CLINICAL PHARMACOLOGY (SOME PRINCIPLES IN PHARMACOLOGY)

Clinical pharmacology is the science that deals with the interaction of medicines with the
body of healthy and sick people and is concerned with the rational, safe and effective use of
medicines. It deals with pharmacokinetics and pharmacodynamics. These constitute the major
subdivisions of clinical pharmacology.

Some principles in pharmacology

 Pharmacokinetics: is currently defined as the study of the time course of drug

absorption, distribution, metabolism, and excretion.
 Clinical pharmacokinetics: is the application of pharmacokinetic principles to the
safe and effective therapeutic management of drugs in an individual patient.

A. Pharmacokinetics
Pharmacokinetics is the quantitative study of drug movement in, through and out of the body.
It describe in a quantitative manner the passage of drugs through the body.
Intensity of response is related to concentration of the drug at the site of action, which in turn
is dependent on its pharmacokinetic properties. Pharmacokinetic considerations, therefore,
determine the route(s) of administration, dose, latency of onset, time of peak action, duration
of action and thus frequency of administration of a drug. All pharmacokinetic processes
involve transport of the drug across biological membranes.

 Pharmacokinetics’ Parameters
There are a series of distinctive parameters, which are considered in pharmacokinetic. These
parameters are used to describe the rate and extent of drug absorption into the bloodstream,
the rate and extend of drug movement out of the bloodstream into the tissues and the rate of
drug removal from the body (elimination).
Knowledge of pharmacokinetic parameters of drugs and patterns of their changes in a
particular patient allows you to choose the optimal dosing regimen and achieve its maximum
effect, maintain this effect for a necessary period of time and ensure minimal risk of
undesirable effects.
These parameters can be used to predict the blood concentration of a drug that will arise with
a given dosage regime. These parameters are;
 Bioavailability
 Volume of distribution
 Clearance of drugs
Bioavailability
Refers to the extent and rate at which the active moiety (drugs or metabolite) enter systemic
circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determine by the properties of the dosage form, which
depend partly on its design and manufacturer
Volume of distribution (Vd)
Is a theoretical concept that relates the amount of drug in the body (dose) to the concentration
(c) of drug that is measured (in blood, plasma, and unbound in tissue water). It can also be
defined as the ratio between total amount of chemical presents In the compartment at a given
time, A(t) and the concentration at a specific site at the same time, C(t)
A (t)
Vd ¿
C (t)
Clearance of drug
It is concerned with the rate at which the active drug is removed from the body. For most
drugs at steady state, clearance remains constant so that the drug input equals drug output. It
can also be defined as the rate of drug elimination divided by the plasma concentration of the
drug. Clearance is influenced by age and by disease, with a reduction in drug clearance being
associated with increase in the half-life of the drug and an increase in clearance being
associated with decrease half-life of the drug
EQUIVALENCE OF DRUGS
• Chemical equivalence: indicate that drugs products contain the same active
compound in the same amount and meet current official standards; however inactive
ingredients in drug product may differ
• Bioequivalence: indicate that the drug products, when given to the same patient in the
same dosage regiment, result in equivalent concentration of drug in plasma and tissues
• Therapeutic equivalence: indicate that the drug products, when given to the same
patient in the same dosage regiment, have the same therapeutic and adverse effects.

Pharmacokinetic Processes
The pharmacokinetic cycle consists of a series of phases considered sequentially, although in
real time they run in parallel, only predominating at certain times.

 The ‘‘ADME’’ of drugs

i. ABSORPTION OF DRUGS
Absorption refers to the passage of a drug substance through biological membranes into the
blood stream (or lymphatic system), which provides a resorptive (overall) action. Absorption
is influenced by the absorption surface area, blood flow and state of microcirculation at the
injection site, dosage form, lipid solubility of the drug.
NB:
This process arise from all forms of drugs used apart from IV injections only
In IV injections, the drug is administered directly into the bloodstream and consequently, this
route lacks the absorption stage
In topical application, the drug is applied to the intended site of and absorption into the blood
stream is not necessaire. However, it is good to remember that while absorption may not be
intended, in many cases, absorption still does take place and the drug may have effect
throughout the body. E. g corticosteroids in oilments and as in asthma inhalers.
It might be thought that no absorption stage is required for IM /SC injections as the drugs
have already been deposited into the body, however, we do not consider a drug to have been
absorbed until it reaches the bloodstream. An IM/SC dose need to undergo absorption into the
bloodstream.

Mechanisms by which drugs cross the biological membrane

Membrane crossing is accomplished by 5 mechanisms:
a. Passive (simple) diffusion
This is the commonest mechanism by which drugs cross the biological membrane.
Lipophilic low molecular weight compounds pass through biological membranes along a
concentration gradient, which depends on the degree of lipophilicity of the substance.
This is the most important mechanism of drug penetration and distribution in body tissues.
The drug penetrates the biological membrane passively at a rate proportional to the
concentration difference on either side of the membrane. No energy is required in this
process. If the drug is a weak acid, it will be in a non-ionised form in an acidic environment,
which improves its penetration through the biological membranes and should be administered
orally after meals, when the acidity of the gastric juice is at its highest. If it has weak basic
properties, however, it is better administered before meals (1-1.5 hours) or 1-2 hours after
meals when the acidity of the gastric juice is lowest.
b. Filtration (convectional transport)
This is the passage of drug molecules through the pores of membranes, which are small in
size due to small pore size (up to 1 nm on average). Apart from the size of molecules,
filtration depends on their hydrophilicity, dissociation ability, ratio of particle charge to pore
charge, as well as hydrostatic, osmotic and oncotic pressures. Water, some ions and small
hydrophilic molecules are absorbed this way.
NB:
Passive diffusion and, to a lesser extent, filtration serve as the main mechanisms of absorption
in the oral cavity, stomach, colon, rectum and from the skin surface.
c. Active transport
This is via the transport systems of cell membranes (carrier molecules), requires energy and
can run against the concentration gradient. This mechanism is characterized by selectivity,
competition of different substances for one carrier and "saturation". The latter lies in the
inability to exceed a certain rate of the process, which is limited by the amount of carrier and
does not increase with a further increase in the dose of the absorbed substance. In this way,
hydrophilic polar molecules, a number of inorganic ions, sugars amino acids etc. In children
and elderly people this way of drug penetration functions poorly.
d. Facilitated transport
This is similar to active transport. It can go against the concentration gradient, but is not
accompanied by energy consumption. The transport systems of this mechanism are strictly
specific for each substance (for example for vitamin B12).
e. Pinocytosis
This is similar to phagocytosis: the uptake of the drug substance results from the invagination
of the cell membrane to form vesicles that migrate along the cytoplasm to the opposite wall
and empty out. In this way, drugs of polypeptide structure and large molecular weight enter
the cells.

