1.

BY GIVING EXAMPLES WHERE PHARMACOTHERAPY HAS BEEN

APPLIED, DISCUSS THE ROLE OF CALCIUM CONCENTRATION IN
GENERATING PHARMACOLOGICAL DRUG EFFECT.
Answers:
Calcium is a very important ion in the body that needs to be well controlled. Calcium
control mechanisms involve the following;

 Controllers of Calcium influx

 Calcium voltage gated channels (L, N, Q types) – cardiac
muscle and nerve endings respectively. These subtypes vary
with respect to their activation and inactivation kinetics, their
voltage threshold for activation, their conductance, and their
sensitivity to blocking agents
 Ligand gated calcium channels
 Store operated calcium channels
 Controllers of Calcium efflux (these controls Calcium extrusion
from the cytoplasm or from the Calcium stores.)
 Calcium pumps
 Sodium-Calcium exchanger
 Ryanodine receptors
 Calcium has various roles the body
 Excitation: during propagation of action potential
o Drugs that reduces membrane permeability :
Verapamil
 Muscle contraction: Calcium is used in smooth, cardiac and
skeletal muscle contraction
o Dantroline inhibits calcium channels/ therefore
reduces muscle contraction
 Secretion: regulates intracellular release of hormones/ like
insulin.
o Sulfonylureas promotes Insulin release by blocking
The ATP dependent Potassium ATPase pump.
 Delayed cellular physiologic response: verapamil inhibits
proliferation

 The mechanism of calcium has been used in studying some diseases

and manipulating them with medication that either directly or
indirectly impact calcium roles

a) Diabetes Mellitus and Sulfonealureas

  In diabetes, there is failure in closure of potassium gated channels
 Impaired depolarization of the cells and in turn decreased insulin
secretion
 Sulfonealureas act by closing potassium channels , resulting in
accumulation of potassium in the cell and generating action potential
resulting in calcium entry therefore stimulating release of insulin

b) Malignant hyperthermia
 Due to unopposed calcium channel prolonged opening following a
genetic mutation of the RYRs on the ER,
 Cause uncontrolled calcium release leading into continuous muscle
contraction
 Dantrolene: acts as a Ryanodine Receptor antagonist
 Blocks the release of calcium from endoplasmic reticulum and is used to
treat malignant hyperthermia

c) Hypertension
 Calcium is involved in smooth muscle contraction (using L type Calcium
receptor, GPCR, Ligand Calcium channel) – increases PVR
 Therefore calcium enters the smooth muscle cell, stimulates calcium
release from the ER then Calcium- bind to calmodulin- activate MLCK-
activate myosin – leads to contraction by binding to actin
 Calcium channel blockers: block L type gated calcium channels –
resulting in smooth muscle relaxation and decreased peripheral vascular
resistance

d) Heart failure and digoxin

 Digoxin blocks Na+/K+ ATPase reducing sodium efflux therefore sodium
increases in the cell leading into hyperpolarization of the myocyte
 In return causes influx of Calcium in the cell generating Action potential -
increasing muscle contraction
QUESTION 01; EXPLAIN WHY ORAL BIOAVAILABILITY IS LESS THAN 100%

1. Physicochemical properties of the drug

2. Route of administration
3. PH and ionization
4. Presence of other drugs
5. Area of absorbing surface
6. Gastrointestinal and other diseases
7. First pass metabolism
8. Hepatic diseases
9. Eneterohepatic cycling
10. Food
QN. 4 BRIEFLY DESCRIBE THE ASSESSMENT OF DRUG EFFECTS
USING BIOMARKERS AND SURROGATE END POINTS AND THEIR
CLINICAL IMPLICATIONS
Biomarkers: are substances or characteristics that can be measured in the body and
used as indicators of a particular disease or condition. Examples of biomarkers of
normal biological responses; BP, Cholesterol levels and Haemoglobin levels,
Response to therapeutic intervention for example; response of BP and Pathological
processes such as; raise in BP.
Surrogate end points; are measures that are believed to predict clinical benefit, but are
not themselves a measure of clinical benefit. They are often used in clinical trials as a
way to assess the effectiveness of a drug in treating a particular condition. If a drug
has a positive effect on a surrogate endpoint, it is assumed that it is likely to have
clinical benefit for the patient.
One key difference between biomarkers and surrogate endpoints is that biomarkers
are directly measured in the body, while surrogate endpoints are indirect measures
that are believed to be related to clinical benefit. For example, tumor size is a
surrogate endpoint for cancer treatment, while the levels of certain proteins in the
blood, such as CA-125, can be measured as biomarkers for ovarian cancer.
In clinical practice it’s imperative to know while surrogate endpoints can be useful in
assessing the effectiveness of a drug, they are not always reliable indicators of clinical
benefit.
In some cases, a drug may have a positive effect on a surrogate endpoint but not
provide any clinical benefit to the patient. It is also possible for a drug to have a
positive effect on a surrogate endpoint but have negative side effects that outweigh
the potential benefits.

7. MENTION INDUCERS AND INHIBITORS OF CP450 ENZYME (5

MARKS)
QUESTION 07.CHARACTERISTIC FEATURES INTERMEDIATE
SOLUBLE DRUGS
1. Has intermediate solubility between water and lipid
2. absorption through GI is adequate though not complete
3. highly protein bound
4. distribution is in both body fluids ICF and ECF
the excretions is mainly through the kidney of uncharged drugs and protein bound is
through the active tubular secretion

QUESTION NO 08. CHARACTERISTIC FEATURES OF ACIDIC DRUGS

Acidic drug normally have a pKa of 2-8 such as NSAIDS, warfarin,
penicillins, phenytoin, and theopentone of which most are weak acids. The
following bellow are their characteristics;
1. They are in unionized form with decrease in PH of a biological system eg.
Aspirin (Pka 3) becomes more unionized and hence more reabsorbed in
the renal tubule by lowering filtrates PH for example in the presence of
probenecid. Most acidic drugs behaves being unionized at PH less than 7.

2. They are in ionized form with increase in PH of a biological system eg.

Aspirin (Pka 3) becomes more ionized and hence trapped and excreted in
urine by increasing urine PH for example in presence of NaHCO3. Most
acidic drugs become more ionized at PH greater than 7.

In plasma they are ionised and compete for plasma protein binding site to be secreted
in bile or urine
QUESTION09. DESCRIBE PROCESS OF METABOLISM AND EXPLAIN
HOW INDIVIDUAL PATIENT DIFFERENCES CAN AFFECT
METABOLISM AND THEREFORE DRUG SELECTION?

Answer.
Part 1.
Drug metabolism/Biotransformation is a chemical alteration of the drug in the body
to non-polar (lipid soluble) compounds polar (lipid insoluble) so that they are
excreted.

