By

Aschalew A.S
School of medicine,
Pharmacology department
wolaita sodo university
Phar 202 PHARMACOLOGY
 Credit hours: 4
 Course Description:
 This course is intended to equip the students with principles and practice
of pharmacotherapy and adverse effects and/or toxicities of drugs; it also
will deal with problems of drug use, misuse and abuse with emphasis to
the situation in Ethiopia.
 Pre-requisite courses: Pathology and Human Physiology
 Learning objectives
 After completing the course, students will acquire sound knowledge on
pharmacotherapeutic basis of therapeutics, which will enable them to:
 Decide on drug treatment, select and apply them effectively and safely for the
benefit of the patient
 Better understand drug adverse effects/toxicities particularly their recognition,
prevention and treatment
 Master the principles and practice of rational therapy
 Share the responsibilities to solve the emerging social, economic and medical
problems of drug use, misuse and abuse in Ethiopia.

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 CHAPTER ONE

GENERAL PHARMACOLOGY
Learning Objectives
At the end of this chapter the student will be able to:
1. Define various terminologies used in Pharmacology.
2. Know about nature and sources of drugs.
3. Understand pharmacodynamics like mechanism of
drug action, dose relation ship and
pharmacokinetics like absorption, distribution,
metabolism and excretion (ADME) of
drugs.
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4. Understand theoritical pharmacokinetics like half-
life, order of kinetics, steady state
plasma concentration.
5. Understand drug safety and effectiveness like
factors affecting drug action and adverse
drug reactions.
6. Understand new drug development and evaluation

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1. General pharmacology
1. Introduction to pharmacology
A. definitions:
-pharmacology: is the study of interaction between
chemicals and living systems. It also includes
history ,source, physicochemical properties, dosage
forms, methods of administration, absorption,
distribution, mechanism of action,
biotransformation, excretion, clinical uses and
adverse effects of drugs.

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 pharmacology
is the science that deals with the actions, mechanism of
action, uses, adverse effects and fate of drugs in animals
and humans.
The word “pharmacology” comes from Greeek word for
drug, Pharmakon.
It is the study of what biologically active chemical
compounds (drugs) do in the body and how the body
reacts to them.

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Drug : A drug is broadly defined as any chemical agent that affects
biologic systems. Drugs are generally given for the diagnosis, prevention,
control or cure of disease.

Clinical pharmacology_ it evaluate the pharmacological action of

drug, preferred route of administration and safe dosage range in human
by clinical trials.

Pharmacy_ is the science of identification, selection, preservation,

standardization, compounding and dispensing of medical substances.

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Pharmacodynamics _ the study of biological and
therapeutics effects of drugs( i.e “ what the drug does
to the body ”).
Pharmacokinetics _ study of absorption, distribution,
metabolism and excretion of drugs.( ADME)… i.e
what the body does to the drug.
 Pharmacotherapeutics: It deals with the proper
selection and use of drugs for the prevention and
treatment of disease
Toxicology _ is the science of poisons. Many drugs in
larger doses may act as poisons. Poisons are
substancces that cause harmful, dangerous or fatal
symptoms in living substances.
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Chemotherapy _ it is the effect of drugs on
microorganisms,parasites and neoplastic cells living
and multiplying in living organisms.
Pharmacopoeia _ an official code containing a
selected list of the estabilished drugs and medical
preparations with description of their physical
properties and tests for their identity , purity, and
potency.

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Sub divisions of pharmacology
 Four major subdivisions of pharmacology

1.Pharmacokinetics – describes “ what the body does to the drug.”

this includes topics such as absorption, distribution, metabolism, and
excretion of drugs.

2. Pharmacodynamics – describes “ what the drug does to the body.”

specifically, it deals with the biochemical and physiological effects of
drugs and their mechanisms of actions.

3. Pharmacotherapeutics – describes the use of drugs for the

prevention, diagnosis, and treatment of disease.

4. Toxicology – describes the undesirable effects of therapeutic agents,

poisons, and pollutants on biologic systems.

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Related areas…
Related Fields

1. Clinical Pharmacology
- it evaluates the pharmacological action of drug
prferred route of administration& safe dosage
range in human by clinical trials.
2. Pharmacy- is the science of identification,
selection, preservation, standardisation,
compounding & dispensing of medical
substances.

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 Related fields…
Definitions…
3. Pharmacodynamics
- the study of the biological & therapeutic effects
of drugs (i.e. “what the drug does to the body”)
4. Pharmacokinetics
- study of the absorption, distribution,
metabolism & excretion (ADME) of drugs (i.e.
what the body does to to the drug”)

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Definitions…
Related fields…

5. Pharmacotherapeutics
- deals with the proper selection & use of drugs for
the prevention & treatment of disease.
6. Toxicology
- is the science of the poisons. Many drugs in
larger doses may act as poisons. Poisons are
substances that cause harmful, dangerous or fatal
symptoms in living substances.

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Definitions…
Related fields …

7. Chemotherapy
- it’s the effect of drugs upon microorganisms,
parasites & neoplastic cells living & multiplying in
living organisms.
8. Pharmacogenomics – relationship of individual’s
genetic makeup to his/her response to specific
drugs

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Pharmacology is the study
of drugs and their actions
on the body.

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 Drug information sources

is an official code containing a selected list of the

established drugs & medical preparations with
descriptions of their physical properties & tests for
their identity, purity & potency e.g. Indian
Pharmacopoeia (IP), British Pharmacopoia (BP).

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 Info sources

 United States Pharmacopeia (USP)

 Physician’s desk reference (PDR)

 Drug information
 Monthly prescribing reference

 AMA drug evaluation

 EMS field guides

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‘Drug’ defined
‘Drug’ defined
The word ‘drug’ has many meanings – is a
substance used as a medicine for the treatment of
disease.
Drug – any substance, natural or artificial, other
than food, that by its chemical or physical nature
alters structure or function in the living organism.
Included in this broad definition is a variety of
psychoactive drugs, medicines, and substances
that many people do not usually consider to be
drugs
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‘Drug’ defined…
‘Drug’ defined…
It may also be used to refer to any biologically
active compound which is taken with the intent of
producing a change in the body, including:
- familiar substances such as caffeine, nicotine &
alcohol

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‘Drug’ defined…
‘Drug’ defined …

- Other chemicals which are abused, such as

cannabis, heroin & cocaine
- Food constituents such as vitamins, minerals &
amino acids
- cosmetics

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 Components of a Drug Profile

 Name  Routes of
 Classification Administration
 Mechanism of  Contraindications
Action  Dosage
 Indications  How Supplied
 Pharmacokinetics  Special
 Side Effects Considerations

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Drugs are chemicals used to
diagnose, treat, and prevent
disease.

