Cholinergic Agents

Pharmaceutical Chemistry 2

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 Content
• Chapter Overview.
• Cholinergic
Neurochemistry.
• Direct
parasympathomimetics.
• Indirect-acting cholinergic
agonists.
 Reversible Inhibitors
(Carbamates).
 Irreversible Inhibitors
(organophosphorous
agents).
• Parasympathetic
Postganglionic Blocking
Agents.
 Solanaceous alkaloids and
synthetic analogs.
 Synthetic Cholinergic
blocking agents.
 Aminoalcohol esters.
 Aminoalcohol ethers.
 Aminoalcohols.
 Aminoamides.
 Miscellaneous.
2
 Chapter Overview
• Neurons that release acetylcholine are
referred to as cholinergic, as are the receptors
on which these neurons synapse.

• These receptors are further classified as either

muscarinic (M) or nicotinic (N), depending on
their ability to bind the naturally occurring
alkaloids muscarine or nicotine, respectively.

• Subtypes of M receptors (M1-to-M5).

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• Acetylcholine does not have exclusive selectivity on
M and N receptor subtypes.
• M2-receptors can serve as autoreceptors on
presynaptic terminals of postganglionic cholinergic
nerves to inhibit ACh release.
• Chemical compounds that cause stimulation of the
PNS are called cholinomimetic or, more specifically,
parasympathomimetic agents.
• Those compounds that possess affinity for
cholinergic receptors but exhibit no intrinsic activity
are called cholinergic antagonists, cholinolytic, or
parasympatholytic agents.
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 Cholinergic Neurochemistry
• ACh is prepared in the nerve ending by the transfer of an
acetyl group from acetyl-coenzyme A (Acetyl-CoA) to choline
catalyzed by acetyltransferase (ChAT).
• Choline is the limiting substrate for the synthesis of ACh. Most
choline comes from the hydrolysis of ACh in the synapse.
• Choline is recaptured by the presynaptic terminal as part of a
high-affinity uptake system.
• Acetylcholine esterase (AChE) hydrolyze ACh into choline and
acetate.

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 Parasympathomimetics
1. Direct Parasympathomimetics: agonists that
act directly on cholinergic receptors.

2. Indirect Parasympathomimetics: function as

inhibitors of acetylcholinesterase (AChE), the
enzyme responsible for hydrolysis of
acetylcholine.
A. Reversible Inhibitors (Carbamates).
B. Irreversible Inhibitors (Organophosphorous agents).
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Structure-Activity relationships of
parasympathomimetics.
• Alterations on the molecule may be divided
into three categories:
1. The onium group.

2. The ester function.

3. The choline moiety.

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1. Onium group ( Quaternary ammonium group)
• Essential for affinity and intrinsic activity and contributes
to the affinity of the molecule for the receptors, because
of its action as a detecting and directing group.
• Its interacts with negative charged of aspartic acid
residue of the receptor
• The trimethylammonium group is the optimal functional
moiety for activity exception in Pilocarpine and nicotine
• Phosphonium, sulfonium, arsenonium isosters, or
substituents larger than methyl on the nitrogen increase
the size of the onium moiety, produce diffusion of the
positive charge, and interfere sterically with proper
drug-receptor interaction, resulting in decreased activity.
• Substitution with largely alkyl groups decreases activity 8
2. The ester group.

• The acetyl group in ACh is not as critical as the size of the molecule.
• Essential for affinity forms H bonds with threonine and asparagine
residues at the receptor site
• When the methyl group is replaced by higher homologous such as
propionyl group, the resulting ester is less potent than Ach
• For maximal muscarinic activity, the quaternary group should be
followed by a chain of five atoms; this has been referred to as the
five-atom rule, (C-C-O-C-C-N).
• Shortening or lengthening the chain of atoms that separates the ester
group from the onium moiety reduces muscarinic activity.
• Aromatic groups possess Cholinergic Antagonist activity

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3. The choline moiety ( Etheylene bridge)
α substitution on the choline moiety decreases both nicotinic and muscarinic
(muscarinic decreased to a greater extent) activity

Beta substitution on the choline moiety decreases both nicotinic and

muscarinic (nicotinic decreased to a greater extent) activity

Shorting or lengthening of ethylene bridge will decrease M activity

Therefore, acetyl α-methylcholine, although less potent than ACh, has more
nicotinic than muscarinic activity. Whereas, acetyl β-methylcholine
(methacholine) exhibits more muscarinic than nicotinic activity

Hydrolysis by AChE is more affected by substitutions on the β than the α

carbon.

