BASIC PHARMACOLOGY

Desalegn Y.

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 Course content

1. Basic principles of pharmacology

2. Drugs acting on the autonomic nervous system
3. Drugs acting on the cardiovascular system
4. Drugs acting on blood and blood forming organs
5. GIT pharmacology
6. Drugs acting on the respiratory system
7. CNS pharmacology
8. Endocrine pharmacology
9. Chemotherapy of infectious diseases

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1. BASIC PRINCIPLES OF
PHARMACOLOGY

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 Learning Objectives
 After completing this chapter, students will be able to
• Summarize important points in the history of pharmacology
• Define some important terminologies
• Discuss stages of new drug development
• Differentiate drug names
• Identify sources of drugs
• Discuss pharmaceutical dosage forms
• Discuss pharmacodynamics
• Discuss pharmacokinetics

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some important points regarding the history of
pharmacology
 medicaments have been used for treating disease in humans
and animals since time immemorial

 Early knowledge about curative powers of plants and certain

substances------?????

rested on empirical information not subjected

to critical examination.
 Claudius Galen (129–200 A.D.)

• first attempted to consider the theoretical background of

pharmacology
 Both theory and practical experience were to contribute
equally to the rational use of medicines 5
 Theophrastus von Hohenheim (1493–1541 A.D.), also called
Paracelsus
 prescribed chemically defined substances with such success
(not irrational concoctions and mixtures)

 Said “All things are poison, nothing is without poison; the

dose alone causes a thing not to be poison.”

 Johann Jakob Wepfer (1620–1695)

 was the first to verify by animal experimentation assertions

about pharmacological or toxicological actions

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 Rudolf Buchheim (1820–1879)

 Founded the first institute of pharmacology at the

University of Dorpat (Tartu, Estonia) in 1847

 Late 19 and early 20 century

 Fundamental concepts such as structure-activity

relationship, drug receptor, and selective toxicity emerged

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 Definition of terms
 Pharmacology:
 from Greek words, pharmacon -drug; logos -discourse in
 is the study of drugs and their interaction with living
systems.
 It studies what our body does to the drug and what the
drug does to our body

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 Drugs:
 chemicals that alter functions of living organisms
 generally given for the diagnosis, prevention, control or cure of
disease

 Clinical pharmacology:
 the study of drugs in humans (patients as well as in healthy
volunteers) about the drug effect, route of administration,
dosage regimen etc

 Pharmacotherapeutics:
 the use of drugs to diagnose, prevent or treat diseases or to
prevent pregnancy

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 Toxicology :

 a branch of pharmacology
 studies harmful effects of chemical agents on living
systems
 i.e the science of poisons

Drugs Vs Poisons ?????

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 pharmacodynamics:
– Deals with the effects of drugs and the mechanisms of drug
actions)

 pharmacokinetics: ADME
– refers the absorption, distribution, metabolism, and excretion
of a drug

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 Drug Names
Chemical
• Use nomenclature of chemistry
name

• Or brand name or proprietary name

• protected by copyright
Trade name • symbol ® after the trade name
• Given by the company producing it

• abbreviation of the chemical name

Generic
name
• approved by international body
• A single and common name for the same type of drugs

Code Name
•Name given during investigation
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Type of drug name Examples
Chemical name N-acetyl-para-aminophenol
Generic name Paracetamol
Trade name Panadol, Tylenol, Dapa,
Valadol, Valorin, Helenol, etc

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 Sources of Drugs
• Drugs are obtained from:
Minerals e.g. magnesium sulfate, magnesium trisilicate,
kaolin, etc.

Animals e.g. Insulin, thyroid extract, heparin etc.

Plants e.g. Morphine, digoxin, atropine, castor oil, etc.

Synthetic source e.g. Aspirin, sulphonamides, paracetamol,
etc.

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 Microorganisms e.g. Penicillin, streptomycin and many
other antibiotics.

Genetic engineering e.g. Human insulin, human growth

hormone etc.

 Traditionally, drugs were derived from natural sources, such as:

plants, animals, minerals

 Out of all the above sources, majority of the drugs currently used
in therapeutics are from synthetic source.

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 pharmaceutical dosage forms
 Dosage form:

– is the pharmaceutical preparation with unique

characteristics
– makes dosage possible
» Is a mixture of active component and non-drug
components

» Can be generally classified as solid dosage forms,

semisolid dosage forms , liquid dosage forms and
aerosols

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Solid dosage forms
– Powders and granules
– Capsules
– Tablets(conventional or modified release
preparations)
– Suppositories
– Implants

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Semisolid dosage forms
– Ointments
– Creams
– Gels
– pastes
Liquid dosage forms
– Solutions
– Emulsions
– suspensions

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Gaseous dosage forms
– Gases such as inhalational anesthetics
– Aerosols like antiasthmatics

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 The pharmaceutical dosage form has influence on the:
Onset of effect
Adverse effects

Acceptability by the patient/convenience of

administration

Compliance by the patient

Stability of the drug

Cost etc

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 Drug categories
I. Non-prescription drugs/over the counter drugs

II. Prescription drugs/legend drugs: Normal and Controlled

Substances
 Pharmacodynamic and chemotherapeutic drugs

What does this mean???? What is the logic behind???

