Basic Concepts of Pharmacology

Pharmacology

It is the science of drugs and its physical and chemical properties and their affect on the body and
how they interact with other substances.

Pharmacology can be divided into 3 sections:

1. Pharmacokinetics: deals with the absorption, distribution, biotransformation and excretion
of the drugs and its metabolites from the body.
2. Pharmacodynamics: deals with the biochemical and physiological effect of the drug as
well as its mechanism of action.
3. Pharmacogenetics: is the study of the role of genes in determining the drug metabolism.
Drug

A drug is anything chemical that enters the body and has some physiological effect on the body.
It is not necessarily a compound that provides a therapeutic effect.

A drug is a molecule that has a specific action on the body that is independent of its source –
synthetic or natural.
Drugs can be used for treatment as follows:

1. Cure and hence taken only for a short period of time e.g. antibiotics Control and needs to
be taken long term e.g. Insulin
2. Alleviate symptoms and these do not cure e.g. analgesics.

Examples of drugs include paracetamol and aspirin

Naming of a Drug

Chemical Name
Derived from the drugs chemical structure and used very rarely. For example the chemical name
for paracetamol is N-(4-hydroxyphenyl)acetamide.
Generic Name

Is the official simplified chemical name of a drug and describes the most active constituent of the
medicine. For e.g. the generic name of paracetamol is acetaminophen.

Brand Name

Is the commercial name under which the drugs are sold. Patent laws apply and can be used only
by the company that has registered it. For e.g. tylenol is the brand name of paracetamol.

Group Name

Describes the drug class to which the drug belongs and this name also reflects the
pharmacological action of the drugs or the therapeutic area of the drug action. For e.g. analgesic
is the group name for paracetamol.

Side effects and adverse effects of the drugs

Side effects are the physiological effects that are not related to the desired drug effect. They are
predictable. They are unavoidable since the action of the drug may not be highly targeted and
influence other organs or tissue parts.

Adverse reaction or adverse effects: are more severe than the side effects and is an
undesirable effect of the drug that can range from mild to severe toxicity and hypersensitivity
reaction and anaphylaxis. All such reactions should be documented and reported for further
analysis. In New Zealand these are documented with the Centre of Adverse Reaction Monitoring
(CARM).
Drug Action

Therapeutic Dose

Is the smallest amount that will elicit a response and the largest dose that can be tolerated without
excessive side effects.

Therapeutic Window

Is the gap between the dose needed to produce its effect in 50% of the population and that needed
for the undesired effect.

Therapeutic Index

Estimates the margin of safety of the drug.

 Narrow: means a narrow margin of safety e.g. Gentamicin, digoxin

 Broad: means a wide margin of safety. E.g aspirin.
Therapeutic drug monitoring is necessary for drugs with a narrow therapeutic index and the
reason for this is that the gap between the amount of drug required for a therapeutic effect and
the amount of drug that causes unwanted effects is very small. Hence when these drugs are given
from one patient to another their effect may vary and hence needs to be monitored each time to
ensure that the drug is having a therapeutic effect and not a adverse reaction. Drug monitoring
may vary from person to person. When a person has just started the medicine drug monitoring
will be more rigorous.

Prescription drugs

Are medicines that need to be prescribed by an authorized person such as Midwives, nurses,
pharmacists, physiotherapists, doctors.

Over the counter drugs

Are available to general public in the pharmacy and the supermarkets.

Pharmacy

Only drugs: can be sold in a community or hospital pharmacy and in an isolated shop that is
licensed to sell such drugs. Different to restricted drugs as these medicines can be sold without
prescription, but should be sold only by a registered pharmacist and should be recorded.

Tolerance

Decreased response to the drug and it is when the dose of the drug should be increased to
achieve the same effect.

Dependence

Is when the patient needs the drug to function normally. Two types of dependence:

1. Physical dependence: develops with an ongoing exposure e.g. cancer patient

2. Psychological dependence: is when the persons mind says that “ I need the drug” e.g.
cup of coffee.
Withdrawal

Occurs when no longer the drug is given to a patient and the side effects of not getting the drug
are visible.

What are Drugs?

Any chemically designed substance which is used to cure, treat, prevent or diagnose any disease
in humans or animals as well is known as drugs. If a chemically created agent promotes physical
and mental well being, then that can also be classified as a drug or a pharmaceutical agent.
Basically, they alter the physiology of the host’s body.
Chemically synthesized drugs have a low molecular mass and low atomic mass as well. When
consumed, drugs enter the body and interact with macromolecules and generate some form of
biological response. When this response is positive, desired and useful then such chemicals come
to be known as medicines.

