Pharmacology I (Lecture 1)

Introduction to Pharmacology

Dr. Leena Abdul-Aziz Muhamed

A brief Background:
• Pharmacology can be defined as:
1. The study of the effects of drugs on the
function of living systems.
2. the study of substances that interact with
living systems through chemical processes,
especially by binding to regulatory
molecules and activating or inhibiting
normal body processes.
A brief Background:
• The interactions between a drug and the body are
divided into two classes:

1. The actions of the drug on the body (termed

pharmacodynamic processes)

2. The actions of the body on the drug (termed

pharmacokinetic processes)
A brief Background:

• Hence Pharmacology can be defined as:

3. The study of the drug pharmacokinetics

(absorption, distribution, metabolism and
excretion) and the drug pharmacodynamics
(drug effect and mechanism of action)
What is a drug?

• A drug can be defined as 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.
• Drugs may be synthetic chemicals, chemicals obtained
from plants or animals, or products of genetic engineering.

• A medicine is a chemical preparation, which usually but

not necessarily contains one or more drugs,
administered with the intention of producing a therapeutic
effect.

• Medicines usually contain other substances (excipients,

stabilizers, solvents, etc.) besides the active drug, to make
them more convenient to use.
• To count as a drug, the substance must be
administered as such, rather than released by
physiological mechanisms.

• Many substances are found as endogenous

hormones but are also drugs when they are
administered intentionally.

• Many drugs are not used in medicines but are

nevertheless useful research tools.
• In everyday speech, the word drug is often
associated with addictive, narcotic or mind-altering
substances — an unfortunate negative concept that
tends to bias uninformed opinion against any form
of chemical therapy.
 Drugs Names and Classes
• Drugs have a specific kind of nomenclature — that is, a drug
can go by three different names:
– The chemical name is a scientific name that precisely
describes the drug’s atomic and molecular structure.
– The generic or nonproprietary, name is an
abbreviation of the chemical name.
– The trade name (also known as the brand name or
proprietary name) is selected by the drug company
selling the product.
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 Drugs Names and Classes

• Example for nomenclature:

7-chloro-1,3-dihydro-1-methyl-5- phenyl-
2H-1,4-benzodiazepin-2-one.

diazepam

Cimapam, Elipam, Ropam, Zepam,

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Yesepam, Valium
 Drugs Names and Classes

• Example for nomenclature:

N-(4-Hydroxyphenyl)acetamide

Paracetamol / acetaminophen

Abimol, Adol, Panadol, Amidol,

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Citymol, Azadol, Elidol
 Drugs Names and Classes

• Types of drug grouping include:

– Pharmacologic class (or family); groups drugs by
their shared characteristics (Drugs that share
similar characteristics are grouped together)

– Therapeutic class; groups drugs by their

therapeutic use.

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 Drugs Names and Classes
• Classification of drugs according to prescription:
– prescription-only medicine controlled drug (POM CD)

– prescription-only medicine (POM)

– pharmacy-only medicine (P)

– general sale list (GSL)

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• Pharmacology & Toxicology

Medical pharmacology, which is often defined

as the science of substances used to prevent,
diagnose, and treat disease.

Toxicology is the branch of pharmacology that

deals with the undesirable effects of chemicals on
living systems, from individual cells to humans to
complex ecosystems.
• Pharmacology & Pharmacotherapeutics

Therapeutics is the branch of medicine

concerned with the prevention of disease and
treatment of suffering.

Pharmacotherapy, or pharmacotherapeutics, is
the application of drugs for the purpose of disease
prevention and the treatment of suffering.
Pharmacokinetics
• Pharmacokinetics may be defined as:

the measurement and formal interpretation

of changes with time of drug concentrations in
one or more different regions of the body in
relation to dosing (‘what the body does to the
drug’).
Pharmacokinetics:
• Drug disposition is divided into four stages
designated by the acronym ‘ADME’:
1. Absorption from the site of administration
2. Distribution within the body
3. Metabolism
4. Excretion.
• In practice, pharmacokinetics usually focuses on
concentrations of drug in blood plasma, since plasma
concentrations are assumed usually to bear a clear
relation to the concentration of drug in extracellular
fluid surrounding cells that express the receptors or
other targets with which drug molecules combine.