Another classification ways of drugs????...

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 Pharmacokinetics
From two words

- pharmacon------------ drug

- kinesis------------------ motion
 It deals with what the body does to the drug
 The four major pharmacokinetic processes are: ADME

I. Drug absorption
 the movement of drugs from the site of administration
into the blood.

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II. Drug distribution

• drug movement from the blood to the interstitial space

of tissues and from there into cells.
III. Drug metabolism
• enzymatically mediated alteration in drug structure.

IV. Drug excretion

• movement of drugs (and their metabolites) out of the

body.

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The four basic pharmacokinetic processes.

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 – All phases of PKs
• involve drug movement
• Determine the concentration of a drug at its sites of action.
• Factors that determine the passage of drugs across
membranes have profound influence on all phases.

Passage of drugs across membranes

– it is translocation of a drug from one side of the
biological barrier to the other.
– biological membrane: a thin structure covering the
outer surface of the cell and also known as plasma
membrane/cell membrane

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Fig-cell membrane
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 – It is composed of lipid and protein molecules.
• The membrane proteins have many functions like:

a) contributing structure to the membrane

b) acting as enzyme

c) acting as carrier for transport of substances

d) acting as receptors.

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• How do drugs cross cellular membranes ?
A. Passive transfer
1) Simple passive diffusion
 solute mov’t from the phase of higher concentration to
phase of lower concentration.
 e.g. highly lipid soluble drugs.
2) Filtration
 water soluble drug of relatively low molecular weight
e.g. urea
 Mov’t through membrane pores as a result of
hydrodynamic pressure gradient across the membrane

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B. Specialized transport

1) Facilitated diffusion e.g. Tetracycline

2) Active transport e.g. Levodopa

3) Endocytosis e.g. protein

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Characteristics Simple Facilitated Active
diffusion diffusion transport
Incidence Commonest Less common Least common

Process Slow Quick Very Quick

Movement Along Along Against

concentration concentration concentration
gradient gradient gradient

Carrier Not needed Needed Needed

Energy Not required Not required Required

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 Routes of Drug Administration
– A drug’s administration route influences the
quantity given and the rate at which the drug is
absorbed and distributed.
– These variables affect the drug’s action and the
patient’s response.
– There are two major routes of drug administration
I. Enteral (by mouth)-eg oral, sublingual
II. Parenteral commonly refers to intravenous,
intramuscular, and subcutaneous routes

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ROA…
I. Enteral

A. Oral/peroral
this is usually the safest, most convenient, and least
expensive route and administration is easy

toxicities or overdose by the oral route may be overcome

with antidotes such as activated charcoal or by inducing
vomiting

 Some drugs are absorbed from the stomach but the

duodenum is a major site of entry to the blood because of
its larger absorptive surface

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• Most drugs absorbed from the GI tract enter the portal
circulation and encounter the liver before they are
distributed into the general circulation

These drugs undergo first-pass metabolism in the liver

and may be extensively metabolized
 First-pass metabolism by the intestine or liver limits the
efficacy of many drugs when taken orally

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– Drugs that exhibit high first-pass metabolism should be given
in sufficient quantities to ensure that enough of the active
drug reaches the target organ

The presence of food in the stomach delays gastric

emptying
– It may increase gastric absorption, delay the intestinal
absorption or expose the drug for the harsh acidic
environment
• Enteric coating of a drug can protect it from the acidic
environment
» in addition, it may prevent gastric irritation and
produce a sustained release effect.

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high variability of absorption, drug inactivation by
gastric pH, first-pass effect, requires compliance,
local GIT irritation are generally disadvantages of
the oral route.
Used to administer drugs to patients who are
conscious and can swallow

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B. Sublingual
– Refers placement of the drug under the tongue

– a drug diffuses into the capillary network and therefore

enter the systemic circulation directly

 Advantages
» rapid absorption, convenience of administration, low
incidence of infection, avoidance of the harsh GI
environment, and avoidance of first-pass metabolism.

