Cardiac Glycosides

digitalis

Mechanism of action:

Positive inotropic action:

• Digitalis ↑ cardiac contractility by increasing free intracellular Ca2+ through inhibition of membrane-bound Na+/K+ ATPase enzyme. This result in inhibition of Na+/K+ pump with subsequent accumulation of intracellular Na+ and Ca2+ via:

• ↑ Ca2+ release from the sarcoplasmic reticulum.

• Displacement of intracellular Ca2+ from its binding sites.

• ↑ Ca2+ entry into the cardiac ms cells.

• ↓ exchange of extracellular Na+ for the intracellular Ca2+.

Autonomic effects:

It restores the vagal tone and abolishes the sympathetic  over activity.

a. Vagal actions:

• Direct stimulation of central vagal nucleus.
• Reflex vagal stimulation due to increased sensitivity of baroreceptors.

b. Sympathetic action:

• In therapeutic doses, digitalis reduces sympathetic discharge to the heart but toxic doses may increase cardiac sympathetic activity.

Pharmacological effects:

CVS: ↑↑ Cardiac contractility and COP leading to better tissue perfusion.

HR: Bradycardia due to:

• Vagal effect: …..see before
• Extravagal effects: Direct inhibition of the A-V conducting system. ↓ sympathetic discharge to the heart due to relieve of hypoxia and improved hemodynamics

Conduction velocity:

• Atrial conduction: small dose ↑ it (vagal stimulation) but toxic dose ↓ it (direct effect).
• A-V conduction: ↓↓ by direct and vagal effects.

Kidney effects:

• ↑ diuresis “The best diuretic in case of CHF is digitalis” due to:
• ↑ COP → ↑ RBF and ↑ GFR.

GIT effects:

• Stimulation of CTZ → nausea and vomiting. = Anorexia and diarrhea.

CNS effects:

• CNS stimulation → excitation and convulsions (in high dose).
• Stimulation of the visual area causing yellow vision

Therapeutic indications:

Absolute:

1. They can be used in case of rapid ventricular rate and other therapeutic options e.g beta blocker fail or contraindicated. The major indication is chronic CHF associated with atrial fibrillation.

2. In patients who have symptoms of heart failure in spite of vasodilators, beta blockers and diuretics. Treatment of heart failure failing to respond to other drugs.

Relative:

1. Atrial flutter: (the atria beat regularly at 200-400 bpm) due to: ↓ A-V conduction and protects the ventricles from the accelerated atria. Improvement of ventricular function.

  2) Atrial fibrillation: (the atria beat irregularly at 400-600 bpm) The same mechanism as atrial flutter.   3) Paroxysmal atrial tachycardia: To ↓ A-V conduction → protects the ventricles from the accelerated atria.

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Absolute contraindications:

• Heart block: because digitalis ↓ conduction by direct and vagal effects.

• Hypertrophic obstructive cardiomyopathy (IHSS): because increasing cardiac contractility will ↑ the outflow tract resistance and accelerate heart failure.

• Wolff-Parkinson-White (WPW) syndrome: although digitalis (also BB and verapamil) ↓ conduction in the normal pathway, they can ↑ conduction in the abnormal pathway leading to ↑ arrhythmia

• Paroxysmal ventricular tachycardia: because digitalis ↑ excitability and automaticity.

Other Relative Contraindications:

(= Factors modifying the response to digitalis)

• Bradycardia or sick sinus syndrome…. Severe bradycardia may occur.

• Hypersensitive carotid sinus…………. Severe bradycardia may occur.

• With beta-blockers or with verapamil… Severe bradycardia may occur.

• In hypertensive HF: digitalis will ↑ the strain of the left ventricle.

• Cardiopulmonary diseases: pulmonary hypertension, chronic lung disease, severe hypoxia, etc.

• Renal or hepatic diseases: digoxin must be avoided in renal patients while digitoxin must be avoided in hepatic patients.

• Myxedema: renders the heart more sensitive to digitalis.

• Concomitant drugs: Narrow therapeutic index

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Dosage and administration:

1-Initial digitalization:

• Slow (cumulative) method:
• It is done by giving the daily maintenance dose (one tablet 0.25 mg /day → 5 days/week) from the start.
• The steady state plasma conc (Cpss) will be achieved after 5 half-lives (i.e. after one week for digoxin and after one month for digitoxin).
• It is the safest method for digitalis administration.

2-Rapid (loading) method:

• It is done to achieve early Cpss and in emergency conditions e.g. in acute heart failure or in rapid AF.
• 2 tablets (0.5 mg) twice daily for 2 days then maintain on one tab/d (2x2x2)
• 2 tablets (0.5 mg) t.d.s for one day then maintain on one tab/d (2x3x1)

3- Maintenance dose: 0.25 mg/day, 5 days/week (AF requires slightly higher dose).

N.B

• The optimum therapeutic plasma level is 1-2 ng/ml
• Arrhythmia occurs when level exceeds 2 ng/ml

Evaluation of EffectivenessAssessment of response to digitalis:

• Relief of dyspnea and orthopnea.
• Relief of tachycardia and tachypnea.
• Relief of edema, lung congestion, and fatigue.
• Increased urinary output
• Improved peripheral pulses.
• Serum digoxin levels 0.5 to 2 ng/mL.

Precautions during digitalis therapy:

• Digitalis toxicity

• Never give digitalis i.v. before being sure that the patient has not received digitalis during the last 14 days to avoid digitalis toxicity

  • Continuous monitoring of plasma K+ level.
  • Reduce digoxin dose in elderly people because renal function is ↓.
  • Other factors modifying the response to digitalis.

Management: Stop digitalis administration.

Correct hypokalemia:

• Stop drugs that cause hypokalemia (e.g. diuretics).
• Give K+ either i.v. or oral (2 gm/4 h).

Antiarrhythmic drugs:

• Lidocaine (ventricular arrhythmia): 1-2 mg/kg i.v. bolus then 1-2 mg /min i.v.i.

• Phenytoin (in ventricular arrhythmia): 100 mg i.v.i. (anti-arrhythmic of choice).

• Atropine: if there is bradycardia or heart block.

• Beta-blockers: if there is tachyarrhythmia.

Specific digitalis antibodies (Fab fragments) to bind digitalis and ↑ its excretion (the most specific therapy).

Prevention of digitalis toxicity:

• Avoid predisposing factors (all…………….).
• Therapeutic drug monitoring for digitalis therapy (mention therapeutic level)
• Allow weekly drug holiday (2 days/week) to prevent digitalis cumulation.
• if bradycardia (heart rate less than 60 bpm) or new arrhythmias occur. No drug intake

Laboratory Values:

• Electrolyte imbalance: potassium, calcium and magnesium values need to be monitored
• Hypokalemia (low potassium)
• Hypomagnesemia (low magnesium)
• (Both can lead to irregular heart rate).