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 Names of Drugs
 Chemical…states its chemical
composition and molecular structure.
 Generic…usually suggested by the
manufacturer.
 Official…as listed in the
U.S. Pharmacopeia.
 Brand…the trade or proprietary name.

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 Names of drugs
Names

 Most Frequently Include Generic and Trade

Names

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 Names of Drugs
Names of drugs
7-chloro-1, 3-dihydro-1,
Chemical Name
methyl-5-phenyl-2h-1

Generic Name diazepam

Official Name diazepam, USP

Brand Name Valium®

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 Classification

 The broad group to which a drug belongs.

Knowing classifications is essential to
understanding the properties of drugs.

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 Routes of Administration

 How the drug is given.

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 Mechanism of Action

 The way in which a drug causes its effects; its

pharmacodynamics.

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 Indications

 Conditions that enable the appropriate

administration
of the drug (as approved by
the FDA).

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 Contraindications

 Conditions that make it inappropriate to give

the drug.
 …means a predictable harmful event will occur
if the drug is given in this situation.

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Side Effects/Adverse Reactions

 The drug’s untoward or undesired effects.

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 Dosage

 The amount of the drug that should be given.

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 How Supplied

 This typically includes the common

concentration of the available preparations;
many drugs come in different concentrations.

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 Legal
 Knowing and obeying the laws and
regulations governing medications and
their administration is an important
part of a paramedic’s career.
 These include federal, state, and agency
regulations.

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 Federal…
 Pure Food & Drug Act of 1906
 Harrison Narcotic Act of 1914
 Federal Food, Drug, & Cosmetic
Act of 1938
 Comprehensive Drug Abuse
Prevention & Control Act of 1970

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 sources of drugs
 Drugs are obtained from:
A. Minerals: liquid paraffin, megenesium sulfate, magnesium
trisiclate,kaolin etc.
B. Animals: insulin, thyroid extract, heparin and antitoxin sera, etc.
C. Plants : morphine, digoxin, atropine castor oil, etc.
D. Synthetic source : asprin, sulphoneamides, paracetamol,
zidovudine,etc.
E. Microorganisms : penicillin,streptomycin and many antibiotics.
F. Genetic engineering: human insulin, human growth hormone
etc
- Majority of drugs currently used in therapeutics are from synthetic
sources.

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2. pharmacodynamics
Pharmacodynamics_ describes the actions of drugs
on the body, and it includes the principles of receptor
interactions, mechanisms of therapeutic and toxic
actions, and dose-response relationships.

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Pharmacodynamics
Receptor: macromolecule or the component of a cell or
organism that interacts with a drug and initiates the chain
of biochemical events leading to the drug’s observed
effects
 Found in target cells or tissues
 Determine the dose or concentration of drug required to form a
significant # of drug-receptor complexes.
 # of receptors may limit maximal effect a drug may produce
 Responsible for selectivity of drug action
 Size, shape, electrical charge of drug determines binding to a receptor
 Changes in a drug’s chemical structure can alter the affinity for the
receptor where therapeutic and toxic effects may be altered
 Receptors mediate the actions of pharmacologic antagonists

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Pharmacodynamics
Types of Receptors
 Most receptors are cellular proteins whose normal function is to act as
receptors for endogenous regulatory ligands – particularly hormones,
growth factors, and neurotransmitters
 Regulatory proteins – mediate the actions of endogenous chemical
signals such as neurotransmitters, autacoids, and hormones
 This class of receptors mediates the effects of many of the most useful
therapeutic agents
 Enzymes – receptors that are inhibited by binding a drug
 Ex: dihydrofolate reductase – receptor for methotrexate
 Transport proteins
 Ex: Na+/K+ ATPase, membrane receptor for digoxin
 Structural proteins
 Ex: tubulin, the receptor for colchicine

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Pharmacodynamics
Three aspects of drug-receptor function
 1. Receptors determine the quantitative relation between drug
concentration and response
 This is based on receptor’s affinity to bind and it’s abundance in target
cells or tissues
 Drug response depends on:
 Affinity of drug for receptor
 Drugs efficacy (degree to which a drug is able to induce maximal effects)
 2. Receptors (as complex molecules) function as regulatory
proteins and components of chemical signaling mechanisms that
provide targets for important drugs
 3. Receptors determine the therapeutic and toxic effects of drugs
in patients

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Pharmacodynamics
Drug concentration-effect  At a low concentration, effect is
curve changing rapidly
 At a high concentration, effect
is changing slowly
 Emax – maximal response that
can be produced by the drug Emax
 EC50 – conc. of drug that

Effect
produces 50% of maximal effect
 Responses to low doses of a
drug usually in direct prop. to
dose EC50
 As a dose ‘s, it reaches a point
at which no in response can Concentration
be achieved

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Pharmacodynamics
Drug concentration- If Kd is low, binding
receptor bound curve affinity is high

 B – drug bound to receptors

 C – concentration of free Bmax
(unbound) drug
B
 Kd – the concentration of free
drug at which half-maximal
binding is observed
(characterizes the binding Kd
affinity of receptor for drug)
 Bmax – total concentration of C
receptor sites (at high
concentration of drug)
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Pharmacodynamics
Receptor-effector coupling

Transduction process between receptor occupancy and

drug response
 Effector – receptor cellular target
 Coupling – products of one reaction become reactants in another
 Transduction – transfer of information from one cell to another.
Conversion of energy from one form to another
Coupling efficiency is determined by:
 1. initial conformational change in receptor
 2. biochemical events that transduce receptor occupancy into
cellular response

