PM716 C13 CHF Slides PDF

PM716 Pharmacology I Chapter 13 CHF RMRocco, PhD PM716 C13 Drugs for Heart Failure 1  Case Study 65 year old man, shortness of breath following a viral illness, swelling of the feet and ankles, BP 110/70 mm Hg, pulse 105 bpm. 3+ edmea in feet and ankles, cra...

PM716 Pharmacology I Chapter 13 CHF RMRocco, PhD PM716 C13 Drugs for Heart Failure 1  Case Study 65 year old man, shortness of breath following a viral illness, swelling of the feet and ankles, BP 110/70 mm Hg, pulse 105 bpm. 3+ edmea in feet and ankles, crackles both lungs Left ventricular ejection fraction is 20% (normal ~ 60%). Diagnosis stage C, class III heart failure, cardiomyopathy secondary to a viral infection. What treatment? PM716 C13 Drugs for Heart Failure 2  Case Study Low sodium diet, diuretic (furosemide). ACE inhibitor added (enalapril). Digoxin was added because of continued shortness of breath. Beta blockers were being considered along with eplerenone (e PLER en one), an aldosterone antagonist to reduce water retention. PM716 C13 Drugs for Heart Failure 3  CHF 5 million patients in the US CHF = decreased cardiac contractility with inadequate cardiac output to meet the needs of the body. Most common cause in US is from coronary artery disease. PM716 C13 Drugs for Heart Failure 4  Homeostatic Response to CHF (1) Tachycardia: increased sympathetic tone (2) Increased peripheral vascular resistance: increased sympathetic tone. (3) Retention of salt and water by the kidney: compensatory response mediated by renin- angiotensin-aldosterone system. Blood volume increases to cause edema. (4) Cardiomegaly: compensatory response mediated by sympathetic discharge. PM716 C13 Drugs for Heart Failure 5  Drug Treatment of CHF (1) Positive Inotropic Drugs (3) Misc (a) cardiac glycosides (a) beta blocker (b) PDE inhibitors (b) spironolactone (c) thazides (2) Vasodilators (a) nitrates (nitroprusside) (b) loop diuretics (c) Angio antagonists (d) nesiritide (BNP) PM716 C13 Drugs for Heart Failure 6  Normal Cardiac Contractility Decrease sensitivity of contractile proteins to calcium Amt calcium released from SR Amt calcium stored in SR Amt trigger calcium Move calcium against its sodium gradient Alter sodium/potasium ATPase (digoxin) PM716 C13 Drugs for Heart Failure 7 Chapter 13 Drugs Used in Heart Failure PM716 C13 Drugs for Heart Failure 8 © The McGraw-Hill Companies, Inc,  Therapeutic Strategies in CHF (1) Remove retained salt and H2O (diuretics) (2) Provide a positive inotropic drug (digoxin) (3) Reduce preload or afterload (vasodilators) (4) Reduce afterload and retained salt and H2O (ACE inhibitors) PM716 C13 Drugs for Heart Failure 9  CHF Systolic failure: decreased pumping action (contractility) and ejection volume Diastolic failure: reduced cardiac output, ejection fraction may be normal. CHF symptoms: tachycardia and cardiomegaly decreased exercise tolerance shortness of breath peripheral and pulmonary edema PM716 C13 Drugs for Heart Failure 10  Cardiac Glycosides TERMS: glycosides steroid nucleus + lactone ring + sugar residue digoxin most frequently used glycoside obtained from foxglove. digitalis L. digitus, finger, looks like foxglove. digitoxin from various species of foxglove, seldom to never used. ouabain Strophanthus gratis, actions similar to digitoxin PM716 C13 Drugs for Heart Failure 11  Digoxin Digoxin (Lanoxin®) and many generics. Obtained from Digitalis lanata. PM716 C13 Drugs for Heart Failure 12  Digoxin William Withering (1741 - 1790) Birmngham, England physician who introduced digoxin into medicine. Utilized a rational and scientific approach to drug study and treatment. Founded a clinic to treat the poor and cared for 3000 patients/year. PM716 C13 Drugs for Heart Failure 13  Digoxin Lunar Society in Birmingham, England Withering was a member of this society which included Eramus Darwin Joseph Priestly James Watt Josiah Wedgwood PM716 C13 Drugs for Heart Failure 14  Digoxin William Withering (1741-1799) PM716 C13 Drugs for Heart Failure 15  Digoxin Withering’s Classic text on digoxin published in 1785. One could learn to use digitalis effectively and safely if one had no other text than Withering’s ‘Account’. Paul Dudley White, 1965. PM716 C13 Drugs for Heart Failure 16  Digoxin PM716 C13 Drugs for Heart Failure 17  Digoxin Pharmacological effect is to inhibit the Sodium-Potassium ATPase pump in cardiac muscle. Normal is to pump Na+ out, decreased Na+ outside leads to increase Ca++ inside which