Debre Berehan University College of Medicine & Health Sciences

Pharmacology for health sciences

By: Bekele Minbale

(B.Pharm,Msc candidate in pharmacology)

Feb, 2018
General Pharmacology
 Objectives
At the end of this topic students will be able to:-

• Define What pharmacology is?

• Define what drugs are?

• know about drug sources

• Explain drug pharmacokinetics, and Pharmacodynamics

• Explain principle of drug action, factors that modify drug effect and drug dosage,
drug interactions, and drug toxicity.
Definitions
Pharmacology :

• study of substances that interact with living systems through chemical processes, by
binding to regulatory molecules and activating or inhibiting normal body processes.

• Pharmacology is The study of drugs, their nature, their sources, and their
properties,absorption,distribution,bio
transformation,elimination,interactions,toxicology and their therapeutic applications.

• Pharmacology is the study of the body’s reaction to drugs or

Pharmacology is study of Pharmacokinetics and Pharmacodynamics of a
drug.
Drug
 A French word ‘Drogue’ which means dried herb.

 Any substance that brings about a change in biologic function through its chemical

action.

 Alters state in the body:

=>can’t create new function but alter existing function.

 Are poisons if they used irrationally.

 Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus

famously stated that "the dose makes the poison,"

 “Poisons in small doses are the best medicines; and useful medicines in too large
 Drug
• The drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific

molecule in the biologic system that plays a regulatory role.

• This target molecules is called receptor

• Receptor is simply a macromolecule found extracellularly or intracellularly, which binded by

ligand(drug) and give a biological function.

• Is plasma protein which binded by different drugs act as a receptor??

• Some times, the drug may act through non-specific physicochemical mechanisms.
Osmotic properties (bulk laxatives, saline purgatives, mannitol) ,Adsorbents (kaolin,

charcoal)
 Areas of pharmacology
Pharmacokinetics: deals with absorption, distribution, biotransformation & excretion of
drugs.

Pharmacodynamics: study of biochemical & physiological effects of drugs & their MOA.

Pharmacotherapeutics: use of drugs in prevention & treatment of disease.

Chemotherapy: effect of drugs upon microorganisms, parasites and neoplastic cells living
& multiplying in living organism.

Toxicology: branch of pharmacology which deals with the undesirable effects of chemicals
on living systems.

Pharmacogenomics: relationship of individual’s genetic makeup to his/her response to

specific drugs.
Sources of drugs

Drugs are obtained from various sources.

Drugs may be synthesized within the body (hormones) or not. i.e. xenobiotics
(from the Greek xenos, meaning "stranger").
Sources of drugs
A. Plants
E.g. . Digoxin from Digitalis purpurea
. Atropine from Atropa belladonna
1.Natural drugs
. Quinine from Cinchona officinalis
B. Animals
E.g.. Insulin from pork/beef
C. Minerals: Iron, Iodine, Potassium salts.
D. Micro – organisms: Penicillin from penicillium notatum, Chloramphenicol
from Streptomyces venezuelae (Actinomycetes).
Penicillin was the world's first antibiotic, which was produced from the
mold Penicillium notatum by Alexander Fleming in 1928
Cont…
2.Synthetic drugs: prepared by chemical synthesis in pharmaceutical laboratories.

E.g. Sulphonamides, quinolones, barbiturates.

3. Semi-synthetic drugs: prepared by chemical modification of natural drugs.

E.g. . Ampicillin from penicillin G.

4. Bioengineered (recombinant)

E.g.. Human insulin (humulin), human GH.

Drug Nomenclature
Drugs can have a variety of name
1. Chemical name
• Drugs, as chemicals, are named according to the rules of chemical naming
such as IUPAC nomenclature and common system of nomenclature.
For example,
• N-acetyl Para amino phenol for Paracetamol,
• Acetyl Salicylic acid for Aspirin, etc…
2. International Nonproprietary/generic name,
- Given by FDA/WHO while approved, the short hand version of chemical
name.
- Recommended in RX.
3. Proprietary/trademark/Brand name,
- Given by the pharmaceutical company.
Pharmacokinetics

 Pharmacokinetics:

• Pharmakon: drug

• Kinesis: motion

• Action of body on drug/ how body handles drugs

• When a drug enters the body, the body begins immediately to work on the drug:
absorption, distribution, metabolism (biotransformation), and elimination. These
are the processes of pharmacokinetics
Pharmacokinetics
• Pharmacodynamics governs the concentration-effect part of the interaction,
whereas pharmacokinetics deals with the dose concentration part

• The pharmacokinetic processes of absorption, distribution, and elimination

determine how rapidly and for how long the drug will appear at the target organ

• Using knowledge of pharmacokinetic parameters; clinicians can design optimal

drug regimens; including the route of administration, dose, frequency & duration
of treatment
FIGURE 3–1 The relationship between dose and effect can be separated into
pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect)
components(.Katzung ,2012)
Figure 1–1. The interrelationship of the absorption, distribution, binding, metabolism, and
excretion of a drug and its concentration at its sites of action
TRANSFER OF DRUGS ACROSS MEMBRANES

• a drug must traverse the plasma membranes of many cells to reach its site of
action.

• This requires that the drug be absorbed into the blood from its site of
administration and distributed to its site of action, permeating through the
various barriers that separate these compartments.

• Finally, after bringing about its effect, a drug should be eliminated at a reasonable
rate by metabolic inactivation, by excretion from the body, or by a combination of
these processes.
Transfer of drugs across membranes

Passive Diffusion

• Simple diffusion of a solute across the plasma membrane

• Diffusion of any solute (including drugs) occurs down an electrochemical

potential gradient

• The lipid and water solubility and the molecular weight and shape of the solute
are determinants of the flux in passive diffusion. How????
Transfer of drugs across membranes

Facilitated Diffusion:

• Diffusion of ions and organic compounds across the plasma membrane may be
facilitated by a membrane transporter.

• Facilitated diffusion is a form of transporter-mediated membrane transport that

does not require energy input.

• It is Passive diffusion, the transport of ionized and un-ionized compounds across

the plasma membrane occurs down their electrochemical potential gradient, but
needs carriers.
Transfer of drugs across membranes

Active Transport:

• Active transport is the form of membrane transport that requires the input of
energy

• It is the transport of solutes against their electrochemical gradients, leading to the

concentration of solutes on one side of the plasma membrane

• Depending on the driving force, active transport can be subdivided in to primary

and secondary active transport
Transfer of drugs across membranes

Primary Active Transport:

• Membrane transport that directly couples with ATP hydrolysis is called primary
active transport. Eg.Na+,K+-ATPase

Secondary Active Transport:

• In secondary active transport, the transport across a biological membrane of one

solute S1 against its concentration gradient is energetically driven by the transport
of another solute S2 in accordance with its concentration gradient
 Transfer of drugs across membranes
• Depending on the transport direction of the solute, secondary active transporters are
classified as either symporters or antiporters.

• Symporters, also termed cotransporters, transport S2 and S1 in the same direction,

whereas antiporters, also termed exchangers,move their substrates in opposite
directions

Phagocytosis & pinocytosis:

• Process by which large molecules are engulfed by the cell membrane forming a vesicle
& releases them intracellularly.

E.g. protein, toxin

Transfer of drugs across membranes
Endocytosis and exocytosis:

• A few substances are so large or impermeant that they can enter cells only by
endocytosis, the process by which the substance is bound at a cell-surface receptor
engulfed by the cell membrane, and carried into the cell by pinching off of the
newly formed vesicle inside the membrane.

• The substance can then be released inside the cytosol by breakdown of the vesicle
membrane
Transfer of drugs across membranes

• E.g. Transport of vitamin B 12 , complexed with a binding protein (intrinsic factor)

across the wall of the gut into the blood, iron is transported into hemoglobin-
synthesizing red blood cell precursors in association with the protein transferrin

• The reverse process (exocytosis) is responsible for the secretion of many

substances from cells

• Neurotransmitter substances are stored in membrane-bound vesicles in nerve

endings to protect them from metabolic destruction in the cytoplasm.
 Transfer of drugs across membranes

• Activation of the nerve ending causes fusion of the storage vesicle with the
cell membrane and expulsion of its contents into the extracellular space
Dosage forms (preparations)
• Dosage forms (DFs) are the means by which drug molecules are delivered to
sites of action within the body
The need for dosage forms:
1. Accurate dose.
2. Protection e.g. coated tablets, sealed ampules.
3. Protection from gastric juice.
4. Masking taste and odour.
5. Placement of drugs within body tissues.
6. Sustained release medication.
7. Controlled release medication.
8. Optimal drug action.
9. Insertion of drugs into body cavities (rectal, vaginal)
10. Use of desired vehicle for insoluble drugs.
Types of Dosage forms
According to route of administration:

Oral
Rectal
Vaginal
Parenteral
Inhaled
Topical
Ophthalmic
Otic
Types of Dosage forms

According to physical form of a drug:

a. Tablets – Conventional
- Chewable
- Sublingual
- Extended release

b. Capsules – Hard gelatin & Soft gelatin

c. Powders –Powder for injections
d. Suppositories
Types of Dosage forms

2. Liquid – Solutions, Suspensions, Emulsions

3. Semisolids – Ointments
- Creams
- Pastes
- Jellies
- Pessaries
4. Gases (pressurized) - aerosols
 According to on set of action
Slow Absorption

• Orally (swallowed)

 Through Mucus Membranes

• Oral Mucosa (e.g. sublingual)

• Nasal Mucosa (e.g. insufflated)

 Topical/Transdermal (through skin)
 Rectally (suppository)
Faster Absorption

 Parenterally (injection)

• Intravenous (IV)

• Intramuscular (IM)

• Subcutaneous (SC)

• Intradermal(ID)

• Intraperitoneal (IP)

• Inhaled (through lungs)

Medication Administration

• Right Medication
• Right Dosage
• Right Time
• Right Route
• Right Patient
• Right Documentation
Routes of Drug administration

