Cardiac Glycoside

Pharmacological actions

1)      On heart (Digitalis)

·         Direct action on myocardial fibers and contractility properties.

·         Force of contraction: due to positive ionotropic effect, increase in force of contraction with increase in dose. This is generally seen in a failing heart. Systolic pressure is less, and diastolic pressure is prolonged.

·         Heart rate is decrease hence, bradycardia is marked in CHF patients.

·         Vagal tone is increased reflexly by sensitization of baroreceptors, as well as by stimulation of the vagal center.

·         a) Action potential: Resting membrane potential is decreased with an increase in dose. Phase ‘0’ depolarization is reduced, so the Na+ channel is inactivated. This action is marked in the A-V node and bundle of his. Increased phase ‘4’ depolarization in the Purkinje fibers.

·         b) Effective refractory period: atrium – decreased vagal action (10^th cranial nerve), increased direct action. Ventricle – ERP is shortened by direct action. A-V node and bundle of his—directly increased.

·         c) ECG: decrease amplitude of ‘T’ wave, increase P-R interval (at toxic dose), and shortening of Q-T interval. Depression of the S-T segment (at high doses).

2)    Blood vessel

·         Digitalis has mild direct vasoconstriction action.

·         In CHF patients: no prominent effect on BP; systolic BP may increase, and diastolic BP may decrease, and pulse pressure increases.

3)    Kidney

·         Diuresis is seen in CHF patients; salt and water are gradually excreted.

4)    CNS

·         In higher dose activates the CTZ (chemoreceptor trigger zone), and that cause nausea and vomiting, hyperpnea (faster breathing), central sympathetic stimulation, mental confusion, disorientation, and visual disturbances.

Pharmacokinetics

·         Digoxin tablets are widely distributed. 

·         It is concentrated in the heart, liver, skeletal muscle, and kidney.

·         Excreted by the kidney.

·         Oral absorption – 60-80%

·         Plasma protein binding – 25%

·         Onset of action—15-30 min.

·         Peak time – 2-5 hrs.

·         Duration of action – 2-6 hrs.

·         Plasma t ½ – 40hrs.

·         Therapeutic concentration—0.5–1.4 ng/ml.

·          Toxic concentration – > 2 ng/ml.

·         Daily maintenance dose—0.125–0.5 mg.

·         Daily elimination – 35%.

·         Route of elimination – Renal

·         Route of administration – Oral / i.v. 

Doses

·         DIGOXIN 0.25 mg tab., 0.05 mg/ml pediatric elixir, 0.5 mg/2 ml inj.

Adverse effect

·         Anorexia, nausea, vomiting, and abdominal pain.

·         Gastric irritation, mesenteric vasoconstriction, and CTZ stimulation.

·         Fatigue, malaise, headache, mental confusion, restlessness, hyperapnoea, disorientation, psychosis, and visual disturbances.

·         Skin rashes and gynaecomastia are rare.

·         Almost all types of cardiac arrhythmias are reported.

Adverse effect treatment

·         If toxicity persists, then stop digoxin immediately.

·         For tachyarrhythmias: infuse KCl 20 m.mol/hour (max. 100 m. mol) i.v. or give orally in milder cases.

·         For ventricular arrhythmias: to suppress the excessive automaticity, lidocaine i.v. is the choice of drug.

·         For supraventricular arrhythmias: in case of urgency, propranolol i.v. may be given.

·         For A-V block and bradycardia: atropine 0.6 to 1.2 mg i.m.; otherwise consider cardiac pacing.

Precautions and contraindications

·         Hypokalemia: enhances digitalis toxicity.

·         Elderly, renal, or severe hepatic disease: patients are more susceptible to digoxin toxicity.

·         Myocardial ischemia: severe arrhythmias.

·         Thyrotoxicosis: patients are more prone to develop digitalis arrhythmias.

·         Myxedema: these patients eliminate digoxin more slowly; cumulative toxicity can occur.

·         Ventricular tachycardia: digitalis is contraindicated because it may precipitate ventricular fibrillation.

·         Partial A-V block: may be converted to a complete A-V block by digoxin.

·         Wolff-Parkinson-White syndrome: Digitalis is contraindicated because it decreases the ERP.

Interaction

·         Calcium: synergizes with digitalis, precipitating toxicity.

·         Quinidine: reduces binding of digoxin to tissue proteins, inhibiting renal and biliary clearance. Toxicity occurs.

·         Verapamil, diltiazem, captopril, propafenone, and amiodarone increase plasma concentration of digoxin.

·         Adrenergic drugs: can induce arrhythmias.

·         Metoclopramide, sucralfate, antacids, neomycin, and sulfasalazine may reduce digoxin absorption.

·         Propranolol, verapamil, diltiazem, and disopyramide: may additively depress A-V conduction.    

·         Succinylcholine: can induce arrhythmias.

Uses

·         Congestive heart failure

·         Cardiac arrhythmias: Atrial fibrillation (AF), atrial flutter (AFI), and paroxysmal supraventricular tachycardia (PSVT).

A, B, C, D, E heart failure treatment

A.    Angiotensin-converting enzyme inhibitors, anticoagulants, amiodarone, AICD (automatic implantable cardioverter-defibrillator),

B.     Beta-blocking agents

C.     Calcium channel blockers, coronary revascularization, cardiac transplant, cardiomyoplasty, surgery.

D.    Diet, Diuretics, Digitalis, Dobutamine

E.     Exercise

Sympathomimetic

·         Dopamine, Dobutamine

·         Dopamine: Stimulation of peripheral post-junctional D₁ and pre-junctional D₂ receptors.

·         Splanchnic (GIT, liver, spleen, and pancreas) and renal vasodilation (increased blood supply).

·         Use: Restore renal blood flow in acute failure.

·         Dobutamine: Stimulates β₁ adrenoreceptor – Peripheral vasodilatation.

·         Use: management of acute failure.

Phosphodiesterase inhibitors

·         Amrinone, Milrinone, Levosimendan

·         Inhibition of type III phosphodiesterase.

·         Increased concentration of cAMP leads to activation of protein kinase A.

·         Calcium influx through L-type calcium channel.

·         Inhibition of calcium sequestration by SR.

Therapeutic uses

·         Support I advance cardiac failure (short term)

·         Not for the long term.

Adverse effects

·         Cardiac arrhythmia

·         Nausea and vomiting

·         Thrombocytopenia (low blood platelet count)

·         Sudden death

RAS inhibitors

·         Drugs of choice in heart failure with diuretics.

·         Use: Acute myocardial infarction.

Diuretics

·         Reduction of preload and afterload: Reduction of excess plasma volume and edema fluid (preload), lowered BP (afterload).

·         Reduction of sympathetic nervous system facilitation.

Vasodilators

·         Reduce preload and afterload.

·         Sodium Nitroprusside, Hydralazine, Ca²⁺ channel blockers, Prazosin.

β-Blockers

·         Blocks the action of epinephrine and norepinephrine.

·         Inhibition of renin release

Aldosterone antagonist

·         Prevention of aldosterone effect on kidney and heart.

·         Remove edema in heart failure.

·         Prolong life in CHF patients.