Mekonnen Sisay (BPharm, MSc, HDP)

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 DEFINITIONS
Pharmacology
is the study of substances that interact with living systems
through chemical process, especially by binding to regulatory
molecules and activating or inhibiting normal body process.
Blend of two Greek words, Pharmakon to mean drug or
medicine, and Logos to mean study
Pharmacokinetics:
refers to the actions of the human body on the drug
what the body does to the drug
Pharmacodynamics:
refers to the actions of the drug on the human body
what the drug does to the body

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 Definition ..
Pharmacotherapeutics:
is the use of drugs to diagnose, prevent, mitigate or treat
disease or to prevent pregnancy.
is the study of the medical use of drugs.

Toxicology:
is the branch of pharmacology which deals with undesirable
effects of chemicals on living systems, from individual cells
to complex ecosystems.

Clinical pharmacology:
the study of drugs in humans (patients and healthy volunteers).

Chemotherapy:
the effect of drugs upon micro organisms, parasites and
neoplastic cells living and multiplying in living organism.

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 Definition
Xenobiotic
from Greek- xenos means stranger
is any substance/chemical that is foreign to the human body
(not synthesized in the body).
Prodrug
is an inactive form of a drug that requires metabolic

activation inside the body (bioactivation) in order to release
the active form of the drug.
Receptor
is the component of a cell or organism that interacts with a
drug and initiates the chain of biochemical events leading to
the drugs observed effects
Pharmacogenomics
is the study of the genetic variations among humans that
cause differences in pharmacodynamics/pharmacokinetics
and lead to individual differences in drug response
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Drugs
any substance that brings about a change in biological
functions.
may be synthesized within the body (e.g., hormones) or may
be chemicals not synthesized in the body, i.e. xenobiotics
Poisons
are drugs that have almost exclusively harmful effects.
However, Paracelsus famously stated that the dose makes
the poison.
Toxins
are poisons of biologic origin, i.e., synthesized by plants or
animals

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 Sources of drugs
Minerals: liquid paraffin, magnesium trisilicate, kaolin.
Animals: insulin, heparin, thyroid extract, antitoxin sera.
Plants:
morphine
digoxin: Digitoxin lanata , digitoxin from Digitalis purpurea
atropine : Atropa belladonna
castor oil
pilocarpine: Pilocarpus microphyllus and Pilocarpus japorandi
Synthetic: Aspirin, sulphonamide, paracetamol, zidovudine.
Micro organisms: penicillin, streptomycin.
Genetic engineering: human insulin, human growth hormone.

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 Naming of drugs
The three name classifications of drugs are
Chemical/Molecular/Scientific name
Generic or Non-Proprietary name and
Brand or Trade or Proprietary name
Chemical Name
depicts the chemical/molecular structure of the drug
states the structure in terms of atoms and molecules
accompanied by a diagram of the chemical structure
are long and useful to a few technically trained personnel
only one chemical name for a drug
E.g. acetyl-p-amino-phenol is for Paracetamol

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 Naming of drugs ..

Generic Name
accepted internationally
only one generic name for a drug
most commonly used in prescriptions
is the abbreviated and approved name of the drug
is not capitalized; e.g. aluminum hydroxide
Brand Name
are names given to the drug by the manufacturing and
marketing company
several name for single drug may occur
have letter
expensive

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Chemical Name Generic Trade Name
Name
acetyl-p-amino-phenol acetaminophen Paracetamol
Panadol
Tylenol ,tempra
(+/-)-2-(p-isobutylphenyl) ibuprofen Advil, Motrin,
propionic acid
Nuprin, Brufen

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 Pharmaceutical Dosage Forms
Dosage forms are different preparations of a drug which help to
facilitate drug administration & delivery

An ideal dosage form should:

Deliver the right amount of the drug to the right site
Minimize drug exposure to unwanted sites
Associated with minimal discomfort or inconvenience
Be economical & need lesser expertise knowledge

But there is no such ideal dosage form

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 Pharmaceutical Dosage Forms

Four types of dosage forms exist

Solid dosage forms
Semisolid dosage forms
Liquid dosage forms
Gaseous dosage forms