One important factor to remember, drugs in large doses are considered poison. They can create
toxic reactions in the body and cause serious damage, even death. Certain drugs can also be
addictive and lead us to form bad habits. And there are certain drugs that are so very harmful, they
have been deemed illegal by most societies. Let us now understand the classification of drugs.

Drug Classification

How Are Drugs Classified?

Drugs are classified chemically according to how they affect the brain and the body. Common
classifications include stimulants, depressants, hallucinogens, and opioids. Additionally, the DEA
legally classifies drugs into schedules (I, II, III, IV, and V) based on their medical use and potential
for abuse and dependence.

Drugs can be categorized in a number of ways. In the world of medicine and pharmacology, a
drug can be classified by its chemical activity or by the condition that it treats. Anticonvulsant
medications, for example, are used to prevent seizures, while mucolytic drugs break down mucus
and relieve congestion.

With regard to addiction treatment and rehabilitation, the drug classifications used most often are
the following five classes regulated by the Controlled Substances Act:

 Narcotics
 Depressants
 Stimulants
 Hallucinogens
 Anabolic steroids

All of these drugs, with the exception of anabolic steroids, are considered to be psychoactive –
meaning they affect one or more of the mental faculties including mood, feelings, thoughts,
perception, memory, cognition, and behavior. Additionally, use of these drugs can be associated
with a host of physical, mental health, and personal complications, including alcoholic liver
cirrhosis, cannabis-induced psychosis, social problems like stigma, occupational difficulties,
financial problems, and even legal problems.

According to the U.S. Drug Enforcement Administration (DEA), substances from any of these
classes may lead to the development of chemical dependence in one or both of the following
forms:
  Physical dependence to a drug suggests that the body has become habituated to the
presence of a drug. Consequently, physical dependence is reflected in both the
development of tolerance and the presence of a withdrawal syndrome. Tolerance refers
to reduced effects compared to what was experienced with a previous amount of the
substance. Withdrawal develops when excessive or prolonged use of a drug is sharply
reduced or stopped. The onset of withdrawal often prompts the dependent individual to
resume use of the drug (or one similar to it) to avoid withdrawal. For example, withdrawal
symptoms such as shaking, sweating, nausea, vomiting, or seizures may occur once
alcohol use is stopped after regular or excessive use.
 Psychological dependence is manifested in the form of craving for a drug. A person with
psychological dependence has an excessive, irresistible, uncontrollable desire to use the
drug. Psychological dependence may not cause physical symptoms but can lead to drug-
seeking behavior.

Chemical Classifications of Drugs

Each of the regulated drugs that act on the central nervous system or alter your feelings and
perceptions can be classified according to their physical and psychological effects. The different
drug types include the following:

 Depressants. Drugs that suppress or slow the activity of the brain and nerves, acting
directly on the central nervous system to create a calming or sedating effect. This category
includes barbiturates (phenobarbital, thiopental, butalbital), benzodiazepines
(alprazolam, diazepam, clonazepam, lorazepam, midazolam), alcohol, and gamma
hydroxybutyrate (GHB). Depressants are taken to relieve anxiety, promote sleep and
manage seizure activity.
 Stimulants. Drugs that accelerate the activity of the central nervous system. Stimulants
can make you feel energetic, focused, and alert. This class of drugs can also make you
feel edgy, angry, or paranoid. Stimulants include drugs such as cocaine, crack
cocaine, amphetamine, and methamphetamine. According to the recent World Drug
Report published by the United Nations Office on Drugs and Crime, amphetamine-derived
stimulants like ecstasy and methamphetamine are the most commonly abused drugs
around the world after marijuana.
 Hallucinogens. Also known as psychedelics, these drugs act on the central nervous
system to alter your perception of reality, time, and space. Hallucinogens may cause
you to hear or see things that don’t exist or imagine situations that aren’t real.
Hallucinogenic drugs include psilocybin (found in magic mushrooms), lysergic acid
diethylamide (LSD), peyote, and dimethyltryptamine (DMT).
 Opioids. These are the drugs that act through the opioid receptors. Opioids are one of
the most commonly prescribed medicines worldwide and are commonly used to treat
pain and cough. These include drugs such
as heroin, codeine, morphine, fentanyl, hydrocodone, oxycodone, buprenorphine,
and methadone.
  Inhalants. These are a broad class of drugs with the shared trait of being
primarily consumed through inhalation. Most of the substances in this class can exist
in vapor form at room temperature. As many of these substances can be found as
household items, inhalants are frequently abused by children and adolescents. These
include substances such as paint, glue, paint thinners, gasoline, marker or pen ink, and
others. Though ultimately all of these substances cross through the lungs into the
bloodstream, their precise method of abuse may vary but can include sniffing, spraying,
huffing, bagging, and inhaling, among other delivery routes.
 Cannabis. Cannabis is a plant-derived drug that is the most commonly used illicit drug
worldwide. It acts through the cannabinoid receptors in the brain. Cannabis is abused
in various forms including bhang, ganja, charas, and hashish oil.
 New psychoactive substances (NPS). These are drugs designed to evade the
existing drug laws. Drugs such as synthetic cannabinoids, synthetic
cathinones, ketamine, piperazines, and some plant-based drugs such as khat and
kratom are examples of NPS.

