Pharmacology

Question 1

Distinguish between absolute and relative risk

Answer 1

absolute risk - the proportion who are/will be affected

relative risk - the ratio of that proportion in one population to the same proportion in another

Question 2

Define, calculate and interpret number needed to treat and number needed to harm

Answer 2

This is the number of patients who must be treated in order to prevent one adverse event. It is referred to as the number needed to harm (NNH) if the treatment is harmful.

NNT/NNH = 1/(Absolute value of risk difference expressed as a proportion).

Question 3

Discuss how variations in the communication of risk can alter the perception of that risk

Answer 3

Whether or not you frame a risk in a positive or negative way can impact how a patient perceives the risk. It remains controversial if the way risk is presented impacts a patient’s decisions. It is agreed that it is best to present risk in multiple ways to maximise patient understanding.

Question 4

Describe three therapeutic uses of agents which act directly as adrenoceptor agonists.

Answer 4

• adrenaline in anaphalactic shock and cardiac arrest

- beta 2 adrenoceptor agonists in asthma

Question 5

Explain the cellular basis of the action of beta-adrenoceptors on smooth muscle

Answer 5

The beta-adrenoceptor is a G(s)-protein-coupled receptor and its activation elevates smooth muscle cAMP

Question 6

Describe three therapeutic uses of adrenoceptor antagonists.

Answer 6

• propanolol to treat ischaemic heart disease
• tamsulosin to treat benign prostatic hypertrophy
• atenolol to treat ischaemic heart disease in asthmatics

Question 7

Describe how sympathomimetics enhance sympathetic function

Answer 7

Like the sympathetic nerves innervating the heart, sympathomimetics stimulate the heart through activation of beta-adrenoceptors, and sympathomimetics cause vascular smooth muscle contraction and vasoconstriction through activation of alpha-adrenoceptors.

Question 8

State the definition of an agonist, a partial agonist and an antagonist.

Answer 8

agonist - activate receptors, full affinity and efficacy
partial agonist - full affinity but only have partial efficacy
antagonist - block receptors, full affinity, no efficacy

Question 9

Identify cellular proteins which are common targets for drugs.

Answer 9

ion channels, enzymes, transporters or pumps, DNA

Question 10

Recognise that the British National Formulary is the essential advice for prescription of drugs.

Answer 10

it gives information on when to use and when not to use a drug, dosage, who can/can’t take it, side effects.

Question 11

Define competitive and noncompetitive antagonism, and indicate, on appropriate graphs, how these may be distinguished.

Answer 11

Many receptor antagonists are competitive and reversible. In these cases, inhibition by the antagonist is surmountable with increasing agonist concentration. Agonist potency (EC50) is reduced in the presence of antagonist, but not its maximum response (Rmax).

Non-competitive antagonists bind at a different (allosteric) site from the agonist on the receptor. There is a reduced Rmax and the effects on responses are non-surmountable.

Question 12

Describe what is meant by the terms efficacy and affinity .

Answer 12

Affinity is the ability of a drug to bind its receptor. Efficacy is the ability of a drug, once bound, to activate the receptor by a conformational change.

Question 13

Explain the concepts of drug selectivity and of drug interactions.

Answer 13

The drugs then interact with cells or tissues where they produce their intended effects (target sites). This interaction is called selectivity.

Question 14

Describe the relationship between drug dose and response, and between log (drug dose) and response.

Answer 14

it is a logarithmic relationship

Question 15

Describe the different classes of sensory receptor.

Answer 15

The sensory systems we possess are visual, auditory, vestibular (balance), olfactory (smell), gustatory (taste), and somatosensory (touch, heat, pain). Sight, sound and balance have receptors which are specialised cells. Taste, touch and pain have modified nerve systems.

Question 16

Describe the molecular and electrical events that underlie mechanotransduction in relation to touch/vibration.

Answer 16

Transduction converts mechanical stimuli to action potentials. This is done by ion-channel events - specially, the mechanosensitive Na+ channel. This is tethered to the cytoplasm by cytoskeletal anchorage. A graded potential is proportional to the amount of pressure applied.

Question 17

Explain the concepts of ‘signal transduction’, ‘adaptation’ and ‘sensitisation’.

