PHARMACOLOGICAL ACTIONS OF TETRAETHYLPYROPHOSPHATE AND HEXAETHYLTETRAPHOSPHATE

¹ Departments of Pharmacology and Physiology, Middlesex Hospital . Medical School, London, W.1.

1. The condensed alkylphosphates, hexaethyltetraphosphate (HETP) and tetraethylpyrophosphate (TEPP) are powerful anticholinesterase substances with actions similar to, but more prolonged than, those of eserine and neostigmine (Prostigmin).

2. In the chloralosed cat HETP (0.4-0.6 mgm./kgm.) produced marked bradycardia, fall in blood pressure, marked salivary and bronchial secretion, respiratory stimulation, and increased activity of gut and bladder leading to defecation and micturition. Muscle fasciculations and minor convulsive movements also occurred. Larger doses (0.8-2.0 mgm./kgm.) produced immediate violent convulsions and very profound visceral effects. Death resulted in less than one hour.

3. TEPP acted like HETP but was about four times as potent. Triethylorthophosphate and sodium pyrophosphate in doses up to 20 mgm./kgm. produced no systemic effects.

4. Atropine antagonised most of the visceral actions of HETP and TEPP, but did not influence the central nervous or muscular effects.

5. HETP and TEPP sensitised the heart in the anaesthetised cat to the inhibitory actions of vagal stimulation or injection of acetylcholine. They also potentiated the effect of chorda tympani nerve stimulation on salivary secretion.

In atropinised cats these compounds enhanced the effect of cervical sympathetic nerve stimulation on the contraction of the nictitating membrane; they also potentiated the nictitating membrane response and the rise of blood pressure produced by large doses (e.g. 10 mgm.) of acetylcholine.

6. HETP and TEPP potentiated the responses to acetylcholine of the isolated perfused rabbit heart, the isolated rabbit duodenum and guinea pig ileum, and the frog rectus abdominis muscle.

7. TEPP in small concentrations (e.g. 1 in 400 million to 1 in 40 million) increased the force of muscular contraction in the rat phrenic nerve-diaphragm preparation; 1 in 4 million was inhibitory. TEPP antagonised the paralysing effects of d-tubocurarine C1 on this muscle.

8. Intravenous injection of HETP or TEPP usually produced constriction of the pupil, but sometimes dilatation occurred. Direct instillation of the drugs into the conjunctival sac produced marked pupillary constriction, which passed off in about 24 hours.