration in the blood to decrease by 50%
o Can be Due to Either:
§ Redistribution T1/2 – decrease in drug concentration due to drug redistribution to the tissues
§ Or Metabolism T1/2 – decrease in blood concentration due to drug elimination
o For a given dose rate, 5xHalf-lives are required for 97% completion of steady state
o Similarly, it takes 5xHalf-lives to clear 97% of drug from the body
- Steady State:
o Where drug concentration remains constant
o Amount of drug entering the system = Amount of drug being eliminated
- Cl - (Clearance):
o The volume of blood Completely cleared of drug per unit time (Measured in L/min)
o Can be calculated for specific organs or for the whole body
- 1st Order & Zero-Order Elimination Kinetics:
o Rate of elimination is usually proportional to the amount of drug:
§ Ie: A 1st–Order Process (Constant % is eliminated per unit time)
§ (Exponential wash-out curve)
o However, when the Drug-Concentration is high (overdose), metabolic pathways become saturated:
§ Ie: A Zero-Order Process (Drug is slowly eliminated at a Fixed Rate)
§ (Linear)
Practical Applications of Pharmacokinetics:
- Loading Dose:
o A big ‘Bolus’ dose given initially to Quickly get Plasma Concentration of Drug to a Therapeutic Level
o This dose is based on the Volume of Distribution (Vd)
- Maintenance Dose:
o Doses given which aim to maintain a Therapeutic Concentration of the Drug
o This dose is based on Clearance Rate and Drug Half-Lives

- Dosage Schedules in the Sick, Elderly, Paediatrics

- Renal Function is important in drug dosing
- Altered Physiological States (Eg: Lean/Ideal/Fat) affect Pharmacokinetics

Applying Pharmacokinetics to Clinical Cases:

Station A – Renal Function and its importance in drug dosing

A patient has a creatinine level of 160 μmol/L. Yesterday the level was 120 μmol/L and the day before it was 80
μmol/L

(Normal Creatinine = 70-120µmol/L)

(Normal GFR = 125mL/min)

1. What additional information is needed before an assessment of the Glomerular Filtration rate (GFR) can
be made?
a. Age
b. Weight
c. Gender
2. Estimate this patients GFR using the additional information you requested above
a. Using Cockroft-Gault Equation, you determine GFR=48mL/min
3. How would this deteriorating GFR influence the clearance of Vancomycin from the body?
a. 90% of Vancomycin is excreted unchanged in the urine – Hence, a ↓GFR → ↑Longevity of Drug
b. Note: Vancomycin is given IV (Can’t be absorbed orally)
4. How would this reduced clearance influence Vancomycin dosing?
a. Same Dose, Less Often
b. Or, Smaller Dose @ Same Frequency
5. What could be causing the deterioration in the patient’s renal function over the past few days?
a. Sepsis (Most likely) → ↓Renal Function
b. Note: Vancomycin can be Nephrotoxic
Station B – Pharmacokinetic models
You are working as an intern in the Emergency Department when a patient is brought in after taking an over-dose of
Paracetamol (forty X 500 mg tablets). The patient states that she took the tablets 8 hours ago and now does not
want to die. On arrival in the ED the serum paracetamol level was found to be 163 mg/L. Drug screen also revealed a
blood alcohol level of 27 mmol/L.

Data:
- Weight = 63kg
- Vd = 1 L/kg
- Bioavailability 90%
- Elimination half-life = 2 hours
- CL = 5ml/min/kg
- Metabolism:
o 80% to glucuronide
o 10% via Cytochrome P450 to highly reactive intermediary that is inactivated by conjugation to
glutathione

1. How much paracetamol did she ingest?

a. 40x500mg = 20000mg
2. What is the bioavailability of the paracetamol?
a. 80%x20000mg = 18000mg
3. What is her Volume of Distribution?
a. 1L x 63kg = 63L
4. What would have been her initial serum concentration?
a. 18000mg ÷ 63L = 285mg/L
b. Note: >350mg/L is lethal
5. How long will it theoretically take to clear the paracetamol?
a. 5 Half Lives = 97% cleared
b. Therefore: 5 x 2hrs = 10hrs
6. What effect does the highly reactive intermediary have on the body?
a. NAPQI (A highly-reactive free radical) is produced by P450 Enzymes of the Phase-1 Reactions once
the Normal Phase-2 (Conjugation) Reactions are saturated
7. Given that the body’s stores of glutathione are minimal, how can continued metabolism of the highly
reactive intermediary be assured?
a. Glutathione is required by Phase-2 enzymes. Hence, once it is used up, the Phase-1 reactions take
over, and produce NAPQI as a by-product
b. Hence, by supplementing Glutathione with Acetylcysteine (a Glutathione precursor), you can prevent
the body resorting to Phase-1 Reactions
Station C – Pharmacokinetics in altered physiological states
Lignocaine is the most frequently utilised local anaesthetic in the western world. It is frequently used to ‘numb’ the
skin prior to the suturing of a minor cut. It is also often used to provide local anaesthesia to an area to assist with
minor surgery such as the removal of skin lesions, tattoo’s etc.

Lignocaine is an amide local anaesthetic and is a poorly soluble weak base with a pKa = 7.9. It comes in a variety of
strengths and compositions, the most frequently used being 1% plain Lignocaine vials for injection. The lignocaine is
provided as the hydrochloride salt (Lignocaine HCl) which renders the compound highly water soluble, with the pH of
1% plain Lignocaine HCl being about 4.0

1. Detail the kinetics involved in a dose of lignocaine HCl spreading from the point of injection to its site of
action?
a. See Diagram
2. What clinical factors can modify these kinetics?
a. Doesn’t work in infected tissues because they are typically acidic
b. Adrenaline → Vasoconstriction → ↓Bleeding & Prolonged Action
3. With the above knowledge, explain the following clinical scenario:
a. A young patient presents with an abscess on the forearm. It is a raised inflammation of some
1.5cm diameter. You decide to lance this in your rooms, and prior to this you infiltrate around the
abscess with 1% plain lignocaine. You wait 5 minutes and when you insert the scalpel, the patient
jumps and complains bitterly of pain. Why?
i. Because Abscesses are due to infection, and Local Anaesthetic doesn’t work in areas of
infection due to the Acidic Environment
PHARMACODYNAMICS:
PHARMACODYNAMICS:

W hat is Pharm acodynam ics? – “W hat the drug does to the body”:
- Study of Drug Interactions with Targets within the Body
- “Interactions (dynamics) between Drugs (Pharmaco) & their Targets”

Principals Behind Pharmaceutical Treatments:

1. Chemical-Receptor Signaling Controls body functioning; Hence, Cell Action doesn’t change if Message Isn’t
Received
2. In Disease, Chemical Signalling is altered, affecting body functioning; Hence, by compensating for the
Altered Signal, we can treat the disease

Things that Influence the Drug:Target Interaction:

- Affinity:
o The tendency of the drug to Bind to the target receptor (High/Low)
o Does it require Co-Factors / Mediators?
- Efficacy:
o The tendency for the drug (once bound), to Activate the target receptor (Fully/Partially)
o Ie: Relationship between Occupation of the Receptor & Effect Elicited (See Dose-Response curve)
§ Partial Agonists:
• Drugs with intermediate levels of Efficacy
• Ie: Even if 100% of receptors were occupied, the tissue-response is sub-maximal
§ Full Agonists:
• Drugs with high Efficacy
• Ie: Elicit a Maximal Tissue Response at or before 100% occupancy
o Note: Antagonists have Zero Efficacy

- Potency:
o Drugs with High Potency, generally have:
§ A high Affinity → Occupy a significant proportion of receptors even at low concentrations
§ AND A high Efficacy → Elicit a stronger response per receptor occupied
o The lower the potency, the higher the dose needed
o If Highly Potent – you only need a small amount of the drug for maximal effect
o Eg: Morphine Vs Codeine – For a given response, less Morphine is required than Codeine; Hence
Morphine is more potent

Efficacy Potency
4 Most Common Drug Targets:
- 1: **Receptors:
o “Protein molecules whose function is to recognise & respond to Soluble physiological mediators
(hormones/NTs/cytokines/etc)” Note: Other Macromolecules that drugs interact with are known as
Drug Targets
o Drugs act as either:
§ Agonists → Range of Effects
§ Antagonists → No Effect
o Eg: β-Adrenergic Receptors in the Heart → ↑HR & Contractility

- 2: Ligand-Gated Ion Channels:

o Ion Channels with a ligand-receptor which, when activated, causes the channel to open
o Drugs act as either:
§ Antagonists → Channel remains Closed
§ Modulators → Increased/Decreased opening Probability
§ Indirect Agonists → in the case of G-Protein-Linked Ion Channels
o Eg: Local Anaesthetics Block Na+ Channels in Nerve Cells → Inhibit Na+ Influx → Inhibit Action
Potential
o Side Note: Ion-Channelopathies:
§ Abnormalities in various Ion-Channels contribute to some Cardiac & Neurological Diseases
§ Eg: Mutated Cardiac K+-Channel → Long QT-Syndrome
§ Eg: Other Mutated K+-Channels → Familial Deafness; & Epilepsy

- 3: Enzyme Targets:
o Endogenous bodily enzymes are often targeted by drugs for multiple reasons
o Drugs act as either:
§ Inhibitors → Normal reaction is Inhibited
• Eg: Captopril – an ACE-Inhibitor;
• Eg: Acetylcholinesterase Inhibitors → Prolongs ACh in Synapse
§ False Substrates → Drug molecules that occupy enzymes by wasting their time
§ Pro-Drugs → The Enzyme converts them into their Active Forms

- 4: Transport/Carrier Proteins (Remember - Symporters & Antiporters):

o Membrane-Bound proteins that aid in transporting molecules that are Too-Big/Polar across the PM.
They exhibit Recognition Sites that make them specific to their ‘cargo’, which can be targets for
drugs.
o Drugs act as either:
§ Inhibitors → Block Transport
§ False Substrates (that fits in the Recognition Sites) → Accumulation of Drug inside cell
o Eg: Glucose Transporters/Amino Acid Transporters/LDL Receptors/Transferrin Receptors
o Eg: Amphetamines – Compete with NA for uptake into Presynaptic Cell, & also competes for
packaging into vesicles → Accumulation of NA in Synapse & Cytoplasm→ NA ‘leaks’ out of
presynaptic cell inappropriately

- Note: Exceptions Include: Some Antimicrobial & Antitumour drugs, as well as Mutagenic & Carcinogenic
Agents, interact directly with DNA rather than cell proteins
Adapted from Rang HP, Dale MM, Ritter JM, et al. Rang and Dale’s Pharmacology. 7th ed. Philadelphia: Elsevier; 2012
Drug-Receptor Interactions:
- Agonists – Keys that Open the Lock:
o Drug binds to, and Activates, the Receptor (Change the Physical Shape of the Receptor)
§ Ie: Has Affinity, Efficacy & Potency
§ Note: These characteristics will vary among Different Agonists
o Partial Agonists:
§ Drugs with intermediate levels of Efficacy
§ Ie: Even if 100% of receptors were occupied, the tissue-response is sub-maximal
§ Note: Partial Agonists are often used as ‘Antagonists’ because they compete with the
Endogenous Ligands for receptors, and elicit a Reduced Response
o Full Agonists:
§ Drugs with high Efficacy
§ Ie: Elicit a Maximal Tissue Response

o Inverse Agonists (Double-Antagonists):

§ Note: Some receptors (eg: For Benzodiazepines, Cannabinoids, Serotonin) exhibit baseline
spontaneous activation, even in the absence of any ligand. This is called “Constitutive
Activation”. It is often too low to have any effect under normal conditions, but it becomes
evident if receptors are overexpressed → Pathophysiological Implications.
§ Ligands that Reduce the level of Constitutive Activation
• Ie: Drugs with NEGATIVE EFFICACY → Produce a conformational change in the
Opposite Direction to the Active Conformation, making it harder for an Agonist to
activate it again
• They are distinct from Antagonists, which have Zero Efficacy
- Antagonists – Keys that fit, BUT DON’T Open the Lock:
o Drug binds to Receptor, but Doesn’t Activate it (Do NOT Change the Shape of the Receptor)
§ Ie: Has Affinity & Potency, but NO Efficacy
o Note: Antagonists occupying binding sites block binding of Agonists
o Types of Receptor-Mediated Antagonists:
§ Competitive Antagonists:
• Have the same Binding Sites as Agonists, & therefore Compete for Occupancy
• Competitive Antagonists can be overcome with a high enough dose of Agonist. Ie:
Agonist can act as an Antidote
• Eg: Beta-Blockers → Reduces effects of NA & Adrenaline by blocking β-Adrenergic
Receptors in the Heart/Brain/Kidneys/etc

§ Irreversible (Non-Equilibrium) Competitive Antagonists:

• Similar to Competitive Antagonism, however, Irreversible Antagonists dissociate very
slowly, if at all, from the receptors
• Ie: → Virtually no change in Antagonist Occupancy occurs when Agonist is added

§ Non-Competitive Antagonists:
• Blocks the effect of the Agonist by either:
o 1: Binding to a different part of the Receptor
o 2: Binding to a different component in the Agonist’s chain of effects
• Non-Competitive Antagonists CANNOT be overcome by Agonist; Ie: Agonist Can’t be
used as Antidote
• Graph is very similar to Irreversible Competitive Antagonism
o Types of Non-Receptor-Mediated Antagonists:
§ Chemical Antagonism:
• Antagonist binds to the Free-Agonist, making it incapable of activating its target
• Ie: Chemical Antagonism → ↓Bioavailability of the Agonist
• Eg: Chelation – Chelating agents bind heavy metals to ↓their Bioavailability
§ Pharmacokinetic Antagonism:
• ‘Antagonism’ by way of:
o Competition for uptake into bloodstream (Hinders Absorption)
o Promoting Ligand Metabolism/Elimination
o Altering its Distribution throughout the body
• Eg: Alcohol Vs Warfarin – Alcohol → ↑Liver Metabolism → ↑Clearance of Warfarin
• Note: Cytochrome P450 Mono-Oxygenases: are Liver Enzymes that
Detoxify/Bioactivate drugs in the bloodstream. Varied expression of these enzymes
across a population leads to significant variability in drug effectiveness
§ Physiological Antagonism:
• When 2 drugs that have opposing actions in the body cancel each other out
• Eg: Histamine (↑Gastric HCl) + Proton-Pump Inhibitor (↓Gastric HCl) → No Change

Biological Specificity of a Drug:

- Does the drug prefer ONE target (Highly Specific), or is it Promiscuous (Low Specificity)?
- For a drug to be useful, it must act selectively on particular cells & tissues (Ie: High Binding-Site Specificity)
- Conversely, proteins that function as Drug Targets generally have High Ligand Specificity

Receptor Families: Receptors are named for their natural chemical interactions:
- Adrenergic:
o Receptors for Catecholamines (eg: Noradrenaline, adrenaline)
o Targets for Drugs (eg: B-Blockers, A-Agonists, etc)
- Cholinergic:
o Receptors for AcetylCholine
o Targets for Drugs (eg: Nicotine)
- Dopaminergic:
o Receptors for Dopamine
o Targets for Drugs (eg: Levodopa, Pramipexole etc)
- Serotonergic:
o Receptors for Serotonin
o Targets for Drugs (eg: Metoclopramide, Sumatriptan, Dihydroergotamine, LSD, etc)
- GABA-ergic:
o Receptors for GABA
o Targets for Drugs (Eg: Gabapentin, Gabamide, Topiramate, Zolpidem)
- Glutamatergic
o Receptors for Glutamate
o Targets for Drugs (eg: Ketamine, Memantine, Amantadine)
- Opoidergic
o Receptors for Opioids
o Targets for Drugs (eg: Fentanyl, Codeine, Morphine, etc)

Receptor Subtypes:
- Groups of different receptors within a single Receptor Family (Ie: Respond the same Ligand) that are
expressed on Different Tissues, and cause widely different (often opposing) Cellular Effects
- Clinical Relevance: by targeting receptor subtypes, you can Target Specific Organs & decrease Side-Effects
- Eg: Adrenergic Receptors
o α1-Adrenergic Receptors → Smooth Muscle Constriction
§ (Vasoconstriction – Useful in Nasal Decongestants & Eye Exams)
o β2-Adrenergic Receptors → Smooth Muscle Relaxation
§ (Useful in treating Asthma → Bronchodilation)
Desensitization: - The Mechanisms by which the following physiological states occur:
- Different States of Desensitization:
o Tachyphylaxis:
§ A rapid decrease in the response to a drug after repeated doses over a short period of time
o Tolerance:
§ Similar to Desensitisation/Tachyphylaxis Describes a more gradual decrease in
responsiveness to a drug, developing over a few days/weeks
o Refractoriness:
§ A term also used to describe a loss of Therapeutic Efficacy for a period of time
o Drug-Resistance:
§ Loss of Effectiveness of Antimicrobial/Antitumour Drugs

- How Desensitization Occurs:

o Change in Receptors:
§ Conformational Change:
• Change in receptor shape, resulting in the inability to ‘activate’, despite binding of
the agonist
• Eg: Ion Channels in the NMJ, change shape, resulting in tight binding of the agonist,
without the opening of the Ion Channel
§ Phosphorylation:
• Phosphorylation of Intracellular Regions of the receptor protein
• Eg: Phosphorylation of G-Protein-Linked Receptors interferes with their Intracellular
Signalling Cascades, despite binding the Agonist
o Downregulation - Loss of Receptors:
§ Internalisation of receptors via Endocytosis, due to prolonged exposure to Agonists
§ Eg: β-Adrenergic receptors fall to ≈10% of normal within 8 hrs of continued stimulation
o Exhaustion of Mediators:
§ Depletion of an essential intermediate substance
§ Eg: Amphetamine, which acts by releasing amines from nerve terminal, shows tachyphylaxis
due to depletion of amine stores
o Increased Metabolic Degradation of the Drug:
§ Repeated administration of the same dose produces a progressively lower plasma
concentration, because of increased metabolic degradation
§ Eg: Alcohol consumption Tolerance
o Physiological Adaptation:
§ Decrease of a drug’s effect due to Homeostatic Response
§ Eg: The BP-lowering effect of Thiazide Diuretics is limited because of a gradual activation of
the Renin-Angiotensin System
o Active Extrusion of Drug from Cells:
§ Mainly relevant in Cancer Chemotherapy
Adverse Reactions to Drugs:
- 2 Major Mechanisms:
o Dose-Related Reactions:
§ Eg: Anticholinergic Side Effects
§ Eg: Tricyclic Antidepressants
o Dose-Independent Reactions:
§ Eg: Allergic Reactions (Type-I Hypersensitivity)
• (Eg: Myositis)
§ Or Altered cellular antigens → Antibody-Mediated attack (Type-II Hypersensitivity)
• (Eg: Drug-Induced Haemolytic Anaemia)

- Other Types of Adverse Drug Reactions:

o Carcinogenesis:
§ Seen with Chronic Hormone Treatment → Promotion of Hormone-mediated Carcinogenesis
§ Also seen with Cytotoxic Agents → DNA Damage
§ Immunosuppressants → Allows unchecked viral-mediated carcinogenesis
o Reproductive Alterations:
§ Infertility:
• (Eg: Cytotoxic Drugs such as Alkylating Agents)
§ Teratogens → Foetal Malformations:
• (Eg: Anti-Epileptics, Thalidomide & Cytotoxics)

Hepatic & Renal Toxicity – Why is it so Common?

- Liver:
o Huge role in Drug Metabolism – Sometimes Detox & Sometimes Toxification
o *During Drug Toxification, Hepatocytes are exposed to high concentrations of toxic metabolites
(M uch higher than other bodily cells) → Hence are susceptible to dam age
- Kidneys:
o Huge role in Drug Excretion - *But Also in fluid balance
o *Water soluble drugs filtered by the kidneys, and are concentrated in the filtrate as water is
reabsorbed → Renal Tubules are exposed to Higher (Often Toxic) Concentrations of Drugs
ANTIMICROBIAL THERAPY & SELECTIVE TOXICITY
 ANTIMICROBIAL THERAPY & SELECTIVE TOXICITY

Review of M icrobial Cell Biology:

- Host (Humans):
o Human cells are Eukaryotes

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- Bacteria:
o Prokaryotes – (Very different from Eukaryotic Host Cells – Therefore Selective Toxicity is possible)
§ (Antibacterials have less side effects than Antifungals because fungi are Eukaryotic)
o Gram Positive & Gram Negative Bacteria also Differ by their Cell Wall Structures:
§ Gram Positive:
• Thick Peptidoglycan Layer
§ Gram Negative:
• Primarily Lipid-Based (Including Lipopolysaccharide – LPS)
• (Negligible Peptidoglycan Layer)

C N X O p e n S t a x , C C B Y 4 . 0 < h t t p s : / / c r e a t i v
- Fungi/Parasites:
o Eukaryotes – (Very similar to Eukaryotic Host-Cells – Therefore Selective Toxicity is Difficult)
§ (Hence why Antifungals have significant side effect profiles)
- Viruses:
o Encapsulated DNA/RNA – (Very different from Eukaryotic Host Cells)
o They are also “Obligate Intracellular Pathogens” – Ie: Hijack Host-Cell Machinery to Replicate
§ → Antiviral treatments often have to inhibit Host-Cell machinery in order to stop the virus

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Principle of Antimicrobial Therapy:
- Origins of Antimicrobial Therapy:
o Note: Most Anti-Microbials are derived from other Organisms
o Eg: Penicillin’s Anti-Bacterial property was discovered by Alexander Fleming as it was killing his
Bacterial Cultures
- Selective Toxicity:
o Critical to Efficacy & Safety of Anti-Microbials
o Exploits Differences in Cell Biology between Host & Pathogen Cells
o Aim → Kill only the Pathogen Cells
- Scope of Activity:
o Specific to Class of Microbe:
§ Ie: Antibacterials aren’t effective against Viruses
o The Effect on the Microbes:
§ Eg: Bacterio-Cidal → Kills Bacteria (Eg: Penicillin)
§ Eg: Bacterio-Static → Slows Bacterial Growth (Eg: Tetracycline)
§ (FYI: Bacteriostatic drugs are more useful than Bactericidal drugs for Sepsis – Because
bactericidal drugs will liberate the bacteria’s Endotoxins → Further Inflammation)
o Synergy:
§ Some antibacterial agents can amplify each-other’s mechanism of action
§ Eg: Aminoglycosides + β-Lactams:
• Aminoglycosides Inhibit Protein Synthesis, but need to gain access into cell
• β-Lactams inhibit Cell Wall Synthesis → ↓Cell wall Integrity → ↑Access into cell
o Broad Spectrum Antibiotics – (“Empirical Therapy”):
§ Compounds active against a wide range of bacteria
§ Eg: Gram + & Gram – Bacteria
o Narrow Spectrum – (“Directed Therapy”):
§ Compounds active against a specific class/type of bacteria
§ Eg: Gram + only
- Antimicrobial Therapy Should be EVIDENCE BASED:
o Ie: KNOW what organism you are dealing with before treatment – (Unless Emergency):
§ Allows treatment to be “Directed” rather than “Empirical”
§ → Maximises Efficacy
§ → Minimises Antibiotic Resistance
- Antimicrobial Resistance:
o Note: Bacteria employ ‘Antibiosis’ of their own to potentiate their Own Survival
§ They also develop Resistance to Antibiosis from other bacteria to potentiate survival
§ - THIS CAN WORK AGAINST US – As Bacteria develop Resistance to Our Drugs!
o Note: Also, Bacterial “Resistance Genes” exist, and Mutation Potential is HIGH!
§ (Due to huge numbers of rapidly proliferating bacteria)
o Antibiotic Usage Preferentially Selects these resistant strains, giving them a Competitive
Advantage over the rest → Transmission of “Resistance Genes” to offspring
o THEREFORE – “Restraint of antimicrobial use is the best way to ensure their efficacy”

Sites for Selective Toxicity:

ANTIBACTERIAL DRUG CLASSES:

- 1: Anti Cell-Wall Synthesis Antibiotics – (Bactericidal):

o Target Peptidoglycan Synthesis on Gram-Positive Bacteria

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

β-Lactam Antibiotics:
Penicillins: Gram Positive Bacteria Block “Penicillin-Binding Proteins” GI Upset & Diarrhoea
Penicillins ‘G’ & ‘V’ (Note: Bacteria (Enzymes) →Inhibit Synthesis of the Allergic Rash
Amoxicillin & Ampicillin Producing β-Lactamase Peptidoglycan Layer of the Bacterial Anaphylaxis (Need
Flucloxacillin are resistant) Cell Wall. Adrenaline Handy)
Methicillin
Ticarcillin (Note: Fluclox – for β-
(Suffix = “-Cillin”) Lactamase Resistant)
Cephalosporins: (Note: Cephalosporins – (As above)
(Ceftriaxone) for Non-β-Lactamase + Mild Renal Toxicity
Resistant)
β-Lactamase Inhibitors: (In Combination with Inhibits β-Lactamase → Allows β- Nausea/Vom/Diarr
Augmentin Penicillins) for Penicillin-Lactams to work on Penicillin- Allergy
Resistant Gram Positive Resistant Bacteria.
Bacterial Infections
Glycopeptide Antibiotics:
Vancomycin Gram Positive Bacteria Prevents incorporation of specific Local Pain
Teicoplanin (As a LAST RESORT for Peptide Subunits into the P h le b itis (V e in In fla m )
Telavancin MRSA) Peptidoglycan Layer of the Bacterial Kidney Damage
(Also if Pt. is allergic to Cell Wall. Hearing Loss
β-Lactams)

- 2: Anti Protein-Synthesis Antibiotics – (Bacteriostatic):

o Exploits differences between Eukaryotic (Human) Ribosomes & Prokaryotic Ribosomes
o Selective Toxicity – Due to specific binding to Prokaryotic Ribosomes
o Note: Aminoglycosides are Solely eliminated by the Kidneys & Are Nephrotoxic (Need to assess
renal function first, then Dose Accordingly)

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

Am inoglycoside Antibiotics:
Gentamicin Gram Negative Bacteria Bind Specifically to Prokaryotic Ototoxic (Hearing Loss Streptomycin
(Used Synergistically Ribosomal Subunits → Causes & Vertigo)
Tobramycin with β-Lactams to ↑ Misreading of mRNA → Inhibits Nephrotoxic (Kidney
drug entry into Bacteria) Synthesis of Proteins vital to Bacteria. Damage)
Tetracycline Antibiotics:
Doxycycline Gram Negative Bacteria Bind Specifically to Prokaryotic Nausea/Vom/Diarr. Tetracycline
Syphilis (G-), Chlamydia Ribosomal Subunits → Inhibits Binding Photosensitivity (Suffix = ‘Cycline’)
(G-), Lyme Disease (G-) of tRNA to mRNA → Inhibits Synthesis Staining of Teeth
(And Malaria -Protozoa) of Proteins vital to Bacteria. Renal/Liver Toxicity.
M acrolides:
Erythromycin, Gram Negative Bacteria Bind Specifically to Prokaryotic Nausea/Vom/Diarr. Azithromycin
Syphilis, Lyme Disease. Ribosomal Subunits →Inhibits release Jaundice
of tRNA → Inhibits Synthesis of
Proteins vital to Bacteria.
 - 3: Anti Nucleic-Acid Synthesis Antibiotics – (Bacteriostatic):
o Exploits differences in the Metabolic Pathways of DNA Synthesis – (Humans rely solely on Dietary
Folate, while Bacteria have to make their own):
§ Eg: Competitive Inhibition of Dihydropteroate-Synthase, a key Enzyme involved in Folate
Synthesis in Bacteria
§ Eg: Competitive Inhibition of Dihydrofolate-Reductase, a key Enzyme involved in Folate
Synthesis in Bacteria (Note: Humans share this pathway, but bacteria require it 100x more
than humans)
§ Eg: Inhibition of Bacterial DNA Gyrase/Topoisomerase → Stops DNA
Replication/Transcription

Classical Agents: Common Uses: Mechanism of Action: Side Effects:

Sulphonamides:
Sulfasalazine Urinary Tract Infections Competitive inhibition of Nausea/Vom/Diarr
(Prefix = “Sulfa”) Dihydropteroate-Synthase, a key Allergy
Enzyme involved in Folate Synthesis. Precipitation in Urine
(Folate is necessary for Nucleic Acid –Kidney Failure
Synthesis → & Hence DNA Synthesis. Leukopenia
Photosensitivity
Trimethoprim:
Nausea/Vom/Diarr
Trim ethoprim Urinary Tract Infections Competitive inhibition of
Dihydrofolate-Reductase, a key Allergy
Precipitation in Urine
Enzyme involved in Folate Synthesis.
(Folate is necessary for Nucleic Acid –Kidney Failure
Leukopenia
Synthesis → & Hence DNA Synthesis.
Photosensitivity
(BIRTH DEFECTS)
Quinolones: Nausea/Vom/Diarr
Ciprofloxacin Urinary Tract Infections Inhibits bacterial DNA Gyrase or
Allergy
Norfloxacin Community Acquired Topoisomerase → Inhibits DNA
(Suffix = “Floxacin”) Pneumonia Replication & Transcription.
Bacterial Diarrhoea
Gonorrhoea
 - 4: Antimycobacterial Drugs:
o 2 Main Types of Mycobacterial Diseases:
§ Tuberculosis
§ Leprosy
o Why are they a Problem?
§ Because Mycobacteria can live inside Macrophages following Phagocytosis
§ Also, Multi-Drug-Resistant strains are on the rise
o Compound Drug Therapy:
§ A frequent strategy to decrease the probability of the emergence of resistant organisms
§ Also requires Long-Term Therapy

Common Uses: Mechanism of Action: Side Effects:

Classical Agents:
Isoniazid:
Isoniazid Combination Treatment MOA unknown. Allergic Skin Eruptions
of M. Tuberculosis (Bacteriostatic & Bactericidal) Fever
Hepatotoxicity
Haemolysis (in G6PD
Deficiency)
Rifampicin: Allergic Skin Eruptions
Rifampicin Combination Treatment Binds to & Inhibits DNA-Dependent
Fever
of M. Tuberculosis Prokaryotic RNA-Polymerase →
Hepatotoxicity
Inhibits DNA Transcription & therefore
Inhibits Protein Synthesis.
(Bacteriostatic & Bactericidal)
Etham butol:
Ethambutol Combination Treatment MOA Unknown. Optic Neuritis
of M. Tuberculosis (Bacteriostatic) Visual Disturbances
Colour Blindness.
Pyrazinamide:
Pyrazinamide Combination Treatment Active in Low pH–(In Phagolysosomes) Gout
of M. Tuberculosis (Bacteriostatic) GI Upset
Hepatotoxicity
ANTIFUNGAL DRUGS:
- Note: Fungi are Eukaryotic:
o Therefore Selective Toxicity is Difficult
- Drug Targets:
o 1: Difference in Lipid Composition of Cell Membrane:
§ Fungi – Ergosterol
§ Humans – Cholesterol
o 2: Inhibition of Ergosterol Synthesis:
§ Fungal Cell Cytochrome Enzymes
o 3: Inhibition of DNA & RNA Synthesis:
§ Intracellular Conversion to Inhibition Substances
- Routes of Administration:
o Systemic (Oral/Parenteral) – For Systemic Fungal Infections
o Oral – For Mucocutaneous Infections
o Topical – For Mucocutaneous Infections (Selective Toxicity is less important)
ANTIVIRAL DRUGS:
- Viruses are “Obligate Intracellular Pathogens” – Ie: Hijack Host-Cell Machinery to Replicate:
o Therefore, Selective Toxicity is Difficult, because you have to inhibit Host-Cell machinery in order to
stop the virus
- Mechanisms of Antiviral Selective Toxicity:
o Nucleoside Reverse Transcriptase Inhibitors
o Non- Nucleoside Reverse Transcriptase Inhibitors
o Protease Inhibitors
o Viral DNA Polymerase Inhibitors
o Inhibitors of Fusion with Host Cells
o Inhibitors of Viral Coat Disassembly
o Biologics & Immunomodulators (Eg: Interferon)
ANTIPARASITIC DRUGS:
- Note: Parasites are Eukaryotic:
o Therefore Selective Toxicity is Difficult
- Drug Targets:
o 1: Unique Enzymes
o 2: Shared Enzymes – but those Indispensable for Parasite
o 3: Common Pathways with Different Properties

- Note: Antimalarial Drugs & G6P-Dehydrogenase Deficiency:

o Eg: Chloroquine/Primaquine/Pamaquine:
§ Must NOT be given to Pts with Glucose-6-Phosphate Dehydrogenase Deficiency, as they can
cause Fatal Haemolysis
§ (Note: G6PD is an essential enzyme in RBC Metabolism)

The Various Antiparasitic Drugs & Their Mechanisms of Actions:

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ANTI-ARRHYTHMIC DRUGS
 ANTI-ARRHYTHMIC DRUGS

General Info:
- 4 Classes of Anti-Arrhythmics (I, II, III, IV):
o Class-I (Ia/b/c): VG-Na+ Channel Blockers – (Prolong Depolarisation → ↓Hyper-excitability)
o Class-II: β-Blockers – (Inhibits Sympathetic-Mediated Tachycardias)
o Class-III: VG-K+ Channel Blockers – (Prolongs Plateau Phase→ ↓Hyper-excitability)
o Class-IV: VG-Ca+ Channel Blockers – (In AV Node – Slows Conductile Depolarisation)

- Other Standalone Agents:

o Digoxin:
§ Myocytes: Na/K-ATPase Inhibitor → ↓2o Active Ca+ Efflux → ↑[Cellular Ca+] → Improved
Contractility
• Use: Heart Failure
§ AV Node: Activates mAChR-Linked K+ Channels → K+ Efflux → Hyperpolarises Conductile AP
→ Slows AV Conduction
• Use: SVT (Supraventricular Tachycardia)
o Adenosine:
§ Use: Diagnostically to distinguish V-Tac from SVT
§ Activate Adenosine Receptors (in AV Node) → Activate ATP-Dependent K+ Channels (KATP) →
Hyperpolarises AV Node → Prolongs Conductile AP → –ve Dromotropic Effect (Slows AV-
Node)
§ (HR will slow if it is an SVT) / (If HR is unchanged, then it is V-Tac)
o Atropine:
§ Use: Acute Bradycardias/Asystole →↑HR (However can cause V-Tac)
§ (M2 Muscaranic Antagonist → Blocks Vagus-Nerve’s Action on Heart →↑HR)