The process of drug metabolism mainly takes place in the liver and involves 2
pathways namely phase I and phase II.

Phase I
Involves Oxidation, Reduction and hydrolysis with the CYP450 enzymes accounting
for most of reactions

Phase II (synthetic phase) involves conjugation of the drug or it Phase I metabolites

through Acetylation, Glucuronidation, Methylation, Glutathione conjugation, amino
acid reaction and sulfate conjugation.
Consequently, the biotransformation process may terminate drug action, activate
prodrugs into active drugs, active drugs into active metabolite, active drug into
inactive metabolite.

Part 2.
Factors affecting drug metabolism
i. Genetic polymorphism which phenotypically presents with slow,
intermediate and fast metabolizers
ii. Disease as in conditions leading to decreased blood flow to the liver and
liver cirrhosis impairing drug metabolizing enzymes.
iii. Age Neonates with immature liver enzymes and elderly with decreased
liver functions metabolizes drugs less efficiently.
iv. Drug interactions some drugs induce or inhibit drug metabolizing
enzymes of other drugs, careful drug selection has to be done
v. Cigarrate smocking Induces some of drug metabolizing enzymes
activities hence drugs and dosage adjustment must be done for a better
therapeutic effect.
vi. Alcohol intake affects the drug metabolizing enzymes with inhibition in
acute alcoholism and induction in chronic alcoholism
vii. Dietary
viii. Sex
ix. Environment

Hence drugs must be selected according to individuals for better therapeutic effects
and avoidance of drugs adverse events.

9. CHARACTERISTIC FEATURES OF A BASIC DRUG

Basic drugs – (Pka 6 -12)
1. Absorption is not favored in the stomach where Ph is acidic(Poor oral
absorption)
2. Less protein binding in plasma compared to acidic drug
3. Clearance is by the kidneys (renals) and is enhanced when the urine is acidic.

Eg of basic drug lidocaine, diazepam, amphetamine

QUESTION10. HOW ARE DRUGS HANDLED BY THE BODY? AZIZI
1. Absorption. Is the transfer of drugs from the site of administration to the
blood sytemic circulation.
a. Drugs can be absorbed by different mechanism i.e passive
diffusion, facilitated diffusion, active transport, endocytosis and
exocytosis
b. Factors determining rate of absorption can be either PATIENT
FACTORS or drug factors
i. PATIENT FACTORS:- age, gastric ph, gut content (MILK
VS TETRACYCLINE), Blood flow to the absorption site,
Total surface area, Contact time at the absorption site and
Disease conditions e.g malabsortion syndrome.
 ii. Drug Factors physico chemical properties such as
solubility, molecular and degree of ionization
2. Distribution. is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and the tissues.
Consist mainly of two phases
a. Initial Phase. This phase is mainly determined by cardiac output
and regional blood flow. Drugs are initially distributed to tissues
with the highest blood flow (e.g., brain, lungs, kidney, and liver)
b. Second Phase. Drugs are distributed more slowly to less perfused
tissues such as skeletal muscle, and even more slowly to to those
with the lowest blood flow such as skin, bone and adipose tissue.
3. Metabolism is a biological process where by liphophilic xenobiotics are
transformed to more polar substances hence being readily excreted by the
kidney. This mainly involves phase I and phase ii reaction, where by a
drug can undergo either or both phase in either order.
a. Phase I drug metabolism reaction involve oxidation, reduction and
hydrolysis
b. Phase II drug metabolism reaction involve conjugation of phase I
metabolites by endogenous compounds such as glucoronic acid,
acetic acetic and sulphuric acid. Involves high –energy
intermediates and specific enzymes known as transferase
4. EXCRETION. Is the process of removing chemically unchanged drug or
its metabolites from the body. Several pathways are involved
a. Renal pathway. This is primarily the main pathways for almost all
drugs which involves :-
i. 1.Glomerular filtration;( bowman’s capsule)
ii. 2.Active tubular secretion;(proximal tubule and loop of
Henle)
iii. 3.Tubular re-absorption;(distal tubule and collecting duct)
b. Others include; biliary (enterohepatic circulation), pulmonary
(volatile e.g halothane), Fecal (bile), mammary, Salivary and Skin.
https://www.nps.org.au/australian-prescriber/articles/therapeutic-drug-monitoring-
which-drugs-why-when-and-how-to-do-it
QUESTION 12.WITH EXAMPLES EXPLAIN HOW PHYSIOLOGICAL
BARRIERS PLAY A ROLE IN DRUG DISTRIBUTION?
Physiological barriers affect drug distribution in various body compartment. Through
these barriers dugs get distributed at different rates.
- Simple Capillary Endothelial Barrier
Drugs (in both ionized and non-ionized form) readily pass through the
capillary endothelial barrier if molecular weight is < 600 Daltons, however
drugs bound to blood component have large molecular and wont readily pass-
through capillary. Examples of drugs.

- Blood Brain Barrier

Highly selective, made up of a tight junction (the endothelial cells) of capillary
cells making it difficult for drugs to pass through. Highly lipid soluble drugs
 (e.g., thiopentone) can pass easily. In disease state (eg meningitis) the barrier
is disrupted and some hydrophobic drugs like penicillin pass through the
barrier.
Drug with very lower molecular weight like lithium and alcohol also pass
through the barrier.
Chemoreceptors Triger zone

- Blood placenta barrier.

Trophoblast basement membrane and endothelium separate maternal and fatal
blood vessels. Highly lipid soluble drugs and those with molecular weight of <
1000 Daltons readily pass through.

C.C- safe in pregnancy it should be 1. water soluble 2. large size 3.

highly protein bound (The use of propylthiouracil (PTU) is chosen over
methimazole and phenobarbitone over other anticonvulsants)

- Blood Testis Barrier.

Located in the sertoli-sertoli tight junction, restricts the passage of drugs to
spermatocytes and spermatids
13.BRIEFLY DISCUSS ABOUT THE DIFFERENT PHASES OF DRUG
DEVELOPMENT AND CLINICAL TRIALS.

New drugs are developed in industrial or academic laboratories. Before a new

drug can be approved for regular therapeutic use in humans, a series of animal
and experimental human studies (clinical trials) must be carried out. Human
testing of new drugs requires approval by institutional committees that
monitor the ethical (informed consent, patient safety) and scientific aspects
(study design, statistical power) of the proposed tests

Phase 1.
- dose-response relationship and the pharmacokinetics of the new drug in a
small number of normal human volunteers (eg, 20–100).
-An exception is the phase 1 trials of cancer chemotherapeutic agents and
other highly toxic drugs; these are carried out by administering the agents to
volunteer patients with the target disease

Phase 2.
-involves evaluation of a drug in a moderate number of sick patients (eg,
100–200) with the target disease. A placebo (negative control) or older drug
(positive control) drug is included in a single-blind or double-blind design.
-often carried out in a hospital research ward. The goal is to determine whether
the agent has the desired efficacy (ie, produces adequate therapeutic response)
at doses that are tolerated by sick patients.