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Pharmacodynamics
Spare receptors – unoccupied receptors
 Maximal response can be achieved by an agonist even if a fraction
of receptors (spare receptors) are unoccupied
 Maximal drug response (the response you want) only requires so many receptors
 Sensitivity of cell to the agonist concentration depends on affinity
of receptor for drug, in addition to, total receptor concentration
 With more receptors available, the chance of binding is greater
 There are spare receptors if the concentration of drug that
produces 50% of the maximum effect (EC50) is less than the
concentration of free drug at which 50% of maximum binding is
observed (Kd)
 Reasons for having spare receptors:
 1. the effect of the drug-receptor interaction may last longer than the interaction
itself
 2. the # of receptors may exceed the # of effector molecules available

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Pharmacodynamics
Chemical antagonists
 Do not require a receptor
 One drug may bind to another drug and inactivate the drug and
it’s actions
 Ex: Protamine (+ charge) will counteract effects of Heparin (- charge)
Agonists
 1. Full agonists
 2. Partial agonists
 Fails to produce maximal effects even if all receptor sites are occupied
 Ex: Stadol® (butorphanol)
 μ antagonist (lowers addiction) and k agonist (analgesic effect)
 Weak partial agonists can seem to be like competitive antagonists

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Pharmacodynamics
Antagonists
 Two classes:
 1. Competitive antagonists
 Ex of concentration of endogenous agonist competing for binding site:
Propranolol (β antagonist)
 Doses sufficient to block the effect of norepinephrine will dec resting HR; however,
exercise, postural change, or emotional stress will inc release of norepinephrine or
epinephrine and may overcome competitive antagonism by propranolol and inc HR
 2. Irreversible antagonist
 Binds covalently to receptor
 Duration of action more dependent upon the rate of turnover of receptor
molecules
 Ex: Phenoxybenzamine (α antagonist)
 Used to dec (control) blood pressure in pheochromocytoma (tumor of adrenal
medulla)
 Tumor will episodically release catecholamines which inc blood pressure
 Do not use an overdose! Very dangerous

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Pharmacodynamics
Antagonists
Bind the receptor, do not activate it
Main effect – prevent agonists (other drugs or
endogenous regulatory molecules) from binding and
activating
Two classes:
 1. Competitive antagonists
 Progressively inhibit agonist response
 The degree of inhibition produced by a competitive antagonist

depends upon the concentration of antagonist

 High concentrations prevent response completely
 Higher concentrations of agonist are required to produce the same
effect of agonist alone

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Pharmacodynamics
Chemical antagonists
 Do not require a receptor
 One drug may bind to another drug and inactivate the drug and
it’s actions
 Ex: Protamine (+ charge) will counteract effects of Heparin (- charge)
Agonists
 1. Full agonists
 2. Partial agonists
 Fails to produce maximal effects even if all receptor sites are occupied
 Ex: Stadol® (butorphanol)
 μ antagonist (lowers addiction) and k agonist (analgesic effect)
 Weak partial agonists can seem to be like competitive antagonists

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Pharmacodynamics
Five basic mechanisms of transmembrane signaling
 1. A lipid soluble ligand (agonist, drug) crosses the membrane and
acts on an intracellular receptor
 Ex: nitric oxide (NO)
 Ex: corticosteroids, mineral corticoids, sex steroids, vitamin D, and
thyroid hormone
 Used to regulate gene expression
 In the nucleus, receptor binds to specific DNA sequences near the gene
 Therapeutic consequences:
 All of the above hormones produce their effect after 30 minutes to several
hours (time required for new protein synthesis)
 The drug will not relieve symptoms right away
 Ex: Glucocorticoids should not be the drug used for acute bronchial asthma

2. Ligand binds to the extracellular domain of the transmembrane

receptor activating enzymatic activity of it’s cytoplasmic domain

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Pharmacodynamics
Five basic mechanisms of transmembrane signaling
3. Ligand binds to the extracellular domain of the
transmembrane receptor which in turn is bound to and
activates tyrosine kinase in the cytoplasm
 Ex of ligands: insulin, EGF (epidermal growth factor), PDGF
(platelet-derived growth factor), ANF (atrial natriuretic factor),
and TGFβ (transforming growth factor-β)
 ANF – regulates blood volume and vascular tone. Intracellular

receptor binding domain guanylyl cyclase → cGMP

 TGFβ – Intracellular receptor binding domain serine kinase

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Pharmacodynamics
Five basic mechanisms of transmembrane signaling
3b. Cytokine receptors
 Ligands bind to the extracellular domain of the transmembrane
receptor which is bound noncovalently to and activates a
separate protein tyrosine kinase, from the Janis Kinase family
 Ex of ligands: growth hormone, interferons, erythropoietin
 Tyrosine residues are phosphorylated
 STAT (signal transducer and activator of transcription) is
phosphorylated
 STAT dimerization and dissociation from receptor
 Dimer travels to nucleus and regulates transcription of specific
genes

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Pharmacodynamics
Five basic mechanisms of transmembrane signaling
4. Ligand binds to and directly regulates the opening
and closing of a transmembrane ion channel
 Ex of ligands: acetylcholine, GABA, excitatory amino acids:
glycine, aspartate, glutamate (synaptic neurotransmitters)
 Rapid signaling mechanism

 Ex of drug: neuromuscular blocking agents like

benzodiazepines or barbiturates

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Pharmacodynamics
 Five basic mechanisms of transmembrane signaling
 5. Ligand binds to a transmembrane receptor linked to an effector
(enzyme or ion channel) by a G-protein
 Ex of ligands: serotonin, adrenergic amines, muscarinic acetylcholine, peptide
hormones, odorants, photons
 Effector increases conc. of 2nd messanger (cAMP, Ca++, etc..)
 Ex: Effector enzyme adenylyl cyclase converts ATP to cAMP
 Duration of activation of adenylyl cyclase depends on longevity of GTP binding
to G protein rather than receptors affinity for drug (like norepinephrine)
 The slow hydrolysis of GTP causes the active G protein to persist long after the
receptor has dissociated from its agonist molecule. Receptors will appear to be
spare
 (Table 2-2) Family of G-proteins
 Each mediates effects of a particular set of receptors to a distinctive group of effectors
 All receptors coupled to G-proteins are structurally related and called
“serpentine receptors”  means receptor polypeptide chain crosses plasma
membrane 7 times
 G proteins interact with AA in the 3rd cytoplasmic loop of receptor polypeptide

