Lecture 58 – Drugs in Clinical Practice Flashcards
Drug definition
A drug is a natural or synthetic substance that affects biological function or structure when administer to the human body
Pharmacogenetics
Individual drug response determined by phenotype
Glyceral trinitrate spray
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
How does vasodilation occur
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
Glyceryl trinitrate pharmacologic principles
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
First pass effect
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
Aspirin
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
heart surgery
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
Modern anaesthesia: propofol
o Hypothesized to target many CNS sites including GABA receptor
o Intravenous infusion by microprocessor-controlled syringe
o Automatically achieves target concentration within plasma
Propofol pharmacologic principles
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
Muscle relaxation – Curare
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
Structure function – NMJ
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
Curare blocks nicotinic receptor
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
Curare: pharmacologic principles
o Competitive antagonism
o Intravenous administration
o Structure-activity relationship SAR
o Drug design of modern compounds
Autonomic control of the heart
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
heart rate - HBS
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).
Autonomic effect on pacemaker cell
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
Biopharmaceuticals
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
Ropivacaine pharmacologic principles
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
Pain pathways during labour
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
Nitric oxide and labour
o Labour is painful Inhalational nitrous oxide commonly used
o Opioids have limited use, cross placenta - cause fetal respiratory depression
Opioid receptor – GPCR
o Distribution throughout CNS
o Primary site spinal cord
o Pre-synaptic action decreases neurotransmitter release
o Post-synaptic action hyperpolarises membrane
GPCR pharmacological principles
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
Propranolol – β1 Adrenoreceptor antagonist
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
Atropine – anticholinergic
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