Phase 3.
 -usually involves many patients (e.g., 1000–6000 or more, in many centres)
and many clinicians who are using the drug in the manner proposed for its
ultimate general use.
-placebo and positive controls in a double-blind crossover design. The goals
are to explore further, the spectrum of beneficial actions of the new drug, to
compare it with placebo and older therapy and to discover toxicities, if any,
that occur so infrequently as to be undetectable in phase 2 studies.

Phase 4.
-represents the postmarketing surveillance phase of evaluation, in which it is
hoped that toxicities that occur very infrequently will be detected and reported
early enough to prevent major therapeutic disasters.

QUESTION 13. BRIEFLY DISCUSS TYPES OF PHARMACOKINETIC

MODELS
compartment model
• Classical pharmacokinetic model which divides the body into hypothetical
compartments to objectively assess pharmacokinetic properties of the drug.
• The body is divided in multiple compartments with varying characteristics
such as blood supply, partition coefficient and permeability
A.One compartment model:
• A one-compartment model assumes that all the tissues in the body are
contained in a single compartment called the “central compartment”.
• Therefore drug is assumed to be equally distributed throughout the whole
body,used in high hydrophilic drugs like aminoglycosides.
B.Two-compartment model:
Describes the body as two compartments:
1) Central compartment
The central compartment represents plasma and highly perfused tissues
including the kidneys and the liver (drug diffuses rapidly and uniformly)
1) Peripheral compartment
 Represents poorly perfused tissues such as muscle, fat,
 In this model, the total amount of drug in the body is simply the sum of
drug present in the central compartment plus the drug present in the
tissue compartment.
 Digoxin, particularly when given intravenously, is an example of a
drug that is well described by two-compartment pharmacokinetics.
 After an IV dose is administered, plasma concentrations rise and then
rapidly decline as drug distributes out of plasma and into muscle tissue.
 After equilibration between drug in tissue and plasma, plasma
concentrations decline less rapidly. The plasma would be the central
 compartment, and muscle tissue would be the peripheral
compartment.
Note:
• Use of only two compartments might not be adequate to analyse
pharmacokinetic characteristics of some drugs.
• A drug that demonstrates the necessity of a three or more-compartment model is
distributed most rapidly to a highly perfused central compartment, less rapidly
to the second or tissue compartment, and very slowly to the third or deep tissue
compartment.
Example Hydromorphone
QUESTION 13.DRUG TRANSPORTERS
These are transmembrane protein which are used to transfer molecules in and outside
the cell present in placenta, BBB, intestinal mucosa, kidney, and biliary system. Eg.
P glycoprotein
Clinical significance
1.multidrug resistance
The drug transporters are used to transfer cytotoxic substances outside the cell.
P glycoprotein expels ant cancer drugs to the extracellular fluid causing low
concentration and drug resistance.
Therefore ant-cancer are given concurrent with drug transporter modulators.

2. drug transporter mediated Drug drug interaction

Some of these transporters have interaction with drugs as can be inhibited.
Eg. P glycoprotein is inhibited with verapamil, and is used to remove intracellular
digoxin so if verapamil is given with digoxin it caused digoxin toxicity

QN 14. DISCUSS THE CLINICAL SITUATIONS WHERE THE PH

PARTITION HYPOTHESIS MAY APPLY
Ph partition hypothesis state that for drug compound with molecular weight more than
100, that are transported by passive diffusion across the cell membrane, the process is
governed by the capability of lipid solubility of un-ionised drug, the dissociation
constant of the drug (pKa) and the pH at the absorption site.
Therefore, for a drug to cross a membrane barrier it must normally be soluble in the
lipid material to get into the membrane (the lipid bilayer) and it has to be soluble in
aqueous phase as well to get out of the membrane. However, many drugs have such
characteristics by being either weak acid or base.
The following are clinical situations where the pH partition hypothesis may apply.
 1. NSAIDS-induced mucosal injury in the stomach is one of the clinical situation
the pH partition hypothesis apply.
In the presence of gastric juice (pH 1-3) the NSAIDS are non-ionised and lipid
soluble. They diffuse across gastric mucosal epithelial cell membrane into the
cytoplasm, where pH is neutral (Ph 7.35-7.45).
In neutral pH, NSAIDS are converted into the re-ionised and relatively
lipophobic form. Therefore, they are trapped and accumulate within the cells,
leading to cellular injury and hence NSAIDS associated PUD.

2. Free-base trapping of some antimalarial drugs in the acidic environment in the

food vacuole of the malaria parasite contributes to the disruption of the
haemoglobin digestion pathway that underlies their toxic effect on the
parasite.

3. Urinary acidification accelerates excretion of weak bases and retards that of

weak acids. For example, probenecid inhibits the reabsorption of urate in the
proximal tubule to increase its excretion. It increases urine pH enhancing
reabsorption unionised forms of weak acid drugs and exacerbating their
toxicity.

Elimination-excretion
4. Urinary alkalinisation reduces excretion of weak bases and increases excretion
of weak acids such as Aspirin (pKa 3.5).

5. Increasing plasma pH (e.g. by administration of sodium bicarbonate) causes

weakly acidic drugs to be extracted from the CNS into the plasma.
Conversely, reducing plasma pH for example, administration of a carbonic
anhydrase inhibitor such as acetazolamide causes weakly acidic drugs to
become concentrated in the CNS, increasing their neurotoxicity. This has
practical consequences in choosing a means to alkalinise urine in treating
aspirin overdose: bicarbonate and acetazolamide each increase urine pH and
hence increase salicylate elimination, but bicarbonate reduces whereas
acetazolamide increases distribution of salicylate to the CNS.