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 Solid dosage forms
are those drug preparations which exist as solids
exist in different forms/preparations
1. Tablets
are most common forms of solid dosage forms
Written as tab or tabs on prescriptions
Several kinds of tablets are available
Scored tablets
Enteric coated tablets
Slow release tablets
Caplets

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 Solid dosage forms..
2. Lozenges
are sweet tablets containing sugar, water & flavoring agents
are to be chewed/held in the mouth not swallowed

3. Pellets/beads
Prepared as sheets or beads for sustained release of drugs
E.g. Norplant
4. Powders
Are solid preparations which need to be reconstituted
before use
E.g. penicillin injection (PPF)

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 Solid dosage forms..
5. Capsules
Written as cap or caps
Prepared in two forms
Soft capsules
are made of soft gelatin
Contain liquid inside & are sealed
E.g. Vitamin A & E capsules

Hard capsules:
are made of hard gelatin
Contain two separable pieces or cups
Contain powder or granules inside
E.g. Amoxicillin, tetracycline capsules
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 Semi-solid dosage forms
are dosage forms that are too soft to be solid and too hard to be
liquid
are mainly used for topical administration
Includes:
Creams
are semisolid emulsions of oil & water
water is the main ingredient
E.g. hydrocortisone cream
Ointments
are semisolid preparations
Oil is the main ingredient
E.g. tetracycline ointment
Suppositories & Pessaries
used for local effects, or for children, vomiting & unconscious
patients
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 Liquid dosage forms
Are found in liquid states
Can be either clear solutions or suspensions
i. Solutions
are clear mixtures/fluids
They dont need to be shaken/mixed even after long period of
storage
are of different forms
Elixirs
are clear solutions which contain alcohol & water as solvent
also contain flavoring agents
are mainly used for pediatric use

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 Liquid dosage forms .
Syrups
are also clear solutions which contain water, sugar & flavoring
agent
dont contain alcohol
E.g. multivitamin syrup
Tinctures
are clear solutions which contain both water & alcohol as
solvent
But, unlike elixirs, they are used for external use and dont
contain flavoring agent
E.g. iodine tincture
Miscellaneous solutions
Includes injectable clear solutions, large volume preparations
E.g. gentamicin injection, glucose preparations
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 Liquid dosage forms .
ii. Suspensions
are not clear liquids
Contain fine, undissolved drug particles suspended in a
liquid
Shaking is necessary before use since the solid particles
sediment upon storage
E.g. antacid suspensions

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 Gaseous dosage forms
Contain medical gases & aerosols
Medical gases:
are preparations for intrapulmonary administration
are inhaled through breathing apparatus
The API is found as gas or volatile liquid
Aerosols:
are another gaseous dosage forms
Contain an active drug suspended in a gaseous vehicle
are dispersions of solid particles or liquid droplets in a
gaseous vehicle

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 Pharmakon=drug, kinetics=movement
The study of what the body does to the drug:
Absorption
Distribution
Metabolism
Excretion

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21
 PASSAGE OF DRUGS ACROSS A BIOLOGICAL-MEMBRANE
How are drugs transferred from site of administration to
circulatory system????
1. Filtration (Aqueous diffusion)
Requirements:
Size of the drug should be less than size of pore (channel)
which is filled with water.
unbound to plasma protein
has to be water soluble
E.g. Na +, glucose, caffeine
The capillaries of the brain, the testes, and some other tissues
are characterized by the absence of pores that permit aqueous
diffusion
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 2. Lipid Diffusion
Drug is supposed to pass through the membrane.
Must be lipid soluble.
Dependent on lipid /aqueous partition coefficient

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3. Carrier mediated absorption
i. Facilitated diffusion: passive diffusion but facilitated.
E.g. levodopa and amino acid in to the Brain
ii. Active transport
Use ATP and carrier proteins
Against concentration gradient.
Can be
primary active transport or
secondary active transport.
E.g. Penicillin secretion by the kidney
Carrier mediated transports are saturated, structure specific,
and competitive

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4. Endocytosis
Pinocytosis
is the engulfing of the extracellular fluid by cells.
is a "cell-drinking".
is important for the cell's absorption of extracellular fluids.

