Digoxin in Anesthesiology

Cardiac glycosides in Anesthesia

Digoxin is the only cardiac glycoside currently in use. Others are not clinically used or marketed.

Pharmacological action

1. Heart
   • Force of contraction: digitalis cause dose dependent increase in force of contraction- a positive ionotropic effect
   • Heart rate is decreased by digitalis. Bradycardia is more marked in CHF patientsbecause improved circulation restores the diminished vagal tone and abolishes sympathetic overactivity
   • The fundamental action of digitalis is to augment the contractile state of the heart, whether normal or failing, but that in the absence of heart failure this improvement is not translated into an increase in cardiac output. ⁽¹⁾
   • Digoxin increases the contractility in normal heart without changes in loading conditions. The rise in ionotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same take place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long term digoxin on the heart rate is partly direct withput autonomic mediation. The effect of digoxin is dose dependent. ⁽²⁾
   • Vagal tone is increased reflexly by sensitization of baroreceptors, as well as stimulation of vagal centre
   • Digitalis use increases the early posthospital mortality of myocardial infacrtion patients with combined electricala nd mechanical dysfunction. ⁽³⁾
   • A direct depressant action on SA and AV nodes.
   • Action potential:
     • The resting membrane potential (RMP) is progressively decreased with increasing doses
     • The rate of 0 phase depolarization is reduced resulting in slowing of conduction
     • The slope of phase 4 depolarization is increased in PFs- ectopic automaticity is enhanced
     • The action potential duration (APD) is reduced and amplitude of AP is iminished
   • Effective refractive period
     • Atrium: decreased by vagal action, increased by direct action
     • AV node and bundle of His: increased by direct, vagomimetic and antiadrenergic actions
     • Ventricles: ERP is abbreviated by direct action
   • Conduction: AV conduction is slowed by therapeutic doses. At high dose, intraventricular conduction in PFs is also depressed by uncoupling of gap junctions.
   • ECG: may produce arrhythmias
     • Decreased amplitude or inversion of T wave
     • Increased PR interval
     • AV block at toxic doses
     • Shortening of Q-T interval
     • Depression of ST segment 

1. Blood vessel
   • Mild direct vasoconstrictor action
   • No prominent action on BP
   • Systolic BP may increase and diastolic may fall in CHF patients – pulse pressure increases
   • No significant effect on coronary circulation
   • In the conscious state, digitalis causes a distincr elevation in the coronary and systemic resistances with no change in cardiac output, while in the anesthetized state, it reduces cardiac output and when heart rate is controlled, does not alter the coronary resistance. ⁽⁴⁾
   • Digitalis increases smooth muscle tone of resistance and capacitance vessels. Constriction of coronary and splanchnic vessels may lead to myocardial or mesenteric ischemia. ⁽⁵⁾

1. Kidney
   • Diuresis occurs promptly in CHF patients, secondary to improvement in circulation and renal perfusion
   • The retained salt and water is gradually excreted
   • Effect of digoxin does not differ by the level of renal function. ⁽⁶⁾

1. CNS
   • Digitalis has little apparent CNS effect in therapeutic dose
   • Higher dose cause CTZ activation – nausea and vomiting
   • Still higher doses produce hyperapnea, central sympathetic stimulation, disorientation and visual disturbances
   • Its effect on the area postrema of the medulla oblongata is responsible for alpha-adrenergic-mediated peripheral vasoconstriction as well as nausea and vomiting. Action on the cerebral cortex leads to visual disturbance, headaches, seizures and coma. The peripheral neurologic effects on baroreceptor and cardiac afferent fibers may: 1) improve the depressed function of these receptors in heart failure. and 2) Reflexly lower peripheral vascular resistance, thereby preventing the vascular constrictor action of the digitalis. ⁽⁵⁾

Pharmacokinetic features of digoxin

There is increased bioavailabilty of digixin with oral coadministration of talinol, which is most likely caused by competition for intestinal P-glycoprotein. ⁽⁷⁾

Mechanism of action:

Digitalis increases the force of cardiac contraction by a direct action independent of innervation. It selectively binds to extracellular face of the membrane associated Na⁺K⁺ATPase of myocardial fibres and inhibits this enzyme.  Inhibition of this cation pump results in progressive accumulation of Na+ intracellularly. This indirectly results in intracellular Ca²⁺ accumulation.