However, the pH partition hypothesis has been tested in large number of studies and
has been found to be only partially applicable in real biologic systems. In many cases,
the ionized and unionized forms of a drug partitions are appreciably transported
across lipophilic membrane.
References
1 Rang and Dales Pharmacology, 8th Ed.
2 Goodmann and Gilmans, the Pharmacological Basis for Therapeutic, 12th Ed
3 Hirofumi Matsui et al, The pathophysiology of NSAIDS-induced mucosal injuries
in stomach and intestine, 2011
QUESTION 14
1. clinical applications of bioavailability:
Bioavailability is the fraction of drug administered by any route that reaches the
systemic circulation in unchanged form. Clinical applications include:
 In drug development to minimize variations of efficiency e.g.
o Relative bioavailability is used to compare 2 formulations e.g. tablet
and syrup.
o Absolute bioavailability is used to compare generic drugs against the
original patented innovator drugs. For most drugs, AUC(0–t) and Cmax
must lie between 80% and 125% of a marketed preparation for the new
generic product to be accepted as bioequivalent to the original patented
drug.
 In route of administration e.g.
o Inhalational route is used for emergency drugs that affect pulmonary
function e.g. glucococorticoids (beclomethasone) and β agonists
(salbutamol) in asthmatic patients. Absorption and therefore
bioavailability are enhanced by the large alveolar surface area and
blood supply. The sublingual route is also used for emergency drugs
e.g. nitroglycerine in ischaemic heart disease. These have better
bioavailability as they bypass first pass metabolism.
 In drug formulations: Utilization of doxorubicin nanoparticles to improve
bioavailability of oral doxorubicin in chemotherapy.
 In management of poisoning:
o Activated charcoal reduces absorption and hence bioavailability.
o Chelators are used to reduce bioavailability of heavy metals e.g.
dimercarprol in lead poisoning.
References:
-Class Notes,
-Rang and Dale, 9th edition.

2. why drug metabolism?

 Metabolism is important to:
o Convert pro drug to active drug e.g. enalapril to enalaprilat,
azathioprine to mercaptopurine, morphine to morphine-6-glucuronide
and zidovudine to zidovudine triphosphate.
o Convert substance to toxic metabolite e.g. NAPQI produced in
acetaminophen overdose.
o Inactivate drug/terminate its action.
o Convert lipophilic drug molecules into polar form to facilitate
excretion.
 Clinical applications of metabolism knowledge include:
o Not using the oral route when rapid drug effect is required e.g. in
emergency situations. Other routes that bypass first pass metabolism
are used e.g. IV or sublingual (e.g. nitroglycerine).
o Doubling the dose of Dolutegravir (DTG) in TB/HIV co-infected
patients on Rifampicin as Rifampicin induces the CYP3A4 enzymes
that reduce the DTG plasma concentration.
 o Avoiding chloramphenicol in neonates as the liver at that age is too
immature to adequately metabolize the drug through glucuronidation
thus administration may lead to grey baby syndrome.
 Examples of defective metabolism are:
o Slow acetylators enjoy a better therapeutic response to isoniazid (half-
life in slow inactivators is 3 h and in rapid acetylators it’s only 1 h).
References:
-Class Notes,
-Rang and Dale, 9th edition
QUESTION 19.DIFFERENCE BETWEEN ABSOLUTE AND
RELATIVE BIOAVAILABILITY
Absolute bioavailability is the systemically available amount of the drug
administered comparing with the same drug of different formulation while
Relative bioavailability is the availability of a drug contained in a test
preparation with reference to a standard preparation. (i.e. the same test drug of
different formulation is given to find which one has higher bioavailability
during the .)

QN.20.WHY IS METRONIDAZOLE CONTRAINDICATED IN PATIENT

WITH ALCOHOL TOXICITY?
Ans.referrence.katzung 11th ed.page 201.
FOR UNDERSTANDING PURPORPOSE 1.
-Alcohol dehydrogenase enzyme (ADH) and Microsomal ethanol-oxidizing
system(MEOS), are the two enzymes for alcohol metabolism found in the hepatocytes
and GUT,they accounts for metabolism in low to moderate levels of ethanol.
-Chronic ethanol consumption induces cytochrome P450 and MEOS activity hence
partially development of tolerance to ethanol.
FOR UNDERSTANDING PRUPROSE 2;MECHANISM OF ACTION OF
ALCOHOL METABOLISM.
1;ETHANOL(the most important alcohol) is oxidised either by ADH or MEOS to
form ACETALDEHYDE
2;ACETYLDEHYDE is rapidly metabolised to ACETATE by ALDEHYDE
DEHYDROGENASE a mitochondrial enzyme found in the liver and many other
tissues.
ANS FOR THE QN ;EFFECT OF METRONIDAZOLE IN ALCOHOL TOXIXITY.
1-METRONIDAZOLE is among drugs which inhibit ALDEHYDE
DEHYDROGENASE ,an enzyme used to convert acetaldehyde(an oxidised form of
ethanol in the liver) to acetate(catalysed form of acetaldehyde) for an easy excretion
of ethanol in urine (other drugs are cephalosporins, oral hypoglycemics and
disulfiram)
2-METRONIDAZOLE is contraindicated in alcohol toxicity because, it will
exacerbate its toxic level as more alcohol will remain in blood circulation and not be
excreted by inhibition of an enzyme aldehyde dehydrogenase action of metronidazole
to form acetate hence more CNS manifestation of alcohol toxicity , liver damage, etc.

QUESTION 21.CHARACTERISTICS OF WATER SOLUBLE DRUGS

 Poorly absorbed because of their inability to cross lipid rich membrane.
 This is one reason why many drugs are either weak acids or
weak bases.
 Absorption from GI route is negligible and parenteral route is required.
 Distribution is restricted to extracellular fluid.
 These drugs do not penetrate into the cerebrospinal fluid.
 Elimination is mainly by urinary excretion of the unchanged drug.
 The drug enters the urine mainly by ultrafiltration, but anions and cations are
also actively secreted into the urine.

E. g. all the aminoglycosides have similar pharmacokinetic Properties. Due to their

hydrophilicity, tissue concentrations may
be sub therapeutic, and penetration into most body fluids is variable. [Note: Due to
low distribution into fatty tissue, the aminoglycosides are dosed based on lean body
mass, not actual body weight]. Concentrations in CSF are inadequate, even in the
presence of inflamed meninges. For central nervous system infections, the intrathecal
(IT) route may be utilized. All aminoglycosides cross the placental barrier and may
accumulate in fetal plasma and amniotic fluid
21: DESCRIBE THE USE OF CLINICAL PHARMACOKINETICS IN
CLINICAL PRACTICE.
(Cover the aspects of ADME and stressing on primary pharmacokinetic
parameters)

1. DRUG BIOAVAILABILITY: This pharmacokinetic parameter helps to

choose appropriate root of administration to achieve optimum plasma drug
concentration, by considering absorption and first pass metabolism of the
drug if a drug is administered through other root than intravenous.

