Parasympathomimetics (Cholinergic Agents) 159acetylcholine at the various cholinergic sites.
The released acetylcholine from the nerve
endings is quickly destroyed by the enzyme
cholinesterase. Anticholinesterase inhibit
this enzyme which results in accumulation
of acetylcholine and continuous stimulation
of muscarinic and nicotinic receptors.
As given in classification, these agents
are of two type e.g. reversible and irrevers-
ible. The reversible anticholinesterases
have a structural resemblance to acetylcho-
line, are capable of combining with anionic
and esteratic sites of cholinesterase as well
as with acetylcholine receptor. The complex
formed with the esteratic site of cholinest-
erase is less readily hydrolyzed than the
acetyl esteratic site complex formed with
acetylcholine. Edrophonium forms revers-
ible complex with the anionic site and has
shorter duration of action. Also, neostigmine
and edrophonium have a direct stimulating
action at cholinergic sites.
Irreversible cholinesterases are mostly
organophosphorus compounds and combine
only with esteratic site of cholinesterase and
that site gets phosphorylated. The hydrolysis
of phosphorylated site produces irreversible
inhibition of cholinesterase. And, because, of
this property, the therapeutic usefulness is
very limited. Most of the compounds are
used as insecticides e.g. parathion, malathion
and war gases e.g. tabun, sarin, soman etc.
REVERSIBLE ANTICHOLINESTERASEPHYSOSTIGMINE
It is a tertiary ammonium alkaloid
obtained from the Calabar bean, the dried
ripe seed of ‘Physostigma venenosum’, which
is indigenous to tropical west Africa.
The pharmacological actions of
physostigmine are similar to those of
cholinergic drugs. Topical instillation into the
eye produces miosis, spasm of accommo-
dation and decrease in intraocular pressure.
Physostigmine is well absorbed after oral as
well as parenteral administration and also
produces central cholinergic actions because
of penetration into blood brain barrier.
The main therapeutic use of
physostigmine is as miotic to treat glaucoma
and also to reverse the mydriatic effect of
atropine and its analogues used in refraction
of the eye. It is also used in the treatment of
atropine intoxication and poisoning with
phenothiazines. It is also used in primary
stages of Alzheimer’s disease.NEOSTIGMINE
It is a synthetic quarternary ammonium
compound, similar to physostigmine and
rapid onset of action and can inhibit both
true and pseudocholinesterases.
It increases the tone and motility of the
gut and enhances the gastric juice
production and also promotes the
propulsion of intestinal contents.
At the neuromuscular junction, it
produces the contraction of skeletal muscle
by its direct action and by inactivation of
anticholinesterase and has got anticurare
action. By virtue of its structural similarity
to acetylcholine, it acts as partial agonist on
motor end plate.
Neostigmine, by its peripheral
vasodilatation action reduces the blood
pressure and heart rate.
On local ophthalmic administration, it