PM 716 Pharmacology I Chapter 12 Vasodilators PDF

PM 716 Pharmacology I Chapter 12 Vasodilators RMRocco, PhD PM716 C12 Vasodilators 1  Case Study 52- year old male, with chest pain induced by exercise, sometimes pain radiates to his lower jaw but pain disappears after rest. Cholesterol 245 mg/dL, LDL 160 mg...

PM 716 Pharmacology I Chapter 12 Vasodilators RMRocco, PhD PM716 C12 Vasodilators 1  Case Study 52- year old male, with chest pain induced by exercise, sometimes pain radiates to his lower jaw but pain disappears after rest. Cholesterol 245 mg/dL, LDL 160 mg/dL. Father died of “heart attack” at age 55. BP 145/90 mm Hg, HR 80 bpm, Assume diagnosis of stable effort angina, what treatment? PM716 C12 Vasodilators 2  Case Study Sublingual or sprayed nitroglycerin. If anginal episodes are frequent a beta blocker (metoprolol) or a medium to long acting calcium channel blocker (verapamil, diltiazem or amlodipine). Suggest low dose daily aspirin. Treat for high cholesterol. PM716 C12 Vasodilators 3 PM716 C12 Vasodilators 4  Antianginal Drugs Terms Angina: from L. angere, to choke Pectoris: chest PM716 C12 Vasodilators 5  Angina 6 million in US alone suffer some form of angina. Angina attacks in the US occur at a rate of 1 000/minute. 8 million go to the ER with chest pain/year 3 Million are discharged 2.5 Million are non-cardiac 1 million are MI 1.2 million unstable angina 0.3 million deaths PM716 C12 Vasodilators 6  Drugs Used to Treat Angina Vasodilators Nitrates Calcium Channel Blockers Cardiac Depressants Calcium Channel Blockers Beta-Blockers PM716 C12 Vasodilators 7  Types of Angina 1. Atherosclerotic Angina: also called angina of effort or classic angina. Lipid plaques partially occlude 1 or more common arteries. Exercise (cold, emotion) stimulate ischemic changes that stimulate nerve endings and produce pain. 90% of all cases. 2. Vasospastic Angina: also called angina of rest, Prinzmetal’s angina and variant angina. Atherosclerotic arteries go into spontaneous spasm. May occur during sleep. May deteriorate into Unstable Angina. PM716 C12 Vasodilators 8 Myron Prinzmetal (1908-1987) MD and Pharmacy Degree from UCSF. First described variant form of angina. Prinzmetal, M. et al. Variant form of angina pectoris: previously undelineated syndrome. JAMA 174:1794-1800 (1960) PM716 C12 Vasodilators 9  Types of Angina 3. Unstable Angina: also called crescendo angina. Caused by combination of pathology (a) atherosclerotic plaques (b) platelet aggregation at plaque (c) vasospasm in artery Characterized by high frequency of attacks, often a precursor of an MI. PM716 C12 Vasodilators 10  Cardiac Oxygen Requirements Drug treatment is based on physiologic factors that control myocardial oxygen requirements which is determined by muscle fiber tension. PM716 C12 Vasodilators 11  Variables That Determine Fiber Tension A. Preload: diastolic filling pressure determined by (1) blood volume (2) venous tone, determined by sympathetic outflow. B. Afterload: systolic determinant, controlled by (1) arterial blood pressure (2) larger artery stiffness PM716 C12 Vasodilators 12  Variables That Determine Fiber Tension C. Heart Rate: at fast rate fibers are at systolic tension levels (low coronary artery blood flow) with less diasystolic time (diastole is time for coronary blood flow). Double Product = systolic blood pressure (heart rate) = cardiac work, which is a measure of cardiac oxygen requirements. PM716 C12 Vasodilators 13  Variables That Determine Fiber Tension D. Cardiac Contractility: force of contraction (a systolic factor) controlled by sympathetic outflow. E. Ejection Time: ventricular contraction inversely related to force of contraction. Increased ejection time increases oxygen requirement. PM716 C12 Vasodilators 14 