Organic nitrates (and nitrite) were introduced into medicine in the 19th century.1 Denitration in the smooth muscle cell releases nitric oxide (NO), which is the main physiological vasodilator, normally produced by endothelial cells. Nitrodilators (a generic term for drugs that release or mimic the action of NO) activate the soluble guanylate cyclase in vascular smooth muscle cells and cause an increase in intracellular cyclic GMP (guanosine monophosphate) con
1 Murrell, W 1879 Nitroglycerin as a remedy for angina pectoris. Lancet 1: 80-81. Nitroglycerin was actually first synthesised by Sobrero in 1847 who noted when he applied it to his tongue it caused a severe headache.
centrations. This is the second messenger that alters calcium fluxes in the cell, decreases stored calcium, and induces relaxation. The result is a generalised dilatation of venules (capacitance vessels) and to a lesser extent of arterioles (resistance vessels), causing a fall of blood pressure that is postural at first; the larger coronary arteries especially dilate. Whereas some vasodilators can 'steal' blood away from atheromatous arteries, with their fixed stenoses, to other, healthier arteries, nitrates probably have the reverse effect as a result of their supplementing the endogenous NO. Atheroma is associated with impaired endothelial function, resulting in reduced release of NO and, possibly, its accelerated destruction by the oxidised LDL in atheroma (see Ch. 25).
The venous dilatation causes a reduction in venous return, a fall in left ventricular filling pressure with reduced stroke volume, but cardiac output (per min) is sustained by the reflex tachycardia induced by the fall in blood pressure.
Pharmacokinetics. The nitrates are generally well absorbed across skin, and the mucosal surface of the mouth or gut wall. Nitrates absorbed from the gut, however, are subject to extensive first-pass metabolism in the liver, as is shown by the substantially larger doses required by that route over sublingual application (this also explains why swallowing a sublingual tablet of glyceryl trinitrate terminates its effect). They are first denitrated and then conjugated with glucuronic acid. The t1/, periods vary (see below) but for glyceryl trinitrate (GTN) it is 1-4 minutes.
Tolerance to the characteristic vasodilator headache comes and goes quickly (hours).2 Ensuring that a continuous steady-state plasma concentration is avoided prevents tolerance. This is easy with occasional use of glyceryl trinitrate, but with nitrates having longer t'/2 (see below) and sustained release formulations it is necessary to plan the dosing to allow low plasma concentration for 4-8 h, e.g. over
2 Explosives factory workers exposed to a nitrate-contaminated environment lost it over a weekend and some chose to maintain their intake by using nitrate impregnated headbands (transdermal absorption) rather than have to accept the headaches and reacquire tolerance so frequently.
night; alternatively transdermal patches may be removed for a few hours if tolerance is suspected.
Uses. Nitrates are chiefly used to relieve angina pectoris and sometimes left ventricular failure. An excessive fall in blood pressure will reduce coronary flow as well as cause fainting due to reduced cerebral blood flow, and so it is important to avoid accidental overdosing. Patients with angina should be instructed on the signs of overdose — palpitations, dizziness, blurred vision, headache and flushing following by pallor — and what to do about it (below).
The discovery that coronary artery occlusion by thrombosis is itself 'stuttering' — developing gradually over hours — and associated with vasospasm in other parts of the coronary tree has made the use of isosorbide dinitrate (Isoket) by continuous i.v. infusion adjusted to the degree of pain, a logical, and effective, form of analgesia for unstable angina.
Transient relief of pain due to spasm of other smooth muscle (colic), can sometimes be obtained, so that relief of chest pain by nitrates does not prove the diagnosis of angina pectoris.
Nitrates are contraindicated in angina due to anaemia.
Adverse effects. Collapse due to fall in blood pressure resulting from overdose is the commonest side effect. The patient should remain supine, and the legs should be raised above the head to restore venous return to the heart.
Nitrate headache, which may be severe, is probably due to the stretching of pain-sensitive tissues around the meningeal arteries resulting from the increased pulsation that accompanies the local vasodilatation. If headache is severe the dose should be halved. Methaemoglobinaemia occurs with heavy dosage.
Interactions. An important footnote to the use of nitrates (and NO-dilators generally) has been the marked potentiation of their vasodilator effects observed in patients taking the phosphodiesterase (PDE) inhibitor sildenafil (Viagra). This agent targets an isoform of PDE (PDE-5) expressed in the blood vessel wall. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma. A
number of pericoital deaths reported in patients taking sildenafil have been attributed to the substantial fall in blood pressure that occurs when used with a nitrate. This is an ironic twist for an agent in first-line use in erectile dysfunction that was originally developed as a drug to treat angina.3
GLYCERYLTRINITRATE (see also above)
Glyceryl trinitrate (1879) (trinitrin, nitroglycerin, GTN) (t1/ 3 min) is an oily, nonflammable liquid that explodes on concussion with a force greater than that of gunpowder. Physicians meet it mixed with inert substances and made into a tablet, in which form it is both innocuous and fairly stable. But tablets more than 8 weeks old or exposed to heat or air will have lost potency by evaporation and should be discarded. Patients should also be warned to expect the tablet to cause a burning sensation under the tongue if it is still contains active GTN. An alternative is to use a nitroglycerin spray (see below); formulated as a pressurised liquid GTN has a shelf life of at least 3 years.
GTN is the drug of choice in the treatment of an attack of angina pectoris. The tablets should be chewed and dissolved under the tongue, or placed in the buccal sulcus, where absorption is rapid and reliable. Time spent ensuring that patients understand the way to take the tablets and that the feeling of fullness in the head is harmless, is time well spent. The action begins in 2 min and lasts up to 30 min. The dose in the standard tablet is 300 micrograms, and 500 or 600 microgram strengths are also available; patients may use up to 6 mg daily in total but those who require more than 2-3 tablets per week should take a long-acting nitrate preparation. GTN is taken at the onset of pain and as a prophylactic immediately before any exertion likely to precipitate the pain. Sustained-release buccal tablets are available (Suscard), 1-5 mg. Absorption from the gastrointestinal tract is good, but there is such extensive hepatic first-pass metabolism that
3 It has been argued that deaths on sildenafil largely reflect the fact that it is used by patients at high cardiovascular risk. But recent postmarketing data shows that death is 50 times more likely after sildenafil taken for erectile failure than alprostadil, the previous first-line agent. Mitka M 2000 Journal of the American Medical Association 283:590.
the sublingual or buccal route is preferred; an oral metered aerosol that is sprayed under the tongue (nitrolingual spray) is an alternative.
For prophylaxis, GTN can be given as an oral (buccal, or to swallow, Sustac) sustained-release formulation or via the skin as a patch (or ointment); these formulations can be useful for victims of nocturnal angina.4
Venepuncture: the ointment can assist difficult venepuncture and a transdermal patch adjacent to an i.v. infusion site can prevent extravasation and phlebitis and prolong infusion survival.
Isosorbide dinitrate (Cedocard) (t1/, 20 min) is used for prophylaxis of angina pectoris and for congestive heart failure (tabs sublingual, and to swallow). An i.v. formulation 500 micrograms/ml (Isoket) is available for use in left ventricular failure and unstable angina.
Isosorbide mononitrate (Elantan) (t]/2 4 h) is used for prophylaxis of angina (tabs to swallow). Hepatic first-pass metabolism is much less than for the dinitrate so that systemic bioavailability is more reliable.
Pentaerythritol tetranitrate (Peritrate) (t'/2 8h) is less efficacious than its metabolite pentaerythritol trinitrate (tV211 h).
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