Nitrates are not used in
Renal colic The main pharmacological action of Nitrates Nitroglycerine relaxes all types of smooth muscle irrespective of the state of the preexisting muscle tone. The most prominent action is exeed on the vascular smooth muscle. - Apa .from vascular smooth muscle nitrates also cause relaxation of the smooth muscles of the bronchi, gastrointestinal tract (including biliary system) and genitourinary tract. Nitrates are rapidly denitrated in the smooth muscle to release nitric oxide which activates cytosolic guanyl cyclase which in turn increases CGMP that leads to vasodilation Effect of nitrate on cardiovascular system Enzymes activates Nitrates --4 NO --> Gyanylcyclase 1' CGMP Vasodilation Nitrates cause relaxation of all the components of vascular system from large aeries to veins, aerioles and capillaries. Veins respond at the lowest concentrations and aeries at slightly higher one (Veins express greater amount of the enzyme that generates NO )from organic nitrates). The primary direct result of an effective dose of nitroglycerine is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. This leads to reduction in pulmonary vascular pressure and hea size. Effect of nitrates on coronary circulation '* In normal subjects without coronary disease - Nitroglycerine can induce a significant if transient increase in total coronary blood flow. In patients with angina due to atherosclerosis - There is no evidence that total coronary .flow is increased in patients with angina due to atherosclerotic obstructive coronary aery disease. However, in these patients - Nitrates cause redistribution of coronary blood flow from normal to ischemic regions which may play role in therapeutic effect. There are two types of vessels in coronary circulation :Larger conducting aeries They run epicardially and send perforating branches to deeper tissue. Smaller resistance vessels These are the perforating branches of larger conducting aeries. These aerioles supply blood to endocardium. If there is ischemia in any region of endocardium the perforating vessels of those region are dilated due to autoregulation (hypoxia causes vasodilation). Nitrates preferentially dilates larger conducting vessels. This pattern of action ours more blood flow towards the ischaemic zone as the smaller endocardial vessels are already dilated as a result of hypoxia / ischaemia. Nitrates in hea failure Nitrates afford relief by causing venous pooling of blood. - Nitrates reduce venous return (preload) decreases end diastolic volume -4 improvement in left ventricular function by Laplace law regression of pulmonary congestion. Nitrates are used in cyanide poisoning Cyanide poisoning results from complexing of cytochrome iron by the CV ion. - Methemoglobin has a very affinity for CN ion. - Methemoglobin combines with CN to form cyamnethemoglobin which is rapidly excreted by the body. It is a well known fact that Nitrates generate generate Methemoglobin when they combine with Hb. - Thus administration of nitrates will generate large amount of methemoglobin. - Due to its high offinity.for cyanide, methemoglobin combines with cyanide .forming cyanmethemoglobin. - This will regenerate active cytochrome. - However this may again dissociate to release cyanide. - The cynamethemoglobin can be fuher detoxified by the intravenous administration of sodium thiosulfate. This results in formation of thiocyanate ion a less toxic ion that is readily excreted. Biliary colic Esophageal spasm Sublingual GIN promptly relieves pain. Nitrates taken before a meal facilitate feeding in esophageal achalasia by reducing esophageal tone. Also remember these impoant propeies of Nitrates. Oral availability of Nitrates is low The liver contains a high capacity organic nitrate reductase that removes nitrate groups in a stepwise _fashion from the parent molecule and ultimately inactivates the drug. Therefore oral bioavailability of the traditional organic nitrates e.g. nitroglycerine and isosorbidedinitrate is very low. For this reason sublingual route is preferred for nitrates. Nitroglycerine and isosorbide dintrate are both absorbed effectively by this route and reach therapeutic blood levels within a few minutes. Nitrates develop tolerance With continued exposure smooth muscles develop tolerance to nitrates. The mechanism by which tolerance develops are not completely understood. As noted above diminished release of nitric oxide resulting from depletion of tissue thiol compounds may be paly responsible ,for tolerance to nitrates. Some student argue that cyanide poisoning should be the answer because nitrites not nitrates are used in cyanide poisoning but we are not convinced. All the standard books group them together and do not differentiate between nitrates or nitrites. More so Nitrates have'nt found wide clinical use in Renal colic - None of the standard text books mention use of nitrates in renal colic. - Both Goodman Gilman and KDT says that unlike its consistent effect on muscles of biliary tract, the action of nitrates on ureteric muscles is variable therefore it has not found application in renal colic. - None of the studies and research papers convincingly state that nitrates should be used in renal colic. Nitrates have been anecdotally used only in uruguay to treat renal colic. A trial was conducted based on this but it did'nt come out with conclusive results. - It states that large trials and studies should be undeaken before nitrates before nitrates use is begun clinically.
CCF
Esophageal spasm
Renal Colic
Cyanide poisoning