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Table 2: The classic SAR for muscarinic agonist activity can be

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.

Cholinester , It is used to treat postsurgical Bethanechol is


4* and postpartum urinary administered orally,
retention and abdominal because there is
is selective danger of a
BRAND distention.
for M- cholinergic crisis if it is
NAME: receptors, given by intravenous
Bethanechol
no N- or intramuscular
Urecholine receptors. injection.

In topical ocular and intraocular ophthalmic solution


Cholinester , administration its principal (i.e. eyedrops).
4* effects are miosis and Benzalkonium chloride
Carbastat, stimulates increased aqueous humour is mixed in to promote
Carboptic, Carbachol
both M&N outflow. Use for treating absorption
Miostat receptors glaucoma, use during
ophthalmic surgery.
Cholinester , is used via inhalation for the is available as a
Methacholin 4* diagnosis of asthma. The powder that is
racemic resulting bronchospasm may be reconstituted for
Provocholi e mixture relieved with bronchodilators inhalation.
ne
Cevimeline Treatment of xerostomia (dry Capsule.
mouth) associated with Half-life 3- 5 hours.
Evoxac HCl Effect on M3 Sjogren's syndrome
receptors
Alkaloid - It penetrates the eye well and Also treatment of
ophthalmic is the miotic of choice for open- xerostomia (dry
Carpine, solution, gel angle glaucoma and to mouth)
Salogen Pilocarpine tablet terminate acute angle closure
(Salogen) attacks.

NICOTINE is a direct-acting agonist at nicotinic


receptors.

• Nicotine is an alkaloid found in the nightshade family of


plants (Solanaceae). Nicotine acts on the nicotinic
acetylcholine receptors, specifically the ganglion type
nicotinic receptor and one CNS nicotinic receptor .
• As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier.
On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of
nicotine in the body is around two hours.
• Nicotinic effects are those of sympathetic overactivity and neuromuscular dysfunction and include tachycardia,
hypertension, dilated pupils, muscle fasciculation and muscle weakness.
• Atropine blocks the receptor site to decrease the stimulant effects produced by the muscarine type poisons, but
has no effect on nicotine receptors.
• Nicotine is used therapeutically to help patients stop smoking.

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.