Control of Fiber Tension and Oxygen Requirements Diastolic Systolic Blood Volume Peripheral Resistance Venous Tone Heart Rate Heart Force Ejection Time Fiber Tension O2 Requirement PM716 C12 Vasodilators 15  Angina PM716 C12 Vasodilators 16  Therapeutic Strategies Treat the defect that causes anginal pain which is caused by inadequate coronary oxygen supply. Two ways: (1) Increase oxygen delivery (2) Reduce oxygen requirement PM716 C12 Vasodilators 17  Drugs Reduce Oxygen Requirements in atherosclerotic Angina Nitrates Calcium Channel Blockers Beta-Blockers Increase Oxygen Delivery in vasospastic angina (reduce spasms) Nitrates Calcium Channel Blockers PM716 C12 Vasodilators 18  Drugs Unstable Angina is a special category which requires myocardial revascularization. (1) bypass grafting (2) angioplasty (enlargement of artery lumen with a catheter) (3) Antiplatelet clotting drugs PM716 C12 Vasodilators 19  How Drugs Relax Vascular Smooth Muscle Increase cGMP (blocks phosporylation of mysosin) NO, nitrates, nitroprusside Decrease intracellular Ca (preventas activation of myosin light chains kinase) Beta blockers and calcium channel blockers. Prevent depolarization of the vascular smooth muscle membrane (increase intracellular potassium to keep membrane at resting potential) Minoxidil opens K channels. PM716 C12 Vasodilators 20  How Drugs Relax Vascular Smooth Muscle Increase cAMP levels in vascular smooth muscle (increased cAMP increases the rate of inactivation of myosin light chain kinase). Beta 2 agonists but these are not used in angina because they stimulate the heart too much. Fenoldopam a D 1 agonist used in hypertensive emergencies. PM716 C12 Vasodilators 21 Chapter 12 Vasodilators & the Treatment of Angina Pectoris PM716 C12 Vasodilators 22 © The McGraw-Hill Companies, Inc,  TERMS Nitrate (NO3) Stable product of Nitric Oxide (NO). Nitrite (NO2) At acid pH these compounds produce NO Nitric Oxide (NO) Potent vasodilator Nitrous Oxide (N2O) Gas anesthetic. PM716 C12 Vasodilators 23  Nitrates Nitrates are available in various forms which provide a wide range of duration of action: Very Short: inhaled (3-5 min) Short: sublingual (10-30 min) Intermediate: oral (4-6 h) Long: transdermal (8-10 h) PM716 C12 Vasodilators 24  Nitrate Drugs Nitroglycerin Isosorbide dinitrate Isosorbide mononitrate PM716 C12 Vasodilators 25 Chapter 12 Vasodilators & the Treatment of Angina Pectoris PM716 C12 Vasodilators 26 © The McGraw-Hill Companies, Inc,  Nitrates Nitroglycerin PM716 C12 Vasodilators 27  Nitroglycerin Discovered by Ascanio Sobrero (1812-1888) at Torino University in 1846. MD and Prof Chem. He mixed glycerol+ nitric + sulfuric acid = NG Destroyed all his lab notes but formula got out. Years latter he wrote: “When I think of all the victims killed during nitroglycerin explosions, and the terrible havoc that has been wreaked, which in all probability will continue to occur in the future, I am almost ashamed to admit to be its discoverer.” PM716 C12 Vasodilators 28 Nitroglycerin Alfred Nobel (1833-1896) A fellow student of Ascanio Sobrero’s at Torino University. Nobel mixes NG with diatomaceous earth and patents Dynamite® also called “Nobel’s Safety Blasting Powder”. PM716 C12 Vasodilators 29  Nitroglycerin Mixture of nitroglycerin (NG) (a liquid) with an inert powder (diatomaceous earth) makes the NG shock resistant. The explosion of NG must be initiated not by shock (a hammer) but by a fuse. Dynamite is 25% diatomaceous earth or 75 g NG/100 g dynamite. Pharmaceuticals are all 0. 