Answer 17

• Sensitivity is the ability to encode and detect a wide range of stimuli strengths (high sensitivity).
• Adaptation is a temporal change in output in response to stimulus.
• Signal transduction (also known as cell signaling) is the transmission of molecular signals from a cell’s exterior to its interior.

Question 18

State how local anaesthetics block signal transmission from pain/sensory receptors.

Answer 18

Local anesthetics block nervous conduction at the level of the action potential.

Question 19

Describe the role of polarity in dictating the way in which local anaesthetics work.

Answer 19

Local anaesthetics are weak bases in an acidic solution. They block voltage-gated Na+ channels and act internally at the inner face of the channel. This blocks action potential conduction. They are ionised at physiological pH. However, polar molecules are membrane impermeable and action is pH dependent.

Question 20

Demonstrate knowledge of clinical uses of local anaesthetics.

Answer 20

Its main uses are dental, minor surgery, injection sites, and mild inflammatory pain. There is a limited region of block, such as the nerve trunk. It is not general, which is used in major operations.

Question 21

Describe the basic structure of the autonomic nervous system. Explain the main physiological functions of the sympathetic and parasympathetic branches of the autonomic nervous system.

Answer 21

• The autonomic nervous system is involuntary and things that we have no control over.
• the ANS is made of the sympathetic nervous system which is responsible for fight or flight, and the parasympathetic nervous system which is responsible for rest and digest.

Question 22

State the principal neurotransmitters that the sympathetic and parasympathetic branches of the autonomic nervous system use.

Answer 22

parasympathetic - acetylcholine

sympathetic - noradrenaline

Question 23

Compare the sources in the CNS of sympathetic and parasympathetic outflow.

Answer 23

sympathetic - spinal cord

parasympathetic - cranio-sacral

Question 24

State the mechanisms underlying muscarinic receptor function.

Answer 24

M3 is glandular and increases Ca2+. It is involved in exocrine secretion and smooth muscle contraction. M2 is cardiac and decreases both cAMP and PKA. This lowers the phosphorylation of Ca2+ channels and inactivates Ca2+ channels.

M2 can also activate K+ channels, which hyperpolarizes the membrane potential and decreases Ca2+ channel activity. These effects combine to decrease the rate of cardiac muscle contraction: bradycardia. M1 is neural and has various actions.

Question 25

Describe some therapeutic uses of muscarinic agonists.

Answer 25

glaucoma is ophthalmic use of muscarinic agonist pilocarpine. Glaucoma causes tunnel vision and blindness, and affects 2% of the population over 40. A buildup of intraocular pressure compresses the optic nerve. It can be treated with an M3 agonist, pilocarpine to promote miosis. This is done to help the constriction of circular muscle, opens up a drainage channel, decreases aqueous humour drainage and decreases intraocular pressure.

Question 26

Describe some therapeutic uses of muscarinic antagonists.

Answer 26

This is the autonomic reflex arc with a higher functional override. Loss of higher control leads to incontinence. This can happen in multiple sclerosis and iabetic neuropathy. Incontinence affects around 6 million people in Britain. Antagonists are used to inhibit the reflex arc at the target organ with M3 receptors. There is a limit due to CNS side effects.

Question 27

Explain the actions of anticholinesterases on muscarinic neurotransmission

Answer 27

Acetylcholinesterase (AChE), also known as cholinesterase. It is located at the pre and postsynaptic membranes. It hydrolyses acetylcholine to acetate and choline. There is a rapid termination of ACh action and choline is recycled for ACh synthesis. Anticholinesterases generally affect all cholinergic neurotransmissions. They act to block AChE, prolong and elevate ACh at receptors. They are indirectly-acting parasympathomimetics.

Question 28

Indicate the advantages and problems associated with drug administration via the common routes (oral, i.v., i.m.)

Answer 28

oral - easy, convenient, economical, safer, requires patient cooperation and compliance. intravenously - rapid effects, suitable for large volumes, increased risk of adverse effects, not suitable for insoluble substances intramuscularly - can be prompt or slow and sustained, suitable for oily and some irritating substances, painful, danger of damage if injected at the incorrect site.

