Question 1 Answer all parts.

A. Draw the structure of a named amino acid.

Glycine

B. What is protein quaternary structure? Give an example of a protein with quaternary

structure.
Many proteins are made up of a several polypeptide chains, these being referred to as protein
subunits. Quaternary structure refers to how these protein subunits are working together with
each other and organize themselves in order to form a larger combined protein complex.
An example of a protein with quaternary structure is haemoglobin

C. What is the role of an antagonist? Give a name example

Antagonists attach to a receptor, usually this is with increased affinity, but they don’t make
an intrinsic cellular response. Antagonists are deficient in effectiveness. The block the
outcome of agonists. (Simmons, 2011)
An example of antagonist that has a specific importance in the central nervous system is
dopamine antagonists. (Human Memory, 2019)

D. What is a therapeutic index of a drug?

Therapeutic index represents a ratio that is comparing the blood concentration at which a
medicine has toxicity effects on the body and the concentration at which the drug is efficient.
If therapeutic index is bigger, it means that the drug is safer to use. If its value is small, then
the medication must dosed carefully and the patients to whom is given the drug must be
carefully supervised for any symptoms of drug toxicity. (AIDSinfo, 2020)

E. IC50 for the drug is

F. Define pharmacokinetics
Pharmacokinetics is the study of the movement of drugs inside and outside of the body and
comprises the principle of absorption, distribution, metabolism, and elimination. (Simmons,
2011)

G. What are Lipinski’s guidelines?

Lipinski rule is also called rule of five (RO5) is a rule of thumb to estimate drug likeness or
establishing if a chemical compound with specific pharmacological or biological activity has
particularities that would make it a likely orally active drug in human beings. (Walters, 2012)
Lipinski’s rule states that, in general, an orally active medication has no more than one
contravention of the following criteria:
● Not more than 5 hydrogen bond donors
● Not more than 10 hydrogen bond acceptors
● A molecular mass less than 500 daltons
● An octanol-water separation coefficient log P not bigger than 5

H. Name a protein involved with distribution in the body.

Albumin

I.Give ONE example of a drug-drug interaction

NSAID + warfarin

J. What is the enzyme target for Aspirin

COX enzyme (cyclooxygenase)

Question 2

Answer all parts (a) and (b)

a) Describe the pharmaceutical difference between an agonist and inhibitor.

Agonists are drugs that attach and trigger receptors. If the drug-receptor interactions

concept is taken into consideration, as “lock and key” form, then agonists represent keys that
go into a lock (receptor) and open (stimulate) them. (TUSOM Pharmwiki, 2019). Once an
agonist has joins to its receptor, its results are transduced into a cellular reply by one of
multiple different systems. A few of the most frequent mechanisms comprise: a) activating
directly the ion canal, b) G-protein activation of an ion channel, c) G-protein activation of a
second messenger system, or d) receptor activation of an intracellular enzyme.
On the other side, an enzyme inhibitor is represented by a molecule that attaches to
an enzyme and is lowering its efficacy. When joining to enzymes' active sites, inhibitors are
decreasing their affinity of substrate and enzyme, this leading to the inhibition of Enzyme-
Substrate complexes' formation. This thing stops catalyzation of reactions and lowering the
quantity of product which results from a reaction. 
Explain using a therapeutically relevant example for each, the effect of one Agonist and
one Inhibitor on its biological for a named condition.
An agonist example is represented by beta adrenergic drugs which are the strongest
bronchodilators at the present time being granted for medical use in asthma and obstructive
lung disease. These are called β2 agonists, but usually are named simply b-agonists.
β2-Receptors are positioned in almost every tissue, but most important in the lung in smooth
muscle, epithelial cells, immune cells, glands, and alveolar walls. β2-receptors are members
of the G protein–coupled superfamily of cell surface receptors. In the lung, β 2-agonists bind
to β2-receptors, activating G proteins and adenylate cyclase in smooth muscle cells, this
leading to activation of protein kinase A and relaxation of bronchial smooth muscle. The
major therapeutic effect of b-agonists is that the function of the airways is becoming to
improve by relaxation of bronchial smooth muscle. They may offer other advantages,
however, by performing on endothelial and inflammatory cells. The medical implication of
these actions is however doubtful. Beta agonists do not seem to have any effect on chronic
inflammatory process in the lung. (Travers, 2012)
An example which stands for an inhibitor is represented by ACE inhibitors, which are
drugs affecting the rennin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors
are drugs which are applied to treat high blood pressure and congestive heart failure. They are also
utilized in prevention of kidney disease in certain patients. These drugs widen the blood vessels and
decrease the blood pressure by inhibiting the actions of angiotensin-converting enzyme (ACE), an
enzyme that helps control blood pressure. However, the nonselective inhibition of angiotensin
receptors has revealed to be valuable because the outcome of angiotensin II through the AT2
receptor may produce in incremental vasodilatation and antiproliferative action. (Messerli,
2018). ACE inhibitors excite the widening of blood vessels by inhibiting the production of
angiotensin II. The major organs that ACE inhibitors is affecting are the kidney, blood vessels, heart,
brain, and adrenal glands. The inhibitory consequences has a result of boosted sodium and urine being
excreted, decreased opposition in kidney blood vessels, increased venous ability, and as well
decreased cardiac productivity.
b) Describe the various phases (1-3) of clinical trials.
Phase 1 studies are looking to find out the pharmacokinetic properties and safety of an IND
in people without any health problems. Nowadays, both men and women are included in this
phase in order to decide if gender has any control on the properties of the IND. (Rang, 2012)
They go through physical examination, imaging studies, and as well chemical and
pharmacokinetic analyses of blood samples and other bodily fluids. These analyses offer a
basis in order to estimate doses to be given in the next phase studies, and the other
examinations look for to decide if the medication is secure to be used in humans.
Phase 2 studies are the first studies to be done in human people who have the exacting
disease for which IND is going to be used. These studies involve a small quota of people in
order to obtain initial evaluation of the drug’s effectiveness and safety in individuals with the
particular disease and as well, to set up a dosage assortment for further clinical studies.
Phase 3 is performed in order to judge the protection and efficiency of the IND with that of
another matter or treatment approach. Phase 3 uses a bigger number of subjects, this
consisting of hundreds or thousands of patients, which are involved in multiple locations and
researchers. Phase 3 studies are strictly planned in order to avoid investigator bias and are
often double-blind and placebo-controlled.