ii. DISTRIBUTION OF DRUGS

This refers to the movement of drugs backward and forward between the bloodstream and the
various tissues of the body.
Binding to blood proteins.
Many of the drugs have a pronounced physico-chemical affinity for macromolecules,
whereby, once in the blood or lymph, they bind to proteins and are present in the blood as two
fractions: free and bound. Most drugs (salicylates, penicillins, sulphonamides and many
others) bind to the main serum protein, albumin. To a lesser extent globulins, acidic alpha 1-
glycoprotein and lipoproteins take part in this process, formamen. Some drugs bind to more
than one structure at the same time.
Only the free, unbound fraction of the drug is pharmacologically active. Only it is able to
penetrate through cell membranes, influence specific targets, undergo transformations by
enzymes or be excreted from the body.
The drug-protein bond is rather fragile and the formation and disintegration of the
"formation” and disintegration of the drug-protein complex occurs rapidly. Due to this fact,
free and bound fractions are in equilibrium: in bound form, the drug circulates in the blood
until the concentration of free fraction decreases, after which it is released, thus ensuring the
stability of the plasma concentration. In other words, once bound to blood proteins, the drug
forms a depot. Protein binding becomes clinically relevant if it exceeds 80-90%.
Distribution in the body.
During this phase of the pharmacokinetic cycle the drug is distributed by blood throughout the
body, penetrates into interstitial spaces, reaches the cells and accumulates in different tissues
and organs. As a result of distribution, the drug reaches its target, binds with it and takes
effect. The distribution process continues until the speed of the drug in the tissue compares
with the speed of its return from the tissue into the bloodstream. When these velocities are
equal, there is a state considered steady state, and concentration of the substance in the blood
at this time is called equilibrium.
The distribution of drugs in the body is never uniform, which depends on a number of
physiological (pathophysiological) and pharmacological factors.
Among the properties of the drug that determine the nature of distribution, one can distinguish
factors that determine the absorption capacity of the substance (overcoming biological
barriers during distribution occurs according to the same laws as during absorption), affinity
(affinity) to individual tissues (which determines the preferential accumulation of the drug), as
well as binding to blood proteins. Hydrophilic substances have a low volume of distribution;
lipophilic substances have a high volume of distribution.
The distribution of drugs can vary considerably depending on a number of characteristics of
the body itself:
- The intensity of regional blood flow under physiological conditions (the heart,
liver, kidneys and endocrine glands are most actively supplied with blood);
- Membrane permeability and associated barriers (eg, membrane permeability (e.g.
blood-brain barrier, placental barrier) for this substance under normal and
abnormal conditions
- Hemodynamic and microcirculatory disturbances due to stress, shock and chronic
cardiac insufficiency, which cause a decrease in blood flow of organs that are
intensively supplied with blood
- presence of congestive and inflammatory effusions in the cavities, in which
hydrophilic drugs can accumulate).
The blood-brain barrier is a mechanism by which the exchange of substances between the
systemic bloodstream and the cerebrospinal fluid is highly selective.
There are a number of characteristics to describe the distribution process, the most important
of which are:
Distribution volume (apparent distribution volume): is the hypothetical volume of fluid
required to evenly distribute the entire amount of a drug at a concentration equal to its
concentration in blood plasma (usually calculated as specific distribution volume per unit
body weight). It reflects the degree of tissue uptake of the drug from blood plasma and relates
the amount of drug in the body to its concentration in blood.
The equilibrium (steady-state) concentration (Cs): is established in blood when the drug
enters the body at a rate equal to its elimination rate, which can be achieved either by constant
intravenous infusion or by administering the same dose at equal time intervals.