The hydrolysis rate of racemic acetyl β-methylcholine is about 50% of ACh;

racemic acetyl α-methylcholine is hydrolyzed about 90% as fast as ACh
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 SAR conclusion:
1. The positively charged nitrogen atom is essential to activity.
Replacing it with a neutral carbon atom eliminate activity.
2. The distance from the nitrogen to the ester group is
important.
3. The ester functional group is important.
4. The overall size of the molecule cannot be altered much.
Bigger molecules have poorer activity.
5. The ethylene bridge between the ester and the nitrogen atom
cannot be extended.
6. Tertiary alkyl “methyl” groups on the nitrogen is tolerated, but
more than one large alkyl group leads to loss of activity.
7. Bigger ester groups lead to loss of activity.
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Design of acetylcholine analogues.
• There are three possible approaches to tackling the
inherent instability of acetylcholine:
1. Steric shields.
• An extra methyl group has been placed on the ethylene bridge
as a steric shield to protect the carbonyl group, thus slowing
down chemical and enzymatic hydrolysis (Methacholine).
2. Electronic stabilization (more resistant to hydrolysis).
• The ester has been replaced by a urethane or carbamate group.
The lone pair of electrons on nitrogen can interact with the
carbonyl group and lower its electrophilic character (Carbachol).
3. The combining steric and electronic effects.
• Example: (Bethanechol).
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 Direct parasympathomimetics.
1. Acetylcholine Chloride.
• A powerful stimulant.
• DOA is too short, because of
rapid hydrolysis by esterase.
• Lack of selectivity when administered for systemic
use.
• Short-acting miotic effect and is especially useful
after cataract surgery during replacement of sutures.
• When applied topically to the eye, it has little
therapeutic value because of poor corneal
penetration and rapid hydrolysis by AChE.
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2. Methacholine Chloride.
• Acetyl-β-methylcholine chloride,
is the acetyl ester of β-methylcholine.
• Methacholine has sufficient stability in the body to
give sustained parasympathetic stimulation, 3 times
more stable to hydrolysis than ACh.
• It can exist as (S) and (R) enantiomers. It is used as
the racemic mixture, its muscarinic activity resides
principally in the (S) isomer.
• The (S)/(R) ratio of muscarinic potency is 240:1.

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3. Carbachol.
• Choline chloride carbamate
is non-specific in its action on muscarinic receptor
subtypes.
• Its activity as ACh. It can also act indirectly by
promoting release of ACh and by its weak
anticholinesterase activity.
• Carbachol forms a carbamyl ester in the active site of
AChE, which is hydrolyzed more slowly than an acetyl
ester. This slower hydrolysis rate reduces the amount
of free enzyme and prolongs the duration of Ach in
the synapse.
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• Carbachol is a miotic and has been used to reduce
the intraocular tension of glaucoma when a response
cannot be obtained with pilocaropine or neostigmine,
also during ocular surgery when a more prolonged
miosis is required than Acetylcholine Chloride.
4. Bethanechol Chloride.
• β-methylcholine chloride carbamate, carbamyl β-
methylcholine chloride.
• Similar to methacholine. Both
are esters of β-methylcholine.
• The main use is in the relief of urinary retention and
abdominal distention after surgery (They shut down with
drugs during surgery).
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• Used orally and SC injection. Must not given by IM or IV
because of the danger from cholinergic over stimulation
and loss of selective action. DOA is 1 hour.
5. Pilocarpine hydrochloride.
• Nonselective agonist.
• Used in glaucoma.
• The pupil constriction and spasm of the
ciliary muscle reduce intraocular tension by establishing
better drainage of ocular fluid through the canal of
Schlemm, located near the corner of the iris and cornea.