• Concentrations of drug in other body fluids (e.g.

urine, saliva, cerebrospinal fluid, milk) may add
useful information in some special situations.
• therapeutic drug monitoring (TDM):

In the case of a few drugs, plasma drug

concentrations are used in routine clinical
practice to individualize dosage so as to
achieve the desired therapeutic effect while
minimizing adverse effects in each individual
patient.
• For most purposes, we can regard the body as a
series of interconnected well-stirred compartments
within each of which the drug concentration is
uniform.

• It is movement between compartments, generally

involving penetration of non-aqueous diffusion
barriers, that determines where, and for how long,
a drug will be present in the body after it has been
administered.
• Drug molecules move around the body in two
ways:

– bulk flow (i.e. in the bloodstream, lymphatics

or cerebrospinal fluid)

– diffusion (i.e. molecule by molecule, over

short distances).
The Movement of Drug Molecules
Across Cell Barriers
• Cell membranes form the barriers between
aqueous compartments in the body.

• Examples for levels of barriers:

1. A single layer of membrane separates the
intracellular from the extracellular compartments.
The Movement of Drug Molecules
Across Cell Barriers
2. An epithelial barrier, such as the
gastrointestinal mucosa or renal tubule,
consists of a layer of cells tightly connected
to each other so that molecules must traverse
at least two cell membranes (inner and outer)
to pass from one side to the other.
The Movement of Drug Molecules
Across Cell Barriers

3. Vascular endothelium is more complicated,

its anatomical disposition and permeability
varying from one tissue to another.
The Movement of Drug Molecules
Across Cell Barriers
• In some organs, especially the central nervous system
(CNS) and the placenta, there are tight junctions
between the cells, and the endothelium is encased in
an impermeable layer of periendothelial cells
(pericytes).
• In other organs (e.g. the liver and spleen),
endothelium is discontinuous, allowing free passage
between cells.
• There are four main ways by which small
molecules cross cell membranes:
1. by diffusing directly through the lipid
2. by diffusing through aqueous pores formed by
special proteins (aquaporins) that traverse the
lipid.
3. by combination with a solute carrier (SLC) or
other membrane transporter.
4. by pinocytosis.
 1- Diffusion Through Lipids
• Non-polar molecules dissolve freely in
membrane lipids, and consequently diffuse
readily across cell membranes.
• The number of molecules crossing the
membrane per unit area in unit time is
determined by the:
1. Permeability coefficient (P).
2. Concentration difference across the membrane.
• Two physicochemical factors contribute to
the Permeability coefficient (P):
– Solubility in the membrane (which can be
expressed as a partition coefficient for the
substance distributed between the membrane
phase and the aqueous environment).

– Diffusivity (which is a measure of the mobility of

molecules within the lipid and is expressed as a
diffusion coefficient).
The Effect of pH and Ionisation

• many drugs are weak acids or bases, and

therefore exist in both unionized and ionized
form, the ratio of the two forms varying with
pH.
The Effect of pH and Ionisation
The ionization reaction The dissociation constant
• For weak bases: • For weak bases:

• For weak acids: • For weak acids:

The Effect of pH and Ionisation
• In either case, the ionised species, BH+ or A−, has
very low lipid solubility and is virtually unable to
permeate membranes except where a specific
transport mechanism exists.

• The lipid solubility of the uncharged species, B or

AH, depends on the chemical nature of the drug; for
many drugs, the uncharged species is sufficiently
lipid soluble to permit rapid membrane permeation.
The Effect of pH and Ionisation
• Ionization generally affects both:

– The rate at which drugs permeate membranes.

– The steady-state distribution of drug molecules

between aqueous compartments, if a pH
difference exists between them.
The Effect of pH and Ionisation

At steady state, an acidic drug will

accumulate on the more basic side of the
membrane and a basic drug on the more acidic
side....ION TRAPPING
The Effect of pH and Ionisation
• Examples for important consequences of pH
partition:

1. Urinary acidification accelerates excretion of

weak bases and retards that of weak acids.