• Is the path by which a drug, fluid, poison or other substance

is brought into contact with the body.
Commonly Used Routes of Drug Administration

• IV = intravenous;
• IM = intramuscular;
• SC = subcutaneous.
Factors governing choice of Route

Drug characteristics

Ease of administration

Site of action

Onset of action

Duration of action

Quantity of drug administered

Liver and kidney diseases

 Enteral Routes

 Enteral - drug placed directly in the GI tract:

• sublingual - placed under the tongue

• Oral - swallowing (p.o., per os)

• Rectal - absorption through the rectum

 Oral Route
DISADVANTAGES
ADVANTAGES
Slow absorption
Safe  slow action
Convenient Irritable and unpalatable
Economical drugs
Usually good absorption Un co-operative for
unconscious pts.
Can be self administered Some drugs destroyed
First-pass effect
 Sublingual Route

ADVANTAGES DISADVANTAGES
 Economical  Unpalatable & bitter drugs

 Quick termination  Irritation of oral mucosa

 First-pass avoided  Large quantities not given

 Drug absorption is quick  Few drugs are absorbed

Can be self administered

 Rectal Route

• ADVANTAGES
Used in children
Little or no first pass effect
Used in vomiting/unconsciuos
DISADVANTAGES
Inconvenient
Absorption is slow and erratic
Irritation or inflammation of
rectal mucosa can occur

Vaginal Routes
 Drug may be administered locally in the vagina in
the form of pessaries.
E.g. Antifungal vaginal pessaries
 First-pass Effect

 The first-pass effect is the term used for the hepatic metabolism of a
pharmacological agent when it is absorbed from the gut and delivered to the liver
via the portal circulation.

 The greater the first-pass effect, the less the agent will reach the systemic
circulation when the agent is administered orally.
 First-pass Effect

Magnitude of first pass hepatic effect:

 Extraction ratio (ER)

ER = CL liver/Q

Where, Q is hepatic blood flow (usually about 90 L per hour for 70 kg adult).

 Systemic drug bioavailability (F) may be determined from the extent of

absorption (f) & the extraction ratio (ER),
F = f x (1-ER)
First-pass Effect
 Systemic Routes

Parenteral

First-pass
metabolism
can occur
with orally
administered
drugs.
Administration of drugs by the Parenteral Route

Needle insertion for

parenteral drug:
A. Intradermal
injection @15⁰.
B. Subcutaneous
injection @45⁰.
C. Intramuscular
injection @90⁰.
D. Intravenous
injection
 Intravascular (IV)
1. Absorption phase is bypassed (100% BA)

2. Precise, accurate and almost immediate onset of action.

3. Large quantities can be given, fairly pain free

4. Greater risk of adverse effects

a. High concentration attained rapidly

b. Risk of embolism and cannot be recalled by strategies such as emesis or by

binding to activated charcoal

5. IV is the most common parenteral route for drugs that are not absorbed orally.
 Intramuscular Route(IM)
Advantages
Disadvantages
 Absorption reasonably uniform
 Only up to 10ml drug given
 Rapid onset of action for drugs in aqueous
 Local pain and abscess
solution.
 Expensive
 Mild irritants can be given
 Infection
 slow release preparations
 Nerve damage
 First pass avoided

 Gastric factors can be avoided

 Subcutaneous route(SC)

1. Slow and constant absorption

2. Absorption is limited by blood flow, affected if circulatory problems

exist

3. Concurrent administration of vasoconstrictor will slow absorption

 Inhalation
1. Aerosols (gaseous & volatile agents)-lungs

2. Rapid onset of action due to rapid access to circulation

A. Large surface area

B. Thin membranes separates alveoli from circulation

C. High blood flow

 Inhalation
Respiratory system

 Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal dripping.
Fairly fast to brain, local damage to septum. Some of the volatile gases also
appear to cross nasal membranes.

 Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine.
Particles or vapors dissolve in lung fluids, then diffuse. Longer action than
volatile gases. Tissue damage from particles, tars, CO.

 Volatile gases: Some anaesthetics (nitrous oxide, ether).

 Lung-based transfer may get drug to brain in as little as five seconds.

Intraarterial

• 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-

labelled 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.
 Topical

 Mucosal membranes (eye drops, nasal drops, antiseptic, sunscreen, callous

removal etc.)

 Skin

A. Dermal - rubbing in of oil or ointment (local action)

B. Transdermal - absorption of drug through skin (systemic action)

i. Stable blood levels

ii. No first pass metabolism

iii. Drug must be potent or patch becomes to large

 Routes of administration

Time of onset
 Intravenous 30-60 seconds

 Intraosseous 30-60 seconds

 Endotracheal 2-3 minutes

 Inhalation 2-3 minutes

 Sublingual 3-5 minutes

 Intramuscular 10-20 minutes

 Subcutaneous 15-30 minutes

 Rectal 5-30 minutes

 Ingestion 30-90 minutes

 Time-release preparations

 Oral - controlled-release, timed-release, sustained-release

 Designed to produce slow, uniform absorption for 8 hours or
longer.
 Better compliance, maintain effect over night, eliminate extreme
peaks and troughs
 Time-release preparations

 Depot or reservoir preparations

Parental administration (except IV), may be prolonged by
using insoluble salts or suspensions in non-aqueous
vehicles.
Example: Implantable contraceptives .
Note
• The ROA is determined by:
 Physical characteristics of the drug,
 Speed which the drug is absorbed and/or released,
 The need to bypass hepatic metabolism and achieve high conc. at
particular sites
 f o r
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i s id
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mi n i st
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d r
o dof es
e t h t an c
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 Drug Absorption

• Transfer of a drug from its site of administration to the bloodstream.