• The colored tissue at the front of the eye that contains the pupil in the center

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 Indirect parasympathomimetics.
• Known as cholinesterase inhibitors.
• 2 types of cholinesterases in humans, AChE
and butyrylcholinesterase (BuChE).
1. AChE: is located outside surface of glial cells
in the synapse and catalyzes the hydrolysis of
ACh to choline and acetic acid.
• AChE inhibitors have been used in the treatment of
Myasthenia Gravis (MG), atony in the GIT, and
glaucoma. Recently, received attention as
symptomatic drug treatments in patients suffering
from Alzheimer disease and cognitive disorders. 19
2. BuChE (pseudocholinesterase): is located in
human plasma. It has catalytic properties similar
to AChE. The substrate specificity is broader.

Two main groups of acetylcholinesterase

inhibitors are considered, carbamates and
organophosphorous agents.

• Three different chemical groupings, acetyl,

carbamyl, and phosphoryl, may react with the
esteratic site of AChE.
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AChE attacks the ester substrate through a serine
hydroxyl, forming a covalent acyl-enzyme complex.

The serine is activated as a nucleophile by the

glutamic acid and histidine residues that serve as the
proton sink to attack the carbonyl carbon of ACh.

Choline is released, leaving the acetylated serine

residue on the enzyme.

The acetyl-enzyme intermediate is cleaved by a

general base catalysis mechanism to regenerate the
free enzyme.
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22
• The rate of carbamylation is slower than the rate of
acetylation. Hydrolysis of the carbamyl-enzyme
intermediate is 107 times slower than that of its acetyl
counterpart.

• The hydrolysis rate of the phosphorylated-enzyme is

considered irreversible.

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A. Reversible Inhibitors.
1. Physostigmine.
• It has sulfate or salicylate salts. In solution, it is
hydrolyzed to methyl carbamic acid and eseroline,
neither of which inhibits AChE.
• It is a relatively poor carbamylating agent of AChE and is
often considered a reversible inhibitor.
• It was first used as a topical application in the treatment
of glaucoma.
• Used systemically as antidote for atropine poisoning.

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2.Neostigmine Bromide.

• Dimethylcarbamic ester of
3-hydroxyphenyltrimethylammonium bromide.
• It is used as an antidote to neuromuscular blocking drugs and
in the treatment of MG.
• Skeletal muscle is stimulated by neostigmine, a property that
physostigmine does not have.
• Neostigmine has a half-life of about 50 minutes, after IV
administration.
• It metabolites to 3-hydroxyphenyltrimethylammonium, which
has activity similar to, but weaker than, neostigmine.
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• Use of physostigmine, as a prototype of an indirect-acting
parasympathomimetic drug, facilitated the development of
stigmine.
• In physostigmine:
 Trimethylamine group was placed para to a methylcarbamate
group in benzene ring.
 Contains a methylcarbamate functional group.
• In neostigmine:
 Better inhibition of cholinesterase was observed when
trimethylamine group were placed meta to a
dimethylcarbamate group in benzene ring.
 Greater chemical stability toward hydrolysis was obtained
with dimethylcarbamyl group instead of methylcarbamate.
 Having a much simpler structure.
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3. Pyridostigmine Bromide.

• 3-hydroxy-1-methylpyridinium
bromide dimethylcarbamate.
• It is a bout one fifth as toxic as
neostigmine and has a longer duration of action.
• It is a better choice for oral therapy of MG.
• The principal metabolite is 3-hydroxy-N-
methylpyridinium.
• Orally administration has a half-life of 90 minutes
and DOA between 3 to 6 hours.
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4. Edrophonium Chloride.

• It is a quaternary ammonium- substituted phenol.

