Nitrovasodilators & Angina

Nitrovasodilators & Angina October 10, 2007 Frank F. Vincenzi

Nitric oxide, NO.: The Physiological Vasodilator ACh, histamine, ADPfrom platelets, andbradykinin (Ca2+)4 CaM endothelial eNOS cell L-arginine citrulline NO smooth NO muscle guanylate cyclase PDE cell GTP cGMP relaxation

Nitric oxide synthase (NOS) • eNOS - endothelial - failure or abnormal function of this system associated with many conditions (atherosclerosis, hypertension, Raynaud’s syndrome, ‘oxidant stress’, etc.) • nNOS - nerve - involved in CNS plasticity? • iNOS - inducible - overactive in sepsis

Pharmacodynamic mechanism of action of nitrovasodilators • Release nitric oxide (NO.) (or simply, NO) • NO activates cytosolic guanylyl cyclase in vascular smooth muscle • Increased cGMP decreases smooth muscle contraction increased removal of Ca2+ ? other mechanisms? • General smooth muscle relaxation

- NO 2 Nitrovasodilators: A mechanism of action ACh, histamine, etc. (Ca2+)4 CaM endothelial eNOS cell L-arginine citrulline organic nitrites & nitrates NO smooth NO muscle guanylate cyclase PDE cell GTP cGMP relaxation

Leslie Activa • Les Activa is a slightly obese 60 year old male accountant. • Five years ago Les was diagnosed with stable angina pectoris. He was prescribed nitroglycerin (0.3 mg, sublingual, PRN chest pain). • He has missed many follow up visits but requests Rx refills on a regular basis. He consumes about two tablets of nitroglycerin per day, although that number has been increasing lately. Efforts to change his lifestyle have been unsuccessful. His activities are limited by angina, but he does not have angina at rest.

Angina pectoris • Stable or exertional: associated with exertion and fixed obstruction(s) of coronary arteries, usually in elderly (also called classic or atherosclerotic) • Unstable: new onset, often severe and/or frequent, or at rest; often exacerbated by extracardiac problems, associated with plaque rupture • Prinzmetal’s or variant: associated with coronary arterial vasospasm (mediators unknown), often near fixed obstructions (Dx with ACh or ergonovine)

Angina: a symptom of ischemia • Ischemia depends on the balance of myocardial • Oxygen demand • Oxygen supply

Nitrates and nitrites (nitrovasodilators) used mainly in acute angina • amyl nitrite (inhalation, rapid onset (<30 sec) short acting (3-5 min) • nitroglycerin (sublingual tablets, rapid onset short duration, 30 min) • isosorbide dinitrate (sublingual 60 min, chewable 3 hours or oral 10 hours) • organic nitrates are readily absorbed via skin and mucous membranes and rapidly biotransformed.

Organic nitrates: pharmacokinetics • High lipid solubility • Rapidly absorbed from almost anywhere rapid onset (seconds to minutes) • Poor bioavailability orally • Relatively short half life 1-3 min for nitroglycerin 45 min for isosorbide dinitrate

Effect of a nitrovasodilator on cardiovascular functions in a normal human volunteer

Cardiovascular effects of nitroglycerin • Venous vasodilation > arteriolar vasodilation(no increase in total coronary blood flow in patients, although there is redistribution into ischemic areas) • Decreased ventricular preload • Decreased afterload (and increased subendocardial perfusion) (can be used in the Tx of CHF) • Reflex tachycardia Acute decrease in cardiac work and O2 demand

Nitrates: adverse reactions and limitations • Headache ! • Orthostatic hypotension (dizziness, weakness) • Tachycardia • Tolerance (substantial) • Short duration of action (a few minutes)

NO-mediated vasodilation of genital vasculature: sildenafil (Viagra®) • sildenafil is a selective inhibitor of phosphodiesterase 5 (PDE5) • PDE5, located in genital vascular beds, terminates the action of cyclic GMP in vascular smooth muscle • sildenafil increases the response to normal physiological signalling of NO in genital vascular beds

Sildenafil: A mechanism of action CNS &/or local input non-adrenergic, non-cholinergic nerve cell (NANC) nNOS L-arginine citrulline . sildenafil NO smooth . muscle NO cell guanylate cyclase PDE5 corpus cavernosum GTP cGMP relaxation

sildenafil (Viagra®) • Indications male erectile dysfunction (impotence) • Contraindications nitrite/nitrate therapy, predisposition to priapism • Caution retinitis pigmentosa (genetic disorders of retinal PDE) • Adverse reactions abnormal color vision (PDE6, 1/10th potency)

sildenafil (Viagra®): pharmacokinetics • Rapidly absorbed, bioavailability 40% • Vd approximately 1.5 liters/kg • Peak plasma concentration, approximately 60 min • Plasma half life (parent & metabolite) approximately 4 hours • Metabolized by CYP3A4 & CYP2C9 • N-desmethyl is an active metabolite • Metabolites mainly in feces