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Pharmacodynamics
Receptor regulation
 Depends on receptor and duration of stimulation
 With time, receptor-mediated responses to drugs or
hormonal agonist reversibly desensitize. After reaching an
initial high level, the response gradually diminishes over
seconds or minutes, even in the continued presence of the
agonist. 15 minutes after the removal of the agonist, a
second exposure to agonist results in a response similar to
the initial response because internalized receptors are not
degraded but instead return intact to the plasma membrane
within several minutes
 If receptor is continually stimulated (prolonged activation),
the receptor will be delivered to lysosomes and undergo
down regulation Ex: β adrenoceptors

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Pharmacodynamics
Receptor regulation (cont)
 Down-regulation
 Increases receptor internalization and degradation
 Slower onset and more prolonged effect than desensitization

 Occurs over hours or days

 Is an agonist-induced decrease in the total # of cell-surface

receptors
 Intensity and duration of action of EGF, PDGF, and other agents

that act via tyrosine kinase receptor are limited because of this
process
 Cells responsiveness to ligand is correspondingly diminished

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Pharmacodynamics
 Relation between drug dose and clinical response
 Want to give a dosage regimen that will produce maximal benefit and
minimal toxicity
 Graded Dose Response
 Measures potency of a drug and efficacy of a drug
 Potency – the amt of drug needed to produce a given effect
 The lower the dose needed to produce a response, the more potent the drug. The smaller the
EC50, the > the potency of the drug.
 Is determined mainly by:
 Affinity of receptor for the drug
 Efficiency with which drug-receptor interactions is coupled to response
 Want a drug to be low in potency if administering in inconveniently large amts
 Clinical effectiveness – depends on maximal efficacy and drugs ability to reach the
relevant receptors
 Depends on route, absorption, distribution, and clearance of drug
 Efficacy – the largest response or maximal effect (Emax) a drug can produce
 Is determined mainly by:
 The nature of the receptor and its associated effector system
 Drugs mode of interaction with receptors
 Partial agonist have lower maximal efficacy than full agonists

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Receptors
Two main functions of receptors:
1. Ligand binding
2. Activation of effector system (message
propagation)
- effectors transduce drug-receptor interactions
into cellular effects.
- There are 4 known effector mzms.

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Effectors:
1. Transmembrane – e.g. Insulin binds to receptors
that have both extracellular & intracellular
components – binding of the extracellular
component stimulates the intracellular
component, w/c is coupled to enzymes, for
example tyrosine kinase
2. Ligand gated ion channels – drugs bind to these
receptors, w/c then alter the conductance of
ions through the cell membrane channels.e.g.
benzodiazepines & acetylcholine
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3. Intracellular – Thyroid & steroid hormones bind
to nuclear receptors to form complexes that
interact with DNA, w/c causes changes in gene
expression.
4. Second messenger system – drugs bind to
receptors that activate second messenger system
involving G proteins

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63
Pharmacodynamics
Graded Dose-Response
Curves

Emax
R R Emax
e e
s s
p p
o o
n n
s s
e e
EC50 EC50

Dose (log) Dose (linear)

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Pharmacodynamics
 Quantal (either-or) dose  A high therapeutic index indicates
response that the drug produces the desired
effect at a dose that is rarely lethal;
there is a large margin of safety
 Considers variability among
patients in severity of disease and

% of individuals responding
responsiveness to drugs
Therapeutic Lethal or Toxic
 Measures the effect (response) in a
large # of individual patients at
various doses <Margin of safety>
 Measures and compares the
potencies of drugs ED50 LD50
 Therapeutic index – relates the dose
of a drug required to produce a
desired effect to that which
produces an undesired effect
 T.I. = LD (lethal dose in 50%) Dose (log)
50
ED50(effective dose in
50%)
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Dose-Response Curves

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Potency Vs Efficacy

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Potency Vs Efficacy
Potency Efficacy
• related to the amount of • related to the maximum
drug needed to produce effect that can be
an effect of a given achieved with a
magnitude particular drug
• usually expressed as • usually expressed as
ED50 Emax

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Agonist types: It’s all relative

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Types of Antagonism
Chemical Physiological
- direct interaction of two drugs - indirect interaction of two
in solution such that the effect drugs with opposing
of one or both drugs is lost e.g. physiological actions e.g.
protamine (acidic histamine: lowers blood
anticoagulant) and heparin pressure through vasodilation
(basic anticoagulant); loss of (on H1 receptor); Adrenaline
activity of both drugs raises Bp through
vasoconstriction (on β-
receptors)

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Types of Antagonism…
Pharmacological Pharmacological
- blockage of interaction of antagonists
one drug with receptor by - Bind to receptors, but do
another drug e.g. not activate them
Cimetidine blocks binding - Biological activity drive
of histamine to H1 from blocking ability of
receptors resulting in agonists (e.g. drug,
lower gastric acid hormone, NTs) to bind
secretion and/or activate a receptor

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Pharmacological antagonists…

Competitive Antagonists  Non-competitive

- Bind to same site on Anatgonists
receptor as agonists - Bind covalently to same site
- Inhibition can be on receptor as agonist
overcome by increasing (irreversible) or to a site
agonist concentration distinct from that of
agonist (irreversible or
(reversible)
reversible)
- Primarily affect agonist
- Inhibition can’t be
potency
overcome by increasing
agonist conc.
- Primarily affect efficacy
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The Lock & key model of ligand-receptor interaction

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Actions of Drugs
 Drugs that Act by Binding to a Receptor
Site
 Drugs that Act by Changing Physical
Properties
 Drugs that Act by Chemically Combining
with Other Substances
 Drugs that Act by Altering a Normal
Metabolic Pathway

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Responses to Drug Administration

 Side Effect—unintended response to a

drug.
 Allergic Reaction—hypersensitivity.

 Idiosyncrasy—drug effect unique to

an individual.

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Responses to Drug Administration

 Tolerance—decreased response to
the same amount.
 Cross Tolerance—tolerance for a drug
that develops after administration of
a different drug.
 Tachyphylaxis—rapidly occurring
tolerance to a drug.

