USIU-Africa

School of Pharmacy
PHM 3471A & B: Basic Pharmacology and Toxicology
Mid-term exam ANSWERS

Date: 26/06/2020. Time: 9:00 am -11:00 am.

Instructions.
Answer all questions.
Write your registration number on the answer sheet.

1. Since we cannot practically measure drug concentration in specific tissues, we measure it

in the plasma and assume that this concentration is the same as that in tissue .A. True B.
False
2. Pharmacodynamics refers to the relationship of drug: A. dose to drug concentration in
plasma. B. dose to drug concentration at the receptor site. C. concentrations to drug
effect. D. dose to drug effect
3. Drug pharmacodynamics are affected by the drug concentration at the site of the receptor,
density of receptors on the target cell surface, mechanism by which a signal is transmitted
into the cell by second messengers, and regulatory factors that control gene translation
and protein production. A. True B. False
4. The EC50 refers to the drug concentration at which: A. one-half the maximum response
is achieved. B. the maximal effect is achieved. C. tolerance is likely to be observed
5. The therapeutic range is the range of plasma drug concentrations that clearly defines
optimal drug therapy and where toxic effects cannot occur. A. True B. False
6. Therapeutic drug concentration monitoring with plasma drug concentration data assumes
that pharmacologic response is related to the drug concentration in plasma. A. True B.
False
7. Factors that cause variability in plasma drug concentrations after the same drug dose is
given to different patients include variations in the: A. drug absorption. B. EC50 of the
drug
8. An example of a situation that would not support therapeutic drug concentration
monitoring with plasma drug concentrations would be one in which: A. a wide variation
in plasma drug concentrations is achieved in different patients given a standard drug
dose. B. the toxic plasma concentration is many times the therapeutic concentration
range. C. correlation between a drug’s plasma concentration and therapeutic response is
good
9. For a drug with a narrow therapeutic index, the plasma concentration required for
therapeutic effects is near the concentration that produces toxic effects. A. True B. False

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 10. Many hormones, neurotransmitters (eg, acetylcholine, histamine, norepinephrine), and
drugs (e.g, morphine, phenylephrine, isoproterenol, benzodiazepines, barbiturates) act as
agonists: A. True B. False
11. Which aspect of drug administration is most likely to control the effect of a drug on a
patient? A. Binding site B. Chemical interaction C. Drug concentration at the site of
action D. Route of administration
12. Which of the following best defines the therapeutic index of a drug? A.Change in
response per unit dose B.Maximal attainable respons C. Ratio of the minimum toxic
concentration to the median effective concentration D. Variation in magnitude of
response among a given population
13. Which of the following is most likely to result from increasing the dose of a drug with a
small therapeutic index? A. Decreased probability of toxicity; no effect on effectiveness
B. Increased probability of safety and effectiveness C. Increased probability of toxicity
or ineffectiveness D. Increased probability of toxicity; no effect on effectiveness
14. A drug’s ability to affect a given receptor is not related to the drug’s affinity (probability
of the drug occupying a receptor at any given instant) and intrinsic efficacy: A. True B.
False
15. If Drug X has greater biologic activity per dosing equivalent than drug Y, But the
maximal efficacy of Drug X is lower than that of Drug Y, then drug Y is more potent
than Drug X. A. True B. False.

Section B. (Short answer questions: 30 marks).

1. Briefly, explain the two major types of pharmacological antagonism, giving an appropriate
example in each case (5 marks).

• Competitive/reversible/surmountable antagonism: Agonist and antagonist compete for

the receptor. EC50 shifts to the right while Emax is unaffected. E.g. Acetylcholine and
atropine; adrenaline and propranolol; naloxone (an opioid receptor antagonist that is
structurally similar to morphine), when given shortly before or after morphine, blocks
morphine’s effects. However, competitive antagonism by naloxone can be overcome by
giving more morphine.

• Non-competitive/irreversible/insurmountable antagonism: Antagonist forms irreversible

receptor binding; E.g. ketamine is a non-competitive antagonist at the NMDA-glutamate
receptor
2. List and explain the three major types of pharmacological agonists, giving an appropriate
example in each case (5 marks).

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 • Full agonist: A full agonist is a drug which is capable of producing a maximum response
that the target system is capable of: "When the receptor stimulus induced by an agonist
reaches the maximal response capability of the system (tissue), then it will produce the
system maximal response and be a full agonist in that system. Examples of full agonists
are heroin, oxycodone, methadone, hydrocodone, morphine, and opium.

• Partial agonist/antagonism: Antagonist has high affinity but low intrinsic activity. For
example, pentazocine activates opioid receptors but blocks their activation by other
opioids.

• Inverse agonist/ antagonism: inverse agonist is a drug that binds to the same receptor as
an agonist but induces a pharmacological response opposite to that of the agonist. A
neutral antagonist has no activity in the absence of an agonist or inverse agonist but can
block the activity of either. Nearly all H1 (Mepyramine; Diphenhydramine) and H2
(Cimetidine; Ranitidine; Famotidine) antihistaminics (antagonists) have been shown to be
inverse agonists. Among the β-blockers, carvedilol and bucindolol demonstrate low level
of inverse agonism as compared to propranolol and nadolol

3. Minocycline at a dose of 1 µg/ml and Doxycycline, at the dose of 1 mg/ml produce the same
clinical outcomes. Compare the efficacy and potency of both drugs (5 marks).

• Both drugs have the same efficacy

• Minocycline is more potent than doxycycline.

4. Differentiate between allosteric and orthosteric drug receptor binding (5 marks).

Orthosteric binding: This is where the drug binds to the receptor at the same site as the
endogenous ligand
Allosteric binding: the drug binds to a different site from that to which the endogenous ligand
binds

5. Write short notes on:

i). Partial antagonism (2.5 marks)

Antagonist has high affinity but low intrinsic activity

E.g. For example, pentazocine activates opioid receptors but blocks their activation by
other opioids

ii). Inverse antagonism (2.5 marks).

Drug binds to the same receptor as an agonist but induces a pharmacological response
opposite to that of the agonist. Examples:

H1 receptor antagonists, e.g. Mepyramine; Diphenhydramine) and,

H2 receptor antagonists, e.g. Cimetidine; Ranitidine; Famotidine

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 β-blockers, carvedilol (β1, β2, α1 ) and bucindolol (β1, β2), propranolol (β1, β2,
nadolol (β1, β2)

Section C (10 marks)

1. Write short notes on second messengers, under the following subheadings:

i). Classification, giving at least two examples in each class (6 marks).

GASES:NO; H2S; CO

HYDROPHOBIC /LIPHOPHILIC: Diacylglycerol; Phosphatidylinositols

HYDROPHILIC: cAMP; cGMP; IP3; Ca 2+

ii). Cellular transduction of nitric oxide (2 marks).

It activates soluble guanylyl cyclase, which when activated produces another second
messenger, cGMP.
It is toxic in high concentrations , but is the cause of many other functions like relaxation
of blood vessels, and apoptosis.

iii). Two examples of Phosphatidylinositol derived second messengers (2 marks).

Diacylglycerol (DAG); Inositol-1,4,5-trisphosphate (IP3)

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 USIU-Africa
School of Pharmacy
PHM 3471Aand B: Basic Pharmacology and Toxicology
Quiz one. ANSWERS

Date: 19/06/2020. Time: 11:00 am -12:00 pm.

Instructions.
Answer all questions.
Write your registration number on the answer sheet.

1. The following are pharmacodynamics components, except: a). Mechanisms of drug

action b). Concentration vs time effect c). Drug receptor interactions d). Dose response
relationships
2. Pharmacodynamics is the study of drug effects at the following levels, except: a).
Biochemical b). Cellular c). Molecular d).Idiosyncratic
3. Pharmacological responses following single drug administration by a given route can
produce the following effects, except: a). Beneficial b). Harmful c). Hazardous d).
Synergistic
4. Drugs produce clinical outcomes following administration while utilizing the following
pathways, except: a). Physical interactions b). Mechanistic interactions c). Chemical
interactions d). Drug-receptor interactions
5. An example of a drug utilizing chemical interactions to produce pharmacological
response is: a). Protoamine b). Mepyramine c). Naloxone d). Ephedrine
6. The following drug produces its effects through drug-receptor interactions: a).
Aluminium hydroxide b). Nifedipine c). Propranolol d). Calcium bicarbonate
7. The part of the drug molecule that binds to the receptor is called: a). Pharmacophore b).
Allosteric site c). Active site d). pharmacological site
8. Drug X could have a high affinity towards a specific receptor, but low intrinsic activity:
a). True b). False c. Both a and b d. None
9. Pilocarpine exhibits orthosteric binding at the muscarinic receptors: a). True b). False c.
Both a and b d. None
10. At equilibrium, the rates of association and dissociation of a drug from the receptor are
not constant: a). True b). False c. Both a and b d. None
11. All the following are receptor types, except: a). Ligand gated b). Tyrosine kinase c).
Intracellular steroid d). Calcium receptors

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12. Drug Z has an association rate of 1 and a dissociation rate of 2. The dissociation constant
of Drug Z is: a). 1 b). 2 c). 0.5 d). 0.2
13. The following are key features of an exponential dose response curve, except: a). Rate of
change is rapid at first b).Dose increments produce no further change c). Dose
increments produce significant change d). Difficult to analyze mathematically
14. In a dose response curve, large ED50 values are indicative of: a). low potency b). high
efficacy c. Low potency and high efficacy d). high efficacy and low potency
15. If two drugs have the same efficacy, and different potency: a). potency is of little clinical
significance b). Large doses of the more potent drug are required c). Low doses of the
more potent drug are required d).a and c
16. The following dose response curve represents a proportion of Covid-19 patients who
responded to dexamethasone treatment: a). Hyperbolic b). Sigmoidal c). Quantal d).
exponential
17. The reversal of anticoagulant effects of warfarin by phenobarbital in an example of the
following type of antagonism: a). Competitive b). Chemical c. Pharmacokinetic d).
Physiologic
18. Administration of epinephrine to reverse histamine induced bronchoconstriction in
asthmatic patients is an example of the following type of antagonism: a). Physiologic b).
Inverse c). Partial d). Pharmacologic
19. In competitive antagonism, the following pharmacodynamics parameter is not affected:
a). Emax b). ED50 c). EC50 d. Bmax
20. An example of a partial antagonist is: a). Mepyramine b).Atropine c). Pentazocine d).
Famotidine