• The rate and efficiency of absorption depend on the route of administration.

• For IV delivery, absorption is complete; that is, the total dose of drug reaches
the systemic circulation.
• Drug delivery by other routes may result in only partial absorption and, thus,
lower bioavailability.
 Factors affecting GI absorption

PH of media & pKa of the drug

Area of absorbing surface

Particle size of the drug

Formulation

Gut motility

GIT blood flow

Gastric secretion

Drug interaction
A drug must be in solution to be absorbed, since most drugs are either weak acids or
weak bases, pH affects their solubility and hence absorption.

Weak bases are absorbed more rapidly from the intestine than stomach.

Small intestine is the major absorption site because:

• It has large surface area (microvilli 200M2)

• There is good blood supply (1L blood/min compared to 150mL/min

stomach)
• Permeability to drugs is greater
 Bioavailability (F)
• Fraction of administered drug that reaches the systemic circulation in a chemically
unchanged form.
• Amount of drug available in the circulation/site of action

• It is expressed in percentage

• It is 100% for drugs given IV.

• For example, if 100 mg of a drug is administered orally and 70 mg of this drug are
absorbed unchanged, the bioavailability is 0.7 or 70%.

Factors affecting bioavailability

• Extent of absorption

• First pass effect

What are pharmaceutically equivalent drugs and
bioequivalent drugs????
Drug distribution
• Following absorption or systemic administration into the bloodstream, a drug
distributes into interstitial and intracellular fluids.

• This process reflects a number of physiological factors and the particular

physicochemical properties of the individual drug

• This Reversible movement of drug from bloodstream to interstitium (extracellular

fluid) and/or cells is drug distribution
 Factors affecting drug distribution

1.Plasma protein binding

• Albumin [acidic & hydrophobic drugs]

• -glycoprotein [basic drugs]

• The binding is usually reversible

2. Tissue uptake of drugs/tissue binding

-Adipose tissue [DDT]

-Bone [TTC]

-Liver [chloroquine]

-Thyroid gland [iodine]

3.Barriers –capillary permeability
 Blood brain barrier (BBB)
 Placental blood barrier (PBB)
 Cell membrane
4. Rate of blood flow
 Brain,
 Kidney, highly perfused
 Liver &
 Lung
5. Plasma concentration
 Drug metabolism

 Enzymatically mediated alteration in drug structure.

 Transforms lipophilic drugs into more polar readily excretable products.

 Liver - major site for drug metabolism, but specific drugs may undergo
biotransformation in other tissues, such as the kidney….

 Note: Some agents are initially administered as inactive compounds (pro-drugs)

and must be metabolized to their active forms.
 Inducers

The cytochrome P450 enzymes are an important target for pharmacokinetic drug
interactions.

Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are

capable of increasing the synthesis of one or more CYP isozymes.

This results in increased biotransformation's of drugs.

1. Decreased plasma drug concentrations.

2. Decreased drug activity if metabolite is inactive.

3. Increased drug activity if metabolite is active.

4. Decreased therapeutic drug effect.

 Inhibitors
Inhibition of CYP isozyme activity is also an important source of drug interactions that
leads to serious adverse effects.

The most common form of inhibition is through competition for the same isozyme.

For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible
for warfarin metabolism.

 If the two drugs are taken together, plasma concentrations of warfarin increase, which
leads to greater inhibition of coagulation and risk of haemorrhage and other serious
bleeding reactions.
 Inhibitors

• CYP inhibitors are erythromycin, cimetidine, ketoconazole, and ritonavir, because

they each inhibit several CYP isozymes

• Inhibition of drug metabolism may lead to;

- Increased plasma levels over time with long-term medications.
- Prolonged pharmacological drug effect.
- Increased drug-induced toxicities.
Microsomal enzyme inducers • Microsomal enzyme inhibitors

Phenobarbitone  Isoniazid
Phenytoin  Disulfiram
 Cimetidine
Rifampicin
 Allopurinol
Carbamazepine  Chloramphenicol
Sulphonamides  Erythromycin
Cigarette smoking  Metronidazole
• First-Pass Effect: significant metabolic inactivation of some drugs by the liver
following oral administration.
- Drugs absorbed from the GI tract enter the portal circulation and are carried
to the liver before entering the systemic circulation.
 Drug excretion
Removal of a drug from the body occurs via a number of routes.

The major routes of excretion include renal excretion, hepatobiliary excretion

& pulmonary excretion.

The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal
fluid & hair.

The rate of excretion influences the duration of action of drugs.

