general pharmacology

Question 1

. Agonists
In the context of drug-receptor interactions, what is the difference between a full
agonist and a partial agonist?

Answer 1

High concentrations of full agonists can evoke a maximal response, whereas partial
agonists cannot evoke a maximal response at any concentration

Question 2

Under what circumstances can a partial agonist act as an antagonist?

Answer 2

In the presence of a full agonist, a partial agonist can act as an antagonist.
Buprenorphine is an example of this.

Question 3

In relation to drug responses, what is the EC50?

Answer 3

The concentration at which an agonist produces half of its maximal effect

Question 4

What are spare receptors?

Answer 4

The concentration of agonist producing the maximal response may not result in
occupancy of a full complement of receptors
These receptors are said to be “spare”

Question 5

What are the 2 main mechanisms of receptors becoming spare?

Answer 5

Temporal spares - the receptor triggers a prolonged response after transient binding
Numerical spares - limited substrate with excess receptors

Question 6

What is the significance of spare receptors?

Answer 6

Increasing the number of receptors coupled to an effector can allow a lower
concentration of agonist to still produce a given proportion of maximal response. This
means the tissue is more sensitive

Question 7

Antagonists
What is an antagonist?

Answer 7

Competitive - competes with the agonist for the active site by binding at the same place
as the agonist. Increasing concentration of agonist will produce the given effect.

Non-competitive or irreversible can bind in such a way that the receptor is no longer
available for binding, either by modifying the active site or by binding with stronger
bonds. In this case, the duration of effect depends on the turnover of receptor-antagonist
molecules and the effect cannot be overcome by increasing concentrations of agonist

Question 8

What effect does a competitive antagonist have on the concentration-effect curve?

Answer 8

Shifts the curve to the right, because higher concentrations of agonist can overcome a
competitive antagonist. The EC50 is increased.

Question 9

What effect does an irreversible antagonist have on the concentration-effect
curve?

Answer 9

Reduced maximal effect
The EC50 may be the same or different

Question 10

Can you define potency?

Answer 10

● Potency refers to the affinity or attraction between an agonist and its receptor and
the amount of a drug required to produce an effect of a certain intensity
● Refers to the concentration (EC50) or the dose (ED50) of a drug required to
produce 50% of that drugs maximal effect.
● Dependent on affinity of a drug for its receptor and the number of receptors
available

Question 11

Can you define efficacy?

Answer 11

● Efficacy is the maximal effect a drug (agonist) can produce (Emax) when all
receptors are occupied, irrespective of the concentration or dose required to
produce that response
● Determined by the drugs mode of interactions with receptors or by characteristics
of the receptor-effector system involved

Question 12

Can you please show the difference between efficacy and potency by drawing
dose response curves

Answer 12

● Graph has dose on the x-axis and response on the y- axis
● Curves are sigmoid or S-shaped
● A curve that is further to the left will have greater potency because less of the
drug is required for the effect
● A curve that is the tallest (or has the greatest y-value) has a greater efficacy
because the y-axis measures the response, regardless of dose required to get
there

Question 13

What factors affect a drugs efficacy?

Answer 13

● Affinity of receptor for drug
● Drug/receptor interaction
● Route of administration, absorption, distribution through the body and the
clearance of the drug from the blood or site of action

Question 14

Secondary Messengers
In reference to drug action, what is a second messenger?

Answer 14

A second messenger is a method of transmembrane signalling. It is an intracellular
substance which has its concentration altered by a process that is initiated by an
extracellular ligand. The second messenger then acts to facilitate an intracellular process

Question 15

What are the steps in action of a drug via a second messenger?

Answer 15

● The drug binds to a receptor on the extracellular side of the plasma membrane
● Triggers the activation of G protein on cytoplasmic side
● Activated G protein changes an enzyme ion channel
● This changes the concentration of intracellular second messenger which
mediates the response

Question 16

Can you give an example of a second messenger and the type of response it
produces?

