Clinical

Pharmacology
1.Membrane transport
1) What is active transport?
2) What is primary active transport? Give example.
3) What is secondary active transport? What are their types? Give
examples.
1) Active transport is the form of membrane transport that
requires energy and transports the solute against its
electrochemical gradient (low to high). Active transport
can be primary or secondary depending on the source of
the driving force.
2) In primary active transport ,energy is obtained directly by
the hydrolysis of ATP. The transporters belong to the
super family of ABC (ATP binding cassette) whose
intracellular loops have ATPase activity.
Eg: Efflux of various anticancer drugs using transporters
like Pgp (P-glycoprotein), NaKATPase
3) In secondary active transport, the energy for the
movement of one solute is obtained from the
downhill movement of another solute. The
transporters belong to SLC (Solute Linked Carrier)
superfamily.
When the concentration
gradients are such that both the solutes move in the
same direction, it is called symport or cotransport.
Eg. Glucose absorption in the intestine coupled with
sodium using sodium-glucose transporter (SGLT-1)
When the solutes move in
opposite directions, it is termed antiport or exchange
transport. Eg. NaH antiport.
 2.Bioavailability

Plasma concentraton time

curve of 3 different
formulations (A,B&C) of the
same drug
1. Define Bioavailability.
2. Explain the variations in bioavailability depicted in the figure by the 3
formulations.
3. Mention the factors that govern the absorption of oral solid dosage
form.
1) Bioavailability refers to the rate and extent of
absorption of drug from a dosage form as determined
by its concentration-time curve in blood or by its
excretion in urine.
2)
• Formulation B is more slowly absorbed than
formulation A.
• The extent of absorption of A & B are the same as is
depicted by the area under the curve but formulation B
does not attain therapeutic concentration & hence will
not be useful. Formulation A can be used as it attains
therapeutic levels.
• Formulation C is absorbed to a lesser extent and has
lower bioavailability.
3)
Particle size
 Disintegration time & dissolution rate of the dosage form
Formulation.
3. Volume of distribution (Vd )

1. Define apparent volume of

distribution (aVd).
2. What is the clinical significance
of aVd?
3. Mention few physiological and
pathological states that alter
aVd..
1) The apparent volume of distribution (Vd) is defined as
the volume into which the total amount of a drug in
the body appears to be uniformly distributed.
Vd= Dose administered i.v / plasma concentration

2) Nonionised, lipid soluble drugs (the vast majority)

readily cross membranes and are distributed
throughout the body; they have large volumes of
distribution(Vd). These drugs have low plasma
concentration and high tissue concentration. Hence
their removal becomes difficult in case of poisoning.
 On the other hand, drugs which are
ionized (gentamicin) remain largely within the vascular
compartment and have very low volumes of distribution
and hence easier to remove by haemodialysis.
3) Physiological : Pregnancy
Pathological : Congestive heart failure, Uraemia,
Cirrhosis of liver and patients with inflammatory
disease.
4.Plasma half-life

1. Explain the given graph

2. What is plasma half life?
3. What are the two variables
which influence half life?
1)This is a log plasma concentration ,time plot graph of a drug which is
eliminated after first order kinetics given by intra venous administration.
It has 2 slopes
Αlpha slope – distribution phase
Beta slope – Elimination phase
2)Plasma half life of a drug is the time taken for the
plasma concentration of a drug to be reduced to half
of its original value. Half life of a drug can be
calculated using the following formula.

t1/2= 0.6932
k
[k=Elimination rate constant= clearance /volume of
distribution]
3)
i)Volume of distribution
ii)Clearance of the drug
For drugs eliminated by—
First order kinetics—t½ remains constant because V and CL do not
change with dose.
Zero order kinetics—t½ increases with dose because CL progressively
decreases as dose is increased.
5.Kinetics of Elimination
1.Explain the graph
2. Give some examples for saturation kinetics.
3. Differentiate first order kinetics and zero order kinetics. Give few
examples
1.The dose rate-Cpss (steady state plasma concentration)
relationship is linear only in case of drugs eliminated by
first order kinetics.
For drugs which follow Michaelis Menten kinetics
(saturation kinetics), elimination changes from first order
to zero order kinetics over the therapeutic range.
Increase in their dose beyond saturation levels causes an
increase in Cpss which is out of proportion to the change in
dose rate

2. Higher doses of drugs like Phenytoin, Digoxin, Warfarin,

Dicoumarol, Tolbutamide and Aspirin follow saturation
(Michaelis menten) kinetics.
First order kinetics(Linear Zero order kinetics(Non
kinetics) linear)
Constant fraction of drug is Constant amount of drug is
eliminated per unit time eliminated per unit time
Rate of elimination is Rate of elimination is
proportional to plasma independent of plasma
concentration concentration