2. DRUG METABOLISM: Knowledge on drug metabolism can guide you to

avoid prescribing certain drugs. For example, avoid prescribing acetyl
salicylic acid in patients with liver cirrhosis

3. INHIBITION AND INDUCTION OF METABOLISM: The knowledge of

inhibition and induction can be used to adjust doses for patients. For example,
patients taking carbamazepine which is CYP450 inducer may required a larger
dose of antiretroviral drugs.
 4. ELIMINATION HALF LIFE: It helps to establish a dose regimen and predict
the dosing interval

5. VOLUME OF DISTRIBUTION: It helps to calculate the loading dose for the

patient
QUESTION 22; DISCUSS THE FOUR MAJOR TRANSDUCTION
MECHANISMS INVOLVED IN DRUG RECEPTOR INTERACTIONS

Transduction is the transmission of a molecular signal from outside the cell to inside.
For a signal to be conveyed and produce a physiological response, there are targets for
a particular physiological responses to occur in response to exogenous or endogenous
molecules.
The pharmacological targets can either be on the cell surface(trans-membraneous
targets-ion channels, G protein coupled receptors, Tyrosine kinase receptors) or within
the cell (intracellular receptors).

1. Ion channels
For fast neurotransmitters, channel opening occur on a millisecond timescale
These channels incorporate a receptor and open only when the receptor is occupied by
an agonist
Coupling mechanism is direct, no second messenger
Ion channels may be Voltage gated or ligand gated
Drugs can open or block the channels
Alteration in ionic conductance may depolarize or hyperpolarize a cell hence a
cellular response
Example;
• Nicotinic receptor for Acetylcholine coupled to Na/K ion channel
• GABAa receptor in CNS for Benzodiazepines coupled to chloride ion channel

2. G protein coupled receptors

Ligand binding to GPCR causes activation of a second messenger, G protein
The G proteins can either be Gs, Gi, or Gq
These Gs proteins molecule can bind to and activate many effector molecules, such as
Adenylyl cyclase, which can then generate an even greater number of second
messenger molecules (cAMP)
Gq activates Phospholipase C which generate IP3 and DAG
Gi inhibit effector molecules through inhibiting Adenylate cyclase
These second messengers phosphorylate different proteins and enzymes hence cellular
response

Recepto G- Enzyme Seco Protein Example of drugs

r protein nd kinase (agonist/antagonist)
mess
enger
β1,β2,D Gs ↑ ↑cA ↑PKA Terbutalline, salbutamol,
1, adenyla MP propranolol, Ranitidine
glucago te
n, H2, cyclase
LH,
FSH,TS
H
α2,M2, Gi ↓cA ↓PKA Methyldopa,
D2,opia ↓adenyl MP Haloperidol,Baclofen,
te, ate Levodopa, Morphine
GABAb cyclase
α1,M1, Gq ↑Phosp ↑IP3 ↑PKC Clonidine, Losartan,
M3,AT1 holipas and Atropine,Pilocarpine,
,5HT3, eC DAG Ondansetron,
H1 promethazine

3. Tyrosine kinase receptors

These are membrane spanning, its effects are mainly at the level of gene transcription
On activation can activate a distinctive set of cytoplasmic tyrosine kinases Janus
kinases (JAKS)
JAKs phosphorylate signal transducers and activators of transcription (STAT)
molecules
STATs dimerize and then dissociate, cross the nuclear membrane and modulate gene
transcription
Has two important pathways;
• Ras/Raf/Mitogen activated proteins(MAP) kinase pathway which controls cell
division, growth and differentiation. Example Imitinib, a tyrosine kinase inhibitor
used for cancer treatment
• Jak/Stat pathway, activated by many cytokines, controls synthesis and release
of inflammatory mediators. Example, Tofacitinib, a JAK inhibitor used in treatment of
Rheumatoid arthritis and Psoriasis

4. intracellular receptors
These are receptors located within the cells
Receptors for lipid soluble ligands
Binding to intracellular receptors causes translocation to the nucleus
Activated receptor binds regulatory DNA regions (enhancers or silencers)
Response are due to modification of gene expression and slower in onset but longer in
duration
Examples include receptors for thyroid hormones, steroids, Vitamin A, Vitamin D

22. GIVING EXAMPLES OF ENDOGENOUS LIGANDS AND SPECIFIC

RECEPTORS INVOLVED, EXPLAIN ANY FOUR SCENARIOS ON HOW G-
PROTEIN COUPLED RECEPTORS (GPCRS) MAINTAIN HOMEOSTASIS
AND THE OPPORTUNITY THEY PROVIDE FOR THERAPEUTIC
LEVERAGE (10 MARKS)
ANSWER
A) Endogenous ligands for G protein coupled protein receptors
1. Hormones: Adrenaline.-, noradrenaline and cortisol
2. Neurotransmitters: dopamine, serotonin and acetyl choline
3. Inflammatory mediators: prostaglandins and leukotrienes
4. Peptides: endorphins, encephalin and somatostatins

B. 1.Hormonal secretions: G protein coupled receptors in the hypothalamus and

pituitary gland when activated releases TRH and Adrenal corticosteroid hormones
that are released in the blood stream to control levels of adrenaline, noradrenaline and
cortisol.
Example of drugs: Beta blockers such as carvedilol which bind to adrenoreceiptors
in the heart for control of hypertension, Salbutamol for bronchodialation
2. Neurotransmitter release: Neurotransmitters in the brain such as dopamine and
seroronin are release for regulation of mood and other cognitive processes
Example: Selective serotonin reuptake inhibitors such as citalopram and dapoxetin
are used as antidepressants
QUESTION 24.THERAPEUTIC DRUG MONITORING IS USED TO
ACHIEVE THE DESIRED THERAPEUTIC EFFECT WHILE MINIMISING
ADVERSE EFFECTS IN EACH INDIVIDUAL PATIENT (I.E.
DETERMINATION OF THERAPEUTIC WINDOW). It may be used to decide
how to adjust patient treatment i.e. whether to discontinue/substitute a drug or
titrate it’s dose up or down and/or distinguish poor adherence from actual
treatment failure (e.g. in HAART). It is used for:
 drugs with narrow therapeutic index (e.g. digoxin, lithium, phenytoin,
aminoglycosides) or narrow therapeutic index and long duration of action
(e.g. lithium).
 situations where lack of efficacy or toxicity are suspected.
 where symptoms of toxicity may be confused with disease being treated.
 where there is considerable individual variation in the plasma
concentration achieved with a given dose e.g. phenytoin where regular
monitoring of plasma concentration has helped considerably in achieving an
optimal therapeutic effect (as opposed to simply giving additional
anticonvulsants).
-Practical issues include:
 It’s useful only if:
o Accurate assays exist (where there is a relationship exists between the
plasma drug concentration and the desired clinical effect or between
the plasma drug concentration and an adverse effect).
o There is no good clinical indicator of drug effect e.g. BP, blood
glucose.
  Timing of sample collection is critical depending on the purpose of drug
monitoring.
 Requires known therapeutic ranges, however, many patients will respond
better at different levels and some patients may have drug-related adverse
events within the listed average therapeutic ranges e.g. for anticonvulsants.
 Not practical for routine use especially in resource-limited settings.
 Serum drug levels may be confounded by poor adherence, white coat
adherence, drug interactions or alterations in protein
concentrations/protein binding.
25: DEFINE THE TERM BIOAVAILABILITY. WHAT METHODS OF DRUG
DELIVERY ARE USED TO OVERCOME BIOAVAILABILITY PROBLEMS?
ANSWER
Bioavailability: Is the fraction of the unchanged drugs that reaches systemic
circulation.
Methods of drug delivery are used to overcome reduced bioavailability of the drug
1. Improved formulations of the drugs: Drugs can be formulated as
nanoparticles, microparticles or micro emulsions to improve their solubility
and stability
2. Pro drug: Given to sustain drug stability and improve its availability in the
blood
3. Route of administration: IV is the ideal route for the drugs which are water
soluble Example: gentamycin
4. Use of drug delivery system such as patches or implantable devices by help
delivering it direct to the site