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BASIC PRINCIPLES IN
PHARMACOLOGY
 HISTORY
Pioneers of medicine and pharmacology

Hippocrates 450 BC
Francois MAGENDIE (1783-1855)
Claude BERNARD (1813 – 1878)
Rudolf BUCHEIM (1820 – 1879)
Hippocrates
Hippocratic Oath
I will remember that there is art to medicine as well
as science, and that warmth, sympathy, and
understanding may outweigh the surgeon's knife or
the chemist's drug.
I will not be ashamed to say "I know not", nor will I
fail to call in my colleagues when the skills of
another are needed for a patient's recovery.
I will respect the privacy of my patients, for their
problems are not disclosed to me that the world
may know.
 what is Pharmacology
• Pharmakon – drug
• Logos – a discourse or treatise (science)

• How chemical entities affect living processes

✓ Hormones
✓ Neurotransmitters
✓ Growth Factors
✓ Drugs
✓ Toxins
• Medicinal organic chemists may create
candidate compounds (New chemical entity)

• The pharmacologist tests for pharmacologic

activity

• This has led to discovery of novel drugs for

treatment of disease
Dr Larry M KIMANI
 What is a Drug?

Drug
Drogue – dry herbs
A single chemical entity present in may
medicines that is used to diagnose, treat or
prevent disease

WHO -1966
 Orphan drugs

Drugs or biological products for diagnosis, prevention and

treatment of a rare disease or a more common disease
(endemic only in poor countries) for which there is no
reasonable expectation that the cost of developing and
marketing will be recovered from the sale of these medicines.

Examples
• Rifabutin – TB substitute of rifampicin used in HIV patients
• Fomezole – For methanol poisoning
• Liposomal Amphotericin B – Cryptococcus Meningitis
 Essential Medicines

Those medicines that satisfy the needs of the

population. They are intended to be available
within the context of functioning health
systems, at all times in adequate quantities, in
appropriate dosage forms with assured quality
and adequate information, and at a price the
individual and the community can afford.

WHO 2003
• Pharmacologist study the effects of drugs and
how they exert their effects

• Paracetamol produces an antipyretic effect by

inhibiting cyclooxygenase (COX) in the CNS. COX
is responsible for the synthesis of inflammatory
mediators

• Penicillin is very effective in the treatment of

bacterial infections. It disrupts cell wall synthesis
by inhibiting cell wall transpeptidase.
 Branches of Pharmacology
Two branches of pharmacology
Pharmacokinetics
Fate of drugs once ingested and the variability of
drug response in varying population groups
ADME
What the body does to the drug
Pharmacodynamics
A study of mechanisms of action
Study of endogenous agents
Pharmacotherapeutics

:Drug use for the prevention and cure of disease

– clinical management of disease
Chemotherapy
Branch of therapeutics concerned with the
effects of drugs on microorganisms and
parasites
Source Drug Therapeutic use
Plants
Sources
Morphine
of drugs
Analgesic
Quinine Antimalarial
Atropine anticholinergic

Animals Insulin DM
Thyroid extract Hypothyroidism

Minerals Magnesium sulfate Laxative

Ferrous sulfate IDA
Magnesium trisilicate Antacid

Microorganisms Penicillin Antibiotic

Bacitracin antibiotic

Synthetic drugs Analgesics ASA

NSAIDs Diclofenac
Anxiolytics Diazepam

Genetic engineering Human insulin Diabetes

 Toxicology
• Science of poisons including detection and
measurement of poisons as well as treatment
of poisoning.
• Poisons are substances causing harm,
dangerous or fatal symptoms in man and
animals
Merci beaucoup coup!
Introduction to Pharmacokinetics
 What is pharmacokinetics?
Study of what the body does (ADME) to a drug
→Helps determines the dose and dosing frequency
Absorption: how the drug gets into the body; depends on
dosage form, API properties (e.g., solubility,
permeability); GI tract is site for orally administered
drugs
Distribution: where the drug goes in the body; needs to
be transported to site of action to treat the condition
Metabolism: Primary site for most drugs is the liver
Excretion: Primarily via the kidneys; liver
 Routes of administration
Choices of routes of administration
Drugs are chemical entities, and may be acidic,
basic or neutral.
They could be small organic molecules, large
polymers (e.g. proteins), and carbohydrates
The choice of the route of administration
depends on various factors including
• Physicochemical properties
❑ physical state : solids/liquids/gases
❑ solubility
❑ pH
• Site of desired action
• Accuracy of dosage required
• Condition of the patient
coma, unconscious, vomiting etc.
Local routes
1. Topical
→lotions,
→ointments,
→creams,
→powders and sprays
2. Deeper tissue →Syringe and needle,
→Intraarticular,
→intra-medullary
→intra-lesion
3. Arterial supply
Closed intra-arterial injection e.g. angiography
and anticancer drugs
Enemata
• Evacuation enema → Soap water enema
600ml

• Retention enema → Solid form meant for

systemic action e.g. prednisolone enema
 First pass metabolism therefore ↓bioavailability

bsorption Tardy onset of action

Systemic routes
Irritant and unpalatable drugs cannot be administe
Oral (enteral)
refore safe with certain drugs Irregular absorption for some drug e.g. aminoglyc

and liquid dosage forms Drugs may induce nausea and vomiting

Not useful for pts with vomiting and diarrhea

Cannot be used in emergencies

Some drugs e.g. peptides, may be digested by gast

• Enteric coated - with acetate phthalate,
glutean, and anionic polymers of methacrylic
acid and its esters
• Prevents gastric irritation and alteration of
drug in the stomach
• For some drugs coating enhances attainment
of desired concentration in plasma
Controlled release (CR)
Examples → Timsules/spansules

→ To provide uniform medication for a

prolonged period of time
Sublingual (buccal) → Under the tongue or crushed
and spread over the buccal cavity
Very well vascularized
Drugs taken via this route do not undergo 1st pass
metabolism

Examples : Glyceryl trinitrate (GTN),

Buprenorphine,
Advantages
• Rapid absorption
• By-passes First Pass metabolism
• Can be administered to unconscious pts
Disadvantages
Only lipid soluble drugs
Cannot be administered in uncooperative pts
May cause irritation of the mucosa
Rectal
Irritant and unpalatable drugs administered via this
route e.g. suppositories or retention enemas
This route can be used in patients who are vomiting
or are unconscious.
Drugs administered through the rectal route are
absorbed by the external hemorrhoid vein and by-
pass the 1st pass metabolism
Examples → diazepam, indomethacin,
aminophylline, paracetamol, prednisolone
Inhalation (pulmonary)
Very rapid absorption due to the large surface area of the
lungs
The lungs are also very well perfused and drains into the
pulmonary vein

Drugs administered via this route by-pass first pass

metabolism

Examples General anesthetics, MDIs, dry powder

inhalations (Rotahalers)
Nasal
Absorption through the mucous membrane in
the nasal cavity
By-pass first pass metabolism

Examples → GnRH agonists like leuprolide,

calcitonin, and DDAVP -desmopressin (used to
stop bleeding in pts with Von Willebrand’s
disease or mild hemophilia A)
Parenteral (beyond the enteral{intestine} parallel to the
enteral )
Advantages
• Unconscious and uncooperative pts
• In the pts with vomiting and diarrhea
• Irritant drugs
• By-passes gastric juices and first pass metabolism
• Rapid onset of action
• Precision of dose
• Can be used in emergencies
Disadvantages

Expensive
Painful
Risk of infection
Injury to the nerves and arteries
Risky (Irreversible)
Intradermal
BCG and sensitivity tests
Subcutaneous
Non-irritant drugs
Small amounts
Self-inject
Avoid shock
Repository depot preparations
Aqueous suspensions
Examples → Insulin
Intramuscular
Soluble substances, mild irritants, suspensions
and colloids
Sites of injection → gluteus maximus, deltoid
muscle
NB not to be used in children before they start
walking
Intravenous
Advantages
Rapid onset of action
Precision in dosing can be attained
By-passes first pass metabolism → 100%
bioavailability
Can be used in emergencies, and in unconscious
and uncooperative patients
Disadvantages
Expensive
Need for specialized skills
Risk of thrombophlebitis and local irritation
Action cannot be halted or reversed
Extravasation may cause severe irritation
Aseptic and antiseptic measures need to be
maintained
Transcutaneous
• Innuction – nitroglycerin in angina pectoris
• Iontophoresis – uses galvanic current for penetration
of drugs into deep tissue
• Jet injection: Painless injection of high velocity jet
produced via a micro-fine orifice
• Transdermal therapeutic system ( novel drug delivery)
examples GTN, Nicotine, estradiol, scopolamine patch
• Implants – Biodegradable and non-biodegradable
norplants
Special delivery systems
• Ocusert – pilocarpine
• Prodrug – levodopa, chloramphenicol
palmitate
• Targeted drug delivery -- MABs
• Liposomes – daunorubicin, doxorubicin,
amphotericin B
Merci beaucoup
Pharmacokinetics – Week 2
 What is Clinical PK
Application of PK principles to the safe and
effective therapeutic management of disease in
individual patients
• Monitor meds with a narrow therapeutic
index e.g. Digoxin
• Minimize the risk of ADE while maximizing the
pharmacologic response to drugs
• Know and apply routes of administration for
optimal benefit to the patient
 Important definitions in PK
Area Under the Curve (AUC)
Area under the plasma concentration time curve after a single dose or during a single
dosing interval

Bioavailability
The fraction (%) of the administered dose that reaches systemic circulation

Clearance
The ratio of the rate of elimination of drug to the concentration of the drug in plasma
Cl =rate of elimination/cp volume of blood cleared of the drug per
unit time (ml/min L/h)