Clearance remains constant Clearance is more at low

concentrations and less at
high concentrations.
Half life remains constant Half life is less at low
concentrations and more at
high concentrations.
First order kinetics Zero order kinetics
Most of the drugs follow Very few drugs follow pure
first order kinetics zero order kinetics eg:
Alcohol
Any drug at high
concentration(when
metabolic or elimination
pathway is saturated) may
show zero order kinetics
Eg: Phenytoin, Tolbutamide,
Theophylline, Warfarin
6.BLOOD BRAIN BARRIER
1. What constitutes the blood brain barrier?
2.What are the factors which increase the permeability of drugs across
Blood Brain Barrier?
3. Mention some drugs whose pharmacological action is influenced by
blood brain barrier.
1.The Blood brain barrier (BBB) is constituted by
Anatomical barriers
1) Tight junctions in capillary endothelial cells
2) Foot processes of astrocytes
3) Lack of paracellular pores
Functional barriers: Efflux transportes (eg – p
glycoprotein, OATP)
Enzymatic barriers - eg:Monoamine oxidase (MAO),
cholinesterase
2. Factors increasing the permeability of drugs across
BBB
Drug factors- Lipid solubility , unionised form of drug
Pathological conditions - Inflammation of meninges/
brain, metastatic brain tumours
3.i)Anticholinesterases
Physostigmine is a lipid soluble drug which crosses BBB.
Hence it is used in the management of Atropine
poisoning to counteract the CNS effects
Neostigmine – non lipid soluble drug, does not cross BBB.
its action is restricted to peripheral neuromuscular
junctions. Hence, it is used in the management of
Myasthenia gravis as it has no CNS side effects.
ii) Dopamine
Dopamine does not cross BBB. Hence, in the
management of Parkinsonism, Levo dopa is used which
crosses BBB and gets converted to dopamine by
decarboxylase enzyme in brain.
7.Biotransformation
1) What is biotransformation?
2) Mention few Enzyme inducers and Enzyme inhibitors.
3) What are the clinical applications of Enzyme induction and Enzyme
inhibition?
1) Biotransformation is the chemical alteration of the
drug in the body. Non-polar(lipid soluble)drugs are
rendered polar(lipid insoluble) so that they are not
reabsorbed in the renal tubules and are excreted.

2. Enzyme inducers:
e.g., Anticonvulsants(Phenytoin, Phenobarbitone,
Carbamazepine), Rifampin
Enzyme inhibitors:
e.g. grape fruit juice, ketoconazole, Erythromycin,
Sulfonamides, Isoniazid
3) Congenital nonhaemolytic jaundice is due to defect in
conjugation of bilirubin. Phenobarbitone induces
glucuronide conjugation of bilirubin and hastens
clearance of jaundice.
Phenytoin(Enzyme inducer) when given
along with Oral contraceptive pills leads to
contraceptive failure.
 Terfenadine (antihistaminic) require CYP3A4 for its metabolism to
active metabolite and at high doses the parent compound caused
torsades de pointes. When co-administered along with
erythromycin(enzyme inhibitor) resulted in drug toxicity. This led to
terfenadine's withdrawal from the market. Subsequently, fexofenadine
was developed, which retained the therapeutic properties of the parent
compound but avoids the step involving CYP3A4.
8. Illustration of drug potency and drug efficacy;
Dose response curve of four drugs producing the
same qualitative effect
13.Potency & Efficacy

1)Define potency & efficacy.

2)Explain the above graph
3) How do u clinically correlate potency and efficacy of
the drug?
1) Potency refers to the amount of drug needed to
produce a certain response
Efficacy refers to the maximal
response that can be elicited by the drug.

2) Fig(a):
The position of DRC on the dose axis is the index of
drug potency. A DRC positioned rightward indicates
lower Potency. Fig (a) shows the relative potency of the
two drugs which implies that drug Y is less potent than
drug X.
 Fig(B):
The upper limit of DRC is the index of drug
efficacy. so higher the position of the curve, the drug
has higher efficacy. Fig(b) shows the relative efficacy of
the two drugs which implies that drug X has more
efficacy than drug Y.
3) Drug potency is clearly a factor in choosing the dose of
a drug.
Efficacy is a more decisive factor in the choice
of a drug.
9. ANTAGONISM

A- agonist
B,C – Antagonists
1) Explain the graph
2) Mention the differences between competitive and Non competitive
antagonism with examples
3) What is the clinical importance of drug antagonism?
1.Graph A : Competitive antagonism
Increasing doses of Antagonist(B) shifts Dose response curve(DRC) of
Agonist (A) to right
Graph B : Non-competitive antagonism
Increasing dosesof Antagonist (C) flattens the DRC of Agonist (A)
3. Importance of drug antagonism

• Correcting adverse effects of drug;

e.g., Antipsychotic induced extrapyramidal reactions due to
cholinergic activation can be countered by benzhexol (anti
cholinergic)

• Treating drug poisoning;

e.g., morphine poisoning treated with naloxone,
organophosphorus compounds with atropine

• Predicting drug combinations which would reduce drug

efficacy:
e.g., the penicillin and tetracycline combination is inferior to
penicillin alone in pneumococcal meningitis
10. Clinical trials
1.What is preclinical trial and clinical trial?
2.Expand the following abbreviations
a) ICH
b) GCP
c) IND
d) NDA
3.What is pharmacovigilance?
1) Preclinical trial comprises of studies undertaken in
animals, initially a rodent (mouse/rat ) followed by a
larger animal (cat/dog/monkey) to expose the whole
pharmacological profile of a newly synthesised/
identified prospective compound.
A clinical trial is an ethically designed
investigation in human subjects to objectively
discover/ verify/ compare the results of two or more
therapeutic measures( drugs). Depending on the
objective of the study, it may be conducted in healthy
volunteers or in volunteer patients .
2)
ICH-International Conference on Harmonization
GCP- Good clinical practice
IND- Investigational New Drug
NDA- New Drug Application
3) Pharmacovigilance is defined as the continuous
monitoring for unwanted effects and other safety
related aspects of marketed drugs. It is the science
related to the detection, assessment, understanding
and prevention of adverse effects or any other drug
related problem.
Notes