QUESTION 26.OUTLINE, WITH EXAMPLES, SOME OF THE PROMISES

OF UNDERSTANDING GENETIC INFLUENCE OF
PHARMACODYNAMICS IN CANCER TREATMENT (5 marks) EFFESO
TRASTUZUMAB AND HER2; Trastuzumab is a monoclonal antibody that
antagonises epidermal growth factor (EGF) by binding to one of its receptors (human
epidermal growth factor receptor 2—HER2) which can occur in tumour tissue as a
result of somatic mutation. It is used in patients with breast cancer whose tumour
tissue overexpresses this receptor. Other patients have not been found to benefit from
it.
DASATINIB, IMATINIB AND BCR-ABL1;
Dasatinib is a dual BCR/ABL and Src tyrosine kinase inhibitor used in
haematological malignancies characterised by the presence of a Philadelphia
chromosome, namely chronic myeloid leukaemia (CML) and some adults with acute
lymphoblastic leukaemia (ALL). The Philadelphia chromosome results from a
translocation defect when parts of two chromosomes (9 and 22) swap places; part of a
‘breakpoint cluster region’ (BCR) in chromosome 22 links to the ‘Abelson-1’ (ABL)
region of chromosome 9. A mutation (T315I) in BCR/ABL confers resistance to the
inhibitory effect of dasatinib and patients with this variant do not benefit from this
drug.
Pharmacogenetic testing is also being evaluated for imatinib, another tyrosine kinase
inhibitor used in patients with CML and other myelodysplastic disorders associated
with rearrangements in the gene for platelet-derived growth factor receptor or for
BCR-ABL.
QUESTION 27. DISCUSS ABOUT ALCOHOLISM IN TERMS OF ENZYME
INDUCTION AND ENZYME INHIBITION. WHAT ARE THE MECHANISMS
THAT MAKE THEM SO. IS THERE A DIFFERENCE IN THE TYPE OF
ALCOHOL ON INDUCTION OR INHIBITION?
Enzyme inhibition
When the normal alcohol metabolic pathway (alcohol dehydrogenase/aldehyde
dehydrogenase) is saturated (remember alcohol, aspirin, and phenytoin metabolism
follow zero order kinetics which means they are saturable), the cytochrome P450
pathway starts metabolizing alcohol. For a person not used to drinking alcohol (acute
alcohol intake), the low-capacity cytochrome P450 is easy to saturate which means it
is no longer available for metabolizing other toxins and drugs (aka it's metabolic and
detoxification actions are inhibited).
Enzyme induction.
Because CYp450 is an inducible system, for someone who is a chronic drinker,
CYP450 is induced so that the capacity of the system increases due to increased
enzyme production in order to both handle the chronic alcohol intake and to perform
the other essential metabolic/detox functions of the CYP450 system.
Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS
activity; this is partially responsible for the development of tolerance to ethanol. The
primary isoform of cytochrome P450 induced by ethanol—2E1, converts
acetaminophen to a hepatotoxic metabolite.
QUESTION 28. DOES SMOKING CAUSES ENZYME INDUCTION OR
INHIBITION? HOW, DOES THIS APPLY TO ALL DRUGS?
Yes, cigarette smoking induces the activity of human cytochrome P450 (CYP) A1A2
and 2B6. These enzymes metabolizes several clinically important drugs such as
antidepressants and antipsychotics including clozapine, olanzapine (CYP1A2), methadone,
clopidogrel and nevirapine (CYP2B6).
The effect of smoking on hepatic enzyme is not related to the nicotine component of
tobacco but its associated chemicals such as polyclic aromatic hydrocarbons. Daily
consumption of 7-12 cigarettes is sufficient to cause maximum induction of clozapine and
olanzapine metabolism resulting to their lower plasma concentration. Warfarin to a lesser
extent is metabolized by CYP1A2 and smoking therefore potentially interact by warfarin by
increasing its clearance and reducing its effects.
Caffeine is one of the highly dependent substrate of CYP1A2 for its metabolism.
Smokers requires up to four times as higher caffeine as non-smokers to achieve the same
plasma caffeine concentration. Therefore caffeine can increase the plasma concentration of
clozapine and olanzapine.
Nicotine (and its metabolite) on the other hand inhibits some CYP450 Isoforms
including CYP2E1 and may results into accumulation of its substrate such as acetaminophen
in plasma.
This does not apply to all drug because cigarette smoking affect only some of
CYP450 isoforms and due to genetic polymorphism of the target CYP450 isoforms affected
by smoking contributing to variability in drug metabolism.
However, smoking does not only affect drug pharmacokinetics but also has
pharmacodynamics drug interactions due to nicotine.

References:
1. Ran & Dale’s Pharmacology, 2016
2. Kartzung, Basic and clinical pharmacology 13th ed, 2015
3. Catherine lucas et.al, smoking and drug interaction; article, 2013
4. www.acs.org/acswebinars

QUESTION 29. WHAT ARE THE CONCEPTS OF CLEARANCE IN

DETERMINING DRUG DOSING?
a) The concept.
Clearance is the rate of elimination (excretion +biotransformation) of the drug from
the plasma per unit time. It is performed by 2major organs, the liver, and kidneys,
other organs includes GIT and the lungs. Clearance undertaken by more than one
organ is additive i.e (CLLiver +CLkidney +CLothers =Total clearance)
The interpretation of measurements of drug concentrations depends on a clear
understanding of three factors that may influence clearance: the dose, the organ blood
flow, and the
intrinsic function of the liver or kidneys.
It is estimated by calculating the area under the curve (AUC) of the time-
concentration profile after a dose if the drug follows first order kinetics.
Clearance is not saturable for drugs that follow first order kinetics, as it is directly
proportional to the plasma concentration; zero order kinetics follows limited capacity
pathway/michaelis menten elimination, which is saturable (concentration dependent)
Clearance = Dose/AUC. Clearance=rate of elimination/concentration
Plasma clearance is the most important PK parameter because it is one of the three
determinants of a dosage rate.

b) Determining drug dosing.