Phagocytosis
Process by which large molecules are engulfed by the cell
membrane and release them in to the cell.
Example: protein, toxin
Vitamin B12 complexed with intrinsic factor is transported across
the gut wall by endocytosis.

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 Route Of Drug Administration
Enteral Route
Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small intestine, or
rectum.
Includes
Oral
Sublingual. Nitroglycerin
Buccal. nitrates
Rectal.. rectal suppository

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 Oral route
Advantage: Disadvantages
Most convenient Irritation to GI(N&V)
safest High first pass effect
Most economical Not given for unconscious,
Reverse of dose uncooperative, vomiting
management is patients
easily done Slow onset of action
Irregular absorption (drug-
food interaction)

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Sublingual
Placing drugs under the tongue (Nitroglycerin)
Rapid absorption, avoids first pass effect
Rectal
Drugs placed in the rectum
Merits
For unconscious & children patients ,
For nauseas or vomiting patients
Can reduce first pass effect by 50%
Good for vomiting inducing drugs
Demerits
Inconvenient, erratic absorption
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 Parenteral Route
drugs delivered to the systemic circulation without crossing
intestinal mucosa
Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC)
Intradermal (ID)
Intrathecal (IT)
Intraarticular (IA)

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 Intravenous (IV)
Is the most common parenteral route for drugs that are not
absorbed orally
Advantage
Fast onset of action(emergency case)
100 % BA
Better for drug with irritation effect
can be given in large volume
Disadvantage
Expertise is needed to give injection
Pain, not convenient
Expensive
Only sterilized solution used
Difficult to titrate over dose (irreversible effect )
No local action

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 Intramuscular
Drugs administered IM can be aqueous solutions or specialized
depot preparations often a suspension of drug in a non aqueous
vehicle such as polyethylene glycol
Absorption of drugs in aqueous solutions is fast whereas that
from depot preparations is slow.
Advantages:
Uniform rate of absorption
Fast onset of action
Can be given in vomiting and diarrhea.
Disadvantages:
Pain at local site of injection
Volume of injection < 10 ml.

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 Intra-arterial
Occasionally, a drug is injected directly into an artery to
localize its effect in a particular tissue or organ, such as:
in the treatment of liver tumors and
Head/neck cancers.
Diagnostic agents sometimes are administered by this route
e.g., technetium-labeled human serum albumin.
Intraarterial injection requires great care and should be
reserved for experts.
The first-pass and cleansing effects of the lung are not
available when drugs are given by this route

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 Intrathecal
Is the only route that bypasses blood brain barrier and blood-
cerebrospinal fluid (CSF) barrier.
used when local and rapid effects of drugs on the meninges
or cerebrospinal axis are desired, as in spinal anesthesia or
treatment of acute CNS infections
Uses to inject drugs directly into the spinal subarachnoid
space
e.g. amphotericin B is used in treating cryptococcal
meningitis

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 Transdermal
achieves systemic effects by application of drugs to the skin,
usually via a transdermal patch.
The rate of absorption can vary markedly, depending on the
physical characteristics of the skin at the site of application.
most often used for the sustained delivery of drugs, such as
the antianginal drug nitroglycerin
the antiemetic scopolamine, and
the once-a-week contraceptive patch (Ortho Evra) that has
an efficacy similar to oral birth control pills

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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.
is used for drugs that
are gases (e.g. some anesthetics) or
those that can be dispersed in an aerosol.
is 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.
E.g. albuterol and
corticosteroids, such as fluticasone.
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 Intranasal
involves administration of drugs directly into the nose.
Agents include
nasal decongestants such as the anti-inflammatory
corticosteroid --mometasone furoate
desmopressin is administered intranasally in the treatment of
diabetes insipidus
salmon calcitonin, a peptide hormone used in the treatment
of osteoporosis
The abused drug, cocaine, is generally taken by intranasal
sniffing.

