Download cholinergic drugs

Cholinergic Drugs
Acetylcholine neurons convey sensory information to the brain and
control muscular tension, including peristalsis and motor control. Cholinergic
neurons are dominant in inhibitory activity inherent to so-called
parasympathetic neurons whic comlpement dopamine/norepinephrine based
neurons in parallel sympathtic structures. Two cholinergic receptor subtypes
have been identified by selective agonists: nicotinic and muscarinic. At least two
subtypes of muscarinic receptors (M1 and M2) have been identified.
In addition to direct agonists, selective antagonists, enzyme inhibitors, and
antidotes to enzyme inhibitors have been developed. Cholinoceptors also serve
as heteroreceptors, presynaptically governing the release of norepinephrine and
other neurotransmitters.
Cholinoceptor Agonista
Nicotine is a selective agonist at nicotinic receptors: it defines this subset
of cholinergic receptors. Muscarine defines the other subset, with further
distinctions of M1 and M2 (at least) existing. Muscarine is produced in trace
amounts in the fly agaric mushroom. Other species of fungus produce greater
amounts. Fly agaric also contains muscarinic antagonists (atropine) and GABA
agonists (muscimol). Atropine used to be applied as an antidote to poisoning by
muscarine in this fungus, before the role of muscimol was elucidated.
The N-hydroxymethyl amide of nicotinic acid is also active as an agonist at
nicotinic cholinoceptors. Carbachol is used opthalmically as a miotic, i.e. to
dilate the pupils. It is also used in large animals, mainly in atonic conditions of
the gut, since its formal positive charge prevents it from entering the brain and
limits its absorption in the gut. In addition to receptor action, it probably
promotes acetylcholine release. Lachesine is a selective muscarinic agonist.
Guanidine exists as the guanidium ion at physiologic pH; it is used as a procholinergic, antiviral, antifungal, antipyretic and muscle stimulant. Bethanechol
activates M1 and M2 subreceptors, releases IP3 (inositol triphosphate), and
activates guanylyl cyclase. Again, as a quaternary, positively charged species, it
is used mainly to mimic acetylcholine in the gut. It is sometimes given to relieve
the antimuscarinic constipation caused by tricyclic antidepressants or other
meds. Pilocarpine is a cholinomimetic which also increases gastric acid
secretion.
Cholinoceptor antagonists
Cholinesterase inhibitors act by poisoning acetylcholinesterase, which
decomposes acetylcholine in the synapse and deactivates it. Cholinesterase is
also distributed systemically in many tissues other than nerve synapses.
Interestingly, a distinct enzyme called butyrylcholinesterase exists which is not
inhibited by the usual organophosphate compounds. Anticholinergic agents
block acetylcholine at its receptors. Other drugs called ganglion blockers or
neuromuscular blockers directly block ion flow in the ion channel gated by the
cholinergic receptor. Hexamethonium, for example, probably works mostly by
ion channel blockade while trimethapan probably blocks the receptor but ot the
channel. Tetraethylammonium is distinguished by having a very short duration
of action. Mecamylamine, a secondary ammonium compound, is absorbed fairly
well.
The atropine class of antimuscarinics block muscarinic receptors but are fairly
inactive at nicotinic terminals. Atropine itself has been used as a war-gas
antidote (see below). It is found in nature in the "deadly nightshade," Atropa
belladonna and in jimsonweed (Datura stramonium), and is isomeric with
hyoscamine. Scopolamine is a similar drug found in Hyoscamus niger
(henbane). Benztropine, a synthetic variant, has been used against
Parkinsonism.
Many of the drugs used by modern pharmacology are "incidentally"
antimuscarinic, especially the phenothiazine (Thorazine) group of antipsychotic
meds and the tricyclic (Elavil) group of antidepressants. Propantheline is an
example of the former group, used as an antimuscarinic; pirenzepine of the
latter. Pirenzepine appears to be selective for M1 receptors.
Cholinesterase Inhibitors
Physostigmine can be found naturally in calabar beans. It has been
shown to improve long-term memory and has been used against Alzheimer's
disease. Pyridostigmine (PD), is an infamous cholinesterase inhibitor given to
soldiers during the Persian Gulf War. Laboratory tests with significantly larger
doses of PD, along with large doses of the insect repellent DEET, were shown
to induce abnormalities in brain tissue in chicken embryos.
Neostigmine and edrophonium have been used as curare antidotes,
but they only act peripherally.
Cholinesterase inhibitors insecticides are a concern because of their
extreme toxicity. A 1995 terrorist attack on a Japanese subway used sarin,
which is more toxic than parathion, which in turn is more toxic than malathion.
It is also suspected that Iraqi stores of sarin were demolished during the Gulf
War. One of the most powerful of the group is VX; it is rumored that Iraq holds
enough of this compound to kill everyone on the planet many times over. These
drugs inhibit cholinesterase, so that acetylcholine is not deactivated once it
enters the synapse. Death occurs by massive convulsion and cardiac arrest.
Cholinesterase Inhibitor Antidotes
A group of compounds with the ability to dislodge organophosphates
from cholinesterase enzymes have been developed using the oxime (N-OH)
group. Pralidoxime and obidoxime are quaternary, positively charged
compounds which cannot enter the brain, but diacetylmonoxime can enter and
reverse cholinesterase in the CNS.