Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
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.

Effect on pain
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.

Effect on healing
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.

Pharmacokinetic Properties