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C. Buccal

– in the pouch between the cheek and gum

 Buccal and sublingual routes speed drugs absorption or
prevent their destruction or transformation in the stomach
or small intestine

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II. Parenteral
 introduces drugs directly into the systemic circulation
or other vascular tissue.
 The three major parenteral routes are
i. intravascular (intravenous or intra-arterial),

ii. intramuscular, and

iii. Subcutaneous

is used for drugs that are poorly absorbed from the GI
tract and for agents that are unstable in the GI tract

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for treatment of unconscious patients
under circumstances that require a rapid onset of
action.
No first-pass metabolism or harsh GI
environments
provides the most control over the actual dose of
drug delivered to the body

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Intravenous (IV):
– the most common parenteral route
no need of absorption; rapid onset; precise
control over levels; can use large volumes of
fluids; used for irritating drugs.
High cost; cannot self-administer; painful, cannot
reverse injection; could cause fluid overload;
increased risk of infection; risk of embolism;
chance of error in administration

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Intramuscular (IM):
The only barrier is capillary wall; used for poorly
soluble drugs; for depot preparations to decrease
number of injections
Inconvenience; discomfort with administration.
– Drugs administered IM can be aqueous solutions
or specialized depot preparations often a
suspension of drug in a non aqueous vehicle

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– Absorption of drugs in an aqueous solution is fast
– As the vehicle diffuses out of the muscle, the drug
precipitates at the site of injection. The drug then
dissolves slowly, providing a sustained dose over
an extended period of time.

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Subcutaneous (SC):
 small amounts of a drug are injected beneath the
dermis and into the subcutaneous tissue, usually in
the patient’s upper arm, thigh, or abdomen
 minimizes the risks associated with intravascular
injection
 Minute amounts of epinephrine are sometimes
combined with a drug to restrict its area of action.
 Epinephrine acts as a local vasoconstrictor and
decreases removal of a drug, such as lidocaine, from
the site of administration.
 Solids can also be implanted eg norplant

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Inhalation:
– provides the rapid delivery of a drug across the
large surface area of the mucous membranes of
the respiratory tract and pulmonary epithelium
– producing an effect almost as rapidly as with IV
injection.
– particularly effective and convenient for patients
with respiratory complaints (such as asthma, or
chronic obstructive pulmonary disease) because
the drug is delivered directly to the site of action
and systemic side effects are minimized

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 Rectal:
– Fifty percent of the drainage of the rectal region
bypasses the portal circulation
– useful if the drug induces vomiting when given
orally, if the patient is already vomiting, or if the
patient is unconscious
– However rectal absorption is often erratic and
incomplete, and many drugs irritate the rectal
mucosa.

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Topical:

 is used to deliver a drug through the skin or a mucous

membrane; it’s used for most dermatologic, ophthalmic, and
nasal preparations.

 Topical application is used when a local effect of the drug is

desired.

 Eg directly on skin or to the eye

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 Transdermal:
 This route of administration achieves systemic effects
by application of drugs to the skin, usually via a
transdermal patch.

 This route is most often used for the sustained delivery

of drugs, such as the antiemetic scopolamine
• Others routes?

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 Absorption
– It is the movement of drugs from the site of administration
into the blood.

» The rate of absorption determines how soon its

effects will begin

» The amount determines the intensity of a drug

effects .

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 Bioavailability(F)
 It is the rate and amount of drug that is absorbed from a
given dosage form and reaches the systemic circulation

 For an IV infusion, all the drug administered appears in the

plasma, and so bioavailability = 100%

 Bioavailability is often expressed as fractional bioavailability,

F.

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 Factors affecting drug absorption
a) Physico-chemical properties of drug

Physical state
Lipid or water solubility
Ionization
» Drugs, like most organic electrolytes, generally do not
completely dissociate (i.e., form ions) in aqueous
solution at a given PH.

» most drugs are either weak organic acids or bases

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 The Henderson-Hasselbach equations:
pH = pKa + log [R-]/[RH] (for acid)
pH = pKa + log [B]/[BH+] (for base)
– when administered orally:
» Acidic drugs: rapidly absorbed from the stomach e.g.
salicylates and barbiturates.
» Basic drugs: absorbed in small intestine e.g. pethidine
and ephedrine.
?????????????????????????

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b) Nature of the dosage form
– Particle size, Disintegration time and
dissolution rate, formulation(ingredients)
– Special drug delivery system
c) Physiological factors
– Gastrointestinal transit time and
– first pass effect
– enterohepatic circulation
d) Pharmacogenetic factors
e) Disease states. eg malabsorption, cirrhosis
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 Distribution
Is drug movement from the blood to the interstitial
space of tissues and from there into cells.
 The distribution of any given drug is determined by three major
factors:
I. Blood flow to tissues
II. Exiting the Vascular System
» Typical capillary beds
» the Blood brain barrier,
» placental barrier ,
» Plasma protein binding (free drug can leave blood)

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III. Entering Cells /tissue tropism: Affinity of drugs to certain
organs Eg Iodine for the thyroid tissue.

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 Volume of distribution

– It is a hypothetical volume of fluid into which a drug is

dispersed.

– Once a drug enters the body, from whatever route of

administration, it has the potential to distribute into
any one of three functionally distinct compartments of
body water or to become sequestered in a cellular site.

