Towards safer treatments for benign anorectal disease: the pharmacological manipulation of the internal anal sphincter

Abstract

Introduction: The internal anal sphincter (IAS) is an important structure that is responsible for the majority of resting tone of the sphincter complex. It has a central role in continence and damage to the muscle has serious implications. Injury is most frequently from obstetric trauma though iatrogenic injury from proctological surgery is also common. This review expands on how developments in understanding of the pharmacology of IAS might identify drug treatments as alternatives for proctological conditions such as anal fissure, avoiding the risk of sphincter injury. It also examines the role of pharmacology in treatment of those patients with established incontinence.

Results: Much of the basic physiology and pharmacology of the IAS has been established through in vitro analysis, particularly in the superfusion organ bath. Further analysis has been undertaken using animal models such the pig. Clinical trials have established the efficacy of a number of agents for reducing IAS tone including glyceryl trinitrate and botulinum toxin. These drugs are probably safer, but less effective, than surgery for sphincter spasm, as is seen in anal fissure, though surgery alone or in combination with drug treatment may be appropriate for some patients. In vitro analysis and small-scale clinical trials suggest that phenylephrine and methoxamine may have a role in treating patients with incontinence primarily attributable to inadequate IAS function.

Conclusions: The pharmacology of IAS has been extensively studied in the laboratory, both in vitro and in animal models. In a short time, this laboratory work has been applied to clinical problems after testing in clinical trials. It is likely, however, that the best drugs and the optimal targets for manipulation have not yet been identified.

Figure 1

Diagram of autonomic innervation of the internal anal sphincter. Internal anal sphincter tone reflects the sum of intrinsic myogenic tone of the sphincter itself (1), which is modified by local reflexes (2). Autonomic inhibitory input to the internal sphincter comes from parasympathetic nerves that synapse in the parasympathetic ganglia (3) and excitatory nerves from sympathetic nerves relaying in the sympathetic trunk (4). PreGSN, pre-ganglionic sympathetic nerve; PostGSN, post-ganglionic sympathetic nerve; PreGPN, pre-ganglionic parasympathetic nerve; PostGPN, postganglionic parasympathetic nerve.

Figure 2

Endo-anal ultrasound appearances after manual dilatation of the anus (left) showing fragmentation of the internal anal sphincter (deficient between 2 and 3 o'clock and 4 and 8 o'clock) and lateral internal sphincterotomy (right) showing a deficient internal sphincter between 2 and 6 o'clock with bunching of the sphincter fibres on the contralateral side.

Figure 3

Representative traces from the superfusion organ bath showing the responses of internal anal sphincter strips to electrical field stimulation (EFS) at 50 Hz in the absence of drugs, showing a relaxation followed by contraction. The contractile element was blocked by the addition of 1 µM guanethidine and the relaxation response was blocked by further addition of 10 µM L-nitroarginine (L-NO Arg).

Figure 4

Characteristic traces for internal anal sphincter strips from control and botulinum treated in response to increasing frequencies of electrical field stimulation.