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Class-I Antiarrhythmics (VG-Na+ Channel Blockers):
- General Info:
o Primary Effect:
§ **Reduces the Rate of Depolarisation of Hyper-Excited Myocytes
• Ie: Typically used for Re-Entrant Tachycardias
o Mechanism of Action:
§ By Blocking Only Voltage-Gated Na+ Channels (in Contractile Cells):
• (Remember Conductile Na-Channels are ‘Leaky’)
• → Slows Rate of Depolarisation → Effectively ↑Refractory Period
• → Delays Channel-Recovery (From ‘Inactive’ → ‘Resting’) → ↑Refractory
§ Ie: – (Prolong Depolarisation → ↑ Effective Refractory → ↓Hyper-excitability)

§ Na+ Channel Blockade is Use-Dependent:

• The Drug Binding-Site is Inside the Channel – Is only available during the ‘Active’ &
‘Inactive’ Phases of the Channel; NOT in the ‘Resting’ Phase:
o Therefore, are somewhat ‘Selective’ for Overactive Cells
• – Ie: Block High-Frequency excitation of the Myocardium that occurs in
Tachyarrhythmias, Without preventing the heart from beating at normal frequencies
• – In other words, they Restore Nodal (Conductile) Control of Heart Rhythm

• Extent of Na+ Channel Block depends on:

o **Drug Association/Dissociation Rates
o *Heart Rate – (Ie: Are Use Dependent)
o Membrane Potential
§ Sub-Grouped by their Characteristics of Na+ Channel Blockade:
• 3 Sub-Groups – (Ia, Ib, Ic):
o 1a – Quinine, Procainamide (Intermediate Association/Dissociation)
o 1b – Lignocaine, Tocainide (Fast Association/Dissociation)
o 1c – Encainide, Flecainide (Slow Association/Dissociation)
§ Typically used for Re-Entrant Arrhythmias:
• → Aim to Give Back Control to the SA-Node
- Class 1a Antiarrythmics:
o Classical Agents:
§ Quinine
§ Procainamide
o Key Distinction from other Class 1 Drugs:
§ Intermediate Association/Dissociation
§ Prolongs Repolarisation → ↑AP Duration
o Mechanism of Action:
§ VG-Na+ Channel Blockade (Selective for Active & Inactive Na+ Channels):
• → Slows Rate of Depolarisation → ↑Absolute Refractory Period
• → Delays Channel-Recovery (From ‘Inactive’ → ‘Resting’) → ↑Refractory
§ (Some VG-K+ Blockade @ the AV Node→ Slows SA Node Rate)
§ Ie: – (Prolong Depolarisation → ↑ Absolute Refractory → ↓Hyper-excitability)
- Class 1b Antiarrhythmics:
o Classical Agents:
§ Lignocaine/Lidocaine
§ Tocainide
o Key Distinction from other Class 1 Drugs:
§ Fast Association/Dissociation
§ Shortens Plateau Phase → ↓AP Duration
o Mechanism of Action:
§ VG-Na+ Channel Blockade (Selective for Active & Inactive Na+ Channels):
• → Slows Rate of Depolarisation → ↑ Absolute Refractory Period
• → Delays Channel-Recovery (From ‘Inactive’ → ‘Resting’) → ↑Refractory
§ (Some Leaky-Na+ Blockade @ the AV Node→ Slows SA Node Rate)
§ Ie: – (Prolong Depolarisation → ↑ Absolute Refractory → ↓Hyper-excitability)
§ Note: Tends to Decrease AP Duration due to Sub-Maximal Depolarisation → Less VG-Ca+
Channels open to sustain the plateau → Shorter Plateau → Shorter Action Potential – (Note:
Although AP is shortened, VG-Na+ Channel Refractory Period is still Increased due to
Prolonged Depolarisation)
- Class 1c Antiarrhythmics:
o Classical Agents:
§ Encainide
§ Flecainide
§ Propafenone
o Key Distinction from other Class 1 Drugs:
§ Slow Association/Dissociation
§ Most Potent → Markedly Prolonged Repolarisation (But no change in AP Duration)
o Mechanism of Action:
§ VG-Na+ Channel Blockade (Selective for Active & Inactive Na+ Channels):
• → Slows Rate of Depolarisation → ↑ Absolute Refractory Period
• → Delays Channel-Recovery (From ‘Inactive’ → ‘Resting’) → ↑Refractory
§ (Some β-Blocking Ability → ↓Sympathetic ; and VG-K+ Blocking → ↓AV Rate)
§ Ie: – (Prolong Depolarisation → ↑ Absolute Refractory → ↓Hyper-excitability)
Class-II Antiarrhythmics (β1-Blockers):
- Classical Agents:
o **Propanolol, Sotalol*, Esmolol, Atenolol, Pindolol
o (*Note: Sotalol, although a ‘β-Blocker’, is classed as Class-III due to VG-K+ Blockade)
- Mechanism of Action:
o – (Block β1-Adrenergic Receptors → Inhibit Sympathetic-Mediated ↑HR & ↑Contractility →
↓ Cardiac W orkload)
o Normally, NorAdrenaline (NorEpinephrine) → Binds to β1-Receptors →G-Protein Activation →↑
cAMP →:
§ ↑Permeability of Leaky Na+ Channels @ SA/AV Nodes → Membrane ‘drifts’ quicker to
threshold → Increased Heart Rate
§ ↑Permeability of VG-Ca+ Channels:
• @ SA/AV Nodes → Quicker Depolarisation → Increased Heart Rate
• @ Cardiac Myocytes → ↑Intracellular Ca+ → ↑Contractility
o β1-Blockers Inhibit the Above Process
§ Ie: ↓Heart Rate & ↓Contractility
- Indications:
o Atrial Fibrillation (Or other Sinus Tachycardia)
o SVT
o Hypertension
o Angina (+ Hypertension)→↓Cardiac Workload – (Little effect on Normotensive Pt)
- Contraindications:
o Respiratory Disorders (Especially Asthma) → Can cause Bronchoconstriction
o Ca+ Channel Blockers – (Since β-Blockers also Inhibit Ca+ Influx) → Fatal Bradycardia
- KEY Side Effect/s:
o Sinus Bradycardia
o Bronchoconstriction in Asthmatic Patients
o (Rebound Tachycardia – if stopped abruptly; Must be weaned off)

Diagram: The Effects of Sympathetic NS on the Heart – Class-II Antiarrhythmics (β-Blockers) Inhibit These Effects:

Effects on SA/AV Nodes Effects on Contractile Cells

Sources: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/

& https://www.austincc.edu/apreview/PhysText/Cardiac.html
Class-III Antiarrhythmics (VG-K+ Channel Blockers):
- Classical Agents:
o **Amiodarone
o *Sotalol – (A β1-Blocker with K+-Channel Blocking Ability)
o Bretylium
o Procainamide
- Mechanism of Action:
o – (Block VG-K+ Channels → Prolongs Plateau Phase→ Prolongs Relative Refractory Period & AP
Duration→↓Hyper-excitability)
- Indications:
o *1st Line in Re-Entrant Tachycardias – Ventricular tachycardia
o A-Fib & Flutter
- KEY Side Effect/s:
o Can cause Early After Depolarisation due to lengthening of AP
o Note: Promiscuity is an Issue:
§ Some Class-I Actions – (Na+ Channel Blockade)
§ Some Class-II Actions – (β-Adrenoceptor Blockade)

Class-IV Antiarrhythmics (VG-Ca+ Channel Blockers):

- Classical Agents:
o **Verapamil – (Selective for the Heart)
o Nifedipine – (Selective for Vessels) – (Used in Angina & Heart Failure)
- Mechanism of Action:
o **Heart:
§ - (*Blocks VG-Ca+ Channels in SA/AV Nodes → Slows Conductile Depolarisation → ↓SA-
Node Heart Rate & Delays Conduction through the AV Node →↓HR)
§ (Note: Also block VG-Ca+ Channels in Myocytes → Shorten Plateau Phase of AP → ↓Ca
Influx → ↓SR Calcium Release → ↓Force of Contraction)
§ →↓Cardiac Workload
o (Vessels – Used in Angina):
§ - Blocks VG-Ca+ Channels in Vascular Smooth Muscle → Vasodilation
§ →↑Blood Supply to the Heart
- Indications:
o SVT (Supraventricular Tachycardias)
o Variant Angina
- Contraindications:
o β-Blockers– (Since Ca+ Channel Blockers also Inhibit Ca+ Influx) → Fatal Bradycardia
- KEY Side Effect/s:
o Heart Block
o Bradycardia
o (Also Hypotension/Dizziness due to ↓Contractility)
Other Standalone Agents:
- Digoxin:
o 2x Clinical Uses:
§ 1: Heart Failure (Especially Pts with coincident Atrial Fib – ‘Kill 2 birds’)
§ 2: Long Term SVT Management (Supraventricular Tachycardia – Including Atrial Fibrillation)
o 2x Mechanisms of Action:
§ 1: Myocytes: Na/K-ATPase Inhibitor → ↓2o Active Ca+ Efflux → ↑[Cellular Ca+] → Improved
Contractility
• Use: Heart Failure
• Side Effect: Accumulation of Na+ & Ca+ → Resting Membrane More Positive
o →Can Lead to A Series of “Early After Depolarisations”

§ 2: AV Node: Activates mAChR-Linked K+ Channels → K+ Efflux → Hyperpolarises Conductile

AP → Slows AV Conduction
• Use: SVT (Supraventricular Tachycardia)

Summary of Actions & Potential Side Effects:

o
§ Note: Not to be given if HR less than 60bpm → Brady/Heart Block
§ Note: Also, Dosage is very important for reducing side effects
§ *(Note: Also require K+ Monitoring - & Supplements if on K+ Wasting Diuretic)
- Adenosine:
o Clinical Use:
§ Diagnostically to distinguish V-Tac from SVT
§ Note: Extremely short T1/2 - Only Effective in Emergency Situations to stop SVT
• (Digoxin is used for long-term SVT Management)
o Mechanism of Action:
§ Activate G-Protein-Linked Adenosine Receptors (in AV/SA Nodes) →
• → Opens K+ Channels → ↑K+ Efflux → Hyperpolarises AV/SA Nodes → Prolongs
Conductile AP → –ve Dromotropic Effect (Slows AV-Node)
• → Also inhibits Ca+ channels
§ (HR will slow if it is an SVT) / (If HR is unchanged, then it is V-Tac)
o KEY Side Effect/s:
§ Overwhelming feeling of IMPENDING DOOM!!! (Pts literally feel like they’re dying)

(A1AR =Adenosine Receptor)

Source: https://journals.physiology.org/doi/full/10.1152/physrev.00049.2017

- Atropine:
o Clinical Use:
§ Acute Bradycardias/Asystole →↑HR (However can cause V-Tac)
o Mechanism of Action:
§ M2 Muscaranic Antagonist → Blocks Vagus-Nerve’s Action on Heart →↑HR
o KEY Side Effect/s:
§ Overdose → Ventricular Tachycardia
COMMON DRUGS USED IN ISCHAEMIC HEART DISEASE
COMMON DRUGS USED IN ISCHAEMIC HEART DISEASE (IHD)

Goals of Drugs Used To Treat IHD:

- 1: Increase Blood-Flow – (eg: Glyceryl Tri-Nitrate):
o Vasodilators – (GTN – An Organic Nitrate, Ca+ Channel Blockers, & K+ Channel Activators)
- 2: Decreasing Oxygen Demand – (eg: β-Blockers & ACE-Inhibitors):
o ↓Heart Rate – (β-Blockers)
o ↓Contractility – (β-Blockers, Ca+ Channel Blockers)
o ↓Cardiac Workload – (ACE-Inhibitors)
- 3: Treatment of Atherosclerosis – (See section on Treating Hypercholesterolaemia):
o Cholesterol-Lowering Drugs:
§ Statins = HMG-CoA Reductase Inhibitors
• →Inhibits of Endogenous Cholesterol Synthesis → Upregulation of LDL-Receptors in
the Liver
§ Ion Exchange Resins:
• →Irreversibly bind Cholesterol in the Gut → Prevent Intestinal Cholesterol
Reabsorption
§ Ezetimibe:
• Blocks absorption of Cholesterol in the Duodenum
o Prophylactic Anticoagulant Drugs:
§ Heparin
§ Warfarin

Organic Nitrates:
- Classical Agents:
o Glyceryl Trinitrate (GTN) – (Arterial & Venous Dilation)
o Isosorbide Mononitrate – (Venous dilation only)
o Isosorbide Dinitrate – (Venous dilation only)
- Mechanism of Action:
o (Provide an Exogenous Source of Nitric Oxide (NO) – A Potent Vasodilator)
o Nitric Oxide → Binds to Guanylate Cyclase (GuCy) in Vascular Smooth Muscle → ↑cGMP → Closes
Ca+ Channels → ↓Intracellular [Ca+] → Smooth Muscle Relaxation → Vasodilation
§ Vasodilation → ↑Coronary Blood Flow → Adequate Perfusion of the Heart
§ Vasodilation → ↓Preload
§ Vasodilation → ↓Afterload
- Clinical Use:
o Acute Angina – (Sublingual Tablets/Buccal Spray)
o Prophylaxis against Chronic Angina – (Patches/Slow-Release Tablets)
- KEY Side Effect/s:
o Note: Tolerance develops rapidly – (Pt requires a Drug-Free period daily to prevent tolerance)
o Hypotension

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

β-Blockers:
- Classical Agents:
o **Propanolol, Sotalol*, Esmolol, Atenolol, Pindolol
o (*Note: Sotalol, although a ‘β-Blocker’, is classed as Class-III due to VG-K+ Blockade)
- Mechanism of Action:
o – (Block β1-Adrenergic Receptors → Inhibit Sympathetic-Mediated ↑HR & ↑Contractility →
↓ Cardiac W orkload)
o Normally, NorAdrenaline (NorEpinephrine) → Binds to β1-Receptors →G-Protein Activation →↑
cAMP →:
§ ↑Permeability of Leaky Na+ Channels @ SA/AV Nodes → Membrane ‘drifts’ quicker to
threshold → Increased Heart Rate
§ ↑Permeability of VG-Ca+ Channels:
• @ SA/AV Nodes → Quicker Depolarisation → Increased Heart Rate
• @ Cardiac Myocytes → ↑Intracellular Ca+ → ↑Contractility
o β1-Blockers Inhibit the Above Process
- Clinical Use:
o Tachy-Arrhythmias (Eg: A-Fib) (Class-II Agents)
o SVT
o Hypertension
o Angina (+ Hypertension)→↓Cardiac Workload – (Little effect on Normotensive Pt)
- Contraindications:
o Respiratory Disorders (Especially Asthma) → Can cause Bronchoconstriction
o Ca+ Channel Blockers – (Since β-Blockers also Inhibit Ca+ Influx) → Fatal Bradycardia
- KEY Side Effect/s:
o Sinus Bradycardia
o Bronchoconstriction in Asthmatic Patients
o (Rebound Tachycardia – if stopped abruptly; Must be weaned off)

Diagram: The Effects of Sympathetic NS on the Heart – Class-II Antiarrhythmics (β-Blockers) Inhibit These Effects:

Effects on SA/AV Nodes Effects on Contractile Cells

Sources: Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/
& https://www.austincc.edu/apreview/PhysText/Cardiac.html
Ca+ Channel Blockers:
- Classical Agents:
o **Verapamil – (Selective for the Heart) – (Also Used in SVT Arrhythmias)
o **Nifedipine – (Selective for Vessels)
- Mechanism of Action:
o Heart:
§ - (*Blocks VG-Ca+ Channels in SA/AV Nodes → Slows Conductile Depolarisation → ↓SA-Node
Heart Rate & Delays Conduction through the AV Node →↓HR)
§ (Note: Also block VG-Ca+ Channels in Myocytes → Shorten Plateau Phase of AP → ↓Ca Influx
→ ↓ SR Calcium Release → ↓ Force of Contraction)
§ →↓Cardiac Workload
o Vessels:
§ - Blocks VG-Ca+ Channels in Vascular Smooth Muscle → Vasodilation
§ →↑Blood Supply to the Heart
- Indications:
o SVT (Supraventricular Tachycardias)
o Variant Angina
- Contraindications:
o β-Blockers– (Since Ca+ Channel Blockers also Inhibit Ca+ Influx) → Fatal Bradycardia
- KEY Side Effect/s:
o Heart Block
o Bradycardia
o (Also Hypotension/Dizziness due to ↓Contractility)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

K+ Channel Activators (Nicorandil):
- Classical Agent:
o **Nicorandil
- Mechanism of Action:
o Activate Smooth Muscle ATP-Dependent K+ Channels (KATP) → Hyperpolarises SM → Vasodilation
o AND...
o Guanylate Cyclase (GuCy) in Vascular Smooth Muscle → ↑cGMP → Closes Ca+ Channels →
↓ Intracellular [Ca+] → Sm ooth M uscle Relaxation → Vasodilation
o Effects of Vasodilation:
§ → ↓Preload
§ → ↓Afterload
§ → ↑Blood Supply
- Clinical Use:
o Angina
- KEY Side Effect/s:
o Transient initial headache
o Ulcers (mouth/perianal/anal/vaginal/GI) – Pathogenesis is unclear
Common Drugs in Myocardial Infarction:
- Aspirin
- O2 Therapy
- Organic Nitrates (Vasodilators)
- Anticoagulants
- β-Blockers
- ACE Inhibitors

Example of an MI Algorithm (Step 1 is commence drug therapy)

[Remember to always check your local guidelines first before treating patients]
COMMON DRUGS USED IN MANAGING CHOLESTEROL & LIPIDAEMIA
COMMON DRUGS USED IN MANAGING CHOLESTEROL & LIPIDAEMIA

TREATING HYPERCHOLESTEROLAEMIA:
- Note: Lifestyle Modification should ALWAYS be the first step!!
o Need to determine the extent to which DIET and LIFESTYLE contribute to elevated Levels
o Can take up to 6mths before drug treatment is commenced (unless severe case)
o 3 Key Lifestyle Issues:
§ Smoking
§ Diet
§ Exercise

- **Statins – (HMG-CoA Reductase Inhibitors):

o Classical Agents:
§ Simvastatin
§ Fluvastatin
§ Pravastatin
§ Lovastatin
§ (Note: These are Aspergillus-Fungus derivatives → Immune Side-Effects)
o Mechanism of Action:
§ Inhibit the Rate-Limiting Enzyme in Cholesterol Synthesis in the Liver
• (HMG-CoA → Mevalonate)
• →Inhibits of Endogenous Cholesterol Synthesis
§ **Major Effect – Upregulation of LDL-Receptors in the Liver:
• (Triggered by decreased cholesterol synthesis)
• →↑Cholesterol Extraction from the Blood
§ (Note: May also decrease arterial wall inflammation → ↓Atherosclerosis Risk)
o Side Effects:
§ (Note: These drugs are Aspergillus-Fungus derivatives → Immune Side-Effects)
§ Myositis – (Inflammation of muscles) → ↑plasma Creatine Kinase levels (Diagnostic)
• Can progress to Rhabdomyolysis (Destruction of Muscle)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Ion Exchange Resins – (‘Bile Acid-Binding Resins’):
o Classical Agents:
§ Colestyramine
§ Colestipol
o Mechanism of Action:
§ Irreversibly bind to Bile Acids (Endogenous Cholesterol) & Dietary Cholesterol in the Gut →
Prevent Intestinal Cholesterol Reabsorption → ↓ Blood Cholesterol
• → Upregulation of LDL Receptors in the Liver → ↑Removal of Cholesterol from the
Blood to make more bile acids
o Side Effects:
§ Can interfere with absorption of Fat-Soluble Vitamins (A,D,E,K) & Folate
§ Marked Constipation – (Requires co-admin of Laxatives)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Ezetim ibe:
o Mechanism of Action:
§ Blocks absorption of Cholesterol in the Duodenum
o Side Effects:
§ Diarrhoea
§ Abdo Pain
§ Headache
§ (Avoid in Lactating Women – Can pass into milk)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

TREATING HYPERLIPIDAEMIA:
- **#1 - Fibrates:
o Classical Agents:
§ Clofibrate, Gemfibrozil, Fenofibrate, Bezafibrate, Ciprofibrate
o Mechanism of Action:
§ Increase Lipolysis by:
• ↑Transcription of Lipoprotein Lipase →↑Conversion of VLDL→LDL
• ↑Uptake of LDLs
• ↓Production of VLDLs
§ →Marked ↓ in VLDLs (& thus Triglyceride); moderate ↓LDLs & small ↓HDLs
o Side Effects:
§ Myositis – (Muscle Inflammation)
§ →↑Production of Bile can → Gallstones
§ (Renal Failure – Rare)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Nicotinic Acid (Niacin) – LAST RESORT:

o Mechanism of Action:
§ Reduces VLDL Production & Secretion from Liver
§ ↓Conversion of VLDL to LDL → ↓LDL levels
o Side Effects:
§ Note: Doses required are very high – (often not well tolerated)
§ Aspirin Co-Admin required to reduce Flushing & Palpitations
§ Impaired liver function
§ Altered Glucose Tolerance
§ Can trigger Gout

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

COMMON DRUGS USED IN MANAGING HEART FAILURE
 COMMON DRUGS USED IN MANAGING HEART FAILURE

Therapeutic Goals of Managing Heart Failure:

- 1: Combating Excessive Preload – (Ventricular Filling Pressure):
o ↓Salt & Fluid Intake:
§ Often overlooked as a treatment to Heart Failure & Hypertension
§ ↓Salt Intake → ↓Fluid Retention → ↓Central Venous Pressure →↓Preload
o Vasodilator Drugs:
§ Eg: Organic Nitrates (Eg: ISMN – Isosorbide Mononitrate):
• Nitric Oxide → Binds to Guanylate Cyclase (GuCy) in Vascular Smooth Muscle →
↑ cGM P → Closes Ca+ Channels → ↓ Intracellular [Ca+] → Sm ooth M uscle Relaxation
→ Vasodilation

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

§ ACE Inhibitors (Eg: Perindopril, Captopril, Enalapril):

• ↓Angiotensin-II → ↓Arterio-Constriction, ↓Fluid/Salt Retention, ↓SNS-Activity →
↓ Central Venous Pressure → ↓ Preload

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Diuretics:
o
§ Eg: Amiloride – (An Epithelial Na+ Channel Inhibitor – K+ Sparing):
• Directly Inhibits the Aldosterone-Activated Na+ Channels in walls of Collecting Ducts
→ Inhibits H2O Resorption
§ Eg: Aldosterone Antagonists – (Also K+ Sparing):
• Prevents Aldosterone from stimulating Expression of these Proteins:
o → ↓Na+ Channel Proteins → ↓Na+ Resorption → Inhibits H2O Resorption
o → ↓TCA Enzymes → ↓ATP → ↓Na+ Pump Function → ↓Na+ Resorption →
Inhibits H2O Resorption
§ (Fluid Excretion → ↓Central Venous Pressure → ↓Preload)
- 2: Com bating Excessive Afterload – (Ejection Pressure):
o Direct Vasodilators:
§ Eg: Organic Nitrates (ISMN):
§ Nitric Oxide → Binds to Guanylate Cyclase (GuCy) in Vascular Smooth Muscle → ↑cGMP →
Closes Ca+ Channels → ↓Intracellular [Ca+] → Smooth Muscle Relaxation → Vasodilation

o Vaso-Selective Ca+ Channel Blockers:

§ Eg: Nifedipine/Amlodipine/Nimodipine
§ – (Note: Do Not use Cardioselective Ca-Channel Blockers → ↓Force of Contraction)
§ Blocks VG-Ca+ Channels in Vascular Smooth Muscle → Vasodilation
§ Vasodilation→↓Afterload →↓Cardiac Workload

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Central Sympathetic Depressants:

o
§ Eg: Clonidine (Aka: Catapres)
§ Stimulates α2-Adrenergic AutoReceptors in CNS → Provides Negative Feedback of NA →
Prevent Sympathetic Outflow → Vasodilation
• (Note: A peripherally acting α2-Agonist would → Vasoconstriction)

https://tmedweb.tulane.edu/pharmwiki/doku.php/clonidine

Peripheral NA-Release Blockers:

o
§ Eg: Reserpine
§ Blocks Noradrenaline Release in the Peripheral NS → ↓NA in Vascular SM → Vasodilation
- 3: Combating Inotropic Insufficiency – (Weak Contraction):
o Digoxin – (A “Cardiac Glycoside”):
§ *Inhibits Na/K-ATPase on Cardiac Myocytes → ↓2o Active Ca+ Efflux → ↑[Cellular Ca+] →
Im proved Contractility
§ (Other unrelated function = Activates mAChR-Linked K+ Channels → K+ Efflux →
Hyperpolarises Conductile AP → Slows AV Conduction)
§ (Major Side Effects = Early-After-Depolarisation Tachycardia; Heart Block)
§ (Note: Also require K+ Monitoring - & Supplements if on K+ Wasting Diuretic)

o β-Adrenergic Agonists:
§ Eg: Dopamine/Dobutamine
§ Increases Renal Perfusion
§ Increase Cardiac Contractility via Increasing Intracellular Ca+ in Myocytes → Inotropic
§ Possible Vasodilatory Action

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

 o Phosphodiesterase Inhibitors:
§ Eg: Milrinone, Amrinone, Vesnarinone
§ Inhibits Phosphodiesterase in Myocytes → Prolonged Action of cAMP/cGMP → Maintained
Opening of Ca+ Channels → ↑Intracellular Ca+ → ↑Contractility

- 4: Using β-Blockers in Heart Failure:

o β-Blockers:
§ There are only 3 SPECIFIC β-Blockers Useful for Heart Failure – All Others will KILL!!
• Carvedilol
• Metoprolol
• Bisoprolol
• Note: These are actually Inverse Agonists, not “Blockers”
§ MOA:
• Isolates the heart from the Sympathetic NS → Triggers Remodelling of the Heart →
o →Change in Sensitivity to Sympathetic Stimulation
o →Change in Receptor/Ion-Channel Profile of Cells
o →Increased Cell Number
• Hopefully makes the heart Stronger (If it doesn’t kill you)
TREATING DIABETES
TREATING DIABETES:

Insulins:
- Sources:
o Animal (old)
o Human (new recombinant DNA technology)
- Clinical Uses:
o Type 1 Diabetes Mellitus
o (Last resort in Type 2 Diabetes Mellitus – if other meds fail)
- Mechanism of Action:
o Stimulates upregulation of GLUT-4 Transporters on Membranes of Insulin-Sensitive Cells (namely
Muscle & Adipose Tissue) → ↑Glucose Uptake from blood
o Insulin is an Anabolic Hormone→
§ →↑Glycogen Synthesis (Glycogenesis)
§ →↑Fatty Acid Synthesis (Lipogenesis)
§ →↑Amino Acid Uptake
§ →↓Proteolysis
§ →↓Lipolysis
§ →↓Gluconeogenesis

Current Trends in Pharmacological Treatment of Type II Diabetes Mellitus - Scientific Figure on ResearchGate.
Available from: https://www.researchgate.net/figure/Mechanism-of-action-of-insulin-17_fig1_325007874

- Side Effects:
o Possible Allergic Reaction
o Overdose → Hypoglycaemia
- Pharmacokinetics of Different Insulin Preparations:
o Ultra-Rapid Acting Insulin Analogues – (Clear):
§ Adding Aspartate (Insulin Aspart) → Short Acting (Exist as monomers)
§ Adding Proline (Inulin Lispro) → Short Acting (Exist as monomers)
o Rapid Acting (Regular Insulin) – (Clear):
§ Regular Insulin stabilised with Low Zinc Concentration
o Intermediate-Acting (Lente) – (Cloudy):
§ Adding Protamine to insulin (isophane insulins):
• (Protamine Prolongs effect of Insulin)
§ Medium Zinc Concentrations:
• ↑[Zinc] = Lente
• (Zinc → Insulin Takes longer for it to be converted to active form)
o Long-Acting (Ultra-Lente) – (Cloudy):
§ High Zinc Concentrations:
• ↑↑[Zinc] = Ultralente
• (Higher [Zinc] → Takes even longer to be converted to active form)
o Long-Acting Insulin Analogues – (Cloudy):
§ Changing pKa → Insulin Crystals Precipitate in Subcutaneous Tissue → Slowly break down →
Slow-release & Long-Action
§ Complexed with a Fatty-Acid Chain → Prolongs Action
§ *Note: Point of these is that they form a ‘Peakless’/Flat Level in the Blood

Ultra-Rapid Acting Insulin Analogues – Prefer to Exist as Monomers → Rapid Diffusion.

Source: https://www.science.org/doi/abs/10.1126/scitranslmed.aba6676
- *Note: Types of insulin preparations also determine Route of Administration:
o (Adding things to insulin not only alters pharmacokinetics, but also H2O Solubility)
o Clear preparations are Soluble – Can be injected IV
o Cloudy preparations are Insoluble – Cannot be injected IV – (Only Sub-Cut)
Insulin Preparation: Chemical Changes Onset: Peak: Duration:
Ultra-Rapid Acting Aspart/Lispro = Amino Acids @ End 15mins 1hrs 5hrs
(Insulin Analogues): of β chain are swapped/substituted
- Insulin Aspart for different amino acids (clear - IV).
- Insulin Lispro (Prevents Polymerisation; Monomers
have quicker uptake into blood, but
shorter duration)
Rapid-Acting: Regular Insulin = Crystals of Within 1Hr 3hrs 8hrs
- Regular Insulin Insulin+Zinc in Phosphate Buffer
(+Zinc) (clear - IV)
Intermediate Acting (Lente): Isophane Insulin = Insulin+ Within 3Hrs 5-12hrs
1Day
- Insulin + Protamine Protamine+Zinc combination in
(Isophane) Phosphate Buffer (cloudy – IM/SC)
- Insulin (+↑Zinc) (Protamine Prolongs effect of Insulin)

Lente Insulins = Insulin+↑Zinc in an

Acetate Buffer; higher [zinc] than
Regular Insulin. (cloudy – IM/SC)
(Higher [Zinc] → Takes longer to be
converted to active form)
Long-Acting (Ultralente): Ultralente Insulins = Insulin+↑↑Zinc Within 4Hrs 12hrs - 1Day
- Insulin (+↑↑Zinc) in an Acetate Buffer; even higher 1- 1.5Days
[zinc] than Lente. (cloudy – IM/SC)
(Higher [Zinc] → Takes longer to be
converted to active form)
Long-Acting Changing pKa → Crystals Precipitate 1hr 6hrs
(Insulin Analogues): in Subcut Tissue → Slowly break down 1Day
→ Slow-release & Long-Action.

