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Dr Ramesh Chandra
Less Common
Diabetes Mellitus Valvular Disease Rare
Anemia, Connective Tissue Disease, Viral Myocarditis, HIV, Hyper/Hypothyroidism, Hypertrophic Cardiomyopathy, Arrhythmias.
Preload
End diastolic volume (EDV) is the amount of blood remaining in the ventricles at the end of the diastole When venous return increases EDV increases Increase in EDV increases preload
Afterload
Afterload is expressed as tension which must be developed in the wall of ventricles during systole to open the semilunar valves and eject blood to aorta/pulmonary artery It is primarily determined by arterial resistance
Goals of treatment
Alleviate Symptoms Improve quality of life Arrest cardiac modeling Prevent sudden death
Factor
1. Preload
2. Afterload
3. Contractility
-positive inotropes
Reduction in afterload : Arteriolar Dilators : Hydralazine. Reduction in Preload and afterload : ACE Inhibitors : Enalapril, Ramipril, Lisinopril. Beta Blockers : Metaprolol, Carvedilol. Aldosterone antagonists : Spirinolactone. Novel Approaches : Natriuretic Peptides : ANP, BNP, CNP NEP Inhibitors : Candoxatril, Sampatrilat
Cardiac Glycosides
Digitalis lanata - Digoxin, Digitoxin Digitalis purpura - Digitoxin
Fox Glove
Structure of Digoxin
Sugar moiety
MOA of Inotropes
Pharmacokinetics
t1/2 : 36 48 Hrs Therapeutic plasma concentration: 0.5- 1.5 ng/ml Toxic plasma concentration: >2 ng/ml Large Vd (main tissue reservoir is Skeletal muscle) Bioavailability : 70% - 80% Metabolized in liver / excreted through kidneys
Uses
CHF Paroxysmal supraventricular tachycardia Atrial flutter and atrial fibrillation
ADVERSE EFFECTS
Cardiac Manifestations Cardiac arrhythmias Delayed AV conduction Heart block Ventricular fibrillation
Interactions
Hyperkalemia: reduces action of digoxin Hypokalemia: precipitates digoxin toxicity Hypercalcemia: the risk of digoxin induced arrhythmia Quinidine and Verapamil displaces Digoxin from tissue binding sites Enzyme inducers digoxin metabolism Antacids decrease digoxin absorption Hyperthyroidism renal clearance of digoxin
Contraindications
Myocardial infarction Hypothyroidism Rheumatic carditis Ventricular fibrillation Partial/complete heart block Wolf- Parkinsons White syndrome
PHOSPHODIESTRASE INHIBITORS
Inamrinone Milrinone
positive inotropic effect.
increase rate of myocardial relaxation.
Mechanism of Action
inhibition of type III phosphodiesterase
intracellular cAMP activation of protein kinase A Ca2+ entry through L - type Ca2+ channels
Pharmacokinetics
Half-life : 2-3 hrs Excretion : In urine Route of administration : Parenteral
Adverse Effects:
Nausea Vomiting Thrombocytopenia Hepatotoxicity Cardiac arrhythmias
Milrinone has more selectivity for PDE III. Additional effectiveness in patients taking Betablockers. Does not stop disease progression or prolong life in CHF patients.
Sympathomimetics
Dopamine
Dobutamine
Mechanism of Action
Stimulation of cardiac b1-adrenoceptors: positive inotropic and chronotropic effect leading to increase in stroke volume and cardiac output.
Stimulation of b2-adrenoceptors: peripheral vasodilatation leading to reduction in afterload Dopamine is beneficial in patients with renal failure
Route Of Administration:
Parenteral
Contraindications:
Pheochromocytoma Tachyarrhythmias
Adverse Effects:
Precipitation or exacerbation of arrhythmias and angina Rapid development of tolerance
Organic Nitrates
Glyceryl trinitrate Moderately volatile Decreases oxygen demand of Myocardium. Reduces Preload.