Half-life
The time required for the amount of drug to fall to 50% of an earlier dose. For first
order kinetics, this number is constant regardless of the concentration
First-pass effect, pre-systemic elimination
The elimination of a drug that occurs after administration
but before the drug reaches systemic circulation

Maximum tolerated concentration

Plasma concentration of a drug above which toxic effects
are manifest

Minimum effective concentration

Plasma concentration of a drug below which sub-optimal
therapeutic effects are manifest
Peak and trough concentrations
The maximum and minimum plasma concentrations of a drug
achieved during repeated dosing cycles
Steady state concentration
The condition in which the average concentration of a drug in
plasma does not change over multiple dosing cycles (rate of
administration is equal to the rate of elimination)
Volume of distribution (apparent volume of distribution)
The ratio of the amount of drug in the body to the plasma
concentration of the drug
Vd = Dose/cp mg/mg/ml = ml
• First order kinetics is when a constant fraction
(exponential) of drug is eliminated per unit of
time.
• Zero order kinetics is when there is a constant
rate of drug elimination and the rate of
elimination is independent of drug
concentration.
 Absorption
• Movement of a drug from the site of
administration to the systemic circulation
• Occurs after disintegration and dissolution of
solid dosage forms or administration of liquid
dosage forms
• Depends on the route and site of
administration
 How do drugs traverse the cell
membranes?
Passive (simple) diffusion
Requires a degree of lipid solubility for a drug to cross the
phospholipid bilayer and moves using the concentration gradient until
equilibrium is reached.

Facilitated diffusion
Requires no energy nor can a drug move against a concentration
gradient, but it sufficiently resembles the natural ligand to bind to the
carrier macromolecule and traverse the membrane.

Active transport
Also capitalizes on the drugs resemblance to the natural ligand
allowing it to bind to carrier macromolecules, however, this process
uses energy to transport a drug against the concentration gradient.
• Other carrier mediated transport mechanisms
exist that are non-specific drug transporters,
for example P-glycoprotein.
• Pinocytosis incorporates the drug into a lipid
vesicle for carrier-mediated transport into the
cell cytoplasm.
• Transport through pores or ion channels can
occur with the concentration gradient for small
water-soluble drugs.
Characteristics Passive diffusion Facilitated diffusion Active transport
Incidence Commonest Less common Least common
Process slow Rapid Very rapid
Movement Along Along Against
concentration concentration concentration
gradient gradient gradient

Carrier Not needed Needed Needed

Energy Not required Not required Required
 Factors that affect drug absorption
and bioavailability

1. Physicochemical properties
• Physical state
• Particle size
• Lipid solubility
• pH and ionization
• Disintegration and dissolution time
• Formulation
2. Route of administration
3. Presence of other drugs
4. Patient’s condition
• Disease
• Presence or absence of food in the stomach
 Distribution
• Random movement of a drug out of the
central compartment/systemic circulation into
various tissues, organ systems and fluid
compartments

• Involves transport of the drug from the blood

to target sites
Factors that affect distribution of drugs
1. Physicochemical properties
• Lipid solubility
• pka of the drug (ionization at physiological
pH=7.4)
2. Physiological factors
• Rate of blood flow
3. Presence of barriers
• BBB
• Placental barrier
Plasma protein binding
• In plasma some drugs are bound to plasma
proteins to various extents.
• Drugs also exist unbound (free)
• Only the unbound drugs are pharmacologically
active
• Only free drugs can interact with the target site
and tissues to elicit a biological response and be
available for elimination
Major plasma proteins that bind drugs
• Albumin
• ἀ - acid glycoprotein
• Lipoproteins
• Globulin
• Hormone binding factors
Redistribution
Redistribution of drugs from the site of action to
other sites or tissues occur e.g thiopental
Highly lipid soluble drugs distribute to the brain,
liver, heart and kidneys followed by
redistribution to peripheral components.
Factors affecting oral absorption
of drugs
What are the barriers to drug absorption?
Physiological factors
• Transit of pharmaceuticals in the GIT
• Gastric emptying rate (5 minutes to 2 hours)
• Small intestine transit time (3-4 hours
• Colonic transit time 2- 48hours
Gastric emptying rates
Gastric empting is characterized by a repeating
cycle of four phases
Phase I Inactivity 40-60 minutes
Phase II similar in duration to Phase I but with
increasing contractions
Phase III powerful peristaltic contractions (house
keeper’s wave)
Phase IV Short transitional period
What factors influence gastric emptying rate
• Posture
• The composition of the food
• Effects of drugs and disease
 Small intestines
Small intestine residence time is particularly
important
Dosage forms that release their drug slowly as
they pass along the length of the GIT
Enteric coated dosage forms which release drug
only when they reach the SI
Drugs that dissolve slowly in intestinal fluids
Drugs that are not absorbed well in the colon
 Colonic transmit
2-48hrs
Contractile activity in the colon can be divided into
two main types

1. Propulsive contractions or mass movement that

are associated with the aboral movement of
contents
2. Segmental or haustral contractions that serve to
mix the luminal contents followed by long periods
of stasis
 Barriers to drug absorptions
1. Environment in the lumen
• Gastrointestinal pH
• Luminal enzymes
• Influence of food in the GIT
a) Complexation of drugs with components in the diet
b) Alteration of pH
c) Alteration of gastric emptying
d) Stimulation of gastrointestinal secretions
e) Competition between food components and drugs for specialized
absorption mechanism
f) Increased viscosity of GIT contents
g) Food-induced changes in pre-systemic metabolism
h) Food-induced changes in blood flow
2. Disease state and physiological disorders
 Metabolism and Excretion
& Pharmacokinetic Modeling
 Metabolism
Definition of terms
Phase I reactions
• Reactions that covert the parent drug to a more
polar (lipophilic) or more reactive product by
unmasking or inserting a polar functional group
Phase II reactions
• Reactions that increase water solubility by
conjugation of the drug molecule with a polar
moiety such as glucuronide, acetate or sulfate
CYP isozymes
• Cytochrome P 450 enzyme species ( e.g. CYP
3A4, CYP 2D6) that are responsible for much of
drug metabolism. Many isoforms of CYP have
been identified
Enzyme Induction
• Stimulation of drug-metabolizing capacity;
usually manifested in the liver by increased
synthesis of smooth endoplasmic reticulum
(SER) ( which contains high concentrations of
phase I enzymes)
P-glycoprotein (P-gp), MDR-1(Multi-Drug Resistance
Mutation - 1)
• An ATP-dependent transport molecule found in many
epithelial and cancer cells. The transporter expels drug
molecules from the cytoplasm into the extracellular
space. In epithelial cells, expulsion is via the external or
luminal face.
• Examples of P-glycoprotein inhibitors – verapamil,
furanocoumarin components of grapefruit juice.
• Examples of drugs expelled by P-gps –digoxin,
cyclosporin, saquinavir
• The major site ( organ) for drug metabolism is
Liver
• Drugs are often eliminated by
biotransformation and or excretion into the
Urine or Bile.
Chemical alteration of the drug in the body.
• Aim: to convert non-polar lipid soluble
compounds to polar lipid insoluble
compounds to avoid reabsorption in renal
tubules.
• Most hydrophilic drugs are less
biotransformed and excreted unchanged –
streptomycin, neostigmine etc.
 Products of metabolism
1. Active drug → its inactive metabolite.
2. Active drug → active metabolite.
3. Inactive drug → active/enhanced activity
(prodrug) e.g. Omeprazole
4. Non-toxic or less toxic drug to toxic
metabolites (Toxic metabolism)
Sites of metabolism
1. Organ level
Liver
GIT ( the most important extrahepatic site e.g
isoproterenol is extensively conjugated in the intestinal
epithelium→ ↓BA,
Other sites include lungs, kidneys, and skin
Nota Bene → Because of its enormous perfusion rate
and its anatomical position, the lung may exert a first
pass metabolism for IV administered drugs
2. Cellular level
Most enzymes involved in metabolism of drugs
are located within the lipophilic membranes of
the Smooth Endoplasmic Reticulum (SER)
The SER complex is referred to as the
microsomal mixed function oxidase (MFO)
system
3. Biochemical level
Phase I reactions
Convert drugs to more polar, water soluble, compounds
by introducing or unmasking polar functional groups such
as OH, -NH₂, or –SH

Some phase I products may need to undergo phase II

reactions involving conjugation of the newly established
polar groups with endogenous compounds like glucuronic
acid, sulfuric acid, acetic acid or amino acids (typically
glycine NH₂ CH₂ COOH)
Glucuronide formation is the most common phase
II reaction.
Most phase I reactions are oxidative in nature and
require a reducing agent (NADPH), molecular
oxygen and a complex of microsomal enzymes.
The terminal oxidizing enzyme is called Cytochrome
P₄₅₀, a hemoprotein so named because its carbon
monoxide derivative absorbs light at 450nm
 Microsomal enzyme induction
Enzyme inducer is a type of drug that increases
the metabolic activity of an enzyme either by
binding to the enzyme and activating it, or by
increasing the expression of the gene coding for
the enzyme e.g., microsomal enzymes (CYP450)
Increases metabolism of other drugs and
sometimes their own e.g. EtOH
 Microsomal enzyme inhibition
• Decreases the rate of drug metabolism, thereby
increasing the amount of drug, leading to
accumulation, extended pharmacological activity, and
potential toxicity
• One drug can inhibit metabolism of another drug – if it
utilizes same enzyme
• However not common because different drugs are
substrate of different CYPs
• A drug may inhibit one isoenzyme while being
substrate of other isoenzyme.
• Some enzyme inhibitors – Omeprazole, metronidazole,
isoniazid, ciprofloxacin and sulfonamide, rotinavir
Suicide inhibitors
These are dugs which irreversibly inhibit the
metabolizing enzmes
Examples : ethinyl-estradiol norethidrone,
spironolactone, secobarbital, allopurinol,
propylthiouracil
• Metabolism may also be decreased by
pharmacodynamic factors such as decreased
blood flow to the metabolizing organ

