Week 10 Pharmacology - Anti-Arrhythmics and Inotropes

Question 1

According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 1 drugs, and examples?

Answer 1

Ia: Procainamide, Quinidine, TCAs
Ib: Lignocaine
Ic: Flecainide

Question 2

What is the effect of class 1a drugs?

Answer 2

Lengthen action potential

Question 3

What is the effect of class Ib drugs?

Answer 3

Shorten action potential

Question 4

What is effect of class Ic drugs?

Answer 4

No effect on action potential

Question 5

According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 2 drugs, and examples?

Answer 5

Beta blockers: metoprolol, bisoprolol, atenolol

Question 6

According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 3 drugs, and examples?

Answer 6

Potassium channel blockers: amiodarone, sotalol (also class II) bretylium

Question 7

According to Vaughn-Williams classification for anti-arrhythmic drugs: What are class 4 drugs, and examples?

Answer 7

Calcium channel blockers, verapamil

Question 8

What are the unclassified anti-arrhythmic drugs in the system?

Answer 8

Adenosine, digoxin, magnesium

Question 9

What is the mechanism of action of digoxin?

Answer 9

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.

Question 10

What are the pharmacokinetics of digoxin?

Answer 10

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

Question 11

What are some adverse/toxic effects of digoxin?

Answer 11

Arrhythmias: AV junctional rhythm, VT, AV blocks
Anorexia, nausea, vomiting, diarrhoea
Disorientation, hallucinations, visual disturbances

Question 12

What effect does potassium levels have on digoxin?

Answer 12

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.

Question 13

What is the mechanism of action of adenosine?

Answer 13

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.

Question 14

What is the the half life of adenosine?

Answer 14

<10 seconds

Question 15

What common ‘adenosine receptor blockers’ can reduce the efficacy of adenosine?

Answer 15

Caffeine
Theophylline

Question 16

Describe the metabolism and excretion of adenosine:

Answer 16

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.

Question 17

What types of drugs predominantly work on nodal tissue to exert anti-arrhythmic effects?

Answer 17

Beta blockers
Calcium channel blockers
Digoxin
Adenosine
Amiodarone

Question 18

What is the mechanism of action of calcium channel blockers?

Answer 18

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

Question 19

What action does B1 AGONISM usually have on conductile cardiac cells?

Answer 19

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

Question 20

What effect do beta-blockers have on pacemaker potential?

Answer 20

Reduced opening of Ca2+ channels on pacemaker membrane, leading to decreased slope of phase 4 and 0, reducing heart rate and contractility

Question 21

What effect do potassium channel blockers have on the myocyte action potential?

Answer 21

Blocks potassium channels during phases 1, 2 and 3

Effect of this is lengthening of the plateau phase, and lengthening of phase 3 (repolarisation)

Question 22

What is the mechanism of amiodarone?

Answer 22

Blocks potassium channels responsible for phase 3 repolarization, delaying repolarisation and increasing effective refractory period (ERP).

Question 23

Pharmacokinetics of amiodarone?

Answer 23

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

Question 24

What is the effect of alpha 1 receptors?

Answer 24

Vascular vasoconstriction

Question 25

What is the effect of B2 receptors?

Answer 25

Vascular vasodilation

Question 26

What is the effect of B1 receptors?

Answer 26

Cardiac stimulation/heart rate

Question 27

What is the receptor profile of noradrenaline?

Answer 27

Significant alpha 1 agonism
Beta 1 agonism (slightly less than adrenaline)
Less B2 agonism, therefore net effect strongly vasoconstrictive

Question 28

What is the receptor profile of adrenaline?

Answer 28

Increased B1 agonism compared to noradrenaline
More even agonism between B2 and alpha 1, therefore ratio is less strongly in favour of vasoconstriction

Question 29

What is the receptor profile of dopamine?

Answer 29

Strong beta 1 and alpha 1 receptor agonism, minimal/no beta 2 activity

Question 30

What is the major difference between dobutamine and dopamine?

Answer 30

Dobutamine more strongly B1 activity, with minimal alpha 1 effects