Legal Classifications of Drugs

The Controlled Substances Act established five classifications, or schedules, for drugs regulated
by law. According to the DEA, these classifications are broken down based on their potential
for abuse and if they have a legitimate medical use:

 Schedule I include the drugs that have a high potential for abuse, that have no currently
accepted medical use in treatment in the United States, and that there is a lack of accepted
safety for use of the drug under medical supervision. Drugs such as cannabis, ecstasy,
GHB, heroin, LSD, mescaline, and methaqualone are included in Schedule I.

 Schedule II includes drugs that have a high potential for abuse, have currently accepted
medical use in treatment in the United States or currently accepted medical use with
severe restrictions, and that the abuse of may lead to severe psychological or physical
dependence. Drugs such as amphetamine, cocaine, fentanyl, hydromorphone oxycodone,
and hydrocodone are included in Schedule II.
 Schedule III includes drugs that have a potential for abuse less than the drugs or other
substances in schedules I and II, have a currently accepted medical use in treatment in
the United States, and that the abuse of may lead to moderate or low physical dependence
or high psychological dependence. Drugs such as anabolic steroids, buprenorphine, and
ketamine are included in Schedule III.
 Schedule IV includes drugs that have a low potential for abuse relative to the drugs or
other substances in schedule III, have a currently accepted medical use in treatment in
the United States, and that the abuse of may lead to limited physical dependence or
psychological dependence relative to the drugs or other substances in schedule III. Drugs
such as benzodiazepines, modafinil, and tramadol are included in Schedule IV.
 Schedule V includes drugs that have a low potential for abuse relative to the drugs or
other substances in schedule IV, have a currently accepted medical use in treatment in
 the United States, and that the abuse of may lead to limited physical dependence or
psychological dependence relative to the drugs or other substances in schedule IV. Drugs
such as diphenoxylate (in combination with atropine), lacosamide, and pregabalin are
included in Schedule V.

The legal and personal consequences of misusing controlled substances can be

severe. With your doctor’s help, you can use these drug classifications as guidelines to help you
determine if a medication or substance is both safe and beneficial.

DRUG STANDARDS AND INFORMATION (Philippines)

Executive Order No. 218

STRENGTHENING THE SUPPORT MECHANISM FOR THE PHILIPPINE DRUG

ENFORCEMENT AGENCY

WHEREAS, by virtue of the Comprehensive Dangerous Drugs Act of 2002 ( Republic Act (R.A.)
No. 9165), the Philippine Drug Enforcement Agency (PDEA) was created for the efficient and
effective law enforcement of all the provisions on dangerous drugs and/or precursors and
essential chemicals as provided in R.A. No.9165;

WHEREAS, pursuant to R.A. No. 9165, the Dangerous Drugs Board (DDB) is the policy-making
and strategy-formulating body in the planning and formulation of policies and programs on drug
prevention and control.