– VD= dose/plasma concentration

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1. Plasma compartment:

– is about six percent (6%) of the body weight or, in a 70-kg

individual, about 4 L of body fluid.

– When a drug is unable to move out through the

endothelial slit junctions of the capillaries, it is effectively
trapped within the plasma (vascular) compartment.

 This occurs:-

» If a drug has a very large molecular weight or

» binds extensively to plasma proteins

• Eg Heparin shows this type of distribution

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2. Extracellular fluid

– It is the sum of the plasma water and the interstitial

fluid

– is about 20% of the body weight, or about 14 L in a 70-

kg individual

Distribution into this compartment involves

movement of drug through the endothelial slit
junctions of the capillaries into the interstitial fluid.
This occurs:-
– If a drug has a low molecular weight but is hydrophilic.
Eg Aminoglycoside antibiotics

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3. Total body water

 Is about 60% of body weight, or about 42 L in a 70-kg

individual.

 A drug can leave blood vessel, interstitial space and enter

cells if:-
It has a low molecular weight and is hydrophobic
eg ethanol

Other sites:
In pregnancy, the fetus may take up drugs and thus increase
the volume of distribution.
extremely lipid-soluble, such as thiopental may also have
unusually high volume of distribution
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– any factor that increases the volume of distribution can lead to
an increase in the half-life and extend the duration of action of
the drug.
» because drug elimination depends on the amount of
drug delivered to the metabolizing organ per unit of
time

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 Binding of Drugs to Plasma Proteins
 Many drugs circulate in the bloodstream bound to plasma
proteins.
 The binding is usually reversible
 Plasma proteins are too large to leave the blood stream
 albumin :
 is a major carrier for acidic drugs
 a1-acid glycoprotein: binds basic drugs
 Bound drugs are pharmacologically inactive; only the free,
unbound drug can act on target sites in the tissues, elicit a
biologic response, and be available to the processes of
elimination
 A drug is said to be highly protein -bound if more than 80% of the
drug is bound to protein
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 Metabolism (Biotransformation)

 Refers enzymatically mediated alteration of drug

structure.
 Liver is the major organ for biotransformation of
drugs.
»but specific drugs may undergo
biotransformation in other tissues, such as the
kidney and the intestines.
 Most drugs are metabolized into inactive metabolites

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 Enzymes responsible for metabolism of drugs
1. Microsomal enzymes:

 Present in the smooth endoplasmic reticulum of the liver,

kidney and GIT

 e.g. glucuronyl transferase, dehydrogenase , hydroxylase and

cytochrome P450

 CYP3A4: 3 - family, A - subfamily, 4- individual isoenzymes

2. Non-microsomal enzymes:

 Present in the cytoplasm, mitochondria of different organs.

 e.g. esterases, amidase, hydrolase.
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Types of biotransformation

 Classified as phase-I and phase – II

 In phase-I reaction the drug is converted to more polar

metabolite.

 Some metabolites may not be excreted and further

metabolised by phase –II reactions.

 Phase-I: Oxidation, reduction and hydrolysis.

» The Phase I reactions most frequently involved in

drug metabolism are catalyzed by the cytochrome
P450 system (also called microsomal mixed function
oxidase)

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 Phase-II: Glucuronidation, sulfate conjugation, acetylation,
glycine conjugation and methylation reactions.

 NB: Not all drugs undergo Phase I and II reactions in

this order.
» For example, isoniazid is first acetylated (a Phase
II reaction) and then hydrolyzed to isonicotinic
acid (a Phase I reaction).

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Therapeutic Consequences of Drug Metabolism
1) Promotion of renal excretion

2) Reduction of therapeutic action

3) Activation of a prodrug

4) Enhancement of therapeutic action and

5) Alteration of toxicity

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70
Factors affecting drug metabolism

1. Age
2. Chemical properties of the drug

3. First Pass Effect

4. Nutritional Status

5. Genetics
6. Dosage

7. Competition between drugs

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 Excretion
 Removal of drugs from the body (altered or not)

 Excretion can be categorized as Renal vs non renal and Major vs minor

 The major processes of excretion include:

renal excretion

i. glomerular filtration

 The glomerular filtration rate (125 mL/min) which is 20% of the

renal plasma flow (600 mL/min)

 Lipid solubility and pH do not influence GF of drugs

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ii. active tubular secretion
– primarily occurs in the proximal tubules by two carrier systems,
one for anions and another for cations and both show low
specificity

iii. passive tubular reabsorption

– Happens in the distal tubule

– Changing the PH of the urine can be used to enhance drug

excretion particularly in drug overdose
– weak acids can be eliminated by alkalinization of the urine,
whereas elimination of weak bases may be increased by
acidification of the urine