Question 3

Answer all parts (a) and (b)

List the routes of drug administration

‘Absorption, distribution, metabolism and excretion of drugs can have major influences on
the potency of a drug. ‘Discuss.

The main routes of administration are:

 Sublingual
 Oral
 Rectal
 Application to epithelial surfaces (e.g. skin, cornea, vagina and nasal mucosa)
 Inhalation
  Injection
 Subcutaneous
 Intramuscular
 Intravenous
 Intrathecal

Absorption is defined as the channel of a medicine from its place of administration

into the plasma. Absorption from the oral cavity is occasionally helpful, when a rapid
reaction is needed, mainly when the drug is either unstable at gastric pH or quickly
metabolized by the liver. However there are some factors which affect gastrointestinal
absorption. As a regulation, about 75% of a medicine which is taken orally is absorbed in 1-3
hours, but a lot of aspects can modify this, a number of them to do with the formulation of the
drug. Therefore, the most important factors which have an effect on gastrointestinal
absorption are: gastrointestinal motility, splanchnic blood flow, particle dimension and
formulation, physicochemical factors.
Drugs of decreased solubility, counting those that are strong acids or bases, are in
general weakly absorbed from the gut. One name that must be taken into reflection when
speaking about potency in terms of absorption is bioavailability. This word is used to point to
the amount of drug that passes into the systemic circulation after oral administration, taking
into account both absorption and local metabolic degradation. This may be decreased because
absorption is not complete, or because the drug is metabolized in the gut wall or liver before
getting in the systemic circulation. ( Rang, 2012)
Taking few examples into consideration, in clinical practice, cutaneous administration
is used mostly when a local outcome on the skin is necessary. Considerable absorption may
nevertheless take place and lead to systemic effects. Most drugs are absorbed very poorly
through unbroken skin, because their lipid solubility is too low. Subcutaneous or
intramuscular injection of drugs usually produces a quicker result than oral administration,
but the rate of absorption depends very much on the site of injection and the physiological
factors, particularly local blood flow. The rate-limiting factors in absorption from the
injection sites are: diffusion through the tissue and elimination by local blood flow.
When distribution is taking place, the equilibrium prototype of distribution of the drug
between the different compartments will thus depend on:
 permeability across tissue barriers
 pH partition
  binding within compartments
 fat: water partition
For nearly all drugs, the metabolism rate in any specified path has a higher limit
(capacity limitation). However, at therapeutic concentrations of most medicines, typically
only a little fraction of the metabolizing enzyme’s sites are engaged, and the metabolism
rate is boosted with drug concentration. In such a situation, called first-order elimination (or
kinetics), the metabolism rate of the drug is a steady part of the drug which remains in the
body (i.e., the drug has a specific half-life). Some drugs are removed from the portal
circulation in a very efficient way by the liver and metabolized. So that the quantity
reaching the systemic circulation is significantly less than the quantity absorbed into the
portal vein. A smaller number are metabolized in the wall of intestine. Lipophilic drugs are
not eliminated in an efficient way as such by the kidney, because they are passively
reabsorbed from tubular fluid as it becomes concentrated. As a result, most lipophilic drugs
are metabolized to more polar products that do not readily cross membrane barriers and so
are well excreted in urine. (Concept Clear, 2020)
In terms of excretion, most drugs, apart from those extremely bound to plasma
protein, cross the glomerular filter freely. Many drugs, in particular weak acids, are actively
secreted into the renal tubule, so are consequently more speedily excreted. On the other side,
lipid-soluble drugs, are passively reabsorbed by diffusion across the tubule, so are not
efficiently excreted in the urine. Because of Ph partition, weak acids are quicker excreted in
alkaline urine, and vice versa. Some significant drugs are removed predominantly by renal
excretion, and are liveable to produce toxicity in old persons and patients with renal disease.