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 Topical
Application could be on mucous, skin or the eye
Mucous membrane include conjunctiva, nasopharynx,
oropharynx, vagina
Topical application is used when a local effect of the drug
is desired.
e.g.
clotrimazole is applied as a cream directly to the skin in
the treatment of dermatophytosis
tropicamide or cyclopentolate are instilled (administered
drop by drop) directly into the eye to dilate the pupil and
permit measurement of refractive errors

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 Process by which the drug leaves the site of administration
and enters into the circulatory system
Drugs can be absorbed from GI tract (oral, sublingual or
rectally), mucous membranes, skin, lungs, muscle or SC
tissues
Factors affecting drug absorption
Route of administration
Physicochemical properties of the drug
Dosage forms
Circulation at the site of absorption
Concentration of the drug
Surface area of absorption site
Contact time at site of absorption
Presence & type of food
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Bioavailability
is fraction of administered drug that reaches the systemic
circulation.
is expressed in %.
The area under the blood concentration-time curve (AUC)
is a common measure of the extent of bioavailability for a
drug given by a particular route.

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 Factors Affecting Bioavailability
I. Extent of absorption
After oral administration, a drug may be incompletely absorbed, e.g.
only 70% of a dose of Digoxin reaches the systemic circulation.
This may be due to :
physicochemical properties
E.g. lipo/hydrophilicity
reverse transporter(p-glycoprotein)
II. First pass elimination
The metabolism of a drug and its passage from the liver into the
circulation
oral route .high first-pass effect
IV ..bypasses the liver

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 Factors Affecting BA
Drug metabolism occurs:
gut wall(CYP3A4 )
portal blood
liver(principal)
Excretion: liver execrates the drug into bile.
These overall processes are called first pass effect (first pass
elimination).
The effect of first pass hepatic elimination on bioavailability is
expressed as the extraction ratio:
ER= CL liver
Q Where Q is hepatic blood flow.
The systemic bioavailability of the drug (F) can be predicted
from the extent of absorption (f) and the extraction ratio.
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F=f x (1-ER)
E.g. Morphine is completely (almost) absorbed (f=1); however,
the hepatic extraction ratio for it is 0.67, calculate the BA?
Clearance of drug is the factor that predicts the rate of
elimination to the drug concentration:
CL=rate of elimination/c
CL renal = rate of elimination k
C
CL liver= rate of elimination L
C
CL OTHER =rate of elimination O
C
CL SYSTEMIC= CL R +CL L+CL O

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III. Rate of absorption
is determined by the site of administration and the drug
formulation.
The mechanism of drug absorption is said to be zero order
when the rate is independent of the amount of drug remaining
in the gut
e.g. when it is determined by the rate of gastric emptying
time or by controlled release drug formulations

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 Distribution of drugs
Is the delivery of drugs from systemic circulation to tissues
is random (every tissues have equal chance)
But concentration of drugs in different tissues differ
Factors Which Influence Drug Distribution
i. plasma protein binding
Drug in systemic circulation exist as bound and unbound
form
Drug ordinarily bind with plasma protein in reversible
fashion and in dynamic equilibrium
D + P [DP] D + P
As free drugs leave the systemic circulation the bound
drug dissociate

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ii. Tissue Uptake
Some drugs have affinity to certain body organs
Adipose tissue :
drugs with extreme lipid solubility (excellent lipid water
partition coefficient)
May result :
decrease therapeutic activity ( eg thiopental)
Prolonged activity (eg fat depot preparation)
Toxicity ( eg-DDT)

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 Factors Which Influence Drug Distribution.

Kidney : contain proteins, methallothionein, that has high affinity

for metals
Cadmium, Lead, Mercury accumulation -----toxicity
Eye drugs which have affinity for retinal pigment, melanin,
accumulate in the eye
Chlorpromazine (other phenothiazine) and chloroquine---
accumulate in eye
Bone- TTC, Lead, Cisplatin
TTC accumulation may cause dysplasia, poor bone development
Lead accumulation result bone brittleness (displace Ca2+ )
Slow release of toxic effect may occur from lead and cisplatine
accumulation
Teeth TTC accumulation result yellow- brown discoloration of
teeth
Liver Chloroquine
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 Factors Which Influence Drug Distribution.