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• For example, a patient presenting with
phenobarbital (weak acid) overdose can be
given bicarbonate, which alkalinizes the urine
and keeps the drug ionized, thereby decreasing
its reabsorption.
• If overdose is with a weak base, such as
cocaine, acidification of the urine with NH4Cl
leads to protonation of the drug and an increase
in its clearance.
 hepatobiliary excretion

– enterohepatic cycling may prolong the drug

action
pulmonary excretion. Eg inhalation anaesthetics

 The minor routes of excretion are saliva, sweat, tears, breast

milk, vaginal fluid, nails and hair.
 The rate of excretion influences the duration of action of drug

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 Clinical Pharmacokinetics/
Time Course of Drug Responses
Plasma Drug Levels

 Clinical significance of plasma drug levels—there is usually

direct correlation between therapeutic and toxic responses
and plasma drug levels.

 Two plasma drug levels defined

a) Minimum effective concentration (MEC)

 is defined as the plasma drug level below which
therapeutic effect will not occur.

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 b) Toxic concentration – the plasma drug level at which
toxic effects begin is termed as toxic concentration.

 Therapeutic range (between MEC and toxic levels)—is the

objective of drug dosing

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Single-Dose Time Course

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Drug Half-Life (t1/2)
– time required for amount of drug in the body to
decrease by 50%

Drug Levels Produced with Repeated Doses

– with repeated administration, plateau level is
achieved
– plateau level is the steady state (elimination
equals administered dose)

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Figure. Drug accumulation with repeated administration.(first
order kinetics)

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 – Time of plateau—Reached in about 4 half-lives

– Decline from plateau—About 94% eliminated in 4 half-lives.

Techniques for reducing fluctuations in drug levels

 Continuous infusion

 Reduce dosage size while reducing dosing interval

 Loading doses - one or a series of doses that may be given at the onset
of therapy with the aim of achieving the target concentration rapidly.

 Maintenance doses. The plateau can be maintained with smaller dose

called maintenance dose.

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 Order of kinetics
 First order:

– the most common process for many drugs

– The rate at which ADME occur are proportional to the concentration of drugs
i.e. constant fraction of a drug in the body disappears in each equal interval of
time.

 Zero order :

– constant amount of the drug is eliminated in each equal interval of time.

– On repeated administration of drug, after certain stage it goes on

accumulating in the body and leads to toxic reactions.

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Zero and 1st order kinetics
clearance
– The total body (systemic) clearance, CLtotal or CLt,
is the sum of the clearances from the various
drug-metabolizing and drug-eliminating organs.
– The kidney is often the major organ of excretion;
however, the liver also contributes to drug loss
through metabolism and/or excretion into the
bile.

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 Dosage regimen
• Fixed dosing
• Variable dosing
– Loading dose

– Maintenance dose

– Intermittent oral dose

1/21/2022 Desalegn Y. MSc. Pharmacology 85
• Questions 1–2. Mr Jones is admitted to the hospital with cough,
shortness of breath, and fever. History, physical examination, and
culture of the sputum lead to a diagnosis of pneumonia due to gram-
negative bacteria. The antibiotic tobramycin is ordered. The
clearance and Vd of tobramycin in Mr Jones are 80 mL/min and 40
L, respectively.
1. What maintenance dose should be administered intravenously
every 6 h to eventually obtain average steady-state plasma
concentrations of 4 mg/L?
(A) 0.32 mg
(B) 19.2 mg
(C) 115 mg
(D) 160 mg
(E) 230 mg
2. If you wish to give Mr Jones an intravenous loading dose to
achieve the therapeutic plasma concentration of 4 mg/L rapidly,
how much should be given?
(A) 0.1 mg
(B) 10 mg
(C) 115.2 mg
(D) 160 mg
(E) None of the above Desalegn Y. MSc. Pharmacology
1/21/2022 86
Qusetion 3 : A target plasma theophylline
concentration of 10 mg/L is desired to relieve
acute bronchial asthma in a normal patient.
Clearance is 2.8 L/h/70kg , IV dosing rate is ?
• After relieve acute asthma, oral theophyline that
maintain plasma concentration intends to be
given every 12 hour, F oral is 96%, what is the
size of each maintenance dose?

1/21/2022 Desalegn Y. MSc. Pharmacology 87

 ADJUSTMENT OF DOSAGE WHEN
ELIMINATION IS ALTERED BY DISEASE
• Renal impairment: adjusted by patients creatinine
clearance
OR

• normal creatinine clearance (approximately 100 mL/min, or 6

L/h)
• ignores nonrenal routes of clearance so…
E.g. if a drug is 50% cleared by the kidney and 50% by the
liver and the normal dosage is 200 mg/d. Therefore, the
corrected dosage in a patient with a creatinine clearance of 20
mL/min will be:
1/21/2022 Desalegn Y. MSc. Pharmacology 88
 Half life/Elimination half life
• is the time taken for its plasma concentration to be reduced
to half of its original value.