(eg.propranolol reduces hepatic blood flow)

 Determinants of biotransformation
rate
1.Genetic factors
Acetylation of amines
Oxidation
2. Other drugs
1. Enzyme induction
2. Enzyme inhibition
3. Inhibition of intestinal P-glycoprotein MDR-1
Genetic factors
Pharmacogenomics has become increasingly
important aspect in determining the choice and
dosing of drugs.
Examples
a) Hydrolysis of esters.
b) Acetylation of amines
c) 0xidation
a) Hydrolysis of esters
Succinylcholine, a skeletal muscle relxant, is
metabolized by plasma cholinesterase (Plasma
ChE).
The process is rapid in majority of people; a single
dose of succinylcholine has a duration of action 5
minutes.
1 in 2500 has an abnormal form Plasma ChE and
paralysis caused by a single dose of succinylcholine
could last hours
b) Acetylation of amines
Isoniazid, Hydralazine, and procainamide are
metabolized in a Phase II reaction by N-
acetylation
Slow acetylators may have prolonged or toxic
responses to normal doses of these drugs
Slow acetylation is inherited as an autosomal
recessive gene
c) Oxidation
The rate Phase I of phenformin,
dextromethophan, and metroprolol and some
Tricyclic antidepressants (TCAs) has been shown
to be genetically determined
 Excretion of drugs
The passage out of a systemically absorbed drug
from the body in the form of metabolites or
unchanged drug
Main Routes of Excretion
• Renal excretion (major organ)
• Hepatobiliary excretion
• Pulmonary excretion (for volatile/gaseous
anesthetics)
Minor Routes of Excretion
• Saliva, sweat, milk, tears
Enterohepatic circulation:
Cycle in which a drug or metabolite is excreted in
bile and then reabsorbed from the intestine either
as the metabolite or after conversion back to the
parent drug
Enterohepatic recirculation
•The recirculation of highly conjugated drugs
between the liver-bile-and the GI
• Involves the release of free drug by the GI
microflora and free drug is reabsorbed back to the
liver
 Assignment 1
Toxic metabolism of paracetamol

lakimani@usiu.ac.ke
Google scholar
PubMed
Cochrane Reviews
Medscape
Pharmacokinetic modeling
• Cmax – maximum Cp attained after a single
dose administration
• Tmax – Time taken to attain max conc after a
single dose admin
• BA – AUC – Rate and extent of absorption
• Elimination is function of both
biotransformation and excretion
• Therapeutic window is range of concs
between MEC & MTC
 Why model PK data
• To understand the relationship between dose and
plasma concentration
• To understand the relationship between plasma
concentration and pharmacological effect
• To determine optimal dosing regimen for the
individual patient
• To determine the dosing adjustment for patient
with impaired physiological functions (e.g.
Hepatic and Renal disease)
• To describe drug levels in the body as a function
of time
• To simplify assumptions made (e.g. the
elimination rate constant determined
mathematically includes both metabolism and
excretion)
• NB For some drugs the plasma concentration may
not predict pharmacological effect ( other
parameters need to be used to monitor patient
therapy)
 Rates of reactions
• Rate is how fast a reaction/process occurs

• e.g. Drug A → Drug B

• Drug A decreases with time and can be expressed

as -dA/dt

• Drug B increases with time and may be expressed

as +dB/dt
 Rate Law
Order Rate law
0 Rate =k [A]⁰ = k x⁰=1
1 Rate =k [A]¹ = k[A] x¹ = x
 Zero order
Consider drug A decreasing per unit time t

→dA/dt = -k₀
(where k₀ is the zero order elimination rate
constant)

Integration yields
→∫dA = ∫ -k₀dt
→A=A₀ - k₀t
( where A₀ is the concentration when t=0)
Time (h) Drug Ω
Conc mg/ml)
0 100
2 95
4 90
6 85
8 80
10 75
12 70
14 65
16 60
18 55
20 50
 Questions
1. Calculate k (elimination rate constant)
2. What equation models these data?
3. What is the half-life of this drug?
Answers
A=100-2.5k (y=100-2.5x )
k=2.5 mg/ml/h
t₀.₅ = 20h
Calculation of half-life for zero order reactions
A=A₀ - kt half-life A= A₀/2
A₀/2= A₀ -kt
A₀/2- A₀ = - kt
kt = A₀ -A₀/2
= A₀/2
t₀.₅= A₀/2/k mg/ml/mg/ml/h =h
 First order reaction/process
• The rate of drug decrease is proportional to
amount of drug A remaining
• dA/dt = -kA
(where k is the first order elimination rate constant)
Rearrangement and integration yields
→dA/A = -k.dt
→∫ dA/A = ∫ -k.dt
→lnA =lnA₀ - kt → A=A₀ . e⁻ᵏᵗ
Practice question (First order
reactions)
Time Conc mg/ml lnConc
0 100 4.61
4 50 3.91
8 25 3.22
12 12.5 2.53
16 6.25 1.83
20 3.13 1.14
24 1.56 0.44
 Questions
1. Calculate k (elimination rate constant)
2. What equation models these data?
3. What is the half-life of this drug?
Answers
1. K=0.173h⁻¹
2. A=100-0.173t
3. t₀.₅ = 0.693/k = 4 hours
• k represents fraction of material that is
reacting (or in the case of a PK profile is
eliminated) per unit time
• E.g., k = 0.173 h⁻¹ indicates that 17.3% of the
material is reacting per hour
• Higher value of k means a higher rate of
reaction in our case elimination
Calculation of half-life from first order equation

• lnA = lnA₀ -kt

• kt= lnA₀-lnA { ln(x/y) = lnx-lny log a/b = loga –logb }

• k = ln (A ₀/A)/t ln(100/50) = 0.693 k =0.693/t₀.₅

• t₀.₅ = 0.693/k
•Order
Order
Rate law Integral rate law Straight line
relationship
Examples

0 Rate = k. [A]⁰ A= A₀ - kt A vs t Aspirin

Ethanol
Phenytoin
1 Rate= k. [A]¹ lnA=lnA₀ -kt lnA vs t Most drugs
 PK Models
Tap and sink model

• Consider a tap and sink with adjustable outlet

• If the outlet is closed and the tap is turned on the
level of the water in the sink goes up
• If the tap is opened further, the level rises faster
• The degree to which the tap is opened
determines the rate at which the water enters
(fills) the sink
Compartment models

Physiological models :
• PK profile of the drug in individual tissues
• Can be used in animal PK studies

Function of models :
• Can be used to write equations which predict the
concentration of the drug over time in each compartment
• Shows the PK constants that are required to describe the
model
• Concentration = Mass/volume

• Cp= Dose /Volume of distribution

• e.g. If 1g of a drug is dissolved in an unknown

volume of water to yield a concentration of
1mg/ml, what is the volume
• Note Vd does not have a true physiological
meaning (therefore sometimes called
apparent Vd)

• Drug concentration is measured in plasma

(not the body as whole)
• If extensive distribution to the peripheral
tissues occurs, then the Vd can be very large (
due to low Cp)
 Practice questions
1. Morphine has a apparent volume of distribution of
220L/70kG and a half-life of elimination of 3h. In a 70kg man,
what is its approximate rate of clearance (Cl)

A. 1300ml/min
B. 850 ml/min
C. 50ml/min
D. 35ml/min

Hint Cl=Vd x k
k is elimination rate constant
Answer

• Cl=Vd*k

• K=0.693/180 = 0.00385/min

• Cl =220*1000*0.00385=847ml/min
PHARMACODYNAMICS
 Definition of terms
Receptor : A molecule to which a drug binds to
bring about a change in the biological system.
Inert binding molecule or site : A molecule to
which a drug may bind without changing any
function.
Receptor site : Specific region of the receptor
molecule to which the drug binds
• Spare receptor : Receptor that does not bind
drug when the drug concentration is sufficient
to produce maximal effect; present when Kd >
EC₅₀
• Effector : Component of a system that
accomplishes the biologic effect after the
receptor is activated by an agonist; often a
channel enzyme molecule, may be part of the
receptor molecule
• Agonist : A drug that activates its receptor
upon binding.
• Pharmacologic antagonist : A drug that binds
without activating its receptor and thereby
prevents activation by an agonist.
• Competitive antagonist : A pharmacological
antagonist that can be overcome by increasing
the concentration of the agonsis
• Irreversible antagonist : A pharmacological
antagonist that cannot be overcome by increasing
the concentration of the agonist.
• Physiological antagonist : A drug that counters
the effect of another by binding to a different
receptor and causing a different effect.
• Chemical antagonist : a drug that counters the
effect of another by binding the agonist drug (
not the receptor)
• Allosteric agonist, antagonist : A drug that binds
to a receptor molecule without interfering with
normal agonist binding units but alters the
response to the normal agonist
• Partial agonist : A drug that binds to its receptor
but produces smaller effect at full dosage than a
full agonist
• Inverse agonist : A drug that binds to the inactive
state of receptor molecule and decreases
constitutive activity
• Graded response curve : A graph of increasing
response to increasing drug concentration.
• Quantal dose response curve : A graph of the
fraction of the population that shows a specified
response at progressively increasing doses
• EC₅₀, ED₅₀, TD₅₀, etc : In graded dose response
curves, the concentration or the dose that causes
50% the maximal effect or toxicity. In quantal
dose response curves, the concentration or dose
that causes a specified response in 50% of the
population in the study
Therapeutic index = TD₅₀/ED₅₀ - Human studies
= LD₅₀/ED₅₀ - Animal studies

Kd : The concentration of a drug that binds 50% of

the receptors in the system

Efficacy, maximal efficacy : The maximal effect that

can be achieved with a particular drug, regardless
of dose
• Pharmacodynamics is the study of drug effects
on physiological systems.
• What the drugs do, and how they do it.
 Types of drug actions
The basic types of drug action can be broadly
classed as:
a) Stimulation
b) Inhibition
c) Irritation
d) Replacement
e) Cytotoxic action
a) Stimulation
Selective enhancement of the level of activity of
specialized cells.
Adrenaline stimulates heart-:
Chronotropic
Inotropic
Pilocarpine stimulates salivary glands-:
Cholinergic → Salivation
b) Inhibition