Generally tissue accumulation of drug may have

Advantageous effect
target tissue therapy e.g. Chloroquine, iodine:
sustained release effect, e.g. fat depot
Disadvantageous effect---mainly toxicity
e.g.
tetracycline bone and teeth
Chloroquine liver
iodine thyroid gland
DDT adipose tissue

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 Factors Which Influence Drug Distribution.

iii. Physiological barriers

Blood Brain Barrier (BBB)
Regulate transfer of drug to the brain

Inflammation due to meningitis or encephalitis increase the

permeability of BBB so permeating the passage of ionized ,
lipid soluble drugs.
Eg:- penicillin and ampicillin not cross BBB ( highly ionized)
but inflammation they can pass BBB --used for antibiotic
48 effect centrally
 Physiological barriers.

placental barrier
Blood vessel of mother and fetus separated by PBB
Highly polar and ionized drugs do not cross placenta readily
Drugs with high lipid solubility shouldn't be given to pregnant
mother Eg
TTC accumulate in bone and teeth of neonate
development of bone and teeth
Chloramphenicol cause gray baby syndrome
Drugs which cross PBB cause fetal abnormalities and called
teratogenic drugs
Testicular Barrier

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 Factors Which Influence Drug Distribution.

iv. Rate of Blood Flow

The rate at which drugs are delivered to a particular tissue is
determined by the blood flow to that tissue.
Different tissue have d/t rate and amount of blood flow
Highly perfused tissue:- heart, lung, brain, liver, kidney
Intermediate perfused tissue:- skeletal muscle
Poorly perfused tissue:- skin, bone, nail, fat tissue
Generally the distribution of drugs to body compartment
determined by volume of distribution (Vd)

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 Volume of distribution (vd)
is the apparent volume to which the drug is distributed
relates drug concentration in the plasma to total drug in the
body
gives rough estimation of overall distribution of a drug in the
body
Vd = amount of drug in body
amount of drug in blood

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 Vd can indicate where the drug is
Drug having high PPB and/ or large molecular weight----
mainly found in plasma ( Vd in plasma)
E.g .Warfarin, heparin, Ibuprofen (Vd=0.14L/kg)
Highly large molecular weight and water soluble drug have
Vd at extracellular water
E.g. Gentamicine
Highly water soluble drugVd is in total body water
E.g. ethanol, phenytoin
Highly lipophilic drug have Vd to adipose tissue
Eg thiopental, DDT, amiodarone ( Vd=60L/kg)

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 Actual volume of distribution
It is the actual volume of body fluid in which the drug is
distributed.
It is difficult to calculate . no any means of measurement
for the body volume.
Practically, polar and large molecule limited to the circulation,
whereas as non polar and small molecules distributed to total
body water

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 Apparent volume of distribution(VD)
It is the volume in to which the total amount of a drug in the
body would have to be uniformly distributed to provide the
concentration of the drug actually measured in the plasma.
Apparent VD = Dose/C
C= concentration in the blood
Dose: total amount of drug in the blood.
VD is greater than total body H2O if the drug is lipophilic and
binds to tissue.
VD becomes less than the total body if the drug is hydrophilic
and binds to plasma protein.

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 A chemical change (transformation) of drugs by body enzyme
to facilitate excretion of drugs by changing to more water
soluble form
Lipophilic hydrophilic
Consequence of BT:-
Activation e.g. codeine to morphine
Maintenance of activity e.g. diazepam to oxazepam
Inactivation e.g. procaine to PABA
Alteration of activity e.g. progesterone to androgen
Accelerated renal excretion e.g. thiopental to pentone
Increased or decreed toxicity
e.g. paracetamol to N-acetyl-P-benzoquinoneimine

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 Metabolism of drugs occur in all body parts
Lung, GI, kidney, liver, blood.
But mainly take place in liver ; b/c it contain large
amount of metabolizing enzyme
Metabolism in liver involve 2 steps
Phase I
Phase II

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 Called functionalizing reaction since include addition
or exposure of functional group
Produce more reactive metabolites and more
hydrophilic
Include:-
Oxidation
Reduction
Hydrolysis
Involve Cytochrome P-450 enzyme; not necessarily
for all