00003 g or less NG. PM716 C12 Vasodilators 30  Nitroglycerin A. Nobel in latter life developed angina and is prescribed nitroglycerin. In a letter to a friend he wrote: It sounds like the irony of fate that I have been prescribed nitroglycerine internally. They have named it Trinitrin in order not to upset pharmacists and the public. PM716 C12 Vasodilators 31  Nitroglycerin Mechanism of action: dilation of blood vessels. Workers in factories who made dynamite (NG) suffered from “Monday Disease” Occupational disease associated with headaches, dizziness and tachycardia. By mid to end of the week tolerance developed. After the week-end it started up again. PM716 C12 Vasodilators 32  Nitroglycerin NG within smooth muscle becomes denitrated which releases NO. NO stimulates guanylyl cyclase which increase cGMP. Increased cGMP dephosphorylates mysoin light chains (dephosphorylation causes inactivation of myosin). Muscle relaxes. PM716 C12 Vasodilators 33  Nitroglycerin Sildenafil (Viagra® ) relaxes smooth muscle in abdominal area through inhibition of a specific phosphodiesterase (isoform 5) which is responsible for the removal of cGMP. Increased cGMP stimulates dephosphorylation of myosin light chains and relaxation of smooth muscle occurs. PM716 C12 Vasodilators 34 Nitroglycerin Isosorbide dinitrate A longer acting source of NO, available po. One of the two drugs in BiDil® used to treat hypertension (FDA approved for use in African American patients). PM716 C12 Vasodilators 35  Nitroglycerin 95% of a po dose lost in the liver due to first pass effects. Sublingual avoids liver first pass. Isosorbid dinitrate used both po and sublingual. PM716 C12 Vasodilators 36 Chapter 12 Vasodilators & the Treatment of Angina Pectoris PM716 C12 Vasodilators 37 © The McGraw-Hill Companies, Inc,  Nitroglycerin Overall reduction in myocardial fiber tension. Primary benefit is in atherosclerotic angina through reduced oxygen requirement. PM716 C12 Vasodilators 38  Endogenous NO Many cells generate NO (endogenous NO synthesis) L-arginine NO synthase L-citrulline + NO NO is the only known gas which acts as second messenger in biological systems, produced by one cell and acts on another cells. PM716 C12 Vasodilators 39 Nobel Prize in Physiology or Medicine, 1998 L. J. Ignarro F. Murad R. F. Furchgott UCLA U. Texas SUNY PM716 C12 Vasodilators 40  NO Discovery Furchgott’s Sandwich: (a) Ach induces aorta muscle relaxation when endothelium present, contraction when endothelium present. Ach induces “EDRF” in endothelium. Ignarro’s Spectral Analysis (b) NO and EDRF caused the same shift in spectral curves of Hb. Murad’s Enzyme Activation: (c) Bubbles NO through tissue and raises cGMP levels. PM716 C12 Vasodilators 41  NO Synthase nNOS found in neurons iNOS inducible enzyme, found in all tissues eNOS found in blood vessels PM716 C12 Vasodilators 42  NO Possible Role In Diabetes NO production in blood vessels found to be reduced in diabetic peripheral neuropathy (Pitei, D. L. Diabet Med 14:284-290, 1997) NO increases blood flow to microcirculation adjacent to wound sites (Veres, A. Diabetes 47:457-463, 1998). Topical NO spray for treatment of painful peripheral neuropathy (Yuen, K. Diabet Care 25:1699-1703, 2002). PM716 C12 Vasodilators 43  Nitroglycerin Patch Kim, P. J. et al Effect of nitroglycerin patch on perfusion to the foot in healthy subjects. J Am. Pod Med Association 96(4):318-322 (2006) July/August PM716 C12 Vasodilators 44  Nitroglycerin Patch Double-blind placebo controlled trial of a nitroglycerin patch (low dose) in normal healthy medical students. No effects on foot temperature or pulsatile blood flow (perfusion). Dose of drug may have been too low according to the authors. PM716 C12 Vasodilators 45  Nitroglycerin Tolerance develops after 8-10 h (see “Monday Disease”). Patches should be removed after 10 -12 h to allow recovery to sensitivity of the drug. Tachycardia from baroreceptor reflex. Orthostatic hypotension from vasodilation. Throbbing headache from