Binding of glycoside to Na⁺K⁺ATPase is slow. Moreover, after Na⁺K⁺ATPase inhibition, Ca²⁺ loading occurs gradually. As such, ionotropic effect of digitalis takes hours to develop, even after iv administration.

Adverse effects of digitalis:

• Extracardiac
  • Anorexia
  • Nausea
  • Vomiting and abdominal pain
  • Gastric irritation, mesenteric vasoconstriction and CTZ stimulation
  • Fatigue, malaise
  • Headache, mental confusion
  • Restlessness
  • Hyperapnea
  • Disorientation, psychosis
  • Visual disturbances
  • Skin rashes and gynacomastia are rare

• Intracardiac
  • Almost every type of arrhythmia may occur
  • Pulsus bigeminus
  • Nodal and ventricular extrasystole
  • Ventricular tachycardia
  • Ventricular fibrillation
  • Partial to complete AV block
  • Severe bradycardia, atrial extrasystoles, AF or AFl may occur

Digoxin antibody:

Developed for measuring plasma concentration of digoxin by radioimmunoassay, it has been found to be effective in treating toxicity as well. The Fab fragment is marketed in Europe as DIGIBIND (38 mg vial).

It is non immunogenic because it lacks Fc fragment. Given by iv infusion, it has markedly improved the survival of digitalis intoxicated patients the digoxin-Fab complex is rapidly excreted by kidney.

Precautions and contraindications:

1. Hypokalemia
2. Elderly, renal or severe hepatic disease
3. Myocardial ischemia
4. Thyrotoxicosis: more prone to cardiac arrhythmias
5. Myxoedema: these patients eliminate digoxin more slowly; cumulative toxicity can occur
6. Ventricular tachycardia: digitalis is contraindicated because it may precipitate ventricular fibrillation
7. Partial AV block: may be converted to complete AV block by digoxin
8. Acute myocarditis: diphtheria, acute rheumatic carditis, toxic carditis – ionotropic response to digitalis is poor, more prone to arrhythmias
9. Wolff-Parkinson-White syndrome: digitalis is contraindicated because it decreases the ERP of bypass tract in 1/3 patients. In them rapid atrial impulses may be transmitted to ventricles – VF may occur. Digitalis may increase the chances of reentry by slowing conduction in the normal AV bundle and accelerating it in the aberrant pathway.

Drug interactions:

1. Diuretics
2. Calcium
3. Quinidine
4. Adrenergic drugs
5. Digoxin absorption is reduced by metoclopramide, sucralfate, antacids, neomycin, sulfasalazine.
6. Propanolol, verapimil, diltiazem and disopyramide may additively depress AV conduction and oppose positive ionotropic action
7. Succinylcholine: can induce arrhythmias in digitalized patients

Uses

1. Congestive heart failure
   • Heart failure may occur due to systolic or diastolic function
   • Digoxin is clinically effective in patients with normal sinus rhythm and mild to moderate chronic heart failure secondary to systolic dysfunction who are treated with diuretics. ⁽⁸⁾
   • Long term digoxin therapy is clinically beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound. ⁽⁹⁾
   • Most patients with long standing CHF have both systolic and diastolic dysfunction
   • Cardiac glycoside afford only symptomatic relief, primarily in systolic dysfunction
   • Best results are obtained when myocardium is not primarily deranged, eg in hypertension, valvular defects, or CHF due to rapid heart rate in atrial fibrillation.
   • Poor response and more toxicity is likely when myocardium has been damaged by ischemia, inflammation or degenerative changes and in thiamine deficiency, as well as in high output failure (in anemia)
   • Cardiac glycoside are incapable of reversing the pathological changes of CHF or even arresting their progress. Digoxin do not affect remodeling
   • In clinical practice, digoxin is likely to affect the frequency of hospitalization, but not survival. ⁽¹⁰⁾
   • Withdrawal of digoxin carries considerable risk for patients with chronic heart failure and impaired systolic function who have remained clinically stable while receiving digoxin and angiotensin-converting-enzyme inhibitors. ⁽¹¹⁾
   • Cardiac glycosides are relatively weak ionotropic agents, have a low therapeutic ratio and are moderately effective in heart failure secondary to ventricular volume overload. When properly used in patients with severe heart failure and sinus rhythm, particularly in patients with atrial fibrillation, cardiac glycosides improve both cardiac performance and the clinical state and can be administered effectively for years. ⁽¹²⁾