WHEREAS, R.A. No. 9165 provides for the abolition of the drug enforcement units of the
Philippines National Police (PNP), the National Bureau of Investigation and Bureau of Customs;

WHEREAS, the same Act also provides that the personnel of the abolished units shall continue
to perform their task as detail service with the PDEA until such time that the PDEA is fully
operational and is able to recruit a sufficient number of new personnel to do the task themselves;

WHEREAS, the PDEA, as the lead agency tasked to enforce R.A. No.9165, is still in its transition
period and still has to develop its institutional capabilities to be able to accomplishment its
mandated task;

WHEREAS, other agencies of the Government have trained drug enforcement personnel who
can help PDEA fulfill its tasks;

WHEREAS, there is an urgent need to pursue a forcefull, intensive and unrelenting campaign
against drug trafficking and the use of illegal drugs whether syndicated or street-level.
NOW, THEREFORE, I, GLORIA MACAPAGAL-ARROYO, President of the Republic of the
Philippines, by virtue of the powers vested in me by law, do hereby order and/or authorize:

SECTION 1. Creation of Task Forces

The Office of the President, the PNP and other agencies which were performing drug law
enforcement and prevention functions prior to the enactment of R.A. No. 9165 shall organize anti-
drug task force to support the PDEA.

SECTION 2. Supervision and Support

The PDEA shall exercise operational supervision and provide technical support to the main task
force created by the PNP. In the case of other task forces, created within the PNP or other
agencies, the President of the Philippines shall determine whether DDB or the PDEA shall
exercise operational supervision.

SECTION 3. Funding

Funds for the operation of the task forces shall be sourced from the mother agencies creating the
task force and from the gross receipts of lotto operations. For this purpose, the Philippine Charity
Sweeptakes Office is hereby ordered to create a standby fund in the amount of One Billion Pesos
(P1,000,000,000.00) to fund the operations of the PDEA and the task forces supporting it.

SECTION 4. Repeal

Executive Order No.206 dated May 15,2003 is hereby repealed. All orders, rules, regulations and
issuances, or parts thereof, which are inconsistent with this Executive Order are hereby repealed
or modified accordingly.

SECTION 5. Effectivity

This Executive Order shall take effect immediately upon approval.

Republic of the Philippines

Congress of the Philippines
Metro Manila

Sixteenth Congress

First Regular Session

Begun and held in Metro Manila, on Monday, the twenty-second day of July, two thousand
thirteen.
[REPUBLIC ACT NO. 10640]

AN ACT TO FURTHER STRENGTHEN THE ANTI-DRUG CAMPAIGN OF THE GOVERNMENT,

AMENDING FOR THE PURPOSE SECTION 21 OF REPUBLIC ACT NO. 9165, OTHERWISE
KNOWN AS THE “COMPREHENSIVE DANGEROUS DRUGS ACT OF 2002″

Be it enacted by the Senate and House of Representatives of the Philippines in Congress

assembled:

SECTION 1. Section 21 of Republic Act No. 9165, otherwise known as the “Comprehensive
Dangerous Drugs Act of 2002″, is hereby amended to read as follows:

“SEC. 21. Custody and Disposition of Confiscated, Seized, and/or Surrendered Dangerous Drugs,
Plant Sources of Dangerous Drugs, Controlled Precursors and Essential Chemicals,
Instruments/Paraphernalia and/or Laboratory Equipment. – The PDEA shall take charge and have
custody of all dangerous drugs, plant sources of dangerous drugs, controlled precursors and
essential chemicals, as well as instruments/paraphernalia and/or laboratory equipment so
confiscated, seized and/or surrendered, for proper disposition in the following manner:

“(1) The apprehending team having initial custody and control of the dangerous drugs, controlled
precursors and essential chemicals, instruments/paraphernalia and/or laboratory equipment
shall, immediately after seizure and confiscation, conduct a physical inventory of the seized items
and photograph the same in the presence of the accused or the person/s from whom such items
were confiscated and/or seized, or his/her representative or counsel, with an elected public official
and a representative of the National Prosecution Service or the media who shall be required to
sign the copies of the inventory and be given a copy thereof: Provided, That the physical inventory
and photograph shall be conducted at the place where the search warrant is served; or at the
nearest police station or at the nearest office of the apprehending officer/team, whichever is
practicable, in case of warrantless seizures: Provided, finally, That noncompliance of these
requirements under justifiable grounds, as long as the integrity and the evidentiary value of the
seized items are properly preserved by the apprehending officer/team, shall not render void and
invalid such seizures and custody over said items.