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Responses to Drug Administration

 Cumulative effect—increased effectiveness

when a drug is given in several doses.
 Drug dependence—the patient becomes
accustomed to the drug’s presence in his
body.
 Drug interaction—the effects of one drug
alter the response to another drug.
 Drug antagonism—the effects of one drug
block the response to another drug.

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Responses to Drug Administration

 Potentiation—one drug enhances

the effect of another.
 Interference—the direct biochemical interaction
between two drugs; one drug affects the
pharmacology of another drug.

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Responses to Drug Administration
(4 of 5)

 Summation—also known as additive

effect, two drugs with the same effect
are given together — similar to 1+1=2.
 Synergism—two drugs with the same
effect are given together and produce a
response greater than the sum of their
individual responses — similar to 1+2=3.

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Pharmacodynamics
Variation in drug responsiveness
 Individuals may vary considerably in their responsiveness to a drug
 Idiosyncratic drug response – unusual, one that is infrequently observed in
most patients
 Caused by:
 Genetic differences in metabolism
 Immunologic mechanism (allergy)
 Hyporeactive – intensity of effect is decreased
 Hyperreactive – intensity of effect is increased
 Hypersensitivity – allergic or other immunologic response to drugs
resulting from previous sensitizing exposure
 Tolerance – responsiveness usually decreases as a consequence of
continued drug administration.
 Need greater doses of a drug to produce original degree of effect as time
progresses or need to substitute different drug
 Tachyphylaxis – responsiveness diminishes rapidly after administration of
a drug (the first few doses), very rapid tolerance

81
Pharmacodynamics
Variation in drug responsiveness
Four general mechanisms:
 1. Patients may differ in the rate of absorption of a drug, in
distributing it through body compartments, or in clearing the
drug from the blood which may alter the conc of drug that
reaches receptor
 This can be due to age, weight, sex, disease state, liver and kidney
function, and genetic differences
 2. Patients may vary in their concentrations of endogenous
receptor ligand
 Can vary in the response to pharmacologic antagonist
 Ex: Propranolol (β blocker)
 Pt with pheochromocytoma as opposed to healthy runner

82
Pharmacodynamics
 Variation in drug responsiveness
 Four mechanisms (cont.)
 3. Patients may have differences in the # of receptor sites or differ in the
function of their receptors due to the efficiency of coupling receptor to effector
 Drug Induced down-regulation
 The “overshoot” phenomena
 Antagonists – when discontinued, the elevated # of receptors can produce an
exagerated response to physiologic conc of agonist
 Agonist – when discontinued, # of receptors that have been dec by down regulation
is too low for endogenous agonist to produce effective stimulation
 Ex: Clonidine (α agonist) decreases blood pressure. When withdrawn, can produce
hypertensive crisis. Pt will have to be weaned slowly
 4. Patients vary in functional integrity of biochemical processes in the
responding cell and physiologic regulation by interacting organ systems
 Can be caused by age of pt or general health of pt. Most importantly, severity and
pathophysiologic mechanism of the disease
 Drug therapy will be most successful when there is correct diagnosis and if
it is accurately directed at the pathophysiologic mechanism responsible
for the disease

83
 Factors Affecting Drug Response

 Age  Time of Administration

 Body Mass  Pathology
 Sex  Genetics
 Environment  Psychology

84
 Pharmacokinetics

 How the drug is absorbed, distributed, and

eliminated; typically includes onset and duration
of action.

85
 Pharmacokinetics of drugs
(ADME)
Are studies of
 Absorption
 Distribution
 Metabolism
 Excretion of drugs

86
87
88
Is the passage of drug through cell
membranes to reach its site of action.

Mechanisms of drug absorption

1. Simple diffusion = passive diffusion.
2. Active transport.
3. Facilitated diffusion.
4. Pinocytosis (Endocytosis).

89
90
91
water soluble drug (ionized or polar) is readily
absorbed via aqueous channels or pores in cell
membrane.

Lipid soluble drug (nonionized or non polar) is

readily absorbed via cell membrane itself.

92
93
Characters
 common.
Occurs along concentration gradient. Non
selective
 Not saturable
 Requires no energy
 No carrier is needed
Depends on lipid solubility.
 Depends
pka of drug - pH of medium.
94
95
Drugs exist in two forms ionized (water soluble &
nonionized forms (lipid soluble) in equilibrium.
Drug ionized + nonionized

Only nonionized form is absorbable.

Nonionized / ionized fraction is determined
by pH and pKa according to Henderson-
Hasselbach
pKa- pH= log protonated / non-protonated

96
PKa of the drug
(Dissociation or ionization constant):
pH at which half of the substance is ionized &
half is unionized.

pH of the medium
.Affects ionization of drugs
– Weak acids  best absorbed in stomach.
– Weak bases  best absorbed in intestine.

97
Which one of the following drugs will be best absorbed in
?stomach (pH=3)
Aspirin pka=3.0
warfarin pka=5.0

Arrange the following drugs in ascending order from

least to greatest in rate of absorption in small intestine
?(pH=7.8)
=Propranolol pka 9.4
Aspirin pka=3.0
warfarin pka=5.0

98
 Relatively unusual.
Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.
 Iron absorption.
Uptake of levodopa by brain.

99
100
 Occurs along concentration gradient.
 Requires carriers
 Selective.
 Saturable.
 No energy is required.

101
102
Active transport Carrier-mediated
facilitated diffusion
Against concentration along concentration
gradient gradient
(From low to high) (From high to low)

Needs carriers Needs carriers

Selective, saturable Selective, saturable

Energy is required No energy is required

103
Passive transport Active transport

Along concentration against concentration

gradient gradient
(From high to low) (From low to high)
No carriers Needs carriers

Not selective Selective, saturable

Not saturable
No energy energy is required

104
Endocytosis: uptake of membrane-bound
.particles
Exocytosis: expulsion of membrane-bound
.particles
High molecular weight drugs or
Highly lipid insoluble drugs

105
106
Enteral
via gastrointestinal tract (GIT).
– Oral
– Sublingual
– Rectal
Parenteral administration = injections.
Topical application