Leslie Activa, revisited a few years later • Has begun to have an occasional attack of angina at rest, or with only minor exercise (the flight of stairs to his office). • What can we do to prevent angina attacks in Les? • “Oh, by the way, Doc, can I also have a prescription for that stuff, Viagra?”

cimetidine diltiazem erythromycin fluconazole indinavir ketoconazole furosemide miconazole nitrites/nitrates nitroprusside omeprazole spironolactone quinidine rifampin saquinavir verapamil sildenafil: some drug interactions

Perspective on pharmacotherapy of angina • Organic nitrites/nitrates are effective in acute treatment but not very effective in prophylaxis of angina; duration of action is short • Beta-blockers are effective prophylaxis for some forms of angina (but may worsen variant angina) • Calcium channel blockers are also effective in prophylaxis of angina

Beta blockers in angina • Decrease heart rate • Decrease myocardial contractility • Decrease blood pressure • Minimize sympathetically induced increases in oxygen demand • Reduce myocardial oxygen consumption Prevent exercise-induced increase in O2 demand

Cardiac effects of beta blockers in angina Potentially beneficial Decreased: • resting HR • resting and exercise systolic pressure • left ventricular dP/dt • velocity of myofibril contraction Potentially harmfulIncreased: • prolongation of systolic ejection period • increased left ventricular end diastolic pressure • increased cardiac volume and wall tension

Effect of a beta-blocker on exercise tolerance in a patient with angina pectoris

Effects of placebo and propranolol on maximal exercise duration (normal human volunteers)

AV block Bronchospasm Diarrhea Exfoliative dermatitis Fatigue Hallucinations Heart failure Hypertriglyceridemia Hypoglycemia Hypotension Impotence Libido decrease Myalgia Nausea/vomiting Nightmares Sinus bradycardia Propranolol: selected adverse reactions

Some factors to consider in choosing a beta blocker for treating angina in Les Activa

Perspective on pharmacotherapy of angina • Organic nitrites/nitrates are effective in acute treatment but not very effective in prophylaxis of angina; duration of action is short • Beta-blockers are effective prophylaxis for some forms of angina (but may worsen variant angina) • Calcium channel blockers are also effective in prophylaxis of angina

Calcium Channel Blockers in Angina • Smooth muscle has low resting potential • Smooth muscle not affected by tetrodotoxin • (action potential spikes carried by Ca) • Ca channel blockers relax arteriolar smooth muscle with little effect on venous muscle • No change in HR x SBP product not increased delivery, but decreased demand for oxygen • Caution: reflexly mediated increases in oxygen demand possible

Calcium Channel Blockers:Probable Mechanisms in Angina • Variant angina: decreased coronary spasm • Unstable: decreased spasm and cardiac work? • Exertional: decreased cardiac work(For angina, the advantage is with verapamil or diltiazem - they suppress cardiac automaticity & contractility. Dihydropyridines activate sympathetic reflexes to a greater extent & do not suppress SA node.

Effect of verapamil in patients with variant angina

Combination therapy in angina:prophylaxis plus treatment of acute attacks • Beta-blocker chronically + nitroglycerin acutely as needed (PRN NTG) • Calcium channel blocker chronically + PRN NTG • With hypertension: Beta-blocker + nifedipine (caution in hypotension - & do not use a beta blocker and verapamil or diltiazem, caution possible heart block)

Summary: Therapy of Angina Pectoris • Stable nitrates beta blockers Ca channel blockers • Unstable admit and rule out MI, heparin then aspirin, consider revascularization or CABG • Variant acute nitroglycerin, short duration nifedipine chronic nitrates, CEBs, possibly prazosin

Malignant hypertension Nifedipine (‘bite and swallow’, use decreasing) Fenoldopam Sodium nitroprusside

Sodium nitroprusside (Nipride®), ‘SNP’ Made fresh for IV infusion. Onset in seconds. Half life ~ 11 min

In vivo transformation of sodium nitroprusside Nitroprusside + oxygen nitric oxide + cyanide + Too much NO causes Oxidation of Hb - methemoglobinemia thiosulfate Too little thiosulfate causes Accumulation of cyanide - treat with thiosulfate thiocyanate Too much accumulation of thiocyanate Causes N&V, rash, tinnitus, CNS changes Dialyze thiocyanate

Nitrovasodilators & Angina