Selective diminution of activity of specialized

cells.
Barbiturates depress CNS
Quinidine depresses heart
Omeprazole depresses gastric acid secretion.
c) Irritation

• A nonselective, often noxious effect on less

specialized cells (epithelium, connective
tissue).
• Strong irritation results in inflammation,
corrosion, necrosis and morphological
damage.
d) Replacement
Use of natural metabolites, hormones or their
congeners in deficiency states.
• Levodopa in parkinsonism
• Insulin in diabetes mellitus
• Iron in anemia.
• Thyroxine in hypothyroidism
e) Cytotoxic action
Selective cytotoxic action on invading parasites
or cancer cells, attenuating them without
significantly affecting the host cells.
Utilized for cure/palliation of infections and
neoplasms
e.g. penicillin, chloroquine, zidovudine,
cyclophosphamide, etc
A handful of drugs act by virtue of their simple physical or
chemical property;
• Bulk laxatives (ispaghula)—physical mass Paraamino
benzoic acid—absorption of UV rays
• Activated charcoal—adsorptive property
• Mannitol, magnesium sulfate—osmotic activity
• Iodine 131 and other radioisotopes—radioactivity
• Antacids—neutralization of gastric HCl – Calcium
carbonate, Magnesium trisilicate,
• Potassium permanganate—oxidizing property
• Chelating agents (EDTA, dimercaprol)—chelation of heavy
metals.
Majority of drugs produce their effects by interacting
with a discrete target biomolecule, which usually is a
protein.
Such mechanism confers selectivity of action to the drug.
Functional proteins that are targets of drug action can be
grouped into four major categories,
• Enzymes,
• Ion channels,
• Transporters and
• Receptors
Enzymes
Almost all biological reactions are catalyzed by
enzymes;
Drugs can either enhance or diminish the rate
of enzymatically mediated reactions.
Enzyme inhibition
Selective inhibition of a particular enzyme is a
common mode of drug action.
Inhibition is either competitive or
noncompetitive
Enzyme Endogenous substrate Competitive inhibitor
Acetylcholine esterase Acetylcholine Neostigmine
Monoamine oxidase A Catecholamines Moclobemide
DOPA decarboxylase Levodopa Carbidopa
Xanthine oxidase Hypoxanthine Allopurinol
ACE Angiotensin 1 Captopril
5 –ά - Reductase Testosterone Finasteride
Aromatase Testosterone Anastrozole
Bacterial Folate synthase PABA Sulfamethoxazole
Ion Channels

• Ligand gated channels (e.g. nicotinic receptor)

• G-proteins and are termed G-protein
regulated channels (e.g.cardiac β1 adrenergic
receptor activated Ca2+ channel).
Drugs can also act on voltage operated and
stretch sensitive channels by directly binding to
the channel and affecting ion movement
through it,
e.g. local anesthetics which obstruct voltage
sensitive Na+ channels.
Certain drugs modulate opening and closing of
the channels, e.g.:
• Nifedipine, a calcium channel blocker, blocks
L-type of voltage sensitive Ca2+ channel.
• Ethosuximide inhibits T-type of Ca2+ channels
in thalamic neurons
Transporters
Several substrates are translocated across mem-
branes by binding to specific transporters which
either facilitate diffusion in the direction of the
concentration gradient or pump the
metabolite/ion against the concentration
gradient using metabolic energy
Many drugs produce their action by directly
interacting with the solute carrier class of
transporter proteins to inhibit the ongoing
physiological transport of the metabolite/ion.
Receptors
Macromolecule or binding site located on the
surface or inside the effector cell that serves to
recognize the signal molecule/drug and initiate a
response, but itself may have no other function.
• Agonist: An agent which activates a receptor to
produce an effect similar to that of the physiological
signal molecule.
• Inverse agonist: An agent which activates a receptor to
produce an effect in the opposite direction to that of
the agonist.
• Antagonist: An agent which prevents the action of an
agonist on a receptor or the subsequent response, but
does not have any effect of its own.
• Partial agonist: An agent which activates a receptor to
produce submaximal effect but antagonizes the action
of a full agonist
• Agonists have both affinity and maximal intrinsic activity
(IA = 1), e.g. adrenaline, histamine, morphine.
• Competitive antagonists have affinity but no intrinsic
activity (IA = 0), e.g. propranolol, atropine,
chlorpheniramine, naloxone.
• Partial agonists have affinity and submaximal intrinsic
activity (IA between 0 and 1), e.g. dichloroisoproterenol (on
β adrenergic receptor), pentazocine (on μ opioid receptor).
• Inverse agonists have affinity but intrinsic activity with a
minus sign (IA between 0 and –1),e.g. DMCM {Methyl 4-
ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole-3-
carboxylate} (on benzodiazepine
receptor),chlorpheniramine (on H1 histamine receptor
G-Protein coupled receptors
Gs : Adenylyl cyclase activation, Ca2+ channel
opening
Gi : Adenylyl cyclase inhibition, K+ channel
opening
Go : Ca2+ channel inhibition
Gq : Phospholipase C activation
Ion channel receptors
• These cell surface receptors, also called ligand gated
ion channels, enclose ion selective channels (for Na+,
K+, Ca2+ or Cl¯) within their molecules.
• Agonist binding opens the channel and causes
depolarization/hyperpolarization/ changes in cytosolic
ionic composition, depending on the ion that flows
through.
• The nicotinic cholinergic, GABAA, glycine (inhibitory
AA), excitatory AA-glutamate (kainate, NMDA and
AMPA) and 5HT3 receptors fall in this category.
Transmembrane enzyme-linked receptors

• Utilized primarily by peptide hormones.

• Made up of a large extracellular ligand binding
domain connected through a single
transmembrane helical peptide chain to an
intracellular subunit having enzymatic property.
e.g. insulin, epidermal growth factor (EGF), nerve
growth factor (NGF) and many other growth factor
receptors.
Transmembrane JAK-STAT binding receptors

• Agonist induced dimerization alters the intracellular domain

conformation to increase its affinity for a cytosolic tyrosine protein
kinase JAK (Janus Kinase).
• On binding, JAK gets activated and phosphorylates tyrosine
residues of the receptor, which now bind another free moving
protein STAT (signal transducer and activator of transcription).
• This is also phosphorylated by JAK. Pairs of phosphorylated STAT
dimerize and translocate to the nucleus to regulate gene
transcription resulting in a biological response.
• Many cytokines, growth hormone, prolactin, interferons, etc. act
through this type of receptor
Receptors regulating gene expression (transcription factors,
nuclear factors)

• These are intracellular (cytoplasmic or nuclear) soluble

proteins which respond to lipid soluble chemical messengers
that penetrate the cell.
• The liganded receptor dimer moves to the nucleus and binds
other co-activator/co-repressor proteins which have a
modulatory influence on its capacity to alter gene function.
• All steroidal hormones (glucocorticoids, mineralocorticoids,
androgens, estrogens, progesterone), thyroxine, vit D and vit A
function in this manner.
Drug potency and efficacy
• Drug potency which refers to the amount of
drug needed to produce a certain response.
• Drug efficacy and refers to the maximal
response that can be elicited by the drug.
 Therapeutic Index
TI= LD₅₀/ED₅₀
TI = TD₅₀/ED₅₀

Median effective dose (ED50) is the dose which

produces the specified effect in 50% individuals
and median lethal dose (LD50) is the dose which
kills 50% of the recipients.
 Combined effect of drugs
Synergism

When the action of one drug is facilitated or

increased by the other, they are said to be
synergistic.
• The effect of the two drugs is in the same
direction and simply adds up:
• Effect of drugs A + B = effect of drug A + effect
of drug B

• Side effects of the components of an additive

pair may be different—do not add up. Thus,
the combination is better tolerated than
higher dose of one component.
 Additive synergism

Aspirin + paracetamol
Nitrous oxide + halothane
Amlodipine + atenolol
Glibenclamide + metformin
Ephedrine + theophylline
 Supra-additive synergism
• The effect of combination is greater than the
individual effects of the components:
• effect of drug A + B > effect of drug A + effect
of drug B
• This is always the case when one component
given alone produces no effect, but enhances
the effect of the other (potentiation).
AChE + NEOSTIGMINE
Levodopa + Carbidopa
Adrenaline + Cocaine
Sulfamethoxazole + Trimethoprim
Enalapril + Hydrochlorthiazide
Tyramine + MAO –Inhibitor
 Antagonism
When one drug decreases or abolishes the
action of another, they are said to be
antagonistic:
→ effect of drugs A + B < effect of drug A +
effect of drug B
 Physical antagonism
Based on the physical property of the drugs, e.g.
charcoal adsorbs alkaloids and can prevent their
absorption—used in alkaloidal poisonings
 Chemical antagonism
• The two drugs react chemically and form an
inactive product, e.g KMnO4 oxidizes
alkaloids—used for gastric lavage in poisoning.
• Chelating agents (BAL, Cal. disod. edetate)
complex toxic metals (As, Pb).
 Physiological antagonism
Two drugs act on different receptors or by
different mechanisms, but have opposite overt
effects on the same physiological function, i.e.
have pharmacological effects in opposite
direction.
• Histamine and adrenaline on bronchial
muscles and BP.
• Glucagon and insulin on blood sugar level.
Competitive antagonism (equilibrium type)
• The antagonist is chemically similar to the
agonist, competes with it and binds to the
same site to the exclusion of the agonist
molecules.
• Because the antagonist has affinity but no
intrinsic activity , no response is produced and
the log DRC of the agonist is shifted to the
right
Non-competitive antagonism
The antagonist is chemically unrelated to the
agonist, binds to a different allosteric site
altering the receptor in such a way that it is
unable to combine with the agonist , or is
unable to transduce the response.
 Briefly differentiate competitive from
non-competitive inhibition
Competitive Non-competitive
Describe the difference between a
pharmacologic antagonist and an allosteric
antagonist. How could you differentiate these
two experimentally?
 Introduction To
Pharmacodynamics And
Theories Of Drug Action
Topics
• Introduction to pharmacodynamics

• Mechanisms of drug action

• Theories of drug-receptor interaction

What is Pharmacodynamics?
• It is the study of how a drug elicits its effects on the organism’s
physiological sysytems
• These effects could be at molecular, cellular or organ level
How do drugs elicit their effects in the body ?

