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Inotropic agents and Diuretics
- 2. INOTROPES
- 3. INTRO.. ▪ A Drug that alters the force or energy of contraction ▪ Greek origin – ino = fiber , tropic = related to 2 Types Positive inotropes Negative inotropes • Agent's strength of muscular contraction • Agents weaken the force of muscular contractions 3
- 4. POSITIVE INOTROPES ▪ Enhances the myocardial contractility Increases the ejection fraction of the heart ▪ Used to support cardiac function in conditions such as : a) Decompensated CHF b) Cardiogenic shock c) Septic shock d) Myocardial infarction e) Cardiomyopathy , etc. 4
- 5. Clinically approved Inotropes ▪ Cardiac glycoside : ▪ Digitalis derivative – Digoxin ▪ Sympathomimetics : ▪ Epinephrine ▪ Dopamine (Intropin) ▪ Dobutamine (dobutrex) ▪ Norepinephrine (Levophed) ▪ Isoproterenol (isuprel) ▪ Phosphodiesterase inhibitors : ▪ Amrinone ▪ Milirinone 5
- 6. Cardiac glycosides ▪ Often called Digitalis or digitalis glycosides ▪ Source : medical plants (digital purpurea) ▪ Chemically similar compounds increasing cardiac contractility ▪ Have been widely used in treating HF ▪ Pharmacodynamics: - Na+/K+ ATPase inhibition + Vagal stimulation ▪ Agents : - Digoxin , Digitoxin 6
- 7. Digoxin ▪ Digoxin is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ▪ Pharmacological class : Cardiac glycoside ▪ Therapeutic class : Inotropes , antiarrhythmic ▪ In a normal heart ▪ Increases the force of contraction ▪ Constriction of blood vessel ▪ HR and CO unchanged CARDIAC EFFECTS 7
- 8. ▪ In heart failure ▪ Increases the contractility and CO ▪ Systole is shortened so that there is more time for ventricular filling ▪ HR is reduced ▪ Decreases conduction velocity of AV node and his-purkinje system and prolongs their ERP (protection of ventricle from AF) ▪ Prolongation of PR interval (delayed Av conduction) ▪ Shortening of QT interval (shorter ventricular systole) ▪ Depression of ST segment ▪ Inversion or disappearance of T wave ECG changes 8
- 9. 1. Cardiac arrhythmias 2. GI side effects – anorexia , nausea, vomiting, diarrhoea, abdominal cramps 3. CNS – headache, fatigue, neuralgia, blurred vision, loss of color perception 4. Endocranial – gynecomastia ▪ Hypokalemia , ▪ children < 10 years and elderly, ▪ myocardial infarction , ▪ hypothyroidism , ▪ myocarditis , ▪ WPW syndrome CONTRAINDICATION A/E and Toxicity 9
- 10. Dopamine ▪ 3,4-dihydroxyphenylethylamine ▪ Endogenous catecholamine and immediate precursor of norepinephrine and epinephrine ▪ It differs from NE and E by absence of –OH group at β carbon atom side chain ▪ Important neurotransmitter, doesn’t cross BBB 10
- 11. 11 ▪ At low therapeutic dose (2-5 μg/kg/min IV), it reacts with vascular D1 receptor , especially in renal, mesenteric and coronary vasculature and produce increase in GRF, renal blood flow and Na excretion ▪ At 5 μg/kg/min, it also stimulates β1 receptors causing increasing Cardiac output, but PVR and MAP are unchanged due to simultaneous dilatation of renal and splanchnic vessels ▪ At still higher doses (>10μg/kg/min) it can cause vasoconstriction by α1 receptors ▪ Conditions with low CO with compromised renal function Cardiovascular effect Therapeutic uses
- 12. Dobutamine ▪ Used clinically as a racemic mixture of 2 enantiomers ▪ I form – potent agonist at α1 d form – potent α1 antagonist , agonist β1 ▪ Net effect is β1 agonist action ▪ Structurally similar to dopamine, but doesn’t have actions on dopamine receptors 12