meningeal artery vasodilation. PM716 C12 Vasodilators 46  Nitroglycerin Sildenafil (and others ERD drugs are PDE5 inhibitors) increase cGMP like NG drugs which brings about smooth muscle relaxation. Drugs used in combination cause critical hypotension. Nitrates also cause methemoglobinemia (MHb) when given in high concentrations. PM716 C12 Vasodilators 47  Cyanide Cyanide ions complex with the Fe in the enzyme cytochrome oxidase in mitochondria and uncouple oxidative phosphorylation which leads to cell death. If the iron in hemoglobin is converted to the ferric form, methemoglobin (MHb) results. Cyanide will bind to the iron in MHb with greater affinity than to the iron in cytochrome oxidase. MHb forms a sink for cyanide and protects the mitochondria from initiating cell death. PM716 C12 Vasodilators 48  Cyanide Unfortunately MHb can not carry oxygen when iron is in the ferrous state (“Blue Babies” etc) Treatment for cyanide exposure: (1) Sodium Nitrite iv to form MHb which pulls cyanide from cytochrome oxidase and/or forms a sink. (2) Sodium thiosulfate iv which converts cyanide-MHb to thiocyanate + MHb. Thiocyanate is nontoxic and excreted in the kidneys. (3) Reduce the MHb levels back to normal with oxygen and supportive therapy and/or methylene blue iv PM716 C12 Vasodilators 49  Nitrite Toxicity (1)Well water contaminated with farm fertilizer run off. (2)Sodium nitrite used to cure meats, mistaken for salt in the kitchen. (3)Nitrite complexes with ferrous iron in Hb (4)Nitrite-Ferric complex = methemoglobin (5)Methemoglobin has reduced capacity to carry oxygen (blue baby syndrome, blue man syndrome). PM716 C12 Vasodilators 50  MHb MHb can form when Hb iron is reduced to ferrous state by drugs and toxic chemicals. MHb is a very poor carrier of oxygen and patient presents with blue skin. PM716 C12 Vasodilators 51  Nitrite Toxicity (6) Cyanide toxicity is treated with sodium nitrite (7) Give sodium nitrite IV, forms large amts of methemoglobin (8) The ferric iron in methemoglobin sucks up cyanide to form cyanmethoglobin PM716 C12 Vasodilators 52  Nitrite Toxicity (9) Administer sodium thiosulfate which pulls out the ferric-cyanide from methemoglobin to form thiocyanate. (10) Thiocyanate is non-toxic and easily excreted. (11) Convert methemoglobin back to Hb with methylene blue. PM716 C12 Vasodilators 53 Drugs Which Can Induce MHb PM716 C12 Vasodilators 54  Calcium Channel Blockers (CCB) All are active po with half lives of 3-6 h. Many approved for use in treatment of angina. PM716 C12 Vasodilators 55  CCB Drugs nifedipine dihydropyridine diltiazem varapamil PM716 C12 Vasodilators 56 Chapter 12 Vasodilators & the Treatment of Angina Pectoris PM716 C12 Vasodilators 57 © The McGraw-Hill Companies, Inc,  CCB All block voltage gated L-Type calcium channels in cardiac smooth muscle. PM716 C12 Vasodilators 58  CCB CCBs block influx of Ca++ and muscle will not fire. L-Channels not found on neurons. (1) Ca++ flows into muscle and binds to calmodulin. (2) Ca-Calmodulin activates myosin-light-chain kinase (MLCK) enzyme (3) MLCK phosphorylates myosin light chain (MLC) (4) Phosphorylated MLC forms cross bridges with actin and muscle fires. PM716 C12 Vasodilators 59  CCB Nifedipine (Procardia®) and others block calcium channels, relax smooth muscle, relieve angina. Also, block calcium dependent AV node conduction and are used to treat arrhythmias and to reduce blood pressure. PM716 C12 Vasodilators 60  CCB Used for prophylactic therapy in both effort and vasospastic angina. Used in combination with nitrates in atherosclerotic angina. Used to treat Raynaud’s syndrome. PM716 C12 Vasodilators 61  Nifedipine Timed Released Capsule Drug Out Drug Permeable Membrane Drug Capsule Drug Push Layer (Osmotic) PM716 C12 Vasodilators 62  