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1. ALDOSTERONE ANTAGONIST IONOTROPIC DRUGS PHOSPHODIESTERASE-3-INHIBITORS ROLL NUMBER 81-85

2. Aldosterone Antagonists

3. •Spironolactone •Eplerenone Aldosterone-antagonist

4. ACTION Convoluted Tubule of kidney.

5. ACTION

6. Mechanism of action Normal- -Aldosterone binds with Intracellular Mineralocorticoids receptors (MR) -formation of Aldosterone Induced proteins(AIPs) -promote Na+ reabsorption by a number of k+secretion -The action of Spironolactone is to inhibit the formation of AIPs by combining with MR

7. USES ✓ primary and secondary aldosteronism ✓CHF ✓Hypertension ✓To counteract the hypokalemia caused by loop diuretics and thiazides ✓Nephrotic oedema, cirrhosis ✓Treatment of digoxin toxicity Aldosterone-antagonist

8. Adverse drug reactions Gynaecomastia - Being a steroid spironolactone interacts with progestin and androgen receptors as well. It alters the peripheral metabolism of testosterone resulting in changes in the ratio of testosterone to estradiol, producing treatment related hormonal side effects. Impotence and loss of libido. Menstrual irregularities in women. Acidosis is a risk, particularly in cirrhotics. Peptic ulcer may be aggravated and it is contraindicated in ulcer patients.

9. Drug interactions Spironolactone and K+ supplements given together can produce dangerous hyperkalaemia. Aspirin blocks spironolactone action by inhibiting tubular secretion of its active metabolite canrenone. More pronounced hyperkalemia can occur in patients receiving ACE inhibitors/ARBs. Spironolactone increases plasma digoxin concentration.

10. Inotropic Drugs CARDIAC GLYCOSIDES SYMPATHOMIMETIC AMINES PHOSPHODIESTERASE-3-INHIBITORS

11. Cardiac Glycosides

12. Drugs Digioxin Digitoxin

13. DIGIOXIN Source- Digitalis lanata Pharmacokinetics- Good oral absorption. Food delays absorption. Crosses blood brain barrier. HALF LIFE- 36-48 hrs Normal plasma conc.- 0.5-2 ngm/ml Therapeutic plasma conc.- 0.5-0.9 ngm/ml Toxicity- >2ngm/ml

14. MOA of Digioxin

15. PHARMACOLOGICAL ACTIONS- Myocardial contractility- Increases force of contraction (+ve ionotropic effect) HEART RATE - Reduces heart rate (-ve ionotropic effect ) by stimulation of vagus ELECTROPHYSIOLOGICAL ACTIONS - Decreases automaticity and resting membrane potential by vagal action in atria and AV node ECG - Prolongation of PR interval,inversion of T wave, EXTRACARDIAC ACTIONS - GIT - Irritation and CTZ stimulation KIDNEY - diuresis CNS- Stimulation confusion , hallucination

16. USES CCF - due to its postive ionotropic effect ATRIAL FIBRILLATION - Due to vagomimetic action on AV node ATRIAL FLUTTER - By depressing AV node PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA (PSVT) ADVERSE EFFECTS Nausea and vomiting ( CTZ Stimulation ) Xanthopsia ( yellow vision ) Arrhythmia - ventricular premature beats , bigeminy and trigeminy Gynecomastia Hyperkalemia

17. DIGIOXIN TOXICITY Factors Affecting Hypokalemia Route - IV Hypocalcemia and hypomagnesaemia

18. Treatment of digioxin toxicity 1. Shift the patient to intensive care unit (ICU). 2. Stop digoxin and potassium-depleting diuretics (thiazides/loop diuretics). 3. Potassium chloride (KCl) orally or intravenously is the drug of choice for tachyarrhythmias, when serum K level is normal/low. 4. Supraventricular arrhythmias are treated with oral or intravenous propranolol. 5. Intravenous lignocaine is the drug of choice for ventricular arrhythmias because it has: Relatively low incidence of toxicity. A rapid onset and short duration of action, so its action wears off immediately after stopping the infusion. No action on AV nodal conduction velocity, hence, does not intensify the AV block in digitalis toxicity.