- 13. 13 ▪ Inactive when given orally, usually given IV ▪ T1/2 is 2 minutes and steady state plasma concentration is achieved in 10 – 12 minutes ▪ Conjugates of dobutamine and its major metabolized compounds are excreted primarily in urine and small amounts in faces ▪ Short term management of cardiac failure following surgery or MI ▪ Cardiac stress testing ▪ Sharp rise in BP and heart rate in some patients, especially in those with history of HTN ▪ Increase in oxygen demand and precipitation of angina or aggravation of MI ▪ Ventricular ectopic activity Adverse effects Therapeutic uses Pharmacokinetics
- 14. Adrenaline (epinephrine) ▪ Pharmacological class: sympathomimetic (direct acting) ▪ Action : Adrenaline acts on β1,β2 and α1 receptors ▪ CVS: Increased heart rate and force of contraction produce an increase in cardiac output. Systolic blood pressure rises ▪ RES: bronchial smooth muscle is relaxed resulting in bronchodilatation through effect of β2 ▪ Metabolic: Adrenaline mobilizes glucose from glycogen and rises blood sugar. Pupillary dilatation (mydriasis) occurs. 14
- 15. ▪ Low cardiac output states ▪ During cardiac arrest ▪ Allergic reactions (anaphylactic shock) ▪ Local anesthetic ▪ Bronchodilator for acute severe asthma attack ▪ Septic shock ▪ DCM ▪ High blood pressure ▪ Sinus tachycardia ▪ Abnormal heart rhythm ▪ Parkinson symptoms ▪ Closed angle glaucoma INDICATION CONTRAINDICATION 15
- 16. Noradrenaline (nor epinephrine) ▪ Noradrenaline (norepinephrine) is a substance released naturally by the nerve cells ▪ Vasopressor (a drug that rises the BP because of its ability to constrict blood vessels) ▪ Pharmacologic class: sympathomimetic ▪ Actions : potent vasoconstrictor ▪ Increases BP by vasoconstriction. Less likely to cause tachycardia than adrenaline 16
- 17. ▪ Acute hypotension states such as septic shock where peripheral vasodilatation occurs ▪ Severe cardiogenic shock ▪ Neurogenic shock ▪ Spinal anesthesia , blood transfusion. ▪ MI ▪ Hemodynamically significant hypotension(SBP < 70 mmHg ) with low total peripheral resistance ▪ High blood pressure ▪ Blood clot , blockage of blood vessels ▪ Excess amount of carbon dioxide in the blood ▪ Decreased oxygen saturation ▪ Decreased blood volume INDICATION CONTRAINDICATION 17
- 18. Phosphodiesterase inhibitors ▪ Drugs that block subtype of enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intercellular second messenger's cAMP and cGMP by respective PDE subtypes. ▪ They are classified into non-selective PDE inhibitors and selective PDE ▪ Non-selective: caffeine, aminophylline, IBMX, paraxanthine, pentoxifylline, theobromine, theophylline. ▪ Selective : PDE1 to PDE 11 18
- 19. ▪ M ▪ Inhibits phosphodiesterase enzyme ▪ CAMP and cGMP levels increase ▪ Calcium levels decrease ▪ Vasodilatation and smooth muscle relaxation ▪ PDE inhibitors : pulmonary hypertension, erectile dysfunction ▪ PDE3 inhibitors : myocardial infarction, intermittent claudication ▪ PDE4 inhibitors : pulmonary disease (asthma, COPD) , Inflammatory conditions (rheumatoid ` arthritis,Inflammatory bowel disease, atopic dermatitis) ▪ Nonspecific inhibitors : pulmonary disease (asthma, COPD) INDICATION MECHANISM 19
- 20. NEGATIVE INOTROPES ▪ Decreases myocardial contractility , and are used to decrease cardiac workload in conditions such as angina ▪ While negative inotropism may precipitate or exacerbate heart failure ▪ Certain beta-blockers ( carvedilol, bisoprolol, and metoprolol) have been believed to reduce morbidity and mortality in congestive heart failure. 20
- 21. NEGATIVE INOTROPES 1. Beta blockers 2. Calcium channel blockers: ▪ Diltiazem ▪ Verapamil ▪ Clevidipine 3. Class 1a antiarrhythmics such as : ▪ Quinidine ▪ Procainamide ▪ Disopyramide 4. Class 1c antiarrhythmic such as : ▪ Flecainide 21
- 22. Note.. ▪ Although inotropic agents improve functional status of CHF, long term benefit on mortality is questionable ▪ In fact, some drugs have shown to increase mortality ▪ At present digoxin remains the only oral inotropic agent available for management of CHF 22