Answer 16

cAMP - via adenylate cyclase, causes:
● Mobilisation of fat and carbohydrates
● Conservation of water by the kidney
● Increased rate and contractility of the heart
● Calcium regulation
● Adrenal hormone regulation
● Relaxation of smooth muscle
Other second messengers include:
● Calcium and phosphoinositides (which is the name for a family of acidic
phospholipids in cell membranes)
● cGMP - via transmembrane guanylyl cyclase

Question 17

Can you give and example of a drug that acts via this second messenger system?

Answer 17

Beta agonists - which act via Gs proteins attached to B-adrenoreceptor and cause
increased intracellular cAMP
Other examples include glucagon, thyrotropin, histamine, serotonin, acetylcholine and
opioids

Question 18

Pharmacokinetics
5. Absorption
What variables influence the extent and rate which a drug is absorbed?

Answer 18

● Route of administration
● Nature of the absorbing surface including the cell membrane i.e. single epithelial
layer in the GIT va layers of skin cells, and the surface area of absorption in the
stomach/small intestine etc
● Blood flow to the area of absorption
● Drug solubility i.e. lipid solubility
● Drug formulation - i.e. the presence of enteric coating

Question 19

Explain why aspirin absorption is enhanced by low pH in the stomach?

Answer 19

Aspirin is an acidic drug with a low pKA, which means it is relatively un-ionised in the
stomach and therefore more soluble here so is absorbed more readily here.

Question 20

How does the ionisation of a drug affect its solubility?

Answer 20

Drugs exist as weak acids or weak bases and in the body they are either ionised or
un-ionised. Ionised are water soluble and un-ionized are more lipid soluble,

Question 21

What are the disadvantages of rectal drug administration ?

Answer 21

● Erratic absorption due to contents in the rectum
● 50% first pass metabolism
● Local irritation
● Uncertainty of drug retention

Question 22

What is bioavailability?

Answer 22

The fraction of unchanged drug reaching the systemic circulation following administration
by any route.

Question 23

What factors affect bioavailability?

Answer 23

● Extent of absorption - drug properties, reverse transporters, gut wall metabolism
● First pass metabolism - where drug is removed by the liver
● Rate of absorption - determined by site of administration and drug formulation

Question 24

What is first pass metabolism?

Answer 24

● After the absorption of orally ingested drug, the portal blood delivers the drug to
the liver
● It can be metabolised in the liver, in the gut and in the portal system before
reaching the systemic circulation
● This reduces the bioavailability of the drug

Question 25

Can you increase a drug’s bioavailability? Give an example

Answer 25

● Change the route of administration - IV, IM, SC, SL, inhalational or transdermal
can avoid first pass metabolism. PR administration can still have 50% first pass
metabolism
● Change the drugs properties - to increase the absorption by making it more
hydrophilic or lipophilic, using a prodrug
● Increase the dose

Question 26

What is the bioavailability of ibuprofen?

Answer 26

It is high. Ibuprofen is a weak organic acid, well absorbed orally and has minimal first
pass metabolism

Question 26

Distribution
Define the volume of distribution of a drug

Answer 26

Defined as the volume in which the amount of drug in the body would need to be
uniformly distributed to produced the observed concentration in blood, plasma or water

Question 27

What factors affect the Vd?

Answer 27

● Drug properties - lipid solubility, pKa, pH, protein binding
● Patient factors - age, sex, disease state, body composition, blood flow

Question 28

How is it possible for a drug to have a Vd of 2500L in an adult?

Answer 28

Higher concentration in extravascular tissues than in the blood - example being lipid
soluble medications that are not homogeneously distributed

Question 29

Give some examples of drugs with high and low volumes of distribution

Answer 29

High - morphine, digoxin, clonidine, beta blockers, diazepam
Low (approx TBW) - aspirin, frusemide, most antibiotics, warfarin

Question 30

What is the relevance of Vd in overdose?

Answer 30

Drugs with a high Vd cannot be dialysed off because most has left the circulation. Those
with a low Vd (i.e. lithium) can be

Question 31

Metabolism & biotransformation
What factors are responsible for differences in drug metabolism between
individuals?

Answer 31

● Genetic - enzyme deficiencies or super metabolisers
● Diet & environmental - exposure to enzyme inducers
● Age and sex - men have an increased metabolic rate, extremes of age have
decreased enzyme activity
● Drug interactions - enzyme induction or inhibition
● Disease states - liver function, thyroid state

Question 32

What is drug biotransformation?