“x x x

“(3) A certification of the forensic laboratory examination results, which shall be done by the
forensic laboratory examiner, shall be issued immediately upon the receipt of the subject item/s:
Provided, That when the volume of dangerous drugs, plant sources of dangerous drugs, and
controlled precursors and essential chemicals does not allow the completion of testing within the
time frame, a partial laboratory examination report shall be provisionally issued stating therein the
quantities of dangerous drugs still to be examined by the forensic laboratory: Provided, however,
That a final certification shall be issued immediately upon completion of the said examination and
certification;
“x x x.”

SEC. 2. Implementing Rules and Regulations (IRR). – To implement effectively the provisions of
Section 21, the Philippine Drug Enforcement Agency (PDEA) shall issue the necessary guidelines
on the IRR for the purpose in consultation with the Department of Justice (DO J) and relevant
sectors to curb increasing drug cases.

SEC. 3. Separability Clause. – If any provision or part hereof is held invalid or unconstitutional,
the remainder of the law or the provision not otherwise affected shall remain valid and subsisting.

SEC. 4. Repealing Clause. – All laws, presidential decrees or issuances, executive orders, letters
of instruction, administrative orders, rules and regulations contrary to or inconsistent with the
provisions of this Act are hereby repealed, modified or amended accordingly.

SEC. 5. Effectivity. – This Act shall take effect fifteen (15) days after its complete publication in at
least two (2) newspapers of general circulation.

RA 9165

Pharmacodynamics

Pharmacodynamics is the study of how drugs have effects on the body. The most common
mechanism is by the interaction of the drug with tissue receptors located either in cell membranes
or in the intracellular fluid. The extent of receptor activation, and the subsequent biological
response, is related to the concentration of the activating drug (the 'agonist'). This relationship is
described by the dose–response curve, which plots the drug dose (or concentration) against its
effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g.
age, disease) and by the presence of other drugs that compete for binding at the same receptor
(e.g. receptor 'antagonists'). Some drugs acting at the same receptor (or tissue) differ in the
magnitude of the biological responses that they can achieve (i.e. their 'efficacy') and the amount
of the drug required to achieve a response (i.e. their 'potency'). Drug receptors can be classified
on the basis of their selective response to different drugs. Constant exposure of receptors or body
systems to drugs sometimes leads to a reduced response (i.e. 'desensitization').

Therapeutic index

When drugs are used in clinical practice, the prescriber is unable to construct a careful dose–
response curve for each individual patient. Therefore, most drugs are licensed for use within a
recommended dose range that is expected to be close to the top of the dose–response curve for
most patients. This ensures that most patients will achieve a good clinical response without the
need for frequent review and dose increases. However, this means that it is sometimes possible
to achieve the desired therapeutic response at doses towards the lower end of the recommended
range (or below).
The adverse effects of drugs are often dose-related in a similar way to the beneficial effects. It is
possible to construct a dose-response curve for these adverse effects in the same way as shown
for the beneficial effects, with higher doses usually required to cause the adverse effect. The
ED50 points for each curve in the Figure indicate that the ratio between the doses that have
similar proportionate effects on the two outcomes is 10/0.1 = 100. This ratio is known as the
‘therapeutic index’. In reality, drugs have multiple potential adverse effects but the concept of
therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For
most drugs, the therapeutic index is greater than 100 but there are some notable exceptions with
therapeutic indices less than 10, which are in common use (e.g. digoxin, warfarin, insulin,
phenytoin, opioids). Drugs with low therapeutic indices are more difficult to prescribe and
hazardous for patients but they are still preferred if there are no alternative drugs with similar
efficacy (e.g. anti-cancer drugs). The doses of such drugs have to be titrated carefully for
individual patients to maximize benefits but avoid adverse effects. This is done by monitoring drug
effects, either clinically or using regular blood tests (often known as ‘therapeutic drug monitoring’).

Pharmacokinetics

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement
of drug into, through, and out of the body—the time course of
its absorption, bioavailability, distribution, metabolism, and excretion.

Pharmacokinetics of a drug depends on patient-related factors as well as on the drug’s chemical

properties. Some patient-related factors (eg, renal function, genetic makeup, sex, age) can be
used to predict the pharmacokinetic parameters in populations. For example, the half-life of some
drugs, especially those that require both metabolism and excretion, may be remarkably long in
the elderly (see Figure: Comparison of pharmacokinetic outcomes for diazepam in a younger man
(A) and an older man (B)). In fact, physiologic changes with aging affect many aspects of
pharmacokinetics (see Pharmacokinetics in Older Adults and see Pharmacokinetics in Children).