1. Chemical or physical effects: this applies to very few drugs

2. Interacting with receptors: this is the most common way in which
drugs produce their effects.
Chemically or physically mediated effects
• Some drugs act by chemical reactions that neutralize the effects of
other drugs/ligands.
• Examples:
1. Antacids drugs such as aluminum hydroxide and calcium
bicarbonate neutralize stomach acid by chemically reacting with
acid

2. Protamine sulfate is neutralizes the effects of heparin by a

chemical reaction because one is basic and the other highly acidic.
Theories of drug-receptor
interaction
Topics
1. Definition of a receptor
2. Types of receptors
3. Lock and key hypothesis
4. Types of chemical interactions between the receptor and the drug
5. Dynamics of drug receptor- interaction – Law of mass action
6. Definition of affinity and efficacy
7. Dose-response relationships
What is a receptor?
• It is a macromolecule of the cell to which a drug binds

• A receptor is the specific chemical constituent of the cell with which a

drug interacts to produce it’s pharmacological effects.

• Most are located on cell membranes

• Some are located intracellularly in the cytoplasm or nucleus

• Most receptors are proteins

• Some receptors have been isolated biochemically

• Some genes encoding receptor proteins have been cloned and

sequenced.
Types of receptors
• Cell-membrane embedded proteins

• Ligand-gated Ion Channels

• G –protein coupled Receptor Systems

• Transcription Factors

• Enzymes
How do drugs interact with receptors?

Lock and key hypothesis

• This hypothesis was developed from the observation that drugs have
highly specific effects

• Receptors were responsible for the highly specific effects.

• According to the theory, a receptor is has an active site

• The drug binds to the active site.

• The ability of a drug to bind to the active site of the receptor is
dependent on its three dimensional structure.

• Its structure should be such that it can fit into the three dimensional
space of the active site.
The ability of a drug to bind to a given receptor
• In order for a drug to bind to a given receptor, a part of it should be a
mirror-like image of the active site receptor

• The part of the drug molecule that binds to the receptor is called the
pharmacophore

• Therefore the chemical structure of a drug determines its ability to

bind
Summary of the Lock and key hypothesis
The drug molecule must fit into the receptor like a key fits into the lock.
-Intrinsic Activity hypothesis because for a drug to intrinsically fit into
a receptor, part of it should be a mirror image of the receptor.
- Receptors are responsible for the specificity of drug action
Stereoselectivity of receptor binding
• Most drugs exhibit isomerism: optical, geometric isomers, etc

• According to the lock and key hypothesis, receptor binding is highly

stereoselective for a given isomer

• Often it is only the Levo optimal isomer that can bind to the active
site.
Orthosteric Vs. Allosteric
Binding
Definition
• Most receptors have endogenous ligands. For example the
endogenous ligand for the muscarinic receptors is acetylcholine

• Orthosteric binding: This is where the drug binds to the receptor at

the same site as the endogenous ligand

• Allosteric binding: the drug binds to a different site from that to

which the endogenous ligand binds
Chemical processes in the of the
interaction between a drug and a
receptor
Reversible and irreversible binding of
receptors
• Most drugs bind to receptors reversibly by non-covalent bonds
which include:
- Van der Waals forces (most common)
- Hydrogen bonding
- Ionic bonding

• However some drugs bind irreversibly by formation of a covalent

bond
Example of formation a covalent bond
between a receptor and a drug

Phenoxybenzamine
 The law of mass action and
occupancy theory
Affinity
Efficacy
Drug concentration – response profiles
Reversible receptor binding
Law of mass action and receptor binding
• Reversible receptor binding obeys the law of mass action

• At equilibrium, the rates of association and dissociation of a drug

from the receptor is are constant.
Law of mass action
KD
• It is called the dissociation constant

• This is a measure of the affinity of a drug for the a receptor

• Affinity is the intrinsic property of a drug to bind to a receptor

• the lower the kd the more potent the drug

Receptor occupancy
• This is the fraction of receptors that are occupied by the ligand

• This fraction can be derived from the law of mass action.

F is the concentration of free unbound drug

Bmax is the maximum number of receptors available for occupation
Receptor occupancy theory
• From the previous equation that was derived from law of mass action
receptor occupancy at equilibrium is a function of ligand
concentration.

• Therefore the higher the concentration of a drug, the greater the

proportion of receptors that are occupied.

• According this theory, particular, the magnitude of the response

elicited by a drug is directly proportional to the amount of drug bound
• The maximum response is elicited once all receptors are occupied at
equilibrium.
• B max

• This is used to measure the maximum possible response that can be

elicited by a given group

• It is a measure of efficacy.

• Efficacy is a measure of the maximal response elicited by a drug.

 DR Complex Effect
Efficacy (or Intrinsic Activity) – is also defined as
ability of a bound drug to change the receptor in a
way that produces an effect

• some drugs possess affinity but NOT efficacy

2004-2005
Dose Response
Relationships
 Plotting the fraction of bound drug against
drug concentration
[ DR] [ D]
=
Rt K D + [ D]

• When the fraction of bound receptor is plotted against the concentration of

drug, an exponential curve is obtained
• It may also be called a hyperbolic curve
 When [D] = KD
[DR]
= 0.5
RT
1.00

[DR]/Rt 0.75

[ DR] [ D]
0.50 =
Rt K D + [ D]

0.25

0.00
0 5 10 15 20

[D]
KD
Receptor Binding

% Bound

KD

Concentration of Ligand
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
What is ED₅₀ ?
• When DR = 50 percent (effect is half maximal),we can get ED50
• EC50 is equal to kd or the reciprocal of the affinity constant response is
a measure of efficacy
Dose response curves

• The is a graph where on the Y axis, the fraction/percentage of the maximal

response is plotted.

• The x-axis is the concentration of the drug

• It is similar to the graph of percentage of receptors occupied vs conc.

• It has an exponential shape

Example of a dose response curve: effect of
acetylcholine on contraction of a muscle
Isolated Muscle Contraction
Arithmetic Scale
Percent Maximum 100

75

50

25

0
0.00 0.25 0.50 0.75 1.00

Dose (ug/ml)
 Key features of an exponential/Arithmetic Dose response curve
• Rate of change is rapid at first and becomes progressively slower as
the dose is increased
• Eventually, increments in dose produce no further change in effect
i.e., maximal effect for that drug is obtained
• Difficult to analyze mathematically

2004-2005
Sigmoidal Dose response curves

• The is a graph where on the Y axis, the FRACTION of the maximal

response.

• The x-axis is the log of concentration of the drug

• The middle section of the graph is almost linear and therefore it is easier to
interpret and obtain ED50.

• Has a sigmoid shape

Example of a Sigmoidal dose response curve
Key features of a sigmoidal dose response curve - Log Dose Scale
• transforms hyperbolic curve to a sigmoid (almost a straight line)
• compresses dose scale
• proportionate doses occur at equal intervals
• Has a linear mid-section
• Easier to analyze mathematically
Interpretation of dose response curves
• The greater the value of Emax, the greater the efficacy
• The larger the value of Kd, the lower the affinity/potency
• drugs that have parallel dose-response curves often have the same
mechanism of action
Potency
• Two drugs may have the same maximal effect.
• However to produce the same effect, one may require a greater amount
of one drug
• Potency refers to amount of drug required to produce a given amount
of clinical effect
• In a dose response curve, large ED50 values are indicative of low
potency
Full Agonists (i.e., equal efficacies) that Differ In Potency:

A
B C

Compare the EC50s

Drug Concentration (log scale)

Clinical significance of Potency

• It two drugs have the same efficacy, potency is of little clinical

significance
• However, large doses of the drug of low potency will be required.
Rank the following drugs in terms of
Relative Potency and efficacy
hydromorphone

morphine

Analgesia codeine

aspirin

Dose
Class exercise: interpret the following dose-
response curves
Quantal dose response
relationships
Quantal dose response relationships
• This apply if the response is all-or-none
• Examples: asleep or awake; death or alive; cured or not.
• The dose response curve is usually a histogram that depict the
proportion of subjects who responded.
 % fall in blood pressure
50
50
40
% fall in blood

40
pressure

30
30
20 Control 20
Control
L-NAME
10 10 L-NAME

0 0
0.31
0.1 3 10 -2 -1 0 1 2
Acetylcholine nmol/kg 0.1 0.3 1 3 10
Acetylcholine nmol/kg
 Ethyl Alcohol:
Arithmetic vs log Sleep
scale of dose

30

Number Responding

% fall in blood pressure

50
50 20 40
% fall in blood

40
pressure

30
30
20 Control 20
Control
10 L-NAME
10 L-NAME
10
0 0
0.31
0.1 3 10 -2 -1 0 1 2
Acetylcholine nmol/kg 0.1 0.3 1 3 10
0 Acetylcholine nmol/kg
5.28 5.40 5.52 5.64 5.76 5.88 6.00

Dose (g/kg)
2004-2005
Spare Receptor Theory
• All receptors do not have to be occupied to produce a full response.
• Because of this hyperbolic relationship between occupancy and
response maximal responses are elicited at less than maximal receptor
occupancy.
• A certain number of receptors are "spare."
• Spare receptors are receptors which exist in excess of those required
to produce a full effect. There is nothing different about spare
receptors. They are not hidden or in any way different from other
receptors.
 Why do have spare receptors?
• Increase sensitivity of the system to the agonist. A
response can be produced even though ligand has low
concentration
• To prevent exaggerated responses because spare
receptors can bind extra ligand if too much ligand is
present
Reference
http://watcut.uwaterloo.ca/webnotes/Pharmacology/Pharmacodynam
ics.html
Agonists and antagonists
What is drug antagonism?
• This is where a drug abolishes the effects of another drug

• There are 4 types of drug antagonism.