iii. METABOLISM OR BIOTRANSFORMATION OF DRUGS

When a drug is introduced into the body, processes are involved to break it down and excrete
it from the body. Some water soluble drugs are excreted unchanged by the kidneys, others are
affected by enzymes.
Biotransformation (metabolism) is a universal concept reflecting the chemical changes to
which xenobiotics (foreign substances, including drugs) undergo in the body.
The basic biological idea of biotransformation is to free the organism from the xenobiotic
either through its utilization as an energy or plastic substrate, or by converting it into a form
suitable for excretion. The relevant biochemical processes could therefore be regarded as a
detoxification system, but such a view would be too simplistic.
Firstly, the toxicity of many xenobiotics is not due to the substance itself, but products of its
biotransformation. This is also true of drugs. For example, the toxicity of lidocaine is
determined by the formation of xylidide monoethylglycine during its biotransformation.
Secondly, a large number of drugs have active derivatives (metabolites), pharmacological
activity of which is comparable or significantly higher than that of the original substance. For
example, the activity of 4-hydroxy-propranololol, formed in the liver during first passage, is
comparable to that of propranolol itself (anapriline, Obzidan); however, as the former has a
shorter half-life, different routes of administration result in different efficacies.
In some cases, some drugs can be transformed into substances used as other drugs: e.g,
codeine can be transformed into morphine or theophylline (in newborns) into caffeine.
Thirdly, there are a number of drugs which, while not pharmacologically active themselves,
are transport agents of sorts. They are metabolized to pharmacologically active substances
only after absorption and passage through the liver, e.g. the mucolytic bromhexin, or when
ingested, e.g, the antiviral drug acyclovir. Such drugs are called prodrugs.
Drugs are biotransformed in many organs. In descending order of importance, the organs and
tissues involved in biotransformation can be arranged as follows: liver, stomach, intestines,
kidneys, lungs, skin, and brain. The adrenal glands, smooth and striated muscles, vascular
endothelium, blood, etc. may also be involved in this process.
Two stages (two phases) are distinguished in biotransformation reactions, each of which may
be of independent importance.
- In the first phase, the drug undergoes oxidation, reduction or hydrolysis.
A key role in this phase is played by the cytochrome P450 isoenzyme system, the main
oxidizing system of the body, associated with the endoplasmic reticulum (endoplasmic or
microsomal system). Liver and intestinal cells are particularly rich in enzymes of the
cytochrome P450 system.
The most important properties of this system are:
- The ability to biotransform almost all known chemical compounds
- The ability to bind molecular oxygen
- High inductivity (increase in enzyme activity under the influence of external
factors).
- Selective induction of certain isoenzymes and more or less non-selective induction
are possible. The latter can occur under the influence of alcohol and tobacco-
smoke ingredients, which can significantly reduce the efficacy of many drugs in
people with so-called bad habits
It is important to emphasize not only the induction but also the inhibition of enzymes in this
system (e.g. by acetic aldehyde, which is formed during ethanol reduction under the influence
of alcohol dehydrogenase).
Although, as stated, the ultimate goal of biotransformation is "detoxification', epoxides and
nitrogen-containing oxides can be formed from drugs that can react with proteins, damaging
them and making them foreign to the body. This triggers an immune response and an auto
aggression process. By damaging cell membranes, disrupting nucleic acid synthesis, epoxides,
nitrogen-containing oxides and some other metabolites cause the processes of carcinogenesis,
mutagenesis or teratogenesis. Examples of such potentially dangerous drugs include
diphenhydramine (dimedrol) and trimethoprim (part of the co-trimoxazole combination drug
biseptol, bactrim, etc.).
- The second stage is the completion of detoxification.
As a result of the formation of conjugates with residues of inorganic and organic acids,
including amino acids (sulphuric, acetic, glucuronic, glutamine, glycine, glutathione) or
methyl groups, the drugs almost completely lose their pharmacological activity and, becoming
water soluble, are eliminated with urine or bile. It should be particularly emphasized that
when each of the phases acts as an independent biotransforming system (e.g., oxidation of
alcohol to carbon dioxide and water or acetylation of sulfonamides), high activity of one of
them is usually combined with low activity of the other (which is genetically determined). For
example, a very high percentage of "fast acetylators" among indigenous northern peoples is
combined with a low capacity for oxidation of xenobiotics and poor tolerance of alcohol.
The biochemical processes of both stages I and II depend on the functional state of many
body systems: the nature of tissue oxygenation, the state of hepatic blood flow (its reduction
can lead to slower biotransformation), the protein and synthetic function in general and the
activity of enzyme synthesis in particular, etc.
Since the activity of protein and enzyme synthesis changes with age, a decrease in
biotransformation of xenobiotics is observed in older age groups (which requires special
caution when dosing them).
Since biotransformation is most active in the liver, all drugs can be divided into
those with high and low hepatic clearance
 iv. ELIMINATION OR EXCRETION OF DRUGS
Drugs can be excreted from the body with any fluids (urine, saliva, sweat, bile, breast milk,
etc.) and volatile ones (gaseous and volatile anaesthetic fluids, essential oils such as
camphor). Also with exhaled air. In practice, however, for the vast majority of drugs the
kidneys and the gastrointestinal tract are clinically important as a route of excretion.
Depending on their hydrophilicity or lipophilicity, their ability to be filtered, secreted and
reabsorbed in the kidneys, their ability to be secreted into the bile and their absorption in the
gut, medicines and their derivatives (if biotransformed) are excreted by one of these two main
routes.
Excretion of drugs with milk is important in breastfeeding mothers and with saliva is
important in the development of adverse oral effects.
- Renal excretion of drugs and their metabolites includes filtration, secretion and
tubular reabsorption.
- The second most important route of excretion is by the GI tract. The entire
volume of the drug excreted by this route consists of several fractions:
 the portion of the dose that has not been absorbed into the GI tract (unchanged);
 unchanged substance and, more often, its derivatives that are secreted by the liver into the
bile and excreted with the bile into the intestinal lumen;
 part of the dose that has been biotransformed in the stomach and intestine (as derivatives);
 unchanged substance or its derivatives excreted by the stomach or intestinal wall.
The first two fractions are of primary clinical importance, as they determine the greatest
volume of drug excretion by this route. Bile excretion is not limited by the high molecular
weight and protein binding. However, this route also has its limitations. In particular, the
substance excreted with the bile into the intestinal lumen can be re-absorbed. This applies
especially to glucuronic acid conjugates, which can be hydrolysed by the intestinal flora,
whereby the originally released substance can be re- absorbed and partly reabsorbed into the
systemic blood stream and partly reexcreted by the liver. This phenomenon is called
enterohepatic circulation or hepatic recirculation.
.
Elimination is generally characterised by an index called clearance (Clgen).
In practice, this indicator is important for the calculation of maintenance doses.
This indicator is important for the calculation of maintenance doses (D-sustained) of difficult
to administer drugs such as digoxy or theophylline. The maintenance dose should equalise the
excretion rate and the rate of drug intake, i.e. turn the achieved concentration into the
equilibrium concentration (CSS):
For most drugs, total clearance is a constant and concentration-independent value. However,
for some, e.g. phenytoin (diphenin), acetylsalicylic acid (aspirin), clearance is not constant
and elimination is a saturable, dose- and concentration- dependent process.
Total clearance is made up of hepatic and renal clearances of the drug.
Pharmacokinetics is therefore the mathematic modelling or calculation of the rates and
completemess of the 4 components of ‘ADME’. In other to predict blood levels of drugs that
will arise from a defined dosage regime. The practical values of pharmacokinetics rest on
assumption that the drug effect depends on the blood concentration of the drug. We assume
that as drug level rise, we see 3 phases
- Too low: when the concentration of the drug in the blood is too low, the drug qill
be ineffective( too low = ineffective + no side effect)
- Optimal phase: this is the level where the concentration of the drug in the blood is
optimal and acceptable. At this level, the drug becomes effective but the risk of
side effects remains terribly low ( optimal= effective +low side effects)
- Too high: here, the concentration of the drug in the blood is too high; the rate of
side effects becomes excessive despite the effectiveness( too high = effective +
high side effects)

