Nitrates

1. NITRATES Demitrost Laloo

2. What are nitrates? P rodrugs that are sources of nitric oxide ( NO) Drugs include: Glyceryl trinitrate (nitroglycerin), isosorbide mononitrate and isosorbide dinitrate

3. History Nitroglycerin was first synthesized in 1846 by Sobrero Alfred Nobel devised a process to stabilize the nitroglycerin and patented a specialized detonator in 1863 In 1857, T. Lauder Brunton of Edinburgh administered amyl nitrite by inhalation and noted that anginal pain was relieved within 30- 60 secs William Murrell surmised that the action of nitroglycerin mimicked that of amyl nitrite

4. Chemistry polyol esters of nitric acid characterized by a sequence of carbon–oxygen–nitrogen (—C—O—NO 2 ) Organic nitrates of low molecular mass ( nitroglycerin ) are moderately volatile, oily liquids high-molecular-mass nitrate esters ( e.g.,isosorbide dinitrate , and isosorbide mononitrate ) are solids

5. Mechanism of action Organic nitrates lead to the formation of the reactive gaseous free radical NO and related NO-containing compounds NO can activate guanylyl cyclase , increase the cellular level of cyclic GMP, activate PKG, and modulate the activities of cyclic nucleotide phosphodiesterases In smooth muscle, the net result is reduced phosphorylation of myosin light chain, reduced Ca 2+ concentration in the cytosol , and relaxation

6. Proposed mechanisms underlying bioactivation of organic nitrates

7. Effects of nitrates promote relaxation of vascular smooth muscle Low concentrations of nitroglycerin preferentially dilate veins more than arterioles decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures Systemic arterial pressure may fall slightly

8. Higher doses of organic nitrates cause: Further venous pooling and may decrease arteriolar resistance as well, thereby decreasing blood pressure and cardiac output Causing pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes

9. Reduces myocardial O₂ demand decreasing both preload and afterload Dilating coronary arteries and thereby increasing coronary blood flow mechanisms not entirely clear Most hypotheses : dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small vessels, which are responsible for ~90% of the overall coronary vascular resistance Limits platelet aggregation/adhesion

10. Other effects Bronchial smooth muscle is relaxed irrespective of the preexisting tone The muscles of the biliary tract, including those of the gallbladder, biliary ducts, and sphincter of Oddi , are effectively relaxed Smooth muscle of the GI tract, including that of the esophagus , can be relaxed and its spontaneous motility decreased Relaxes ureteral and uterine smooth muscle

11. Therapeutic uses Mainly used in: Stable angina pectoris CCF Unstable angina pectoris and NSTEMI Acute myocardial infarction Prinzmetal angina Others : Portal hypertension Asthma and as a diuretic (obsolete)

12. Portal HTN Nitroglycerin has been used in combination with vasopressin to control acute variceal bleeding. The rate of infusion of nitroglycerin is 50 to 400 μg /min, provided that the systolic blood pressure > 90 mmHg Nitrates are no longer recommended, either alone or in combination with a ß blocker, for primary prophylaxis to prevent first variceal bleeds For secondary prophylaxis (to prevent variceal rebleeding ), isosorbide mononitrate may be added to a beta blocker if the beta blocker alone has not resulted in an appropriate decrease in HVPG

13. Adverse effects Headache Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop High doses of organic nitrates causes postural hypotension, facial flushing, and tachycardia Prolonged therapy causes endothelial dysfunction

14. Interactions Phosphodiesterase V inhibitors such as sildenafil , tardenafil , and vardenafil potentiate the action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated.

15. Tolerance Tolerance to the actions of nitrates develops rapidly and blood vessels become desensitized to vasodilation Reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO: True vascular tolerance Activation of mechanisms extraneous to the vessel wall: Pseudotolerance Multiple mechanisms have been proposed to account for nitrate tolerance PETN is the only organic nitrate in clinical use, which is devoid of induction of oxidative stress and related side-effects such as endothelial dysfunction and nitrate tolerance

16. Strategies to prevent Tolerance Tolerance can be overcome by providing a daily “nitrate-free interval” to restore sensitivity to the drug This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time

17. Other strategies Sulfhydryl Group Donors N- acetylcysteine and L- methionine Antioxidants ACE Inhibitors and Angiotensin-1 Receptor Blockers Hydralazine Carvedilol Statins

18. Nitrates is also… Found in groundwater and soil Use as preservatives in processed food Drinking water that contains high levels of nitrates can be toxic to humans especially infants Causes Methemoglobinemia , also known as ‘ Baby Blue Syndrome ’ in infants Excess nitrates ingestion also implicated in cancer, thyroid hypertrophy

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