Cardiovascular drugs

Digitalis

Cardiac glycosides include digoxin, digitoxin and ouabin. These are derived from plant Foxglove (Digitalis purpurea). Cardiac glycosides composed of steroid nucleus linked to a lactone ring and a series of sugars.

Clinical uses: treatment of congestive heart failure and management of supraventricular rhythm disturbances.

Pharmacokinetics: digoxin is taken orally, well absorbed but in some patients (10%) the presence of some enteric bacteria may cause degradation of the drug and the use of broad spectrum antibiotics may cause sudden increase in serum digoxin level causing toxicity. Cardiac glycosides are widely distributed to tissues including CNS. Digoxin is excreted unchanged by the kidney; the dose should be adjusted in patients with renal impairment. Digitoxin is metabolized in the liver and excreted in bile.

Digoxin has narrow therapeutic index; the toxic dose is 2 ngm/ml which is near to the therapeutic dose which is 1.1 ngm/ml.

Cardiac effect

1-    Mechanical effect

Through inhibition of Na­⁺/K⁺ ATPase enzyme (membrane bound enzyme). This enzyme keep K⁺ inside the cell and Na­⁺ outside the cell; so when this enzyme is inhibited K­⁺ transport back into the cell is blocked and its concentration in the extracellular fluid increases, at the same time Na ions will enter the cell and this will promote or facilitate the entry of Ca ⁺² which are essential for the contraction of actin and myosine.

2-     Electrical effect  ( direct effect and autonomic effect)

a-    Direct effect

It causes brief prolongation of the action potential followed by a period of shortening especially the plateau phase. The decrease in the action potential duration is probably the result of increase potassium conductance that is caused by increase intracellular ca ions. All these effects can be observed at therapeutic concentration in the absence of over toxicity.

Shortening of the action potential contributes to the shortening of atrial and ventricular refractoriness.

At higher concentration resting membrane potential is redused (made less negative) as aresult of inhibition of sodium pump and reduced intracellular K⁺, this lead to appearance of ascillatory depolarizing afterpotential which followed normally evoked action potentials. The afterpotentials also known as delayed afterdepolarizations are associated with overloading of the intracellular Ca⁺² store.

·        When below threshold, these afterpotentials may interfere with normal conduction.

·        When afterpotential reach threshold it elicits an action potential (premature depolarization or ectopic beat).

·        If afterpotentials in the purkinje conducting system regularly reach threshold bigeminy will be recorded on the electrocardiogram (ECG).

NSR: an inverted T wave and depressed ST segment are present.

PVB: is a manifestations of depolarization evoked by delayed oscillatory afterpotential.

With further intoxication, each afterpotential evoked action potential will itself elicit a suprathreshold afterpotential, lead to tachycardia and fibrillation.

b-    Autonomic action (indirect)

Indirect action include sympathetic and parasympathetic.

At low dose parasympathomimetic effects predominate, lead to decrease heart rate, decrease conduction velocity, prolongation of refractory period so digoxin used in the treatment of supraventricular arrhythmia.

At toxic level sympathetic out flow is increased  lead to increase heart rate and contraction.

Manifestation of digitalis toxicity

1-     Gastrointestinal effect: anorexia, nausea and vomiting. They are the earliest signs of toxicity.

2-    Visual effect: blurred vision, loss of visual acuity and yellow-green halos.

3-    CNS effect: headache, fatigue and confusion.

4-    Cardiac effect: sever dysrhythmia moving from decreased or blocked atrioventricular nodal conduction, paroxysmal supraventricular tachycardia to the conversion of atrial flutter to atrial fibrillation, premature ventricular depolarization, ventricular fibrillation and finally complete heart block.

5-    Endocrinological effect: gynecomastia due to antiandrogenic effect of the drug.

Factors predisposing to digitalis toxicity

1-    Electrolyte disturbances: hypokalemia, hypomagnesemia and hypercalcemia predispose digitalis toxicity.

2-     Hypothyroidism, hypoxia, renal failure and myocarditis are predisposing factors to digitalis toxicity.

3-     Drugs: quinidine can cause digitalis intixicationboth by displacing digitalis from plasma protein binding sites and by competing with digitalis for renal excretion.

Verapamil also diplace digitalis from plasma protein binding site and can increase digoxin levels by 50-75%, this may require a reduction in the dose of digoxin.

Potassium depleting diuretics, corticosterois and a variety of drugs can also increase toxicity.

4-     Use of antibiotic lead to kill microorganisms like Eubacterium lentum so lead to toxicity.

Treatment of digitalis toxicity

1-     Removing of ingested drug by vomiting, gastric lavage, use of adsorbant agents eg. Activated charcoal, cholestyramine and colestepol.

2-     Maintenance of a normal potassium concentration: hypokalemia is more common after chronic digitalis toxicity, while massive acute overdoses often causes hyperkalemia. Potassium compete with digoxin on Na⁺/K⁺-ATPase pump so decrease K⁺ level and increase digoxin activity and toxicity.

Hyperkalemia may require treatment with insulin, dextrose, bicarbonate and sodium polystyrene sulfonate. In case of hypokalemia continuous potassium replacement may be sufficient. Potassium administration may correct arrhythmias restoring intracellular concentration.

3-     Reversal of arrhythmias: for atrial and ventricular arrhythmias that do not respond to potassium therapy the treatment of choice includes phenytoin and lidocaine. Phenytoin increase AV nodal conduction and directly reverse the toxic action of digitalis at AV node without interfering with its inotropic action. While quinidine and procainamide are not used because they slow AV nodal conduction.

If digitalis has produced AV block, the vagolytic action of atropine may increase heart rate and AV conduction. Catecholamines are contraindicated for the treatment of bradyarrhythmias because they increase the risk of precipitating more serious ectopic arrhythmias. Β-blockers such as propranolol are useful to suppress  supraventricular and ventricular arrhythmias induced by digitalis toxicity.

4-     Increase removal of unabsorbed drug: the use of dieresis or hemodialysis have not been successful because of the large volume of distribution for digitalis. Hemodialysis may be equired to control hyperkalemia.

5-     Use of specific antidote digoxin immune Fab: these are antibody fragments prepared by conjugation of digoxin to human or bovine serum albumin. This is then used to immunize sheep, which produce antibodies. Their sera are obtained and purified yielding the drug.

The fragments are less immunogenic and can be eliminated by glomerular filtration.

Adverse effects to digoxin immune Fab are minimal including