Other factors are related to individual physiology. The effects of some individual factors (eg, renal
failure, obesity, hepatic failure, dehydration) can be reasonably predicted, but other factors are
idiosyncratic and thus have unpredictable effects. Because of individual differences, drug
administration must be based on each patient’s needs—traditionally, by empirically adjusting
dosage until the therapeutic objective is met. This approach is frequently inadequate because it
can delay optimal response or result in adverse effects.

Knowledge of pharmacokinetic principles helps prescribers adjust dosage more accurately and
rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed
therapeutic drug monitoring.

Graded dose response

- "A response to a drug such that as the dose of drug increases the intensity of the response
increases. A graded dose-response relationship can be measured on a continuous scale."

Dose-response relationship is an association between dose and the incidence of a defined

biological effect in an exposed population usually expressed as a percentage.
Efficacy

- maximum effect that a drug can produce regardless of dose

Potency

- amount of a drug that is needed to produce a given effect

- e.g., EC50 is the concentration or dose of drug that causes 50% of maximum effect
- determined by affinity of drug for receptor and number of receptors available

Main types of drug targets and their mechanisms of action

Drug Target Description Example(s)

Receptors

Coupled directly to an ion channel.

Activation opens the channel, making a
cell membrane permeable to specific
Channel- ions. These channels are known as Nicotinic acetylcholine receptors;
linked ‘ligand-gated’ because it is receptor gamma-Aminobutyric acid (GABA)
receptors binding that operates them (in contrast to receptors
‘voltage-gated’ channels that respond to
changes in membrane potential) (see B in
figure).

Coupled to intracellular effector Muscarinic acetylcholine receptors;

mechanisms via a family of closely
related 'G‐ proteins' that participate in beta-Adrenoceptors;
signal transduction by coupling receptor
G-Protein binding to intracellular enzyme activation Dopamine receptors;
coupled or the opening of an ion channel. 5-hydroxytryptamine (Serotonin)
receptors Secondary messenger systems include receptors;
the enzymes, adenylyl cyclase and
guanylyl cyclase, which generate cyclic Opioid receptors
AMP and cyclic GMP, respectively (see A
in figure).

Kinase- Linked directly to an intracellular protein

linked kinase that triggers a cascade of Insulin receptors
receptors phosphorylation reactions.
 Intracellular and also known as 'nuclear Steroid hormone receptors;
Nuclear receptors’. Binding of a ligand promotes
hormone or inhibits synthesis of new proteins, Thyroid hormone receptors;
receptors which may take hours or days to promote
a biological effect. Vitamin D receptors

Other targets

Found in excitable tissues and a potential

Voltage-
target for drugs that can block the Na+ channels that are blocked by local
sensitive ion
channel or interfere with conductance in anesthetics such as lidocaine
channels
other ways.

Catalyze biochemical reactions, some of

which involve the production of key
mediators of physiological processes in Inhibitors of cyclooxygenase such as
body systems. Drugs interfere with the aspirin;
active site of the enzyme or affect co‐
Inhibitors of angiotensin converting
Enzymes factors required by the enzyme for
enzyme such as enalapril;
activity. In most cases inhibition of the
active site is competitive although in Inhibitors of xanthine oxidase such as
some cases it may be long-lasting and allopurinol
effectively irreversible (e.g. aspirin) (see
C in figure)

Specialized proteins that carry ions or

molecules across cell membranes.
Movement may be in either direction, and
may involve exchange of one substance
for another, co-transport of two or more
Transporter substances in the same direction, or Inhibitors of serotonin reuptake
proteins ‘pumping’ of a single substance into or transporter such as fluoxetine
out of a cell or organelle. Drugs may act
on transporters to inhibit their activity or
may also act as ‘false substrates’,
preventing the transport of the normal
biological substrate (see D in figure).

Type-1 membrane glycoproteins that β2 integrins on leukocytes which are

mediate cell-cell and cell-matrix adhesion essential for effective immune
Cell by acting as transmembrane linkers to responses. Adhesion class GPCRs.
adhesion connect ligands on the outside of the cell Cadherins such as E-cadherin required
proteins (other cell membrane molecules, ECM for endothelial cell-cell contact, and
components) to the actin cytoskeleton. tissue morphogenesis during embryonic
Includes the adherins and integrins. development.
Drug–receptor interaction
As noted above, drug receptor interaction can generally be defined as specific, dose-related and
saturable. These characteristics of a drug at a receptor are described by KDand ED50 and can
be obtained from ligand binding and dose–response curves
Receptors are macromolecules involved in chemical signaling between and within cells; they may
be located on the cell surface membrane or within the cytoplasm. Activated receptors directly or
indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation,
DNA transcription, enzymatic activity).

Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands.
The binding can be specific and reversible. A ligand may activate or inactivate a receptor;
activation may increase or decrease a particular cell function. Each ligand may interact with
multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype,
but most have relative selectivity. Selectivity is the degree to which a drug acts on a given site
relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular
receptors.

A drug’s ability to affect a given receptor is related to the drug’s affinity (probability of the drug
occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which
a ligand activates receptors and leads to cellular response). A drug’s affinity and activity are
determined by its chemical structure.

The pharmacologic effect is also determined by the duration of time that the drug-receptor
complex persists (residence time). The lifetime of the drug-receptor complex is affected by
dynamic processes (conformation changes) that control the rate of drug association and
dissociation from the target. A longer residence time explains a prolonged pharmacologic effect.
Drugs with long residence times include finasteride and darunavir. A longer residence time can
be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug
occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes
toxicity.

Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptor-
mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd
messenger substances) may be interposed between the initial molecular drug–receptor
interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules can
often be used to produce the same desired response.

Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory

mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary
from tissue to tissue. Drugs, aging, genetic mutations, and disorders can increase (upregulate) or
decrease (downregulate) the number and binding affinity of receptors. For
example, clonidine downregulates alpha2-receptors; thus, rapid withdrawal of clonidine can
cause hypertensive crisis. Chronic therapy with beta-blockers upregulates beta-receptor density;
thus, severe hypertension or tachycardia can result from abrupt withdrawal. Receptor
upregulation and downregulation affect adaptation to drugs (eg, desensitization, tachyphylaxis,
tolerance, acquired resistance, postwithdrawal supersensitivity).

Ligands bind to precise molecular regions, called recognition sites, on receptor macromolecules.
The binding site for a drug may be the same as or different from that of an endogenous agonist
(hormone or neurotransmitter). Agonists that bind to an adjacent site or a different site on a
receptor are sometimes called allosteric agonists. Nonspecific drug binding also occurs—ie, at
molecular sites not designated as receptors (eg, plasma proteins). Drug binding to such
nonspecific sites, such as binding to serum proteins, prohibits the drug from binding to the
receptor and thus inactivates the drug. Unbound drug is available to bind to receptors and thus
have an effect.

Agonists and antagonists

Agonists activate receptors to produce the desired response. Conventional agonists increase the
proportion of activated receptors. Inverse agonists stabilize the receptor in its inactive
conformation and act similarly to competitive antagonists. Many hormones, neurotransmitters (eg,
acetylcholine, histamine, norepinephrine), and drugs
(eg, morphine, phenylephrine, isoproterenol, benzodiazepines, barbiturates) act as agonists.

Antagonists prevent receptor activation. Preventing activation has many effects. Antagonists
increase cellular function if they block the action of a substance that normally decreases cellular
function. Antagonists decrease cellular function if they block the action of a substance that
normally increases cellular function.

Receptor antagonists can be classified as reversible or irreversible. Reversible antagonists readily

dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly
permanent chemical bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists
slowly dissociate from their receptor.

In competitive antagonism, binding of the antagonist to the receptor prevents binding of the
agonist to the receptor.

In noncompetitive antagonism, agonist and antagonist can be bound simultaneously, but

antagonist binding reduces or prevents the action of the agonist.

In reversible competitive antagonism, agonist and antagonist form short-lasting bonds with the
receptor, and a steady state among agonist, antagonist, and receptor is reached. Such
antagonism can be overcome by increasing the concentration of the agonist. For
example, naloxone (an opioid receptor antagonist that is structurally similar to morphine), when
given shortly before or after morphine, blocks morphine’s effects. However, competitive
antagonism by naloxone can be overcome by giving more morphine.

Structural analogs of agonist molecules frequently have agonist and antagonist properties; such
drugs are called partial (low-efficacy) agonists, or agonist-antagonists. For
example, pentazocine activates opioid receptors but blocks their activation by other opioids.
Thus, pentazocine provides opioid effects but blunts the effects of another opioid if the opioid is
given while pentazocine is still bound. A drug that acts as a partial agonist in one tissue may act
as a full agonist in another.