Anticholinesterases - Pharmacological Actions & Pharmacokinetics

PHARMACOLOGICAL ACTIONS

The actions of antiChEs are qualitatively similar to that of directly acting cholinoceptor stimulants. However, relative intensity of action on muscarinic, ganglionic, skeletal muscle and CNS sites varies among the different agents.

Lipidsoluble agents (physostigmine and organophosphates) have more marked muscarinic and CNS effects; stimulate ganglia but action on skeletal muscles is less prominent.

Lipidinsoluble agents (neostigmine and other quaternary ammonium compounds) produce more marked effect on the skeletal muscles (direct action on muscle endplate cholinoceptors as well), stimulate ganglia, but muscarinic effects are less prominent. They do not penetrate CNS and have no central effects.

Ganglia Local hydrolysis of ACh is less important in ganglia: inactivation occurs partly by diffusion and hydrolysis in plasma. AntiChEs stimulate ganglia primarily through muscarinic receptors present there. High doses cause persistent depolarization of the ganglionic nicotinic receptors and blockade of transmission.

CVS Cardiovascular effects are complex. Whereas muscarinic action would produce bradycardia and hypotension, ganglionic stimulation would tend to increase heart rate and BP. Action on medullary centres (stimulation followed by depression) further complicates the picture, so does ganglionic blockade with high doses. Thus, the overall effects are often unpredictable and depend on the agent and its dose.

Skeletal muscles After treatment with antiChEs, the ACh released by a single nerve impulse is not immediately destroyed—rebinds to the same receptor, diffuses to act on neighbouring receptors and activates prejunctional fibres → repetitive firing → twitching and fasciculations. Force of contraction in partially curarized and myasthenic muscles is increased. Higher doses cause persistent depolarization of endplates resulting in blockade of neuromuscular transmission → weakness and paralysis. Direct action of

neostigmine and its congeners at the muscle endplates results in augmentation of these features.

Other effects These result from stimulation of smooth muscles and glands of the gastrointestinal, respiratory, urinary tracts and in the eye.

PHARMACOKINETICS

Physostigmine It is rapidly absorbed from g.i.t. and parenteral sites. Applied to the eye, it penetrates cornea freely. It crosses bloodbrain barrier and is disposed after hydrolysis by ChE.

Neostigmine and congeners These are poorly absorbed orally; oral dose is 20–30 times higher than parenteral dose. They do not effectively penetrate cornea or cross bloodbrain barrier. They are partially hydrolysed and partially excreted unchanged in urine.

Organophosphates These are absorbed from all sites including intact skin and lungs. They are hydrolyzed as well as oxidized in the body and little is excreted unchanged.