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Pharmacology of Organic Nitrates

This document provides an overview of organic nitrates and their role in regulating vascular tone and treating cardiovascular conditions like angina. It discusses how nitric oxide (NO) is produced in endothelial cells and causes vasodilation by stimulating guanylate cyclase in vascular smooth muscle cells. Organic nitrates are metabolized to release NO, causing smooth muscle relaxation and vasodilation. Different preparations provide varying durations and routes of nitrate delivery for conditions like angina attacks or long-term management. Tolerance can limit long-term use, requiring nitrate-free intervals. Adverse effects include headache and hypotension. Sodium nitroprusside is also discussed as an intravenous vasodilator used for hypertensive emerg

Health & Medicine◦
CVS Pharmacology (V) Organic Nitrates Dr Htet Htet MBBS, MMedSc Lecturer (Clinical Pharmacology) Faculty of Medicine All rights reserved
Lecture objectives • At the end of the lecture, students should be able to • Understand the role of NO (nitrous oxide) in regulation of vascular tone. • Explain the pharmacology of nitrates and nitrites. • Role of nitrates and cardiovascular pharmacology.
Learning outline • Physiologic control of vascular tone • Role of nitrous oxide in regulation of vascular tone • Pharmacology of organic nitrates
Regulation of vascular tone • Governed by a wide variety of mechanisms. • Interaction between vascular endothelial cells and vascular smooth muscle.
Regulation of vascular tone • Autonomic nervous system • Neurohormonal mediators • Vascular smooth muscle contraction and relaxation • Vasoconstriction • vasodilation
Role of NO (nitrous oxide) in regulation of vascular tone
Endothelial regulation of nitric oxide- mediated vascular smooth muscle relaxation • Production of NO is stimulated by agonists such as acetylcholine or bradykinin. • Stimulation of receptors by these agonists activates Ca2+ second messenger systems and promotes direct entry of Ca2+ into the cytosol. • The increased cytosolic Ca2+ activates a Ca2+ - calmodulin complex that stimulates endothelial nitric oxide synthase (eNOS), an enzyme that catalyzes the formation of NO from L-arginine (L-Arg, an amino acid). • NO diffuses from the endothelial cell into subjacent vascular smooth muscle cells, where it activates guanylyl cyclase, promoting smooth muscle cell relaxation. • NO can also directly activate Ca2+ -dependent K+ channels. • This parallel signaling pathway contributes to relaxation by hyperpolarizing the smooth muscle cell. The active form of each enzyme is italicized and blue.
Effects of endothelin on the blood vessel wall • Endothelin mediates both contraction and relaxation of vascular smooth muscle cells. • Endothelin precursors in endothelial cells are processed to endothelin-1. • Endothelin-1 is secreted on the basal side of the endothelial cell, where it interacts with ETA and ETB receptors on vascular smooth muscle cells. • Activation of these receptors stimulates contraction by incompletely understood mechanisms. • ETB receptors are also expressed on endothelial cells. Endothelial cell ETB activation stimulates cyclooxygenase (COX), which catalyzes the formation of prostacyclin from arachidonic acid. • Prostacyclin diffuses from the endothelial cell to the vascular smooth muscle cell membrane, where it binds to and activates the isoprostanoid (IP) receptor. • ETB activation also stimulates endothelial nitric oxide synthase (eNOS), which catalyzes the formation of NO from arginine (L-Arg). • Both prostacyclin and NO stimulate vascular smooth muscle cell relaxation.
Pharmacology of organic nitrates • One of the oldest cardiac therapies still in use • Was first employed for relief of angina symptoms over 100 years ago.
Mechanism of action of nitrates • In the body, organic nitrates are chemically reduced to release NO (nitrous oxide), a gas that can dissolve in biological fluids and in cellular membranes. • Nitrates  formation of NO (nitric oxide)  activate guanylate cyclase   cGMP  activate protein kinase  dephosphorylation of light chain myosin  relaxation of actin-myosin  smooth muscle relaxation  vasodilatation
Pharmacological action/effects at organ level • Low dose  preferentially venodilation more than arteries  Venour return to the heart   preload of the heart • higher dose   arteriolar resistance afterload • Dilation of coronary arteries   coronary blood flow  Oxygen supply Relief of angina Relief of hypertension Cardiac workload  oxygen demand Vasodilation of both arteries and veins
Other Pharmacological actions • Relaxation of other smooth muscles: esophageal, bronchial, biliary, intestinal and genital urinary. • Action on platelets: • NO release from nitroglycerine activate Guanylate cyclase in platelets -  cGMP – responsible for decrease in platelet aggregation.