• First order kinetics-t1/2 remains constant because V and CL

do not change with dose. Zero order kinetics - t1/2 increases
with dose because CL progressively decreases as dose is
increased.
• 1 t1/2- 50 % drug is eliminated.
2 t1/2 - 75% (50+ 25)drug is eliminated.
3 t1/2- 87.5 % (50+ 25 + 12.5)drug is eliminated
4 t1/2 - 93.75"/'(50 + 25 + 12.5+ 6.25)drug is eliminated.
• Larger t1/2 needs loading dose, short t1/2 doesn’t require
loading dose
1/21/2022 Desalegn Y. MSc. Pharmacology 89
 Pharmacodynamics
 The basic principles of pharmacology include:-
Pharmacokinetics:
– deals with what the body does to the drug (ADME)

Pharmacodynamics:

– Is the study of what drugs do to the body

(biochemical and physiological effects) and how they
do it (mechanisms).

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 Principle of drug action
• Unless gene based, drugs doesn’t impart new
function

• Common types of drug action

– Stimulation
– Depression
– Replacement
– cytotoxic
Mechanisms of drug action
1. Receptor involving mechanism
» the drugs act by interacting with a cellular
component called receptor
» Is the mechanism for most drugs

2. non-receptor mechanisms:
» Some drugs act through simple physical or
chemical reactions without interacting with any
receptor. Eg antacids, charcoal, osmotic
diuretics

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 Receptor:-
 a macromolecule typically made of proteins
 either on the cell surface or with in the cell eg
adrenergic receptors, steroid receptors
 Functions of receptor:
 Ligand binding
 Activation of an effector system

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 Major Receptor Families

 These receptors may be divided into four families:

1. ligand-gated ion channels,
2. G protein coupled receptors,
3. enzyme-linked receptors, and
4. intracellular receptors

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A. Ligand-gated ion channels

 This family of receptors are responsible for regulation

of the flow of ions across cell membranes by binding
with ligands
 Response to these receptors is very rapid (durations
of a few milliseconds)

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B. G protein coupled receptors
 G protein - refers guanine nucleotide binding
proteins
 These receptors are comprised of a single peptide
that has seven membrane-spanning regions
 The specific binding sites for agonists occur at the
extracellular surface, while the interaction with G
proteins occurs with the intracellular portions of the
receptor.

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– signal transduction
» the general term for any chain of events initiated by
receptor activation
– G proteins couple the activation of several different receptors
to the next step in a chain of events
– Many receptors are coupled to adenylate cyclase through
either a stimulatory (GS) or an inhibitory (Gi) G protein.
– Stimulation of these receptors results in responses
that last several seconds to minutes.

98
 – The transduction process that links drug occupancy
of receptors and pharmacologic response is often
termed coupling
 Second messengers:

 are essential in conducting and amplifying signals

coming from G protein receptors.
 Eg cyclic adenosine monophosphate (cAMP),
inositol-1,4,5-trisphosphate and diacylglycerol,
cGMP

99
C. Enzyme-linked receptors
– These family of receptors have cytosolic enzyme
activity as an integral component of their structure
or function
» Binding of a ligand to an extracellular domain
activates or inhibits this cytosolic enzyme activity.
» Duration of responses to stimulation of these
receptors is on the order of minutes to hours.

– The most common enzyme-linked receptors are

those that have a tyrosine kinase activity as part of
their structure. Eg insulin

100
 – The activated receptor phosphorylates tyrosine
residues on specific proteins
D. Intracellular receptors

– the receptor is entirely intracellular

– the ligand must have sufficient lipid solubility to
be able to move across the target cell membrane.
– The time course of activation and response of
these receptors is much longer than that of the
other mechanisms described above.

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 Affinity- refers to ability of a drug to bind a receptor
 Efficacy (intrinsic activity)- is the ability of a drug to
produce an effect at a receptor

 Potency- a measure of the amount of drug necessary to

produce an effect of a given magnitude

 Commonly the concentration producing an effect that

is fifty percent of the maximum (EC50)is used to
determine potency

 (Emax Vs potency) Vs therapeutic importance

?????

102
 Agonist- a drug that is able to stimulate a receptor and
therefore mimics the endogenous transmitter.
– An agonist has both an affinity and efficacy

 Antagonist- a drug that blocks a receptor and therefore blocks

the action of the endogenous transmitter (i.e. it will prevent
the natural chemical from acting on the receptor).

– antagonist has affinity but not efficacy or intrinsic

activity.

» also can decrease the actions of another drug

103
 Partial agonists/antagonist:
 Partial agonists have efficacies (intrinsic activities) greater
than zero, but less than that of a full agonist
 Has Emax less than a full agonist
» They may reduce effects of a full agonist
through competition
» 0<X<1

 Inverse agonist:
Opposite to agonist

104
– most drug binding is reversible and hence there will be
competition between the drug and the natural stimulus to the
receptor.

