Medical Pharmacology Topics   

Preliminary Outline

Increase Heart Contractility   Na+/K+ ATP Inhibitors      Digitalis Glycosides          Digoxin          Digitoxin   Sympathomimetic Amides          Dobutamine          Dopamine   PDE Inhibitors          Amrinone          Milrinone

Cardiac Contractility

Contractility is the state of cardiac muscle involved in generating a contraction. The force that a ventricular muscle will generate is directly related to the length of the sarcomere. If the myofibrils are stretch or squashed due to disease, the force of contraction is diminished.

Drugs used to increase contractility include cardiac glycosides (digoxin, digitoxin), sympathomimetic amines (dobutamine, dopamine) and phosphodiesterase inhibitors (amrinone, milrinone).

The cardiac glycosides digoxin and digitoxin come from the foxglove plant (digitalis purpurea). Toad skin and monarch butterfly wings also contain cardiac glycosides. The glycosides are competitive inhibitors of the Na+/K+ ATPase. Increased intracellular Na+ slows the rate of the Ca2+/Na+ transporter, allowing Ca2+ to accumulate in the cytosol. The sarcoplasmic reticulum takes up the extra Ca2+ and releases it in the next action potential, enhancing the contraction. As a result, digitalis shortens the atrial refractory period, increases the AV node refractory period, decreases AV node conduction velocity, lengthens the PR interval, increases abnormal automaticity of the ventricles and Purkinje system, depresses the ST interval and inverts the T wave. Secondary effects of digitalis glycosides that also increase cardiac contractility include reduced sympathetic tone, diuresis, and decreased blood volume, heart size, and pulmonary and venous pressures.

Digitoxin is absorbed more extensively than digoxin, but it is highly bound to proteins so higher doses of digitoxin than digoxin are needed (they have the same potency). Digitoxin is metabolized by the liver, while digoxin is mostly excreted in urine. Digoxin has a half-time of 5 days, digoxin's is 36 hrs. They both have very low toxicity indices, so multiple loading doses are recommended.

Progressive digitalis toxicity leads to premature ventricular depolarization, bigemy (2 ventricular beats for each auricular beat), ventricular tachycardia, and ventricular fibrillation. Toxicity symptoms include cardiac arrhytmias, headache, fatigue, disorientation, visual disturbances, convulsions, anorexia, nausea and vomiting. To treat digitalis toxicity: (1) stop administration, (2) stop administration of diuretic, (3) administer potassium if hypokalemic, (4) administer anti-digitalis antibody.

An electrolyte imbalance will alter plasma digoxin levels, so diuretics will increase sensitivity to the drug due to K+ loss. Some drug interactions will alter digoxin plasma levels. Quinine, verapamil, aminodarone and spironolactone will increase plasma digoxin levels while antiacids and cholestyramine decrease plasma levels.

The sympathomimetic amines dobutamine and dopamine are used only IV for short-term management. They are metabolized by COMT, and have very short half-lifes (~2min). Dobutamine is a selective beta1 agonist, and may cause excessive cardiac stimulation and arrythmias.

Dopamine is an agonist of dopamine-A1, alpha and beta adrenergic receptors, and is also metabolized by MAO. Low dose (<2 µg/kg/min) dilate renal, mesenteric, coronary and intracerebral vasculature. Medium doses (2-10 µg/kg/min) activate dopamine and beta1 receptors, increase organ perfusion, renal blood flow and urine production plus increased cardiac contractility. At high doses (> 10 µg/kg/min) dopaminergic effects are overridden by alpha-adrenergic stimulation, causing vasoconstriction and increased total peripheral resistance, so they are used to support circulation during resuscitation.

The phosphodiesterase (PDE) inhibitors amrinone and milrinone increase cardiac contractility and relax vascular smooth muscle by increasing cAMP (second messenger in the beta1 signaling cascade). They are used mainly for short term management when digitalis, diuretics or vasodilators have not been effective. Their elimination is both hepatic and renal, have a half-life of 3-4 hrs and are subject to zero-order elimination. Potential problems include tachycardia, arrhytmias, vomiting, diarrhea, hypotension, hepatic toxicity and thrombocytopenia.

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