B. Pharmacodynamics
Pharmacodynamics studies biological and therapeutic effects of drugs on the body, their
mechanism of action. The pharmacodynamics properties define the group to which a drug
belongs and are crucial in selecting a drug for the treatment or relief of symptoms of a
particular disease.

 THE MECHANISMS OF ACTION OF THE DRUGS.

The actions of drugs are determined by their ability to influence the general reactions of the
body and the individual links of biologically important processes. This effect is mediated
through controlling systems: receptors, enzymes, transport systems, specialized
macromolecules, such as DNA. Some drugs interact with a number of controlling systems,
causing many pharmacological effects, other drugs bind only to specialized cell components,
modifying their function and that of the system they control. Biologically, they are more
selective and have a specific structure, by making small changes to which the nature of their
action can be significantly altered.
TYPES OF MECHANISMS OF ACTION OF DRUGS
Several types of mechanisms of action of drugs can be distinguished.
1. Action on specific receptors.
Most receptors are protein macromolecules that are selectively sensitive to specific
chemical compounds. Drugs that directly stimulate or increase functional activity of a
receptor are called agonists (stimulants), and drugs preventing interaction of endogenous
and exogenous agonists with receptors are called antagonists (blockers). Some drugs that
block a receptor can also partially stimulate it, i.e. they have both agonist and antagonist
properties. They are called partial agonists.
The receptor type of interaction also includes the effect of drugs when they bind to the cell
genome (steroid hormones, vitamins A and D).
The speed and strength of drug binding to receptors is referred to by the term 'affinity'. When
receptor affinity is high, the desired effect is achieved at low drug concentrations. When the
dose, and therefore the drug concentration, is increased, the drug binds to receptors to which it
has a lower affinity, leading to Increasing the number of pharmacological effects, decreasing
the selectivity of the drug action.
The number of receptors in the body varies according to individual differences, age and
different diseases. Depending on their sensitivity to natural mediators and antagonists,
receptors are divided into cholinergic (acetylcholine-sensitive), adrenergic, histamine,
dopamine, opioid, etc.
2. Interaction with enzymes.
Drugs may have a structure similar to the natural substrate and compete with it for the
enzyme, thus inhibiting it and blocking the formation of biologically active substances. For
example, the covalent binding of acetylsalicylic acid to cyclooxygenase irreversibly inhibits
the platelet enzyme, as it lacks the system that synthesizes the new protein. Therefore, small
doses of this drug have a persistent and pronounced anti-aggregation effect.
3. Physico-chemical effect on cell membranes.
Certain drugs, e.g, agents for general anesthesia and local anesthesia alter transport of ions
through cell membranes by altering the transmembrane electric potential, thus affecting nerve
and muscle cell activity.
4. Direct chemical interaction.
Drugs can interact directly with molecules and ions. For example, interaction between
antacids and hydrochloric acid, the action of many antidotes for chemical poisoning.