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 CypP-450 enzyme have different families and sub families
CYP3A4 (30%)
CYP1A2 (15%)
CYP1A6 (4%)
CYP2C9 (20%)
CYP2D6 (5%)
CYP2E1 (10%) are the most abundant
Enzyme induction:- synthesis of microsomal enzyme ----
metabolism ---- excretion
E.g. Phenobarbitone: non selective inducer
DDT: induces CYP1A1
Enzyme inhibitor:- liver enzyme function ---- metabolism ---
excretion----toxicity
e.g. Cimetidine, Ketoconazole, Erythromycin, Chloramphinicol
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 called conjugation reaction
Involve conjugation of more polar molecule to water
solubility
Drug + endogenous polar cpd
Type of phase II rxn:
i. Glucornide conjugation
Using glucuronosyl transferase (GTs) enzyme
Eg drug: Chloramphinicol (CAF), morphine , Dapsone
NB: Morphine phase II metabolism active metabolite
CAF not given for infants why????
GTs enzyme less developed .CAF metabolism . excretion
.. blood CAF level .cross CNS cause gray baby
syndrome

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ii. Acetylation reaction
Involve N-acetyl transferase
E.g. isoniazide (INH), hydralazine
Acetylation of isoniazide show genetic polymorphism
New study shows that AIDS down regulate this enzyme
Slow acetylator
Acetylation ----- excretion ------ plasma level ------ toxicity
( peripheral neuropathy)
Fast acetylator
Excessive enzyme---- Acetylation----- excretion.
plasma level --------out come of therapy

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iii. Sulphate conjugation:
Use sulfotransferase enzyme
E.g. steroids
iv. Methyl conjugation Use methyl transferase
Eg catecholamine, histamine
v. Glutathione conjugation
Use glutathione - - transferase
Glutathione protect cells from reactive electrophilic cpds
Paracetamol Phase I NAPQI( highly reactive) Phase II

detoxification but at high concentration of paracetamole,

since glutathione are limited more NAPQI ------cause
hepatotoxicity

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 figure: Phase I and phase II reactions, and direct elimination, in drug biodisposition
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 Phase II reactions may also precede phase I reactions: e.g INH

Figure : Phase II activation of isoniazid (INH) to a hepatotoxic metabolite

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 is a process of drug transfer from the internal to the external
environment
Occurred in the Kidney, biliary system, sweat, saliva, milk, lung
Renal excretion
Principal organ for most drug removal especially for water
soluble and non volatile drug
Excretion of drug through kidney involve 3 steps
Glomerular filtration
Tubular secretion
Tubular reabsorption

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65
 It is a process, which depends on

1) The concentration of drug in the plasma

(2) molecular size, shape and charge of drug

(3) glomerular filtration rate.

Only the drug which is not bound with the plasma proteins can pass
through glomerulus. All the drugs which have low molecular weight
can pass through glomerulus e.g. digoxin, ethambutol, etc

In congestive cardiac failure, the glomerular filtration rate is

reduced due to decrease in renal blood flow

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 The cells of the proximal convoluted tubule actively transport
drugs from the plasma into the lumen of the tubule

e.g. acetazolamide, benzyl penicillin, dopamine, pethidine,

thiazides, histamine.

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 The reabsorption of drug from the lumen of the distal convoluted

tubules into plasma occurs either by simple diffusion or by active

transport.

When the urine is acidic, the degree of ionization of basic drug

increase and their reabsorption decreases.

Conversely, when the urine is more alkaline, the degree of

ionization of acidic drug increases and the reabsorption decreases.

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8
 Biliary excretion
Mainly conjugated drugs
Enterohepathic recirculation is common
Highly conjugated drug excreted in the bile ----then to GIT---GI
flora and enzyme hydrolyze-----reabsorbed
Pulmonary excretion
Mainly for drugs that are volatile and gas
Depend on blood solubility , cardiac out put and respiratory
rate
Eg; ethanol and NO
Other excretion route
Milk, sweat, saliva

69
 Study of action of drugs to the body :
mechanism of action of the drug
Mainly concerned on interaction of the drug with receptors
What the drug does to the body

70
 Types of Drug-Receptor Interactions
Binding of the drug to a receptor is essential in order to bring
about a pharmacological effect
AGONISTS are drugs that bind to and activate the receptor,
which will bring about the pharmacological effect.