increases muscle contraction. Positive inotropic effects. PM716 C13 Drugs for Heart Failure 18  Digoxin Inhibits Na+/K+ ATPase pump in cardiac muscle cells. This results in (1) Increased intracellular sodium (2) Increased intracellular sodium alters Na+/Ca++ exchanger which reduces the Ca++ removed from the cell. (3) Increased intracellular Ca++ moves to the SR and increases the contractile force. PM716 C13 Drugs for Heart Failure 19  Digoxin Little biostransformation in the liver, mostly excreted as unchanged drug by kidney. t1/2 ~ 40 h Vd 6.3 F = 75% TI 1.2 - 2.0 ng/mL (very narrow TI) Narrow TI requires plasma monitoring (Cp) Dosage adjustments required for renal clearance (CC levels) PM716 C13 Drugs for Heart Failure 20  Digoxin Cardiac Effects: (1) Mechanical (a) increased contractility (b) increased ventricular ejection volume (c) increased cardiac output (d) increased renal perfusion (2) Electrical (see K Table 13-2) (a) early and toxic response PM716 C13 Drugs for Heart Failure 21  Digoxin Clinical Uses Include CHF reduces symptoms but does not prolong life. Atrial Fibrillaton acts as a parasympathomimetic at AV node to reduce atrial flutter and fibrillation. PM716 C13 Drugs for Heart Failure 22  Digoxin Drug-drug interaction with quinidine which increases the Cp levels of digoxin. Quinidine displaces digoxin from its tissue binding site. Digoxin toxicity includes arrhythmias nausea vomiting diarrhea visual disturbances (color changes) PM716 C13 Drugs for Heart Failure 23  Digoxin Drug-Drug Interactions Angirasa, A. K., Koch, A. Z. P-glycoprotein as the mediator of itraconazole-digoxin interaction. J Am Pod Med Association 92(8):471-472 (2002). PM716 C13 Drugs for Heart Failure 24 Itraconazole Drug Interactions Itraconazole (Sporanox®) Oral and iv dosing Dose varies with infection, ususal up to 400 mg/d for up to 6 months. Note: digoxin is once per day for life of the patient. PM716 C13 Drugs for Heart Failure 25  Itraconazole Drug Interactions with azole antifungals divided into: (1) additive dangerous interactions (2) kinetics of antifungal altered by other drugs. (3) kinetics of other drugs altered by azoles (itraconazole and digoxin) PM716 C13 Drugs for Heart Failure 26  Itraconazole Azoles alter CYP 450 enzymes. However, digoxin is not biotransformed by CYP450, > 90% of drug dose eliminated unchanged through kidney. P-glycoprotein ATP dependent efflux pump in renal tubules moves digoxin into the urine. Itraconazole inhibits this pump. PM716 C13 Drugs for Heart Failure 27  Itraconazole Authors review extensive literature showing that itraconazole increase digoxin Cp to toxic levels when antifungal is given at usual po dose of 200 mg/day. “Caution is necessary when digoxin and itraconazole are used concurrently, and the serum digoxin concentration should be monitored closely to avoid potentially serious and harmful consequences.” PM716 C13 Drugs for Heart Failure 28 White Oleander PM716 C13 Drugs for Heart Failure 29 White Oleander Michelle Pfeiffer Robin W. Penn Renee Zellweger Alison Lohman from the novel by Janet Fitch PM716 C13 Drugs for Heart Failure 30 Digoxin Toxicity Portrait of Dr. Gachet. Narrow TI Cp 1-2 ng/mL GI disturbances CNS, drowsiness, confusion Visual: halos, photophobia, color perception problems. PM716 C13 Drugs for Heart Failure 31 Digoxin Toxicity PM716 C13 Drugs for Heart Failure 32  Digoxin Overdose Treatment (1) Correct potassium deficiency (low potassium due to diuretic effects of digoxin). Use potassium supplements, monitor Cp levels to keep potassium below 5.0 meq/L. (2) Use digoxin antibodies to bind digoxin. PM716 C13 Drugs for Heart Failure 33  Digoxin Immune Fab Fragment Digibind® antibody used to bind digoxin and treat overdose. PM716 C13 Drugs for Heart Failure 34  IgG Structure Note: Fab vs Fc fragment Light chain also called lambda chain Heavy chain also called kappa chain PM716 C13 Drugs for Heart Failure 35 IgG Structure PM716 C13 Drugs for Heart Failure 36  Digoxin Overdose 1996 = 2 862 cases reported. 16 documented fatalities. Each vial of Digibind® contains 38 mg of antibody which will bind ~ 0.5 mg digoxin. 