TYPES OF DRUG ACTION

The action of drugs, depending on how they are administered, may be systemic (generalized)
or local (localized). The latter effect occurs when using ointments, creams, powders, rinses,
applications. If the drug penetrates the blood and other body fluids, its pharmacological effect
may appear anywhere in the body. This should be considered by dentists as the oral mucosa is
an ideal site for absorption. The main effect of a medicine is the one that is used for
therapeutic purposes in a given patient. Other pharmacological effects are called secondary
effects. If they cause functional impairment, they are considered adverse effects (AEs).
In various cases the same effect may be considered primary and secondary, e.g. anesthetic and
antiarrhythmic effect of lidocaine. There is also a reflex effect, when the drug effect is
mediated by physiological reactions of the nervous system and is associated with irritation of
sensitive endings in the skin, mucous membranes or vascular walls.
Depending on the breadth of the spectrum of action, the drugs can be divided into those with
specific and non-specific effects. The latter include those that have a wide range of
pharmacological effects and affect different biological support systems. It is usually very
difficult to identify and accurately assess their effects. These include vitamins
As a rule, if a drug has low selectivity and acts on many tissues and organs, it may cause a
greater number of adverse reactions.
If a drug affects the receptor apparatus of certain systems as an agonist or antagonist, its
actions are considered specific.

MEDICATION DOSING
The therapeutic as well as the toxic effects of the drug are highly dependent on the dose. Drug
dosage is influenced by factors such as age, sex, body weight, physiological condition, co-
existing conditions, drug interactions. The dosing regime (amount of drug administered and
frequency of administration) allows individualization of therapy according to the
pharmacokinetic characteristics of the drug in a particular patient. A distinction is made
between:
Single dose - the amount of a drug per administration;
Daily dose - quantity of medication taken during a day;
Ccal dosage - quantity of medication taken during a whole course of treatment;
Average therapeutic dose - drug dose most frequently used in therapeutic practice;
Loading dose - when it is necessary to quickly build up high blood concentrations of a
medication, the first dose (loading dose) is higher than the subsequent ones;
Maintenance dose - the amount of medication needed to maintain therapeutic drug
concentrations in blood.
The highest single dose - the amount of medication to be used when the therapeutic effect of
the average single therapeutic dose is insufficient;
Therapeutic upper daily dose - quantity of medication used when the therapeutic effect of
the average daily therapeutic dose is insufficient;
Toxic dose - quantity of medication causing toxic effects;
Lethal dose - the amount of medication that causes death.
The efficacy and safety of the drug also depend on the dose.
Definitions
a. Effective dose ( ED50): this is the dose of a drug that produces 50% of maximum
response or the dose that produces a specific response in 50% of subjects
b. Lethal dose (LD50): this is the dose of a drug that is lethal (kills) to 50% of
subjects. Lab animals are used to determine the LD
c. Therapeutic index (TI): it is the safety of a drug. The higher the TI value, the
safer the drug. It’s the measure of the safety of a drug
L D 50
TI =
E D50
 d. Onset of a drug action: this is the time required for effects of the drug to begin.
Onset is short if a drug is given IV and longer if oral due to absorption barrier
e. Duration: this is the length of time a drug effect last and it is related to a drug’s
half life (T1/2)
f. Half life (T1/2) of a drug: this is the time required for the serum concentration of
a said drug to decrease by 50% of its initial concentration.
g. Potency: this is the amount of drug needed to produce an effect. The more the
potent agent is, the lower the effective dose needed to produce an effect
Potency is inversely proportional to dose effectiveness
h. Efficacy: this is the desired effect elicitated by a drug. It is not dose dependent
i. Therapeutic effect: it is the desired pharmacological effect

3. LOCAL ANESTHESIA
This is the temporal abolition of pain sensation of a region of the body using a local anesthetic
agent.
Characteristics of an ideal local anesthetic agent
 It should be potent
 It should be reversible
 It should have no systemic anesthesia
 It should have no localn or systemic allergic reaction
 It should have a rapid onset
 It should have a satisfactory duration
 It should be able to penetrate tissues adequately
 It should be of low cost
 It should be stable in solution, that is long self-life
 It can be sterilized by autoclaving without denaturing the drug
 It should be metabolized and excreted easily
Chemistry of local anesthesia agents (LAA)
LAA has 3 components common to all
i. The aromatic ( lipophilic) group
ii. The intermediate chain
iii. The hydrophilic amino group

 The aromatic ( lipophilic) group

This is the component that contain the benzene ring and dissolved readily in lipids that are in
the cell membrane
 The intermediate chain
It contains either an ester (mostly typical) or an amide (most commonly used). This
intermediate chain determines the type of the LA. If it contains an ester, then the LAA is an
ester type or group of LAA, and if it contains an amide group, the LAA is an amine type of
LAA.
 The hydrophilic amino group
This is an amino group, which is water-soluble
Examples of intermediate chain ester LAA
These are mostly topical LAA and includes
- Cocaine
- Ethylaminobenzoate (Benzocaine)
- Tetracaine (Pontocaine)
- Procain (Novacaine)
- Propoxicain(Ravocain)
Examples of intermediate chain amide LAA
- Lidocaine (Xylocaine)
- Mepivacaine (Carbocaine)
- Prilocaine (Citanest)
- Bupivacaine (Marcaine)

Mechanism Of Action LA
Nerve fibers susceptibility
Nerves and sensations are generally abolished in this order; autonomic, temperature (cold and
warm), pain, touch; pressure, vibration, proprioception, and motor sensation (sensory). Nerve
functions are also regain in reversed order.
Specific- receptor theory
Anesthetic agents bind to receptors on the sodium channel. Permeability to sodium ions is
decreased when nerve conduction is interrupted. Base and salts forms of LA are both needed.
The base penetrates lipid membrane and the salts transverse the cellular fluid. In this theory,
the pH determine the amounts of salt and base on each sides of the equilibrium equation
Inflammation reduced LA effect
Acid environment (pH 5.5) of inflammation increases ionized form and decrease anesthetic
effects
Oedema dilute LA because of fluids present
Increase tissue vascularity and hence increase blood circulation carries away LAA, therefore
duration of action is shorten
Pharmacokinetics Of LAA
1. Absorption
a. Effect on vasculature (blood vessels)
They produce vasodilatation (except cocaine). Vasoconstrictors are therefore added to
counteract vasodilators and thus produce vasoconstriction.
b. Absorption and distribution
Absorption and distribution of LAA are determined by the pH of the environment.
Inflammation leads to decrease pH (more acid), this leads to more ions and thus changed form
of LA
c. Solubility
Lipid soluble non- ionized forms penetrates cell membranes while water soluble ionized
forms traverses cells and exert its effect on the nerve

Rate Of Absorption
a. Fast absorption
The faster the rate of absorption, the greater the chance of systemic activity and the shorter the
duration of action
b. Rate of administration
The rate of administration alters the rate of absorption. Topical LAA can be absorbed easily
Distribution Of LAA
Levels of LAA in the body is determined by, movement of LA around the body. Side effects
occur if LA reaches a high enough level in other organs (CNS, heart, etc.)
Blood level of LAA is determined by;
- Rate of injection
- Speed of absorption depends on proximity to blood vessels
- Speed of distribution to other organs
- Metabolism (biotransformation) of LAA
a. ESTERS
There are hydrolyzed by plasmapseudocholenesterases in blood and are not dissolved in the
kidney/ liver
Procaine: there are metabolized by paraaminobenzoic acid in the kidney
In congenital cholinesterase deficiency, the LAA containing esters are contra-indicated
b. AMIDES
They are metabolized in the liver hence liver functions must be healthy/ perfect. LA
containing amides should be given cautiously because they may be metabolized more slowly
and toxic levels can build up if repeated doses are given.
Prilocain (citanest); is metabolized to orto-toludine which can produce
methaemoglobinaemia (which is a situation where the Hb is trapped by methyl and resulting
to a low oxygen carrying capacity thus anemia)