Types of Drug Antagonism

Propranolol &
Pharmacologic norepinephrine

Dimercaprol &
Chemical heavy metals

Pharmacokinetic
Phenobarbital &
warfarin

Physiologic
Epinephrine &
histamine
What is chemical antagonism?
• This where a drug neutralizes the effects of another by chemical
reactions
• No receptors are involved
• Examples:
- basic drugs neutralizing acid in the stomach
- The toxic effects of heavy metals such as mercury are neutralized
using chelating agent like EDTA or dimercapol
- Protamine and heparin
What is physiological antagonism?
• Here, there is receptor involvement
• However, the two opposing drugs act on different receptors.
• Though the different receptors they produce opposing physiological
actions
• Examples of physiological antagonists are:
1. Histamine and adrenaline: histamine cause hypotension and
adrenaline causes hypertension
2. Acetylcholine and adrenaline

In some text books it is called non-competitive antagonism

What is pharmacological antagonism?
• Here two drugs oppose the effects of each other by acting on the same
receptor.
Pharmacological
Antagonism
Types of ligands on a receptor
• Agonist – are molecules that activates receptors.
- a drug that has both affinity and high
intrinsic activity.

• Antagonist - molecules that acts against and blocks

drug action. It has affinity but lacks intrinsic
activity
Definitions
• Affinity – allows the agonist to bind to receptors.

• Intrinsic Activity – allows the bound agonist to

activate or turn on its receptor
function.
Drug-Receptor Theories
• Paton’s Hypothesis
“ Effectiveness of a drug does not depend on the actual occupation of
the receptor but by obtaining proper stimulus”
This is also known as the Rate Theory.
Types of Antagonism
• Partial Antagonism
• Antagonist has high affinity but low intrinsic
activity
• Irrevisible Non-equilibrium Antagonism
• Antagonist forms irreversible receptor binding
• Competitive Antagonism
• Agonist and antagonist compete for the receptor
• Inverse antagonism
Receptor ligand types
Competitive antagonists
What is Competitive Antagonism?

• Drug (agonist) is displaced from drug-receptor binding by the antagonist.

• It is reversible

• depends on actual drug and antagonist concentration

• The higher the concentration of the antagonist, the greater the antagonistic
effect

• It can be reversed by increasing the concentration of the agonist

• Usually the agonist and antagonist have some chemical similarity

• It obeys the Law of mass action
Key differences between an agonist and its
competitive antagonist
Agonist Competitive Antagonist

activates or enhances signaling Binding does not trigger the

pathways signaling pathways
Has intrinsic activity Lacks intrinsic activity

They simply occupy the receptor

and prevent the binding and the
action of agonists
Examples
• Atropine and Acetyl choline

• Propanolol and adrenaline

Competitive Antagonism Shifts The Agonist D-R Curve
(Potency)

AG alone AG + ANT

EC50 EC50

Drug Concentration (log scale)

To summarize, the key features of a competitive antagonist are:
1.Reversible binding to the receptor.
2.The blockade can be overcome by increasing the agonist concentration.
3.The maximal response of the agonist is not decreased.
4.The agonist dose-response curve in the presence of a competitive antagonist is
displaced to the right parallel to the curve in the absence of agonist.
Irreversible Inhibition
What is irreversible inhibition?

• In this case, the antagonist form a covalent bond with the receptor

• It hard to break the bond and the agonist can not longer bind

• It cannot be surmounted by increasing the concentration of the agonist

• Irreversible receptor antagonists are chemically reactive compounds.
• These ligands first bind to the receptor.
• Following this binding step, the ligand then reacts with the functional
groups of the receptor.
• The inhibitor remains attached to the receptor for a long period of
time.
• The synthesis new receptor protein may be required to generate a
receptor free of an irreversible blocker.
Noncompetitive Antagonism Decreases Agonist (Efficacy)

AG alone

% Max response
AG + NC ANT

AG + higher dose
NC ANT

Log Drug Concentration

To summarize, the properties of irreversible receptor blockers are:
1.Chemically reactive compound, therefore covalently binds with the receptor
2.The receptor is irreversibly inactivated and the blockade can not
be overcome with increasing agonist concentration..
3. Shifts the agonist dose-response curve to the right and depresses
maximal responsiveness because of reduced amount of receptor available for
binding
Partial Agonists and Antagonists

• Partial Agonist or Partial Antagonist –

• Has affinity but lower efficacy than full agonist.

• It the absence of an agonist, it behaves like an

agonist. However has reduced efficacy.

• In the presence of an agonist, it behaves like an

antagonist
Partial agonists lack maximal effect

A
B

% Max response
C

Log Drug Concentration

INVERSE ANTAGONIST
Inverse agonist
Inverse agonist can exist where an appreciable level of
activation may exist even when no ligand is present
For example: receptors for benzodiazepines, cannabinoids
and dopamine

Under such condition it may be possible for a ligand to

reduce the level of activation. such drugs are known as
inverse agonist
Spare receptors
Receptors
Emax are said to be ‘spare’ for a given pharmacological
response when the maximal response can be elicited by an
agonist at a concentration that not result
Agonist with in occupancy of the
Agonist with
Agonist
full complement of availablenoncompetitive
receptors noncompetitive
Respones(%)

alone
antagonist in antagonist in
presence of spare absence of
receptor spare receptor

Log Concentration
 Desensitization and Tachyphylaxis

➢Changes in receptor
➢Desensitization
➢Loss of receptor
➢Tolerance
➢Refractoriness How? ➢Exhaustion of mediators
➢Drug resistance ➢Increased metabolic degradation
➢Physiological adaptation
➢Active extrusion of drug from cells
Factors modifying drug action
(Second messenger systems)
Introduction
• Second messengers are molecules that relay signals from receptors on the cell
surface to target molecules inside the cell.
• They greatly amplify the strength of the signal, cause some kind of change in
the activity of the cell.
• They are components of cell signaling pathways.
• Earl Wilbur Sutherland Jr., discovered second messengers, for which he won
the 1971 Nobel Prize
Second messengers
oShort lived intracellular signaling molecules
oElevated concentration of second messenger leads to rapid alteration in the
activity of one or more cellular enzymes
oRemoval or degradation of second messenger terminate the cellular response
oFour classes of second messengers:
• Cyclic nucleotides
• Membrane lipid derivatives
• Ca2+
• Nitric oxide/carbon monoxide
 Types of second messengers

GASES:

• NO
• H2S
• CO

Hydrophobic /Liphophilic:
• Diacylglycerol
• Phosphatidylinositols

Hydrophilic:
• cAMP
• cGMP
• IP3
• Ca 2+
o
o Cyclic AMP (cAMP)
o cAMP is a second messenger that is synthesized from ATP by the action of the enzyme
adenylyl cyclase.
o Binding of the hormone to its receptor activates a G protein which, in turn, activates
adenylyl cyclase.
o Leads to appropriate response in the cell by either (or both):
• using Protein Kinase A (PKA) — a cAMP-dependent protein kinase that
phosphorylates target proteins;
• cAMP binds to a protein called CREB (cAMP response element binding protein),
and the resultant complex controls transcription of genes.
o Eg. of cAMP action - adrenaline, glucagon, LH
THE MECHANISM OF RECEPTOR-MEDIATED ACTIVATION AND INHIBITION OF cAMP
o The ligand binds to the receptor, altering its conformation and increasing its
affinity for the G protein to which it binds.
o The G subunit releases its GDP, which is replaced by GTP.
o The α subunit dissociates from the G complex and binds to an effector (in this
case adenylyl cyclase), activating the effector.
o Activated adenylyl cyclase produces cAMP.
o The GTPase activity of G hydrolyzes the bound GTP, deactivating G.
o G reassociates with G, reforming the trimeric G protein, and the effector ceases its activity.
o The receptor has been phosphorylated by a GRK
o The phosphorylated receptor has been bound by an arrestin molecule, which inhibits the
ligand-bound receptor from activating additional G proteins.
GLUCOSE MOBILIZATION: AN EXAMPLE OF A RESPONSE INDUCED BY
cAMP
o Binding of hormone: Hormone binds to a receptor in the plasma membrane
o Activation of enzyme and formation of cAMP: Binding leads to activation of
an enzyme that changes ATP to cAMP
o cAMP binds to PKA & activates it.
o PKA phosphorylates 2 enzymes:
• 1. Phosphorylase kinase: Phosphorylates glycogen phosphorylase, which
stimulates glycogen breakdown.
• 2. Glycogen synthetase: inhibition – prevents conversion of glucose to
glycogen.
CYCLIC GMP (cGMP)
o cGMP is synthesized from the nucleotide GTP using the enzyme guanylyl
cyclase.
o Nitric oxide stimulates the synthesis of cGMP .
o Many cells contain a cGMP-stimulated protein kinase that contains both
catalytic and regulatory subunits.
o Some of the effects of cGMP are mediated through Protein Kinase G (PKG)
o cGMP serves as the second messenger for:
• nitric oxide (NO)
• the response of the rods of the retina to light.
PHOSPHATIDYLINOSITOL-DERIVED SECOND MESSENGERS
o Phosphatidylinositol (PI) is a negatively charged phospholipid and a minor component
in eukaryotic cell membranes.
o The inositol can be phosphorylated to form:
• Phosphoinositides
• Phosphatidylinositol-4-phosphate (PIP)
Phosphoinositides
• Phosphatidylinositol-4,5-bis-phosphate (PIP2)
• Phosphatidylinositol-3,4,5-trisphosphate (PIP3)
o Intracellular enzyme phospholipase C (PLC), hydrolyzes PIP2 which is found in the
inner layer of the plasma membrane.
o Hydrolysis of PIP2 yields two products:
• Diacylglycerol (DAG)
• Inositol-1,4,5-trisphosphate (IP3)
Diacylglycerol

