Nitrates

·        Mechanism of action.

·        Pharmacokinetics.

Mechanism of action

1.    The nitrates and nitrites are denitrated in smooth muscle to release nitric oxide (NO).

2.    NO activates guanylate cyclase and increase the synthesis of cyclic GMP.

3.    A cGMP-dependent protein is stimulated and this leads to the dephosphorylation of the light chain of myosin and resulting in smooth muscle relaxation.

Pharmacokinetics

1.    The nitrates are generally well absorbed through oral and intestinal mucosal and the skin and are used by these routes.

2.    They are subject to extensive and rapid metabolism in the liver at first-pass after absorption from the gut.

3.    They are first denitrated to mononitrates and then conjugated with glucuronic acid.

4.       Preparations and routes of administration:

5.       Sublingual glyceryl trinitrate is the most frequently used preparation for the relief of anginal symptoms because of its ease of administration and rapid onset of action.

Effects on Heart

1.    The nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure.

2.    The basic action of the nitrates is to relax all smooth muscles, the relaxation being more in veins than in arteries.

3.       Venodilation and venous pooling:

a.       reduces venous return to the heart resulting in a reduction in ventricular end-diastolic herat pressure and heart size.

b.       improve subendocardial perfusion.

4.       Arteriolar dilatation reduces peripheral resistance and myocardial workload and further reducing myocardial demand for oxygen.

5.    The nitrates relieve anginal symptoms by reducing the myocardial demand for oxygen and improving myocardial perfusion rather than by increasing coronary blood flow.

6.       Apart from angina pectoris, the nitrates may be used for relieving esophageal spasm managing heart failure and for controlling postoperative hypertension.

Adverse effects

1.       Dizziness: due to postural hypotension.

2.       Palpitations: due to compensatory increase in heart rate.

3.       Throbbing headache: due to meningeal artery pulsations.

4.       Methaemoglobinaemia at high doses.

5.       Tolerance:

a.    More likely with high doses of nitrates with longer half-life giving a steady plasma concentration.

b.       There is cross-tolerance between different nitrates.

c.       Tolerance can be avoided using intermittent dosing.

6.       Contraindications:

a.       Ventricular outflow obstruction.

b.    Low output cardiac failure.

c.       Raised intracranial pressure.

d.       Glaucoma.

e.       Mitral valve collapse.

Individual nitrates

1.       Glyceryl trinitrate:

a.    An oily, nonflammable liquid with a half-life of 3min.

b.       Tablets more than 8 weeks old or exposed to heat or air will have lost potency by evaporation and should be discarded.

c.    Drug of choice in the treatment of an attack of angina pectoris; the tablets should be chewed and dissolved under the tongue, where absorption is rapid and reliable.

d.    It is taken at the onset of pain, when stopping exercise to find and take the tablet and as a prophylactic before any exertion.

e.    For prophylaxis, glyceryl trinitrate can be given as an oral sustained-release formulation or via the skin as a patch; these formulations are useful for noctural angina.

2.       Isosorbide dinitrate:

a.    Half-life: 20min.

b.    Used for prophylaxis of angina pectoris and for congestive heart failure.

3.       Isosorbide mononitrate:

a.    Half-life: 4h.

b.    Used for the prophylaxis of angina.

Printable Version