NITRATES 20/01/2011

Organic Nitrates Organic nitrates & nitrites are simple nitric & nitrous esters of glycerol. These agents cause a rapid decrease in myocardial oxygen demand leading to rapid resolution of symptoms. Nitrates are effective for all types of angina.

(angina- occurs when oxygen supply to the myocardium is insufficient for its needs. The pain has a characteristic distribution in the chest, arm and neck) Activation of guanylate cyclase increases cGMP (cyclic 3’5’-guanosine monophosphate) activating a cGMP kinase leading to dephosphorylation of myosin light chains decreasing contractile force.

Organic Nitrates Organic nitrates which are important are the glyceryl trinitrate and isosorbide mononitrate These are organic esters of nitric acid Are sufficiently lipid soluble to penetrate cell membranes. The molecules can be regarded as carriers of nitrite ion (NO2-) that is the precursor of the active species nitric oxide

Nitrates-Actions Smooth muscle -Blood vessels-relaxation of vascular smooth muscle leading to vasodilatation. The effect on veins and venules is greater than that on the arteriolar tree, resulting in skin flushing. The filling pressure at the heart (pre-load) is reduced to a greater extent than total periphery resistance (after-load)

Nitrates-Action -other smooth muscle: organic nitrates are capable of relaxing all kinds of smooth muscle, including that of bronchi, biliary tract, gut and genitourinary tract

Nitrates-Action The heart: Tachycardia arises reflexly from nitrate-induced vasodilatation. However, the load on the heart (principally pre-load) is also reduced so that the cardiac work required per unit of cardiac output is reduced

Mechanism of Action Organic nitrates are metabolized with release of NO (Nitric oxide). At concentrations achieved during therapeutic use, this involves an enzymic step and possibly a reaction with tissue sulfhydril (SH-) groups. NO activates soluble guanylate cyclase increasing formation of cGMP,

which activates protein kinase G and leads to a cascade of effects in smooth muscle culminating in dephosphorylation of myosin light chains and sequestration of intracellular Ca++, with consequent relaxation.

Pharmacokinetics Glyceryl trinitrate is rapidly inactivated by hepatic metabolism. It is well absorbed from the mouth and is taken as a tablet under the tongue or as a sublingual spray, producing its effects within a few minutes If swallowed it is ineffective because of first-pass metabolism

Pharmacokinetics… Given sublingually, the trinitrate is converted to di- and mononitrates. Its effective duration of action is approximately 30 minutes Well absorbed through the skin, and a more sustained effect can be achieved by applying it as a transdermal patch.

Pharmacokinetics… Once a bottle of the tablets has been opened, its shelf life is quite short because the volatile active substance evaporates. Spray preparations avoid this problem. Isosorbide mononitrate & isosorbide dinitrate are long acting nitrates that are relatively resistant to hepatic catabolism t1/2 ~ 1- 4 hours. Swallowed rather than taken sublingual

Adverse Effects The most common side effect of nitrates is headache due to veno-dilation, patients whom intermittently used nitrate preparation should be asked about headaches after nitrate use; lack of headache often indicates degradation of agent with a loss of therapeutic effect. Postural hypotension & syncope particularly with sublingual use.

Adverse Effects (cont.) Tachycardia Methaemaglobinemia can occur with chronic use of long term agents, this may occur when sublingual use is combined with long acting agents.

Adverse Effects (cont) Withdrawal symptoms may occur (an indication of tolerance) when nitrate agents are tapered or discontinued, this may precipitate anginal attacks.

Tolerance Tolerance to the actions of nitrates develops rapidly for their vasodilatory effects. Sustained treatment with nitroglycerin in vivo is associated with reduced biotransformation of nitrate to NO by endothelial mitochondrial enzyme aldehyde dehydrogenase-2 , this abnormality in nitrate biotransformation is associated with increased mitochondrial formation of free radical oxygen species.

Tolerance can be avoided by providing a “nitrate free” interval daily; for most angina patients this is at night when myocardial demand is low.

Clinical Uses of Organic Nitrates Stable angina -prevention (e.g. regular isosorbide mononitrate or glyceryl trinitrate sublingually immediately before exertion) -treatment (sublingual glyceryl trinitrate) Unstable angina: i/v glyceryl trinitrate Acute heart failure: i/v glyceryl trinitrate

Clinical Uses of Organic Nitrates Chronic heart failure: isosorbide mononitrate, with hydralazine when angiotensin converting enzyme inhibitors (which are more effective) are contraindicated Uses related to relaxation of other smooth muscles (e.g. uterine, biliary) are being investigated