• Has more rapid onset and
shorter DOA than neostigmine and pyridostigmine.
• It is a specific anticurare agent and acts within 1 minute to alleviate
overdose of d-tubocurarine, dimethyl d-tubocurarine or gallamine
triethiodide.
• It is of no value, however, in terminating the action of the depolarizing
(noncompetitive) blocking agents, such as decamethonium and
succinylcholine.

• Because it is a phenol rather than a carbamate ester of a phenol, it does not

carbamylate AChE. It does, however, inhibit AChE in a reversible manner,
and also exhibits a direct cholinomimetic effect at skeletal muscle. 28
• In addition to inhibiting AChE, edrophonium chloride has
a direct cholinomimetic effect on skeletal muscle, which
is greater than that of most other anticholinesterase
drugs.
5. Rivastigmine.
• Is a pseudoirreversible
noncompetitive carbamate inhibitor of AChE.
• Although the half-life is approximately 2 hours, the
inhibitory properties of this agent last for 10 hours,
because of the slow dissociation of the drug from the
enzyme (act centrally).
• Used in mild-to-moderate Alzheimer disease since 2000.
In 2007, it was granted approval for use in managing
mild-to-moderate dementia associated with Parkinson
disease.
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 B. Irreversible Inhibitors.
• Organophosphorous esters, these chemicals are nerve poisons
and have been used in warfare, in bioterrorism, and as
agricultural insecticides.
• They permit ACh to accumulate at nerve endings and
exacerbate ACh-like actions.
• It is possible to reactivate the enzyme if action is taken soon
after exposure to these poisons.
• Several compounds can provide a nucleophilic attack on the
phosphorylated enzyme and cause regeneration of the free
enzyme. Such as pyridine-2-aldoxime methiodide (2-PAM).
• Pralidoxime is a medication used in the management and
treatment of organophosphate poisoning
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• Cholinesterases that have been exposed to
phosphorylating agent (Sarin) become refractory to
reactivation by cholinesterase reactivators. The process is
called aging and occurs with AChE and BuChE in vivo and
in vitro.
• Aging occurs by partial hydrolysis of the phosphorylated
moiety that is attached to the serine residue at the
esteratic site of the enzyme.

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Organophosphate (OP) and carbamate esters can inhibit
acetylcholinesterase (AChE) by binding covalently to a serine
residue in the enzyme active site, and their inhibitory potency
depends largely on affinity for the enzyme and the reactivity
of the ester

Phosphorylated cholinesterases may undergo a dealkylation

reaction of the organophosphorus moiety leading to "aged"
enzyme, i.e. conversion of the inhibited enzyme into a non-
reactivable form

Pralidoxime or 2-PAM, usually as the chloride or iodide salts,

belongs to a family of compounds called oximes that bind to
organophosphate-inactivated acetylcholinesterase. It is used to
treat organophosphate poisoning in conjunction with atropine and
either diazepam or midazolam 32
• Insecticidal agents are toxic and must handle with extreme
cautions.

• Symptoms of toxicity are nausea, vomiting, excessive sweating,

salivation, miosis, bradycardia, low blood pressure, and
respiratory difficulty, which is the usual cause of death.

• The organophosphate insecticides of low toxicity, such as

malathion, generally cause poisoning only by ingestion of
relatively large doses. Parathion or methylparathion, however,
cause poisoning by inhalation or dermal absorption.

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1. Parathion.
• o,o-diethyl o-p-nitrophenyl phosphorothioate.

• It is used as an agricultural insecticide. It is a relatively

weak inhibitor of cholinesterase.

• Enzymes present in liver microsomes and insect

tissues convert parathion to paraoxon, a more potent
inhibitor of cholinesterase.