2. Urinary alkalinization reduces excretion of

weak bases and increases excretion of weak
acids.
The Effect of pH and Ionisation
• Examples for important consequences of pH
partition:

3. Free-base trapping of some antimalarial drugs (e.g.

chloroquine) in the acidic environment in the food
vacuole of the malaria parasite.

4. Increasing plasma pH (e.g. by administration of

sodium bicarbonate) causes weakly acidic drugs to
be extracted from the CNS into the plasma.
 2- Carrier-mediated Transport
• Many cell membranes possess specialised
transport mechanisms that regulate entry and exit
of physiologically important molecules, such as
sugars, amino acids, neurotransmitters and metal
ions.

• These transport mechanisms can be divided into:

1. solute carrier (SLC) transporters
2. ATP-binding cassette (ABC) transporters.
solute carrier (SLC) transporters
• Two structurally related SLC carriers of importance in
drug distribution:

1. Organic cation transporters (OCTs)

2. Organic anion transporters (OATs).

• This transport systems involve a carrier molecule, i.e. a

transmembrane protein that binds one or more molecules
or ions, changes conformation and releases them on the
other side of the membrane.
solute carrier (SLC) transporters
• the main sites where SLCs, including OCTs and OATs,
are expressed and carrier-mediated drug transport is
important are:

1. the blood–brain barrier

2. the gastrointestinal tract

3. the renal tubule

4. the biliary tract

5. the placenta.
 ATP-binding cassette (ABC)
transporters
• An example for ATP-binding cassette transporters are
the P-glycoproteins (P-gp; P for ‘permeability’),

• P-glycoproteins are the second important class of

transporters, and responsible for multidrug resistance in
cancer cells. They are present in renal tubular brush
border membranes, in bile canaliculi, in astrocyte foot
processes in brain microvessels, and in the
gastrointestinal tract.
• In addition to the processes which govern the
transport of drug molecules across the
barriers between different aqueous
compartments, two additional factors have a
major influence on drug distribution and
elimination. These are:

1. Binding to plasma proteins

2. Partition into body fat and other tissues.

 1- Binding of Drugs to
Plasma Proteins
• At the therapeutic concentration of the drug in the
plasma, many drugs exist mainly in bound form.

• The fraction of drug that is free in aqueous

solution can be less than 1%, the remainder bein
associated with plasma protein. It is the unbound
drug that is pharmacologically active.
• The most important plasma protein in relation to
drug binding is albumin, which binds many acidic
drugs (e.g. warfarin, NSAID, sulfonamides) and a
smaller number of basic drugs (e.g. tricyclic
antidepressants and chlorpromazine).

• Other plasma proteins, including β-globulin and an

acid glycoprotein that increases in inflammatory
disease, have also been implicated in the binding of
certain basic drugs, such as quinine.
• The amount of a drug that is bound to protein
depends on three factors:

1. the concentration of free drug

2. its affinity for the binding sites

3. the concentration of protein.

 2- Partition into body fat and
other tissues
• Fat represents a large, non-polar compartment. In
practice, this is important for only a few drugs,
mainly because:

• The effective fat : water partition coefficient is

relatively low for most drugs.

• The low blood supply to fatty tissues — less than

2% of the cardiac output.
• Examples for other tissues in which drugs can
accumulate include:

1. Retina of the eye (rich in melanin granules) –

accumulation of Chloroquine.

2. Bones and teeth (rich in calcium) –

acummulation of Tetracyclines.

3. Liver and lung – acummulation of amiodarone.

 (1)
Drug Absorption and
Routes of Administration
• Absorption is defined as the passage of a
drug from its site of administration into the
plasma.

• It is important for all routes of administration

except intravenous injection, where it is
complete by definition.
Bioavailability and Bioequivalence
• Bioavailability is a term used to indicate the
fractional extent to which a dose of drug reaches its
site of action or a biological fluid from which the
drug has access to its site of action.