Answer 32

The process of drug metabolism which allows drugs to become inactive or increases
excretion by making them more hydrophilic or by metabolising them to a less active
agent.

Question 33

What are the main sites of biotransformation?

Answer 33

● Liver
● GIT
● Skin
● Kidneys

Question 34

What is the role of the cytochrome P450 enzymes?

Answer 34

● These are part of the biotransformation system to detoxify drugs/substrates.
● They act by oxidation (phase 1 reaction) and make substances easier to
conjugate
● Located on the smooth ER

Question 35

Describe phase 1 and phase 2 reactions

Answer 35

● Phase 1 - unmasking the sunctional group (-OH, -NH2, -SH) to become a more
polar metabolite, induced oxidation, deamination, hydrolysis, reductions
● Phase 2 - conjugation with endogenous substrate to become highly polar
Note - phase 1 and 2 can occur alone, sequentially or simultaneously. The metabolites
can be more active or toxic then the parent drugs.

Question 36

How is suxamethonium metabolised?

Answer 36

Rapid phase 1 hydrolysis by butyryl-cholinesterase and pseudocholinesterase in the liver
and plasma

Question 37

Why might a patient have a prolonged paralysis following sux use?

Answer 37

Patients who have a genetic deficiency in butyryl-cholinesterase have a slower
metabolism

Question 38

What is meant by the term enzyme induction ?

Answer 38

Drugs can cause an increased rate of synthesis or decreased rate of degradation of
some enzymes leading to accelerated substrate metabolism. This can lead to decreased
pharmacological action of the co-administered drug.

Question 39

Clearance
What is drug clearance?

Answer 39

Measure of the availability of the body to eliminate a drug. Rate of elimination in relation
to the concentration of the drug or volume of plasma cleared of the drug per unit time.
Note: elimination and clearance can be referred to as the same thing but there are
different questions in the past papers for these topics. Elimination of a drug is used to
describe the “irreversible removal of the drug from the body” and clearance is
defined as above, being the “volume of fluid cleared of drug per unit time”

Question 40

What factors affect clearance?

Answer 40

● Concentration - which depends on the dose/bioavailability
● Elimination - which depends on specific organ function, blood flow, protein
binding. Major sites of elimination are the kidneys and liver - therefore factors that
affect these organs function and blood flow will have the most effect

Question 41

What is the difference between capacity limited and flow dependent drug
elimination?

Answer 41

● Capacity limited - is saturable (zero order) where clearance varies depending on
the drug concentration. E.g. aspirin, phenytoin, ethanol
● Flow dependent - is not saturable (1st order) - where most of the drug is cleared
by the 1st pass of blood through an organ so elimination depends on the rate of
drug delivery to the organ and thus on blood flow. Plasma protein binding may
also have a small role. E.g amitriptyline, labetalol, morphine, verapamil,
lignocaine

Question 42

What factors affect renal clearance?

Answer 42

● Renal function
● Renal blood flow
● Plasma protein binding

Question 43

What are some drugs that are predominantly cleared by the kidneys?

Answer 43

Gentamicin (the main one to mention), vancomycin, digoxin, ampicillin

Question 44

Elimination
Define elimination half life

Answer 44

The time taken to change the amount of drug in the body by half during elimination
T1/2 = 0.7 x Vd/Clearance

Question 45

How does knowing a drugs half life help us clinically?

Answer 45

Aids in dosing regimen planning, identifies timelines in overdose and can help establish
time to steady state after dose change

Question 46

What disease states can affect the elimination half life?

Answer 46

Liver, renal, cardiac disease

Question 47

What is first order elimination kinetics?

Answer 47

A constant fraction or percentage of the drug is eliminated per unit time. Rate of
elimination is proportional to the amount of drug in the body. Half life remains constant.
Most drugs are eliminated this way.

Question 48

How does this differ to zero order kinetics?

Answer 48

With zero order, a constant amount of drug is eliminated per unit time, rate of elimination
is constant and is independent of drug concentration. In overdose the half life will be
prolonged. Examples - ethanol, phenytoin, salicylates