PH And Inflamed Tissues

When the pH of the inflamed tissue is low, pH 5-6, more cations exist and therefore more
sodium ions is bound at the nerve receptor site. Less diffusion into surrounding tissues causes
slower onset and hence ineffective anesthetic. The surrounding tissues are not able to buffer
more acidic solutions because of lower pH.
Effects Of LA On Respiratory System
LAA relaxes the action of bronchial smooth muscles even at a non- over dose level
At over dose levels, it can lead to respiratory arrest, which is secondary to CNS depression
Excretion Capacity of LAA
Esters are almost completely hydrolyzed before being excreted. Amide also are almost
completely metabolized before being excreted. In the presence of a significant renal disease,
LA metabolites can accumulate.
Adverse Reaction Of LAA
Factors influencing toxicity
- Drug concentration
- Mode of administration
- Vascularity (tissues inflammation)
- Vasoconstrictor
- Weight of patient
- Rate of metabolism and excretion
Symptoms Of LAA Toxicity
The CNS and CVS are affected and the severity of effect is related directly to the amount of
LA in the blood stream
The CNS Response To LA Toxicity
The response to LA toxicity is firstly stimulation followed by depression. The CNS
stimulation is excitatory and produces restlessness, shivering, tremors and confusion
The CNS depression results in sedation, drowsiness, respiratory and CV depression. The CNS
depression can occur without previous excitation

The CVS Response To LA Toxicity

Anti-dysarrythemic action: this is so because lidocaine is used in the treatment of
dysarrythmia
Vaso-dilation produces hypotension: this is achieved by releasing vascular smooth muscles,
which then lowers resistance to blood flow
TOXICITY
The higher the number of LA cartridges, the more likely the LAA will be toxic. ‘Absolute’
toxicity considers only the drug dose of the LAA whereas ‘relative’ toxicity considers the LA
available in the blood stream.
DOSE CALCULATION OF LA
Dose calculation is based on;
- Size of patient
- General health of the patient
- Type of LAA
- Concentration of LAA
- Vasoconstriction
Dose calculation for LA depends on;
- Maximum recommended dosage foe each LA
- Weight of patient
- Anesthetic %
NOTE
 To change % in gram of LAA to milligram, first divide by 100 and then multiply
by1000
 To find maximal recommended dosage of LA, multiply patient’s weight by
established maximum recommended dosage in Mg
 To find ml of anesthetic solution, divide the maximum recommended dosage in mg by
mg/ ml of LA solution
 To find the number of cartridges in maximum, recommended dosage ml of solution of
anesthetic solution, divide by 1.8 ml / cartridge (or 2ml if the cartridge is 2ml)
EXAMPLES
1. Change 2%g of LA to mg
Solution
2%
×100=20 mg /ml
100

2. Convert 2% of LA to mg/ml of LAA cartridge

Solution
2%
×1000=20 mg/ml
100
20mg/ml ×1.8ml/car = 36 mg/ml/car
 OR
20mg/ml ×2ml/car = 40 mg/ml/car
3. Find the Maximum recommended dosage (MRD) of 2mg/kg body weight of a patient
who has 60kg
Solution
MRD = 2×60 = 120mg for the patient
4. Calculate the maximum number of cartridge which the patient will need
Solution
MRD/ml 6 ml
= =3.3 cartridges
1.8 ml 1.8 ml

TOPICAL ANESTHESIA
There are useful for providing light localized anesthesia to ta depth of 2-3mm of mucosa
It is given before injection of LAA by means of a needle

ACTION OF TOPICAL ANESTHESIA

Most topical anesthetics have a high concentration of injectable anesthetics and are thereby
increase diffusion of the active ingredient through the mucous membrane or in open wounds.
They get to free nerve endings lying 2-3mm below the surface

POINTS TO NOTE ABOUT TOPICAL ANESTHESIA

- They do not contain vasoconstrictors
- Efficient diffusion of topical anesthetic leads to faster onset of action
- Increased water solubility increases diffusion and onset while water insolubility
decrease diffusion and onset of action but increases the duration of action
- Without vasoconstrictor, the duration is decreased but the potential for over dose is
increased, because of the faster washed off of LAA into the blood stream
- Increase concentration increases the potential for over dose because of the uptake of
LA into the vascular system is greater.
TYPES OF TOPICAL ANAESTHESIA
There also come as esters and amides forms
E.g. Of Esters Groups
- Benzoccaine
 - Tetracaine
They come in liquid, gel, oilments, spray
Their onset is faster; duration of action is from 15-20minutes
E.g. Of Amide Groups
- Lidocaine based
They are 2 types of lidocaine based topical anesthesia;
- Xylocaine
- Alphacaine
They come as oilments and spray
They should not be used in non- intact skin (broken tissues)
- Lidocaine hydrochlorides E.g. lidocaine
They come in gel or liquid
Duration of action is about 15minutes