Complexed with a Fatty-Acid Chain →

Prolongs Action.
*Note: Point of these is that they
form a ‘Peakless’/Flat Level in the
Blood.
Oral Hypoglycaemic & Euglycaemic Agents:
- Strategic Approaches:
o Hypoglycaemic Agents – Lower BSL to below the normal range → Hypoglycaemia:
§ Are the drugs that Stimulate Insulin Secretion (The “Secretagogues”)
§ Examples:
• Sulphonylureas
• Meglitinides
§ (Note: Useless in Type-I Diabetes as there are No β-Cells to stimulate)
o Euglycaemic Agents – Lower BSL to an acceptable range, but don’t produce Hypoglycaemia:
§ Are the drugs that Increase Insulin Sensitivity of tissues (The “Sensitisers”)
§ Examples:
• Biguanides
• Thiazolidinediones (TZDs)
o GI-Glucose Absorption Inhibitors - Inhibits enzymes needed to digest carbohydrates:
§ → ↓Complex Carbohydrate digestion → ↓Glucose Absorption in Intestines
§ Example: Acarbose
- Clinical Use:
o Type 2 Diabetes Mellitus
- Physiological Mechanisms of Action – (Note: Depends on Specific Drug):
o To Lower Blood Glucose via various mechanisms
§ Stimulate Insulin Release from the Pancreas
• – (Useless in Type-I Diabetes as there are No β-Cells to stimulate)
§ Reduce Hepatic Glucose Output (↓Liver Gluconeogenesis)
§ Stimulate Peripheral Tissue Glucose Utilisation
§ Slow Glucose Absorption

Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Mechanisms-involved-in-

hyperglycemia-in-T2D-and-site-of-action-of-metformin-and_fig1_298431279
- Hypoglycaem ic Agents - “Secretagogues” – (Pro Insulin-Secretors):
o *Sulphonylureas – (Eg: Glibenclamide, Glipizide):
§ Mechanism of Action:
• - Directly Stimulate Insulin Release from the Pancreas by activating ATP-Dependent
K+-Channels on Pancreatic β-(Islet)Cells
o ↑K+-Efflux → ↑Insulin Release from Pancreas
• – Indirectly Inhibits Gluconeogenesis in Liver (Via Insulin)
• – Indirectly Stimulates Glycolysis in Periphery (Via Insulin)
§ Side Effects:
• Insulin Can Stimulate Appetite → Weight Gain
o (Opposes the aim in Type-II DM management)
• Can have prolonged action in the Elderly → Hypoglycaemia
• Cardiotoxicity
• Liver/GI Disturbances

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Meglitinides – (Eg: Repaglinide, Nateglinide & Mitiglinide):

o
§ Mechanism of Action:
• (Like Sulphonylureas, they →↑Insulin Release)
• Directly stimulate Insulin Release from the Pancreas by De-activating ATP-Dependent
K+-Channels on Pancreatic β-(Islet)Cells
• ↓K+-Efflux→Activates Ca+ Channels →↑Insulin Release from Pancreas

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Euglycaem ic Agents – “Sensitisers” – (Increases Insulin Sensitivity of Tissues):
o Biguanides – (Eg: Metformin):
§ Mechanism of Action:
• - Stimulates Insulin Receptors:
o ↓Hepatic Glucose Output – (By Inhibiting Gluconeogenesis)
o ↑Peripheral Glucose Uptake – (By Stimulating Glycolysis)
• – Inhibit Glucose Absorption

Pernicova, Ida and Márta Korbonits. “Metformin—mode of action and clinical implications for diabetes and
cancer.” Nature Reviews Endocrinology 10 (2014): 143-156.
 o Thiazolidinediones:
§ Classical Agent:
• Rosiglitazone
§ Mechanism of Action:
• Bind to Transcription Factors → Stimulate Transcription of Insulin Dependent
Enzymes → Better Glucose Handling:
o ↓Hepatic Glucose Output
o ↑Peripheral Glucose Uptake

- GI-Glucose Absorption Inhibitors:

o Acarbose:
§ Mechanism of Action:
• Inhibits enzymes needed to digest carbohydrates (Eg: Amylase)
• → ↓Complex Carbohydrate digestion → ↓Glucose Absorption in Intestines
• (Note: Is ineffective against simple sugars – Ie: Monosaccharides)
§ Side Effects:
• Flatulence
• Diarrhoea

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

TREATING THYROID DISORDERS
 TREATING THYROID DISORDERS

Thyroid Hormone Analogues:

- Classical Agents:
o *Thyroxine/levothyroxine (T4)
o Tri-Iodo-Thyronine/liothyronine (T3)
- Clinical Uses:
o Hypothyroidism – (Insufficient thyroid hormone) - (Causes host of metabolic disruptions)
- Mechanism of Action:
o Thyroid Hormone Replacement – To restore basal metabolic rate, HR & GI function
o Note: Thyroxine is the preferred agent as it is the least biologically active – (Longer Half-life), and can
be Deiodinated by the body to T3 (Thyronine) when needed

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Anti-Thyroid Agents:
- Thionamides - Block Thyroid Hormone Synthesis:
o Classical Agents:
§ *Carbimazole
§ Propylthiouracil
o Clinical Uses:
§ Hyperthyroidism
o Mechanism of Action:
§ Blocks the Thyroid-Peroxidase Enzyme in Synthesis of Thyroid Hormones

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Radioactive Iodine - Destroy Thyroid Follicular Tissue:
o Classical Agents:
§ Radioactive Iodine (I125)
o Clinical Uses:
§ Hyperthyroidism (As an alternative to thyroidectomy)
o Mechanism of Action:
§ Thyroid selectively takes up Iodine (Including I125) → Kills off follicular cells
§ (Note: The trick is to only kill SOME thyroid tissue; NOT TOO MUCH → Hypothyroidism)
o Side Effects:
§ Overdose can kill too much thyroid tissue→ Hypothyroidism

https://www.chrisnutting-oncology.co.uk/treatments/thyroid-cancer/thyroid-cancer-treatments/

- Drugs that Inhibit Peripheral Deiodination (Activation) of T4 → T3 Hormones:

o Classical Agents:
§ **Dexamethasone
§ Iomeprol
§ Lithium Carbonate
o Clinical Uses:
§ Hyperthyroidism
o Mechanism of Action:
§ (Remember, that T3 is the Most Biologically-Active; but T4 is the Most Abundant)
§ (Remember that Deiodination of T4 → T3 occurs in peripheral cells via Deiodinase)
§ Therefore, by preventing peripheral Deiodination of T4, Less T3 will be available to act on
tissues

Metabolism of Thyroid Hormones

https://www.slideserve.com/samuel-buck/thyroid-drugs
TREATING HYPERINFLAMMATORY DISORDERS
TREATING HYPERINFLAMMATORY DISORDERS

Glucocorticoids:
- (Remember, Glucocorticoids are a subset of Adrenal Steroids – Bind Mineralocorticoid Receptors)
- Classical Agents:
o Natural (Cortisol/Hydrocortisone – BUT is quickly Inactivated to Cortisone by the Kidney →
Ineffective)
o Synthetic – (For Better Anti-Inflammatory Action/Oral Absorption/ Receptor Affinity /T1/2)
§ *Fluticasone – (used in Asthma)
§ Budesonide
§ Mometasone
- Mechanism of Action:
o MOA: Activate Corticosteroid (GRα) Receptors → Activate Transcription factors in the Nucleus →
Reduces Expression of Cytokines → ↓Inflammation in sub mucosa
§ – Also inhibits COX2 → ↓Prostaglandin Production → Vasoconstriction & Reduces Immune
Cell Migration
§ – Also upregulates β2 Receptors → ↑Adrenergic Sensitivity
§ – Also Reduces IL-3 → ↓Mast Cell Proliferation → ↓Hypersensitivity
- Clinical Uses:
o Therapeutic Focus is Inflammatory & Immune Diseases:
§ (Glucocorticoids = Potent Anti-Inflammatory & Immunosuppressive agents)
§ – (Eg: Rheumatoid Arthritis)
§ - (Eg: Asthma)
§ - (Others: Inflammatory Bowel, Organ Transplant, Cancer, etc)
o Also used to manage Adrenocortical Insufficiency – (Eg: Addison’s Disease)
- Routes of Administration:
o Oral
o Intra-Articular
o Topical (Including Inhaled CS for asthma) – Important for avoiding systemic side-effects
o Injected
- Systemic Side Effects:
o Immunosuppression → Susceptibility to Infection/Cancer
o *↑Sympathetic Sensitivity →Hypertension
o Fluid Retention, Oedema → Hypertension
o Thin Skin, Easy Bruising, Impaired Wound Healing
o Cushings Symptoms
§ Central Obesity
§ “Moon” Face
§ Buffalo hump
o Hirsutism
o Muscle Atrophy
o *Osteoporosis → Pathological Fractures
(Unattributable)
Corticosteroids & Rheumatoid Arthritis:
- What is Rheumatoid Arthritis?
o An Autoimmune Condition marked by Chronic Inflammation of Joint Connective Tissue due to
Deposition of Rheumatoid Factor Complexes
- Main Pathophysiology of Rheumatoid Arthritis:
o **Autoantibodies called Rheumatoid Factors are generated (Aetiology unknown) and Accumulate
in Joint Tissue →
§ →Inflammation Via Inflammatory Mediators (Bradykinins, Prostaglandins, Cytokines)
• →Vascular Changes in Joint → Accumulation of Immune Cells
• →Phagocytosis of Immune Complexes
• →Release of Enzymes → Attack Joint Tissues
• →Free Radical Production
§ →→JOINT DAMAGE
o Note: Both Humoral Responses & Cell-Mediated are thought to play a part:
o (Therefore Type -IV & -III hypersensitivities involved)
§ CD4-Th-Cells → Activate Macrophages → Release Cytokines (TNFa, IL-1 & IL-6) →
Inflammation:
• →↑Production of Rheumatoid Factors (IgM Anti-IgG-Abs) by RF-B-Cells
• →Activate Osteoclasts → Bone Erosion
• →→Joint Destruction
§ Plasma Cells → Secrete Rheumatoid Factors (IgM Anti-IgG-Antibodies) → Immune
Complexes →Deposition in Joints & Periphery
• (Note: Systemic Complications are due to peripheral deposition of Immune
Complexes)
• RF:IgG Complexes in Articular Cartilage →
o →Complement Activation → Lysis of Chondrocytes
o →Opsonisation of Chondrocytes → Phagocytosis/Cytotoxic Killing
- Treatment: Anti-Rheumatoid Drugs:
o Corticosteroids – (Eg: Prednisone, Hydrocortisone, Prednisolone, Dexamethasone):
§ → ↓Cytokine Secretion → ↓Inflammation
§ → Immunosuppression
o NSAIDs – (Non-Steroidal Anti-Inflammatory):
§ → Symptomatic Relief
o DMARDs – (Disease-Modifying Anti-Rheumatic Drugs):
§ (Mild Chemotherapy drugs, used due to their Immunosuppressive ‘Side-Effects’)
§ Eg: Methotrexate (an Antimetabolite)→ Inhibits folate-dependent DNA Synthesis → Inhibits
Lymphocyte Proliferation
§ Eg: Leflunomide (an Antimetabolite) → Inhibits Pyrimidine Synthesis
§ Eg: Cyclosporin – Inhibits IL-2 Receptors → (↓Antigen-Induced Lymphocyte Proliferation)
o Biological Drugs:
§ Direct inhibitors of Pro-Inflammatory Cytokines:
• TNFα Inhibitors
• IL-1 Inhibitors
• IL-6 Inhibitors
§ Inhibitors of T-Cell Co-Stimulation
Corticosteroids & Asthma:
- What is Asthma?
o Chronic inflammation of the Airway Submucosa due to a Type-1 Hypersensitivity Response
- Main Pathophysiology of Asthma:
o Re-exposure of an Antigen → Binds to IgE-Bound-Mast-Cells → Mast Cell Degranulation →
§ →Releases Inflammatory Mediators → Vasodilation & Smooth Muscle Contraction
• Mediators Include:
o Histamine
o Leukotrienes →Cause Symptoms of Allergic Reaction
o Prostaglandins
§ →Releases IL-4 → Potentiates & Amplifies IgE Production by Plasma Cells
(↑ IgE = ↑ Mast cell Activation = ↑ Inflammatory Mediators & Inflammatory cells = ↑ IgE)

Creative Commons: Pavón-Romero, Serrano-Pérez, García-Sánchez, Ramírez-Jiménez and Terán.

https://www.frontiersin.org/articles/10.3389/fcell.2021.663535/full
 - Corticosteroid Treatment – (eg: Fluticasone, Budesonide, Mometasone):
o MOA: Activate Corticosteroid (GRα) Receptors → Activate Transcription factors in the Nucleus →
Reduces Expression of Cytokines → ↓Inflammation in sub mucosa
§ – Also inhibits COX2 → ↓Prostaglandin Production → Vasoconstriction & Reduces Immune
Cell Migration
§ – Also upregulates β2 Receptors → ↑Adrenergic Sensitivity
§ – Also Reduces IL-3 → ↓Mast Cell Proliferation → ↓Hypersensitivity

Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Anti-inflammatory-effects-

of-glucocorticoids-Glucocorticoids-cross-the-cell-membrane-and_fig2_51530440
Corticosteroids & Addison’s Disease:
- What is Addison’s Disease?
o Deficiency of endogenous Corticosteroid Production
o Many Symptoms:
§ Muscle Weakness, Hypoglycaemia, Easily Fatigued, Anorexia, Weight loss
§ Low BP
§ Depression
§ Hyperpigmentation of skin (particularly sun exposed skin)’
§ Electrolyte disorders (eg: hyperkalaemia, hyponatraemia)
- Main Pathophysiology of Rheumatoid Arthritis:
o Either Autoimmune Damage to Adrenal Gland;
o Or Secondary destruction of Adrenal Gland due to chronic inflammatory condition (Eg: Tuberculous
Adrenalitis)
- Treatment: Corticosteroid Replacement:
o Glucocorticoid Supplementation (Hydrocortisone 15mg on waking & 5mg at 6pm)
o Mineralocorticoid Supplementation (Fludrocortisone 0.05-0.1mg daily)

https://www.news-medical.net/health/What-is-Addisons-Disease.aspx
Corticosteroids & Cushing’s Syndrome:
- What is Cushing’s Syndrome?
o Excessive Corticosteroid Levels due to any Aetiology – (Endogenous or Exogenous)
§ (Eg: From ACTH-Secreting Tumour, or Prolonged Administration of Glucocorticoids)
- Signs/Symptoms:
o Central Obesity
o “Moon” Face
o Buffalo hump
o Hypertension
o Easy Bruising, Poor Wound Healing
o Osteoporosis
- Treatment:
o If source of Cortisol is Exogenous – Wean Patient off Steroid
o If source of Cortisol is a Tumour – Surgical Removal + Temporary Cortisol Replacement

https://www.ohsu.edu/brain-institute/cushing-disease-cushing-syndrome
MODIFYING SEX-HORMONE PROFILES
MODIFYING SEX-HORMONE PROFILES

Female Sex Hormones:

- Oestrogen – (Natural/Synthetic) – (Note: Synthetic has better oral absorption)
o Clinical Uses:
§ HRT in Post-Menopausal Women
§ Contraception
§ Delayed Menarche
o MOA:
§ Contraception - Inhibit Ovulation (Suppress LH secretion)
§ Other MOAs depend on the tissues affected – However, know that since these are steroid
hormones, their receptors are Intra-Nuclear → Stimulates Transcription Factors
o Side Effects:
§ ↑Blood Coagulability
§ Nausea
§ Breast Development (Gynecomastia in men)
§ ↑HDL
§ Weight Gain, Fluid Retention, Oedema, Hypertension
- Progesterone – (Natural/Synthetic) – (Synthetics: Progestogens, Progestins)
o Clinical Uses:
§ Contraception
o MOA:
§ Thickens cervical mucus
§ Other MOAs depend on the tissues affected – However, know that since these are steroid
hormones, their receptors are Intra-Nuclear → Stimulates Transcription Factors
o Side Effects:
§ Acne, ↑Masculinisation of women
§ Nausea
§ Weight Gain, Fluid Retention, Oedema, Hypertension
§ Breast Tenderness

Male Sex Hormones:

- Androgens & Anabolic Steroids – (Natural/Synthetic):
o Clinical Uses:
§ Androgens:
• Hormone replacement therapy where males are androgen deficient
• Libido enhancement
• High dose therapy in anaemias (although largely superseded)
§ Anabolic Steroids:
• Reverse Protein Loss in Post-Surgery
• Promote Protein Synthesis – (Athletes)
• ↑Strength/Aggressiveness/Performance
o MOA:
§ MOAs depend on the tissues affected – However, know that since these are steroid
hormones, their receptors are Intra-Nuclear → Stimulates Transcription Factors
o Side Effects:
§ Aggression (‘Roid’ Rage)
§ Baldness but ↑Body Hair
§ Acne
§ Testicular Atrophy (& Infertility)
§ Gynecomastia
§ Liver Disease
§ Masculinisation of Women
§ Feminisation of Men (if High Doses)
Anti-Sex Hormones:
- Anti-Oestrogens:
o Clinical Uses:
§ Cancers – Inhibit Oestrogen-Mediated Growth of Oestrogen-Receptor+ Cancers
§ Ovulation Stimulators
§ Osteoporosis Treatment
o MOA:
§ SERM – Selective Oestrogen Receptor Modulators – (Competitive Antagonists of Oestrogen
Receptors but are not antagonists – Instead they are modulators because they cause a
conformational change in the receptor)
§ SERD – Selective Oestrogen Receptor Downregulators – (Binds to Oestrogen Receptors &
Stimulates Endocytosis or the Receptors)
§ Aromatase Inhibitors → Inhibit conversion of Androstenodione & Testosterone to
Oestrogen →↓Oestrogen production
o Side Effects:
§ Menopausal Symptoms (Flushing, Vaginal Dryness, Mood Swings, Sweating)
§ Irregular Menstruation
- Anti-Androgens:
o Clinical Uses:
§ Prostate Cancer
§ Chemical Castration of sex offenders
§ Treatment of undesired masculinisation in women
o Mechanism of Action:
§ Receptor Antagonists
§ Or α-Reductase Inhibitors (Blocks Activation of Testosterone)
§ Or GnRH receptor Antagonists → ↓FSH/LH →↓Testosterone Production
o Side Effects:
§ ↓Sperm Count → Infertility
§ ↓Libido
§ Impotence

Sites of Action of Sex Hormone Antagonists

GASTROINTESTINAL DRUGS
GASTROINTESTINAL DRUGS

Acid Neutralizers:
- Antacids – (Are 1st line in GORD/GERD):
o Mechanism of Action:
§ Direct Neutralisation of Excessive Gastric Acid Secretion
o Common Preparations:
§ Aluminium Salts
§ Calcium Salts
§ Magnesium Salts
§ Sodium Bicarbonate
§ Magnesium-Aluminium Combos

- Alginates – (Often Combined with Antacids):

o Mechanism of Action:
§ Believed to Increase the Viscosity & Adherence of Mucus to the Oesophageal Mucosa,
forming a protective barrier

Adapted from Lullmann H et al. https://tmedweb.tulane.edu/pharmwiki/doku.php/antacids

Side Effects of the Different Antacid Preparations:

Aluminium Salts - Constipation
- Al+ Accumulation in Renal Impairment
- Hypophosphataemia.
Calcium Salts - Constipation
- Milk-Alkali Syndrome (High Doses)
- Rebound Hyper-Acidity.
Magnesium Salts - Diarrhoea
- Mg+ Accumulation in Renal Impairment
Sodium Bicarbonate - Milk-Alkali Syndrome (High Doses)
- Avoid in Sodium-Restricted Pt’s.
Mg-Al Combos - Minor Changes in Bowel Function.
Alginates - Altered Eating Behaviour due to Bloating
- Note: Antacids can affect the Pharmacokinetics of other Oral Drugs due to pH Change.
Inhibitors of Acid Production:
- H2 Histamine Receptor Antagonists:
o Mechanism of Action:
§ Decreases Histamine Stimulation on Parietal Cell → ↓Gastric Acid Secretion.
o Classical Agents:
§ Ranitidine, Cimetidine
§ (Nizatidine, Famotidine)
o Side Effects:
§ Diarrhoea
§ Dizziness
§ Muscle Pains
§ Alopecia (Hair-Loss/Baldness)
§ Rashes

- Proton Pump Inhibitors (PPIs):

o Mechanism of Action:
§ Note: Administered as a Pro-Drug (Activated by Acidic environment of stomach)
§ Irreversible Inhibition of the H+/K+ ATPase (The “Proton Pump”)
o Classical Agents:
§ Omeprazole
§ (Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole)
o Side Effects – (Uncommon):
§ Headache
§ Diarrhoea
§ Rashes

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

3 Mucosa Cytoprotective Agents
- Bismuth-Chelate:
o Mechanism of Action:
§ (Toxic effects on Helicobacter Pylori – A combination treatment of Peptic Ulcers)
§ Coats the base of Ulcers
§ Adsorbs Pepsin
§ Enhances Local Prostaglandin Synthesis:
• Stimulates Goblet Cells → ↑Mucin Secretion → ↑Mucus
• Parietal Cells → Inhibits Proton Pump →↓Acid Secretion
§ Stimulates Bicarbonate Secretion
o Side Effects:
§ Nausea
§ Vomiting
§ Blackening of the Tongue
§ Blackening of the Faeces
- Sucralfate
o Mechanism of Action:
§ (Basically Creates a Physical Barrier in the Stomach)
§ Strong Negative Charge → Binds Cationic Groups in Proteins & Glycoproteins
• → Forms complex Gels with Mucus → ↓Degradation of Mucus by Pepsin
• → Limits diffusion of H+ through Mucus Layer
§ Enhances Local Prostaglandin Synthesis:
• Stimulates Goblet Cells → ↑Mucin Secretion → ↑Mucus
• Parietal Cells → Inhibits Proton Pump →↓Acid Secretion
§ Also Stimulates Bicarbonate Secretion
o Side Effects:
§ *Constipation
§ Dry Mouth
§ Nausea
§ Vomiting
§ Headache
§ Rashes

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- M isoprostol (Prostaglandin Analogue)
o Mechanism of Action:
§ Stimulates PGE2 Receptors on:
• - Goblet Cells → ↑Mucin Secretion → ↑Mucus
• - Parietal Cells → Inhibits Proton Pump →↓Acid Secretion
§ Also increases mucosal blood-flow → Augments secretion of Mucus & Bicarbonate
o Side Effects:
§ *Diarrhoea
§ Abdominal Cramps
§ (Avoid in Pregnancy → Can Cause Uterine Contractions [used to induce abortion])

Credit: https://tmedweb.tulane.edu/pharmwiki/doku.php/antacids
Anti-Emetics/Anti-Nausea/Anti-Vomiting Drugs:
- (Agonists & Receptors):
o These are agonists @ the CTZ (Chemoreceptor Trigger Zone) & VC (Vomiting Centre)

o …Therefore, Antagonists should inhibit Vomiting (See Below):

- Receptor Antagonists:
Drug: Classical Agent: Indications: Mechanism of Action: Side Effects:
H1 Histamine-Receptor Cyclizine Motion Sickness Central action on CTZ Sedation
Antagonists (Cinnarizine, Vestibular Disorders Dry Mouth
(Antihistamines/ Meclizine, (Eg: Vertigo)
Antipsychotic Drugs) Promethazine) Morning Sickness

Muscarinic Antagonists Scopolamine Motion Sickness Central action on VC Sedation

(Anti-Muscarinics/Anti-(or pine) Dry Mouth
Cholinergics)
D2 Dopamine-Receptor Metoclopramide Vomiting Caused by: Central action on CTZ Sedation
Antagonists (domperidone) Uraemia Extrapyramidal
(Antidepressants & Radiation - Note: Also on basal (M otor Jerks)
Parkinson’s Treatment) GI Disorders ganglia→Motor Side
Cytotoxic Drugs Effects.

P e rip h e ra l: ↑ G I M o tility
Selective 5HT3 Central action on CTZ
Odansetron Vomiting Caused by: Sedation
Serotonin Antagonists (Granisetron, Cytotoxic Drugs Headache
Radiation Dizziness
Tropisetron, Post-Op Vomiting
Dolasetron)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Laxatives:
- Bulk Laxatives (Eg: Methylcellulose, Bran, Husk):
o Consist of Non-Soluble Fibres which aren’t digested → Form a bulky Hydrated Mass in the gut lumen
→ Promotes Peristalsis & Improves Faecal Consistency
o (No unwanted side effects)
- Osmotic Laxatives (Eg: Lactulose, Macrogols):
o Consist of Poorly-Absorbed Solutes → Increase Intra-Luminal Osmolarity → Trap fluid in the lumen of
the bowel
o → Over Distension of the Colon → Purgation of Faeces
o (Abdominal Cramps & Vomiting can occur)
- Stimulant Laxatives (eg: Docusate):
o Act by increasing Electrolyte (& hence Water) Secretion by the Mucosa
o Also stimulate Enteric Nerves → Increase Peristalsis
o (Abdominal Cramps can occur)

Anti-Motility / Spasmolytic Agents – (For Diarrhoea):

- Opioids:
o Loperamide (AKA: “Imodium”) & Codeine:
§ Note: Loperamide Doesn’t cross the Blood-Brain Barrier (Ie: Not Addictive)
o Mechanism of Action:
§ Increases GI tone & rhythmic contractions
§ But diminishes propulsive activity by Contacting Ileocolic & anal sphincters
- Adsorbents:
o (Adsorption = “The adhesion of a thin layer of molecules of a substance to the surface of a
solid/liquid”)
o Eg: Chalk, Charcoal, Silicate, etc
o Mechanism of Action:
§ Symptomatic Treatment of Diarrhoea (But MOA largely unknown)
§ Act by adsorbing Micro-organisms or Toxins
§ Alter the intestinal flora by coating & protecting the intestinal mucosa

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

GENERAL NERVOUS-SYSTEM DRUGS
GENERAL NERVOUS-SYSTEM DRUGS

Potential Afferent Nervous System Drug Targets:

- 1: Peripheral Nervous System Targets:
o TRPVR Receptors (Vanilloid Receptors –+1 Sensitive to H/Capsaicin/Heat/Mechanical):
§ Capsaicin:
• Activates TRPV1R Receptors on C-Fibres → Causes Substance-P release
o → Depletes the terminal of Substance-P (A Peptide)
o → There will be a period of Analgesia while Sub-P is re-synthesised
• Eg: Topical Arthritis Cream
o Prostanoid Receptors (Sensitive to Prostaglandins):
§ Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) – (Aspirin/Ibuprofen)
• Anti-Inflammatory Analgesic:
• →↓Prostaglandin Production by inhibiting the enzyme Cyclo-Oxygenase (COX) →
↓Prostaglandin-Mediated Hypersensitivity of Nociceptive Neurons
§ COX-2 Inhibitors – (Celebrex)
• Anti-Inflammatory Analgesic:
• More specific than NSAID’s – Target COX-2 Enzyme – Less Side-Effects
• →↓Prostaglandin Production by inhibiting the enzyme Cyclo-Oxygenase-2 (COX-2)
→↓Prostaglandin-Mediated Hypersensitivity of Nociceptive Neurons

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Opioid Receptors:
o
§ Opioid Drugs – (Codeine, Morphine, Fentanyl):
• On Distal Nerve Endings – (Periphery):
o →Opens K+ Channels → K+-Efflux → Hyperpolarisation
- 2: Central Nervous System Targets:
o Pain-Gate Mechanism
§ Opioid Drugs – (Codeine, Morphine, Fentanyl):
• On Proximal Nerve Ending – (Spinal Cord):
o →Mimic Autoreceptors → Closure of Ca+ Channels → ↓Ca+-Mediated NT
Release
• On Periaqueductal Grey Matter (PAG) – (Brain):
o →Remove Inhibition of PAG (Activates PAG) → Activates NRM → Inhibits
Dorsal Horn Synapse

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

§ Descending Inhibitory Neurons:

• Tri-Cyclic Antidepressants:
o Low-Dose Tri-Cyclic Anti-Depressants → block re-uptake of NE, Serotonin, &
Encephalins in Dorsal Horn Synapse → Maintained Inhibition of Nociceptive
Transmission

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Brain:
o
§ General Anaesthetic → Unconscious
Potential Efferent Nervous System Drug Targets:
- ACh-Receptors:
o Nicotinic Agonists:
§ Drugs which Enhance the Action @ the Nicotinic ACh-Receptor
§ Eg: Nicotine/ACh(Endogenous)/CarbacholTopical (Constricts Pupils → Treats Glaucoma)
o Nicotinic Antagonists (Anti-Nicotinics):
§ Drugs which Inhibit the Action @ the Nicotinic ACh-Receptor
§ Eg: Suxamethonium (Muscle Relaxant)/Champix (Helps Quit Smoking)
o Neuromuscular Blockers:
§ Clinically used as a Paralytic/Muscle-Relaxant in Ventilated General Anaesthesia
§ Non-Depolarising – Act as Competitive nAChR-Antagonists at the ACh-Receptors →
Prevents ACh from binding nAChRs
• Antidote: Acetyl-Cholinesterase Inhibitor → ↑[ACh]
• Side Effects: Ganglion Block →
o Hypotension
o Bradycardia
§ Depolarising – Act as nAChR-Agonists →Maintained depolarisation @ the NMJ → Loss of
Electrical Excitability
• Side Effects:
o Bradycardia
o Hyperkalaemia (Due to K+ Release from Muscle)
o ↑Intraocular Pressure (Due to Contraction of Extraocular Muscle)
o Prolonged Paralysis (If Acetyl-Cholinesterase is Abnormal – (Below))
o Malignant Hyperthermia (If SR-Ca+ Channel is Mutated – (Below))
• Special Cautions:
o Prolonged Paralysis can occur If Acetyl-Cholinesterase is
Abnormal/Mutated/Absent/Inhibited
o Malignant Hyperthermia can occur if SR-Ca+ Channel is Mutated → Intense
Muscle Spasms & ↑Body Temp → High Mortality
- Acetyl Cholinesterase:
o Acetyl-Cholinesterase Inhibitors:
§ Drugs that Inhibit the Cholinesterase Enzyme from degrading ACh in the Synapse
§ Eg: Physostigmine/Organophosphates
• → Prolonged Action of ACh in the Synapse
• → ↑[ACh] in the Synapse
§ Used to Treat Myasthenia Gravis
§ Also used as Nerve Gas (Chemical Warfare)
§ Note: AChEi’s Have Parasympathomimetic Side Effects
o Eg:: Tacrine – An Acetyl-Cholinesterase Inhibitor:
§ Originally used to treat Alzheimer’s Disease
§ (Alzheimer’s: characterised by loss of cholinergic neurons in Basal Nuclei)
§ Hence, an AChE-Inhibitor compensates for loss of Cholinergic Signalling
- Choline Reuptake Transporter:
o Choline Reuptake Inhibitor:
§ Drugs that inhibit Choline Reuptake by Blocking the Choline Transporter
• → Prolonged Action of ACh in the Synapse
• → ↑[ACh] in the Synapse
- Exocytosis of ACh Vesicles:
o Eg: Botulinum Toxin:
§ Blocks Exocytosis of ACh-Vesicles from Cholinergic Nerve Terminals
§ - Proteolytically degrades the adhesion proteins required for vesicle fusion with PM
Potential Autonomic Nervous System Drug Targets:
- Sympathetic:
o Sympathomimetics:
§ Drugs that Mimic the Effects of the Sympathetic NS
§ May be Directly Acting (Adrenergic Agonists):
• α-Adrenergic-Agonists
• β-Adrenergic-Agonists
§ -Or Indirectly Acting (NE-Synthesis/Storage/Release/Uptake/Degradation):
• ↑NE-Synthesis
• ↑Vesicular Repackaging of NE (rather than destruction)
• ↑NE-Release
• Blocking NE-Reuptake from synapse
• ↓NE-Degradation (By inhibiting Mono-Amine-Oxidase)
o Sympatholytics: (“Adrenergic Antagonists/Blockers”):
§ Drugs that Inhibit the Sympathetic NS
§ May be Directly Acting (Adrenergic Antagonists):
• α-Adrenergic-Antagonists
• β-Adrenergic-Antagonists
§ -Or Indirectly Acting (NE-Synthesis/Storage/Release/Uptake/Degradation):
• ↓NE-Synthesis (eg: By inhibiting Tyrosine Hydroxylase)
• ↓Vesicular Repackaging of NE (Ie: More is degraded by MAO)
• ↓NE-Release
- Parasympathetic:
o Parasympathomimetics: (“Muscarinic Agonists”):
§ Drugs that Mimic the Effects of the Parasympathetic NS
§ Most are Muscarinic Agonists
§ Effects:
• Bradycardia & Hypotension
• Contraction of Smooth Muscle (Eg: Bronchoconstriction)
• Increased GI Motility (Peristalsis)
• Increased Secretions (Salivary/Lacrimal/Bronchial/Intestinal)
• Pupillary Constriction (Useful in Closed-Angle Glaucoma → ↓IOP)
§ Note: Acetylcholinesterase Inhibitors also have Parasympathomimetic Effects (→Potentiates
AChE Action in Parasympathetic Synapses)
§ Hence: Not all Parasympathomimetics are Muscarinic Agonists; Some affect:
• ACh Synthesis/Packaging/Vesicle Mobilisation/Release/Etc
o Parasympatholytics: (“Muscarinic Antagonists” or “Anti-Muscarinics”):
§ Drugs that Inhibit the Parasympathetic NS
§ Effects:
• Tachycardia
• Relaxation of Smooth Muscle (Eg: Bronchial/Biliary/Urinary tracts)
• Decreased GI Motility (Peristalsis)
• Decreased Secretions (Salivary/Lacrimal/Bronchial/Sweat Glands)
• Pupillary Dilation (Dangerous for Closed-Angle Glaucoma → ↑IOP)
Sympathomimetics Mechanism of Action Therapeutic Use
(Adrenergic Agonists)
α-Agonists
Specific α-Adrenergic-Agonists Sm ooth M uscle Effects:
- Vascular Constriction (Used in Hypotension)
o Also in Nasal Decongestants (Ephedrine)
- Bronchoconstriction
- Pupillary Constriction
Cardiovascular Effects:
- ↑Heart Rate
- ↑Force of Contraction
Sm ooth M uscle Effects:
β-Agonists Specific β-Adrenergic-Agonists
- Vascular Dilation (Used in Hypertension)
- Bronchodilation (Used in Asthma)
- Smooth-Muscle Relaxation.
o (Ritodrine) Stops Premature Labour
Cardiovascular Effects:
- ↑Heart Rate
- ↑Force of Contraction
Immune Effects:
- Inhibition of Histamine Release from Mast Cells
Vasoactive Effects:
Adrenaline Non-Specific α- & β-Agonist - Redistribution of Blood towards Heart/Muscle,
(Secreted by Adrenal (Slightly better for β-actions; & away from Periphery/GIT. (Helpful in Shock)
M edulla) hence more commonly used in Sm ooth M uscle Effects:
Heart-Indications) - Vascular Dilation
- Bronchodilation
Cardiovascular Effects:
- ↑Heart Rate
- ↑Force of Contraction
Immune Effects:
- Inhibition of Histamine Release from Mast Cells
- Useful in Anaphylaxis.
M ainly Sm ooth M uscle Effects:
NorAdrenaline Non-Specific α- & β-Agonist - Vascular Constriction
(Sympathetic (Slightly better for α-actions; - Bronchoconstriction
Neurotransmitter) hence more commonly used as a - Pupillary Constriction
Vasopressor Drug) Cardiovascular Effects:
- ↑Heart Rate
- ↑Force of Contraction
Symptoms Of Exposure
Sym patholytics Mechanism/s of Action
(Adrenergic Blockers)
α-Antagonists Specific α-Adrenergic-Antagonists Used as Anti-Hypertensives:
- Vasodilation → ↓Arterial Pressure
- Note: Can lead to Postural Hypotension
Also Used in Prostatic Hypertrophy
β-Antagonists Specific β-Adrenergic-Antagonists Mainly Used for Cardiovascular Indications:
- Treats Angina Pectoris (by ↓HR & Contraction)
- Treats Heart Failure (by ↓HR & Contraction)
Used to be used as Anti-Hypertensives (Not any more)
Glaucom a: (Eye Drops → Pupil Constriction)
Note: Can Exacerbate Respiratory Conditions
(Eg:Asthma) by inhibiting Bronchodilation.
Parasympathetic Blockers: Mechanism of Action Therapeutic Use
- Ie: Muscarinic Antagonists
Atropine Non-Selective Muscarinic Antagonist
In Anaesthesia:
- ↓Secretions
- Bronchodilation
Treats AChE-Inhibitor-Poisoning:
- By Reducing ACh-Signalling
Treats Bradycardia - By ↑Heart Rate
Ipratropium Selective (Lungs) Muscarinic In Asthma & COPD:
Antagonist - Bronchodilation
Tolterodine Selective (Bladder) Muscarinic In Urinary Incontinence:
Antagonist - Inhibits Micturition
(Under Parasympathetic Control)
Selective (Gastric) Muscarinic In Peptic Ulcers:
Pirenzepine
- Inhibits Gastric Secretion
Antagonist
Mechanism/s of Action Symptoms Of Exposure
M uscarinic Toxins
(Target Parasympathetic):
Mamba Toxin Selective M1 Antagonist Sympathomimetic Symptoms
(Ganglia/Glands/CNS-Cortex)
Botulinum Toxins Blocks ACh-Exocytosis from No ACh-Signalling →
Cholinergic Neurons.
- Locally = Muscle Paralysis
- Systemic = Parasympathetic Paralysis
α-Bungarotoxin Blocks All Post-Synaptic AChRs
No ACh-Signalling →
- Locally = Muscle Paralysis
- Systemic = Parasympathetic Paralysis
Parathion Irreversible AChE-Inhibitor ↑ ACh-Signalling →
(An Organophosphate) - Bradycardia
→ ≈M uscarinic Agonist - Hypotension
Curare Non-Depol. Neuromuscular Blocker Nicotinic Antagonist → Neuromuscular Block.
–Competitive nAChR-Antagonists
Below are a Summary of the Functions of the Parasympathetic & Sympathetic Nervous Systems For your Reference:

Source: Unattributable
EPILEPSY & ANTI-EPILEPTIC DRUGS
EPILEPSY & ANTI-EPILEPTIC DRUGS

Epilepsy in General:
- Epilepsy is a Clinical Diagnosis; Requires:
o Occurrence of 2 or More Seizures, for which all external triggers have been eliminated
o Detailed History
o Detailed Description (or video) of the Seizures
o EEG Information
o (No single test is enough to diagnose)
o Note: 1x Seizure ≠ Epilepsy
- Prevalence: 0.5 - 1% of Adults
- Age of Onset:
o Generally before 20yrs
o 1st seizure before 10yrs
o Note: Can be Acquired (eg: Head Injury/Toxins)