 If the drug is excreted slowly, the concentration of drug in the body is maintained
and the effects of the drug will continue for longer period
 Routes of drug excretion

a. Renal excretion

 For water soluble and non volatile drugs.

The three principal processes that determine the urinary excretion of a drug.

• Glomerular filtration

• Active tubular secretion

• Passive tubular reabsorption

The function of glumerular filtration and active tubular secretion is to remove

drug out of the body, while tubular reabsorption retain the drug
b. Hepatobiliary Excretion

The conjugated drugs are excreted by hepatocytes in the liver.

After excretion of drugs through bile to the intestine; certain amount of drug is
reabsorbed in to the portal vein leading to an entrohepatic cycling which can
prolong the action of drug.
 E.g. Chloramphenicol, estrogen.
c. Gastro intestinal excretion

When a drug is administered orally, part of the drug is not absorbed and excreted
in the faeces.

The drug which do not undergo enterohepatic cycling after excretion in to the bile
are subsequently passed with stool.
 E.g. Aluminum hydroxide changes the stool color in to white, Ferrous sulphate
darkens it and Rifampicin gives orange red color to the stool.
Pulmonary excretion

 Many inhalation anesthetics and alcohol are excreted through the lungs.

e. Sweat

 E.g. Rifampcine, metalloids like arsenic are excreted in to the sweat.

Mammary excretion

Many drugs are excreted in to breast milk.

Lactating mothers should be cautious about the intake of these drugs

because they may enter in to baby through milk and produce harmful
effects in the baby.
 E.g. Ampicillin, Aspirin, Chlorodizepoxide, Streptomycin.
 Parameters of kinetics
The physiological and pathophysiological variables that dictate adjustment of
dosage in individual patients often do so as a result of modification of

pharmacokinetic parameters.

1.Volumes of distribution

2.half – life and clearance

3.steady state and drug accumulation

4. maintenance dose, loading dose and dosing intervals

 Pharmacodynamics

Pharmacodynamics include:
 Mechanism of actions of the drug.

How does a drug act in the body?

 Effects of the drug: both beneficial & harmful effects.

What does a drug do in the body

Pharmacodynamics

• Define Pharmacodynamics.

• what, how and where drug acts

• Differentiate harmful effect and useful effect of the drugs.

• Identify factors affecting drug effect.

• Describe adverse drug reaction

Pharmacodynamics

• It is what the drug do to the body.

• It is concerned with;-

The biochemical and physiological effects of drugs.

Drug mode of action.

The dose effect relation ship.

Factors modifying drug effect and dosage

Drug toxicity.
Principles of drug actions

General principle

• “Drugs do not create new function, drugs modify the existing function”

• The basic types of drug action can be broadly classed as;-

A.Stimulation
Selective increase in activities in specialized tissues.

 Adrenaline produces increase in heart rate and force of contraction.

Principles of drug actions

B. Depression
• Selective decrease in activity in specialized tissue

• Barbiturates depress the central nervous system

C. Replacement
• This refers to the use of natural metabolites, hormones in deficiency states,
• Insulin in diabetes mellitus.
• Iron in anemia
Principles of drug actions
D. Cytotoxic action
• Selective cytotoxic action for invading parasites or cancer cells,
attenuating them without significantly affecting the host cells is utilized
for cure of infections and neoplasm's.
• Antibacterial drugs

• Antivural drugs

• Anticancer drugs

• Antihelmentics
Mechanisms of drug action

 It is of two types:

A. Receptor mediated mechanism

Receptors- targets of drug action.

May present either on the cell surface or inside the cell.

D + R → DR → Biological effect
Where; D=Drug, R=Receptor, DR=Drug Receptor Complex
Pharmacodynamics

B. Non-receptor mechanisms

 Simple physical or chemical reaction.

 Antacids: neutralization reaction

Bulk purgative, Osmotic diuretic
Receptor
• Is a molecule which binded by a ligand (drug) and give a biological function

• Are those components of a cell that serve as sensing elements of chemical signals
(such as hormones and neurotransmitters).

• Many therapeutically useful drugs interact with receptors for endogenous

molecules and modulate their signaling

A. Extracellular

B. Intracellular
Properties of Receptors

1. Sensitivity

• Receptors exhibit sensitivity, i.e. a small amount of drug / ligand is required to

sensitize the receptor and produce response.
• There is a signal amplification system

2. Selectivity

• The molecular size, shape, and electrical charge of a drug determine whether - and
with what affinity it will bind to a particular receptor.

• Receptors interact only with molecules that are complementary to them.

Cont…

3. Specificity

• The response obtained at a given receptor remains the same in spite of the
difference in the type of agonist.
 Models of D-R interaction…
 Lock & key
 Drug acts as key, receptor as lock, combination yields response.

 Induced-fit models
 Dynamic & flexible interaction.
Types of receptors

• Based on molecular structure and their signal transduction mechanism , receptors

may be grouped into the following types, or superfamilies'

1. Ligand-gated ion channels

• These are membrane proteins with a ligand-binding (receptor) site in the

extracellular domain associated with an ion channel
Cont….