– Drug - receptor interaction involves chemical bonds and they are

hydrogen bond, ionic bond, covalent bond and Vander waals
force.
» most commonly electrostatic/ionic and hydrogen bonds
» Covalent bond is the strongest bond and the drug-
receptor complex is usually irreversible.

• the size, shape, and charge distribution of the drug molecule

determines its binding with a receptor

106
Site of drug action:
 A drug may act:

I. Extracellularly e.g: osmotic diuretics, antacids,

chelating agents
II. On the cell surface e.g: digitalis, penicillin,
catecholamines
III. Inside the cell e.g: anti-cancer drugs, steroid
hormones.

107
Dose Response relationship
 Is the relationship between intensity of drug effect
and drug dosage (drug level)
 When a logarithm of dose as abscissa and
responses as ordinate are constructed graphically,
the “S” shaped or sigmoid type curve is obtained.
 The lowest concentration of a drug that elicits a
response is minimal dose, and the largest
concentration after which further increase in
concentration will not change the response is the
maximal dose

108
Fig. Log dose – Response curve
109
1. Graded dose effect:
 As the dose administered to a single subject or tissue
increases, the pharmacological response also increases
in graded fashion up to ceiling effect.
 It is used for characterization of the action of drugs.
 The concentration that is required to produce 50 % of
the maximum effect is termed as EC50 or ED50.

110
Graded dose…
2. Quantal dose effect:
 it is all or none response
 the sensitive objects give response to small doses of a drug while
some will be resistant and need very large doses for a given effect
 The quantal dose effect curve is often characterized by stating the
median effective dose and the median lethal dose.
 Median lethal dose or LD50: the dose (mg/kg), which would be
expected to kill 50% of a population of the same species and
strain.

 Median effective dose or ED50: the dose (mg/kg), which

produces a desired response in 50% of test population.

112
A DRC positioned rightward indicates
A. lower potency? B. Higher potency?
Figure : Typical dose-response curve for drugs showing
differences in potency and efficacy. (EC50 =drug dose
that shows fifty percent of maximal response.)

116
 Drug Antagonism
– One drug may antagonize the effect of another drug
– The several types of antagonism can be classified as follows:
1. Chemical antagonism eg chelating agents

2. Functional antagonism eg acetylcholine and NE

3. Competitive antagonism

» Most common

» either reversibly competitive or irreversibly competitive

4. Noncompetitive antagonism: - same as the effect of

irriversible competitive antagonist

117
Figure : Effects of drug antagonists on dose response relation

118
 Assignment 1 7% (indiv)
Importance of drug antagonism
Therapeutic index
Receptor
– Spare receptor
– Desensitization of receptors
– Receptor Tachyphylaxis
– Receptor Down regulation
– Receptor upregulation

119
 Adverse drug reactions (ADR)

• ADR is any response to a drug that is noxious and unintended and that
occurs at doses used in human for prophylaxis, diagnosis or therapy.

• What are the adverse effects?

 Side effects :pharmacological extension: produced with

therapeutic dose of the drug, predicted
– Eg dryness of mouth with atropine

 untoward effects/ADR: unexpected/is not a pharmacological

extension- develop with therapeutic dose of a drug
– Eg Diarrhoea with ampicillin

120
 allergic reactions : may be mild or very severe like
anaphylaxis [immunologic]
Idiosyncratic reactions : are one’s peculiar response to
drugs (genetically determined)
– glucose -6 phosphate dehydrogenase defeciency Vs primaquine

teratogenic effects: congental abnormalities on the fetus.

eg thalidomide cause absence of limbs in new born babies
– Other drugs with teratogenic potential include anti convulsants,
lithium, tricyclic antidepressants and warfarin.

121
Drug -drug interactions
– It is a phenomenon which occurs when the effects
of one drug are modified by the prior or concurrent
administration of another drug(s).
– It may result in beneficial or harmful effects
Level of D/I
a) Pharmaceutical drug interactions:
– Eg diazepam if added to infusion fluid there will be
a precipitate forma on → loss of therapeu c effect.

122
b) Pharmacokinetic drug interactions:
1) Interaction during absorption
– Eg interaction in the gastrointestinal tract resulting in either
decreased or increased absorption.
• Tetracycline + Calcium → Decreased absorp on of
tetracycline.
2) Interaction during distribution
– A drug which is extensively bound to plasma protein can be
displaced from its binding sites by another drug or
displacement from other tissue binding sites. eg Sulfonamide
by salicylates

123
3) Interactions during biotransformation:
– Affects biotransformation rate, intensity and duration of action
as well as toxicity
i. Enzyme induction
• biotransformation of drugs is accelerated

• Warfarin (anticoagulant) + Barbiturate (enzyme

inducer) → decreased an coagula on

• Enzyme inducers: Rifampicine, phenytoin,

sulfonamides, etc.

124
 ii. Enzyme inhibition
• Warfarin + Metronidazole (enzyme
inhibitor) → Haemorrhage.
• Enzyme inhibitors: Disulfiram, isoniazid,
allopurinol, cimetidine, etc.
4) Interactions during excretion
– e.g. Penicillin (antibiotic) + Probenecid (antigout drug)
→ Increases the dura on of ac on of penicillin (Both
drugs excreted through tubular secretion).

125
C. Pharmacodynamic interactions: at site of action

Types of D/I:

 Drug Synergism-the therapeutic effect of two drugs is greater than the

effect of individual drugs- (AB > A + B) (Aminoglycosides + penicillin)

 Additive effect( A+B = AB)

» e.g. Combination of ephedrine and aminophyllin in the treatment of

bronchial asthma.

 Potentiation effect (AB > A + B) A or B has no effect

 Amoxicillin with calvunilic acid

 Levo dopa with carbidopa

 Antagonism: 1+1<2
126
Drug Antagonism
– One drug may antagonize the effect of another drug
– The several types of antagonism can be classified as
follows:
1. Chemical antagonism eg chelating agents
2. Functional antagonism eg acetylcholine and NE
3. Competitive antagonism

» Most common
» either reversibly competitive or irreversibly competitive
4. Noncompetitive antagonism

127
Factors modifying the dosage and action of drugs :
– Individuals differ both in the degree and the character of
the response that a drug may elicit
– therefore the optimum dose of a drug which produces
the desired therapeutic effect varies from person to
person.
– The important factors which influence the effect of a
drug are:

128
1. Drug intolerance/hypersusceptibility

– inability of the individual to tolerate a drug

» a quantitative deviation from the anticipated response to
a given dose of a drug
2. Sex difference

– pregnancy
• Most of drugs can produce teratogenicity
(congenital)malformation when they are used in pregnancy. Eg
tetracyclines, phenytoin, ACEI, ARBs, Vitamin A, valproic acid.

– Breast feeding- eg avoid tetracyclines

– 2 up to 3 hours between lactating and drugs is recommended
129
3. Body Weight

– nutritional factors can sometimes alter drug

metabolizing capacity and this should be kept in mind
in malnourished patients.
• Body weight
– Dose= BW X average adult dose
70
- Dose=BSA X average adult dose
1.7
– BSA(m2)= BW (kg)0.425 x Height (cm) 0.725 x 0.007184

4. Age

– children may not react to all drugs in the same fashion

as young adults.
– With a few exceptions, drugs are more active and
more toxic in the new born than the adults. 130
• Age
– Pediatric
• Child dose = age X adult dose (Young’s formula)
age +12
• Child dose = (age/20)*Adult dose (Dilling’s
formula)

– manufacturers give dosage recommendations on

mg/kg basis
5. Disease state

6. Pharmacogenetics

 Geneticallymediated variations in drug

responses
 Eg fast and slow acetylators
7. Drug interactions

8. Repeated administration and drug cumulation:

132
9. Drug tolerance
 Refers when an unusually large dose of a drug is
required to elicit an effect ordinarily produced by the
normal therapeutic dose of the drug

10. Emotional factors

 eg. Placebo and Nocebo response.

133
  New Drug Development
 Changed from trial and error to systematic scientific research

 expensive and lengthy process

 comprises of two steps : preclinical and clinical

a) Preclinical development
• to explore the biological effects (efficacy and safety) of a new
substance before it is administrated to patients

• varying drug doses are tested on animals and/or in vitro

systems eg isolated cells, and isolated organs

134
b) Clinical development
• Includes testing on human beings to determine tolerable
dose, duration of action, comparing it with standard
treatment.

• Then licensing for market and post marketing surveillance

will be done

 This clinical evaluation is divided into four phases

135
 Clinical development
matching
A B
a) Postmarketing surveilance
1. Phase 1
b) Test on healthy people
2. Phase 2
c) Test on few patients
3. Phase 3
d) Test on large group of patients
4. Phase 4

136
 The development and testing process required to bring a drug to market in the
USA. Some of the requirements may be different for drugs used in life-
threatening diseases

1/21/2022 Desalegn Y. MSc. Pharmacology 137

Any question?!
 Assignment
1. Drugs for constipation
2. Drugs for diarrhea
3. Drugs for hemorrhoids
4. Drugs for helminths
5. Oral contraceptives
6. Drugs for COPD
7. Drugs for Anemia
8. Anticoagulant, antithrombin and antiplatelet
9. Coagulants
10. Drugs for epilepsy
11. Drugs for psychosis
12. Local Anesthesia
13. Drugs for Parkinson's
14. Drugs for Alzheimer's
15. Drugs implicated for COVID -19