Mechanism Of Action
Pharmacokinetics
t1/2 of 1-3 minutes
Adverse effects
Headache Postural hypotension Facial Flushing Tachycardia
Loop diuretics
MOA Inhibit the activity of the Na+K+2Cl- symporter in the thick ascending limb of the loop of Henle Increase in the urinary excretion of Na+ and ClOther actions: excretion of Ca2+, Mg2+ and K+ Acutely, increase the excretion of uric acid; on chronic administration - reduced excretion of uric acid
Adverse effects
Hyponatremia associated with hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in patients with liver disease, hepatic encephalopathy. Hypochloremic alkalosis. Hypokalemia, Hypomagnesemia, Hypocalcemia Ototoxicity Plasma levels of LDL and triglycerides while decreasing plasma levels of HDL cholesterol Skin rashes, photosensitivity, paresthesias, bone marrow depression, and gastrointestinal disturbances
Contraindications
Severe Na+ and volume depletion Hypersensitivity to sulfonamides
Drug interactions
1) Aminoglycosides (synergism of ototoxicity caused by both drugs) 2) Anticoagulants (increased anticoagulant activity) 3) Digitalis glycosides (increases digitalis toxicity) 4) Lithium and Propranolol (increase in levels of the respective drugs) 5) Sulfonylureas (hyperglycemia) 6) Cisplatin (increased risk of diuretic-induced ototoxicity) 7) NSAIDs, probenecid (blunted diuretic response) 8) Amphotericin B (increased potential for nephrotoxicity and intensification of electrolyte imbalance).
Thiazides
Inhibitors of Na+-Cl- symport Sulfonamide derivatives Increase the excretion of K+
Adverse Effects
CNS - vertigo, headache, paresthesias and weakness Gastrointestinal - anorexia, nausea, vomiting, cramping, diarrhea, constipation, cholecystitis, and pancreatitis Hematological - blood dyscrasias Dermatological - photosensitivity and skin rashes Erectile dysfunction
Drug interactions
Diminish the effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas, and insulin Increase the effects of anesthetics, diazoxide, digitalis glycosides, lithium, loop diuretics, and vitamin D. Efficacy reduced by NSAIDs, bile acid sequestrants (reduced absorption of thiazides)
ALDOSTERONE ANTAGONISTS
Mineralocorticoids cause retention of salt and water and increase the excretion of K+ and H+ by binding to specific mineralocorticoid receptors. Spironolactone and Eplerenone block the effects of Aldosterone
Mechanism of action
Competitively inhibit the binding of aldosterone to the mineralocorticoid receptor They have the additional benefit of preventing remodelling because of activation of RAAS system in CHF thereby reducing morbidity and mortality
Adverse effects
Hyperkalemia. Induce metabolic acidosis in cirrhotic patients. Gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice, and menstrual irregularities. Diarrhea, gastritis, gastric bleeding, peptic ulcers CNS adverse effects - drowsiness, lethargy, ataxia, confusion, and headache. Skin rashes and blood dyscrasias.
Vasodilators
Sodium nitroprusside
Acts by donating NO thereby increasing cGMP levels Reduces both preload and afteroad
Hydralazine
Reduces afterload Has additional antioxidant and moderate positive inotropic effect
Mechanism Of Action
Inhibits angiotensin converting enzyme (ACE) Prevents conversion of AT I to AT II Reduce after load Produce natriuretic action Reduces the effects of elevated RAAS Prevent cardiac remodeling Reduce mortality by 20% Improvement in ventricular function
Adverse Effects
Cough Angioneurotic edema Hypotension Hyperkalemia Teratogenic
Beta Blockers
Carvedilol, bisoprolol, labetolol, metoprolol Recommended for advanced heart failure Started with low doses (1/10 th of target dose) and increased slowly over a period of time Block compensatory sympathetic stimulation Reduces left ventricular mass & size
Advantages
Reduces the incidence of sudden death Reduces remodelling
Renin Inhibitors
Aliskiren, Enalkiren, Remikiren Inhibit renin action inhibit conversion of angiotensinogen to angiotensin-I; which is the rate limiting step in angiotensin-II secretion. Trials show decrease in mortality due to CHF when renin inhibitors were given with betablockers/ACEIs/ARBs
Natriuretic Peptides
ANP, BNP & CNP Increase cGMP levels especially in kidneys facilitating Na+ and water excretion. Inhibits renin and aldosterone sectretion Has no effect on cardiac contractility
NEP inhibitors
Candoxatril, Ecadotril, Omapatrilat, Sampatrilat. ANP, BNP & CNP are degraded by neutral endopeptidases in the brush border cells of PCT. NEP inhibitors inhibit this enzymes and thereby raises natriuretic peptide levels; facilitating diuresis.
Bibliography
1. Basic and Clinical Pharmacology. Bertram Katzung, 11th edition. 2. Goodman & Gilmans Pharmacological Basis of Therapeutics. Laurence L Brunton. 12th edition. 3. Principles of Pharmacology. HL Sharma, KK Sharma. 2nd edition.