• Binding of a ligand on the extracellular domain modulates the opening/closure or

conductance of the ion channel.

Conformational changes

• Nicotinic acetylcholine,

• Gamma-aminobutyric acid type A (GABAA)

The nicotinic acetylcholine receptor, a ligand-gated ion channel
 Cont …
2. G-protein-coupled receptors

• They are membrane receptors that are coupled to intracellular effectors systems via
a G-protein

• Binding of an extracellular ligand on cell-surface receptor  activation of the

receptor/ conformational changes in the receptor/  The receptor in turn triggers the
activation of a G protein located on the cytoplasmic face of the plasma membrane 
• The activated G protein then changes the activity of an effectors element, usually
an enzyme or ion channel.
Cont…

• Effectors controlled by G-proteins

• Adenylate cyclase (AC) / cAMP:

• Phospholipase C / inositol trisphosphate (IP3) / diacylglycerol (DAG)

• Ion channels (e.g. potassium and calcium channels, thus affecting membrane
excitability, transmitter release, contractility, etc.).
3. Kinase-linked and related receptors

• These receptors comprise an extracellular ligand-binding domain linked to an

intracellular domain by a single transmembrane helix

• Binding of a ligand results in change in receptor conformation  receptor

molecules to bind to one another/ receptor dimerization/  which in turn brings
together the protein kinase domains  autophosphorylation of tyrosine residues
which become enzymatically active  phosphorylate additional downstream
signaling proteins
Cont…

4. Intracellular Receptors
• These are receptors for ligands which have sufficiently lipid-soluble to cross
the plasma membrane.
• E.g. Thyroid hormone, Steroid hormones, Vitamin D, Retinoic acid.
• These receptors may be located in the cytoplasm or inside the nucleus.
Cont…

• The receptor-mediated regulation of DNA transcription.

• Receptors consist of a conserved DNA-binding domain attached to variable

ligand-binding and transcriptional control domains.
• Effects are produced as a result of altered protein synthesis.
Site of drug action
• Drug may act on:-

• On cell membrane

• On Enzymes and pump

• Ion channels

• Intracellular constituents

• Nuclear receptor

• Enzymes

• Carrier molecules

• DNA/RNA
Cont…

• Outside the cell

• Chemical interaction

• Antacids, chelating agents, alkalizing.

• Physical mechanism

• Osmotic diuretics, Osmotic purgative

• Possess antimicrobial action.

Drug effect

• Beneficial,

• Detrimental or dangerous.

• As each person is different, each person’s reaction to a drug may be different.

Thus, each patient must be monitored closely to ensure that his response to the
drug
• Beneficial effect

• The desired action of a drug in the treatment of a particular disease state or

symptom is referred to as a Therapeutic effect.
• The effect can be :-

• Local effect which confined to a specific part of the body.

• A systemic effect which has a generalized all-inclusive effect on the

entire body.
• Some time drugs are prescribed to prevent the occurrences of an infection
or disease.
• This effect is called Prophylaxis.
 Implications of drug-receptor interaction

 Drugs can potentially alter rate of any function in the body.

 Drugs cannot impart entirely new functions to cells.

 Drugs do not create effects, only modify ongoing ones.

 Drugs can allow for effects outside of normal physiological range.

 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.

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

 Dose response relationship
 Dose: amount of a drug required to produce desired response in an individual.

 Dosage: the amount, frequency and duration of therapy.

 Potency: measure of how much a drug is required to elicit a given response. The
lower the dose, the more potent is the drug.

 Efficacy: the intrinsic ability of the drug to produce an effect at the receptor.

 Maximal efficacy: largest effect that a drug can produce.

 Dose response relationship

Drug response depends on:

 Affinity of drug for receptor.

 Intrinsic activity (degree to which a drug is able to induce intrinsic effects).

 Agonism and Antagonism

 Agonists facilitate receptor response.

 Antagonists inhibit receptor response.

 Types of drug-receptor interactions
 Agonist drugs: bind to and activate the receptor which directly or indirectly brings
about the effect.
 Some agonists inhibit their binding molecules to terminate the action of
endogenous agonists.
 E.g. slowing the destruction of endogenous acetylcholine by using acetyl
cholinesterase inhibitors.

 Antagonist drugs: bind to a receptor to prevent binding of other molecules, but

lack intrinsic activity.
 E.g. Atropine decrease acetylcholine effects
 Types of drug-receptor interactions…
 Partial agonist drugs: acts as agonist or antagonist depending on the
circumstance, have affinity but have lowered maximal efficacy.
 E.g. Pindolol can act as an antagonist if a “full agonist” like Isoproterenol is
present.

 Inverse agonist: is a ligand which produces an effect opposite to that of the

agonist by occupying the same receptor.
 Full agonist- A drug with high positive efficacy & produce the system
maximal response.
 Partial agonist- maximal response to the ligand is below the system maximal
response.
 Antagonists- no efficacy or such a low level of efficacy with no visible
response.
 Inverse agonist- A ligand with negative efficacy can reduce the basal response.
Graded dose–response relations

As the concentration of a drug increases, its pharmacologic effect also

gradually increases until all the receptors are occupied (the maximum
effect).

