Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Kyowa Kirin Ltd, Galabank Business Park, Galashiels, TD1 1QH, UK
Pharmacotherapeutic group: Muscle relaxants
ATC Code: C05AE01
The principal pharmacologic action of glyceryl trinitrate is relaxation of vascular smooth muscle mediated via the release of nitric oxide. When glyceryl trinitrate ointment is applied by the intra-anal route, the internal anal sphincter becomes relaxed.
Hypertonicity of the internal but not the external anal sphincter is a predisposing factor in the formation of anal fissures. The blood vessels to the anoderm course through the internal anal sphincter (IAS). Therefore hypertonicity of the IAS may thereby decrease blood flow and cause ischaemia to this region.
Distension of the rectum results in the anorector inhibitory reflex and relaxation of the internal anal sphincter. The nerves mediating this reflex lie in the wall of the gut. Release of the neurotransmitter NO from nerves of this type play a significant role in the physiology of the internal anal sphincter. Specifically, NO mediates the anorector inhibitory reflex in man, relaxing the IAS.
The link between IAS hypertonicity and spasm and the presence of an anal fissure has been established. Patients with chronic anal fissure have a significantly higher mean maximum resting anal pressure than controls and anodermal blood flow in chronic anal fissure patients was significantly lower than in controls. In patients whose fissures healed following a sphincterotomy, a reduction in anal pressure and improvement in anodermal blood flow was demonstrated, providing further evidence for the ischaemic nature of anal fissure. Topical application of a NO donor (glyceryl trinitrate) relaxes the anal sphincter, resulting in a reduction of anal pressure and an improvement in anoderm blood flow.
In three Phase III clinical trials Rectogesic 4 mg/g Rectal Ointment has been shown to improve the average daily pain intensity associated with chronic anal fissure compared with placebo, measured using a 100mm visual analogue scale. In the first study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 13.3mm (baseline 39.2mm) compared to 4.3mm (baseline 25.7mm) for placebo (p<0.0063) and over 56 days by 18.8mm compared to 6.9mm (p<0.0001), respectively. This corresponds to a treatment effect (difference between the percentage change for Rectogesic and placebo) of 17.2% over 21 days and 21.1% over 56 days. In the second study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 11.1mm (baseline 33.4mm) compared to 7.7mm (baseline 34.0mm) for placebo (p<0.0388) and over 56 days by 17.2mm compared to 13.8mm (p<0.0039), respectively. This corresponds to a treatment effect of 10.6% over 21 days and 10.9% over 56 days. In the third study, Rectogesic 4 mg/g Rectal Ointment decreased average daily pain intensity over 21 days by 28.1mm (baseline 55.0mm) compared to 24.9mm (baseline 54.1mm) for placebo (p<0.0489) and over 56 days by 35.2mm compared to 33.8mm (p<0.0447), respectively. This corresponds to a treatment effect of 5.1% over 21 days and 1.5% over 56 days.
In all three studies, healing of anal fissures in patients treated with Rectogesic 4 mg/g Rectal Ointment was not statistically different from placebo. Rectogesic is not indicated for healing of chronic anal fissure.
The volume of distribution of glyceryl trinitrate is about 3 L/kg and is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow. The known sites of extrahepatic metabolism include red blood cells and vascular walls. The initial products in the metabolism of glyceryl trinitrate are inorganic nitrate and the 1,2 and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than glyceryl trinitrate, but they are longer lived in the serum. Their contribution to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolised to non-vasoactive mononitrates and ultimately to glycerol and carbon dioxide. In six healthy subjects, the average bioavailability of glyceryl trinitrate applied to the anal canal as a 0.2% ointment was approximately 50% of the 0.75 mg dose.
No systemic toxicity studies have been conducted with Rectogesic. Published data suggest that high oral doses of glyceryl trinitrate may have toxic effects (methaemoglobinaemia, testicular atrophy and aspermatogenesis) in long term treatment. However, these findings represent no special hazards for humans under the conditions of therapeutic use.
Data from preclinical studies with GTN indicate genotoxic effects in the repair deficient S. typhimurium strain TA1535 only. Lifetime dietary administration of GTN to rodents led to the conclusion that nitroglycerin has no carcinogenic effects relevant for the therapeutic dose range in humans.
Reproductive toxicity studies, in rats and rabbits with intravenous, intraperitoneal, and dermal administration of glyceryl trinitrate did not show any adverse effects on fertility or embryonic development at dosages which did not induce parental toxicity. No teratogenicity had been observed. In rats foetotoxic effects (decreased birth weights) were seen at dosages above 1 mg/kg/d (i.p.) and 28 mg/kg/d (dermal) after in utero exposure during foetal development.
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