D e fin itio n s:
- Seizure:
o “An Episode of Inappropriate Electrical Discharge involving Disordered Activity that is Synchronised
and Rhythmic”
o Simply – “An Electrical Storm somewhere in the Brain”
- Epilepsy:
o “A Condition in which there is Repetitive and largely Unpredictable Episodes of Seizure Activity”
o Note: Sometimes you don’t see the ‘seizure’
Seizures:
- Common Triggers (In Normal Individuals):
o Excessive Caffeine
o Fever
o Alcohol Withdrawal
o Drugs or Toxins
o Head Injury
o Metabolic/Electrolyte Disturbances
o Note: The above triggers have to be eliminated before Epilepsy is Diagnosed
§ (Epilepsy is an ‘Innocent until proven guilty’ disease)
o Note: 1x Seizure ≠ Epilepsy
- Common Triggers (In People with Epilepsy):
o **Strobe Lights are most common → (Often used for Diagnosis)
o Note: Some cases are Idiopathic (Ie: No apparent trigger)
- Common Symptoms:
o Symptoms Depend on the Type of Epilepsy
o Seizure may be Associated with an “Aura” - Sensory Associations:
§ Smells
§ Tastes
§ Sounds
§ Colours
§ Visual Field Alterations
o Seizure may consist of Aura only; Or may be preceded by an Aura
- Epileptic Foci:
o Groups of Hyper-Excitable Neurons (usually in Cortex) which Fire Inappropriately → Initiate Seizures
o Epileptic ‘Foci’ may occur in virtually Any Region of the Cerebral Cortex
§ Ie: If it occurs in a Motor Area → Motor Seizure
o Note: “Housekeeping” centres (Thalamus, Brain-Stem, Cerebellum) Don’t exhibit Epileptic Foci
§ However, they can still Receive excitatory waves generated by Epileptic Foci
o Note: Temporal Lobe Epilepsy is Unique
o Note: Thalamus is Implicated in Absence Seizures (Petit Mal) – Involved in signal
Generation/Propagation
Seizure Classification in Epilepsy:
- Systems of Classification:
o Note: Old-School Nomenclature:
§ Grand Mal (“Big Bad”) Seizure:
• Eg: Full ‘Tonic Clonic’ seizures
§ Petit Mal (“Little Bad”) Seizure:
• Eg: Absence seizure
• Note: Some old doctors regard Petit Mal seizures as any seizure that is not Grand
Mal
o Currently: “International Classification of Epileptic Seizures” (ICES):
§ The most commonly used classification
§ We will focus on this one
o New System: “Semiological Seizure Classification”:
§ Just introduced; likely to gain supremacy

- New Classifications (Not fully adopted yet; Just be Aware):

o “Without Impairment of Consciousness/Responsiveness”:
§ If it Involves Motor/Autonomic Components → Correlates with “Simple Partial” Seizures
§ If it Involves Sensory/Psychic Phenomena →Correlates with an “Aura”
o “With Impairment of Consciousness/Responsiveness”:
§ Correlates with “Complex Partial” Seizures
o “Seizures Evolving to Bilateral, Convulsive Seizure”:
§ (Includes Tonic, Clonic & Tonic/Clonic Seizures)
§ Correlates with “Complex Generalised” Seizures

- “International Classification of Epileptic Seizures” (ICES):

o Location?:
§ Partial (Focal):
• Seizure that occurs within a Localised Area of the Brain
• Typically starts in a Unilateral Brain Network
• Location of Epileptic Focus Determines Nature of Seizure
o Note: Electro-Encephalogram (EEG) used to identify Focus Location
• Can involve Cortical AND Sub-Cortical Structures
• Can involve Contralateral Hemisphere
• Onset location is typically consistent between Seizures → Symptoms are consistent
• Note: Some people can have Multiple Foci → Multiple separate seizures @ one time
§ General:
• Seizure that appears Throughout the Forebrain, & Involve Both Hemispheres from
the Beginning
• Typically starts in a Bilateral Brain Network → Hence affects Both Hemispheres
• Can involve Cortical AND Sub-Cortical Structures
• Don’t necessarily include the entire cortex
• Can be Asymmetric
§ - 2oGeneral:
• Note: A Single Focus, responsible for Partial Seizures may spread through the brain
to become Secondary Generalised Seizures
o Conscious?:
§ Simple:
• Little/No Disruption of Consciousness or Cognitive Ability
§ Complex:
• Major/Complete Disruption of Consciousness or Cognitive Ability
• Note: Typically causes some Amnesia (Patients don’t remember the seizure)
Using the ICES System:
- “Simple Partial Seizure”:
o Ie: Conscious & Localised Seizure
o Symptoms Depend on Cortical Region Affected:
§ Typically – Small, Rapid Muscle Movements
§ Others include:
• Sensory Anomalies (Numbness / Tingling)
• Autonomic Alterations (Blushing / Nausea)
• Behavioural Alterations (Hallucinations / Deja Vu)
o Duration:
§ Very Short Duration (Less than 1min)
o Note: Preservation of Consciousness & Memory is Key

- “Complex Partial Seizure”:

o Ie: Impaired Consciousness & Localised Seizure
§ Note: ‘Impaired Consciousness’ = Dazed / Vague / Dream-like / Inability to Respond /
Amnesia
o Symptoms Often Associated with Purposeless Movements:
§ Hand-Wring
§ Pill-Rolling
§ Face-Washing
§ Taking off Clothes
§ Fidgeting
§ Walking Around
§ Mumbling
o Duration:
§ Less than 2 min
o Note: Impaired Consciousness → Little/No Memory of Seizure

- “Partial with 2o Complex Generalised Seizure” (“Tonic-Clonic”/“Grand-Mal”):

o Ie: Simple or Complex Partial Seizure, Progressing to Complex (Unconscious) Widespread
(Generalised) Seizure
o Symptoms of “Grand-Mal”/“Tonic-Clonic” Seizures:
§ Loss of Consciousness (Semi-Consciousness is Rare)
§ Momentary Central Apnoea
§ Loss of Bowel Control
§ 4 Phases:
• 1: Pre-Seizure Period:
o Often involving Aura
o Gives Pts time to find a Comfortable/Safe Position
• 2: Tonic Phase:
o Sustained Tonic Contraction (‘Rigid Extension’) of all Muscles of the Body
• 3: Clonic Phase:
o Repetitive Synchronous Jerks (‘Clonic’) of all Muscles of the Body
• 4: Post-Ictal Coma:
o Patients may not regain consciousness for a while
o Can be Tired/Sore upon waking
o Duration:
§ 1-2mins
§ Usually 2mins
§ However, can last for many minutes
https://www.health.harvard.edu/diseases-and-conditions/seizure-overview-a-to-z

Other Types of Seizures:

- “Myoclonic”:
o Brief, Marked Contraction of Muscles (Ie: A “Shock-Like Jerk” or a “Startle”)
o ‘Myoclonic’ is an Umbrella Term for:
§ Juvenile Myoclonic Epilepsy
§ Lennox-Gastaut Syndrome
§ Progressive Myoclonic Epilepsy
o Symptoms:
§ Contraction may be restricted to a Specific Muscle Group or a number of Muscle Groups
§ Typically Upper Body Muscles
§ Generally Bilateral
o Duration:
§ Typically 1-5sec
§ Can last up to 30sec

- “Temporal Lobe Epilepsy”:

o Unique type of Seizure
o Once thought to be a type of Absence Seizure, but it Isn’t
o Note: Because the Temporal Lobe is responsible for many different functions
(memory/hearing/smell/motor), symptoms differ greatly in nature depending on Focus Location
o Typically Manifests as some type of Behavioural Alteration or Complex Activity
o Symptoms:
§ Universal General Symptoms:
• Activity Doesn’t Cease
• Awareness/Memory is Compromised & Amnesia often covers the Seizure
o However, some patients can ‘Feel’ an impending Seizure as part of an Aura
• Personality Changes are Common
• Symptoms may include One or a Combination of the Below Symptoms
 § - Automatic Activity but Without Conscious Awareness:
• Person Appears to interact with others or the environment, but it is Involuntary
• Any Physical Activity @ the moment of seizure will be Perpetuated
o (Provided it is a well-learned pattern – Walking/Driving/Etc)
• Automated Activity continues until Seizure Stops or the Activity is Prevented
• If Addressed, person Replies with Stereotyped Responses or Nonsense Comments
§ - Religiosity:
• Some patients manifest Hallucinations of Religious Figures
• Others Believe They are Reincarnations of Religious Figures
• Patients can Verbally/Physically Attack those acting in an “Immoral” Fashion
• The above experiences may Occur Pre- & Post-Seizure
§ - Sexually Inappropriate Behaviour:
• Patient may make Crude Physical/Verbal Sexual Advances
• May Enact Inappropriate Sexual Behaviour in Public
§ - Aggression:
• Verbal/Physical Violence against others
§ - Relived Experiences:
• Patients may Relive Memories or Music
• Awareness of surroundings is also lost during such seizures
o Very Hard to Diagnose:
§ Other people may not realise the altered behaviour
§ Symptoms can easily be discounted (Vivid Memories/Song in head/Smells/Anger)
§ The Patient may know that they have some Amnesia, but make up stories to cover the lost
time (Confabulation)
§ Patients also Don’t Remember Experiencing any Symptoms → Don’t Report any Problem
§ Because TLE is often Behavioural, it can easily be Mis-Diagnosed as Behavioural Disorders or
Schizophrenia
o Treating Temporal Lobe Epilepsy - Carbamazepine (AKA: Tegretol)is 1st Line:
- “Absence Seizures” (The Classic “Petit Mal”):
o Ie: Abrupt Onset of Impaired Consciousness
o Symptoms:
§ Typically Staring & Cessation of Activity
§ Loss of Movement, however:
• Possible ‘Lip-Smacking’
• Possible Rapid Eye-Blinking
• Possible Head-Lolling/Rolling
§ Amnesia covers the seizure
§ Pt is Unaware of the Time Lapse → Pick up Exactly where they left off
§ Note: No Incoming Sensory/Outgoing Motor activity is Processed Properly during seizure
o Duration:
§ Up to 30sec
§ However, may occur multiple times in a day
o Note: Impaired Consciousness → Little/No Memory of Seizure
o Note: Thalamus plays an Important Role by Propagating the Seizure Activity Through the Entire Brain
§ Although The Focus is in the Cortex, it has Rapid Access to the Thalamus → Drives Seizures
§ Thalamic Ca+ Channels are Responsible → Ie: Treatment = Blockade of these Ca+ Channels
(By Ethosuximide)
§ Note: Surgical Option – Involves Excision of Cortical Focus
o EEG: Seizure Activity Resembles Static Interference of all Electrical Activity in the Brain
o Treating Absence Seizures – Ethosuximide

Nocturnal Epilepsies:
-
o Are sometimes mistaken for Bedwetting or Behavioural Problems
o Are hard to diagnose because no one ever sees them
Source: https://www.grepmed.com/images/3775/generalized-types-seizures-diagnosis-focal
“Status Epilepticus” – The Epileptic Emergency:
- A term that describes An Episode of Seizures of Any Type that have 1 of 2 Properties:
o 1: Seizures Don’t Stop Spontaneously
o 2: Seizures Occur in Rapid Succession Without Recovery
- A Status Epilepticus Seizure = Absolute Neurological Emergency:
o High Risk of Cerebral Hypoxia
o High Risk of Permanent Brain Damage
o Often Results in Permanent Loss of Neurons due to Excito-Toxicity
§ (Hippocampus & Pyramidal Tracts are Particularly Sensitive → ↓Memory & Motor)
o Surviving Neurons may exhibit Synaptic Reorganisation
- The Problem = Cell Death:
o Seizures can Trigger Cell Death; How?:
§ ↑Intracellular Ca+ from ↑Ca-Mediated-NT-Release → Release of Cytochrome-C from
Mitochondria → Triggers Apoptotic Pathway
§ Energy Depletion → ↑Free Radicals → Widespread Protein/Membrane/DNA Damage
o Also, Attempts made by the brain to Restore Function favour The Excitatory Pathways → ↑Seizures
- Occurs mostly in the Young and the Elderly (Typically not middle-aged)
o Note: Mortality is highest in Elderly Patients
o Average Mortality Rate ≈20%
- Treating Status Epilepticus:
o Benzodiazepines are the 1st Line Drugs:
§ The Drugs:
• *Diazepam – (Generally #1; But Short Acting)
• Lorazepam – (Some argue that it’s #1 due to Higher Seizure-Termination Rate)
• Midazolam
§ Mechanism of Action:
• ↑Frequency of GABA-Channel Opening (Agonist-Like but NOT an Agonist)
• → Increased General Inhibition
• → Inhibits spread of Signals from Epileptic Focus
o Phenytoin – A Common Adjunct to ‘Benzos’:
§ Indication:
• All Seizure Types EXCEPT Absence Seizures & Temporal Lobe
§ Mechanism of Action:
• Identical MOA to Carbamazepine
• ↑Time of Recovery of Voltage-Gated Na+ Channels from Inactive to Resting States
o Note: Like Local Anaesthetics, it is Use-Dependent →
o – Therefore, Drug is Selective for Rapid-Firing Neurons
• → ↓Repetitive Neuronal Firing
• @ Higher Doses → Augmented GABA Activity
§ Common Side Effects:
• Gum Hyperplasia (Overgrown Gums)
• Hirsutism (Inappropriate Hair Growth)
• Note: These side effects are a problem for Teenage Girls → Non-Compliance
Mechanisms of Seizure Development:
- **Neurons are Hyperexcitable**; 3 Possibilities:
o 1:**Resting Membrane Potential has been Altered in a Subset of Neurons**:
§ Pushes Neurons Closer to Threshold → Spontaneous Activity
§ Neurons are more Sensitized to Small Changes in Ion Availability
• (Note: Less Sensitive After Seizure)
§ Note: The ‘Epileptogenic’ Foci can Recruit Neighbouring Neurons → Spread
o 2:**Ion-Channelopathy → Decrease in Threshold of Voltage-Gated Channels**:
§ Eg: Mutation in Amino Acid sequence in Voltage-Gated Channels → Channel Responds to
Lower Voltage (Ie: More Negative Potentials) → Hence, are More Easily Activated
o 3:**Neurotransmitter Imbalance**:
§ Inappropriate Activity of the Epileptic Focus can be due to Excess of Glutamate Activity or a
Deficit of GABA Activity:
§ ↑Excitatory (Glutamate= Primary Excitatory Neurotransmitter):
• Too many Glutamate Receptors
• Glutamate Receptors Active for Too Long
• Too Much Glutamate Synthesized
• Too Much Glutamate Available
• Too Little Glutamate Breakdown
• Too Many Glutamatergic Synapses/Neurons
• Hypersensitive Glutamate Receptors
• Main Receptor = NMDA Receptor:
o Primarily a Ca+ Channel (also permissive to Na+) (Ie: Mediates Depolarisation)
§ Or ↓Inhibitory (GABA= Primary Inhibitory Neurotransmitter):
• Too Few GABA Receptors
• GABA Receptors Not Active for Long Enough
• Too Little GABA Synthesized
• Too Little GABA Available
• Too Much GABA Breakdown
• Too Few GABA Synapses/Neurons
• Hyposensitive GABA Receptors
• Main Receptor = GABAA Receptor:
o Primarily a Cl- Channel (Ie: Mediates Hyperpolarisation)

https://ppt-online.org/296144
Pharm acological Interventions in Epilepsy:

Goals of Treatment:
- 1: Suppress Existing Seizure
- 2: Decrease Probability of Future Seizure
- 3: Avoid any agent that may Exacerbate Seizure Probability
- 4: Evaluate Patient/History/Type of Seizures, then Tailor Treatment to Suit the Individual

Management in Pregnancy:
- Virtually all Anti-Epileptics have been Associated with Some Type of Birth Defect
o Valproate (Valproic Acid) has the highest incidence
o Phenytoin also has high incidence
- Birth Defects Include:
o Spina Bifida
o Cleft Palate
o Congenital Heart Defects
o Microcephaly
- Lamotrigine = 1st Line:
o - In Pregnant Women & Women of Child-Bearing Age
- Note: Pregnancy can alter Drug Metabolism & Seizure Activity can Change in Pregnancy
- Folate Supplements – Can further reduce risk of Spinal Cord Defects (Ie: Spina Bifida)

Anti-Epileptic (Anticonvulsant) Drugs – Grouped by Site of Action:

Site of Action: Sodium Channels:

- Phenytoin:
o Indication:
§ All Seizure Types EXCEPT Absence Seizures
§ Note: Can be used with Diazepam (a Benzo) for Status Epilepticus
o Mechanism of Action:
§ Identical MOA to Carbamazepine
§ ↑Time of Recovery of Voltage-Gated Na+ Channels from Inactive to Resting States
• Note: Like Local Anaesthetics, it is Use-Dependent →
• – Therefore, Drug is Selective for Rapid-Firing Neurons
§ → ↓Repetitive Neuronal Firing
§ Note: Has NO effect on GABA or Glutamate Transmission
o Common Side Effects:
§ Teratogenic Effect
§ Gum Hyperplasia (Overgrown Gums)
§ Hirsutism (Inappropriate Hair Growth)
• Note: These side effects are a problem for Teenage Girls → Non-Compliance
§ Vertigo
§ Skin Rashes
§ Anaemia
§ Foetal Malformations
§ Note: Has Numerous Drug Interactions
- Carbamazepine (AKA: Tegretol):
o Indications:
§ 1st Line in Temporal Lobe Epilepsy
§ 1st Line in Most Forms of Epilepsy
§ Is effective in All Seizures EXCEPT Absence Seizures
§ Note: Generally preferred to Phenytoin due to better Side-Effect Profile
o Contraindication:
§ Carbamazepine also has activity @ Adenosine Receptors...
• Therefore, Methylxanthines (Adenosine Antagonists) + Carbamazepine can trigger
Tonic-Clonic (Grand-Mal) Seizures
o Mechanism of Action:
§ Identical MOA to Phenytoin
§ ↑Time of Recovery of Voltage-Gated Na+ Channels from Inactive to Resting States
• Note: Like Local Anaesthetics, it is Use-Dependent →
• – Therefore, Drug is Selective for Rapid-Firing Neurons
§ → ↓Repetitive Neuronal Firing
o Common Side Effects:
§ Anti-diuretic Effect – (Note: of Concern in older Pts, or Pts with mild Heart Conditions – Ie:
Hypertension/Angina/Heart Failure)
§ Sedation/Ataxia
§ Nausea
§ Blurred Vision/Lens Opacity
§ Mental Disturbances
Lam otrigine (Lam ictal):
- o Indications:
§ Partial OR General Seizures
o Mechanism of Action:
§ Na+ Channel Blocker (Similar MOA to Phenytoin & Carbamazepine)
§ ↑Time of Recovery of Voltage-Gated Na+ Channels from Inactive to Resting States
• Note: Like Local Anaesthetics, it is Use-Dependent →
• – Therefore, Drug is Selective for Rapid-Firing Neurons
§ → ↓Repetitive Neuronal Firing
§ Note: Also seems to Prevent Glutamate Release → Prevents Excitatory Transmission
o Side Effects:
§ Dizziness/Ataxia
§ Blurred/Double Vision
§ Nausea/Vomiting

(Note: The Above Diagram Applies to both Carbamazepine & Lamotrigine)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO
Site of Action: Calcium Channels:
- Ethosuximide:
o Indications:
§ Absence Seizures
§ NOT effective against other types of Seizures
o Contraindication:
§ Sufferers of Tonic-Clonic (Grand-Mal) Seizures - Ethosuximide can induce these seizures
o Mechanism of Action:
§ Blocks Ca+ Channels in Thalamic Relay Neurons (Which are implicated in Absence Seizures)
• → Reduces Spread of Seizure Activity Through the Thalamus → Rest of Brain
• → Prevents Absence Seizures
§ Note: Has NO effect on GABA/Glutamate/Other Ion Channels
o Side Effects:
§ May Aggravate Tonic-Clonic (Grand-Mal) Epilepsy
§ Gum Hypertrophy
§ Hirsutism
• Note: These 2 side effects are a problem for Teenage Girls → Non-Compliance
§ Nausea
§ Vomiting
§ Mood Changes (Euphoria, Night Terrors, Irritability, Aggressiveness)
§ Headache
§ Anorexia

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Site of Action: GABAA Receptors:
- Barbiturates (Ie: Primidone, Phenobarbitone):
o Indications:
§ All Seizure Types EXCEPT Absence Seizures
§ Note: Not used in adults due to Abuse Potential
o Mechanism of Action:
§ GABAA Channel Modulators (Not Agonists as they don’t bind to GABA Binding Sites)
§ → Prolongs Opening of GABA Channel (But Not Frequency) → ↑Cl- Influx
• (Acts like a chemical stent → Potentiates Channel Activation→ ↑Cl- Influx)
• Ie: ↑Cl- Influx → Hyperpolarisation →Stabilises Membranes of Target Neurons
o →Inhibits Initiation of Discharges
o →Inhibits Spread of Discharges from Epileptic Focus
§ Note: However, they Limit Sustained Repetitive GABA Firing @ High Concentrations
§ Can Also Inhibit Voltage-Gated Ca+ Channels:
• → ↓Glutamate Release → ↓Excitatory Neurotransmission
o Side Effects:
§ Phenobarbitone:
• Some Sedative Effect at first (Tolerance develops rapidly)
• Abuse potential in Adults
§ Primidone:
• Sensation of Intoxication
• Sedation
• Vertigo
• Nausea
• Abuse Potential
• Leukopenia, Thrombocytopenia
• Lymphadenopathy

https://ppt-online.org/296144
 Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Benzodiazepines (Diazepam, Lorazepam, Midazolam, Clonazepam):

o Indications:
§ Are 1st Line for Status Epilepticus
§ Generally Not 1st Line for general Seizures
§ Sometimes used in Paediatric Myoclonic and Absence Seizures
§ (Note: Benzos are also used as Hypnotics, Sedatives & Anxiolytics)
o Mechanism of Action:
§ Benzos are GABAA Channel Modulators
§ Agonist-Like Effect but NOT an Agonist → Causes Conformational Change in GABA Channel
§ → Makes it easier for GABA to Open the Channel
§ →↑Frequency of GABA-Channel Opening:
• Ie: ↑Cl- Influx → Hyperpolarisation →Stabilises Membranes of Target Neurons
o →Inhibits Initiation of Discharges
o →Inhibits Spread of Discharges from Epileptic Focus
o Side Effects:
§ Sedation is #1
§ Abuse Potential

Gabapentin (Neurontin):
-
o Indications:
§ Used for Partial Seizures (Including 2oGeneralised)
o Mechanism of Action:
§ A GABA-Analogue (But NOT a Receptor Agonist)
• Mechanism of Action is Unclear
§ → General Neuronal Inhibition of the Brain
o Side Effects:
§ Drowsiness
§ Dizziness
§ Fatigue
§ Ataxia
 (Benzodiazepines & Gabapentin Sites of action)
Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO
Site of Action: Na+ Channels, Ca+ Channels & GABAA Receptors:
- Valproate (Valproic Acid):
o Indications:
§ Absence Seizures
§ Also Effective Against ALL Other Seizure Types
o Contraindication:
§ Pregnancy: Strong Teratogenic Effect → Risk of Foetal Abnormalities
• Neural Tube Defects
• Cleft Lip/Palate
• Heart Abnormalities
• Genitourinary Defects
• Many many more!!
o 3 Mechanisms of Action:
§ 1: Delays Recovery Time of Na+ Channels (Prevents Rapid Action Potentials)
• → ↓Repetitive Firing of Neurons
§ 2: Inhibits Thalamic Ca+ Channels
• → Prevents Spread of Signals from Epileptic Focus
§ 3: ↑GABA Production & ↓GABA Breakdown→ ↑ GABA (Inhibitory) Signalling
o Side Effects:
§ Baldness
§ Weight Gain
§ Liver Damage
§ GI Disturbances
§ Sedation
§ Ataxia

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

 Side Note: Surgical Interventions In Epilepsy:

W hy Surgery:
- Up to 30% of Epilepsies are Unresponsive to Pharmacological Treatment
- If the Epilepsy is Unresponsive to drugs, Surgery is Essential to prevent Permanent Progressive Brain Damage
o Note: Risk of Brain Damage Increases the longer the condition continues
o Note: Seizures bring about More Seizures (Ie: Untreated Seizures make Future Seizures more Likely)

Surgical Options:
- 1: Resections:
o Removal of Epileptic Focus
o Hemispherectomy (Removal of an entire Hemisphere)
o Anteromedial Temporal Lobectomy
- 2: Disconnections:
o Cut the Corpus Callosum (Bridge between Hemispheres)
o Multiple Sub-Pial Transections (Small cuts made into cortex hoping to isolate neuronal networks)
Prognosis:
- ≈80% of Surgery Patients are Seizure-Free 10yrs later
- (Note: Precise mapping of the Epileptic Focus is an Essential Prerequisite to Surgery to ensure that removal
won’t render the patient Paralysed/Unable to Speak/Other Serious Deficit)

Dietary Intervention: The Ketogenic Diet:

W hat is the Ketogenic Diet?

- 1gram/KgBody-Weight of Protein
- 5-10grams of Carbs/Day (Ie: Virtually NO Carbs)
- Remainder of Calories is made up in Fats
- Note: Side Effect – Bloating & Constipation (Lack of Fibre)

Proposed Mechanism/s of Action:

- ↑GABA Availability:
o Through ↑Metabolic Conversion of Ketone Bodies → GABA
§ ↑GABA Availability →General Inhibition of Neuronal Activity
- Altered Metabolic Activity:
o ↑Protein & ↓Carbs → Forced Re-Adaptation of Energy-Utilisation → ↓Glutamate Availability
§ ↓Glutamate Availability → Decreased Stimulation of Neuronal Activity
- ↑Activity of Na/K-ATPase:
o → Drives Neurons Away from Threshold → Hyperpolarises
ANESTHESIA & ANALGESIA
 ANESTHESIA & ANALGESIA

Treating Pain – RULES OF THUMB:

1. Evaluate the Pain Experience (Pain-Scale):
o Necessitates good information on:
§ Patient Self-Pain Report
§ Nature of Injury
§ Patient History
§ Social Status, Culture, Background
o **Note: Evidence Suggests that if you Match the Analgesic to the Pain, Addiction IS NOT an Issue!!
2. Choose Appropriate Analgesic:
o *Match the Analgesic to the Pain*
§ Ie: Don’t give Aspirin for Severe Back Injury
§ Ie: Don’t give Fentanyl for Tennis Elbow
o The ‘WHO-Analgesic Ladder’ – Can be Helpful (See Next section)
o Combination therapies may be used
o Eg: Exam Q: “Mr X Presents with Severe Pain, what would you give?
§ A: Don’t start with Panadol; Match the Pain Report with the Analgesic – Eg: Morphine

3. Start with Lowest Dose Possible, then Titrate Up to Desired Clinical Effects:
o Different people are affected differently by the same dose of Analgesic
§ Ie: For some, the ‘normal’ dose = Overdose
§ Whereas, for Others, the ‘Normal’ dose = Ineffective
o Therefore, Better to be Safe than Sorry
4. Monitor & Re-Evaluate Changing Pain Experience or Side Effects:
o Allows for Adjustments of:
§ Drug Type (Strong Opioid → Weak Opioid → NSAID → No Drug)
§ Drug Dose
o Patient Should know that Opioids are Short-Term and that their need decreases as healing
proceeds
§ Get the patient onboard with a Long-Term Step-Down Goal → Eventually No Drugs
§ This is especially important for Opioid (Narcotic) Analgesics to prevent addiction
o Note: Sometimes when a Patient is Relieved of pain, they sleep for ages – Don’t Mistake this for
Sedation. They are simply catching up on sleep lost while during pain
o Note: Step-Down Plan IS NOT needed when treating Chronic / Neuropathic Pain
FAILURE TO ADEQUATELY MANAGE PAIN IS UNETHICAL & CRIMINAL!!

The WHO-Analgesic Ladder: Choosing the Appropriate Analgesic:

- Originally designed for the management of Chronic Cancer Pain
- But the Key Principle =
o “You must Assess the Degree of Pain FIRST, then come into the Ladder @ the Appropriate Level”
o Don’t start at the bottom & work up
Potential Targets for Analgesic Treatment:
- 1: Peripheral-Targeting Drugs:
o TRPVR Receptors (Vanillo+1id Receptors – Sensitive to H/Capsaicin/Heat/Mechanical):
§ Capsaicin (Eg: Topical Arthritis/Back-Pain/Muscle-Pain Cream):
• Activates TRPV1R Receptors on C-Fibres →Depolarisation → Substance-P release
o → Depletes the terminal of Substance-P (A Peptide)
o → There will be a period of Analgesia while Sub-P is re-synthesised
• Therefore, temporarily Inactivates Neurons by Depleting Peptide Neurotransmitters
o Prostanoid Receptors (Sensitive to Prostaglandins):
§ Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) – (Aspirin/Ibuprofen)
• - Are ‘Cyclo-Oxygenase’ (COX)-Inhibitors:
o →Decreased Prostaglandin Production
o →↓Prostaglandin-Mediated Hypersensitivity of Nociceptive Neurons
• - Also Decreases the Impact of Bradykinin
• Note: Aspirin – Is an Irreversible COX-Inhibitor & explains why it is the only NSAID
used as an Anti-Platelet Drug (Ie: Since platelets don’t have a nucleus to resynthesize
the COX-Enzymes, they are rendered useless)
o Therapeutic Side Effect: Some Gastric Bleeding
o Toxic Side Effect: Respiratory & Metabolic Acidosis
• Note: Paracetamol – Very Mild NSAID
o Mechanism Still Unknown
§ – Appears to Act Centrally, rather than Peripherally
§ – Appears to Inhibit-COX3
o Often used in Conjunction with Opioid Analgesics (Codeine/Morphine)
§ → Is Synergistic
§ COX-2 Inhibitors – (Celebrex)
• Anti-Inflammatory Analgesic:
• More specific than NSAID’s – Target COX-2 Enzyme – Less Side-Effects
• →↓Prostaglandin Production by inhibiting the enzyme Cyclo-Oxygenase-2 (COX-2)
→↓Prostaglandin-Mediated Hypersensitivity of Nociceptive Neurons
o Opioid Receptors:
§ Opioid Drugs – (Codeine, Morphine, Fentanyl):
• On Distal Nerve Endings – (Periphery):
o →Opens Non-VG-K+ Channels → K+-Efflux → Hyperpolarisation

Source: Unattributable
- 2: Central Targets:
o Pain-Gate Mechanism
§ Opioid Drugs – (Codeine, Morphine, Fentanyl):
• On Proximal Nerve Ending – (Spinal Cord):
o Inhibit Adenylate Cyclase → ↓cAMP Activity → Blocks VG-Ca+ Channels →
↓ Ca+-M ediated NT Release
o (Ie: Decreased NT-Release → Reduced Nociceptive Signal Transmission)
• On Periaqueductal Grey Matter (PAG) – (Brain):
o →Remove Inhibition of PAG (Activates PAG) → Activates NRM → Inhibits
Dorsal Horn Synapse
§ Descending Inhibitory Neurons:
• Tri-Cyclic Antidepressants:
o Low-Dose Tri-Cyclic Anti-Depressants → block re-uptake of NE, Serotonin, &
Encephalins in Dorsal Horn Synapse → Maintained Inhibition of Nociceptive
Transmission
o Ie: Augments Action of Descending Inhibitory Pathways on the Pain Gate
§ Brain:
• General Anaesthetic → Unconscious
The Specific Drugs Themselves:

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

- (Aspirin/Ibuprofen)
o - Are ‘Cyclo-Oxygenase’ (COX)-Inhibitors:
§ →Decreased Prostaglandin Production
§ →↓Prostaglandin-Mediated Hypersensitivity of Nociceptive Neurons
o - Also Decreases the Impact of Bradykinin
- Note: Paracetamol – Very Mild NSAID
o Mechanism Still Unknown
§ – Appears to Act Centrally, rather than Peripherally
§ – Appears to Inhibit-COX3
o Often used in Conjunction with Opioid Analgesics (Codeine/Morphine)
§ → Is Synergistic
- COX-2 Inhibitors – (Celebrex)
o Anti-Inflammatory Analgesic:
o More specific than NSAID’s – Target COX-2 Enzyme – Less Side-Effects
o →↓Prostaglandin Production by inhibiting the enzyme Cyclo-Oxygenase-2 (COX-2)
→ ↓ Prostaglandin-M ediated Hypersensitivity of Nociceptive Neurons

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

O p ia te s & O p io id s:
- (Note: Opiates = Substances Extracted from Opium Poppies; Opioids = Substances related to Opiates)
- – Are Opioid Receptor Agonists:
o Ie: Act on Opioid Receptors (Of Which there are 3 Subclasses):
§ µ (‘Mu’):
• Defined by Binding Morphine
• → Spinal/SupraSpinal Analgesia, Respiratory Depression, ↓GI-Motility & Sedation
§ δ (‘Delta’):
• Defined by Binding Dynorphin
• → Appears to Contribute to Analgesia
§ κ (‘Kappa’):
• Defined by Binding Ketocyclazocine
• → Spinal/SupraSpinal Analgesia, ↓GI-Motility, Diuresis, Sedation & Psychotomimesis
o They are all G-Protein Linked Receptors
- – Mechanisms of Action:
o On PRE-Synaptic Neuron: - Inhibition of Adenylate-Cyclase Activity:
§ → ↓cAMP Activity → Blocks VG-Ca+ Channels → ↓Ca+-Mediated NT Release
§ (Ie: Decreased NT-Release → Reduced Nociceptive Signal Transmission)
o On POST-Synaptic Neuron: - Activation of Non-VG-K+ Channels:
§ → Hyperpolarises Post-Synaptic Neuron → ↓Excitability of Post-Synaptic Neuron
§ (Ie: ↓Excitability → Reduced Nociceptive Signal Transmission)
Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO
Summary Table:
O p io idIndication:
D ru g s: Mechanism of Action:
(Ascending)
Codeine Mild – Moderate - Metabolised by Cyt-P450 Liver Enzymes → De-Methylated to Morphine.
- 1/6th Potency of Morphine
- Morphine → µ-Opioid Receptor Agonist
(Side Effect – Respiratory Depression)
(Side Effect – Constipation)
TramadolMild – Moderate - Weak µ-Opioid Receptor Agonist
- Also Inhibits NA & Serotonin Reuptake → Augments Descending
Inhibitory Pathways.
(Side Effect – Respiratory Depression – But less than Morphine)
(Side Effect – Constipation – But Less Than Codeine)
(Toxicity → Seizures & Serotonin Syndrome: Due to Excess Serotonin)
Moderate – Severe - Weak µ-Opioid Receptor Agonist (less potent than morphine)
Pethidine
(Mostly Obs/Gyn) (Side Effect – Norpethidine, a Toxic Metabolite of Pethidine → is a Pro-
(M eperidine
/Demerol)
Convulsant & Hallucinogen)
(Side Effects – Respiratory Depression, Agitation, Tremor, Twitching)
Note: When used for Labour Pain, it Can cross Placental Barrier :.
Naloxone is kept handy to reverse any Respiratory Depression in the
Neonate.
MorphineModerate – Severe - The ‘Standard’ µ-Opioid Receptor Agonist
(Ie: All µ-Opioid Agonists are compared to Morphine)
- Can be Administered via Any Route.
(Side Effect – Respiratory Depression)
- Strong µ-Opioid
Hydromorphone ModerateReceptor
– SevereAgonist
(8x Potency
(M ostly Severe) of Morphine)
(Note: Often used in Opioid-Tolerant Patients)
- ≈Equivalent
Oxycodone Moderateto–Morphine:
Severe µ-Opioid Receptor Agonist, but Oral
Bioavailability is Much Higher than Morphine.
(M ostly Chronic)
- Most effective when used with Non-Opioid Analgesics.
- (Note: Argued to have strong abuse potential)
SEVERE PAIN ONLY - Very Strong µ-Opioid Receptor Agonist (80x Morphine)
Fentanyl
- Also very quick acting. (5 mins vs. 15mins for morphine)
(Note: High Doses → Muscle Rigidity)