It is used to determine affinity, potency, efficacy and characteristics of

antagonists.
 Potency
 Is relative strength of response for a given dose.

 Effective concentration (EC50) is the concentration of an agonist needed to elicit

half of the maximum biological response of the agonist.

 The potency of an agonist is inversely related to its EC50 value.

 D-R curve shifts left with greater potency

 Efficacy

 Maximum possible effect relative to other agents.

 Indicated by peak of D-R curve.
 Full agonist = 100%
 Partial agonist = 50%
 Antagonist = 0%
 Inverse agonist = -100%
Quantal(cumulative) dose response r/ship:

Is between the dose of the drug and the proportion of a population that responds to it.

For any individual, the effect either occurs or it does not (‘all’ or ‘none’).

Are useful for determining doses to which most of the population responds; ED50%,
TD50%, LD50%, TI(r/ship b/n dose & toxicity) & inter subject variability in drug
responses.

They do not predict idiosyncratic reactions and hypersensitivity.

 Therapeutic index
 Median Lethal Dose (LD50): dose which would be expected to kill one half of a study
population.

 Median Effective Dose (ED50): dose which produces a desired response in 50% of the
test population.

 Therapeutic Index: gives a rough idea about the potential effectiveness and safety of the
drug in humans.

Therapeutic Index (TI) = LD50/ED50

The smaller the TI, the less safer the drug is.

 Margin of safety=LD1/ED99
Factors modifying the dosage & action of drugs

1. Age
2. Sex
3. Body weight
4. Genetics
5. Drug tolerance
6. Drug intolerance
7. Disease states
 Factors modifying the dosage & action of drugs

Age
The prescribers can use a variety of formulas when prescribing medication
for elderly and pediatric patients
Pediatric patients and the elderly may require less of a drug because of
their smaller size or inability of the liver to metabolize the medication
adequately to metabolized the medication adequately.
Cont…
Sex
This also needs to be considered when prescribing some medications
since men and women have different amount of hormones.

Body weight

Physiological factors
The mental state of a patient can influence the body’s ability to release
chemical substance needed to appropriately absorbed or metabolize a drug.
Pathological states

Patients with specific diseases may be unable to absorb,

metabolize, or excrete various medications.
• Impaired G.I function may affect absorption.
• Impaired liver may affect metabolism.
• Impaired kidney function may affect elimination.
In adequate nutritional intake may also adversely affect the
metabolism of drugs.
Therefore, the patient’s disease condition must be evaluated before
prescribing medications.
Genetic factors
Genes can also control the release of chemical and how the body
absorb or metabolism various medications. Unfortunately, this factor
are less predictable they age and sex disease condition. However, if
the patient dose not seems to be responding to a medication, this
factor should be considered
Habituation
Addiction, tolerance, individual variation and resistance affect drug
action.
Psychological state
Rout of administration

Some drug may produce different effect by different routes.

MgSO4 Orally  Purgative

IV  CNS depression

Caster oil Orally  purgative

Topically  Soothing

Alcohol Orally  CNS depression

Locally antiseptic
Properties of the drug

 Solubility, molecular weight, osmotic action, particle size, can also affects drug
Cont…
Drug interaction (DIs)

When two or more drugs are given together or close to each other they
may act independently of each other or interacts.
Drug interaction is a phenomenon of two or more drugs interacting in such
away that the effectiveness or toxicity of one or more drugs is altered.
The interaction may be beneficial or adverse
Cont…
 When drugs combine their effect may be:-

 Additive (simple summation of effects)

 Synergism

 Potentiating

 Antagonism (opposing action)

 Pharmacological antagonism

 Chemical antagonism

 pharmacokinetics Antagonism

 physiological antagonism
Cont...

Sites and mechanism of drug interaction

• In vitro interaction (drug interaction which takes place out side the body).

• In vivo interaction (drug interaction which takes place inside the body).

• There are two important type of in vivo drug interaction, these are:-

• Pharmacokinetics drug interaction

• Pharmcodynamics drug interaction

 Drug- Drug interactions
Consequences of Drug- Drug Interactions
1. Intensification of effects: increased therapeutic or adverse effects.
Additive Drug Effects (Summation): 1 + 1 = 2.
 Most frequently seen when two drugs possess similar intrinsic activity.
E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol, benzodiazepines
(diazepam, etc.) administered in combination will produce additive effects resulting
in over-sedation.
Synergism - the effect of two drugs in combination is greater than the sum of the
drugs administered alone (1 + 1 > 2).
E.g. Aminoglycosides with penicillins.
Potentiation – one substance alone does not have effect but when added to another
chemical, it becomes effective. (1 + 0 > 1).
2. Reduction of effects – inhibit drug effects; Either beneficial or detrimental.

Antagonism: it occurs when the effect of one drug is diminished by another

drug.(1+1<1).