107
 Advantages Disadvantages
Easy Slow effect
Self use No complete absorption
Safe (Low bioavailability).
Convenient Destruction by GIT
cheap First pass effect
No need for GIT irritation
sterilization Food–Drug interactions
Drug-Drug interactions
Not suitable for vomiting,
unconscious, emergency.
108
 First pass Metabolism
Metabolism of drug in the gut wall or portal
circulation before reaching systemic circulation
so the amount reaching system circulation is less
than the amount absorbed
Where ?
 Liver
 Gut wall
 Gut Lumen
Result ?
Low bioavailability.
Short duration of action (t ½).
109
First pass effect

110
Dosage forms
Capsules
Tablets
Syrup
Suspension
Hard- gelatin capsule Soft- gelatin capsule
Tablets Spansule

111
 Advantages Disadvantages
• Rapid effect (Emergency) Not for
• No first pass metabolism. irritant drugs
• High bioavailability Frequent use
• No GIT destruction
• No food drug
interaction
Dosage form: friable tablet

112
 Advantages Disadvantages
Suitable for Not for
–Vomiting & children. – Irregular
&unconsciousness absorption &
– Irritant & Bad taste drugs. bioavailability.
– less first pass metabolism – Irritation of
(50%) rectal mucosa.

Dosage form:
suppository or enema
113
Intradermal (I.D.) (into skin)
Subcutaneous (S.C.)
Intramuscular (I.M.)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)

114
115
 Advantages Disadvantages
• high bioavailability – Infection
• Rapid action (emergency) – Sterilization.
• No first pass metabolism – Pain
Suitable for – Needs skill
–Vomiting &unconsciousness – Anaphylaxis
– Irritant & Bad taste drugs. – Expensive.
– No gastric irritation
– No food-drug interaction
Dosage form:
Vial or ampoule 116
Ampoule Vial

117
 Produce local effect to
 Skin (percutaneous) e.g. allergy testing,
topical local anesthesia
 Mucous membrane of respiratory tract
(Inhalation) e.g. asthma
 Eye drops e.g. conjunctivitis
 Ear drops e.g. otitis externa
 Intranasal, e.g. decongestant nasal spray
118
 Advantages Disadvantages
• Mucous membrane of Only few
respiratory system drugs can be
• Rapid absorption used
(large surface area)
•Provide local action
• Minor systemic effect
• Low bioavailability
• Less side effects.
• No first pass effect
Dosage form: aerosol, nebulizer 119
Nebulizer Atomizer

120
 a medicated adhesive patch applied to skin
Slow effect (prolonged drug action) *
produce systemic effect *
e.g. the nicotine patches

121
 Is the fraction of unchanged drug that enters
systemic circulation after administration and
becomes available to produce action
I.V. provides 100% bioavailability.
Oral usually has less than I.V.

Bio = AUC oral / AUC IV X 100

122
123
Factors Affecting Bioavailability:

 Molecular weight of drug.

Drug Formulation (ease of dissolution).
(solution > suspension > capsule > tablet)
 Drug solubility of the drug
 Chemical instability in gastric pH
(Penicillin & insulin )
 First pass metabolism reduces bioavai

124
Factors Affecting Bioavailability (BAV):

 Blood flow to absorptive site

Greater blood flow increases bioavailability
Intestine has greater blood flow than stomach
 Surface area available for absorption.
Intestinal microvilli increases it
Rate of gastric emptying
rapid gastric emptying fast transit to
intestine
 pH of gut

125
Intestinal motility (Transit Time)
Diarrhea reduce absorption
Drug interactions
Food
slow gastric emptying
generally slow absorption
Tetracycline, aspirin, penicillin V

126
Know the 6 Rights of Medication
Administration
 Right Medication
 Right Dosage
 Right Time
 Right Route
 Right Patient
 Right Documentation

127
Special Considerations

 Pregnant Patients
 Pediatric Patients
 Geriatric Patients

128
Pregnant Patients
 Ask the patient if there is a possibility
that she could be pregnant.
 Some drugs may have an adverse
effect on the fetus of a pregnant female.
 Teratogenic drug…is a medication
that may deform or kill the fetus.

129
130
131
Routes Routes
of administration
of Administration
Drugs generally enter the body through one of four
methods: ingestion, injection, inhalation, and
absorption.
Ingestion, or oral administration, is the entry of drugs
through the mouth and into the digestive tract.

132
Routes… Routes…
Injection refers to the use of a needle to insert a drug
into the body
With inhalation, the drug enters the body through
the lungs.
Absorption refers to the administration of a drug
through the skin or mucous membranes.

133
134
135
136
137
138
Oral Oral
Advantages Disadvantages
- Convenient - Drug metabolism
- Large surface area for - Incomplete absorption
absorption - First pass effect
- Gastrointestinal (GI)
upset

139
IV Intravenous (IV)
Advantages Disadvantages
- Direct - Requires IV access
- No first pass effect - Hard to remove
- Slow infusions or rapid - Vascular injury, exctra-
onset of action vasation
- Easier to titrate dose

140
IM Intramuscular (IM)
Advantages Disadvantages
- Good for depot storage - Pain at site of injection
(if oil based)
- Rapid onset of action

141
SC Subcutaneous (SC)
Advantages Disadvantages
- Non irritating - Pain at site of injection
- Even slow absorption
- Adrenaline in local
anesthetic

142
Topical Topical
Advantages Disadvantages
- Convenient - Effects are limited to
- Limited systemic area of application
absorption
- Localized

143
Inhalation Inhalation
Advantages Disadvantages
- Rapid delivery to blood - Must be in gas, vapor or
- Local or systemic action aerosol form
- Immediate action in
lungs

144
Buccal Buccal
Advantages Disadvantages
- Rapid onset of action - Must be lipid soluble
- No first pass effect

145
 Transdermal
Transdermal
Advantages Disadvantages
- Direct application - Irritation at site of
- Rapid onset of action application
- Delayed onset of action

146
Most emergency
medications are given
intravenously to avoid drug
degradation in the liver.

147
What student should know

 Major body fluid compartments

 Concept of compartments.
 Apparent volume of distribution (vd).
 Plasma protein binding.
 Tissue binding.
 Redistribution

149
Is the process by which drugs leave blood
circulation and enters the interstitium and/or
the cells of the tissues.

150
151
 Sites of Absorption & distribution Elimination
Administration

152
The major body fluid compartments are
Extracellular fluid (22%)
- Plasma ( 5 % of body weight = 4 liters ).
- Interstitial fluid ( 16 % = 10 liters).
- Lymph ( 1 % ).