• Another definition: the fraction of drug absorbed as

such into the systemic circulation.
Bioavailability and Bioequivalence

• Two pharmaceutically equivalent drug products are

considered to be bioequivalent when the rates and
extents of bioavailability of the active ingredient in
the two products are not significantly different
under suitable test conditions.
 Routes of Administration
• The main routes of administration are:
– oral
– sublingual
– rectal
– application to other epithelial surfaces (e.g. skin,
cornea, vagina and nasal mucosa)
– inhalation
– Injection (e.g. subcutaneous, intramuscular,
intravenous, intrathecal, intravitreal)
 1- Oral Administration
• Most drugs are taken by mouth and swallowed.
Little absorption occurs until the drug enters the
small intestine.

• Few non-polar drugs applied to the buccal mucosa

or under the tongue are absorbed directly from the
mouth (e.g. organic nitrates).
• Oral ingestion is the safest, most convenient, and
most economical route of administration.

• Disadvantages to the oral route include:

1. Limited absorption of some drugs because of

their physical characteristics (e.g., low water
solubility or poor membrane permeability),

2. Emesis as a result of irritation to the GI mucosa,

3. Destruction of some drugs by digestive enzymes
or low gastric pH,

4. Irregularities in absorption or propulsion in the

presence of food or other drugs

5. The need for cooperation on the part of the

patient.
• Absorption from the GI tract is governed by
factors such as:
– surface area for absorption,

– blood flow to the site of absorption,

– particle size and the physical state of the drug

– physicochemical factors.

– drug’s concentration at the site of absorption.

– gastrointestinal motility
• Following absorption across the gut wall, the
portal blood delivers the drug to the liver
prior to entry into the systemic circulation.
• A drug can be metabolized in the gut wall
(e.g. by the CYP3A4 enzyme system) or even
in the portal blood, but most commonly it is
the liver that is responsible for metabolism
before the drug reaches the systemic
circulation.

(First Pass Effect)

• Sublingual Administration:

Drugs absorbed from the mouth pass

directly into the systemic circulation without
entering the portal system, and so escape
first-pass metabolism by enzymes in the gut
wall and liver.
 2- Rectal Administration
• Rectal administration is used for drugs that are
required either to:

– Produce a local effect (e.g. anti-inflammatory

drugs for use in ulcerative colitis) or

– Produce systemic effects.

• Absorption following rectal administration is
often unreliable, but this route can be useful in
patients who are vomiting or are unable to take
medication by mouth (e.g. postoperatively)
3- Application To Epithelial Surfaces
• Cutaneous Administration:

– Cutaneous administration is used when a local

effect on the skin is required (e.g. topically
applied steroids).

– Most drugs are absorbed very poorly through

unbroken skin.
– Transdermal dosage forms, in which the drug is
incorporated in a stick-on patch applied to the skin
produce a steady rate of drug delivery and avoid
presystemic metabolism. However, the method is
suitable only for lipid-soluble drugs and is relatively
expensive.
3- Application To Epithelial Surfaces
• Eye Drops:

– Many drugs are applied as eye drops, relying on

absorption through the epithelium of the
conjunctival sac to produce their effects.

– Desirable local effects within the eye can be

achieved without causing systemic side effects.
 3- Administration by Inhalation
• Inhalation is the route used for volatile and
gaseous anaesthetics, the lung serving as the
route of both administration and elimination.

• Drugs used for their effects on the lung are

also given by inhalation, usually as an aerosol.
(E.g. Glucocorticoids and bronchodilators).
• drugs given by inhalation are usually partly
absorbed into the circulation, and systemic
side effects can occur (e.g. tremor following
salbutamol inhalation).
 3- Administration by Injection
• Intravenous injection:

– Intravenous injection is the fastest and most certain

route of drug administration.

– Bolus injection rapidly produces a high concentration

of drug.

– The peak concentration reaching the tissues depends

critically on the rate of injection.
 3- Administration by Injection

• Subcutaneous or intramuscular injection of

drugs usually produces a faster effect than oral
administration, but the rate of absorption
depends greatly on the site of injection and on
local blood flow.
• The rate-limiting factors in absorption from
the injection site are:

– diffusion through the tissue

– removal by local blood flow.

• It may be desirable to delay absorption, either

to produce a local effect or to prolong
systemic action.