• Metabolism by liver microsomes also yield p-

nitrophenol and diethylphosphate, the latter is
inactive as an irreversible cholinesterase inhibitor. 34
35
 Pralidoxime Chloride.
• 2-pyridine aldoxime methyl chloride,
2-PAM chloride. It is used as an antidote
for poisoning by parathion and related
pesticides.
• It is also an effective antagonist for some carbamates
such as neostigmine methylsulfate and
pyridostigmine bromide.
• The biological half-life of 2-PAM chloride in humans
is about 2 hours and most effective by IM, SC or IV
administration.
• Most effective if given within a few hours. Little will
be accomplished if the drug is used more than 36
hours after parathion poisoning has occurred. 36
• Because pralidoxime has a quaternary nitrogen, it is fully
charged and cannot pass through BBB into the CNS.
• This means that the antidote cannot work on any
enzymes that have been inhibited in the brain.
• Pro-2-PAM is a prodrug of pralidoxime.
• As a tertiary amine it can pass through
BBB and is oxidized to pralidoxime once
it has entered the CNS.
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 Parasympathetic Postganglionic
Blocking Agents.
• Known as antimuscarnics, anticholinergics,
parasympatholytics, or cholinolytic drugs.
• Act by competitive antagonism of ACh binding
to muscarinic receptors.
• These are generally larger molecules capable
of additional binding to the receptor surface.
• The most potent anticholinergic drugs are
derived from muscarinic agonists that contain
one or sometimes two large or bulky groups.
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 Therapeutic actions:
1. Mydriatic effect: dilation of the pupil of the eye,
used topically to reduce systemic side effects.
2. Antispasmodic effect: lowered tone and motility
of the GIT and the genitourinary tract.
3. Antisecretory effect: reduced salivation
(antisialagogues), reduced perspiration (anhidrotic) and
reduced acid and gastric secretion.
• The principal goal of anticholinergics in the
treatment of Parkinsonism is to decrease the
activity of cholinergic neurons in the basal
ganglia.
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• Atropine is an effective blocking agent at
parasympathetic postganglionic terminals.
• Like most classic blocking agents, it acts on
all muscarinic receptor subtypes.

• d-tubocurarine blocks the effect of ACh

on skeletal muscle, which is activated by
N1 nicotinic receptors.

• Hexamethonium blocks transition at

N2 nicotinic receptors located in
autonomic ganglia.
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• A wide variety of compounds possess
anticholinergic activity.
Classification:
1. Solanaceous alkaloids and analogs.
2. Synthetic Cholinergic blocking agents.
A. Aminoalcohol esters.
B. Aminoalcohol ethers.
C. Aminoalcohols.
D. Aminoamides.
3. Miscellaneous.
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1. Solanaceous alkaloids and analogs.
• Represented by (-)-hyoscyamine, atropine and
scopolamine (hyoscine).
Structural considerations:
1. All of the solanaceous alkaloids are esters of the bicyclic
aminoalcohol (3-hydroxytropane) or of related
aminoalcohols.
2. Chair conformation is the commonly accepted form
because it has the lowest energy requirement.
• In tropine, hydroxyl group, trans to the nitrogen bridge, is
designate α, and the alternate cis is designated β.
• Antimuscarinic activity is associated with all of the
solanaceous alkaloids that possess the tropine-like chair
orientation of the esterified hydroxyl group.
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43
3. The tropic acid portion (3-hydroxy-2-phenylpropanoic
acid) is highly specific for the anticholinergic action.
• The earliest attempts to modify the atropine molecule
retained the tropine portion and substituted various acids for
tropic acid.
4. Other changes have been directed toward the
quaternization of the nitrogen as (methscopolamine
bromide, and homatropine methylbromide).
• When the groups attached to nitrogen are larger than methyl,
a possible decrease in affinity for the cholinergic receptor, due
to greater electron repulsion and greater steric interference to
the approach of the cationic head.
• In general, quaternization reduces parasympathomimetic
action much more than parasympatholytic action.
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45
1. Atropine.
• Is the tropine ester of
racemic tropic acid.
• It has a plasma half-life
of about 2 to 3 hours.
• It is metabolized in the liver to several products,
including tropic acid and tropine.
• Atropine is administered in small doses before general
anesthesia to reduce oral and air passage secretions.
• Administered with morphine to reduce the respiratory
depression induced by morphine.
• Atropine is a specific antidote against
organophosphorous poisoning.
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• It is also used as an adjunct to anesthesia to protect
against bradycardia, hypotension and even cardiac arrest
induced by the skeletal muscle relaxant succinylcholine
chloride.
• Atropine causes restlessness, prolonged pupillary
dilation, loss visual accommodation, and arrhythmia.
2. Hyoscyamine.
• Hyoscyamine is the levo form of the racemic mixture of
atropine. The dextro form does not exist naturally but
has been synthesized.
• They criticize the use of hyoscyamine exclusively because
it tends to racemize to atropine easily in solution, so that
atropine sulfate becomes the more stable of the two.
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3. Scopolamine.
• It is effective in preventing motion sickness.
• Whereas atropine stimulate the
CNS, causing restlessness and
talkativeness, scopolamine usually
acts as a CNS depressant.
• Scopolamine hydrobromide as
salt soluble in water.
4. Homatropine HBr.
• Used topically as a mydriatic.
• It is like atropine but weaker and
less toxic and shorter duration.
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5. Ipratropium bromide.
• It is a quaternary ammonium
derivative of atropine.
• Inhalation therapy to produce
dilation of bronchial smooth muscle for acute asthmatic
attacks.
• DOA about 6 hours and half-life of 3.5 hours.
• Also act on the surface of mast cells to inhibit ACh-
enhanced release of chemical mediators.
• It has a slow onset of action, within 5 to 15 minutes after
being administered by inhalation, and should not be used
alone for acute asthmatic attacks.
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2. Synthetic cholinergic blocking agents.
SARs.