- 23. DIURETICS
- 24. DIURETICS ▪ These are drugs which cause a net loss of Na+ and water in urine ▪ Diuretics are among the most widely prescribed drugs ▪ Application of diuretics to the management of hypertension and in edema 24
- 25. Classification 1. High efficacy diuretics (inhibitors of Na+ - k+ - 2Cl cotransport) ▪ Eg: Furosemide , Bumetanide , Torsemide 2. Medium efficacy diuretics (inhibitors of Na+_Cl- symport) ▪ Benzothiadiazines (thiazides): Hydrochlorothiazide, Benzthiazide ▪ Thiazide like (related heterocyclics): Chiorthalidone, Metolazone 3. Weak or adjunctive diuretics ▪ Carbonic anhydrase inhibitor: Acetazolamide ▪ Potassium sparing diuretics: Spironolactone, Triamterene, Amiloride ▪ Osmotic diuretics: Mannitol , glycerol 25
- 26. 26
- 27. Carbonic anhydrase inhibitors ▪ Acetazolamide, dorzolamide ▪ Site of action: proximal convoluted tubule ▪ Inhibits carbonic anhydrase activity ▪ Decreases HCO3 reabsorption – alkaline diuresis ▪ Glaucoma: acetazolamide, dorzolamide ▪ Urinary alkalinization: UTI , to promote excretion of certain acid drugs ▪ metabolic alkalosis ▪ Acute mountain sickness Therapeutic uses 27
- 28. 28 ▪ Acidosis ▪ Renal stones ▪ Hypokalemia ▪ Drowsiness, fatigue ▪ Hypersensitivity Adverse effects
- 29. Osmotic diuretics ▪ Mannitol ▪ Freely filtered at the glomerulus ▪ Not reabsorbed at the renal tubules ▪ Relatively inert pharmacologically ▪ Non – metabolizable ▪ Increases the plasma osmolarity ▪ Decreases sodium reabsorption ▪ Dilute tubular fluid and increase water excreation 29
- 30. 30 ▪ Head injury or stroke ▪ Glaucoma ▪ In case of poisoning ▪ To maintain GRF and urine flow in patients with impaired renal function ▪ Headache, nausea , vomiting, pulmonary edema Therapeutic uses Adverse effects
- 31. High efficacy (loop) diuretics ▪ Site of action : Thick ascending limb of loop of Henle ▪ Inhibits the luminal Na+ - k+ - 2Cl transporter – reduce reabsorption of NaCl ▪ Prevent reabsorption of Ca2+ and Mg2+ ▪ Acute pulmonary edema (IV-Furosemide) ▪ Renal edema ▪ Hypertension associated with renal failure and CHF ▪ Hypercalcemia and renal calcium stones ▪ Hyperkalemia ▪ Forced diuresis – in case of poisoning Therapeutic uses of loop diuretics 31
- 32. 32 ▪ Hypokalemia, Hypocalcemia, Hypomagnesemia, Hypochloremia ▪ Metabolic alkalosis ▪ Hypovolemia ▪ Loss of hearing ▪ Gout (hyperuricemia) Adverse effects
- 33. Thiazide diuretics ▪ Medium efficacy diuretics ▪ Site of action : distal convoluted tubule ▪ Blocks Na+/Cl- transporter – inhibit NaCl reabsorption ▪ Increase Ca+ reabsorption ▪ Mild hypertension ▪ Edema associated with CHF/kidney disease ▪ hypercalciuria/osteoporosis Therapeutic uses 33
- 34. 34 ▪ Hypokalemia ▪ Metabolic alkalosis ▪ Gout (hyperuricemia) ▪ Hypercalcemia Adverse effects
- 35. Potassium sparing diuretic ▪ Site of action : late distal tubule and collecting duct ▪ Spironolactone – aldosterone antagonist competitively inhibits the binding of aldosterone to mineralocorticoid receptor inhibits formation of aldosterone– induced protein prevent sodium reabsorption and potassium excretion ▪ Hyperaldosteronism (cardiac failure, liver and kidney disease, conn syndrome) ▪ hypertension ( with thiazide/loop diuretics) Therapeutic uses 35
- 36. 36 ▪ Hyperkalemia ▪ Drowsiness , confusion ▪ Abdominal upset ▪ Impotence ▪ Menstrual irregularities Adverse effects
- 37. Contraindications ▪ Contraindicated in patients: • With known hypersensitivity to the drugs, electrolyte imbalances, severe liver or kidney dysfunction, anuria, hypokalemia and hyponatremia Mannitol : contraindicated in patient with active intracranial bleeding potassium – sparing diuretics : Contraindicated in patients with hyperkalaemia ; Not recommended for children 37
- 38. Thank you 38