Types of antagonism;
 Chemical antagonism or inactivation
 Physiological (functional) antagonism
 Pharmacologic or Receptor antagonism
 Pharmacokinetic/Dispositional antagonism
Basic mechanisms of Drug- Drug interactions
Direct chemical or physical interaction - can occur with drugs mixed together.

Pharmacokinetic interaction – can alter all four processes.

 Absorption – increase or decrease (e.g., PH, laxative, changes in blood flow).

 Distribution – competition for protein binding or changes in extra cellular PH.

 Metabolism - induction of drug metabolizing enzymes, inhibition of metabolizing,

and competition of metabolism.
 Excretion - altered renal excretion (e.g. filtration, reabsorption, and secretion).
 Pharmacokinetic interaction
• It is alteration in the delivery of drugs to their site of action.
• Absorption
• Direct interaction in the gut.

• By affecting gut motility

• By affecting gut contents

• Displacement interaction (competition for plasma protein binding)

• Drugs with greater binding affinity or capacity cause displacement from tissues and plasma
binding sites of those drugs which are less strongly bound
Cont…
Metabolism

• Depending on the action of the drug on many enzymes they can be divided in to
two. (Enzyme inducer and enzyme inhibitors).
• Enzyme inducer

• Inducer can induced the activity of the enzymes there by facilitating the
metabolism of other drugs.
• Phenytoin

• Cigarette

• Barbiturate
Cont…

• Enzyme inhibitor

• Inhibitor can inhibit the activity of enzymes there by reduced the

metabolism of other drug.
• Chloramphenicol----inhibit Hepatic microsomal enzymes.

• Allopurinol --------inhibit Xantine xoidase

• MAO inhibitor -----inhibit Monoamine oxidase

• Disulframe ---------inhibite Aldehyde dehydrogenase

Cont…

• Excretion site

• Interferes with passive diffusion:

• Weak acids in alkaline pH are more ionized so less reabsorbed and

more excreted.
• Interference with urinary secretion:

• Probenecid and Penicillin (Probencid is competitors for renal secretion

or reabsorption of penicillin.)
 Basic mechanisms of Drug- Drug interactions
Pharmacodynamic interaction

 Interactions at same receptor – almost always inhibitory.

 Interactions resulting from actions at separate sites (if drugs influence same
physiologic process).
• Competition at receptor site.
• Atropine blocks cholinergic drugs
• Inhibition of neural uptake.
• Potentiation of CNS depressant.
• Influence of electrolyte.
• Drug causing hypokalmea such as Thiazidae diuretics and digitalis results in increase
digitalis toxicity.
 Drug- Food interactions
 Impact of Food on Drug Absorption

• Decreasing rate and/or extent of absorption

• Some foods can increase extent of drug absorption.

 Impact of Food on Drug metabolism

• The grapefruit juice effect (can inhibit metabolism of certain drugs 

increased drug levels).

 Impact of Food on Drug Toxicity

• Caffeine with theophylline

 Drug- Food interactions

 Impact of Food on Drug Action

• Vitamin K with warfarin.
How to minimize DIs

• The occurrence of drug interaction can be minimized if the following are

observed.
• Careful history from the patent is taken

• Multiple drug therapy (poly pharmacy) is avoided.

• By giving proper instructions of possible danger if the patient changes or

adds other drugs with out consulting physician.
 Adverse drug reactions (ADRs)
• Any noxious or unintended reaction to a drug that is administered in standard
doses by the proper route of administration for the purpose of prophylaxis,
diagnosis or treatment.

• ADR is any undesirable effect of a drug beyond its anticipated therapeutic effect
occurring during clinical use.

• Most ADRs are related to dose of the drug administered. Dose related ADRs are
often predictable.

• Few ADRs are not related to the dose and are often unpredictable
 Adverse drug reactions (ADRs)
 Any undesired response to a drug.

 Can range in intensity from annoying to life threatening.

Types of adverse drug reactions

 Side Effects: unavoidable secondary drug effect produced at therapeutic drugs

doses.

E.g. 1. Drowsiness that often accompanies the use of antihistamines

2. Gastric bleeding that can be produced by low therapeutic doses of aspirin.

 Adverse drug reactions (ADRs)
 Toxicities: an adverse drug reaction caused by excessive levels of drug.

E.g. Coma caused by overdose with morphine.

 Allergic reactions:

• Prior sensitization of the immune system.

• Re- exposure to that drug can bring on an allergic response.

E.g. Penicillin allergy

• Idiosyncratic effects: an unusual drug response resulting from a
genetic predisposition
 Physical dependence: a state in which the body has adapted to prolonged
drug exposure in such a way that if drug use is discontinued abstinence syndrome
will result.
Develop during long-term use of certain drugs (e.g. Opoids, barbiturates etc)

 Carcinogenic effects: ability of certain mediations /chemicals to cause

cancer.
Although a number of carcinogenic compounds have been identified, very few of these are
employed therapeutically.

 Teratogenic Effects: drug- induced birth defect

 all things are poison and not without poison; only the dose makes a
thing not a poison”

Paracelsus, (the father of toxicology)

• It is not the nature of the drug that determines toxicity, but
rather the amount
• everything, in excess, is potentially toxic
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