6-20 vials usually required to reverse toxicity. PM716 C13 Drugs for Heart Failure 37  Digoxin Treatment Use the following formula Dose # vials = Cp digoxn ng/mL (body kg)/100 Product insert provides guidelines on number of doses required. (10 tablets, use 4 vials). PM716 C13 Drugs for Heart Failure 38  Digoxin in the Body Forms in which digoxin exists (1) 70% in free form, unattached to protein. The only form with pharmacological activity. (2) Inactive bound to albumin form. (3) Drug bound to tissue receptors (Na+/K+ ATPase pump on myocyte cell walls. Digibind antb binds all three forms of the drug. PM716 C13 Drugs for Heart Failure 39  PDE Inhibitors Second class of drugs (including digoxin) which are inotropic agents used in CHF. Historically theophylline was used but has now been replaced with inamrinone (eye NAM ri none) and milrinone. PM716 C13 Drugs for Heart Failure 40  PDE Inhibitors Inhibition of the Phosphodiesterase (PDE) enzyme causes an increase in cAMP and cGMP. Both drugs are selective inhibitors of PDE 3 isoenzyme found in cardiac and smooth muscle. Results in increased intracellular calcium and increased contraction force (inotropic) PM716 C13 Drugs for Heart Failure 41  PDE Inhibitors milrinone. Used iv only in acute heart failure. PM716 C13 Drugs for Heart Failure 42  ACE Inhibitors Reduced renal arterial pressure causes release of renin (an enzyme) by the kidney. Renin converts angiotensinogen (a polypeptide) into Angiotensin I (inactive Ang I) Ang I converted by angiotensin converting enzyme (ACE) in vascular tissue to Ang II. Ang II is 40x more potent vasoconstrictor than NE. Aminopeptidase enzyme converts Ang II to inactive fragments. PM716 C13 Drugs for Heart Failure 43  Renin Angio System Angio II Vasoconstriction Aldosterone Secretion Increased peripheral Increased Na+ and H2O resistance retention Increased BP PM716 C13 Drugs for Heart Failure 44  ACE Inhibitors captopril (Capoten®) enalapril (Vasotec®) benazepril (Lotensin®) Typical doses 6 - 150 mg tablets 2-3 times per day. PM716 C13 Drugs for Heart Failure 45  ACE Inhibitors 30% of patients develop a cough Renal damage to the fetus (never to be used in pregnancy). PM716 C13 Drugs for Heart Failure 46  Angiotensin Antagonists Block Angio II formation (ACE inhibitors) A second class of drugs used in CHF which are antagonistic to the renin-angiotensin system. Block Angio II receptor (receptor blockers) PM716 C13 Drugs for Heart Failure 47  Angio II Receptor Blockers Losartin and other analogs block the receptor for Angio II. Same clinical effects as ACE inhibitors with a lower incidence of cough. Still cause fetal kidney damage and must never be used in pregnancy. PM716 C13 Drugs for Heart Failure 48  BNP Agonist Brain natriuretic peptide (BNP) is a naturally occurring peptide hormone synthesized in the ventricles, 32 amino acid ring structure. Atrial natriuretic peptide (ANP), 28 amino acid peptide hormone synthesized in the atria. PM716 C13 Drugs for Heart Failure 49  BNP Both BNP and ANP act to counter balance the renin-angiotensin-aldosterone system and lower blood pressure. PM716 C13 Drugs for Heart Failure 50  BNP High Arterial Pressure BNP/ANP Release vasoconstriction Na+/H2O loss Na+/H2O retention vasodilationrenin/aldosterone release Low Arterial Pressure PM716 C13 Drugs for Heart Failure 51  Nesiritide Nesiritide (Natrecor®) IV only, t1/2 18 min Measurement of Cp of natural endogenous BNP (not the drug) is often used to screen for cardiac disease because plasma levels rise in disease. PM716 C13 Drugs for Heart Failure 52  Beta Receptors B1 Heart receptors stimulated by NE Increase heart rate Increase BP through vasoconstriction Increase oxygen demand. B2 Peripheral receptors stimulated by NE Vasoconstriction PM716 C13 Drugs for Heart Failure 53 ANS System PM716 C13 Drugs for Heart Failure 54  NE at B1 Receptors NE binding to B1 receptors in heart results in Ca++ influx into cardiac cell. Increased intracellular Ca++ causes contraction, a positive inotropic effect. Both force and rate of contraction are increased. PM716 C13 Drugs for Heart Failure 55 NE Receptors PM716 C13 Drugs for Heart Failure 56 Beta Blockers NE (norepinephrine) Endogenous neurotransmitter. Metoprolol (Lopressor®) PM716 C13 Drugs for Heart Failure 57  Beta Blockers Bisoprolol beta 1 antagonist Carvedilol Metoprolol beta 1 antagonist PM716 C13 Drugs for Heart Failure 58  Beta Blockers Actions may block high endogenous concentrations of catecholamines. May cause up regulation of beta receptors. Cause a decrease in heart rate. PM716 C13 Drugs for Heart Failure 59  Summary of Drug Therapy for CHF Mild diuretics ACE inhibitors Nitrovasodilators Moderate Digoxin ACE inhibitors Diuretics Nitrovasodilators Severe Digoxin diuretics ACE inhibitors Nitrovasodilators PM716 C13 Drugs for Heart Failure 60