Brand - Contraindicate: in In poisoning by 2 common : bradycardia


name glaucoma b/c organophosphate and as a preoperative
increase intraocular nerve agents and agent to reduce
Atropine pressure during insecticides, atropine secretions before
Nonselective mydriasis. Its is used to decrease surgery.
Alkaloid , isolation prolonged duration the muscarinic Others: Parkinson;
from Solanaceae of mydriasis makes cholinergic actions: paralyze the iris and
(plant) to give (±)- other drugs more associated with this ciliary muscle in the
hyoscyamine or attractive for this poisoning. It only treatment of iritis and
atropine. purpose. treats the symptoms uveitis and as a
Half-life : 4 hours/ and does not reverse cycloplegic/mydriatic
adults and 6.5 the underlying AChE agent.
hours / children inhibition
Hyosci Scopololami - similar to Treatment of uveitis, Scopolamine is a CNS
ne, atropine. iritis, and depressant at usual
ne Scopolamine is the parkinsonism, but its therapeutic doses,
(Solanaceous generic name given most widespread use whereas atropine and
Pamin
alkaloid) to (–)-hyoscine, -The is for the treatment of other antimuscarinic
e Nonselective racemic compound, motion sickness. agents are CNS
- Half-life is 8 isolated during (transdermal patch - stimulants.
hours. extraction of the behind the ear).
alkaloid from plants,
is atroscine.
- a methylated derivative of scopolamine, structurally similar to
Methscopolamine the acetylcholine.
Extendryl, 4*(4* = - treat peptic ulcers , GI spasms, to reduce salivation, and to
AlleRx, quarternary treat motion sickness
Rescon ammonium)
Tiotropium M1 = M2 = M3 (affinity to receptors) Half-life is 5-6 days Use in COPD
Spiriva 4* (Chronic obstructive pulmonary disease): inhalation
Trospium
Sanctura 4* M1 = M3 Half-life is 20 hours. Use in Urinary & GI antispasmodic
Ipratropium Nonselective Slow onset after inhalation . Half-life is 2 hours. Use in
Atrovent 4* Bronchodilator (inhalation), Seasonal rhinitis (spray)
Glycopyrrolate
Robinul 4*
Ditropan (oral) Oxybutynin
Oxytrol 4* Half-life is 2-5 hrs - Overactive bladder
(transdermal) Nonselective
Tolterodine
Detrol 4*
Nonselective Half-life is 2-4 hrs- Overactive bladder
Vericare Solifenacin Half-life is 55 hrs - Overactive bladder
4* Nonselective
Enablex Darifenacin 4* M3 . Overactive bladder
It blocks acetylcholine.
Propantheline Br Use in excessive sweating (hyperhidrosis), cramps or spasms of GI or
4* bladder, enuresis
Flavoxate Use to muscle relaxant . Its action directs on the smooth muscle rather
than by antagonizing muscarinic receptors
Gastrozep
in Pirenzepine 4* Use in peptic ulcers
(it reduces gastric acid secretion and reduces muscle spasm)
Terodiline 4* Use in urology as an antispasmodic
USE in Parkinson's disease, parkinsonism, akathisia, and dystonia.
Benzatropine USE to reduce the side effects of antipsychotic treatment (parkinsonism
Cogentin 4* and akathisia ).
It combines of the tropine portion of the atropine molecule and the
benzohydryl portion of diphenhydramine
Table 5 Overview: These, competitive They produce skeletal muscle
antagonists bind to cholinergic relaxation that facilitates
NICOTINIC nicotinic receptors but have no operative procedures such as
RECEPTOR efficacy. abdominal surgery.
There are two subclasses: Furthermore, they reduce the
ANTAGONISTs skeletal neuromuscular depth requirement for general
blocking agents and ganglionic anesthetics
blocking agents.
short action time, similar Use
Decamethoniu to Ach and acts as a in anesthesia
Syncuri depol partial agonist to
ne m ar induce paraly
sis.
It imitates the action Use for It is degraded not
of ACh at neuromuscul by
Anectin the neuromuscular ar blockade acetylcholinesterase
e, Succinylcholin
depol junction, acting non- and short but
Scoline e ar competitively on muscle duration by butyrylcholinester
type nicotinic receptors ase
Skeletal Muscle Relaxant Reaction of d-tubocurarine with
Intravenously. Relatively methyl iodide affords metocurine
long duration of action. iodide, in which the two phenolic
d- non- The main disadvantage in the hydroxyl groups of d-tubocurarine
Tubocurarine de use of tubocurarine is its are changed to the methyl ethers
significant ganglion blocking and the tertiary amine becomes
effect (hypotension). Caution quaternary. This agent is
in patients with myocardial approximately fourfold more potent
ischaemia.
than d-tubocurarine in
neuromuscular blocking activity
Pancuronium, a long-acting agent, is more active
than tubocurarine. Should not be used in pt with Malouetine
Pavulo Pancuronium non- coronary artery disease ( it increases in heart (aminosteroi
n Br de rate and blood pressure) d found in
a long-acting neuromuscular blocking agent, the rain
exhibits minimal cardiovascular effects. Use in
Ardura Pipecuronium non- pts w/ coronary artery dz, but neuromuscular
forest of
n Br de blockade is prolonged in pts w/ renal failure. central
an intermediate-acting agent with a duration of Africa)
action similar to vecuronium and atracurium but
Zemur Rocuronium non- with a more rapid onset. It does’t appear to
on Br de cause significant histamine release.
Intermediate-acting agent (removal of –CH3 from
the quaternary piperidinium). Advantage:
Norcur Vecuronium non- Vecuronium not inducing histamine and not
on Br de exhibiting cardiovascular effects.
the 4* are located in two substituted
tetrahydroisoquinoline rings separated by an Tetrahydro
aliphatic diester. It has a duration of action -
slightly longer than that of succinylcholine. isoquinolin
non- Because Termination of the effects of atracurium
Tracriu Atracurium de are independent of renal elimination,it is useful
e derivatives
m besylate in pts w/ hepatic or renal dz.
Mivacr Mivacurium Mivacurium is short acting
non-
on chloride de
It is not metabolized by plasma cholinesterase or
Nurom Doxacurium non-
de
hepatic enzymes and does not undergo Hofmann
ax chloride elimination.
Act in autonomic ganglia by binding mostly in or on
the NN receptor, and not the Ach binding site itself. Ganglionic
No have any effect on mAChR located on target Blockers:
Hexamethoniu organs of the PNS but act on the nicotinic Ach bind with
m SAR receptors at the neuromuscular junction (NM) that nicotine
are responsible for skeletal muscle motor response. receptors
Mecamylamin a nonselective and noncompetitive antagonist of of all
e the nicotinic ACh receptors ; Use in treatment autonomic
hypertension ganglia.
Arfonad treat a hypertensive crisis and dissecting aortic
Very rarely
aneurysm, pulmonary edema, and reduce bleeding
Trimethaphan during neurosurgery. Rarely use. use
Short-acting. Intravenously. clinically
 NICOTINE initially stimulate the ganglia and then block them because of a
persistent depolarization