Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2018 Publisher: Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics, 58 Richard Pearse Drive, Airport Oaks, Mangere, AUCKLAND Telephone: (09) 918 5100 Fax: (09) 918 5101
Pharmacotherapeutic group: isosorbide-5-mononitrate
ATC code: C01DA14
Isosorbide-5-mononitrate has a directly relaxing effect on the vascular smooth muscles and leads to vasodilation.
In this respect, the post-capillary capacitance vessels and major arteries – particularly those sections of coronary arteries that are still responsive – are more affected than resistance vessels. Vasodilation in the blood stream leads to an increase in venous capacity (“pooling”), blood flow back to the heart is reduced and ventricular volumes and filling pressures are lowered (“preload” reduction).
The smaller ventricular radius and reduced systolic wall tension lower myocardial energy requirements and O2 requirements.
The decrease in cardiac filling pressures promotes perfusion of subendocardial wall layers threatened by ischemia; regional wall movement and ejection fractions can be improved.
Dilation of the major pericardial arteries leads to a decrease in both systemic (“afterload” reduction) and pulmonary ejection resistance.
Isosorbide-5-mononitrate causes relaxation of the bronchial muscles, lower urinary tract and muscles of the gallbladder, biliary tract, oesophagus, small intestine and colon, including sphincter muscles.
On a molecular level, nitrates most probably act on the formation of nitrogen (NO) and cyclic guanosine monophosphate (cGMP), which is considered to be a mediator of relaxation.
Following oral administration, isosorbide-5-mononitrate is rapidly and completely absorbed.
Systemic availability is 90–100%. Isosorbide mononitrate is almost completely metabolised in the liver. The metabolites formed are inactive.
The plasma half-life is 4–5 hours. Isosorbide mononitrate is almost exclusively excreted in the form of its metabolites via the kidneys. Only approximately 2% is renally eliminated in unchanged form.
Bioavailability studies (performed in 1981 and 1989) on 12 subjects yielded the following pharmacokinetic characteristics (mean values ± standard deviation):
| Parameters | Ismo retard 40 mg ISMN n=12 |
| Peak plasma concentration (Cmax) [ng/ml] | 510.0 ± 70.0 |
| Time to peak plasma concentration (tmax) [h] | 3.6 ± 0.57 |
| Area under the concentration-time curve (AUC) [ng/ml h] | 4954 ± 776 |
Despite a constant dosage at constant nitrate levels, a decrease in efficacy has been observed. Any existing tolerance resolves within 24 hours upon discontinuation of therapy.
No tolerance development was observed with analogous intermittent administration.
Chronic toxicity studies on rats revealed no evidence of any toxic effects. Following daily oral administration of 191 mg/kg isosorbide-5-mononitrate over a 43-day period, a 2.6% rise above baseline in the methaemoglobin level was measured in dogs. After 191 mg/kg isosorbide-5-mononitrate per os, the serum nitrite concentration was at the limit of detection (less than 0.02 mg/l); alkaline phosphatase and GPT did not change.
These findings may be clinically relevant for patients with methaemoglobin reductase deficiency, as well as in patients with diaphorase deficiency and abnormal haemoglobin structure.
Long-term studies on rats revealed no evidence of any tumorigenic potential for isosorbide5-mononitrate.
Studies in several mutagenicity tests (in vitro and in vivo) were negative.
No evidence of any teratogenic effect was revealed for isosorbide-5-mononitrate in animal studies.
In peri/postnatal toxicity studies, foetotoxic effects were only seen after very high doses within the maternally toxic range.
There is insufficient human experience with use during pregnancy and lactation. When administering to breast-feeding women, it is recommended that infants be observed for any pharmacological effects of isosorbide-5-mononitrate.
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