19. 6. AV block and bradyarrhythmias are treated with atropine and cardiac pacing. 7. Digoxin antibodies (Digibind): It is used only in case of serious digitalis toxicity. It neutralizes circulating digoxin/digitoxin and rapidly reverses the toxicity, but it is expensive.

20. CONTRAINDICATIONS - HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY WPW SYNDROME - blocks AV node HYPERCALCEMIA HYPOKALEMIA HYPOMAGNESAEMIA MYOCARDIAL INFARCTION - increase permeability to calcium RENAL FAILURE

21. Drug Interactions 1. Cholestyramine/colestipol X digoxin: Cholestyramine and colestipol (bile acid binding resins) bind to cardiac glycosides in the gut and reduce its absorption. 2. beta-blocker/verapamil X digoxin: These drugs have additive depressant effect on SA and AV nodes and may precipitate AV block. 3. Thiazides/loop diuretics X digoxin: Hypokalaemia caused by diuretics, may potentiate digoxin toxicity. Hypokalaemia increases the binding of digoxin to Na + K + -ATPase. 4. Calcium X digoxin: Calcium increases the incidence of digoxin toxicity. 5. Digoxin X sympathomimetic/succinylcholine: The chances of cardiac arrhythmias are more with sympathomimetic/succinylcholine in patients on digoxin.

22. SYMPATHOMIMETIC AMINES

23. Dopamine It is a dopaminergic as well as weaker β1 and very weak α receptor agonist. The D1 receptors in renal and mesenteric blood vessels are the most sensitive i.v. infusion of low dose of dopamine dilates these vessels. This increases g.f.r. Moderately higher doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but little chronotropic effect on heart.

24. Vasoconstriction (α1 action) occurs only when large doses are infused. At normal doses , it raises cardiac output and systolic BP with little effect on diastolic BP. Dopamine does not penetrate blood-brain barrier—no CNS effects.

25. USES - Dopamine is used in patients of cardiogenic or septic shock and acute heart failure wherein it increases BP and urine outflow. It is administered by i.v. infusion (0.2–1 mg/min) which is regulated by monitoring BP and rate of urine formation.

26. Dobutamine It is a derivative of dopamine, but not a D1 or D2 receptor agonist. Dobutamine acts mainly on β adrenergic receptors, and is a weak α agonist. The only prominent action of clinically employed doses (2–8 μg/kg/min i.v. infusion) is increased force of cardiac contraction and output, without significant change in peripheral resistance and BP. As such, it is considered to be a relatively selective β1 agonist.

27. USES :- Dobutamine is used as an inotropic agent in pump failure accompanying myocardial infarction, cardiac surgery, and for short term management of severe congestive heart failure.

28. Phosphodiesterase inhibitors Inamrinone, Milrinone, Levosimendan They inhibit phosphodiesterase enzyme and increase cAMP levels They exert both positive inotropic and vasodilator action And increase the cardiac output and decrease the afterload. Inamrinone:-rapidly acting and action last for 2 -3hours. It increases cardiac output and decreases peripheral vascular resistance.

29. Thrombocytopenia is main adverse effect Others are nausea, diarrhoea, abdominal pain, liver damage, fever, arrhythmia. Milrinone:-its action is similar to inamrinone but it is more selective for PDE3 and 10 times more potent. Thrombocytopenia is not prominent Levosimendan:-acts by sensitizing myocardial troponin C to calcium and by inhibiting PDE3

30. It also open ATP sensitive Potassium channels in vascular smoot muscles and causes vasodilatation. Used for short term treatment of acutely decompensated severe chronic heart failure. Other drugs that can be used are:- Nesiritide :-recombinant brain natriuretic peptide. Used to relieve dyspnea. It enhances salt and water excretion Tolvapton can be used for correction of Na and water retention.