Some receptors, once activated, can directly bring about the

pharmacological effect, such as the case of enzymes and ion
channels.

Other receptors are linked through one or more coupling

molecules to a separate effector molecule; as a result, activating
this particular type of receptor will indirectly bring about the
pharmacological effect
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Some drugs mimic the effect of a receptor agonist by
inhibiting the molecules responsible for terminating the action
of an endogenous agonist
e.g. phosphodiesterase inhibitors
acetylcholinesterase inhibitors

Although these drugs dont bind to the receptor, they

are able to extend/amplify the pharmacological effect
of the receptor agonist(endogenous )

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 FULL AGONISTS are drugs that can activate the receptor-
effector system to the maximum extent of which the system is
capable when administered at sufficiently high concentrations.
produces the maximal pharmacologic effect at its receptor-
effector system.

PARTIAL AGONISTS are drugs that bind and activate the

receptor; however, the evoked response or effect is not as high
as the effect obtained from the binding of a full agonist.
may act as either an agonist (in the absence of a full agonist)
or as an antagonist (in the presence of a full agonist).
E.g. pindolol a 2 recepter partial agonist

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INVERSE AGONISTS
are drugs that bind to the receptor and stabilize it in its inactive
(nonfunctional) conformation, thus reducing/eliminating any
constitutive activity of the receptor
generates effects that are the opposite of the effects produced
by conventional agonists at the receptor

ALLOSTERIC AGONISTS
also known as Allosteric Activators
are drugs that enhance the efficacy/binding affinity of the
receptor agonist by binding to allosteric sites on the receptor
molecule

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PHARMACOLOGIC ANTAGONISTS
also known as Blockers
are drugs that bind to the receptor molecule without activating
the receptor, thereby preventing (or blocking) the binding of
agonist molecules (and preventing activation of the receptor by
an agonist).
can be either
Competitive Antagonists concentration dependent or
Noncompetitive Antagonists not concentration dependent

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ALLOSTERIC ANTAGONISTS
are drugs that inhibit/reduce the efficacy/binding affinity of
the receptor agonist by binding to allosteric sites on the
receptor molecule
are Noncompetitive Antagonists that bind either reversibly or
irreversibly to their allosteric binding sites on the receptor
molecule.
Allosteric inhibition/antagonism is not overcome by increasing
the concentration/dose of the agonist.

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 Dose response relationship
Two types of dose response relationship curves:
Graded dose- response relationship and
Quantal dose -relationship.

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 Graded dose response relationship curve
As the dose (concentration) of drug increases, the magnitude of
its pharmacologic effect also increases. The relationship
between dose and response is a continuous one and can be
mathematically desired by application of the law of mass of
action

Response

Phenobarbital Dose

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% response

Log Dose
Fig. graded dose response relationship curve

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QUANTAL DOSE-RESPONSE RELATIONSHIP CURVE

In this relationship, the influence of the magnitude of

the dose is on the proportion of a population that
responds.
These responses are known as quantal response,
because, for any individual, the effect either occurs or
does not.(all or none principle)
Even graded response can be considered to be quantal
if a predetermined level of the graded response is
designated as the point at which a response occurs or
not.

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81
 Quantal dose response relationship is used to calculate therapeutic
index (TI).

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 TD50(LD50)=the drug dose that produces a toxic
effect in half of the population.
ED50=the drug dose that produces a therapeutic or
desired response in half of the population.
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 Narrow therapeutic index drug

Warfarin Phenytoin
heparine Gentamycin
Lithium Amphotericin B
Digoxin 5-fluorouracil
AZT (zidovudine)

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 Drug interactions
is a situation in which the effect of one drug are
altered by prior or concurrent administration of
another prescribed drug
Over the counter drug
Herbal products
two type
Pharmacokinetic drug interaction
Pharmacodynamic drug interaction

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 Is an interaction at the level of ADME
Interaction at the level of absorption
E.g.
TTC with milk
TTC with antacid
antacid with ketoconazole
Ergotamine + caffeine