– Side Effects & Things to Monitor:

- Common Side Effects Things to Monitor
- Respiratory Depression - Respiratory Rate & O2 Sats
- Decreased GI Motility → - Hear Rate
Constipation - Blood Pressure
- Histamine Release - Sedation
- ↑Sphincter Tone - Hallucinations/Mood Changes
- Mood Changes - Constipation
- Somnolence (Ie: Sedation) - Hives/Itching/Sweating
- Tolerance over time with - Urinary Retention
continued use - Evidence of Hypothyroidism
(↑Dose for same effect) - Frequency/Quantity of Use

Naloxone (“NARCAN”) – The Antidote for Opioids:

- o – Is an Opioid Receptor Antagonists:
§ Blocks Opioid Drugs from binding to Opioid Receptors
§ → Can Increase Pain Experience
§ → However the Main Use is to Reverse Respiratory Depression & other side effects
Atypical Analgesics:
- Indications:
o Chronic Pain
o Neuropathic Pain
o Pain Unresponsive to Opioid Analgesics
- – Rely on Manipulation of Other Mechanisms of Nociception – (Other than NSAIDS & Opioids):
o Eg: TriCyclic Antidepressants:
§ Low-Dose Tri-Cyclic Anti-Depressants → block re-uptake of Noradrenaline & Serotonin in
Dorsal Horn Synapse → Prolongs action of NE & 5HT
§ →Ie: Augments Action of Descending Inhibitory Pain Pathways on the Pain Gate
§ → Maintained Inhibition of Nociceptive Transmission
§ (Side Effects = Improvement of Mood, Sleep & Anxiety – Ie: GOOD Side Effects)
o Eg: Anti-Arrhythmics (Na+ Channel Blockers):
§ (Lignocaine/Lidocaine/Tocainide/Mexiletine)
• → Block VG-Na+ Channels → Reduce Ectopic Firing Neurons → ↓Hyperexcitability of
CNS (& Heart)
o Eg: Anti-Convulsants:
§ (Carbamazepine)
• Delays Recovery Rate of VG-Na+ Channels → ↓Frequency of Firing of Hyperactive
Neurons
• Recommended for:
o Trigeminal Neuralgia
o Other Sharp, Shooting or Electric Shock-like Pain
§ (Gabapentin)
• – Augments GABA (Inhibitory) Release to Dampen Nociceptive Signalling in CNS

- - Treating Neuropathic Pain:

o 1st Line = Tricyclic Antidepressants (TCAs):
§ See above for MOA
o Residual Pain After TCAs:
§ Na+ Channel Blockers:
• Lignocaine/Lidocaine/Tocainide
• Mexiletine
§ An Anti-Convulsants:
• Carbamazepine
• Gabapentin (GABA Analogue)
• Can be effective in Nerve-Injury Pain & Diabetic Neuropathy
o Treatment must be Constantly Reassessed
§ For Residual Pain
§ For Ongoing Pain
o Last Line = Invasive Treatments:
§ Eg: Intrathecal Opioids (Ie: Opioid infusion into CSF)
§ Eg: Spinal Cord Stimulation
§ Eg: Deep brain Stimulation
§ Neurosurgery
- Note: Serotonin Syndrome – A Potential Side Effect:
o Risk Factors = Any Serotonergic Agents:
§ - Eg: Tri-Cyclic Antidepressants
§ – Eg: Monoamine Oxidase (MAO) Inhibitors
o – A Neurological Disturbance associated with Excess Serotonin:
Impaired Cognition CNS Alterations GI Disturbances Motor Alterations Blood Changes
- Agitation - Fever - Nausea - Hyper-Reflexia - Leukocytosis
- Incoherent Speech - Tachycardia - Vomiting - Myoclonic Twitching (Sudden - D IC →
- Mild Confusion - Diaphoresis - Diarrhoea Muscular Contraction) Thrombocytopenia
(Sometimes Delirium) (Sweating) - Clonus (rapid repetitive - ↑ M uscle Enzym es
- Coma (Possible) - Pupil Dilation contractions)
- BP Instability - Trembling
- Ataxia (inability to
coordinate movements)
Local Anaesthetics (Suffix = -Caine):
- Mechanism of Action:
o Primarily Voltage-Gated Na+ Channel Blockers:
§ Affects ALL Types of Neurons (Hence the need to administer locally to prevent CV Effects)
§ Blocking of VG-Na+ Channels (Required for Nerve Depolarisation) Prevents Depolarisation →
Prevents Action Potential Formation & Propagation
o Factors Effecting Mechanism:
§ Rate of Activity – (Na+ Channel Blockers are “Use Dependant”)
• Ie: Affect the most Active Neurons because their Binding Site is Exposed ONLY in the
Active & Inactive States; Not Resting State)

§ Lipid Solubility of the Drug – (Since the Binding Site is on the Inside Face of the Ion Channel)
• Therefore, the More Lipid Soluble, the Easier it gains Access to the Binding Site
§ pH of the Target Tissue – (The Drugs Charged/Uncharged State affects Lipid Solubility)
• Ie: The Drug has to be Water-Soluble in the Syringe, but Lipid-Soluble in the Tissues
• How? – Most LA’s are Weak Bases (pKa ≈ 8) so that @ Physiological pH (7.4), they
are fairly Neutral or Slightly Ionised
o Therefore, there is always Some Unionised drug able to Cross Membranes to
act on their targets
• Note: Inflamed Tissue is often Quite Acidic → Drug Becomes Highly Ionised &
therefore Resistant to Cross Membranes → Diminished Effect

- Principles of Use:
o Goal = To Block Transmission of Painful Stimuli by Blocking Ability of Neurons to Transmit Signals
o 2 ‘Groups’ of LA Agents:
§ Those with an Amide Bond connecting the Aromatic Ring
§ Those with an Ester Bond connecting the Aromatic Ring
§ Note: Amide LA’s are Preferred for Topical Anaesthesia for the Following Reasons:
• Rapid Onset of Action
• Prolonged Duration
• Greater Potency
• Less Reliance on Vasoconstrictors
o Vasoconstrictors (Eg: Adrenaline) – Are often used to ensure Local Action of Anaesthetic & Prolong
Effects by ↓Blood Flow to/from the Area
§ Note: This also counteracts the Potential Side Effect of ↓Sympathetic Activity
- Routes of Administration:
o Topical Anaesthesia:
o (Tetracaine, Lignocaine and Cocaine) - the latter is only used for Ear/Nose/Throat areas
§ Note: Cocaine has added advantage of having vasoconstrictive properties
o Typically in an Ointment/Cream Form → Topical Application
o Co-administration of Adrenaline is NOT Effective because Adrenaline Can’t Penetrate Skin
o Advantage: Effective for Mucous Membranes (eg: mouth, nose, throat, genitourinary tract)
o Disadvantage: Drugs Rapidly Access the Systemic Circulation, →↑Systemic Side Effects

o Infiltration Anaesthesia:
o (Lignocaine, Procaine and Bupivacaine)
o Injection of Anesthetic Directly into the Target Tissue
§ Used for both Deep Superficial Targets
o Adrenaline →↑Duration by almost 2x
§ Note: Adrenaline Shouldn’t be used in Extremities (eg: fingers, toes, ears, nose,
penis)
• Profound Vasoconstriction → Tissue Starvation and possibly Gangrene
o Advantage: No interference with normal physiological activity
o Disadvantage: Large Doses of Drug are Necessary for comparatively Small Regions

o Field Block Anaesthesia:

o Subcutaneous Injection Targeting Tissue Distal to the Injection Site
o Primary target tissues include forearm, scalp, anterior abdominal wall, and lower extremities
o Advantage: Lower drug concentrations are needed compared to infiltration, greater area of
coverage
o Disadvantage: Neuroanatomical knowledge is essential to success

o Nerve Block Anaesthesia:

o Injection into or around peripheral nerves or nerve plexuses
o Particularly useful for Large / Ischaemic / Necrotic / Encapsulated Targets
o Advantage: Larger area of coverage compared to aforementioned methods
o Disadvantage: Potential for irreversible nerve damage

o Intravenous Regional Anaesthesia (AKA: Bier’s Block):

o Uses vasculature to transport drug to target area, which is generally an extremity
§ Blood Supply to Target is First Cut Off by a Double Cuff/Tourniquet
§ Local Anesthetic is Injected into a pre-inserted Cannula just Distal to Double Cuff
§ The Distal Cuff is released to allow some blood to circulate for a short time
§ Complete Anaesthesia follows
o Advantage: Covers a huge area; Eg: An entire arm
o Disadvantages:
§ Risk of systemic toxicity if tourniquet is released prematurely
§ Pain
§ Ischaemia
§ Damage, only works for small subset of regions
o Spinal Anaesthesia:
o (Lignocaine, Procaine and Bupivacaine)
o Injection into the cerebrospinal fluid (CSF) of the lumbar region
o Nerve damage is minimised with Intrathecal Injections between the L2 Vertebra and the end
of the Thecal Sac in the Sacrum (has a reasonable volume of CSF to inject into)
o Advantages: Very Effective on Intestines for Bowel Surgery (It Inhibits Peristalsis and takes
on a small, Contracted Configuration)
o Disadvantages:
§ Side effects are largely the consequence of sympathetic blockade → ↑Sympathetic
• Notably - Vasodilation (ok in an otherwise healthy individual; but bad in
patients with compromised cardiovascular systems)
§ Depending upon the location of the injection there can be Inhibition of
Cardioacceleratory Neurons
§ BP is Monitored and Therapy is required to Maintain Cardiac and Brain Perfusion
§ Headaches commonly occur after the procedure

Epidural Anaesthesia:
o
o (Bupivacaine, Etidocaine, Lignocaine)
o Drug is injected into the epidural space - Primary action is on spinal cord roots
§ Indwelling Catheters allow either Repeated Injections or Continuous Administration
§ Action is prolonged by Adrenaline, with systemic toxicity decreased
o Advantages:
§ Convenient for Labour Pain
§ No Sympathetic Blockade with an Epidural
§ Opioid drugs can be administered Epidurally to provide region-specific analgesia
o Disadvantages:
§ Risk of Neurological Problems if Target is Missed and drug enters the subarachnoid
§ Differs from spinal anaesthesia in that Higher Dose is Used for Epidural
• (Note: can allow high concentrations to enter the bloodstream)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Systemic Side Effects of Local Anaesthetics:
o (Note: Since LA’s essentially have the Same Mechanism of Action, they tend to have the
sam e/sim ilar Side Effects)
o CNS
§ Ironically, Moderate-High doses will Cause ↑CNS Activity → restlessness, tremor, confusion
and agitation (Note: Tremors can lead to convulsions)
§ However, Higher Doses will cause CNS depression (decreased neuronal activity)
o Cardiovascular/Respiratory
§ Pronounced and potentially fatal respiratory depression
§ Affects Contractile Tissue in Heart (Not Conductile – Na Channels are ‘Leaky’ not VG):
• → Slows Depol & Shortens Plateau → Possible Re-Entry → Arrhythmias
§ ↓Sympathetic Activity (therefore often co-administered with adrenaline or a vasopressin)
§ In High Systemic Quantities, the patient will experience a progression from Restlessness →
Convulsions → Respiratory depression → Hypotension and possibly Heart Failure
o Muscle
§ Block Skeletal Muscle @ Neuromuscular Junction (Blocks Nicotinic ACh-Na+Channels)
§ Spinal, Epidural and Intraperitoneal LA can → Sympathetic Paralysis →↑GI Tone
o Other
§ Hypersensitivity, manifesting as Allergic Dermatitis, and in rare cases Anaphylactic Shock
§ Mucosal Irritation

Credit: https://www.nysora.com/topics/complications/local-anesthetic-systemic-toxicity/

- Metabolism & Elimination of Local Anesthetics:

o Predominantly Metabolised by the Liver
§ Drug is transported to liver by Plasma Proteins
§ Free (Unbound Drug) is Toxic
§ Note: Neonates (who don’t have such proteins) are highly sensitive to LA toxicity
General Anaesthesia:
- 2 Theories of Mechanism of Action:
o 1: The Lipid Theory:
§ Based on the Relationship between Anaesthetic Potency & Lipid Solubility
• Ie: Lipid Solubility of the Agent is the Key Determinant of Anaesthetic Potency
• (↑Lipid Solubility = ↑Potency)

§ 2 Hypotheses of the Lipid Theory:

• A) Volume Expansion:
o Small Molecules of Inhaled Agent Dissolve in the Membrane → ↑Volume of
that Membrane
o ↑Volume in Confined Space of the Brain → Compression of Membrane-
Bound Proteins (eg: Ion Channels & Receptors) → Change in Level of Activity

• B) Increased Membrane Fluidity:

o Small Molecules of Inhaled Agent Dissolve in the Membrane → Change in
Fluidity of the Membrane
o If Fluidity Changes, then Activity of Ion-Channels & Receptors changes too
o Note: However, although ↑ Temp → ↑Fluidity, it decreases Potency of
Anaesthetics
§ Problems with Lipid Theory:
• The linear relationship between Lipid Solubility & Potency only extends to a point,
above which Potency Drops Dramatically
• Various Parts of the Brain are Not Equally Susceptible to the Inhaled Anaesthetics

2: The Protein (GABA) Theory:

§ Based on Interaction Between Inhaled General Anaesthetics & Protein Receptors in Brain:
o • **Bind to GABA Receptors → Augment Action of GABA (Inhibitory)
• Bind to Glutamate Receptors → Inhibit Action of Glutamate (Stimulatory)
• Also affect some K+ Channels → K+ Efflux → Hyperpolarisation (General Inhibition)
§ Note: GABA Distribution in the brain Correlates with Sensitive Brain Regions
- Principles of Anaesthesia Use:
o Components of Anaesthesia – “The Anaesthetic Triad”:
§ 1: Analgesia:
• Prophylactic Analgesia
• Decrease Anxiety/Stress
§ 2: Loss of Consciousness (With Amnesia):
• Allows intervention of a more Controlled & Dignified Nature
§ 3: Muscle Relaxation:
• Ease of Surgery
• Decreases amount of Inhaled Anaesthetic Required → ↓CV-Depression

o Anaesthesia Induction:
§ 1: Propofol – Induction Agent
§ 2: Fentanyl – Narcotic Analgesic
§ 3: Vecuronium – Muscle Relaxant
§ 4: Midazolam – Anxiolytic & Amnesiac
§ 5: Nitrous + Isoflurane + Oxygen – Maintenance
• Nitrous @ 0.65 MAC (0.65 x 105 = 68.25% Nitrous)
• Isoflurane @ 0.65 MAC (0.65 x 1.2 = 0.78% Isoflurane)
• Oxygen (100% - 68.25% - 0.78% ≈ 69%; Therefore 31% left for
Oxygen – (Plenty))
§ Note: Rate of Induction Depends on the Rate of Increase in Partial Pressure of Gas In the
Brain (Ie: The Faster the Gas gets into the Brain, the Faster you go under)
o Depth of Anaesthesia:
§ 4 Stages of Anaesthesia:
• 1: Analgesia
• 2: Delirium
• 3: Surgical Anaesthesia
• 4: Medullary Paralysis → Death
§ Depth of Anaesthesia Depends on The Partial Pressure of the Agent in the Brain:
• (Ie: The more Gas in the Brain, the Deeper the Anaesthesia)
§ Determining Depth of General Anaesthesia:
• Patient Is Not Adequately Anaesthetised if:
o Eyelids blink when lashes are stroked
o Patient is Swallowing
o Respiration Rate/Depth is Irregular
• In “Light” Anaesthesia, Surgical Attempts may Trigger:
o ↑Respiratory Rate
o ↑BP
o Tightening of Jaw Muscles
o Note: Attempting to insert an Airway → Coughing/Gagging/Vomiting/Spasm
• EEG (Electro-EncephaloGram) Has be used:
o –But are UNRELIABLE
o However, they can Give an Index of Depth of Anaesthesia

o Choice of General Anaesthetic Agents:

§ All GA’s can induce Unconsciousness
§ Therefore, GA’s are Chosen Based on OTHER Properties:
• Induction Properties – (Interestingly, while N2O isn’t a very good Anaesthetic, it is a
Powerful Adjunct because it acts as a “Carrier Gas” → Facilitates Movement of Other
Drugs into the Blood)
• Muscle Relaxation
• Analgesic Properties – (Ie: If GA has intrinsic Analgesic Properties, then less Narcotic
Analgesics are needed → ↓Risk of Respiratory Depression)
- **The Concept of MAC – (Minimum Alveolar Concentration) – of Inhaled Anaesthetics:
o 1MAC = The Minimum Dose/Partial-Pressure of a specific drug Required to Prevent Responsiveness
in 50% of Patients (Ie: 50% are Fully Anaesthetised)
§ Note: Expressed as a Percentage of Inspired Air (Inspired Concentration)
§ Note: 1MAC of Some Agents are Impossible to Give @ Atmospheric Pressures
• (eg: Nitrous Oxide: 1MAC = 105%)
o 1.3 MAC = The Concentration/Partial-Pressure of agent Required for ≈95-100% of Recipients to be
Fully Anaesthetised
§ Note: Some Agents are Lethal @ 1.3MAC (Eg: Isoflurane), & Therefore must be Combined
with Other Agents (eg: Nitrous Oxide)
o Note: Different Anaesthetic Agents have Different MAC-Values Depending on Potency
§ (Note: Potent Agents require Lower Dose for Same Effect)
§ Eg: 1MAC Nitrous Oxide = 105.0%
§ Eg: 1MAC Isoflurane = 1.2%
o Note: Mac is Independent of Weight & Height
§ Weight/Height only affect Rate of Uptake
o MAC Values are ADDITIVE!
§ Ie: You can Combine Anaesthetic Agents in Any Proportions, so long as their Total MAC =
1.3
§ Note: Sometimes this is essential to allow room in the Mixture for >21% Oxygen:
§ Eg: 0.65MAC + 0.65MAC:
• Nitrous @ 0.65 MAC (0.65 x 105 = 68.25% Nitrous)
• Isoflurane @ 0.65 MAC (0.65 x 1.2 = 0.78% Isoflurane)
• Oxygen (100% - 68.25% - 0.78% ≈ 69%; Ie: 31% left for O2)
o What Affects It?
§ Age – (Young & Old – Have Low MAC)(Mid Age – Have Normal MAC)
§ Temperature
§ Other Drugs
§ Severity of Illness
M AC-Equivalents:
- o 1 MAC-Equivalent = The Plasma Concentration of a Specific Injected Agent Required to Prevent
Responsiveness in 50% of Patients (Ie: 50% are Fully Anaesthetised)
o MAC-Equivalents are ADDITIVE to ‘True’-MAC Values:
§ Ie: MAC Equivalents can be Added to MAC Values of Inhaled Gases
§ The Therapeutic Range for True MAC + MAC Equivalent = 2-4 MAC
Route of Administration – Best Way = By Inspired Air (Ventilation):
o Why? – Drug Administration Via the Lungs gives the dose to the Entire Cardiac Output
- o As Opposed to IV – Takes ages to Diffuse into all the Blood
o Vapour Uptake:
§ Rapid Initially
§ Near Constant rate @ 30 mins
• Once constant, Uptake=Clearance
§ Titrate Concentration to Effect
o Note: At Equilibrium, Expired Drug Concentration ≈ Drug Concentration In the Brain
- 4 Factors Affecting Anaesthetic Uptake:
o 1: Concentration of the Drug in the Inspired Gas (Ie: The ‘MAC’):
§ ↑Concentration Of Drug → ↑Rate of Drug Uptake
o 2: Pulmonary Ventilation During Drug Delivery:
§ ↑Pulmonary Ventilation → ↑Rate of Drug Uptake
§ Note: Respiratory Depression (Eg: Associated with Pre-Op Opioids) will ↓Rate of Drug
Uptake
o 3: Gas Exchange in the Lungs:
§ Ie: Movement of Inhaled Agents Across the Alveolar Membrane
§ Three Factors Affect Gas Exchange:
• I) Solubility of the Drug in Blood (Ie: Blood:Gas Coefficient):
o (Ie: The Level of Water-Solubility)
o (Ie: The Ratio of Drug Dissolved in Blood:Gasseous Form @ Equilibrium)
o Low Blood:Gas Coefficient = Best → Drug Comes out of solution quickly & is
readily Available to Target Tissues
o High Blood:Gas Coefficient = Poor → Drug Stays in Solution
o Note: Low BG-Drugs are Poorly Absorbed: So How do we get around the
Absorption Issue? – Solved by Administering @ a High Partial Pressure
§ (Ie: Drugs with Low BG-Coefficients have High MAC Values)
• II) Rate of Blood Flow Through the Lungs:
o Note: Blood Flow Through the Lungs ≈ Cardiac Output
o Note: Rate of blood flow DOES NOT affect the Time Taken to Equilibrium,
Rather, it Changes the Shape of the Acquisition Curve
• III) Partial Pressures of the Drug in Arterial Vs Mixed-Venous Blood:
o Remember, Drugs are NOT Brain-Specific, and Therefore will be absorbed by
Other Tissues
o Ie: Equilibrium Between [Blood] & Inspired [Drug] only occurs once ALL
Tissues are at Equilibrium (Including Brain)
o 4: Loss (Distribution) of Drug to Tissues (Other than Brain):
§ (As Above): Equilibrium Between [Blood] & Inspired [Drug] only occurs once ALL Tissues are
at Equilibrium (Including Brain)
§ Three Factors Affect Rate of Distribution:
• I) Solubility of Drug in Organ-Tissue (Ie: Tissue:Blood Coefficient):
o (Ie: The Level of Lipid-Solubility)
o (Ie: The Ratio of Drug Dissolved in Tissues:Gasseous Form @ Equilibrium)
o Note: Drugs with High Tissue:Blood Coefficients Distribute Readily into
Fatty/Adipose Tissue → Therefore High Potency
§ → Quick Recovery in Lean Patients
§ → Slow Recovery in Obese Patients
• II) Rate of Blood Flow to the Organ/Tissue (Ie: Drug Delivery):
o If Blood Flow to an Organ/Tissue is High, then the Drug Concentration in that
organ will Increase Rapidly
• III) Partial Pressures of the Drug in Arterial Blood Vs Organs/Tissues:
o The Difference Between these Pressures Determines Rate of Absorption into
that Organ/Tissue

o Time Constants (Relevant to Overweight People):

§ Big volumes take a long time to fill unless the flow is rapid
§ 1 Time Constant = The time taken to get 30% of a Volume to a Desired Concentration @ a
Given Flow Rate
§ Ie: ≈3 Time Constants – Required to get the Whole Volume to the Desired Concentration
- Qualities of Good Anaesthetic Agents:
o 1: Low MAC
§ (Ie: Very Potent)
o 2: Low Blood-Gas Coefficient
§ (Ie: Relatively Insoluble in Water/Blood)
- Other Issues Re: Anaesthesia:
o Drug Interactions
o Adequate Depth of Anaesthesia
o Good Haemodynamic Control
o Patient Awakes Quickly
o Minimum Cardiac Side Effects

Anaesthesia Reversal:
- o 1: Withdrawal (Cessation) of Anaesthetic Agents – (By Anaesthetist)
o 2: Redistribution of Drug from Brain → Rest of Body – (By the Body)
o 3: Metabolism of Drug – (By the Body)
o 4: Reversal of Muscle Relaxants – (By Anaesthetist)
§ Neostigmine – Acetyl-Cholinesterase Inhibitor
§ Atropine – Muscarinic Antagonist → Sympathomimetic → ↑Heart Rate
o Note: Rate of Withdrawal Depends on the Rate of Decrease in Partial Pressure of Gas In the Brain
(Ie: The Faster the Gas gets out of the Brain, the Faster you Wake Up)
General Anaesthesia – Step By Step Summary:
- Pre-Meds:
o Anxiolytics: Benzodiazepines (Diazepam, Midazolam, Temazepam)
o Analgesics: Opioids (Fentanyl, Morphine)
o Antiemetics: Metoclopramide or Odansetron
o Antibiotics:
Procedure Likely Pathogen/s Antibacterial Cover
General Surgery:
- Appendectomy (Non-Enteric G-Negs Cephalexin / Gentamicin
Perforated) Enteric G-Negs + G-Pos Cephalexin + Metronidazole
- Colorectal Surgery Enterococcus, Anaerobes
Enteric G-Negs + G-Pos Cocci Cephalexin + Metronidazole
- Biliary/Duodenal Surgery
Orthopaedic Surgery Staphs + Streps + G-Neg Bacilli Cephalexin / Gentamicin
+ Anaerobes
Vascular Surgery Staphs + G-Neg Bacilli + G-Pos Cephalexin / Gentamicin /
Enterococcus Augmentin
Urologic Surgery G-Neg Bacilli + G-Pos Cephalexin / Ciprofloxacin
Enterococcus
Gynaecologic Surgery:
- C-Section Staphs + Strep + G-Pos Cephalexin / Gentamicin
- Hysterectomy Enterococcus Cephalexin / Gentamicin /
Enteric G-Negs + Group B Strep Ampicillin
+ G-Pos Enterococcus
§ Note: Triple Therapy: –Ampicillin, Gentamicin, Metronidazole- give great 'Broad Cover'
(Remember by AGM – Annual General Meeting...If you want to be around next year, take
these 3)

- Process of Anaesthesia:
o 1: Induction:
§ Hypnosis: IV Propofol (or Thiopental if Allergic)
§ Paralysis: Suxamethonium / Vecuronium
o 2: Airway Control:
§ A) Initial Bag-Mask Ventilation → Maximise Sats
§ B) Secure Airway (Either LMA or ET-Tube Intubation)
• (Note: Intubation requires Paralysis)
o 3: Maintenance Options:
§ Volatile Gas (N2O + O2 + Sevoflurane or Desflurane)
§ IV Propofol Infusion
§ High-dose Opiates
o 4: Reversal:
§ 100% O2
§ Cease Anaesthetic Infusions
§ Reverse Muscle Paralysis (Neostigmine [AChEi] or Atropine [Muscarinic])
PSYCHOSIS & ANTI-PSYCHOTICS
PSYCHOSIS & ANTI-PSYCHOTICS
Psychosis – What is it?
- = Cognitive/behavioural disturbances that manifest as either:
o Inability to recognise reality
o Or Inability to differentiate between reality and surreal experiences
o Note: Often Impairs a person’s ability to function in society
- The Psychoses are Classed according to their Origins:
1. Those associated with organic brain syndromes (eg:, Korsakoff syndrome)
2. Those less clearly organic and having some functional component(s) (eg:, the schizophrenias, bipolar
disorder)

Schizophrenia:
- A Group of Psychosis-Related Disorders
o Prevalence = 1-2%
o 10% Increased risk if 1st Degree Relative is Affected
- Characterised by:
o Altered Perception and/or Content of Thought
o Delusions and/or Hallucinations
§ »may involve personality “splitting” (but this is not multiple personality disorder)
o “Psychotic” symptoms only appear in the Acute Phase (Ie: “An Episode”)
§ Asymptomatic Periods
o Gradual worsening of Social and Occupational Functioning over time
- Patient Presentation:
o Symptoms may be either ‘Positive’ (Ie: Distortions), or ‘Negative’ (Ie: Diminished Function):
Positive Symptoms: Negative Symptoms:
Hallucinations Poor fluency of Speech/Thought
Delusions Poor Drive/Motivation
Disorganised speech/thought Poor Concentration
Disorganised & Bizarre Behaviour Blunted Affect (Emotionless)
No Concept of Time

Note: Patient may seem to show Self-Neglect –

(Ie: Forget to take pills/eat/go to toilet) but this
is just a manifestation of the above symptoms

- Aetiology:
o No one knows the exact cause of Schizophrenia
o So What is the Common Denominator?
§ It seems that ALL Psychoses involve Alterations to Emotion, Thought & Mood
§ Therefore, Primary CNS Systems Involved Are:
• MesoLimbic System
• Nigrostriatal Dopamine System (Basal Ganglia)
§ Therefore, the Primary Neurotransmitter in question is DOPAMINE
• (Note: Glutamate, GABA, Noradrenaline & Serotonin may also be involved)
§ Note: There may also be a genetic component – as it tends to run in families
• 10% Increased risk if 1st Degree Relative is Affected
• Possible Genes: Catechol-O-Methyltransferase (COMT)
§ Note: Possible Environmental Factor
- Pathophysiology: TWO Current Hypotheses:
o Note: Both Assume that Dopamine is Out of Control
§ Stems from the fact that certain drugs that modify Dopamine release can mimic/exacerbate
symptoms of Psychotic disorders (Ie: Schizophrenia)
o **1: Dopamine Hypothesis (Dopamine Theory):
§ Hypothesis = Overactivity of Dopaminergic Pathways
§ Either from ↑Dopamine Release; or ↑DA-Receptor Density
§ Problems with Hypothesis:
• Only Explains Positive Symptoms, NOT Negative Symptoms
• Doesn’t explain why Anti-psychotics are inactive for the first 2-3 weeks of treatment
o 2: Dysregulation Hypothesis:
§ Hypothesis = An extension of the ‘Dopamine Hypothesis’: Psychosis is due to Improper
Activity of the Dopaminergic Pathways AND OTHER Pathways Due to:
• Alteration of Receptor Number
• Alteration of Receptor Sensitivity
• Alteration of Signalling Cascade Activation
o (Note: Dopamine receptors are G-Protein-Linked → Adenylate Cyclase →
Intracellular Signalling Cascade)
• Alteration of Neurotransmitter Biosynthesis/Metabolism
• Alteration of Reuptake Rate
§ Note: Other Neurotransmitters (aside from Dopamine) implicated in Schizophrenia:
• Serotonin (Modulation of Dopaminergic Transmission & Cognitive Function)
• Glutamate (Recognised that NMDA-Glutamate-R’s can cause → Psychosis)
• GABA (Loss of GABA “Sensory Gate”)

*DOPAMINE – What does it do in the brain?:

-
o Dopamine Neurotransmission:
§ DA-Receptors are G-Protein-Linked → Adenylate Cyclase → Intracellular Signalling Cascade
o Dopamine Receptor Subtypes:
§ D1-like Receptors: (Now includes D1 & D5)
• → Activates Adenylate Cyclase → ↑Signalling
• Note: No clear relationship between D1 family & Schizophrenia
§ *D2-like Receptors: (Now includes D2, D3, D4)
• → Inhibits Adenylate Cyclase → ↓Signalling
• (The ones implicated in Schizophrenia)
• Note: Most of the known functions of dopamine involve D2-like Receptors

Source: https://www.news-medical.net/whitepaper/20200407/An-Overview-of-Dopamine-Receptors.aspx
o Note: Most Neuroleptic Drugs are D2R-Antagonists, but can affect others somewhat
§ D2R’s are most dense in the Mesocortical-Mesolimbic Pathway – Ie: The pathway affected
in Schizophrenia
§ However, D2R’s are also important in the Basal Ganglia - for Initiation of Movement, &
hence D2R-Antagonists may cause ‘Extra-Pyramidal’ (Motor) side effects due to “apparent”
Dopamine Depletion → Parkinson-like Symptoms (Side Effect)
• (Note: Parkinson’s is caused by insufficient formation of Dopamine in the basal
ganglia)

Dopamine is Used by Several Predominant Pathways – Relevant for Side Effects:

o
§ *Mesocortical-Mesolimbic Pathway:
• (The one affected in Schizophrenia – Therefore is TARGETED in Treatment)
• (Also associated with Reward & Addiction)
§ Nigrostriatal of the BASAL GANGLIA:
• (Voluntary Movement & Parkinson’s)
• Ie: Are Responsible for the ‘Extra-Pyramidal’ (Motor) side effects of Neuroleptics
o Motor side effects due to “Apparent” Dopamine Depletion due to blockade
§ Tuberoinfundibular
• (Prolactin & MSH Secretion)
§ Medullary-Periventricular
• (Eating Behaviour)
Note: Therefore, any Pharmacological Intervention will affect all other Dopamine pathways
o
NEUROLEPTICS – What are they?
- = Any class of drug used to treat psychosis
- Key MOA:
o All are D2-Like Receptor Antagonists → Inhibition of Adenylate Cyclase → ↓Intracellular Signalling
§ Note: Some also block D4-Receptors
o Note: Some block other monoamine receptors (Ie: Serotonin)
o Note: REMODELLING also takes place – Responsible for ‘Lag-Period’

- Classified by: (a) Whether they trigger Motor Side Effects:

Typical Atypical
Motor Yes No (or Much Less)
(“Extrapyramidal”) (Drugs work non-specifically dopamine (Drugs work specifically on the Mesocortical-
Side Effects? pathways – Including Basal Ganglia Aka: Mesolimbic Pathway – Little/no influence on
“Nigrostriatal Pathway”) Basal Ganglia, Aka: “Nigrostriatal Pathway”)
MOA: D2-Receptor Antagonists Selective as D4-Receptors Antagonists
Are also 5HT-Receptor Antagonists
(Also D2-Receptor Antagonists)
Clozapine
Examples: Chlorpromazine (THORAZINE)
Sulpiride
Haloperidol (HALDOL)

- Classified by: (b) Structural Differences:

o Phenothiazines:
§ Clorpromazine (THORAZINE)
§ Fluphenazine
§ Perphenazine
§ Triflourperazine

o Heterocyclics:
§ Haloperidol
§ Risperidone
§ Clozapine
§ Loxapine
§ Olanzapine
- Side Effects – Note: Significant variability between drugs; Therefore, Treatment is Individualised:
o Motor (Extrapyramidal) Disturbances: (From Dopamine Antagonism in Basal Ganglia)
§ Akathisia – Motor Restlessness
§ Pseudoparkinsonism (or Parkinson-like symptoms) – rigidity, tremor, dyskinesia
§ Dystonia – spasms of the face and neck
§ Tardive dyskinesia – involuntary movements of face (smacking lips, tongue), trunk and limbs
o Endocrine Disturbances:
§ Prolactin secretion → Menstrual alterations, Gynecomastia, lactation, loss of libido
• (Dopamine is Prolactin inhibiting factor :. ↓Dopamine → ↑Prolactin)
o Antimuscarinic Effects: (Muscarinic Antagonism)
§ Dry Mouth/Blurred Vision/Tachycardia/Urinary Retention/Constipation
o Anti-Adrenergic Effects: (From α1-Adrenergic Antagonism)
§ Hypotension
o Antihistamine Effects:
§ Sedation
§ Increased Appetite → Weight Gain (Can be severe)
o Hypersensitivity Reactions:
§ Jaundice: ‘Obstructive Jaundice’
§ Rare: Leukopenia & Agranulocytosis: Low WBCs & No Granulocytes → Potentially Fatal
§ Rare: Antipsychotic Malignant Syndrome (Unknown Cause):
• hyperthermia and Parkinson-like symptoms (especially muscle rigidity)

Effects of First- and Second- Generation Antipsychotics

- Compliance – A Significant Problem:

o Paranoid Pts may resist taking drugs due to ‘Lag Period’ of Side Effects
o Pts may have No Sense of Time → forget when to take meds
o Pts may Enjoy aspects of their condition (Eg: Creativity, consoling hallucinations etc)
o Note: Long-Term “Depo” (Intradermal Implants) are available in place of Oral Tablets for those
with memory problems & paranoia etc
So Why Do Neuroleptics (Anti-Psychotics) take 2-3 Weeks Before Any Change is Seen?
- Hypothesis = Remodelling:
o It is thought that the Antagonist Action is a Trigger for Remodelling Events that Alter the Capacity of
the Dopaminergic Pathways to Respond to stimuli
§ (Note: Similar to LTP)
o Note: Remodelling = Change in Synaptic Strength due to:
§ Ie: Change in Receptor Number (Ie: Up/Down-Regulation)
§ Ie: Change in Receptor Subtype Profile (Ie: Change in Sensitisation)
§ Ie: Change in G-Protein Number (Ie: Change in Sensitisation)
§ Ie: Change in Ability to Respond (Ie: Change in Sensitisation)
§ Ie: Change in Enzymes (Ie: Change in Sensitisation)
o Just Remember that in addition to the MOA’s of Neuroleptics, they also cause the synapse to
undergo Remodelling

Note: Similar to LTP – Long Term Potentiation:

Credit: http://www.expertsmind.com/topic/neuroscience/long-term-potentiation-93811.aspx
AFFECTIVE DISORDERS, ANTI-DEPRESSANTS AND MOOD-STABILISING DRUGS
 AFFECTIVE DISORDERS, ANTI-DEPRESSANTS AND MOOD-STABILISING DRUGS

Affective Disorders – What Are They?