Question 4
Answer all parts (a), (b), (c) and (d)
Explain the following toxicological parameters and testing procedures using diagrams where
appropriate (each part carries equal marks):
a) The No Observed Adverse Effect Level (NOAEL).
NOAEL is defines as the maximum exposure of a chemical, determined in toxicity tests etc
without having any undesirable outcome (e.g., onset of sickness) even when the chemical is
taken (exposed) on a daily basis for the rest of one’s life. In practice, mice, rats or other
animals are strained to take a chemical for a certain period of time. This experiment is
repetitive several times at changing amount levels. The highest dose level which causes no
unpleasant consequence in these tests is adopted as NOAEL (No Observed Adverse Effect
Level). Typically, NOAEL is expressed in the amount of a chemical taken daily per kg body
weight (e.g., mg/kg/day).
The idea of threshold dose for the toxic effect is an important one in toxicology because it
implies that there is a ‘no observed adverse effect level’. The NOAEL is important for setting
exposure limits For example, the satisfactory daily intake (ADI) is based on the NOAEL.
This is a factor used to determine the safe intake for food additives and contaminants such as
pesticides and residues of veterinary medicines and, therefore, to set up the protected level in
food. (Timbrell, 1995)

(b) Lethal Dose (LD50)

 In toxicology, LD50 (Lethal Dose, 50%) represents a toxic substance or radiation is

the dose that needs to kill half the members of a population which is being tested.
LD50 figures are often which is being used as a general thing which indicates of a substance's
acute toxicity.

The LD50 is usually expressed as the mass of substance administered per unit mass of test
subject, such as grams  of substance per kilogram of body mass. Stating it this way allows the
relative toxicity of different substances to be compared, and normalizes for the variation in
the size of the animals exposed (although toxicity does not always scale simply with body
mass). Typically, the LD50 of a substance is given in milligrams per kilogram of body weight.
In the case of some neurotoxins such as batrachotoxin, one of the most deadly venoms
known, the LD50 may be more conveniently expressed as micrograms per kilogram (µg/kg)of
body mass.
The choice of 50% lethality as a benchmark avoids the potential for ambiguity of making
measurements in the extremes, and reduces the amount of testing required. However, this also
means that LD50 is not the lethal dose for all subjects; some may be killed by much less, while
others survive doses far higher than the LD 50. Measures such as 'LD1' and 'LD99' (dosage
required to kill 1% or 99% respectively of the test population) are occasionally used for
specific purposes.[3]
1. The Human Memory, 2019. Antagonists. [online] Available at: <www.human-
memory.net/antagonists/> [Accessed 12 April 2020].
2. Simmons, Mark, A., 2011. Pharmacology: an illustrated review. New York: Thieme
Medical Publishers, Inc.
3. AIDS info, 2020. HIV/AIDS Glossary. [online] Available at:
<www.aidsinfo.nih.gov/understanding-hiv-aids/glossary/865/therapeutic-index/>
[Accessed 13 April 2020].
4. Walters P.V., 2012. Going further than Lipinski's rule in drug design, Expert Opinion
on Drug Discovery, 7(2), pp. 99 – 107.
5. TUSOM Pharmwiki, 2019. Basic Principles of Pharmacology. Available at: <www.
tmedweb.tulane.edu/pharmwiki/doku.php/basic_principles_of_pharm/> [Accesed on
16 April 2020].
6. P. Rang, M.M. Dale, and J. M. Ritter, 2012. Adapted from Pharmacology, third
edition. Churchville Livingstone, Inc.
7. Travers AH, Milan SJ, Jones AP., 2012. Addition of intravenous beta(2)-agonists to
inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev;
12:CD010179.
8. Messerli, F.H., 2018. Angiotensin-Converting Enzyme Inhibitors in Hypertension,
13(71), pp. 1475-1481.
9. Concept Clear. 2020. Factors affecting drug metabolism – biotransformation [Online]
Available at: <www.conceptclear.in/factors-affecting-drug-metabolism-biotransformation/
10. Timbrell, J,A., 1995. Introduction to Toxicology, London, Taylor and Francis.
11.