Interaction at the level of distribution

E.g. warfarin with phenylbutazone

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 Pharmacokinetic drug interaction cont
Interaction at the level of biotransformation
E.g. warfarin with enzyme inducers/inhibitors

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 Interaction at the level of excretion

Mostly occur at two level:

Tubular secretion :- since there is carrier case

Eg probencide + pencillin : since pencillin have short

duration of action ---- duration ---by excretion
Tubular reabsorption: since there is pH based ionization of
drug and further degree of reabsorption
Eg weak acid drug + bicarbonate ------- ionization --------
excretion

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 Is an interaction at the level of receptors
Can be either additive, synergistic, potentiation or antagonism

Is when two or more drugs are taken at the same time and the
action of one plus the action of the other results in an action
as if just one drug had been given.
represented by 1+1= 2
e.g. barbiturate and a tranquilizer given together before
surgery to relax the patient

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 pharmacodynamics drug interaction cont.

Is when two drugs are taken together that are similar in action,
an effect exaggerated out of proportion to that of each drug
taken separately at the given dose occurs
expressed by 1+2= 5
E.g.a person taking a dose of alcohol and a dose of a barbiturate
Normally, taken alone, neither substance would cause serious
harm, but if taken together, the combination could cause coma
or death.

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 pharmacodynamics drug interaction cont.

Is when two drugs are taken together and one of them

intensifies the action of the other.
Expressed by 0+1>1
E.g. Amoxicillin + clavulanic acid
antacids + simethicone

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 pharmacodynamics drug interaction cont.

chemical antagonism
Involve direct chemical interaction b/n agonist and antagonist
Eg chelating agent (dimercaprol) + heavy metals(Hg, Au)
Functional (physiologic) antagonism
Involve interaction of two drugs that act independently of each other
but happen to cause opposite effect
Eg acetylcholine + epinephrine
insulin + glucagon
pharmacological antagonism/receptor
Is most frequently encountered type of drug antagonism in clinical
practice
Is competition of agonist and antagonist for same site in receptor

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Efficacy refers to the ability of the drug to accomplish a specified
effect.
Potency reflects the amount of drug (i.e., the dose) required to cause
an effect.

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Most potent B; A & B more potent than C and D

Least potent D
Highest efficacy A, C, D
Lowest efficacy B
Full agonist A, C, D (high Emax)
Partial agonist B (low Emax)
*None are pure antagonist b/c pharm effect is produced pure antagonist =
no effect!
*B can be used as antagonist competitive antagonist

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 The drugs that produce useful therapeutic effect may also produce unwanted or toxic
effects. It has been estimated that about 0.5% of patients who die in hospitals do so as a
result of their treatment rather than the condition for which they were treated.
Serious systemic drug toxicity may result from overdoses. If is always an exaggeration of
its pharmacological actions and some times it is predictable
Type A ADRs
Pharmacologically predictable

e.g. Hypotension following antihypertensive drugs.

Hypoglycaemia following insulin
Type B ADRs
Occurs at normal dosages and are bizarre reactions

Unpredictable

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An adverse drug reaction is defined as any response to a drug that is

noxious and unintended and that occurs at doses used in man for
prophylaxis, diagnosis or therapy (WHO).

Side effects are in fact pharmacological effects produced with therapeutic

dose of the drug.

May be beneficial or harmful

e.g: Dryness of mouth with atropine which is troublesome in peptic ulcer

patients and useful when used as a pre-anaesthetic medication.

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 Idiosyncratic reactions

With the increasing knowledge of pharmacogenetics, many

idiosyncratic reactions have been found to be genetically
determined.

e.g: Drugs like primaquine, sulfonamides and dapsone may cause

haemolysis in patients with glucose -6 phosphate dehydrogenase
defeciency.

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 Teratogenic effect

Some drugs given in the first three months of pregnancy may cause
congenital abnormalities and are said to be teratogenic.

The best known example is thalidomide which results in early easily

recognizable abnormalities such as absent or grossly abnormal limbs.

Other drugs with teratogenic potential are androgens, steroids, anti

convulsants, anti neoplastic drugs, cortisone, lithium, pencillamine,
tricyclic antidepressants and warfarin

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