- = Disorders in which there is a Major Disruption of Mood:
o Eg: Major Depression:
§ Prevalence: 4-9% Women; 3% Men
§ Mental disorder of SUSTAINED Depression of Mood, Loneliness, Despair, Insomnia, Appetite
Loss, and feelings of Worthlessness, Guilt, & Hopelessness
§ May be Acute Or Chronic
§ May include Agitation & Withdrawal from Social Contact
o Eg: Bipolar Disorder (AKA: Manic-Depressive Disorder):
§ Prevalence: <1% (No gender difference)
§ Mental disorder characterised by PERIODS of abnormally Elevated Mood (Hyperactivity/
Talkativeness/Insomnia/↑Libido; and PERIODS of Depressed Mood
o Eg: Dysthymia (minor depression)
o Eg: Schizoaffective Disorder
o Eg: Cyclothymic Disorder

- WHO Diagnostic Criteria:

o Part A)
§ Daily depressed mood
§ Loss of interest in almost all activities
§ Significant Weight Loss
§ Daily Insomnia or Hypersomnia
§ Daily Agitation or Retardation
§ Fatigue/No Energy
§ Feelings of Worthlessness
§ Poor Concentration
§ Suicidal Ideations
o Part B)
§ No Organic cause for the above
§ Not caused by Bereavement (Ie: Depression is normal in bereavement)
o Part C)
§ No Delusions/Hallucinations
o Part D)
§ Not superimposed on Schizophrenia or other Psychoses

- Aetiology:
o Common Denominator = Alterations in Mood & Motivation:
§ (May involve Delusions or Delirium)
§ (May be Cyclic or Sporadic)
o Recognition that Monoamine Oxidase Inhibitors (MAOi’s) → Improved Mood/Mania:
§ (Therefore, the opposite must cause depression)
§ Note: Monoamine Oxidase Metabolises Norepinephrine & Serotonin (& Dopamine)
§ Therefore if MAO-Inhibitors cause → Surplus of NE & 5HT → Mania; then...
• Depression must be a result of - NE & 5HT Deficiency
o Also Recognised that Pts with Depression have Lower levels of NA & 5HT in the CSF
§ Ie: Reinforced that Deficient NE & 5HT → Depression
- Current Hypotheses:
o *The Amine (Monoamine) Hypothesis:
§ Mood Disorders are due to a Deficiency (Depression) or Surplus (Mania) of at least one of
three monoamine neurotransmitters (Norepinephrine, Serotonin, or Dopamine) in their
respective pathways (NE & 5HT are the Relevant ones here)
§ (NE/5HT Deficiency → Depression)
• :. Anti-Depressant Drugs all act to → Increase NA &/or 5HT Signalling
§ (NE/5HT Surplus → Mania)

(Note: NA is the Neurotransmitter of Wakefulness & Mania)

(Note: 5HT is the Neurotransmitter of Sleep, Mood, Feeding & Appetite)
- Possible Antidepressant Drug Targets (See Diagram):
o 1: Inhibition of Reuptake Transporters:
§ → Prolongs the duration of the Neurotransmitter in the Synapse
o 2: Blocking Pre-Synaptic Autoreceptors:
§ → Removes Inhibition of Neurotransmitter Release → ↑NT Levels in the Synapse
o 3: Inhibition of Mono Amine Oxidase:
§ → Inhibits Normal Breakdown of Amine-NT’s → ↑NT Release following stimulation
o 4: ∆ in Sensitivity of Post-Synaptic NT-Receptors:
§ → ∆Magnitude of Responses to Stimulation

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

MOOD-STABILISING DRUGS:
- *Antidepressant Drug Groups: (Anti-Depressant Drugs all act to → ↑NA and/or 5HT Signalling)
o Tricyclic Antidepressants (TCA’s)(3-Ringed Structures); & Tetracyclics (4-Ringed Structures):
§ MOA: Block BOTH Noradrenaline AND Serotonin (5HT) Reuptake
• Intermediate Duration
§ “Classic” agents = Imipramine & Amitriptyline
§ Adverse Effects:
• Sedation
• Antimuscarinic Effects – Dry Mouth, Blurred Vision, Constipation, Urinary Retention
• Postural Hypotension
• Toxicity in Overdose
o → Convulsions & Arrhythmias; Respiratory Depression & Coma

o Selective Serotonin Reuptake Inhibitors (SSRI’s):

§ MOA: Block Serotonin (5HT) Reuptake
• Long Duration
§ “Classic” agent = Fluoxetine (PROZAC)
§ Adverse Effects:
• Nausea, Vomiting & Diarrhoea
• Anorexia
• Insomnia
• Loss of libido & anorgasmia

o Selective Noradrenaline Reuptake Inhibitors (SNRI’s):

§ MOA: Block Noradrenaline Reuptake
• (Note: Also act as α2-Antagonists)
• Short Duration
§ “Classic” agent = Mianserin
§ Adverse Effects: (Same as TCAs)
• Sedation
• Antimuscarinic Effects – Dry Mouth, Blurred Vision, Constipation, Urinary Retention
• Postural Hypotension
• Toxicity in Overdose
o → Convulsions & Arrhythmias
o → Respiratory Depression & Coma

o Monoamine Oxidase Inhibitors (MAOi’s):

§ MOA: Inhibit Monoamine Oxidase Function:
• (Ie: ↓Catecholamine Breakdown → Surplus of NE and/or 5HT → Improved Mood)
• Very Short Duration
§ “Classic” agent = Phenylzine
§ Adverse Effects:
• Hypotension (although Counter-Intuitive) – (↑Serotonin appears to displace↑NA →
‘effectively’ less NA)
• Tremors
• Insomnia
• ↑Appetite → Weight Gain
• Antimuscarinic Effects – Dry Mouth, Blurred Vision, Constipation, Urinary Retention
• Toxicity in Overdose:
o Convulsions
§ Note: Dietary Restriction – Tyramine (fermented/smoked foods, chocolate, avocados):
• Normally tyramine in foods is broken down before entering the systemic circulation
• - Blocking MAO → ↑Tyramine in Bloodstream → Displaces NA from storage
o → ↑↑Catecholamines in blood → Adrenergic Crisis:
§ →Tachycardia & ↑BP → Heart-attack or Stroke
 Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Note: Serotonin Syndrome – A Potential Side Effect of Serotonergic Agents:

o Risk Factors = Any Serotonergic Agents:
§ – Ie: (TCA’s, SSRI’s, MAOi’s)
o – A Neurological Disturbance associated with Excess Serotonin:
Impaired Cognition CNS Alterations GI Disturbances Motor Alterations Blood Changes
- Agitation - Fever - Nausea - Hyper-Reflexia - Leukocytosis
- Incoherent Speech - Tachycardia - Vomiting - Myoclonic Twitching (Sudden - DIC →
- Mild Confusion - Diaphoresis - Diarrhoea Muscular Contraction) Thrombocytopenia
(Sometimes Delirium) (Sweating) - Clonus (rapid repetitive - ↑Muscle Enzymes
- Coma (Possible) - Pupil Dilation contractions)
- BP Instability - Trembling
- Ataxia (inability to
coordinate movements)

o Complimentary Medicines:
§ St-Jon’s Wort:
• Apparently as effective as Tri-Cyclics for mild-moderate depression
• MOA:
o Animal experiments show a downregulation of beta-adrenergic receptors
and an upregulation of serotonin 5-HT(2) receptors in the frontal cortex
• However – Significant Drug Interactions with Prescription Meds
• Many take this as a “Mood Supplement” rather than for Major Depression
- *Bipolar Drugs:
o Lithium (Lithium Carbonate):
§ Used to stabilise Bipolar Disorder (Manic/Depressive)
• – Ie: Counteract both Mania & Depression
§ Note: Very Narrow Therapeutic Index (Overdose = Very Toxic)
§ MOA:
• Increases Serotonin Levels → Counteracts Depression
• Decreases Noradrenaline Levels → Counteracts Mania
• Alters Na+ transport across membranes (as Na+ and Li+ are univalent ions)
• Blocks Inositol Triphosphate (2nd Messenger Molecules) Signal Cascades
§ Adverse Effects:
• GI Problems
• Neurological Damage
• Tremor
• Kidney Impairment
• Thyroid Problems

o Use of Anticonvulsant Drugs:

§ MOA: Enhance GABA’s Action → Thought to Stabilise Neurotransmission in this pathway
• → Prevents mood swings & Reduces Mania
§ Note: Less toxic than Lithium
DRUGS FOR HEMOSTASIS
 DRUGS FOR HEMOSTASIS

REVISION OF HAEMOSTASIS:
- Purpose of Haemostasis:
o To Stop blood loss from Damaged Vessels
- Factors Involved – (Those in red are targeted by different Drugs to modulate Haemostasis):
o Platelet Aggregating Agents:
§ Sub-Endothelial Collagen (activates Platelets)
§ Thromboxane (Stimulates Expression of Glycoprotein Receptor “GP-IIb/IIIa” → Aggregation)
• (Produced by Cyclo-Oxygenase in Platelets)
§ ADP (Stimulates activation of Glycoprotein Receptor “GP-IIb/IIIa” → Platelet-Aggregation)
§ Glycoprotein Receptor “GP-IIb/IIIa” – Allow platelets to physically combine with each other
• Promoted by ADP Receptor Activation
o Anti-Platelet-Aggregating Factors:
§ ↑cAMP→↑cAMP Inhibits Platelet Aggregation by decreasing Cytosolic Ca+ Levels
• ↓Ca+ → Inhibits Ca-Mediated Vesicular Exocytosis of Pro-Aggregation Factors from
the Platelet (Particularly Thromboxane)
o Pro-Coagulating Agents:
§ Vitamin K (A Coenzyme in the synthesis of Prothrombin, Factors II, VII, IX & X (TV Channels)
§ Coagulation Factors I-XIII
§ Activated Factor X (Complex)
§ Prothrombin → Thrombin (Factor II)
§ Fibrinogen → Fibrin
o Anti-Coagulating Agents (In Non-Damaged Tissue):
§ Antithrombin-III (Inactivates Thrombin {Factor II}→ Fibrinogen Activation →Fibrin)
o Fibrinolysis Factors:
§ Tissue Plasminogen Activator → Activates Plasminogen to become Plasmin
§ (Plasmin degrades fibrin clots)
- PROBLEM: If Haemostasis is Unregulated, it can be FATAL!! (Major Haemorrhage/Thrombosis)

3 Phases of Hemostasis:
- 1: Primary Hemostasis:
o Primary Platelet Plug Formation:
§ When vessel is damaged → Sub-Endothelial Collagen is exposed....
• Platelets (+ Von Willebrand Factor [glue]) adhere strongly to the Collagen Fibres...
• Primary Platelet-Plug ‘Sandwich’:

Surface Glycoproteins on Platelets

Von Willebrand Factor
Sub-Endothelial Collagen

o Platelet Aggregation:
§ Once attached, Platelets → Activated → Release Several Chemicals:
• GP-IIb/IIIa: Form the basis of the ‘bridge’ between platelets
• Thromboxane A2: Stimulates GP-IIb/IIIa Expression on Platelets
• ADP: Activates GP-IIb/IIIa → Enabling aggregation
• Calcium (Factor IV): A cofactor that Activates other Inactive Pro-Coagulation
Factors
§ Initiates a Positive Feedback Cycle → Activates & Attracts more & more Platelets
• Within 1min, a platelet plug is built → further reduces blood loss

o Platelet-Plug Localisation:
§ Prostacyclin:
• A Prostaglandin Produced by Intact Endothelial Cells
• A Strong Inhibitor of Platelet Aggregation
- 2: Secondary Haemostasis:
o Coagulation Cascade:
§ Coagulation (ie: Blood ‘Clotting’): Where Blood; Liquid → Gel
§ Series of enzymatic conversions of Inactive Coagulation Factors → Active Coagulation
Factors
§ Intrinsic Pathway:
• →Triggered by Exposed Sub-Endothelial Collagen
• All factors needed for clotting are in the blood
§ Extrinsic Pathway:
• →Triggered by Exposed Tissue Factor (Factor III)

→→
§ Both Pathways eventually lead to Activation of Factor-X
• Activated Factor-X combines with other factors to form→
• Prothrombin Activator→ converts the plasma-protein: Prothrombin → Thrombin
Fibrin Deposition:
o
§ Thrombin Catalyses Conversion & Deposition of Fibrinogen→Fibrin
§ Fibrin Mesh →+ Active Factor-XIII → Stabilises the Platelet-Plug → Seals the hole
• Primary Platelet Plug + Mesh → Secondary Platelet Plug
Regulation:
o § Pro-Coagulating Agents:
• Vitamin K (A Coenzyme in the synthesis of Prothrombin, Factors II (Thrombin), VII, IX
& X (TV Channels)
• Coagulation Factors I-XIII
• Activated Factor X (Complex)
• Prothrombin → Thrombin
• Fibrinogen → Fibrin
§ Anti-Coagulating Agents (In Non-Damaged Tissue):
• Antithrombin-III (Inactivates Thrombin → Fibrinogen Activation →Fibrin
- 3: Fibrinolysis:
o Thrombi aren’t permanent solutions to vessel injuries
o :. Fibrinolysis removes un-needed thrombi after healing has occurred...by:
o By Breaking Down Fibrin:
§ Plasminogen Activator (Incorporated into a forming clot, but dormant until after healing)
• → Activates Plasminogen → Plasmin
§ Plasmin → Degrades fibrin & :. The thrombus as well
 OVERVIEW:

CNX OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

PATHOLOGY OF HAEMOSTASIS:
A “Clot” is Different to a “Thrombus”:
- Clot:
o Occurs In-Vitro (Ie: Outside the Body)
o Also structurally different
- Thrombus:
o Occurs In-Vivo (Ie: Inside the Body – Typically forms in moving blood)
o Also structurally different

Virchow’s Triad: – Formation of Thrombosis:

- Three Conditions Predispose to Inappropriate Thrombus Formation:
o 1: Endothelial Injury:
§ Eg: Atherosclerosis
§ Eg: Aneurysm
§ Eg: Blood Vessel Disorders (Eg: Hereditary Haemorrhagic Telangiectasia)
o 2: Decreased Bloodflow (Or Stasis):
§ Eg: Atrial Fibrillation
§ Eg: Deep Vein Thrombosis
§ Eg: Incompetent Venous Valves
o 3: Hyper-Coagulability:
§ Eg: During Pregnancy
§ Eg: Drug Side Effects
§ Eg: Hyperproliferative Blood Conditions (eg: Polycythemia Vera)
ANTI-COAGULANTS: (Note: NOT ‘BLOOD THINNERS’!! (In an Exam you’ll get ZERO)):
- Heparin (Including Low Molecular-Weight Heparins):
o Mechanism of Action:
§ Binds & Activates Antithrombin-III to form an AT-III:Heparin Complex
§ The AT-III:Heparin Complex →:
• 1: → Inactivates Thrombin (Factor-II):
o Therefore Inhibits activation of Prothrombin to Thrombin
• 2: → Inactivates Factor-X:
o Therefore Inhibits activation of Fibrinogen to Fibrin
• 3: →Also Inhibits Most Intrinsic Pathway Factors (IX, XI, XII)

SteveKong3, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

o Indications:
§ Any Acute Coronary Syndrome (eg: NSTE-MI/Unstable Angina/Peripheral Arterial Occlusion)
§ Atrial Fibrillation
§ Deep-Vein Thrombosis & Pulmonary Embolism
§ Heart Surgery
o Side Effects:
§ *Haemorrhage – (However Protamine is an antidote)
§ *Thrombocytopenia – (See Next Page)
§ (Osteoporosis)
§ (Hypoaldosteronism with Hyperkalaemi)
§ (Allergic Reactions/Local Reactions – Skin Necrosis, Irritation, Haematomas)
o Other Info:
§ Rapid (Almost Instant) Onset of Action
§ Heparin is ONLY used in a Clinical Setting (Ie: Pts can’t be sent home on it)
§ Cannot be administered orally (too lipophobic → Poor absorption)
• Therefore Delivered IV → MUST BE MONITORED
- *Thrombocytopenia – As a Side-Effect of Heparin:
o What is Thrombocytopenia?
§ Thrombocytopenia = Low number of Platelets
o What is Heparin-Induced Thrombocytopenia?
§ Type-I:
• Occurs during the first 1-2days of Treatment
• Transient & Asymptomatic
• Clinically Insignificant
§ Type-II:
• Occurs around Day 5 of Treatment
• Consequence of an Immune Reaction
• Associated with a Thrombo-embolic Risk
o Theory behind Heparin-Induced Thrombocytopenia:
§ Antibodies (IgG & IgM) directed against Complexes of Heparin & Platelet-Factor-4
§ Binding of Antibodies to Heparin:PF4 forms an Immune Complex (Ab:Hep:PF4) which
Activates Platelets → Thrombus Formation (→Thrombocytopenia)

Low Molecular-Weight Heparins (LMWH) – Eg: ENOXAPARIN:

-
o What are they?:
§ = Small Heparin Fragments
o Mechanism of Action:
§ Binds & Activates Antithrombin-III to form an AT-III:Heparin Complex (Same as Heparin)
• #1: → Inactivates Factor-X:
o Therefore Inhibits activation of Fibrinogen to Fibrin
§ Note: However, LMWHs are Too Small to inactivate Thrombin :. Only target Factor-X
o Advantages over Normal Heparin:
§ Longer T1/2
§ Self-Administration (Sub-Cut Injection)
§ Dose-Effects are more predictable
§ NO need for monitoring (Ie: Pt can go home → Frees up a hospital bed)
§ (However, it is quite expensive)

I m a g e c r e d i t : R a n g , D a l e , e t a l . P h a r m
- Coumarins/Coumadins (Warfarin):
o Mechanism of Action:
§ A Vitamin-K Analogue → Inhibits synthesis of Pro-Coagulation Factors:
• ↓Prothrombin
• ↓Factor-II (Thrombin)
• ↓Factor-VII
• ↓Factor-IX
• ↓Factor-X
§ Explanation:
• Normally: Vit-K is activated by ‘Epoxide Reductase’, allowing it to aid in the synthesis
of the above coagulation factors
• Warfarin: Warfarin Competes with Vit-K for ‘Epoxide Reductase’, reducing synthesis
of coagulation factors

SteveKong3, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

o Side Effects:
§ *Bleeding – (However Vitamin-K is an antidote)
§ Note: Many factors influence effectiveness:
• (Diet/Alcohol/Body Mass/Other Meds/Alternative Meds/Comorbidity/genetics)
§ Is TERATOGENIC – CONTRAindicated in Pregnancy
Drug Interactions:
o
§ Warfarin is metabolised by Cytochrome-P-450 Liver Enzymes
§ Therefore, any drug that Induces CYP-450 enzymes significantly reduces effect of Warfarin
• Eg: Carbamazepine, Phenytoin, Phenobarbitone – ANTI-EPILEPTICS!!!
Other Info:
o
§ Slow Onset – (Takes several days for sufficient competition to occur & for pre-existing
coagulation factors to be used up)
§ Used for Long-Term home-management & doesn’t require monitoring
§ Note: Vitamin-K can be used as an Antidote for Warfarin Overdose
• Similarly, a high Vit-K diet can decrease warfarin’s effectiveness
ANTI-PLATELET DRUGS:
- **Aspirin:
o Mechanism of Action:
§ COX-I Inhibitor – Irreversibly Inhibits Cyclo-Oxygenase-1 (COX-1)→ Prevents Thromboxane
formation from Arachidonic Acid
• (COX-1 (and COX-2) is responsible for Prostanoid synthesis [Ie: Prostaglandins,
Thromboxane & Prostacyclin] from Arachidonic Acid, and is expressed by all cells)
o (Cox-2 is only expressed during inflammation & wound healing)
• (Note: Thromboxane is a Platelet-Aggregator – Acts by stimulating the expression of
the Glycoprotein receptor “GP-IIb/IIIa” → Aggregation)
§ Note: Aspirin blocks a Platelet’s Thromboxane-forming abilities for the life of the platelet
• Why? – Because platelets have NO Nucleus → Can’t Re-synthesize Cyclo-oxygenase
• Therefore – Aspirin has an ‘apparent’ selectivity for Platelets

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Indications:
o
§ Reduce risk of Myocardial Infarction/Angina
§ Acute Stroke
o Side Effects:
§ GI-Bleeding (due to loss of Prostaglandins [which are protective by ↓Acid & ↑Mucus])
§ Toxic dose can cause Respiratory Alkalosis
o Other Info:
§ Note: Antiplatelet effects of Aspirin occur at Low Doses (≈100-300mg/day)
• Headaches ≈ 600-900mg/day
• Anti-Inflammatory ≈ 5000mg/day (BUT → Now Obsolete due to GI Problems)
- Dipyridamole:
o 2x Mechanisms of Action:
§ Phosphodiesterase (PDE) Inhibitor:
• (Note: PDE normally inactivates cAMP)
• PDE-Inhibitors Prevent inactivation of cAMP (& cGMP)→ ↑cAMP →
§ Adenosine Uptake Blocker:
• → Increased Intracellular Adenosine (the major constituent of cAMP)→ ↑cAMP →
• (Adenosine also acts as a Vasodilator)

• →↑cAMP→↑cAMP Inhibits Platelet Aggregation by decreasing Cytosolic Ca+ Levels

o ↓Ca+ → Inhibits Ca-Mediated Vesicular Exocytosis of Pro-Aggregation
Factors from the Platelet (Particularly Thromboxane)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Indications:
o
§ Secondary Prevention of Ischaemic Stroke
§ Secondary Prevention of Transient Ischaemic Attacks (TIAs – ‘Mini strokes’)
Side Effects:
o§ Headache
§ GIT Disturbances
§ Hypotension
§ Allergy
- Clopidogrel:
o Mechanism of Action:
§ ADP-Receptor Antagonists → Prevents Binding of ADP to platelet→
• → Prevents ADP-Mediated activation of Glycoprotein Receptor “GP-IIb/IIIa” →
o → Prevents Platelet-Aggregation
o Indications:
§ (Originally used for Patients Intolerant to Aspirin – now also used in conjunction with Aspirin)
§ Myocardial Infarction (Prevention & Treatment)
o Side Effects:
§ Bleeding
§ GI Discomfort
§ Rashes
o Other Info:
§ Is a ‘Pro-Drug’ → Must be metabolised by Cytochrome-P450 enzymes to be Activated
• (Note: Active metabolite is unknown)
§ Onset Takes ≈ 8-10 days
§ Action is augmented by other Antithrombotic Drugs

A B C IX IM A B (Y e s, th a t is its a ctu a l n a m e ):
- o Mechanism of Action:
§ GP-IIb/IIIa Antagonist:
§ A Monoclonal Antibody against the Platelet Glycoprotein Receptor “GP-IIb/IIIa”
• (GP-IIb/IIIa Destruction → No Aggregation)
§ Surface-Proteins:
• Vitronectin Receptors (which play a major role in platelet aggregation)
o Indications:
§ Used in Angioplasty (Ie: Widening a narrowed/obstructed vessel – Typically Atherosclerotic)
§ Possible use in preventing Thrombus/Embolus complications during Neurovascular Surgery
o Side Effects:
§ Bleeding
§ Thrombocytopenia
o Other Information:
§ Note: The name is simply the ‘well number’ + MAB (monoclonal antibody)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

THROMBOLYTICS:
- Note: Schematic of Fibrin Formation & Degradation:

- Streptokinase:
o Mechanism of Action:
§ An exogenous Plasminogen Activator (Catalyses conversion of Plasminogen to Plasmin)
• → Plasmin Degrades Fibrin
o Indications:
§ Thrombolysis of Inappropriate Blood Clots:
• Pulmonary Embolism
• Myocardial Infarction
• Stroke
o Side Effects:
§ Risk of Haemorrhage
o Other Info:
§ Derived from Haemolytic-Streptococci Bacteria
§ *Inhibited by Lipoproteina (an endogenous lipoprotein now considered a risk factor for MI)
- (Exogenous) Recombinant Tissue Plasminogen Activator (r-tPA):
o Note: Tissue Plasminogen Activator (tPA) is normally a protein expressed on Endothelial Cells
lining Undamaged Blood Vessels:
§ Its role is to prevent inappropriate fibrin-clot formation in Intact Vessels
§ However, tPA can be Manufactured using Recombinant Biotechnology → r-tPA:
• Ie: “Alteplase/Tenecteplase/Reteplase”
o Mechanism of Action:
§ Exogenous Plasminogen Activator (Catalyse conversion of Plasminogen to Plasmin)
• → Plasmin Degrades Fibrin → Thrombolysis
o Indications:
§ Thrombolysis of Inappropriate Blood Clots:
• Pulmonary Embolism
• Myocardial Infarction
• Deep Vein Thrombosis
• Stroke
§ Novel use = Frostbite → fewer amputations
o Side Effects:
§ Risk of Haemorrhage (However, is ‘clot-specific’ → fewer haemorrhages)
• (However, in tPA Overdose, Aminocaproic Acid is an Antidote)
§ Nausea/Vomiting
§ *Inhibited by Lipoproteina (an endogenous lipoprotein now considered a risk factor for MI)
o Other Info:
§ Very expensive (Sometimes Not Cost-Effective)
 SUMMARY OF HAEMOSTASIS DRUGS & SITES OF ACTION:

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

DRUGS FOR FLUID & ELECTROLYTE BALANCE
DRUGS FOR FLUID & ELECTROLYTE BALANCE

Why Maintain Fluid & Electrolyte Balance?:

- Critical for Normal Cell Function
- Critical for Chemical Stability (Homeostasis) of Surrounding Fluids
- *Electrolyte Balance (Particularly Na+ & K+) – Critical for function of Excitable Tissues
- Critical for Blood Pressure Homeostasis

The Renin-Angiotensin System (RAS): - Regulates Extracellular Fluid Volume & Systemic Blood Pressure
- The Juxtaglomerular (“beside the glomerulus”) Apparatus:
o The ‘sensor’ for the RAS
o A region in the Nephron containing 2 Types of Receptor Cells:
§ 1: Juxtaglomerular Cells:
• Mechanoreceptors – Detect Changes in Blood Pressure in Afferent Arteriole
• Release Renin in response to:
o LOW BLOOD PRESSURE
o ANGIOTENSIN-II (Direct Stimulation of JG-Cells)

§ 2: Macula Densa:
• Osmoreceptors – Detect Osmolarity of Distal Tubule Contents
• Stimulate Renin Release from JG-Cells in response to:
o HIGH FILTRATE OSMOLARITY

§ Renin Release Leads To → ↑[Angiotensin II] →:

• →Systemic Vasoconstriction → Increase in Blood Pressure
• →Aldosterone Release from Adrenal Glands → ↑Na+ Resorption
• →ADH Release from Posterior Pituitary → ↑H2O Permeability of Collecting Ducts
• →↑Sympathetic Activity → ↑HR etc → ↑Blood Pressure

A. Rad (me), CC BY-SA 3.0 <http://creativecommons.org/licenses/by-sa/3.0/>, via Wikimedia Commons

Significant Electrolytes:
- Na+ = Major Extracellular Cation Account for 80% of Osmolarity of Interstitial Fluid & Plasma
- Cl- = Major Extracellular Anion
- K+ = Major Intracellular Cation - Accounts for 50% of Osmolarity of Intracellular Fluid

W hy M aintain Electrolytes
- Na+ = Important for Heart & Nerve Function/Cellular Transport
- K+ = Important for Heart Function/Cellular Transport
o (Note: too high Extracellular K+ interferes with Cardiac Function = Fatal)
- Ca+ = Important for Muscle, Heart & Nerve Function/Bone Formation
- Mg+ = Important for AcetylCholine Release → Important for Neural & Cardiac Function
- HPO2-4 = Important for Bone Formation (Bone salts – primarily calcium & phosphates)

Na+: The Primary Extracellular Electrolyte:

- Primary role in Fluid & Electrolyte Balance (Because Water Follows Na+ Movement)
- Extracellular [Na+] is normally stable & is Regulated by levels of Aldosterone:
- Regulated by: ALDOSTERONE:
o Aldosterone = Steroid Hormone Released from The Adrenal Cortex
o Released in response to:
§ **Angiotensin-II, Part of the Renin-Angiotensin System (Due to Renin Release by Kidneys)
§ *Hyponatraemia (Low Na+ in Blood)
§ *Hyperkalaemia (High K+ in Blood)
§ Stress
§ If Aldosterone is High – All Na in Filtrate is reabsorbed
§ If Aldosterone is Low – No Na in Filtrate is reabsorbed
o Works by:
§ a) ACTIVATING the Na/K-ATPases in the Principal Cells of Collecting Ducts:
• Increases Na+ & Cl- Reabsorption
• Increases K+ Secretion
§ b) PROMOTING Na+-Channel Synthesis & Insertion into Luminal Membrane:
• Facilitates the Na+ Reabsorption mentioned above
o The Effect = Increased Na+ Reabsorption in Collecting Ducts of the Nephron

https://jasn.asnjournals.org/content/27/9/2554/tab-figures-data
 FLUID IMBALANCES: Volume Vs Osmolar

Volume Imbalances:
- Hypervolaemia:
o A Gain of Extracellular Fluid (And an Associated gain in Na+)
o Symptoms:
§ Hypertension
§ Oedema
o May Be Due To:
§ Excessive Fluid Intake
§ Chronic Renal Failure (↓Urine Output)
§ Endocrine Imbalances (Eg: ADH & Aldosterone)
o Treatment:
§ Diuretics

