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summarized as follows
Direct-Acting Cholinergic • The molecule must possess a nitrogen atom
Agonists capable of bearing a positive charge, preferably
Stimulation of cholinergic nerves is achieved either a quaternary ammonium salt.
directly or indirectly. Direct acting agents (agonists) • For maximum potency, the size of the alkyl
activate the receptor site by mimicking the effects of groups substituted on the nitrogen should not
acetylcholine. Cholinesterase inhibitors act indirectly by
preventing the enzyme from hydrolyzing (inactivating) exceed the size of a methyl group.
acetylcholine at the receptor site. This inhibition • The molecule should have an oxygen atom,
permits the buildup of acetylcholine and results in more preferably an ester-like oxygen, capable of
intensive and prolonged activation of the receptor site. participating in a hydrogen bond.
The effects of cholinergic stimulation include: • There should be a 2-carbon unit b/w O atom and
vasodilation of blood vessels; slower heart rate; N atom.
constriction of bronchioles and increased secretion of
mucus in the respiratory tract; intestinal cramps;
secretion of salvia; sweat and tears; and constriction of
eye pupils.
Table 3: Indirect- The active site in the enzyme probably These drugs have only a few
has similar characteristics to the nerve clinical uses, mainly in
Acting receptor sites. However, the two sites augmenting gastric and
Cholinergic are sufficiently different since chemicals intestinal contractions (in
which inhibit the enzyme do not effect treatment of obstructions of
Agonists the nerve receptor site. The active the digestive tract), in
Inhibiting the cholinesterase center of acetylcholinesterase consists generally augmenting
enzyme, thus permitting a of a negative subsite, which attracts the muscular contractions (in the
build up of acetylcholine on quaternary group of choline through treatment of myasthenia
the nerve receptor sites. As a both coulombic and hydrophobic forces, gravis), and in constricting the
result, acetylcholine increases and an esteratic subsite, where eye pupils (in the treatment of
in quantity with successive nucleophilic attack occurs on the acyl glaucoma).
nerve impulses so that large carbon of the substrate.
amounts of acetylcholine can
accumulate and repetitively
stimulate receptors
• The reversible drugs complete with Ach for the active site on Cho-enzyme (4* amines and
carbamates). Ending: “-stigmine” , “-nium”: EDRONIUM – NEOSTIGMINE – PHYSOTIGMINE
- PYRIDOSTIGMINE
• The irreversible drugs phosphorylate the enzyme and inactivate it. (Phosphate esters are very
stable to hydrolysis). They are widly used as insecticides and are referred to as nerve gases.
Because the organophosphates are lipid soluble, they rapidly cross all membranes
(including skin and the blood-brain barrier): DFP - ECHOTHIOPHATE - MALATHION -
PARATHION - SARIN
4* amines: Do not cross membrane barriers - GI, BBB absorption impaired – Typically no
CNS effect.
Simple alcohol Edrophonium is used to rapidly reverse
(phenol) with 4* intravenously for the effects of non-
Tensilon, Edrophoniu
amine diagnosis of depolarizing
Enlo, m Rapid, reversible myasthenia gravis (it neuromuscular blocking
Reversol block b/c non- acts rapidly to agents (d-tubocurarine
covalent drug- increase muscle and gallamine)
AChEI -re -4*
enzyme bond strength)
Prostigmi B/c its 4*amine, it Use prophylaxis of postoperative CARBAMI
Neostigmin lacks central abdominal distension and urinary C ACID
n,
Vagostig
e activity. retention, myasthenia gravis, ESTERs
half-life: 15 - 90 reversal of neuromuscular
min AChEI –Re mins blockade.
-Carbamate-4* Longer
It is more lipophilic than many inhibition
Alkaloid obtained
from seeds of the other AChEIs and can diffuse
Calabar bean. It across BBB. labile
Physotigmi inhibits AChE by Used for the treatment of covalent
ne acting as a glaucoma. Used (emergency) bond after
substrate and rooms to treat overdoses of HOH by
AChEI –Re carbamylating the atropine and tricyclic ACh
-Carbamate-3* enzyme antidepressants
Mestinon Pyridostigm Orally effective It is a better choice for oral
and, compared to therapy of myasthenia gravis. It
is approved for U.S. military use
as an adjunct for prophylaxis of
neostigmine, has a soman nerve gas exposure. It is
ine longer duration of also udsed toreverse the effects
action and a lower of nondepolarizing neuromuscular
AChEI –Re incidence of side blocking agents. Half-life is 1 to 2
-Carbamate-4* effects. hours.
Isoflurophat Use as a miotic agent in treatment of chronic Organo-
e, DFP- Diisopropyl glaucoma, as a miotic in veterinary medicine, and Phosphates
Diflurophat fluorophosphates as an experimental agent in neuroscience because Irreversible
e, Diflupyl, AChEI –Ir - OrganoP- of its acetylcholinesterase inhibitory properties and
Dyflos 4* ability to induce delayed peripheral neuropathy Very stable
complex after
Echothioph It is used as an ocular antihypertensive in the HOH & Aging
Phospholi ate treatment of chronic glaucoma and, in some cases,
Strong
ne Iodide AChEI –Ir - OrganoP- accommodative esotropia. Its effects can last a
nucleophiles
4* week or more.
can
Malathion Malathion in low doses (0.5% preparations) is sometimes
Ovide AChEI –Ir - OrganoP- used as a treatment for: head lice, body lice, recover
4* and scabies. enzymes
Bladan, Eg. pralidoxim
ME605, Parathion
Metaphos,E6 AChEI –Ir - OrganoP- the most dangerous pesticides Its use is
01. 4* banned or restricted.
Sarin
GB Chemical weapon. Production and stockpiling
AChEI –Ir - OrganoP-
of sarin was outlawed.
4*
FDA approved four AChEIs for the treatment of AD: tacrine (Cognex), donepezil (Exelon),
rivastigmine, and galantamine (Razadyne) Foye’s book , page 377.
Table 4: Overview: They act as They decreased contractions
competitive (reversible) of smooth muscle of GI and
MUSCARINIC antagonists of acetylcholine. urinary tracts, dilation of the
RECEPTOR pupils, and reduced gastric,
mucociliary, and salivary
ANTAGONISTs secretions.