From the concept of clearance, we can determine the therapeutic and toxic dose
(dosage adjustment) and individualize the doses from patient to patient, drug to drug
i.e drugs that follows michaelis menten elimination, flow depend elimination.

QUESTION 33.BIOMARKERS
a. Define the following: Biomarker, Surrogate endpoint, clinical endpoint
b. With examples discuss applications of biomarkers in patient care
Answer
Biomarker: is a characteristic that is measured as an indicator of
 Normal biologic responses: BP/ cholesterol/ HB
 Pharmacological response to therapeutic intervention: response of
BP
 Pathological processes: elevation of BP

Surrogate Endpoint: biomarker that is meant to serve as a substitute of clinically

meaningful endpoint

Clinical Endpoint: clinically meaningful measure of how a patient feel, functions and
survive.

a. With examples discuss applications of biomarkers in patient care

 Diagnosis: DM and OGTT/ glycated HB

 Screening: prostate cancer
 Drug effect: ARV and CD4
 Drug development: negative or positive
 Risk stratification: coronary artery disease CAD / Heart score
 Prognostic values: staging of disease

QUESTION 38. EXAMPLES OF TRANSPORTERS INVOLVED IN

ABSORPTION, DISTRIBUTION AND
METABOLISM

ANSWER
Transporters are membrane proteins whose primary function is to facilitate the flux of
molecules in and out of the cells across the lipid bilayer membrane. They are
responsible for the transport of a wide variety of solutes, including ions, sugars, amino
acids, and other small molecules.
Examples:
 Channel proteins
 Carrier proteins
 Sodium - potassium pumps
  Sodium – Glucose transporter
 Proton Pumps
 Calcium ATPase
 Sodium – calcium Pump
 P glycoprotein efflux pump
QUESTION 40.CLINICAL SIGNIFICANCE OF REABSORPTION/
REDISTRIBUTION OF DRUGS
As the drug is administered, it will move to the highly vascularized
compartment like the Central nervous system and then distributes evenly from
the CNS to the areas of low blood supply like the skeletal muscles and fat
tissues with rapid cessation of its action in the CNS, this phenomenon is
referred as Redistribution.
The clinical use/ significcance is seen in the most injectable anesthetic such
as Thiopental characterized by a short duration of action, causing
unconsciousness within about 20 s, lasting for 5–10 min meaning that the drug
concentration falls in the brain and rises in the periphery with no sedative
effects

Thus; With Redistribution, the effect of the drug subsides before the it has left
the body

What are isomers and enantiomers, mention their examples and clinical significance.
QUESTION 43. WHY IS GENTAMICIN GIVEN INTRAVENOUSLY?
Gentamicin is an aminoglycoside antibiotic which interferes with bacterial protein synthesis
by binding to 30S and 50S ribosomal subunits,
Gentamicin is given as slow bolus injection over two to three minutes or via intravenous
infusion over 30 minutes, it is highly hydrophilic ( polar) therefore it is not absorbed by the
gut when given orally.
QUESTION 44. SIGNIFICANCE OF PLASMA CONCENTRATION OF A DRUG IN
RELATION TO PHARMACOTHERAPY
Plasma concentration is the concentration of a drug in plasma (Cp) given by dividing the
amount of drug in the compartment (D) by the distribution volume of the compartment.
Plasma concentration are used to define major Pharmacokinetics and Pharmacodynamics
parameters of a drug. A plasma concentration profile versus time (AUC) can be used to
characterize the therapeutic effect of a drug for a specific dosage or formulation in relation to
its absorption, distribution, metabolism, and excretion as well as its therapeutic effect as
discussed below.
-Regarding absorption, the higher the rate of absorption from its site of administration of a
drug the higher its plasma concentration.
-Concentration gradient influences distribution of drug molecules from plasma to other organs
or compartment such as tissues. However, this depends also on the degree of perfusion of a
tissue and physicochemical properties of a drug.
-Plasma concentration defines the rate of metabolism of a drug in biological systems. The
elimination rate of most drugs increases with the increase in plasma concentration (Those
obeys first order reaction) and elimination rate of some drugs such as ethanol, and phenytoin
are independent of their plasma concentration.
-The rate at which a drug molecule (changed or unchanged) is cleared from the body depends
on plasma concentration. Clearance is inversely proportion to plasma concentration.
-The responses to low doses of a drug usually increase in direct proportion to plasma
concentration (or dose). As plasma concentration increase, however, the response increment
diminishes; finally, doses may be reached at which no further increase in response can be
achieved
QUESTION 49. Which Pharmacokinetics parameters are primary and which are
secondary?
Pharmacokinetics is what the body does to the drug. Pharmacokinetics means the movement
of a drug in the body and this includes the processes of absorption, distribution, metabolism
and excretion.
Therefore, Pharmacokinetics parameters are used to translate and understand how a drug
interacts with the body. Those parameters can describe how the drug is absorbed, distributed,
metabolized and excreted from the body.
Quantitative description of Pharmacokinetic actions uses use pharmacokinetic parameters
which are either primary or secondary.
The primary Pharmacokinetic parameters are those directly determined by physiological
variables which are:

1. Volume of distribution (Vd), a measure of apparent space in the body

available to contain the drug basing on how much is given versus what is
found in the circulation (Vd=D/Cp).
 2. Clearance (Cl), a measure of body’s efficiency in eliminating the drug from
systemic circulation i.e that volume of plasma from which the drug is removed
in unit time .
The secondary Pharmacokinetic parameters are those parameters that are derived from
primary parameters, including:

1. Elimination half-life of adrug, given as t1/2=0.693Vd/Cl for first order reaction

2. Bioavailability (F), the fraction of unchanged drug reaching the systemic
circulation following administration by any route.
Others include i/Protein binding ii/Dosing rate iii/ Loading dose iv/
Maintainence dose v/

QUESTION 50. WHY DO WE SOMETIMES GIVE LOADING DOSE AS A

BOLUS AND SOMETIMES AS IN INTERVALS?
Loading dose: Sometimes rapid obtainment of desired plasma levels is needed (for
example, in serious infections or arrhythmias). Therefore, a “loading dose” of drug is
administered to achieve the desired plasma level rapidly, followed by a maintenance
dose to maintain the steady state.
In general, the loading dose can be calculated as
Loading dose = (Vd) × (desired steady-state plasma concentration)/F
Loading dose takes account of the drug with large volume of distribution.

Loading doses can be given as a single dose or a series of doses.