1. Cardiac arrhythmias
   • Atrial fibrillation:
     • Digitalis is used in controlling ventricular rate in AF, whether associated with CHF or not
     • It reduces ventricular rate in AF by decreasing the impulses that are able to pass down the AV node and bundle of His it increases ERP of AV node by direct, vagomimetic and antiadrenergic actions
     • After a brief episode of atrial fibrillation (AF), digoxin auhments the shortening that occurs in atrial refractoriness and predisposes to the reinduction of AF. These effects occur in the setting of autonomic blockade and are more likely to be due to the effects of digoxin on intracellular calcium than to its vagotonic effects. ⁽¹³⁾

• Atrial flutter (Afl)
  • Digitalis enhance the AV block, reduces the ventricular rate and prevents sudden shift of AV block to a lower degree
  • Digitalis may convert AFl to AF by reducing atrial ERP and making it inhomogenous this is a welcome response because control of ventricular rate is easier in AF than in AFl

• Paroxysmal supraventricular tachycardia (PSVT)
  • Digitalis increases the vagal tone and depresses the path through the SA/ AV node, or the ectopic focus, and terminates the arrhythmia
  • Adenosine or verapimil are more effective, less toxic and act faster
  • Digitalis is now reserved for preventing recurrences in selected cases

References:

1. Edmund H Sonnenblick, John F Williams, Gerald Glick, Dean T Mason, Eugene Braunwald. Effects of cardiac glycosides on myocardial force-velocity relations in the nonfailing human heart. Circulation 1966;34:532-539. 
2. J Partanen, J Heikkila, T Pellinen, MS Nieminen. Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study. Br J Clin Pharmacol. MAr 1988;25(3):331-340
3. AJ Moss, HT Davis, DL Conard, JJ DeCamilla, CL Odoroff. Digitalis-associated cardiac mortality after myocardial infacrtion. Circulation 1981;64:1150-1156. 
4. Stephen F Vatner, Charles B Higgins, Dean Franklin, eugene Braunwald. Effects of a digitalis glycoside on coronary and systemic dynamics in conscious dogs. Circulation Research 1971;28:470-479. 
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8. Barry F Uretsky, James B Young, F Eden Shahidi, Larry G Yellen, Maria C Harrison, M King Jolly. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of PROVED trial. J Am Coll Cardiol. 1993;22(4):955-962. 
9. Daniel Chia-Sen Lee, Robert Arnold Johnson, John B Bingham, Marianne Leahy, Robert E Dinsmore, Allan H Goroll, John B Newell, H William Strauss, Edgar Haber. Heart Failure in outpatients- A randomized trial of digoxin versus placebo. N Engl J Med. 1982;306:699-705. 
10. Garg R, Gorlin R, Smithg T, Yusuf S. The effect of digoxin on mortality and morbidity in patients with heart failure. New England Journal of Medicine. Feb 1997;336:525-33. 
11. Milton Packer, Mihai Gheorghiade, James B Young, Peter J Costantini, Kirkwood J Adams, Robert J Cody, L Kent Smith, Lucy Van Voorhees, Lynn A Gourley, M King Jolly. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. The New England Journal of Medicine. July 1993;329(1). 
12. Eugene Braunwald. Journal of American College of Cardiology. 1985;5(5s1):51A-59A. 
13. Christian Sticherling, Hakan Oral, Julie Horrocks, Steven P Chough, Robert L Baker, Michael H Kim, Kristina Wasmer, Frank Pelosi, Bradley P Knight, Gregory F Michaud, Adam Strickberger, Fred Morady. Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness. Circulation 2000;102:2503-2508.