Lecture 58 – Drugs in Clinical Practice

Question 1

Drug definition

Answer 1

A drug is a natural or synthetic substance that affects biological function or structure when administer to the human body

Question 2

Pharmacogenetics

Answer 2

Individual drug response determined by phenotype

Question 3

Glyceral trinitrate spray

Answer 3

o Class: rapidly acting nitrate
o Action: coronary artery vasodilation, flow redistribution to ischaemic heart, venodilation
o Effect: relief of anginal chest pain
o Delivery: sublingual spray, or tablet
o Metabolism: hepatic, half-life of 1.5 mins

Question 4

How does vasodilation occur

Answer 4

o Glutathione S-transferase in vascular smooth muscle acts on GTN
o Release of nitrite ion and conversion to nitric oxide
o Activation of guanylyl cyclase enzyme increases cGMP
o Dephosphorylation of myosin light chain
o Vasodilation

Question 5

Glyceryl trinitrate pharmacologic principles

Answer 5

o HSF : vascular reactivity
o Transmucosal administration
o A pro-drug converted to nitric oxide
o Specific biological target - sGC enzyme
o High first pass effect

Question 6

First pass effect

Answer 6

o Hepatic metabolism is high for GTN and decreases amount of drug reaching systemic circulation when given orally
o Oral bioavailability is therefore low
o Sublingual or transdermal administration avoids the first pass effect

Question 7

Aspirin

Answer 7

o Class: acetyl salicylate
o Action: binds irreversibly to platelet cyclooxygenase enzyme Inhibits prostaglandin synthesis, preventing platelet aggregation
o Inhibits clot formation within coronary vessel
o Antiplatelet therapy improves survival in AMI

Question 8

heart surgery

Answer 8

o Specialised pharmacology
o Anaesthesia and monitoring
o Patient must be immobile
o Reflex movement prevents surgical repair
o Heart standstill via heart-lung machine
o Analgesia post-surgery

Question 9

Modern anaesthesia: propofol

Answer 9

o Hypothesized to target many CNS sites including GABA receptor
o Intravenous infusion by microprocessor-controlled syringe
o Automatically achieves target concentration within plasma

Question 10

Propofol pharmacologic principles

Answer 10

o Central compartment represents central blood, brain and liver that receive high proportion of cardiac output
o Rapid equilibration of drug with brain
o Propofol action is determined by rate of infusion, redistribution to secondary compartments and hepatic clearance

Question 11

Muscle relaxation – Curare

Answer 11

o Alkaloid derived from plant species
o Arrow Poison used in hunting
o Active component d-tubocurarine (Boehm 1895)
o Competitive antagonist at nicotinic receptor

Question 12

Structure function – NMJ

Answer 12

o Pre-junctional motor nerve
o Synaptic cleft 20-30 nm wide
o Folded post-junctional membrane
o Neurotransmitter Ach
o Nicotinic pre and post-synaptic membranes

Question 13

Curare blocks nicotinic receptor

Answer 13

o Ligand-gated ion channel
o Ach binds to extracellular domain of alpha subunit
o Curare competively binds and prevents contraction activation
o Abolishes reflex movement during surgery
o Many modern drugs developed

Question 14

Curare: pharmacologic principles

Answer 14

o Competitive antagonism
o Intravenous administration
o Structure-activity relationship SAR
o Drug design of modern compounds

Question 15

Autonomic control of the heart

Answer 15

o Sympathetic tone (noradrenaline)
 heart rate increased
 contractility increased
o Parasympathetic tone (acetylcholine)
 heart rate decreased
o Clinically used drugs:
 β1-adrenoceptor antagonists (β blockers) Anticholinergic drugs

Question 16

heart rate - HBS

Answer 16

o Ventricular muscle cell - membrane depolarisation results from sequential activation of ion channels during phase 1-4.
o Pattern of membrane potential determined by changes in Na, Ca and K conductance
o In the sinoatrial node pacemaker cells spontaneously depolarise during phase 4 due to If Na channel (Phases 1 and 2 are absent).

Question 17

Autonomic effect on pacemaker cell

Answer 17

o Sympathetic tone increases rate of depolarisation (phase 4) and shortens refractory period (via noradrenaline) - increased HR
o Parasympathetic tone decreases rate of depolarisation (phase 4) and lengthens refractory period (via acetylcholine) -slower HR

Question 18

Biopharmaceuticals

Answer 18

o A revolution in therapy
o Biologics - Recombinant protein-based therapeutics, produced by living organisms (plants, animals, yeast, bacteria). Revolutionary treatment for cancer and autoimmune disease

Question 19

Ropivacaine pharmacologic principles

Answer 19

o The hydrophobic aromatic group confers lipid solubility
o The charged lipophilic amide group confers water solubility
o Rapid diffusion in CSF to spinal nerves
o Biological target – neuronal Nav 1.7 channel

Question 20

Pain pathways during labour

Answer 20

o HSF
 Nerves that supply uterus and birth canal.
 Arise from lumbosacral region of spine
o Epidural: injection of drug nerve nerves
 Provides anaesthesia to lower body

Question 21

Nitric oxide and labour

Answer 21

o Labour is painful Inhalational nitrous oxide commonly used
o Opioids have limited use, cross placenta - cause fetal respiratory depression

Question 22

Opioid receptor – GPCR

Answer 22

o Distribution throughout CNS
o Primary site spinal cord
o Pre-synaptic action decreases neurotransmitter release
o Post-synaptic action hyperpolarises membrane

Question 23

GPCR pharmacological principles

Answer 23

o GPCR’s are largest group of membrane surface receptors.
o 7-Transmembrane domain coupled to G protein (α β γ subunits)
o Drug binding initiates a chain reaction that amplifies signal via second messenger
o Immediate cellular response

Question 24

Propranolol – β1 Adrenoreceptor antagonist

Answer 24

o Treatment of tachycardia
o Early β1 blocker - propranolol
o Modification of “catecholamine” structure
o Competitive antagonist at b1-AR - G-Protein Coupled Receptor (GPCR)
o Inhibits sympathetic tone, HR decreased

Question 25

Atropine – anticholinergic

Answer 25

o Treatment of bradycardia
o Plant source “deadly nightshade”
o Blocks Ach receptor site on muscarinic receptor
o Inhibits parasympathetic tone of Vagus
o Increased HR