- Hypovolaemia:
o A Loss of Extracellular Fluid (And an Associated loss of Na+)
o Symptoms:
§ Hypotension
§ Tachycardia
§ High Respiratory Rate
§ Thirst
o May Be Due To:
§ Insufficient Intake of Fluids
§ Haemorrhage
§ Diarrhoea
§ Vomiting
§ Endocrine Imbalances (Eg: ADH & Aldosterone)
o Treatment:
§ Fluid Replacement (Saline IV Fluids or Electrolyte Drink)
O sm olar Im balances:
- Sodium (Na+):
o Hypernatraemia:
§ Higher-Than-Normal Blood [Na+]
§ May Be Due to:
• Decreased H2O Intake/Increased H2O Loss (Due to Reverse-Dilution Effect)
• Over-Ingestion of Na+
• Renal Insufficiency
§ Leads to:
• Cell-Shrinking (Due to Osmosis)
• If due to H2O Loss, then Hypotension → Tachycardia (to ↑Cardiac Output)
• Excessive Thirst
§ Treatment:
• Water

o Hyponatraemia:
§ Lower-Than-Normal Blood [Na+]
§ May be Due to:
• Loss of Na+ from body Fluids...OR
• Excessive Gain in Extracellular Water (Dilution Effect)
• (Diuretic Therapy)
• (Adrenal Insufficiency)
§ Leads to:
• Cell-Swelling (Due to Osmosis) → Oedema
• Especially Cerebral Oedema → Headache → Eventually Coma
§ Treatment:
• Withdrawal of Diuretic
• Reduce Fluid Intake

https://www.austincc.edu/apreview/EmphasisItems/Electrolytefluidbalance.html
- P o ta ssiu m (K +):
o (Note: K+ is needed to repolarise excitable membranes)
o Hyperkalaemia:
§ Higher-Than-Normal Blood [K+]
§ May Be Due to:
• Excessive K+ Intake...OR
• Renal Failure (Insufficient K+ Excretion in Urine)
• Large Crush/Trauma Injuries (Rupturing of Cell membranes → Release of K+)
§ Leads to:
• Slower/Poor Repolarisation of Excitable Membranes:
o →Muscle Cramping
o → ↓Conductivity of the Heart
§ Treatment:
• Calcium Supplements – Not to lower K+, but to ↓Cardiac Excitability
• IV Insulin → Shifts K+ into the cells
• Bicarbonate Therapy – Stimulates Na/K-ATPase (Exchanges K+ for Na+)
• Severe Cases may require Dialysis
o Hypokalaemia:
§ Lower-Than-Normal Blood [K+]
§ May Be Due to:
• Insufficient K+ Intake...OR
• Excessive Loss of K+
• (Use of Diuretics)
§ Leads To:
• Faster/Hyper- Repolarisation of Excitable Membranes:
o → Decreased Excitability of Muscle/Nerve Cells
o → Cardiac Irritability → Dysrhythmias
§ Treatment:
• Treat the Cause (Eg: Diet/Diarrhoea/Medication)
• Or – Potassium Supplements

Source: Unattributable
- C a lc iu m (C a +):
o (Note: Ca+ is needed for normal Heart/Cardiac-Nerve Function, as well as Bone Formation)
o Hypercalcaemia:
§ Higher-Than-Normal Blood [Ca+]
§ May be Due to:
• Increased Dietary Calcium
• Decreased Ca+ Excretion
• Shift from Bone → Extracellular Fluid
§ Leads to:
• Shortened AP-Plateau → Cardiac Arrhythmias
• Muscle Weakness
§ Treatment:
• Overhydration +Salt → Then Loop Diuretics to depress renal Ca+ Resorption
o Hypocalcaemia:
§ Lower-Than-Normal Blood [Ca+]
§ May be Due to:
• Insufficient Dietary Calcium
• Increased Ca+ Excretion
§ Leads to:
• Prolonged Depolarisation of Cardiac Action Potentials
• Impaired Contraction
§ Treatment:
• IV Calcium Replacement

- Phosphates (HPO2-4):
o (Note: HPO2-4 are important for bone formation – Bone Salts = calcium & phosphates)
o Hyperphosphataemia:
§ Higher-Than-Normal Blood [HPO2-4]
§ May be Due to:
• Hypo-Parathyroidism: Low (PTH) → Phosphate Reabsorption From bone
• Renal Failure: Increased Phosphate Retention in the Kidneys
§ Leads to:
• Deposition of Ca+ Salts in Soft Tissues → Hypocalcaemia
§ Treatment:
• Phosphate Binders (→↓Dietary Absorption of Phosphates)
• Dietary Phosphate Restriction
o Hypophosphataemia:
§ Lower-Than-Normal Blood [HPO2-4]
§ May be Due to:
• Decreased Intake
• Chronic Alcoholism
• Long-Term Antacid Use
§ Leads to:
• Decreased ATP (As phosphates are needed for ATP synthesis)
o →Muscle Weakness
o →Impaired Cardiac Function
o →Impaired Neural Function
§ Treatment:
• IV Phosphate Replacement
DIURETICS:

Drugs that ↓Na+ Reabsorption in the Kidneys → ↑H2O Excretion:

- → Net Loss of Na+ and therefore Water as well

Note: The [Na+] decreases as you travel down the Nephron:

- Therefore, the Effectiveness of the Diuretic depends on its Site of Action:
o Eg: If Proximal Tubule (Osmotic Diuretics) [65% Na+] – Very Effective
o Eg: If Loop of Henle (Loop Diuretics) [25% Na+] – Effective
o Eg: If Distal Tubule (Thiazide Diuretics) [5% Na+] – Low Effectiveness
o Eg: If Collecting Ducts (K+ Sparing Diuretics) [2% Na+] – Very Low Effectiveness

Source: http://www.pathophys.org/diuretics/

- The Catch: It is difficult to only manipulate Na+ (Some are ‘K+-Wasting’; some are ‘K+-Sparing’):
o Hence why Combinations – often used to balance K+ Movement
o However, even a ‘balanced diet’ of Diuretics can slowly lead to Hypokalaemia if not monitored

W hy Use Diuretics?:
- Treatment of Mild Hypertension:
o Note: Diuretics are better than β-Blockers in Every Way (↓Cost/Side Effects)
- Treatment of Acute Renal Failure
- Treatment of Oedema
- Treatment of Congestive Heart Failure:
o - to ↓Fluid Volume & ↓BP → ↓Preload → Treat Heart Failure
Loop Diuretics: (Most Powerful – BUT Potassium-Wasting)
- Site of Action:
o The Thick Ascending Loop of Henle
- Mechanism of Action:
o Inhibiting the Na/K/Cl-Transporter in the Thick-Ascending Loop of Henle
o → prevents Na+ Resorption into Interstitium (Therefore Prevents H2O Resorption)
§ (Note: Also prevents K+ & Cl- Reabsorption)
o *→Prevents formation of the ‘Hyperosmotic Medullary Interstitium’ that ordinarily facilitates Water
Resorption (under the influence of ADH)
- Indications:
o Acute Pulmonary Oedema
o Heart Failure
o Ascites (due to hepatic cirrhosis)
o Renal Failure
o (Note: Thiazides are preferred for Hypertension)
- Side Effects:
o Hypovolaemia & Hypotension
o Hypokalaemia (Due to inhibition of K+ Reabsorption):
§ May require Potassium Supplements, Or coupling with K+-Sparing Diuretics
§ (Note: Can increase Digoxin Toxicity)
o Metabolic Alkalosis (Due to reverse dilatation effect of H2O loss, but no HCO3 Loss):
§ Aka: “Concentration Alkalosis”
o Hyperuricaemia → Gout
o Reversible Hearing Loss (Same co-transporter is found in the Ear)
- Classical Agents:
o *Frusemide
o Bumetanide
o Ethioyic acid

https://tmedweb.tulane.edu/pharmwiki/doku.php/loop_diuretics
Thiazide Diuretics: (Not as powerful as Loop Diuretics – And Still Potassium-Wasting)
- Site of Action:
o Distal Convoluted Tubules
- Mechanism of Action:
o Inhibiting the Na/Cl Symporter in the DCT
o → prevents Na+ Resorption into Interstitium (Therefore Prevents H2O Resorption)
§ (Note: Also prevents Cl- Reabsorption)
§ (Note: Still K+ Wasting)
o Maintains a High Filtrate Osmolarity → Retaining Water in the Tubule
- Indications:
o **Uncomplicated Hypertension – (One of the 1st lines of treatment for hypertension)
o Severe Resistant Oedema
o Mild Heart Failure
o Ascites (due to hepatic cirrhosis)
o Renal Failure
- Side Effects:
o Hypovolaemia & Hypotension
o Hypokalaemia:
§ May require Potassium Supplements, Or coupling with K+-Sparing Diuretics
§ (Note: Can increase Digoxin Toxicity)
o Hyponatraemia:
§ Can be Fatal
o Hypomagnesaemia
o Hypocalciuria (Hypercalcaemia):
§ (Note: May be beneficial in elderly patients for Bone Metabolism)
o Metabolic Alkalosis (Due to reverse dilatation effect of H2O loss, but no HCO3 Loss):
§ Aka: “Concentration Alkalosis”
o Hyperuricaemia → Gout
o Hyperglycaemia:
§ Can unmask latent Diabetes Mellitus
o Reversible Erectile Dysfunction
- Classical Agents:
o *Chlorothiazide
o Chlortalidone

https://tmedweb.tulane.edu/pharmwiki/doku.php/thiazides?s[]=thiazide
- K+ Sparing Diuretics:
o Site of Action:
§ Collecting Ducts
o Indications – (Common for both):
§ Used in Pts where K+ Loss is Hazardous – (Eg: Pts on Digoxin or Amiodarone)
§ Heart Failure
§ Hyperaldosteronism
§ Resistant Essential Hypertension (Eg: Low-Renin Hypertension)
§ Ascites (Due to Hepatic Cirrhosis)
o 1: Epithelial Na+ Channel Inhibitors:
§ Mechanism of Action:
• Directly Inhibits the Aldosterone-Activated Na+ Channels in walls of Collecting
Ducts:
o → Inhibits H2O Resorption
• K+ Sparing Effect comes from a Loss of Na+-Concentration Gradient which normally
powers a Secondary-Active Na/K-Symporter on Basal Membrane
§ Classical Agents:
• *Amiloride
• Triamterene
§ Side Effects:
• Hyperkalaemia – (Potentially Fatal)
o Hence: Avoid in Pts with Renal Failure/ACE-Inhibitors/K+ Supplements
• Avoid NSAID Use – (Possible drug interaction)
o 2: Aldosterone Antagonists:
§ Background on Aldosterone Function:
• Aldosterone is a Steroid Hormone → Causes Expression of Proteins:
o Na+ Channel Proteins – (Responsible for Na+ Resorption)
o TCA-cycle Enzymes → ↑ATP – (ATP is responsible for Na Pump)
• Therefore, Aldosterone is Responsible for Na+ Resorption in Collecting Duct
§ Mechanism of Action of Aldosterone Antagonists:
• Prevents Aldosterone from binding to its Nuclear Receptor → Prevents Expression
of the Above Proteins
o → ↓Na+ Channel Proteins → ↓Na+ Resorption → Inhibits H2O Resorption
o → ↓TCA Enzymes → ↓ATP → ↓Na+ Pump Function → ↓Na+ Resorption
• Ultimately → ↓ H2O Resorption
• Note: ONLY works when Renin-Angiotensin System is Active
o Ie: Efficacy depends on Endogenous Aldosterone Level
• K+ Sparing Effect comes from a Loss of Na+-Concentration Gradient which normally
powers a Secondary-Active Na/K-Symporter on Basal Membrane
§ Classical Agents:
• *Spirinolactone
§ Side Effects:
• Hyperkalaemia – (Potentially Fatal)
o Hence: Avoid in Pts with Renal Failure/ACE-Inhibitors/K+ Supplements
• GI Upset
• Gynaecomastia
• Menstrual Disorders
• Testicular Atrophy
https://tmedweb.tulane.edu/pharmwiki/doku.php/potassium_sparing_diuretics
- Osmotic Diuretic Drugs:
o Site of Action:
§ Filtered in the Glomerulus
§ Affects Any Nephron that is Freely Permeable to Water
§ **- Mainly The Loop of Henle
o Mechanism of Action:
§ Inert Substances (Eg: Sugars) that are filtered by the Kidneys, but not reabsorbed
• →Increases Filtrate Osmolarity to:
o →Inhibit Passive Water Reabsorption
o →Facilitate Passive Water Excretion
§ Ie: An example of Physiological Antagonism
o Indications:
§ Acute Renal Failure – Prevent kidneys from drying out
§ Cerebral Oedema & Intraocular Pressure:
• Simply by increasing Plasma Osmolarity
• Relieves such pressures via osmosis
o Classical Agent:
§ *Mannitol
§ Isosorbide
§ Glycerin
o Side Effects:
§ Transient Hypervolaemia (Ie: ↑Extracellular Fluid – due to ↑Plasma Osmolarity)
• Can →Dilution Hyponatraemia
• Can →Heart Failure
• Can →Pulmonary Oedema
§ Headache, Nausea & Vomiting

OpenStax, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons

DRUGS ALTERING THE pH URINE:

Clinical Significance:
- The pH of the Urine affects the Excretion Rates of different Drugs (Depending if drug is acidic or basic)
- Urine Alkalinisation:
o Excretion:
§ Increases the Excretion of Weak-Acid Drugs (Eg: Salicylates/Aspirin & Barbiturates)
• Ie: Bicarbonate is sometimes used to treat Overdoses of the above
§ Decreases the Excretion of Weak-Base Drugs
o Precipitation:
§ Can prevent Weak-Acid Drugs from Precipitating in the Urine (↓kidney stones)
§ Also decreases Precipitation of Uric Acid Crystals in the Urine (↓kidney stones)
- Urine Acidification – (Rarely Ever Used):
o Excretion:
§ Increases the Excretion of Weak-Base Drugs
§ Decreases the Excretion of Weak-Acid Drugs (Eg: Salicylates & Barbiturates)
o Precipitation:
§ Can prevent Weak-Base Drugs from Precipitating in the Urine (↓kidney stones)

Urinary Alkalizers:
- Carbonic Anhydrase Inhibitors:
o Mechanism of Action:
§ Blocks Bicarbonate Reabsorption → Alkaline Urine (but Metabolic Acidosis)
- Oral Citrate:
o Mechanism of Action:
§ Metabolised via TCA-Cycle → Produces Bicarbonate as a by-product

Urinary Acidifiers – (Rarely Ever Used):

- Ammonium Chloride:
o Only Used Clinically for an oral Acid-Loading test to Diagnose Renal Tubular Acidosis
FLUID REPLACEMENT THERAPY:
Crystalloid Vs Colloid Solution:
- Crystalloids:
o = Aqueous Solutions of Mineral Salts or other water soluble molecules
o Crystalloids have a Low Osmotic-Pressure in Blood due to Haemodilution
- Colloids:
o = Mixtures of Larger Insoluble Molecules (Note: Blood itself is a colloid)
o Colloids Preserve a High Colloid-Osmotic Pressure in the Blood

Crystalloid Solutions:
- *Saline:
o The Most Commonly used Crystalloid
o Advantage – Is Isotonic → Does not cause dangerous fluid shifts
o Disadvantage – If you only replace fluid, O2 Carrying Capacity goes down (Dilution Anaemia)
§ Also, since it raises Extracellular Fluid, it’s not suitable for patients with Heart
Failure/Oedema
o Used for General Extracellular Fluid Replacement
- Dextrose:
o Saline with 5% Dextrose – Used if Pt is at risk of Hypoglycaemia; or Hypernatraemia
o Note: Becomes Hypotonic when Glucose is Metabolised → Can cause fluid overload
- Lactated Ringer’s/Hartmann’s Solution:
o A Solution of Multiple Electrolytes:
§ Sodium
§ Chloride
§ Lactate
§ Potassium
§ Calcium
o Used in Pts with Haemorrhage, Trauma, Surgery or Burns
o Also used to Buffer Acidosis

Colloid Solutions:
- Albumin:
o Albumin 40g/100ml - Used in Liver Disease, Severe Sepsis, or Extensive Surgery
o Albumin 200g/100ml – Used in Haemorrhage/Plasma loss due to Burns/Crush Injury/Peritonitis/
/Pancreatitis; or Hypoproteinaemia; or Haemodialysis
- Polygeline (Haemaccel):
o = Gelatin Cross-linked with urea
o Used in Dehydration due to GI Upsets (Vom/Diarrhoea)

Blood Products:
- Whole Blood:
o RBCs, WBCs, Plasma, Platelets, Clotting Factors, Electrolytes (Na/K/Ca/Cl)
o Used to Replace Blood Volume & Maintain Haemoglobin Level → ↑O2-Carrying Capacity
- RBCs:
o Used to Increase Haematocrit (proportion of RBCs) → ↑O2-Carrying Capacity
- Plasma:
o Plasma (With Plasma Proteins), Clotting Factors, Fibrinogen, Electrolytes (Na/K/Ca/Cl)
o Used to restore Plasma Volume in Hypovolaemic Shock & Restore Clotting Factors
DRUGS USED IN HYPERTENSION
DRUGS USED IN HYPERTENSION

Therapeutic Approach to Managing Hypertension:

- Non-Pharmacological:
o Increased Exercise/Fibre
o Reduced Salt/Saturated fats
o Weight Loss
- Pharmacological:
o #1: ACE Inhibitor; OR Angiotensin-II Antagonist
§ (Typically in Pts with a normal/raised plasma Renin – Ie: Younger/White People)
o + Thiazide Diuretic; OR Calcium-Antagonist
§ (Typically in Pts with a low plasma Renin – Ie: Elderly/African People)
o β-Blockers (β-Adrenoceptor Antagonists):
§ (Less well tolerated than ACE-Inhibitors or AT-Antagonists)
§ - Most useful in patients who require β-Blockade In Addition to Antihypertensives (Ie:
Angina/HF)
o (α-Blockers (α-Adrenoceptor Antagonists)):
§ - Most useful in Hypertensive Males who also have Prostatic Hypertrophy
§ (Postural Hypotension is the main side effect)

ACE Inhibitors (“Prils”):

- Mechanism of Action:
o Inhibits Angiotensin-Converting Enzyme – (Normally Converts Angiotensin-I to Angiotensin-II)
o → ↓Angiotensin-II:
§ → ↓Vasoconstriction (Ie: Vasodilation)
§ → ↓ADH Secretion by the Posterior Pituitary → ↓Fluid Retention
§ → ↓Aldosterone Secretion by Adrenal Cortex → ↓Na+ (& H2O) Reabsorption
§ → ↓Sympathetic Activity
o → → Decreases Blood Pressure
- Indications:
o Hypertension
o Heart Failure
o Post Myocardial Infarction
o Patients at risk of Ischaemic Heart Disease
o Diabetic Nephropathy
o Renal Insufficiency
o (Note: Contraindicated for Severe Renal Artery Stenosis → Renal Failure; as Angiotensin II is
maintaining their GFR)
- Classical Agents:
o *Captopril, Enalapril, Ramipril, Perindopril, Trandolapril
- Side Effects:
o Hypotension, Dry Cough, Hyperkalaemia (Due to ↓Aldosterone Secretion)
Angiotensin-II Receptor Antagonists (“Sartans”):
- Mechanism of Action:
o Directly inhibits Angiotensin-II Receptors (Particularly on Vascular Smooth Muscle) →:
§ → ↓Vasoconstriction (Ie: Vasodilation)
§ → ↓ADH Secretion by the Posterior Pituitary → ↓Fluid Retention
§ → ↓Aldosterone Secretion by Adrenal Cortex → ↓Na+ (& H2O) Reabsorption
§ → ↓Sympathetic Activity
o → → Decreases Blood Pressure
- Indications:
o Hypertension (Especially Young Pts/Diabetics)
o Heart Failure
o Diabetic Nephropathy
- Classical Agents:
o *Valsartan/Losartan/Candesartan/Irbesartan
- Side Effects:
o Hypotension
o Hyperkalaemia (Due to ↓Aldosterone Secretion)
o (Note: No Dry Cough)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

Beta-Blockers (β1-Adrenoceptor Antagonists) (“Olols”):
- Mechanism of Action:
o Directly inhibits β1-Adrenergic Receptors (Particularly on Cardiac Muscle Cells)→:
§ →↓Cardiac Output (↓HR & Contractility)
§ →↓Renin Release→ ↓Vasoconstriction, ↓ADH & Aldosterone, & ↓Sympathetic Activity
§ →↓Sympathetic Activity
- Indications:
o Hypertension
o Angina
o Prophylaxis in Post MI Patients
- Classical Agents:
o *Atenolol
o Oxprenolol
- Side Effects:
o Bronchoconstriction (Dangerous in Asthma & Emphysema)
o Potential Heart Block/Failure in Pts with Coronary Disease
o Cold Extremities
o Fatigue

Alpha Blockers (α1-Adrenoceptor Antagonists) (“Osins”):

- Mechanism of Action:
o Directly inhibits α1-Adrenergic Receptors (Smooth Muscle, Bladder & Cardiac Muscle)→:
§ → Vasodilation → ↓Blood Pressure
• Note: Rebound Hypertension (A reflex response to the ↓BP)
§ →↓Bladder Sphincter Tone
• (Note: Also inhibits hypertrophy of Bladder neck & Prostate)
- Indications:
o Severe Hypertension
o Benign Prostatic Hypertrophy
- Classical Agents:
o *Prazosin
o Tamsulosin
- Side Effects:
o Postural Hypotension → Dizziness
o Insomnia
o Priapism (Persistent/painful erection)
o Abnormal Ejaculation

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

DRUGS USED IN CHEMOTHERAPY
DRUGS USED IN CHEMOTHERAPY

The Basics behind Chemotherapy:

- The Old Focus:
o Growth:
§ - DNA Replication – (Ie: Target Rapidly-Dividing Cells)
§ - Cellular Metabolic Activity – (Ie: Target Rapidly-Dividing Cells)
- PROBLEMS:
o NOT EXCLUSIVE (Explains Side Effects):
§ Not all Tumour-Cells replicate rapidly
§ Also, many Normal cells divide rapidly – Are killed by Chemotherapy:
• GI (→ Vomiting/Ulcers/Nausea)
• Bone Marrow (→Immunosuppression)
• Skin
• Hair (→ Hair Loss)
• Gametes (→Infertility)
- The New Focus:
o Angiogenesis – (Ie: If we can cut off the blood supply to the tumour, the tumour will die)
- Note: BOTH Methods are often used in Combination for Optimum Results

Combating Cancer
- ‘The Holy Grail’ = Selective Toxicity:
o Focus directly on characteristic differences between normal and cancerous cells
o → Kill only the cancer cells (This has not yet been achieved)
- Finding Drugs:
o Random Screening of natural and synthetic products for anti-tumour activity
o →Identify “lead” compounds, then optimize them to attempt to create true selectivity

Overview of Mechanisms of Action of Anti-Tumour Agents:

- Chemotherapy Drugs Target Phases of the Cell Cycle:
o S-Phase Specific – Interfere with DNA Synthesis
o M-Phase Specific – Interfere with Cell Division
o Phase-Nonspecific – Interferes with Cell Metabolism
Overview of Approaches to Chemotherapy:
- Typical Cytotoxic Agents:
o Alkylating Agents:
§ (Disrupts DNA replication in Rapidly-Dividing Cells)
o Antimetabolites:
§ (Provide cells with False Nuclear Substrates → Interferes with DNA Synthesis)
o Cytotoxic Antibiotics:
§ (Directly Damages DNA →Disrupts DNA Replication/Transcription & Produces Free Radicals)
o Plant alkaloids:
§ (Antimitotic Agents – Disrupts mitotic cellular machinery)

- Hormones and Anti-Hormones:

o (Interfere with Hormone-Related Growth of Tumours)
o Immunosuppressants:
§ Glucocorticoids – HAEMATOLOGICAL CANCERS:
o Hormone Agonists:
§ Oestrogens
§ Progestogens
o Hormone Antagonists:
§ Anti-Oestrogens – BREAST CANCER:
• Selective Oestrogen Receptor Modulators (SERMs)
• Selective Oestrogen Receptor Downregulators (SERDs)
§ Anti-Androgens – PROSTATE CANCER
o Inhibitors of Hormone Synthesis:
§ GnRH-Receptor Agonists & Antagonists
§ Reductase Inhibitors
§ Aromatase Inhibitors

- Thalidomide:
o 1: Antiproliferative/Pro-Apoptotic Actions
o 2: Inhibition of Cell-Adhesion Molecule expression on Bone-Marrow Stroma
o 3: Inhibition of Angiogenesis (Cytokine mediated)
o 4: Immunomodulation (Primarily ↑NK-Cell Activity)

- Novel Chemotherapeutic Approaches:

o Biological Response Modifiers:
§ Interferons:
• Amplifies Cytotoxic Activity of the Immune System
o → ↑NK, ↑T-Cell, ↑Macrophage Activity
• Inhibits Cell Proliferation
• Alters Antigen Expression on Tumour & Immune Cells
§ Interleukin-2:
• In Vitro – Used to Stimulate Lymphocyte Proliferation & Cellular Immunity against an
Introduced Tumour-Specific Antigen
o Resultant Lymphocytes are Re-Infused into the Patient → Attack Tumour
o Monoclonal Antibodies
§ Antibodies are Directed against Tumour-Cell Antigens → Lyses Tumour Cells Directly
§ Or, are Directed against Tumour-Cell Secretions → Denies tumour of Growth Factors
GENERAL SIDE EFFECTS:
- Alopecia – (Hair Loss)
- Nausea/Vomiting
- Blisters, Sores
- Myelosuppression
- Impaired Healing
- Stunted Growth (Children)
- Organ Toxicity (Heart, Nervous System, Liver, Kidneys)

SPECIFIC SIDE EFFECTS:

- Antimetabolites:
o 3: Purine Analogues - *Mercaptopurine:
§ Hepatotoxicity
- Cytotoxic Antibiotics:
o *Bleomycin:
§ Significant Cardiotoxocitity → Tachycardia, Arrhythmias, Hypotension, Pericardial Effusion,
Congestive Heart Failure)
- Plant Alkaloids:
o 1: Vinca Alkaloids – *Vincristine:
§ Neurotoxicity because it inhibits the microtubules needed for Axonal NT-Transport
- Thalidomide:
o Severe Foetal Malformation (DO NOT take if Pregnant!)

GENERAL TREATMENT ‘COMPLICATIONS’ – (As opposed to ‘Side Effects’):

- (Complications = Events that cause the treatment to be Less/Not-Effective)
o Note: If asked in an exam for Complications, Do not give Side Effects
- Drug Resistance:
o What is it?
§ Cells acquire mutations which provide resistance to treatment drugs
o How can we get around this?
§ Multi-Drug approach
§ Change treatment Timeline → Reduce Adaptation
- Tumour Sanctuaries:
o What is it?
§ Tumour cells are Inaccessible to Drugs due to:
• Encapsulated Tumour
• Quiescence (Ie: Non-dividing)
o How can we get around this?
§ Radiotherapy
§ Surgery
- Dose Exhaustion:
o What is it?
§ Patient has reached the Maximum Therapeutic dose – (Any higher → Toxicity)
§ → Remaining cells re-establish malignancy
o How can we get around this?
§ Multi-Drug Therapy
§ + Surgery/Radiotherapy
- Myelosuppression:
o What is it?
§ Under-Proliferation of Myeloid Cells (Neutrophils/Macrophages/Granulocytes/RBCs)
o How can we get around this?
§ Stimulation of Bone Marrow by Growth Factors → Promote blood cell production
CHEMOTHERAPY DRUGS:

CYTOTOXIC DRUGS:
- Alkylating Agents:
o Background Info:
§ (Note: Alkylating agents are Pro-Drugs → Activated to Highly-Reactive free-radical
substances)
§ (Note: Liver cells have natural protection against alkylating agents since they possess
Inactivating Enzymes; However, Tumour cells tend to accumulate the toxic metabolites)
o Phase:
§ Phase Non-Specific
o Goal:
§ Disrupts DNA Replication (S-Phase) & Transcription (All Phases) in Rapidly-Dividing Cells
o Classical Agents:
§ **Cyclophosphamide – (Nitrogen Mustards)
§ Cisplatin – (Alkylation-like Drugs)
§ Nitrosureas
o Indications:
§ Lymphomas (Hodgkin’s & Non-Hodgkin’s)
§ Chronic Lymphocytic Leukaemia
§ Ovarian/Breast/Testicular/Cervix/Bladder/Endometrial Cancers
§ (Also used as an immunosuppressant in Rheumatoid Arthritis)
o Mechanism of Action:
§ Forms Cross-Links Within/Between DNA Strands → Impairs Replication & Transcription:
• → Forces Cell to ‘Cut Out’ & Repair these errors → Causes Strand-Breaks to occur
o → Non-Homologous Joins (Highly Error-Prone) → Potentiates further errors
• →→APOPTOSIS
§ (Note: Certain tumours have mutated repair proteins, & are very sensitive to alkylating
agents)
o Side Effects:
§ *Myelosuppression (& Immunosuppression)
§ GI Disturbances
§ (Rare: Leukaemia, Infertility)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Antimetabolites:
o Phase:
§ S-Phase Specific – (Ie: Impairs DNA Synthesis)
§ (Note: Also affects RNA Synthesis & therefore impedes Housekeeping functions too)
o Goal:
§ Provide cells with False Nuclear Substrates → Interferes with DNA Synthesis
o 3 Types:
§ 1: Folate Antagonists:
• Classical Agent:
o *Methotrexate
• Mechanism of Action:
o Inhibits Dihydrofolate-Reductase (A folate-dependent enzyme):
§ → Interferes with Purine Synthesis (Adenine & Guanine)
§ → Interferes with Thymidylate Synthesis (Thymine)
o → Therefore interferes with DNA Synthesis
• Indications:
o Acute Lymphoblastic Leukaemic (Children)
o Choriocarcinoma (Placental Cancer)
o Lymphomas
• Side Effects:
o *Myelosuppression (& Immunosuppression)
o GI Disturbances

§ 2: Pyrimidine Analogues:
• Classical Agent:
o *Fluorouracil
• Mechanism of Action:
o Inhibits Thymidylate Synthase:
§ → Interferes with Thymidylate Synthesis (Thymine)
o Is a Pyrimidine Analogue → Gives rise to Fraudulent Nucleotides:
§ Cytosine
§ Thymine
o → Therefore, Interferes with DNA Synthesis
• Indications:
o Cancers of the GIT (Upper GI/Gastric/Colorectal)
o Breast Cancer
• Side Effects:
o *Myelosuppression (& Immunosuppression)
o GI Disturbances

§ 3: Purine Analogues:
• Classical Agents:
o *Mercaptopurine
o Azathioprine (Metabolised to Mercaptopurine)
o 6-Thioguanine
• Mechanism of Action:
o Is a Purine Analogue → Gives rise to Fraudulent Nucleotides:
§ Adenine
§ Guanine
• Indications:
o Leukaemias
• Side Effects:
o *Myelosuppression (& Immunosuppression)
o Hepatotoxicity
- Cytotoxic Antibiotics:
o Background:
§ Cytotoxic antibiotics are a widely used group that mainly produce their effects through direct
action on DNA
o Phase:
§ S-Phase Specific – (Ie: Impairs DNA Synthesis)
o Goal:
§ Directly Damages DNA →Disrupts DNA Replication/Transcription & Produces Free Radicals
o Classical Agents:
§ Doxorubicin
§ Dactinomycin
§ Bleomycin (Note: Can act on Non-Dividing Cells) – (However, Significant Cardiotoxocitity →
Tachycardia, Arrhythmias, Hypotension, Pericardial Effusion, Congestive Heart Failure)
§ (Mitomycin-C)
o Indications:
§ Doxorubicin–Acute Leukaemias, Hodgkin/non-Hodgkin Lymphomas, Breast/Ovarian Cancer
§ Dactinomycin – Paediatric Cancers, Rhabdomyosarcoma, Soft-Tissue Sarcomas, Uterine
Cancer
§ Bleomycin – Germline Cancers
o Mechanism of Action:
§ Some insert themselves between pairs in DNA → Prevent/Disrupt Replication
• → Apoptosis
§ Some bind to RNA → Prevent/Disrupt protein Synthesis
• →Cell dies
§ Some Degrade DNA by Blocking Topoisomerase → Causes DNA Breaks & Inhibits Relegation
• (Note: Topoisomerase is the enzyme that unwinds & winds DNA in replic/trans)
• → Apoptosis
§ Some Generate Free-Radicals → Directly destroy DNA
• →Apoptosis
o Side Effects:
§ Fever/Allergies/Rash
§ Myelosuppression
§ Hair Loss
§ GI Upset
§ (Bleomycin – Significant Cardiotoxocitity → Tachycardia, Arrhythmias, Hypotension,
Pericardial Effusion, Congestive Heart Failure)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

- Plant Alkaloids:
o Phase:
§ M-Phase Specific
o Goal:
§ Antimitotic Agents - (Disrupts mitotic cellular machinery)
o 3 Groups:
§ 1: Vinca Alkaloids:
• Classical Agents:
o *Vincristine, Vinblastine
• Mechanism of Action:
o Inhibits Tubulin Polymerisation → Prevents Microtubule formation →
→ Prevents Spindle Form ation
o → Chromosomes can’t align @ the Midline
§ → Cell arrests at Metaphase
o (Secondary Actions: ↓Axonal NT Transport, ↓Chemotaxis, ↓Phagocytosis)
• Indications:
o Leukaemias, Lymphomas, Breast, Lung Cancers
• Side Effects:
o GI Disturbances, Hair Loss, Neurotoxicity
o (Note: Neurotoxicity because microtubules are needed for Axonal Transport)
§ 2: Taxanes:
• Classical Agents:
o Paclitaxel
• Mechanism of Action:
o “Freezes” Microtubules → Prevents Spindle Formation
o → Aberrant microtubules accumulated during mitosis
§ → Cell arrests at Metaphase
• Indications:
o Ovarian/Breast Cancer, Lung Cancer, Head/Neck Cancer
• Side Effects:
o Hypersensitivity, Myelosuppression, Hair Loss, GI-Disturbances
§ 3: Campothecins:
• Classical Agents:
o *Irinotecan, Topotecan
• Mechanism of Action:
o Inhibit Topoisomerase → Prevents unwinding/winding of DNA during
Replication & Transcription
o →Also Prevents Religation of Strand-Breaks
§ → Stops cell in all phases
• Indications:
o Metastatic Colon/Rectal/Ovarian Cancers
• Side Effects:
o GI Disturbances, Interstitial Pulmonary Disease
Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO
HORMONE DRUGS:
- Hormones and Anti-Hormones:
o Background Info:
§ Tumours derived from Hormone-Sensitive Tissues may be Hormone-Dependent
§ Therefore, their growth can be inhibited by:
• Opposing Hormones
• Hormone Antagonists
• Agents inhibiting endogenous hormone synthesis
§ However, Growth-Retardation is the only effect →Therefore Other Drugs are required as
w e ll to K ill th e tu m o u r c e lls
o Goal:
§ Interfere with Hormone-Related Growth of Tumours
o Summary of Drugs & their Indications:
§ Immunosuppressants:
• Glucocorticoids – Leukaemias/Lymphomas
§ Hormone Agonists:
• Oestrogen Analogues – Palliative care of Prostate Cancer
• Progesterone Analogues – Endometrial/Renal Cancers
§ Hormone Antagonists:
• Anti-Oestrogens – (Tamoxifen) – Breast Cancers
• Anti-Androgen – (Flutamide) – Prostate Cancer
§ Inhibitors of Hormone Synthesis:
• GnRH Agonists/Antagonists (Both ↓Sex Hormones) – Prostate & Breast Cancers
• Aromatase Inhibitors – Breast Cancer (in Post-Menopausal Women)
• Reductase Inhibitors – Benign Prostatic Hypertrophy (Men)
- IMMUNOSUPPRESSANTS:
o Glucocorticoids – HAEMATOLOGICAL CANCERS:
§ Classical Agents:
• Cortisol, Prednisone, Dexamethasone
§ Mechanism of Action:
• Prevent Lymphocyte Growth
• → Remission of Lymphoid Cancer is more rapid with Glucocorticoids
§ Indications – Haematological Cancers:
• Leukaemias & Lymphomas

- HORMONE AGONISTS:
o Oestrogens:
§ Classical Agents:
• Diethylstilbesterol
• Ethinyloestradiol
§ Mechanism of Action:
• Oestrogen Receptor Agonist
§ Indications:
• Palliative Care of Prostate Cancer
o Progestogens:
§ Classical Agents:
• Megestrol
• Norehisterone
• Medroxy-Progesterone
§ Mechanism of Action:
• Progesterone Receptor Agonist
§ Indications:
• Used in Endometrial & Renal Cancers
- HORMONE ANTAGONISTS:
o Anti-Oestrogens – BREAST CANCER:
§ Selective Oestrogen Receptor Modulators (SERMs):
• Classical Agent:
o *Raloxifene, *Tamoxifen
• Mechanism of Action:
o – Competitive Antagonists of Oestrogen @ Oestrogen Receptors
• Indication:
o Breast Cancer – (Combination Treatment)

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

§ Selective Oestrogen Receptor Downregulators (SERDs):

• Classical Agent:
o *Fluvestrant
• Mechanism of Action:
o – Binds to Oestrogen Receptors & Stimulates Endocytosis or the Receptors
o (Ie: Causes Downregulation of Oestrogen Receptors)
• Indication:
o Breast Cancer – (Combination Treatment)

Anti-Androgens – PROSTATE CANCER:

o
§ Background Info:
• Note: Surgery is 1st line Treatment for Localised Prostate Cancer
o However, if Metastatic – Hormone Therapy is Critical
§ Classical Agent:
• Flutamide
§ Mechanism of Action:
• Medical Castration:
o Either Blocks effects of Androgens
o Or Reduces Androgen Production
§ Indication:
• Prostate Cancer – (Combination Treatment)
• Generally used in combination with GnRH Agonists → Complete Androgen Blockade
- INHIBITORS OF HORMONE SYNTHESIS:
o GnRH-Receptor Agonists & Antagonists:
§ Common Aim:
• To Decrease Gonadotropin Release (LH & FSH) to Decrease Testosterone/Oestrogen
Synthesis
• (Testosterone is a potent promoter of Prostate Growth)
• (Oestrogen is a potent promoter of Breast Cancer Growth)
§ Mechanism of Action:
• GnRH Agonists:
o Cause an Initial Increase in LH & FSH → Followed by a Reduction in LH & FSH
§ → ↓Testosterone Synthesis
§ OR → ↓Oestrogen Synthesis
• GnRH Antagonists:
o Cause a Rapid Reduction of LH & FSH
§ → ↓Testosterone Synthesis
§ OR → ↓Oestrogen Synthesis
§ Indication:
• Prostate Cancer – (Combination Treatment)
• Generally used in combination with Anti-Androgens → Complete Androgen Blockade
§ Reductase Inhibitors:
• Background Info:
o 5a-Reductase is responsible for the Activation of Testosterone
o (Testosterone is a potent promoter of Prostate Growth)
• Example:
o Finasteride
• Mechanism of Action:
o Direct inhibition of 5a-Reductase → ↓Activation of Testosterone
§ → ↓Prostatic Growth
• Indication:
o Benign Prostatic Hyperplasia

Image credit: Rang, Dale, et al. Pharmacology; available from: https://amzn.to/3Hr51dO

 § Aromatase Inhibitors:
• Background Info:
o Aromatase is responsible for Conversion of Androgens to Oestrogens in
Peripheral Tissues – Particularly Post-Menopausal Women)
o Therefore Inhibition – Causes Marked Reduction in Oestrogen – (In Post-
Menopausal Women)
• Examples:
o Anastrozole
o Letrozole
• 2 Types:
o Type 1 Inhibitors:
§ Androgen analogues which Irreversibly bind to Aromatase →
Inactivating it
o Type 2 Inhibitors:
§ Agents which bind Reversibly to the Haem-group of the Enzyme →
Inactivating it
• Indication:
o Breast Cancer – (Combination Treatment)

Smith, I.E., & Dowsett, M. (2003). Aromatase inhibitors in breast cancer. The New England journal of medicine, 348
24, 2431-42 .
THALIDOMIDE (& LENALIDOMIDE):
- Proposed Mechanisms of Action:
o 1: Antiproliferative/Pro-Apoptotic Actions
o 2: Inhibition of Cell-Adhesion Molecule expression on Bone-Marrow Stroma
o 3: Inhibition of Angiogenesis (Cytokine mediated)
o 4: Immunomodulation (Primarily ↑NK-Cell Activity)
- Side Effects:
o Severe Foetal Malformation (DO NOT take if Pregnant!)

Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Mechanisms-of-action-of-

lenalidomide-in-cell-tissue-processes-BFGF-Basic_fig2_24033923

https://upload.wikimedia.org/wikipedia/commons/c/cd/Thalidomide_effects.jpg
NOVEL CHEMOTHERAPEUTIC AGENTS:
- Biological Response Modifiers:
o Interferons:
§ Indication:
• Melanomas & Lymphomas
§ Mechanism of Action:
• Amplifies Cytotoxic Activity of the Immune System
o → ↑NK, ↑T-Cell, ↑Macrophage Activity
• Inhibits Cell Proliferation
• Alters Antigen Expression on Tumour & Immune Cells
o Interleukin-2:
§ Indication:
• Renal Tumours
§ Mechanism of Action:
• In Vitro – Used to Stimulate Lymphocyte Proliferation & Cellular Immunity against an
Introduced Tumour-Specific Antigen
o Resultant Lymphocytes are Re-Infused into the Patient → Attack Tumour
- Monoclonal Antibodies:
o Classical Agents:
§ *Rutiximab
§ Trastuzumab
§ Cetuximab
o Indication:
§ Lymphomas
§ Chronic Lymphocytic Leukaemia
o Mechanism of Action:
§ Antibodies are Directed against Tumour-Cell Antigens → Lyses Tumour Cells Directly
§ Or, are Directed against Tumour-Cell Secretions → Denies tumour of Growth Factors
o Problems:
§ Tumour-Cell Antigens MUST be VERY SPECIFIC
§ MABs are Immunogenic – (Ie: They stimulate the immune system)
§ Hard to calculate dose
Summary of Chemotherapeutic Drugs:
INTRO TO TOXICOLOGY
INTRO TO TOXICOLOGY

Principles behind Toxicology:

- Everything is “Toxic”:
o Just depends on Dose, and Route
- What is it?:
o Study of Toxicity
o Toxicity = “The ability of a chemical/physical agent to cause harm to a living organism”
o Toxicant = “Any Chemical that is Toxic”
o Toxication = “Metabolic Activation of a Chemical to create a Toxicant”
- Assumes that the Agent Gains Access to the Organism:
o Inhalation
o Absorption through Membranes (Skin/Mucosa/Lens/Conjunctiva/GIT)
o Ingestion

Pathways to Toxicity:
- Toxicity can be reduced by intervening at any of the potential stages (Diagram)
o (However, you need to Know these steps to be able to intervene)
o Note: The later you intervene, the greater the Chance/Extent of Toxicity
- A) Delivery:
o The net balance of Pharmacokinetic factors during delivery of toxicant determines How Much
toxicant gets to interact with the Target Molecule (2)
o Influenced by:
§ Absorption:
• Size of Molecule
• Solubility (Lipid/H2O)
• Porosity of the Capillary Endothelium
o Eg: Hepatic/Renal Capillaries Vs Blood-Brain Barrier
§ Distribution:
• Solubility (Lipid/H2O)
o Affects distribution to Storage Sites (Ie: Adipose Tissue) - & Therefore
sequestering drug away from other tissues
o (Note: However, this can prolong Excretion)
• Specialised Membrane Transporters
o – Ie: Whether the cell actively Stores or Extrudes the Toxicant
o (Note: Resistant cells have active pumps to extrude many toxic substances)
• Association with blood proteins
o – Decreases Drug Availability to Tissues (Protective)
• Association with Intracellular Proteins
o Eg: Melanin → Enhanced Distribution
o Eg: Metallothionein (a metal-binding protein in kidneys)→Protects
§ Toxication/Detoxification (Ie: Biotransformation):
• Ie: Changing a compound’s physicochemical properties:
o Can → ↑Excretion Rate (Ie: Conjugation – Phase II Reactions)
o Can → Alter Degree of Activity (Ie: Red/Ox/Hydro – Phase I Reactions)
§ (May be a good thing – Activation of a desired pro-drug)
§ (May be a bad thing – Toxication)
§ Excretion:
• CV Integrity
• Renal Function

- B) Cellular Dysfunction:
o Self-Explanatory – If the cell doesn’t perform its normal role, it can influence other cells around it →
Damage (& Therefore Toxicity)

- C) Disrepair:
o Self-Explanatory – If the cell doesn’t maintain itself, it will die → also influencing other cells around it
→ Damage (& therefore Toxicity)

Factors That Affect Toxicity:

- Properties of the Chemical:
o Reactivity
o Target
o Nature of Clearance
- Dose:
o Bolus / Chronic / Accumulated
- Duration of Exposure:
o Acute High Exposure Vs Low Dose Chronic Exposure
o Half Life
- Route of Exposure:
o Affects the Access to its Target
o Affects Access to Liver (& Hence Bioactivation/Toxication)
o Affects Access to Kidneys (& Hence affect Clearance)
Biotransformation – (Drug Metabolism):
- Can be Good or Bad:
o Bioactivation = Activation of a desired pro-drug → Active Metabolite
o Toxication = “Metabolic Activation of a Chemical to create a Toxicant”

- Liver enzymes can Change a compound’s physicochemical properties:

o Can → ↑Excretion Rate (Via Conjugation – Phase II Reactions)
§ Conjugation →↑H2O Solubility → ↑Excretion
o Can → Alter Degree of Activity (Via Red/Ox/Hydro – Phase I Reactions)
§ (Ie: Efficiency of binding to its target – Enzymes/Lipids/Nucleic Acids)
§ - May be a good thing – Activation of a desired pro-drug
§ - May be a bad thing – Toxication

- “2 Phases of Biotransformation”:
o Phase I:
§ Functional Groups on the Drug are Added/Unmasked via Reduction/Oxidation:
• →Alter Bioactivity
• →Allow for Conjugation
§ Key Phase-I Enzymes:
• **Cytochrome P450 Mono-Oxygenase (CYP) Family – OUR FOCUS:
o Responsible for Oxidative Reactions:
§ Eg: Drug Metabolism
§ Eg: Bile Synthesis – (From Cholesterol)
§ Eg: Vit-D Synthesis
§ Eg: Fatty Acid Synthesis/Catabolism
o Are a family of 12 Membrane-Bound Enzymes:
§ Are NADPH & Haeme Fe3+ - Dependent Enzymes
§ Most concentrated in Liver – (But also in GI Mucosa & Kidney)
• Not Present in Skeletal Muscle/RBCs
§ Different Isozymes – act on Different Substrates (Drugs)
§ Huge Variability in Population → Variability of Drug Effectiveness
o CYP “2D6” – The Most Relevant CYP:
§ Metabolises 30% of clinical drugs
§ Some Genetic Variability – Gives rise to Poor/Normal/Rapid/Ultra-
Rapid M etabolisers - (based on activity of the Enzym e)
• (Monoamine Oxidase – Degrade Monoamine NTs [Serotonin/NE/Epi/Dopamine])
• (Alcohol & Aldehyde Dehydrogenase)
• (Xanthine Oxidase (Key enzyme in Uric Acid Production))
o Phase II:
§ Adding Chemical Groups to the Drug to Increase Water-Solubility → Facilitate Excretion:
• **Glucuronide Conjugation – OUR FOCUS:
o The most common Phase-II Reaction
o Aim – To ensure excretion through the Kidneys
o How – By Merging Glucuronide (A Polar Compound) with a Lipophilic
D rug/M etabolite → ↑ H 2O Solubility
o Reagent – “UDP-GA”
o Targets – Alcohols/Carboxylic Acids/Amines/Sulfhydryl groups
• Glutathione Conjugation – (NAPQI Inactivation during Paracetamol Metabolism)
• Amino Acid Conjugation
• Acetylation – (Eg: DE-Acetylation of Aspirin [Acetyl Salicylic Acid → Salicylic Acid])
• Sulfation
• Methylation
Factors That Affect Metabolism (Therefore Toxicity):
- Age:
o (Newborns Vs Children Vs Adults Vs Elderly)
o Newborns (0-6mths):
§ More Prone to Toxic Effects for 2 Reasons:
• 1: They have no Phase II Reactions (Can’t Conjugate Drugs → Excretion)
• 2: Have Inefficient Renal Function
• (Therefore, elimination of drugs requiring Conjugation will be slower than adults)
o Children (1-8yrs):
§ Metabolise Drugs Much Faster than Adults (Especially Oxidation (Phase-I) Reactions):
• If Metabolism Produces the Toxic Agent, High Metabolic Rate → ↑Toxicity
• If Metabolism De-Toxifies the Toxic Agent, High Metabolic Rate → ↓Toxicity
o Elderly (>70yrs):
§ Metabolise Drugs Much Slower than Adults (Especially Oxidation (Phase-I) Reactions):
• If Metabolism Produces the Toxic Agent, Low Metabolic Rate →↓Toxicity
• If Metabolism De-Toxifies the Toxic Agent, Low Metabolic Rate →↑Toxicity

- Pharmaco-Genetics:
o (Pharmacogenetics = “Study of Hereditary Variations in Drug/Toxicant responses)
o Genetic Polymorphisms:
§ Variation of Alleles @ one genetic locus, between Individuals/Populations
§ In Our Case – Metabolism-Related Polymorphisms:
§ Eg: Slow Vs Rapid Acetylators (Big racial differences):
• Slow Acetylators:
o ↓Liver Metabolism →↑[Un-Metabolised Drug] in Periphery:
§ If Un-Metabolised Drug is Toxic →
• →↑Peripheral Toxicity
• →But ↓Chance of Hepatotoxicity
§ If Metabolised Drug is Toxic →
• →↓Peripheral Toxicity
• → But ↑Chance of Hepatotoxicity
• Rapid Acetylators:
o ↑ Liver Metabolism →↓[Un-Metabolised Drug] in Periphery:
§ If Un-Metabolised Drug is Toxic →
• →↓Overall Toxicity (Peripheral & Hepatic)
§ If Metabolised Drug is Toxic →
• →↑Liver Toxicity
• →↑Renal Toxicity
o (Note: Doses of drugs Bio-Inactivated by this pathway will need to be higher
than normal for Therapeutic Levels)
§ Eg: Aldehyde Dehydrogenase – (Alcohol Metabolism):
• Typical Aldehyde Dehydrogenase:
o Maintains low Acetaldehyde during Alcohol Oxidation
• Atypical (Mutant/Absent) Aldehyde Dehydrogenase:
o → High Levels of Acetaldehyde in blood → ‘Hang-over’ Symptoms:
§ Facial Flushing
§ Light-Headedness
§ Palpitations
§ Nausea
o Drug Idiosyncrasy:
§ Unexpected/Anomalous Responses to a Drug
§ (Ie: When the reaction is inconsistent with the mechanism of action)
- Drug Interactions:
o Metabolic Enzyme Inhibition – (Typically Acute):
• (Good if Metabolism Toxifies Drug; Bad if Metabolism Detoxifies Drug)
• (Also can prolong bioavailability of therapeutic drugs)
§ 1: Competitive Inhibition:
• Either: 2 Drugs compete for the active site of the same enzyme → ↓Metabolism of
Both
o →↓Clearance of both
o →↑T1/2 of both
• OR: The Inhibitor is NOT a substrate for the Enzyme, but interacts with the enzyme in
a Competitive fashion (eg: With a cofactor or regulator) to block its activity
o →↓Clearance of the initial drug
o →↑T1/2 of the initial drug
§ 2: Non-Competitive Inhibition:
• Either: Where the Inhibitor Irreversibly Binds (Covalently) & Inactivates the Enzyme,
requiring Synthesis of a new enzyme to restore function
• OR: Where the Inhibitor Semi-Permanently Binds (Non-Covalently) & Inactivates the
Enzyme for an Extended Period of Time
o Metabolic Enzyme Induction – (Typically Chronic):
§ (= an Increase in Drug Metabolism → Lowers Drug-Levels in Blood)
§ Mechanisms:
• ↑mRNA Synthesis
• ↑mRNA Stability (↓Degradation)
• ↑Protein Synthesis
• ↑Protein Stability (↓Degradation)
§ Note: Balance between Synthesis & Degradation

Physiological Status/Disease Status:

- o Gender:
§ Primarily due to Availability of Hormones:
• Male Vs Female
• Pre Vs Post-Menopausal Women
o Cardiovascular Integrity:
§ Affects Distribution
o Renal & Hepatic Integrity:
§ Affects Clearance
o Nutritional Status:
§ Availability of Metabolites/Vitamins/Minerals/etc. May affect Uptake/Metabolism/Clearance
Toxicity of Commonly Used Chemicals/Drugs:
- Approach to a Poisoned Patient:
o 6 key features of the initial approach:
§ Resuscitation/Stabilization
§ History and Physical Exam
• Includes evaluation for a specific toxidrome*
§ Decontamination (of GI tract, skin, eyes)
§ Laboratory tests, ECG, radiographic studies
§ Antidotes, if indicated (see handout)
§ Enhanced Elimination Techniques (for selected toxins)
- Decontamination:
o Via Administration of Activated Charcoal for GI Decontamination:
§ Should be given within 1hr of toxin ingestion
§ Multiple Doses may be necessary with life-threatening dose of some drugs
• (» eg: carbamazepine, phenobarbitone, quinine, theophylline)

- Toxidromes:
o Toxidrome = A Syndrome caused by Dangerous levels of a Toxin in the Body
§ (Often the consequence of a drug overdose)
o Classification of Toxidromes is based on the Symptom Profile – (Just know distinguishing features):
§ Anticholinergic Toxidrome:
• Symptoms include:
o blurred vision
o choreathetosis (abnormal body movements)
o dilated pupils
o flushing
o urinary retention
• Complications include:
o Hypertension
o Hyperthermia
o Tachycardia
• Common Culprits include:
o Atropine, Tricyclic Antidepressants

§ Cholinergic Toxidrome:
• Symptoms include:
o Lacrimation, Salivation,
o Defecation, diarrhoea, vomiting
• Complications include:
o Bradycardia
• Common culprits include:
o Organophosphate Pesticides (remember that these are generally
Acetylcholinesterase Inhibitors (AChE))

§ Hallucinogenic Toxidrome:
• Symptoms include:
o Hallucinations
o Disorientation
o Panic
o Seizures
• Complications include:
o Hypertension
o Tachycardia
o Tachypnea
• Common culprits include:
o Amphetamines, Cocaine, Phencyclidine (PCP)
§ Opiate Toxidrome:
• Symptoms include:
o Altered mental state
o Dysphoria
o Lack of Responsiveness
• Complications include:
o Bradycardia, hypotension, hypothermia,
o *Respiratory Depression
• Common culprits include:
o Opioid drugs (eg: morphine, fentanyl, oxycodone)

§ Sedative/hypnotic Toxidrome:
• Symptoms include:
o Confusion
o Delirium
o Ataxia (inability to coordinate voluntary muscle movement)
o Deterioration of CNS function, coma
• Complications include:
o Apnoea
• Common culprits include:
o Benzodiazepines
o Barbiturates
o Anti-epileptic Agents
o Ethanol

Sympathomimetic Toxidrome:
§
• Symptoms include:
o Perspiration
o Hyperreflexia
o Anxiety
• Complications include:
o Hypertension, Tachycardia
• Common culprits include:
o Amphetamines, cocaine
o Ephedrine, pseudoephedrine
o Tyramine (in patients taking (MAOI)
- Very Common Adverse Drug Reactions:
o Paracetamol Poisoning:
§ Due to Hepato-Toxic Metabolite – NAPQI:
• Normally Conjugated by Glutathione – However, Glutathione stores can be
exhausted → Accumulation of NAPQI → Extremely HEPATO-TOXIC
§ Biochemical Investigations – Determine Severity:
• Paracetamol Levels
• LFT (Liver Function Tests)
§ Decontamination:
• Oral Charcoal → Binds & prevents absorption of more Paracetamol in the GIT
§ Antidotes:
• N-Acetylcysteine – (A Precursor for Glutathione)
• Or Methionine

https://commons.m.wikimedia.org/wiki/File:Paracetamol_metabolism.svg
o Digoxin Poisoning:
§ 2 Primary Purposes:
• Improve Contractility in Chronic Heart Failure
• Management of SVT (Supraventricular Tachycardia)
§ Toxic Effects:
• Cardio – Tachys/Bradys/Conduction-Blocks/Syncope (Fainting)/Palpitations
• CNS – Confusion/Lethargy/Hallucinations/Altered Vision/Facial Neuralgia
• GIT – Vomiting/Diarrhoea/Anorexia/Weight Loss/Abdo Pain
§ Acute – Due to Overdose
§ Chronic – Due to Hypokalaemia/Reduced Renal Function/Drug Interactions (Eg: Ca-Channel
Blockers/Tamoxifen/Neuromuscular Blockers)
§ Management:
• GI Decontamination:
o Oral Charcoal within 6 hours
• Digoxin Antibodies (Fab)
o Fab → Binds & Clears Digoxin
• Supplemental K+, Mg+2
o If Hypokalaemic
o K+ →↓Affinity of digoxin for Na+/K+ ATPase pump → ↓Tachycardias
• (Sometimes Ca+ Supplement):
o However care must be taken as it can ↑ the digoxin-mediated arrhythmias
• Management of Dysrhythmias:
o Conduction Blocks:
§ Atropine or Cardiac Pacing
o Asystole and Pulseless Electrical Activity:
§ Adrenaline or Atropine
o Bradyarrhythmias or Tachyarrhythmias:
§ Fab is treatment of choice
§ Bradys: Atropine, Dopamine, Adrenaline or Isoproterenol + Pacing
§ Tachys: Cardioversion or Defibrillation, with phenytoin (in its role as
Na+ channel blocker and ability to suppress automaticity)
o Aspirin (Salicylates) Poisoning:
§ 2 Most Serious Complications:
• “Reye’s Syndrome” in Infants:
o →Encephalopathy
o Vomiting
o Agitation
o Lethargy
o (Coma; if intracranial Hypertension →Death)
• Chronic Salicylate Toxicity in the Elderly:
o Severe Dehydration, Hypotension
o Encephalopathy → Altered Mental State, Seizures
o Hyperventilation
o Pulmonary Oedema
o (High Mortality)
§ Salicylism = “Toxic effects of overdose with Salicylic Acid”:
• Nausea
• Vomiting
• Tinnitus or Deafness
• Disorientation/Agitation/Hallucinations/Lethargy/Seizures/Coma
• Renal Failure
§ Decontamination:
• Oral Charcoal → Binds & prevents absorption of more Aspirin in the GIT
• OR Stomach Pumped in Acute Overdose
• OR Whole-Bowel Irrigation for enteric coated aspirin
§ Treatment of Brain-Related Symptoms:
• (Ie: Agitation/Seizures/Coma/Resp-Failure)
• Sedation, Paralysis, Intubation → Mechanical Ventilation

Source: http://www.emdocs.net/em3am-salicylate-overdose/
o Laxative Poisoning:
§ Those at risk of Toxicity:
• Accidental Overdose (Children)
• Laxative Abusers:
o Eating Disorders
o To Control Weight
o Elderly with Chronic Constipation
§ Stimulant Laxatives:
• Acute Toxic Effects:
o Nausea, Vomiting, Abdominal Cramping, Diarrhoea
o (Rarely Dehydration and Electrolyte Imbalances in Acute Toxicity)
o (Children – Possible Shock, Multi-organ Failure, Pulmonary Oedema,
Cerebral Oedema, Metabolic Acidosis)
o (Extreme cases in Adults can →Fatal Hepatic Failure and DIC)
• Chronic Toxic Effects:
o Watery diarrhoea
o Muscle weakness
o Hypokalaemia
o Chronic Constipation, may alternate with the Diarrhoea
o Bloating and Abdominal pain
§ Complications include:
• » GI bleeding, anaemia, pancreatic dysfunction, renal failure,
osteom alacia, m etabolic acidosis, hepatotoxicity
§ Osmotic Laxatives:
• Acute Toxic Effects:
o Carpopedal spasm (Spasm of the Hand/Foot)
o Lethargy due to hypocalcaemia
o (Severe Cases - Hyperventilation, coma, seizures, tachycardia, heart block,
diuresis, cardiac arrest)
§ Herbal Laxatives – (Mineral-Oil Based Laxatives):
• Can trigger Lipoid Pneumonia if the oil is aspirated into the lungs
§ Management:
• Acute Laxative Poisoning:
o Decontamination – Oral Charcoal
o Isotonic Saline – for fluid Imbalance; Then Dextrose
o Correct Electrolyte Disturbances
• Chronic Laxative Poisoning:
o Correct Electrolyte Disturbances
o Increase Dietary Fibre
o Increase Fluid Intake
o Psychiatric Evaluation – (If use relates to Eating Disorders)
o Antidepressant Poisoning – (Overdose is Common):
§ Toxic Effects:
• Delirium, Coma, Myoclonus/Seizures
• Sinus Tachy, 1st Degree Conduction Block, Ventricular Tachy, Hypotension
• Decreased Bowel Sounds/Motility, Urinary Retention
• Variable pupil diameter
§ Tricyclic Antidepressants:
• Management:
o (Note: Rapid Deterioration is common, therefore IV access, & Monitor Vitals)
o Decontamination: Activated Charcoal
o Ventilate if necessary
o Diazepam for delirium and seizures
o Antiarrhythmic Drugs –(Avoid: Class IA, IB Antiarrhythmics)

§ SSRIs – (Selective Serotonin Reuptake Inhibitors):

• Toxic Effects:
o Acute Toxicity:
§ Drowsiness
o Serotonin Syndrome:
§ Confusion, Agitation, Anxiety, Coma, Euphoria/hypomania,
Hallucinations,
§ Seizures, Myoclonus, Hyperreflexia, Muscle Rigidity, Restlessness,
Tremor, Teeth Chattering
§ Sinus Tachycardia, Ventricular Tachycardia, Hypotension
§ Tachypnea, , unreactive pupils,
§ Nausea, Diarrhoea, Abdominal Cramping
§ Hyperthermia
• Management:
o Overdose:
§ Activated charcoal
§ Benzodiazepines for Agitation/Seizures
o Serotonin Syndrome:
§ Fluids, Correct Electrolyte Disturbances
§ Benzodiazepines for Rigidity/Agitation/Seizures
§ External Cooling for the Hyperthermia (Antipyretics don’t work)
 Side Note: ‘Warrior’ Plants:

Drugs & Toxins:

- Many drugs started life as a Self-Defence Toxin produced by plants → Selective Advantage
o Tannins (eg: in tea leaves, coffee beans):
§ Impair digestion in insects, some small mammals
o Nicotine:
§ Insects consuming tobacco leaf die (primarily due to nicotine poisoning)
o Caffeine:
§ Mice that eat raw coffee beans become violently ill (gastrointestinal and CNS disruption)

- Structural Similarities Between Drugs & Plant-Derived Toxins:

o Eg: Alkaloids:
§ Morphine
o Eg: Glycosides:
§ Digoxin
o Eg: Oxalates:
§ Oxalic Acid = A Poison
o Etc

- Benefits Vs Toxicity:
o Many drugs are “Janus Figures” – (Ie: Have 2 Sides):
§ Medicinal Benefit:
• Small Amounts
• Hormesis Effect – Repeated low-dose exposure to toxin/stressful agent → Beneficial
o Whereas higher concentrations are stressful
o (Eg: Ischaemic Preconditioning → Protects heart against future ischaemias)
o (Eg: Alcohol Tolerance – White man Vs Indigenous)
§ Deleterious Effects:
• Large Amounts

- Note: Natural ≠ Healthy:

o Some of the world’s most potent poisons are natural:
§ Arsenic is Natural
§ Hemlock is Natural
o Also, Natural Therapies are fraught with danger:
§ No regulation of Dose
§ Inconsistent concentrations of active ingredients (Batch-Batch Variation)
§ Not Regulated
§ Many Contaminants
Toxicological Emergencies
Overview:
- ABCs for Toxicology
- Red Flags:
o Note: 2 Tablets can kill a 10kg child
o Be aware of the meds that are toxic
o “Nice” or “Nasty”
- Know where to get help:
o Poisons Information Centre

Causes of Toxic Syndromes:

- Accidental:
o Household Drugs/Toxins (Typically little children)
o Occupational Exposure – (Acute/Chronic)
- Intentional Self-Poisoning:
o Recreational
o Parasuicidal Gesture (Call for attention)
o Suicide Attempt
- Inappropriate use of Medication
- Envenomation

Toxidromes:
- Paracetamol Overdose:
o No “Toxidrome” & Mostly Asymptomatic
o → Secondary Metabolite is Highly Hepatotoxic
o Antidote: N-Acetyl Cysteine (*A Precursor to Glutathione – A Conjugator for Paracetamol)
§ Give if the Blood-Paracetamol Level is Above the ‘Toxicity Line’ @ 4hrs
§ (Small risk of Anaphylaxis)

- Cholinergic (Eg: Organophosphates – ACh-Esterase Inhibitors) – “SLUDGE”

o Salivation, Lacrimation, Urination, Defecation, GI Upset, Emesis
o Antidotes: Atropine (An Anti-Muscarinic) & Pralidoxime (An Ach-I-Inhibitor)
§ Note: Atropine can → VF/SVT/VT

- Anticholinergic Syndrome (Eg: TCA’s, Antihistamines, Atropine) – “Anti-SLUDGE”:

o Dry Mouth, Dry Eyes, Urinary Retention, Constipation, …
o TCA Overdose → Widening QRS + Right-Axis Deviation
o Antidote: Sodium Bicarbonate:
§ Works by preventing the combination of acid with the ionic form of TCA to form the TCA
molecule (which is absorbed by cells)
§ Also prevents the positive feedback loop of acidosis (which increases the level of TCA
M olecules)

- Extrapyramidal (Eg: Antipsychotics) - “TROD”

o Tremor, Rigidity, Opisthotonos (Abnormal Posture), Dysphagia (Difficulty Swallowing)

- Opioid:
o Triad: Coma, Respiratory Depression, Miosis (Pinpoint Pupils)
o Antidote: Naloxone (An Opioid Receptor Antagonist)
§ Given ASAP after overdose
§ Note: Naloxone is often shorter-acting than the Opioids taken :. Require constant infusion
• Wears off after 45mins
- Sedative/Hypnotic (Eg: Benzodiazepines):
o Triad: Coma, Respiratory Depression, Impaired Airway
o Antidote: Flumazenil (Rarely Used)
§ Note: If Patient is a Benzo Addict, Flumazenil can → Acute Withdrawal. :. Titrate Dose
- Sympathomimetic (Eg: Amphetamines, Cocaine):
o Paranoid Schizophrenia, Very Excited, Tachycardia, Hypertension

- Serotonergic (Eg: SSRI Antidepressants):

o Agitation, Confusion, Diarrhoea, Fever, Shivering, Tremor

- Withdrawal Syndromes (Eg: Alcohol/Sedatives (Benzos)/Narcotics):

o Restlessness, Irritability, Chills, Hallucinations, Confusion, Sympathetic Overactivity (Sweating,
Tachycardia, Hypertension), Seizures

Approach to the Poisoned Patient:

1) Primary Survey:
a. ABCD:
i. Airway (eg: Vomiting/Aspiration/Allergic Reaction → Swelling/Altered Consciousness → Loss
o f A b ility to m a in ta in A irw a y )
ii. Breathing (Eg: Too Much/Too Little)
iii. Circulation (Eg: Tachy/Brady/Hypertension/Hypotension) – (Monitor with ECG & BP)
iv. Disability (Conscious State)/Danger (What did they take/When/How Much)
b. Drug Manipulation (Decontamination &/Or Decrease Absorption/Specific Antidotes):
i. Ipecac (Induce Vomiting) - Minimal Use in ED
ii. Gastric Lavage (Useful within the 1st hour) – Now de-emphasized in ED
iii. Activated Charcoal
1. (Binds free drug in lumen of gut → ↓drug concentration → ↓Absorption)
2. Only effective for things that will bind (won’t bind small ionic compounds, heavy
m etals, or alcohols)
3. Very Time Dependent
iv. Whole Bowel Irrigation (Eg: Polyethylene Glycol – Golytley: An osmotic agent → Flushes
out bowel)
v. Skin Decontamination (eg: Organophosphate Poisoning)
vi. Left Lateral Position → Delays Gastric Emptying
vii. Cathartics (flush things through)
viii. Urine pH Alteration
ix. Dialysis
x. Chelation
c. Differential Diagnosis:
i. Impaired Conscious State (SMASHED):
1. S Substrate/Sepsis
2. M Meningitis/Mental Illness
3. A Alcohol/Accident (CVA/SAH/Subdural/CHI)
4. S Seizures/Stimulants
5. H Hypo/Hyper- (Thyroidism/Thermia/Glycaemia/Tension/Carbia)
6. E Electrolytes/Encephalopathy/Envenomation
7. D Drugs
ii. Don’t Forget Blood Sugar
iii. ECG: Screening for Lethal Toxicologies

2) Emergency Antidotes:
a. Paracetamol N-Acetyl Cysteine
b. Opiates Naloxone
c. Benzos Flumazenil
d. Ca Antagonists Insulin & Glucose
3) Secondary Survey:
a. Examination & History:
i. Directed History:
1. Who
2. What
3. Where
4. When
5. Why
6. How
ii. Systematic Examination:
1. Identify Problems
2. Recognition of Toxic Syndromes
iii. Focused Investigations:
1. BSL
2. ECG
3. Electrolytes
4. LFTs (liver function tests)
5. EtOH
6. ABG
7. FBE
8. Paracetamol Level
9. Toxic Screen
b. Education:
i. To Prevent Accidental Poisonings (eg: In kids)
ii. Put drugs in childproof containers
c. Funny Behaviour:
i. Underlying Psychodynamics:
1. Intent? – What did you think would happen?
2. Suicidal? – Do a “SAD PERSONS” score
3. Predisposing Psychiatric Illness (Eg: Psychosis, Depression)
Definitive Care:
a. Serious or Potentially Serious → ICU
4) b. Mild → Observe in ED
c. Self-harm → Psychiatric Evaluation
END