Isosorbide mononitrate

Isosorbide mononitrate is a drug used principally in the treatment of angina pectoris^[1] and acts by dilating the blood vessels so as to reduce the blood pressure. It is sold by AstraZeneca under the trade name Imdur®.

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Uses

Isosorbide mononitrate is used for the prophylactic treatment of angina pectoris; that is, it is taken in order to prevent or at least reduce the occurrence of angina. Research on Isosorbide mononitrate as a cervical ripener to reduce time at hospital to birth is supportive.^[2]

Pharmacology

Isosorbide mononitrate is an active metabolite of isosorbide dinitrate and exerts qualitatively similar effects. Isosorbide mononitrate reduces the workload of the heart by producing venous and arterial dilation. By reducing the end diastolic pressure and volume, isosorbide mononitrate lowers intramural pressure, hence leading to an improvement in the subendocardial blood flow. The net effect when administering isosorbide mononitrate is therefore a reduced workload for the heart and an improvement in the oxygen supply/demand balance of the myocardium.

Nitrates are highly effective in the prophylaxis of symptomatic and asymptomatic myocardial ischaemia. Nitrates dilate coronary arteries not only in prestenotic and poststenotic vessels, but also in eccentric lesions. The natural initiator of vascular relaxation is thought to be endothelium-derived relaxing factor (EDRF), which has both the clinical and biological characteristics of nitric oxide (NO). Organic nitrates are metabolised to NO in the muscle cell via a sulfhydryl dependent mechanism. They are therefore thought to be the physiological substitute for EDRF.

Pharmacokinetics

Isosorbide mononitrate has an elimination half-life of around five hours. GenRx Isosorbide Mononitrate 60 mg sustained release tablets provide a sustained release presentation of isosorbide mononitrate, with approximately 85% bioavailability. The release mechanism in GenRx Isosorbide Mononitrate comprises active drug distributed within a hydrophobic cellulose matrix with release occurring by diffusion. Drug particles close to the tablet surface are released relatively rapidly, but those incorporated more deeply are released more slowly. Administration of GenRx Isosorbide Mononitrate 60 mg Sustained Release tablets results in a gradual, non-pH dependent release of the active substance, which is completed after approximately ten hours. Compared to ordinary tablets, the absorption phase is prolonged and the duration of effect is extended. The absorption of GenRx Isosorbide Mononitrate 60 mg Sustained Release tablets has been shown not to be influenced by food intake.

After repeated once daily administration of GenRx Isosorbide Mononitrate 60 mg Sustained Release tablets, the maximum plasma level (about 3,000 nanomol/L) of isosorbide mononitrate is achieved at about four hours. The plasma concentration remains above 1,400 to 1,500 nanomol/L for approximately ten hours, dropping to under 500 nanomol/L by the end of the dosage interval (24 hours after dose). This nitrate low period minimises the possibility of nitrate tolerances developing during prolonged treatment with GenRx Isosorbide Mononitrate 60 mg Sustained Release tablets.

Isosorbide mononitrate is less than 5% plasma protein bound. The distribution volume of isosorbide mononitrate is about 0.6 L/kg, indicating that it is mainly distributed into total body water. Elimination takes place predominantly by hydrolysis of the nitrate and conjugation in the liver. The metabolites are excreted mainly via the kidneys, with only about 2% of the dose being excreted intact.

In placebo controlled studies, isosorbide mononitrate sustained release tablets have been shown to significantly increase exercise capacity in patients with angina pectoris taking no other chronic treatment, as well as in patients taking concomitant beta-blocker therapy.

It is known that the clinical effects may be attenuated during repeated administration with nitrates in high doses and/or frequent administration. However, the pharmacokinetic characteristics of GenRx Isosorbide Mononitrate 60 mg Sustained Release tablets produce a nitrate low period following once daily dosage. No development of tolerance with respect to antianginal effect has been detected when isosorbide mononitrate sustained release tablets are given at a dose of one or two tablets (60 or 120 mg) once daily. The drug is not recommended for twice daily administration.

There is insufficient evidence to show that one halved tablet of GenRx Isosorbide Mononitrate delivers exactly half the dose of one full tablet, or whether the rate of release is the same. In vitro dissolution testing showed that dissolution was slightly faster with halved isosorbide mononitrate sustained release tablets than with whole tablets.

Side effects

The adverse reactions which follow have been reported in studies with isosorbide mononitrate:

Very common. Headache predominates (up to 30%) necessitating withdrawal of 2 to 3 % of patients, but the incidence reduces rapidly as treatment continues .

Common. Tiredness, sleep disturbances (6%) and gastrointestinal disturbances (6%) have been reported during clinical trials with isosorbide mononitrate modified release tablets, but at a frequency no greater than for placebo. Hypotension (4 to 5%), poor appetite (2.5%), nausea (1%).

Adverse effects associated with the clinical use of the drug are as expected with all nitrate preparations. They occur mainly in the early stages of treatment.

Hypotension (4%) with symptoms such as dizziness and nausea (1%) have been reported. These symptoms generally disappear during long-term treatment.

Other reactions that have been reported with isosorbide mononitrate modified release tablets include tachycardia, vomiting, diarrhoea, vertigo and heartburn.

Interactions

• Sildenafil (Viagra). Concomitant administration of isosorbide mononitrate and sildenafil (Viagra) can potentiate the vasodilatory effect of isosorbide mononitrate with the potential result of serious side effects such as syncope or myocardial infarction. Therefore, sildenafil should not be given to patients already receiving isosorbide mononitrate therapy.

• Sulfhydryl containing compounds. The metabolism of organic nitrates to nitric oxide is dependent on the presence of sulfhydryl groups in the muscle. The combination of oral N-acetylcysteine and a single dose of sustained release isosorbide mononitrate 60 mg significantly prolonged the total exercise time in patients with angina pectoris and angiographically proven significant coronary artery disease, when compared with isosorbide mononitrate alone. Concomitant administration of other exogenous sources of sulfhydryl groups such as methionine and captopril may produce a similar interaction.

• Phenylalkylamine calcium antagonists. The addition of a calcium channel blocker of the verapamil type, such as gallopamil 75 mg, has been shown to further improve left ventricular functional parameters when given in combination with isosorbide mononitrate in a sustained release formulation.

• Propranolol. The addition of isosorbide mononitrate to propranolol treatment in patients with cirrhosis and portal hypertension caused a marked fall in portal pressure, a reduction in hepatic blood flow, cardiac output and mean arterial blood pressure, but no additional change in azygos blood flow. The additional effect of isosorbide mononitrate was especially evident in patients whose portal pressure was not reduced by propranolol.

• Calcium antagonists (general). Marked symptomatic orthostatic hypotension has been reported when calcium antagonists and organic nitrates were used in combination. Dose adjustments of either class of agent may be necessary.

Notes

1. ^ http://www.astrazenecacardiovascular.com/article/503963.aspx
2. ^ http://www.biomedcentral.com/1471-2393/6/25