Transdermal Nitroglycerin (Glyceryl Trinitrate

Summary

Synopsis

Nitroglycerin (glyceryl trinitrate) has been used for many years via the sublingual route for treating acute anginal attacks. In recent years transdermal delivery of nitwglycerin has gained popularity for prophylaxis against angina. However, nitrate tolerance appears to be a therapeutic problem with all long-acting nitrates regardless of delivery mechanism, and it occurs in most patients with stable angina treated with continuous 24-hour application of nitwglycerin patches. Since continuous 24-hour plasma concentrations of nitwglycerin do not appear to be desirable, alternative approaches to therapy are needed. A simple method to minimise tolerance with transdermal nitwglycerin patches is to remove the patch at bedtime and reapply a new patch in the morning. Such intermittent therapy allows a patch-free period during the night, when most patients experience few angina attacks, but optimises nitrate sensitivity during the daytime. However, the place of intermittent nitwglycerin patch therapy in the treatment of stable angina needs clarification with further study, particularly comparisons with other long-acting forms of nitrates. There are insufficient data to recommend the use of transdermal nitwglycerin patches in the treatment of patients with unstable angina or congestive heart failure

In conclusion, transdermal nitwglycerin patches offer a convenient and cosmetically acceptable dosage form which has potential use in stable angina if administered as an intermittent regimen providing a patch-free period each night

Pharmacological Profile

The numerous formulations of nitroglycerin patches, while using different technologies in their manufacture, essentially achieve the same pharmacological end-point at equivalent doses, i.e. the constant release of the drug across the skin into systemic circulation for 24 hours which achieves constant steady-state plasma concentrations of nitroglycerin

The primary anti-ischaemic mechanism of action of nitroglycerin is believed to be relaxation of vascular smooth muscle. The biochemical events leading to vascular relaxation remain unknown, but are thought to include effects on cyclic guanosine monophosphate production to induce contractile protein relaxation, and the possibility that nitrates may be physiological substitutes for endothelium-derived relaxing factor (EDRF). Nonetheless, consequent vasodilatation leads to a reduction in preload and cardiac oxygen demand. A number of other mechanisms have been hypothesised, with recent evidence strongly suggesting an additional direct anti-ischaemic effect produced by improved coronary blood flow. In patients with congestive heart failure the higher doses that are generally used may produce a reduction in afterload from arteriolar dilatation, as well as the more important reduction in preload

Systemic bioavailability of nitroglycerin is about 75 to 90% following patch administration. The drug is detected in plasma 30 to 60 minutes after application, steady-state plasma concentrations persist from 2 to 24 hours, and no drug is measurable in plasma within 1 hour of patch removal. Mean steady-state plasma concentrations are about 0.2 µg/L after a patch dose of 0.4 mg/h and are directly proportional to the dose administered. There may, however, be wide intra-and interindividual variation; up to 10-fold differences have been noted. This is probably related to the large volume of distribution (3 L/kg); plasma nitrate probably accounts for no more than 1% of the total body nitrate pool. The site of patch application does not affect absorption, but exercise or sauna may increase the rate of absorption from nitroglycerin patches. A phasic release nitroglycerin patch has recently been developed which delivers about 75% of the dose in the first 12 hours and only 10 to 15% in the last 6 hours

Metabolism of nitroglycerin is rapid (half-life of a few minutes): the action of glutathione-organic nitrate reductase yields 1-and 2-mononitrates, 1,2-and 1,3-dinitrates, and glycerol which are mainly excreted renally. Relatively high dinitrate concentrations may be achieved in plasma and may contribute to the pharmacological activity of the drug

Therapeutic Use

Controlled clinical trials of the continuous application of nitroglycerin patches throughout each 24-hour period indicate that tolerance may develop to the antianginal and anti-ischaemic effects of the drug in the majority of patients with stable angina. Attenuation of the response occurs as early as 8 to 12 hours after patch application, and opinion is divided whether any benefit is gained during long term continuous therapy. Therefore, as indicated by recent studies ‘intermittent’ therapy may provide a more rational approach to therapy. Removal of the patch for 10 to 12 hours in each 24-hour period provides a patch-free period which may allow the re-establishment of sensitivity to nitroglycerin. Use of a phasic-release nitroglycerin patch, which provides a ‘nitrate-low’ interval in each 24-hour period, may reduce the likelihood of developing tolerance. Comparisons with continuous patch application in fact do show improved maintenance of therapeutic effect with intermittent therapy. Longer term studies in larger numbers of patients are therefore required with ‘intermittent’ and phasic-release patch therapy to define more precisely the clinical efficacy of their anti-ischaemic and antianginal action, in particular compared with other established long-acting nitrate treatments such as isosorbide dinitrate. In addition, with intermittent therapy a decreased exercise capacity to angina onset has been noted prior to patch application with long term treatment compared with placebo, raising the possibility of a rebound haemodynamic phenomenon. The clinical relevance of this observation is unknown. Until this has been investigated further, patients should be monitored carefully for any increase in angina frequency or severity during the patch-free period of intermittent therapy

Studies of transdermal nitroglycerin in other therapeutic areas, including unstable angina and congestive heart failure, have been relatively few, but have generally indicated that continuous patch application is unlikely to be of use

Adverse Effects

The adverse effect profile of nitroglycerin is well established and results from the drug’s vasodilatory properties. Unwanted effects usually occur early in therapy and may disappear spontaneously or with a dosage reduction. They occur in about 20 to 30% of patients, leading to withdrawal in about 5 to 10% of patients. Headaches account for about three-quarters of all reported effects. This is followed less frequently by cutaneous reactions and postural hypotension (dizziness, weakness, rare syncope, and reflex tachycardia with occasional worsening of angina). Other adverse effects include bradycardia, flushing, nausea and vomiting. Cutaneous reactions usually involve mild erythema but may on occasions involve severe macular erythematous lesions usually related to the nitroglycerin itself and occasionally some component or excipient of the patch

Dosage and Administration

The suggested starting dose of transdermal nitroglycerin in patients with angina is between 0.2 and 0.4 mg/h. Doses of between 0.4 and 0.8 mg/h have shown continued effectiveness for 10 to 12 hours/day for at least one month of intermittent administration. Although the minimum nitrate-free interval has not been defined, a nitrate-free interval of 10 to 12 hours in each 24-hour period, usually at night, limits the potential for tolerance. Thus, an appropriate dosing schedule for nitroglycerin patches would include a daily ‘patch-on’ period of 12 to 14 hours and a daily ‘patch-off’ period of 10 to 12 hours