o Diacylglycerol stimulates protein kinase C activity by greatly

increasing the affinity of the enzyme for calcium ions.
o Protein kinase C phosphorylates specific serine and threonine
residues in target proteins.
o Known target proteins include calmodulin, the glucose transporter,
HMG-CoA reductase, and cytochrome P450.
INOSITOL TRIPHOSPHATE, IP3
o This soluble molecule diffuses through the cytosol and binds to
receptors on the endoplasmic reticulum causing the release of
calcium ions (Ca2+) into the cytosol.
o The rise in intracellular calcium triggers the response.
o Example: the calcium rise is needed for NF-AT (the "nuclear factor
of activated T cells") to turn on the appropriate genes in the nucleus.
MODE OF ACTION
o Peptide and protein hormones like vasopressin, TSH, and
neurotransmitters like GABA bind to GPCRs
o This activate the intracellular enzyme phospholipase C (PLC).
o PLC in turn cleaves PIP2 to yield two products – DAG and IP3.
o Both of these products act as second messengers.
• So, the cleavage of PIP2 by PLC is the functional equivalent of the
synthesis of cAMP by adenylyl cyclase
CALCIUM IONS
o Many cells respond to extracellular stimuli by altering their intracellular
calcium concentration.
o Ca++ acts as a second messenger in two ways:
• it binds to an effector molecule, such as an enzyme, activating it;
• it binds to an intermediary cytosolic calcium binding protein such as
calmodulin.
o The binding of Ca++ causes profound conformational changes in
calmodulin that increase calmodulin`s affinity for its effector molecules.
o Calmodulin, when activated, causes contraction of smooth muscles.
NITRIC OXIDE
o Nitric oxide (NO) acts as a second messenger because it is a free
radical that can diffuse through the plasma membrane and affect
nearby cells.
o It is synthesised from arginine and oxygen by the NO synthase.
o It activates soluble guanylyl cyclase, which when activated produces
another second messenger, cGMP.
o It is toxic in high concentrations , but is the cause of many other
functions like relaxation of blood vessels, and apoptosis.
CONCLUSION
o Signal transduction pathways allow cells to respond to
environmental signals.
o In these pathways, a signal is amplified.
o This signal amplification is brought about by second messengers like
cAMP, c GMP, Calcium ions, IP3, DAG and NO.
o Second messengers essentially serve as chemical relays from the
plasma membrane to the cytoplasm, thus carrying out intracellular
signal transduction.
REFERENCES
o Karp, Gerald. Cell and Molecular biology, 6th edition, John Wiley and
Sons, Inc.
o Rastogi S.C, Cell and Molecular biology, 3rd edition (2010), New Age
International (P) Limited, publishers.
o Twyman R.M, Advanced Molecular Biology (2003), Viva Books Private
Limited, New Delhi.
o http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/
S/Second_messengers.html
o http://en.wikipedia.org/wiki/Second_messenger_system
FACTORS AFFECTING DRUG
ACTION
INDIVIDUAL VARIATION TO DRUG EFFECTS
SUMMARY OF FACTORS AFFECTING
THERAPEUTIC RESPONSIVENESS TO DRUGS
PATIENT FACTORS DRUG RELATED DISEASES

Age 1 Drug-drug Liver disease

Gender interactions
Body mass index 2. Tolerance and Renal disease
Pharmacogenetics tachyphlaxis
Diet 3. Hypersensitivity
Environmental factors 4. Drug induced
Smoking toxicity
Alcohol consumption 5. Rebound effects
DRUG-DRUG INTERACTIONS
Definition of drug-drug interactions

• It is the modification of the effect of one drug (the object

drug ) by the prior concomitant administration of another
(precipitant drug).
Impact of drug-drug interaction
• Reduced therapeutic efficacy

• Increased toxicity
MECHANISMS OF INTERACTIONS

Types of
interaction

Chemical Pharmacodynamic Pharmacokinetics

Chemical/physical interactions - examples
• IV incompartability: Two drugs cannot be given together in the same
IV giving set because one cause precipitation of the other

• Lente insulin cannot be co-administered with soluble insulin because

zinc in lente insulin causes precipitation of soluble insulin
Pharmacodynamic drug interactions
• These are mediated at receptor level
• Includes:

- Drug antagonism : physiological or pharmacological

- Synergism: acting of the same or different receptors to enhance the overall

effect. The net effect is a sum of the individual effects

- Potentiation: The joint effect of two drugs is far greater than the sum of
the individual effects
Pharmacokinetic drug-drug interactions
• In this type of interaction one drug increases or reduces the plasma
levels of another drug by affecting:
1. Absorption

2. Distribution

3. Metabolism/Biotransformation

4. Excretion
Drug interactions at the levels of drug
absorption
• Fluoroquinolone and tetracycline Antibiotics cannot be co-
administered with drugs containing divalent/trivalent metal ions eg
Ca and Ferrous. The divalent ions form complexes with the antibiotics
and therefore they cannot be absorbed.
• Bile salt binding resins such as cholestyramine bind to many drugs
and therefore they cannot be absorbed.
• Acid lowering agents increase stomach pH and this affects absorption
of basic drugs eg ketoconazole
• Drugs that reduce GIT mortility delay gastric emptying and this delays
absorption.
Cont. examples of drug interactions at the
level of drug absorption
• Anticancer drugs affect the gastrointestinal tract and this affects
absorbtion of many drugs
Examples of interactions at Drug distribution
• Highly plasma bound drugs displace other drugs from albumin thus
increasing the free plasma concentration.

• Aspirin, warfarin, methotrexate, phenytoin etc tend to displace other

drugs.
Interactions at the levels of drug metabolism
• This occurs by either enzyme inhibition or induction.

• Phenytoin increases hepatic metabolism of theophylline leading to

decreased levels.

• Enzyme inhibition is the decrease of the rate of metabolism of a

drug by another one.
• This will lead to the increase of the concentration of the target drug
and leading to the increase of its toxicity .
Examples of enzyme inhibition

• Erythromycin inhibit metabolism of astemazole and terfenadine.

• Increase the serum conc. of the antihistaminic leading to increasing
the life threatening cardiotoxicity

• Omeprazole inhibits the metabolism of diazepam

TOLERANCE AND
TACHYPHYLAXIS
Definition of Tolerance and Tachyphylaxis
• When a drug is given repeatedly, it may loose its effectiveness.

• Tachphylaxis: this the loss of the activity of drug that occurs a few
minutes after a drug is administered. It is also called
DESENSITIZATION

• Tolerance: this the loss of the activity of drug that occurs after
prolonged administration – takes place after a long time
Physiological role of desensitization and
tolerance
• many receptor-effector systems incorporate desensitization
mechanisms

• This prevents excessive activation when agonist molecules continue

to be present for long periods.
Key differences between tolerance and
tachyphylaxis
• Tolerance takes place over a long time, Tachyphylaxis occurs over a
few minutes

• Tolerance is more difficult to reverse. Tachyphylaxis can be easily

reversed by stopping administration briefly
 TOLERANCE
Refractoriness: Loss of therapeutic efficacy
Examples of tolerance
• the blood pressure-lowering effect of thiazide diuretics is limited
because of a gradual activation of the renin-angiotensin system

• Many side effects of drugs such as nausea and sleepiness tend to

subside even though administration is continued

• People who take alcohol chronically need increasing amounts to

achieve the same effect.
Mechanism of tolerance
1. Physiological adaption or hemostasis: another physiological system
becomes activated to counteract the effect of the drug.
Eg. activated RAAS system to counteract the effects of thiazide
• Physiological adaption tends to occur very slowly

2. Increased metabolic degradation

Example: barbiturates and ethanol induce the expression of
cytochrome P450s). This is an example of AUTO INDUCTION

3. Down-regulation of receptors that are chronically stimulation.

More on Receptor down-regulation
• This is a gradual decrease in the actual number of receptors
expressed on the cell surface

• It takes place over a long period

Examples of receptors that can be down-
regulated
• Many G protein–coupled receptors and many hormone receptors are

• Chronic salbutamol (b2 agonist) use

How does down-regulation occur
• ligand-induced endocytosis/internalization and delivery to lysosomes
for break down. Endocytosis is usually triggered by phosphorylation

• Reduced receptor synthesis

Caveat about internalization of receptors
• Internalization can also occur after brief periods of ligand binding

• It does not always result in down-regulation of receptors

• Instead the internalized receptor is recycled intact to the plasma

membrane.

• This requires entry into endocytic vesicles for dephosphorylation of

receptors
TACHYPHLAXIS
Examples of tachyphylaxis
1. When an indirect acting sympathomimetic is given repeatedly, it
after a few minutes it looses its activity.
• WHY? Because, the enter adrenergic neurons and promote the
release of Noradrenaline.
• Once the neurotransmitter is depleted the drug can no longer act.

2. All nicotinic receptors

Mechanisms for desensitization
• Changes to the receptor

• Depletion of mediators or neurotransmitters or second messengers

prolonged stimulation of G-protein coupled receptors can lead to depletion of intracellular
secondary messengers
 HYPERSENTIVITY
Not the word hypersensitivity can have two meaning:
- An immunological response to a drug
- Exaggerated response to a drug
HYPERSENSITIVITY
• This is an exaggerated response to a drug

• It may be caused by genetic factors or receptor upregulation

What is receptor upregulation?
• It is increased number of receptors on the cell surface

• It can be caused by chronic administration of an antagonist.

• Example: chronic propranolol (b blocker) can cause increased synthesis of β1 receptors in the heart →
less antagonism
Examples of receptor changes
• A slow conformational change in the receptor such that agonist binds
molecule without any effect.
Eg the opening of the ionic channel (e.g., ligand-gated ion channels such as
nicotinic receptors at the neuromuscular junction undergoes such changes

Phosphorylation of intracellular region of the receptor protein, leading to:

- Desensitized ion channels
- Interference with the receptor’s (e.g., GPCR) ability to activate second
messenger cascade