Intracellular fluid ( 35 % )
fluid present inside all cells in the body (28 L).

Transcellular fluid ( 2%)

cerebrospinal, intraocular, synovial, peritoneal,
pleural & digestive secretions.
153
 Total body fluids
(60% of body weight in 70-kg individual)

Plasma (4 L)

Total body
Fluids Interstitial fluids (10 L)
(42 Liters)
Intracellular volume ( 28 L)

154
 Apparent Volume of Distribution (Vd)
is the ratio of drug amount in the body to
the concentration of drug in blood

Vd (L)= total amount of drug in body (mg)

concentration in blood (mg/L)

Large Vd = means long duration of action

155
FACTORS AFFECTING DISTRIBUTION
1.Cardiac output and blood flow.
2. Physiochemical properties of the drug.
Molecular weight
Pka.
Lipid solubility.

3. Capillary Permeability
4. Plasma protein binding
5. Tissue binding.
156
Blood flow to organs

The greater the blood flow to tissues,

the more distribution that occurs from
plasma to interstitial fluids.

Drugs distribute more rapidly to brain,

liver and kidney > more than skeletal
muscles & fat.
157
 Physiochemical properties

Most lipid soluble drugs cross biological

membranes

Hydrophilic drugs do not readily cross

membranes but go through slit junctions

158
 Volume of Distribution (Vd)

Drugs with high Vd

 Have higher concentrations in tissues than in

plasma.
 Relatively lipid soluble.
 Distributed intracellularly
 Not efficiently removed by haemodialysis.
 e.g. phenytion, morphine, digoxin

159
 Volume of Distribution (Vd)

Drugs with low Vd

 confined to plasma & interstitial fluid.
 distributed in extracellular compartments.
 Polar comp or lipid insoluble drugs. e.g.
Carbenicillin, vecuronium, gentamycin.
 High MW e.g. heparin – insulin.
 High plasma protein binding e.g. warfarin.
 Do not cross BBB or placental barriers.
160
 Capillary permeability
Endothelial cells of capillaries in tissues
other than brain have wide slit junctions
allowing easy movement & distribution.

Brain has tight junction Blood Brain

Barrier (BBB).

161
Blood brain barrier (BBB):
 Only lipid soluble drugs or carrier mediated
transport can cross BBB.
 Hydrophilic drugs (ionized or polar drugs)
can not cross BBB.
 Inflammation as in meningitis increase
permeability to hydrophilic drugs
 e.g. penicillin & gentamycin

Placental barrier
 Lipid soluble drugs can cross placental
barrier and enter the fetal blood.
162
163
164
165
166
Binding of Drugs

Plasma proteins binding.

Tissue proteins binding.

167
Plasma protein binding

 Drugs can bind to plasma proteins (acidic

drug bind to albumin while basic drugs bind to
glycoprotein)

 Drugs exist in two forms bound and unbound

forms in equilibrium

Drug unbound drug (free) + bound drug

168
 Tissues Binding
Drugs can bind to specific tissue

Tetracycline bind to bone

Iodides accumulate in salivary & thyroid glands

169
bound form of drug Unbound form of drug

 non diffusible form  diffusible form

 can not combine with  combine with receptors
receptors
 not available for
available for elimination
elimination

 has long duration of

has short duration of
action (t ½).
action (t ½).
170
Characters & consequences of Binding

Usually reversible.
 determines volume of distribution (vd)
Slows drug metabolism & excretion.
Prolongs duration of drug action (t1/2).
Result in clinically important drug
interactions.

171
 Redistribution
Redistribution of the drug from its site of action
to other tissues e.g. thiopental

Termination
 Biotransformation.
 Excretion.
 Redistribution.

172
By the end of this lecture, students should:
Recognize the importance of biotransformation
Know the different sites for drug metabolism
Define the major phase I and phase II metabolic reactions.
Describe the modulation of liver microsomal enzymes by
inducers and inhibitors
Mention two drugs that are known as enzyme inducers and
inhibitors.
Know the impact of first pass metabolism on drug bioavailability.

174
 Drug Metabolism
(Biotransformation)
Definition
Chemical reactions which lead to modification of

drugs.

Importance of metabolism
Termination of drug action
Enhance excretion by transforming the drug to a

less lipid soluble, less readily reabsorbed form.

175
Organ sites of drug metabolism
Liver (the major site).
Intestinal Mucosa and Lumen
Kidney
Skin
Lung
Plasma

176
 Cellular sites of drug metabolism

Cytosol
Mitochondria
Lysosomes
Smooth endoplasmic reticulum
(microsomes)
Microsomal enzyme system = mixed
function oxidase = mono-oxygenase =
Cytochrome P-450.
177
TYPES OF METABOLIC REACTIONS

Phase I Reactions

Phase II Reactions

178
Phase I reactions
Oxidation.
Reduction.
Hydrolysis.

Phase II reactions
 Conjugation reactions

179
Oxidation Reactions
.Microsomal oxidation (CYT-P450)
Oxidation by cytochrome P450 enzymes
.Non-microsomal oxidation
Oxidation by soluble enzymes in cytosol or
mitochondria of cells (as oxidases and
dehydrogenases) e.g. monoamine oxidase (MAO)
.and alcohol dehydrogenase

180
Reduction reactions
Microsomal reduction
Non microsomal reduction

Hydrolysis
All are non microsomal
Drugs affected are either esters or amides
Hydrolysis occurs by enzymes (esterases or
amidases) e.g. acetylcholine and lidocaine
181
 Phase I reactions can result in

 Inactivation of drug (termination of action)

 Conversion of active drug to another active
metabolite.
 Conversion of drugs to toxic metabolites.
Paracetamol  acetaminophen hepatotoxicity
 Activation of pro-drug
 Product might undergo phase II.

182
 Phase II Conjugation Reactions

Conjugation of metabolite (phase I) with

endogenous substance as methyl group, acetyl
group, sulphate, amino acid or glucouronic
acid to produce conjugate that is water soluble
.and easily excreted

183
 Types of conjugation reactions
Conjugation reaction Enzyme required

glucouronide conjugation glucouronyl transferase

Acetylation N-acetyl transferase

Sulphation Sulfotransferase

Methylation methyl transferase

Amino acids conjugation

184
Phase II reactions:

All are non microsomal except

glucouronidation
Deficieny of glucouronyl transferase enzyme

in neonates may result into toxicity with

chloramphenicol (Gray baby syndrome).

