Week 10 Pharmacology - Anti-Arrhythmics and Inotropes Flashcards
According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 1 drugs, and examples?
Ia: Procainamide, Quinidine, TCAs
Ib: Lignocaine
Ic: Flecainide
What is the effect of class 1a drugs?
Lengthen action potential
What is the effect of class Ib drugs?
Shorten action potential
What is effect of class Ic drugs?
No effect on action potential
According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 2 drugs, and examples?
Beta blockers: metoprolol, bisoprolol, atenolol
According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 3 drugs, and examples?
Potassium channel blockers: amiodarone, sotalol (also class II) bretylium
According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 4 drugs, and examples?
Calcium channel blockers, verapamil
What are the unclassified anti-arrhythmic drugs in the system?
Adenosine, digoxin, magnesium
What is the mechanism of action of digoxin?
Inhibits Na+ K+ ATPase (by binding the K+ site on the pump), which leads to increased intracellular sodium, and increased activity of Na+/Ca2+ anti porter, which causes increased intracellular Calcium –> increased myocardial contractility. Also acts to potentiate vagal tone and increase K+ efflux through muscarinic GPCR activity on K+ channel opening.
What are the pharmacokinetics of digoxin?
A: 65-80% oral bioavailability
D: Wide Vd, 6.3L
M: Long T1/2, 40 hrs, clearance proportional to Cr clearance, minimal liver metabolism
E: 2/3 excreted unchanged by kidneys, partially excreted in bile
What are some adverse/toxic effects of digoxin?
Arrhythmias: AV junctional rhythm, VT, AV blocks
Anorexia, nausea, vomiting, diarrhoea
Disorientation, hallucinations, visual disturbances
What effect does potassium levels have on digoxin?
Digoxin competes with K+ for binding site on ATPase pump.
Therefore, low K+ will lead to decreased competition for binding and increased digoxin action.
High K+ will decrease the efficacy of digoxin for the same reason.
What is the mechanism of action of adenosine?
Adenosine is a naturally occurring nucleotide, which has a receptor on nodal tissue. It binds to adenosine receptor, a GPCR, which has 3 subunits. Gamma subunit acts on K+ channels, causing K+ efflux leading to hyperpolarisation –> prolongation of phase 4 (funny current) of pacemaker cells. Also small effect of inhibiting L-type calcium channels through inhibition of adenylate cyclase.
What is the the half life of adenosine?
<10 seconds
What common ‘adenosine receptor blockers’ can reduce the efficacy of adenosine?
Caffeine
Theophylline
Describe the metabolism and excretion of adenosine:
Adenosine rapidly transported into red blood cells (and other cell types) where it is rapidly deaminated by adenosine deaminase to inosine, then further broken down to hypoxanthine, xanthine, and uric acid which is excreted by the kidneys. Adenosine deamination also occurs in plasma, but at a lower rate than that which occurs within cells.
What types of drugs predominantly work on nodal tissue to exert anti-arrhythmic effects?
Beta blockers
Calcium channel blockers
Digoxin
Adenosine
Amiodarone
What is the mechanism of action of calcium channel blockers?
Block L-type calcium channels on nodal tissue, leading to decreased Ca2+ influx during phase 4 and phase 0, which will lead to shallower phase 4 and phase 0 slopes, slowing conduction and therefore heart rate
What action does B1 AGONISM usually have on conductile cardiac cells?
GPCR –> G -stimulatory protein –> activation of adenylate cyclase –> cAMP and PHA –> phosphorylation of L-type calcium channels and increased calcium conduction, therefore increased speed of action potentials
What effect do beta-blockers have on pacemaker potential?
Reduced opening of Ca2+ channels on pacemaker membrane, leading to decreased slope of phase 4 and 0, reducing heart rate and contractility
What effect do potassium channel blockers have on the myocyte action potential?
Blocks potassium channels during phases 1, 2 and 3
Effect of this is lengthening of the plateau phase, and lengthening of phase 3 (repolarisation)
What is the mechanism of amiodarone?
Blocks potassium channels responsible for phase 3 repolarization, delaying repolarisation and increasing effective refractory period (ERP).
Pharmacokinetics of amiodarone?
A: variable/erratic oral absorption, 20-80%
D: very lipophilic, very wide Vd, 65L, t1/2 up to 114 days
M: Liver metabolism
E: Biliary/GI tract excretion primarily
What is the effect of alpha 1 receptors?
Vascular vasoconstriction
What is the effect of B2 receptors?
Vascular vasodilation
What is the effect of B1 receptors?
Cardiac stimulation/heart rate
What is the receptor profile of noradrenaline?
Significant alpha 1 agonism
Beta 1 agonism (slightly less than adrenaline)
Less B2 agonism, therefore net effect strongly vasoconstrictive
What is the receptor profile of adrenaline?
Increased B1 agonism compared to noradrenaline
More even agonism between B2 and alpha 1, therefore ratio is less strongly in favour of vasoconstriction
What is the receptor profile of dopamine?
Strong beta 1 and alpha 1 receptor agonism, minimal/no beta 2 activity
What is the major difference between dobutamine and dopamine?
Dobutamine more strongly B1 activity, with minimal alpha 1 effects
