Cardiac glycosides(Pharmacology)

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1. CARDIAC GLYCOSIDES Presented By : Gajraj Singh Bika

2. HEART FAILURE - Heart failure is a progressive disease that is characterized by a gradual reduction in cardiac performance(Cardiac output is inadequate to provide the oxygen needed by the body). - Coronary artery disease and hypertension are most common cause of heart failure.

3. Stages of heart Failure

4. DRUGS USED IN HEART FAILURE Digitalis Other positive inotropic drugs used in heart failure Bipyridines : Milrinone Beta- adrenoceptor agonists : Dobutamine Drugs without positive inotropic effects used in heart failure - Diuretics - ACE inhibitors - Angiotensin receptor blocker - Vasodilators - Beta- adrenoceptor blocker

5. CARDIAC GLYCOSIDES The cardiac glycosides are often called digitalis or digitalis glycosides. They are group of chemically similar compounds that can increase the contractility of the heart muscle and, therefore, are used in treating heart failure. The digitalis glycosides have a low therapeutic index, with only a small difference between a therapeutic dose and doses that are toxic or even fatal. The most widely used cardiac glycosides is digoxin.

6. DIGOXIN

7. CARDIAC GLYCOSIDES POLAR (hydrophilic) : Strophanthin K, Corglycone Water soluble Bioavailability < 5% 2. NON-POLAR (lipophilic) : Digitoxine Lipid soluble Bioavailability 95-100%. 3. RELATIVELY POLAR : -Partly hydrophilic, -Partly lipophilic NOTE : Digoxine , Lantoside (Bioavailability 35-80%.)

8. Mechanism of action 1. Regulation of cytosolic calcium concentration: By inhibiting the Na+/K+ adenosine triphosphatase (ATPase) enzyme, digoxin reduces the ability of the myocyte to actively pump Na+ from the cell. This decreases the Na+ concentration gradient and, consequently, the ability of the Na+/Ca2+ exchanger to move calcium out of the cell. When Na+/K+ ATPase is markedly inhibited by digoxin, the resting membrane potential may increase(-70mV instead of -90mV). 2. Increased contractility of the cardiac muscle: Digoxin increases the force of cardiac contraction, causing cardiac output to more closely resemble that of the normal heart. 3. Neurohormonal inhibition: Low dose digoxin inhibits sympathetic activation with minimal effectson contractility.

9. Generally…… In the heart, increased intracellular calcium causes more calcium to be released by the  sarcoplasmic reticulum , thereby making more calcium available to bind to troponin-C, which increases contractility ( inotropy ) Inhibition of the Na + /K + -ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction. By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart rate; negative chronotropy ) and reduces conduction velocity of electrical impulses through the atrioventricular node ( negative dromotropy ).

10. Mechanism of positive inotropic action of cardiac glycosides. SR-Sarcoplasmic reticulum; TnC -Troponin C;

11. DIGOXIN Other effects of digoxin: Blood vessels: Digitalis has mild direct vasoconstrictor action and increases peripheral resistance in normal individuals. Kidney: Diuresis occurs promptly in CHF patients. No diuresis occurs in normal individuals or in patients with edema due to other causes. CNS: In higher doses cause digoxin activates CTZ.

12. CARDIAC GLYCOSIDES • Pharmacokinetics: Absorbed orally. Absorption varies from zero to nearly 100%. Distributed widely to tissues, including the central nervous system. Digoxin is not extensively metabolized in humans Almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance, and the half-life is 36–40 hours in patients with normal renal function.

13. Adverse effects : Cardiac glycosides Toxicity of digitalis is high, margin of safety is low (therapeutic index :1.5-3). Higher cardiac mortality has been reported among patients with steady state plasma digoxin levels >1.1 ng/ml but still within the therapeutic range during maintenance therapy. Antidote for Overdose of digoxin: Digoxin immune tab or Digoxin-specific antibody Digibind

14. ADVERSE EFFECTS : CARDIAC GLYCOSIDES Non-cardiac: Anorexia, nausea, vomiting, abdominal pain are due to gastric irritation, mesenteric vasoconstriction and CTZ stimulation. Fatigue, malaise headache, mental confusion, restlessness, disorientation, psychosis and visual disturbances are other complaints. Skin rashes and gynaecomastia are rare.

15. ADVERSE EFFECTS : CARDIAC GLYCOSIDES Cardiac: Almost every type of arrhythmia can be produced by digitalis.

16. USES OF CARDIAC GLYCOSIDES Used in the treatment of congestive heart failure(systolic and diastolic dysfunction ) and cardiac arrhythmias (atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia ).