Outline the kinetic characteristics and the mode of action of digoxin. (75% of marks)
List the cardiovascular effects of digoxin (25% of marks).
The Syllabus for the Primary examination describes an outline to be “Provide a summary of
the important points.” Thus candidates were expected to briefly mention the fundamental
pharmacokinetic characteristics (eg highly lipid soluble, well absorbed from small intestine,
oral bioavailability of 60 - 90%, protein binding of 20 - 30%, volume of distribution, half life,
etc) and mode of action. This was poorly done and candidates’ answers often lacked
structure.
The question outlines the distribution of marks, being 25% for listing cardiovascular effects.
Thus candidates were expected to broadly list the important cardiovascular effects relating to
mechanical (eg increase intensity of myocardial contraction, direct venous and arteriolar
constriction, etc) and electrical ( increase phase 4 slope & automaticity, hyperpolarization,
shortening of atrial action potentials, decrease AV conduction velocity and prolong AV
refractory period, increase PR & QT intervals, dose and baseline autonomic activity
dependent actions, etc).
Syllabus – C2c 2a, b
Reference: Basic and Clinical Pharmacology, Katzung. 9TH Ed. Chapter 13 page 206
Goodman & Gilman's The Pharmacological Basis of Therapeutics
| Class | Antiarrhythmic |
| Chemistry | Cardiac glycoside |
| Routes of administration | Oral and IV; theoretically also IM |
| Absorption | Oral bioavailability 80% (some is secreted back into the gut lumen by P-glycoprotein, an enterocyte efflux pump) |
| Solubility | pKa = 7.15; basically insoluble in water. |
| Distribution | VOD=5.1–7.4 L/kg; 25% protein-bound |
| Target receptor | Digoxin inhibits Na+/K+ ATPase. |
| Metabolism | Hepatic metabolism accounts for only abut 16% of clearance |
| Elimination | Elimination is renal, as unchanged drug, and slow because of the large VOD. Half-life is about 36-44 hrs |
| Time course of action | Onset of effect is relatively rapid with IV infusion, or delayed by 2-3 hrs following oral loading. |
| Mechanism of action | By inhibiting Na+/K+ ATPase, digoxin increases intracellular sodium, which increases sodium-calcium exchange by the Na+/Ca2+ exchanger (INCX) during Phase 1 of the cardiac action potential. The resulting increase in intracellular calcium promotes inotropy. It also acts as a vagotonic agent, which slows conduction through the AV node, and decreases the duration of the action potential mainly by reducing the duration of Phase 2. The slope of Phase 4 is increased, promoting automaticity, but then automaticity is overall suppressed by the vagotonic effects. |
| Clinical effects | Bradycadia, AV block, prolonged PR interval, shortened QT interval, tachyarrhythmias (including VF and Vt which can be bidirectional), nausea, anorexia, depressed level of consciousness, and arterial vasoconstriction. Toxicity is exacerbated by hypokalemia |
| Single best reference for further information | FDA data sheet |
Worthley, L. I., and A. W. Holt. "Digoxin in the critically ill patient." Critical Care and Resuscitation 1.3 (1999): 252.