185
Characteristics of Phase II
Products
Usually Pharmacologically inactive.
Polar
more water soluble.
more readily excreted in urine.

186
187
Factors affecting metabolism
Age
Nutrition
Genetic Variation
Diseases
Gender
Degree of Protein Binding
Enzyme Induction & inhibition
Route of Drug Administration

188
Modulation of liver microsomal enzymes
 Efficacy of liver microsomal enzymes may be
changed.
 Drugs that increase activity of liver microsomal
enzymes are called liver microsomal enzymes
inducers.
 Drugs that decrease activity of liver microsomal
enzymes are called liver microsomal enzymes
inhibitors.

189
 Microsomal Microsomal
Inducers Inhibitors

Cimetidine
Alcohol
Erythromycin (antibiotic)
Cigarette smoking Ketoconazole (antifungal)
Phenobarbitone hypnotic Grape fruits
Phenytoin (antiepileptic) Isoniazid
Rifampicin (Anti TB) Disulfuram
Grisofulvin (antifungal) Chloramphenicol
Primaquine
Probenicid

190
Enzyme induction may result in:
increase metabolism of the inducer.
Tolerance : decrease in its pharmacological
action
Drug interactions: increase the metabolism and
excretion of co-administered drugs
phenytoin & Oral contraceptives.

191
 Enzyme inhibition may

Delay the metabolism and excretion of the

inhibitor and co-administered drugs.

Prolong the action of the inhibitor & co-

administered drugs.

192
Drug Disposition

193
 Excretion of Drugs
By the end of this lecture, students should be able to
Identify main and minor routes of Excretion including
renal elimination and biliary excretion
Describe enterohepatic circulation and its
consequences on duration of drugs.
Describe some pharmacokinetics terms including
clearance of drugs.
Biological half-life (t ½), multiple dosing, steady state
levels, maintenance dose and Loading dose.

194
Routes of Excretion
Main Routes of Excretion
 Renal Excretion
 Biliary Excretion

Minor Routes of Excretion.

 Exhaled air (Exhalation)
 Salivary
 Sweat
 Milk
 Tears

195
 Renal Excretion
Structure of kidney
The structure unit of kidney is nephron
That consists of :
 Glomerulus
 Proximal convoluted tubules
 Loop of Henle
 Distal convoluted tubules
 Collecting ducts

196
Kidney
197
Renal Excretion includes

Glomerular filtration.
 Passive tubular reabsorption.
 Active tubular secretion.

198
199
Polar drug= water soluble
Non polar drug = lipid soluble

200
Glomerular filtration (GFR):
 Depends upon renal blood flow (600 ml/min)
 GFR 20% of RPF = 125 ml/min.
 Glomerular filtration occurs to
 Low MW drugs
 Only free drugs (unbound to plasma proteins)
are filtered.

201
Tubular secretion:
 occurs mainly in proximal tubules; increases
drug conc. in lumen
 organic anionic and cationic tranporters
mediate active secretion of anioinc and
cationic drugs.
 can transport drugs against conc. gradients.
 Penicillin is an example of actively secreted
drug.
 Passive diffusion occurs for uncharged
drugs

202
Passive tubular reabsorption
In distal convoluted tubules & collecting ducts.
Passive diffusion of unionized, lipophilic drugs
Lipophilic drugs can be reabsorbed back into
blood circulation and urinary excretion will be
Low.
Ionized drugs are poorly reabsorbed & so
urinary excretion will be High.

203
Urinary pH trapping (Ion trapping)
 Changing pH of urine via chemicals can inhibit or
enhance the tubular drug reabsorption. used to
enhance renal clearance of drugs during toxicity.
 Urine is normally slightly acidic and favors excretion
of basic drugs.
 Acidification of urine using ammonium chloride
(NH4Cl) increases excretion of basic drugs
(amphetamine).
 Alkalization of urine using sodium bicarbonate
NaHCO3 increases excretion of acidic drugs
(aspirin).
204
Renal Excretion
Drugs excreted mainly by the kidney include:
 Aminoglycosides antibiotics (Gentamycin)
 Penicillin.
 Lithium

These drugs are contraindicated in

 Renal disease.
 Elderly people

205
Biliary Excretion
 Occurs to few drugs that are excreted into
feces.
 Such drugs are secreted from the liver into bile
by active transporters, then into duodenum.
 Some drugs undergo enterohepatic circulation
back into systemic circulation

206
Enterohepatic circulation
Drugs excreted in the bile in the form of
glucouronides will be hydrolyzed in intestine
by bacterial flora liberating free drugs that
can be reabsorbed back if lipid soluble.
This prolongs the action of the drug. e.g.
Digoxin, morphine, thyroxine.

207
208
Plasma half-life (t ½)
is the time required for the plasma concentration of
a drug to fall to half.
Is a measure of duration of action.
Determine the dosing interval

Drugs of short plasma half life

Penicillin, tubocurarine.
Drugs of long plasma half life
Digoxin, thyroxine, arsenic.

209
Factors that may increase half-life (t ½ )
Decreased metabolism
Liver disease.
Microsomal inhibitors.

Decreased clearance
Renal disease.
Congestive heart failure.

High binding of drugs

Plasma proteins.
Tissue binding.

Enterohepatic recycling

210
Loading dose
is the large initial dose that is given till the required
therapeutic plasma level is rapidly reached.

Maintenance doses
are the doses required to maintain the therapeutic level
of the drug. These doses balance the clearance of the
drug.

211
Steady state levels.
A state at which the plasma concentration of the
drug remains constant.
Rate of drug administration = Rate of drug
elimination.

212
Steady state of a drug

213
Polar drugs are readily excreted and poorly
reabsorbed. Summary
Lipid soluble drugs are reabsorbed back and
excretion will be low
Acidic drugs are best excreted in alkaline urine
(sodium bicarbonate).
Basic drugs are best excreted in acidic urine
(ammonium chloride).
Enterohepatic circulation prolongs half life of the
drug.

214
Questions?

215