Question 29

Give examples of drugs administered by other routes, and the reasons for choice of such routes

Answer 29

subcutaneous - used for insulin, most effective way of absorption topically, such as cream and eye drops inhalation for asthmatics.

Question 30

Give instances where incorrect route or accidental misdirection of a dose may be damaging to a patient

Answer 30

vincristine - only injected intravenously, fatal if used intrathecally.

Question 31

Describe the terms ‘therapeutic window’ and ‘therapeutic range’

Answer 31

- The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. - The therapeutic range of a drug is the dosage range or blood plasma or serum concentration usually expected to achieve the desired therapeutic effect.

Question 32

Describe the relationship between plasma level and therapeutic response

Answer 32

directly proportional

Question 33

List three reasons why there may be no simple relationship between plasma level of parent drug and magnitude of the therapeutic response

Answer 33

This is assumed to be true in vivo, but we must use blood levels as an approximation of concentration at the site of action. This is demonstrable for most drugs.

Question 34

Define the terms ‘clearance’ (CL), half-life’ (t½), volume of distribution’ (V), and ‘area under the curve’ (AUC) as they relate to drug kinetics

Answer 34

clearance - the volume of plasma cleared of a drug in unit time half life - the time it takes for the concentration to decrease by 50% Vd - the apparent volume in which a drug is dissolved in the body area under curve - the area under the plot of plasma concentration of a drug versus time after dosage (called “area under the curve” or AUC) gives insight into the extent of exposure to a drug and its clearance rate from the body

Question 35

Define the term ‘first-pass effect’ and understand its relationship to organ extraction

Answer 35

The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation.

Question 36

Understand the basic principles of toxicology (xenobiotic, toxic response), and associated glossary of terms

Answer 36

Xenobiotic – any foreign substance to our body (opposite to endobiotic). Toxic agent –agent that can cause toxicity (eg. chemical or physical agents). Poisons – agents that produce toxicity or even death, generally at low doses (e.g. botulinum toxin). Toxin – toxic compounds produced by biological systems (e.g. phytotoxins of plants, mycotoxins of fungi, etc.). Intoxication – when a compound reaches values above the safe maximum dose. Toxic syndrome/toxidrome - constellation of toxic effects comprising a set of clinical fingerprints for a group of toxic chemicals (e.g. cholinergic)

Question 37

Understand classification of xenobiotics, and major routes and durations of exposures

Answer 37

can be classified by target organ, according to use in public domain, according to source, according to effects, according to phyiscal state and according to biochemical properties. major routes: oral, intranasal, inhalation, parentenal. duration of exposure: acute, subacute, chronic, subchronic.

Question 38

Consider toxic effects upon target organs

Answer 38

The effects could be allergic, hypersensitivity, local or systemic, idiosyncratic, reversible or irreversible, immediate or delayed. Chemical interactions can be agonistic, antagonistic, potentiation or synergistic, or additive.

Question 39

Understand the principles and description of graded and quantal dose-responses, therapeutic index, ED50, TD50, LD50, IC50, and NOAEL and LOAEL values

Answer 39

A graded dose response is the relationship of an individual test subject or system to an increasing and/or continuous dose of a chemical. A quantal dose response is determined by the distribution of responses to increasing doses in a population of test subjects or systems. Generally classified as an all or nothing effect, where the test system or organisms are quantified as either responders or non-responders. The therapeutic dose is known as the ED50. it is the median effective dose. This is the dose that produces an effective dose (quantal effect) in 50% of the population that takes it. The toxic dose, TD50, is the median toxic dose. It is the dose at which toxicity occurs in 50% of the population that takes it. The lethal dose, LD50, is the dose that causes death in 50% of the animals tested. The therapeutic window is the values between the ED50 and TD50. The IC50 concentration is the inhibitory concentration. This is the concentration necessary to inhibit 50% of a measured response in an in vitro system. This allows for comparisons of concentrations necessary to inhibit any measurable parameter. The threshold dose is the point at which toxicity first appears. It is the highest concentration beyond which adverse effects are witnessed. NOAEL is the no observed adverse effect level. LOAEL is the lowest observed adverse effect level. This is the lowest concentration or amount of a substance that causes an adverse effect.