Different preparation of nitrates • Several different preparations of organic nitrates are currently available. • The most commonly used organic nitrates include NTG , isosorbide dinitrate , and isosorbide 5-mononitrate . • Although these organic nitrates share a common mechanism of action, they differ in their routes of administration and pharmacokinetics, leading to important differences in their therapeutic utility in a variety of clinical settings.
Inhaled nitric oxide gas • can be used to selectively dilate the pulmonary vasculature. • As NO is rapidly inactivated by binding to hemoglobin in the blood, NO gas has little effect on systemic blood pressure when administered by inhalation. • Therapy with inhaled NO has established efficacy in the treatment of primary pulmonary hypertension of the newborn, but the therapeutic value of inhaled NO in other conditions characterized by elevated pulmonary artery pressures (including heart failure and various forms of lung disease) remains to be established.
Different preparations for different clinical conditions • Sublingual GTN (glyceryl trinitrate) – for rapid relief of angina attack. (High hepatic first pass effect in liver + & low bioavailability – use SL in emergency. ) • IV administration of nitrates – when continuous titration is necessary – in unstable angina or acute heart failure. • Slow release transdermal or buccal preparations – provide stable therapeutic level of GTN for prevention of angina. • Long acting, oral – for long term management of angina. • Inhaled NO – very short half life – effects on pulmonary vasculature
Pharmacokinetics • Low bioavailability – due to high first pass effect in liver. • Half life – depend on preparation – • NTG (nitroglycerine)T ½ - short – approximately 5 minutes • Isosorbide dinitrate – t ½ - around 1 hour • Isosorbide 5 mononitrate –T ½ - 2-4 hours • Isosorbide 5 mononitrate – • LongT ½ • Well absorbed from GIT and not susceptible to hepatic first pass effect • Bioavailability – nearly 100%.
Nitrate tolerance • Physiologic tolerance • Effects can be offset by sympathetic nervous system responses (by increasing the tone) & due to compensatory responses (eg. Salt and water retension) • Pharmacological tolerance • “Monday morning headache” in munition workers – headache tended to disappear as the week progressed, proving this “tolerance”. • Headache is one of the adverse effects (tolerance is desirable) • But tolerance to clinical effects (antianginal effects) – • Treatment – “nitrate free interval” • Eg. Removal of nitrate patch during night time for transdermal preparations.
Therapeutic uses • Acute attack of angina • Prevention of angina attacks (long term management) • Clinical efficacy of slow release forms in maintenance therapy is limited by the development of tolerance. Nitrate free period of at least 8 hours between doses should be observed to prevent tolerance.
Untoward effects • Acute adverse effects • Transdermal patches should be removed before defibrillation. • Arteriolar dilatation in face and neck  facial flush • Dilation of meningeal vessels  throbbing headache • At higher dose  SBP & DBP  CO  pallor, weakness, dizziness • Postural Hypotension  reflex tachycardia • Impaired vision • Smooth muscle  bronchial smooth muscle relaxation , GI (biliary tract) relaxation
Untoward effects • Tolerance • Long acting preparations (oral, transdermal) or continuous IVI used for more than a few hours without interruption. • Carcinogenicity • Nitrosoamines are molecules result from combination of nitrates with amines. • Nitrosoamines are powerful carcinogens. • No direct evidence of nitrates used in angina can result high level of nitrosoamines.
Contraindications • Hypotension • Patients with elevated ICP intracranial pressure • Angina due to HOCM (reduction in preload can worsen the condition) • Should be used with caution in patients with diastolic heart failure (who depend on preload for optimal cardiac output) • Patient who are taking sildenafil or other PDE inhibitors for ED.
Sodium Nitroprusside • Sodium nitroprusside is a nitrate compound that consists of a nitroso group, five cyanide groups, and an iron atom.
Mechanism of action & Pharmacological action • As with the organic nitrates, sodium nitroprusside effects vasodilation by release of NO. • Sodium nitroprusside’s action does not appear to be targeted to specific types of vessels and, consequently, the drug dilates both arteries and veins.
Therapeutic uses • Sodium nitroprusside is used intravenously for powerful hemodynamic control in hypertensive emergencies and severe heart failure. Because of its rapid onset of action, short duration of action and high efficacy.
Danger of sodium nitroprusside • Spontaneously decompose to liberate NO and cyanide • Cyanide converted into thiocyanate in the liver • Thiocyanate is excreted via kidney. • Patients with impaired renal function • Excessive cyanide accumulation • Lead to acid base disturbances • Cardiac arrhythmias and even death. • Other features: disorientation, psychosis, muscle spasms and seizures.
References