Digoxin

Question 1

What is the class and chemistry of digoxin

Answer 1

It is an anti-arrhythmic agent

It is a cardiac glycoside derived from the Balkan Foxglove plant

Question 2

How can digoxin be administered

Answer 2

PO - 2 - 3 hours onset of action

IV - immediate onset of action

(theoretically IM too)

Question 3

What is responsible for the portion of digoxin not absorbed

Answer 3

80%

P-glycoprotein (PGP) is an enterocyte efflux pump that secretes digoxin back into the GIT after absorption.

Question 4

Describe the important pharmacokinetics of digoxin especially with relevance to administration to critically ill patients

Answer 4

Hepatic clearance 16%

Kidneys: most of digoxin is excreted by the kidneys unchanged.

Protein bound: 25%

Basically insoluble in water

So overall:

1. High volume of distribution
2. Cleared by kidneys

In the critically ill: often increased Vd (increased third spa

Question 5

Describe the presentation of digoxin with explanation

Answer 5

40% Propylene glycol
10% Ethyl alcohol
50% Distilled water

It has a pKa of 7.15 and is basically insoluble in water.

Question 6

Why is a loading dose required for Digoxin

Answer 6

Because it has a very high volume of distribution 5.1 - 7.4 L/kg. Loading dose is therefore required to achive a steady state concentration in the body fluids within a reasonable time frame.

Further more, the high volume of distribution makes digoxin entirely unsuitable for dialysis

Question 7

Summarise digoxin’s elimination and excretion

Answer 7

1. 16% metabolised in the liver
2. The rest is excreted unchanged in the kidneys
3. Vd 5.1 - 7.4 (HIGH)
4. High lipid solubility

So Elimination t1/2 = 36 - 44 hours

Poor efficacy of dialysis

Question 8

Describe the mechanism of action of Digoxin

Answer 8

INCREASED MYOCARDIAL CONTRACTILITY

1. Na is exchanged for Ca by the Na/Ca exchanger during phase 1 of the action potential.
2. Increased availability of intracellular Na leads to increased subsequent Ca+ entry
3. Increased Ca availability –> increased contractility
4. Na usually pumped out of cell by Na/K ATPase

DIGOXIN BLOCKS Na/K ATPase –> increased IC Na –> increased IC Ca –> increased contractility

ANTIARRHYTHMIC EFFECT (INCREASE VAGAL TONE)

1. AV node blocker (like BB, CCB, Amiodarone)
2. Slowed conduction time through AV node (rate control in AF) but does not change conduction time in HIS (narrow QRS)
3. Mechanisms (Potentiates the PSNS)
   - -> Activate baroreceptors (stimulating vagus)
   - -> Sensitise PSNS ganglia
   - -> Sensitize myocardium to Ach

INCREASED AUTOMATICITY (in pacemaker tissues)

1. Phase 4 of cardiac action potential –> digoxin increases the gradient of the slope of this phase in pacemaker tissues

INCREASED IRRITABILITY (ectopics)

1. Phase 4 of cardiac action potential –> digoxin increases the gradient of the slope of this phase in purkinje fibres

Question 9

Summarise the effects of digoxin on the cardiac action potential

Answer 9

Phase 0 - Lengthened
Phase 1 - shortened
Phase 2 - shortened
Phase 3 - lengthened
Phase 4 - increased slope in pacemaker tissue and purkinje fibres

Question 10

When is digoxin indicated?

Answer 10

1. AF in patients with heart failure
   - -> USA: Digoxin is 2nd line agent (i.e. added to a beta blocker)
   - -> Europe: Digoxin is 1st line for severely volume overloaded or haemodynamically unstable patients, but in combination with amiodarone
2. A possible addition for heart failure
   - -> Consider in symptomatic patients in sinus rhythm to reduce all cause heart failure hospitalizations
   - -> but no effect on mortality

Question 11

Should digoxin be used in the ICU as an inotrope with rate control properties

Answer 11

Other agents are better

Question 12

List the ECG findings characteristic of the digoxin effect vs digoxin toxicity

Answer 12

Digoxin effect

1. Salvadore Dali sagging (reverse tick) ST segments
2. Flat, inverted or biphasic t waves
3. Short QT
4. PR prolonged
5. Prominent U waves / Peaked terminal portion t waves)
6. J point depression

DIGOXIN TOXICITY

1. Supraventricular tachycardia (increased automaticity)
2. Slow ventricular response (AV node block)

Also
PVCs, Sinus brady, 1/2/3rd degree block, Slow AF, Regularized AF, VT, polymorphic and bidirectional VT

Question 13

Why does digoxin have many drug interactions despite having minimal hepatic metabolism

Answer 13

1. Depends on active secretion in renal tubule

2. GIT P-glycoprotein efflux pump (clogged by competing substrates)

Question 14

List the pharmacokinetic and pharmacodynamic drug interactions for digoxin

Answer 14

PHARMACOKINETIC

1. Decrease absorption (Antiacids)
2. Increased absorption
   - -> Amiodarone, verapamil, rifampicin - block PGP efflux
   - -> Macrolides and tetracyline - decr. Gi bacteria metab

PHARMACODYNAMIC

1. Diuretics: decrease Mg and K –> predispose to digoxin toxicity
2. Succinylcholine: ? mechanism –> increased irritability –> VF
3. BB, CCB –> additive AV blockade

Question 15

List the side effects of digoxin

Answer 15

Cardiac

• Bigeminy and ectopics
• Bradycardia + heart block

Non-Cardiac

• N,V
• Visual disturbance
• Delirium and agitation

Question 16

List the characteristic features of severe digoxin toxicity

Answer 16

1. Heart block / asystole
2. Tachyarrhythmias (almost any)
3. Vasoconstriction
4. CNS toxicity (almost any)
5. Hyperkalaemia (Na/K ATPase blocked)

Question 17

Describe the pathophysiology of changing concentrations of potassium on resting membrane potential and nerve excitability

Answer 17

DECREASED POTASSIUM
(State Nernst potential becomes more negative)
–> The [K] in vs [K} gradient is now increased –> more positively charged K exits intracellular space and moves extracellular –> less positive charge inside cell (neuron) –> greater electrical potential difference in vs. out –> hyperpolarisation –> reduced nerve excitability –> weakness, ECG changes, bradycardia.

INCREASE POTASSIUM
Opposite effect to above
–> Increase chance of spontaneous action potentials –> high risk VF.

CALCIUM

• -> Ca+ ensures normal function of Na channels
• -> Low Ca activates Na channels –> this brings the threshold potential more negative and closer to the resting membrane potential –> spontaneous depolarisation of neurons, tetany and paraesthesias.

Also Ca++ administration (in hyperkalaemia) creates a membrane stabilising effect. Ca++ bind glycoproteins on the outside surface of membrane providing increased positive charge directly apposed to the extracellular side of the membrane which causes temporary hyperpolarization of the RMP.

Question 18

What is the surface charge hypothesis and when is it applicable

Answer 18

The administration of Ca++ in hyperkalaemia for ‘membrane stabilisation’. Ca++ attaches to glycoproteins on the extracellular surface of neurons increasing the amount of positive charge directly opposite intracellular side –> temporary hyperpolarisation of RMP and reduces likelihood of spontaneous action potential