Disadvantages of loading doses include increased risk of drug toxicity and a longer
time for the plasma concentration to fall if excess levels occur. A loading dose is most
useful for drugs that have a relatively long half-life. Without an initial loading dose,
these drugs would take a long time to reach a therapeutic value that corresponds to the
steady-state level.
For drugs with narrow therapeutic range, it is safer to give as interval/series of doses
to limit toxic effects, and those with wide therapeutic range can be given as bolus.
ole of therapeutic drug monitoring in quality care and practical issues in
therapeutic drug monitoring:
References:
-Rang and Dale’s Pharmacology, 9th edition.
-Katzung Pharmacology, 12th edition.

https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-
science/therapeutic-drug-monitoring

https://hospitalpharmacyeurope.com/news/editors-pick/criteria-for-therapeutic-drug-
monitoring-in-hiv/

61.DIFFERENCE BETWEEN MONOCLONAL AND

POLYCLONAL ANTIBODY:
Monoclonal antibodies
Monospecific antibodies that are identical because
they are produced by immune cells of a single type
and all these cells are clones of a single parent cell.
MAbs have lower specificity than PAbs but the
concentration and purity levels of specific antibody
are higher in MAbs.
MAbs take much longer (at least a year) to generate
(months), at higher expense, and with more technical
skill than is required to produce PAbs.
Small changes in the structure of an epitope (e.g., as
a consequence of genetic polymorphism,
glycosylation, and denaturation) can markedly affect
the function of a MAb. For that reason, MAbs
should be generated to the state of the antigen to
which it will eventually need to bind.
MAbs can be highly susceptible to
small changes in both pH and salt concentration.
For MAbs, once the desired hybridoma has been
generated, MAbs can be generated as a constant and
renewable resource.
-MAbs are not generally useful for assays that
depend on antigen cross-linking (e.g.,
hemagglutination) unless dimeric or multimeric
antigens or antigens bound to a solid phase are used.
-Additionally, they may not activate complement.
readily because activation requires the close
proximity of Fc receptors.
-Modification of antibodies by covalently linking a
fluorochrome or radionuclide may also alter antibody
binding.
Many of the disadvantages of MAbs can be
overcome by pooling and using multiple MAbs of
desired specificities. The pooled product is consistent
over time and available in limitless quantity.
However, it is frequently difficult, too expensive, and
too time consuming to identify multiple MAbs of
desired specificity.
.Main reference:
https://academic.oup.com/ilarjournal/article/46/3/258/738903
You can also read a summary at:
Polyclonal antibodies
Polyspecific- produced by a large number of B cell
clones each generating antibodies to a specific
epitope.
PAbs frequently have better specificity than MAbs
because they are produced by a large number of B
cell clones each generating antibodies to a specific
epitope, and polyclonal sera are a composite of
antibodies with unique specificities.
PAbs can be generated much more rapidly (months),
at less expense, and with less technical skill than is
required to produce MAbs.
In contrast, because PAbs are heterogeneous and
recognize a host of antigenic epitopes, the effect of
change on a single or small number of epitopes is less
likely to be significant.
PAbs are also more stable over a broad pH and salt
concentration
In contrast, PAbs generated to the same antigen using
multiple animals will differ among immunized
animals, and their avidity may change as they are
harvested over time. The quantity of PAbs obtained is
limited by the size of the animal and its lifespan.
This potential is less of a concern when using
PAbs, which recognize a host of epitopes, but it can
be significant for MAbs if the change affects its
monospecific binding site.
https://www.sepmag.eu/blog/monoclonal-vs-polyclonal-antibodies#:~:text=Monoclonal%20antibodies
%20are%20all%20made,by%20many%20different%20B%20cells
QUESTION 62.H1 BLOCKERS (H1 RECEPTOR ANTAGONISTS)
Mechanism: H1-antihistamines are members of G-protein coupled receptors, they are
competitive inverse agonists that have prefential affinity for the inactive state of the receptor
and stabilize it in this conformation; they reduce the basal level of constitutive activity at
histamine H1 receptors as well as blocking the agonist effects of histamine.

Pharmacokinetics: H1-antihistamines are well absorbed after oral and parenteral administratio
n. They are distributed widely throughout the body, metabolized extensively in liver and
excreted in urine.
First generation H1 blockers: These are lipophilic drugs that readily cross the BBB, they
include diphenhydramine, promethazine and chlorpherinamine.
Second generation H1 blockers: these are more hydrophilic and do not cross the BBB, they
include cetirizine, loratadine, levocetirizine, desloratadine, mizolastin and fenoxifenadine.
H2 blockers (H2 receptor antagonists)
Mechanism: They are relatively selective H2 blockers which decrease in cAMP thus prevents
activation of protein kinase A and subsequent phosphorylation of proteins that take part in
transport of hydrogen ions therefore reducing stomach acid secretion.

Pharmacokinetics: They are orally active, with half-lives of 1–3 h. Because they are all
relatively nontoxic, they can be given in large doses, so that the duration of action of a single
dose may be 12–24 h.

There are four H2 blockers, cimetidine, ranitidine, famotidine and nizatidine.

QUESTION 65. WHAT ARE ISOMERS AND ENANTIOMERS, MENTIONS

THEIR EXAMPLES AND CLINICAL SIGNIFICANCE
Isomers: Are chemical compounds with similar molecular formula but different
structure. Can be classified as structural isomers, stereoisomers and geometric isomers
Stereoisomers: Compounds that have the same molecular formula but spatial
different atomic arrangements. Includes enantiomers and diastereoisomers.
Enantiomers and stereo isomers are compounds that are mirror image but none
superimposed. Have the same physicochemical properties.
Example of enantiomers drugs
1. Thalidomide-for reducing morning sickness to pregnant women( no longer in
use because of teratogenicity
2. Ibuprofen
3. Naproxen
4. L-dopa
QUESTION 66. BRIEFLY DISCUSS ABOUT BIOLOGICS
ANSWER
Biologics are a type of medical product that is derived from living organisms or their
products. They are often used to treat diseases such as cancer, autoimmune disorders,
and infectious diseases.
Examples of biologics include
 Monoclonal antibodies - Rituximab
 Interferons – Interferon alpha, beta
 Vaccines – Flu vaccine, HPV vaccine
 Growth factors – erythropoietin
 Insulin

Absorption
 Generally poor oral bioavailability due to their instability in the GI and their
larger size to permeate the intestinal epithelium hence are generally
administered parenterally.
Distribution
 Mostly are hydrophobic and therefore tend to have a volume of distribution
that lie between that of plasma.
Metabolism
 Virtually all protein drugs are eliminated by metabolism; except for a few
small peptides, which are primarily eliminated by renal excretion.

Generally, the effectiveness of biologics varies depending on the specific product and
the condition being treated. Biologics can cause side effects, and patients receiving
biologic treatments must be carefully monitored by healthcare providers.