CCB ADRs Constipation, nausea, pretibial edema, flushing, dizziness. PM716 C12 Vasodilators 63 Peripheral Artery Disease (PAD) PAD often caused by atherosclerosis causes poor blood flow and intermittent pain (intermittent claudication). Exercise tolerance is greatly reduced, chronic ischemic ulcers can develop, infection soon follows. PM716 C12 Vasodilators 64  PAD Drugs Used To Treat: Cilostazol, a phosphodiesterase (PDE-3 form) inhibitor, increased cAMP leads to vasodilation and increased blood flow. Sildenafil (Viagra®) has same MOA but inhibits PDE-5. PM716 C12 Vasodilators 65  Beta-Blockers All beta-blockers are effective in the prophylaxis of atherosclerotic angina. PM716 C12 Vasodilators 66  Beta Blockers Used only for prophylaxis therapy of angina. No value for acute attack. Not protective against vasospastic form. PM716 C12 Vasodilators 67  Summary All Drugs Nitrates BB or CCB Nitrate + BB or CCB Heart Rate r increase decrease decrease Aterial Pres decrease decrease decrease Diastolic pr decrease increase decrease Contractil r increase decrease no effect Ejection tim r decrease increase no effect PM716 C12 Vasodilators 68 Chapter 12 Vasodilators & the Treatment of Angina Pectoris PM716 C12 Vasodilators 69 © The McGraw-Hill Companies, Inc,  Summary Nitrates Decrease cGMP which blocks muscle contraction. CCB Block in-flow of calcium BB Increase cAMP which speeds up activation of MLCK enzyme. PM716 C12 Vasodilators 70  Vasodilators Drugs dilate the blood vessels by acting directly on the smooth muscle cells through nonautonomic mechanisms: (1) Release of Nitric Oxide (NO) (2) Hyperpolarization by opening potassium channels (3) Block calcium channels (4) Activate dopamine (D1) receptors. PM716 C12 Vasodilators 71  Vasodilators Release NO from endothelial cells Hydralazine’s mechanism of action Toxic in high doses (tachycardia, salt retetion, lupus erythematosus) Less toxic at < 200 mg/d PM716 C12 Vasodilators 72  Vasodilators Opens potassium channels hyperpolarized cell is relaxed Minoxidil is a prodrug converted to minoxidil sulfate which binds to potassium channels. PM716 C12 Vasodilators 73  Vasodilators Calcium Channel Blockers nifedipine, verapamil, diltiazem cause vasodilation K Chap 12 Nitroprusside IV drug used to lower BP in emergencies Direct source of NO PM716 C12 Vasodilators 74  CCB All block voltage gated L-Type calcium channels in cardiac smooth muscle. PM716 C12 Vasodilators 75  CCB CCBs block influx of Ca++ and muscle will not fire. L-Channels not found on neurons. (1) Ca++ flows into muscle and binds to calmodulin. (2) Ca-Calmodulin activates myosin-light-chain kinase (MLCK) enzyme (3) MLCK phosphorylates myosin light chain (MLC) (4) Phosphorylated MLC forms cross bridges with actin and muscle fires. PM716 C12 Vasodilators 76  Nitroprusside Within smooth muscle drug becomes denitrated which releases NO. NO stimulates guanylyl cyclase which increase cGMP. Increased cGMP dephosphorylates mysoin light chains (dephosphorylation causes inactivation of myosin). Muscle relaxes. PM716 C12 Vasodilators 77 Nitroprusside Used since 1929 to lower blood pressure. Drug acts through release of NO which causes vasodilation. PM716 C12 Vasodilators 78  Vasodilators Fenoldopam Dopamine D1 receptor agonist results in arterial vasodilation iv only, used for hypertensive crisis PM716 C12 Vasodilators 79 Peripheral Artery Disease (PAD) & Intermittent Claudication Atherosclerosis leads to ischemia of the peripheral muscles just like in the heart. Pain (claudication) occurs with exercise, reduced with rest. Chronic ischemic ulcers and susceptibility to infection can occur. Pentoxifylline, a xanthine derivative, reduces blood viscosity. Cilostazol, PDE type 3 inhibitor, a vasodilator. PM716 C12 Vasodilators 80