• Anticholinergic compounds may be considered chemicals

that have some similarity to ACh but contain additional
substituents that enhance their binding to the cholinergic
receptor.
• Anticholinergic agent may contain a quaternary
ammonium function or a tertiary amine that is protonated
in the biophase to form a cationic species.
• The nitrogen is separated from a pivotal carbon atom by a
chain that may include an ester, ether, or hydrocarbon
moiety.
50
51
• The substituent groups R1 and R2 contain at least one
aromatic moiety capable of Vander Waals interactions to
the receptor surface and one cycloaliphatic or other
hydrocarbon moiety for hydrophobic bonding
interactions.
• R3 may be hydroxyl or carboxamide to undergo hydrogen
bonding with the receptor.
1. The cationic head:
• It is generally considered that the anticholinergic molecules
have a primary point of attachment to cholinergic sites
through the cationic head.
• Steric factors that cause diffusion of the onium charge or
produce a less-than-optimal drug-receptor interaction result
in a decrease of parasympathomimetic properties and allow
the drug to act as an antagonist.
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2. The hydroxyl group:
• Not requisite for activity, a suitably placed alcoholic hydroxyl
group enhances antimuscarinic activity over that of a similar
compound without the hydroxyl group.
• It is assumed that the hydroxyl group contributes to the
strength of binding, probably by hydrogen bonding to an
electron-rich portion of the receptor surface.
3. The esteratic group:
• Many of the highly potent antimuscarinic compounds possess
an ester grouping, and this may be a contributing feature for
effective binding.
• Not necessary for activity, because several types of
compounds do not possess such a group (ether,
aminoalcohols).
53
4. Cyclic substitution:
• At least one cyclic substituent (phenyl, thienyl, or other) is a
common feature in almost all anticholinergic molecules.
• Use of aromatic acids leads to low activity of these
compounds as anticholinergic but potential activity as local
anesthetic.

54
 Synthetic anticholinergics groups.
A. Aminoalcohol esters.
Used primarily as antispasmodics or mydriatics.
1. Clidinium Bromide.
• It is marketed alone and in combination
with the minor tranquilizer chlordiazepoxide
(Librax®), to treat GI complaints.
• It is suggested for peptic ulcer, ulcerative
or spastic colon, hyperchlorhydria, anxiety states with GI
manifestations, and nervous stomach.
• It is contraindicated in glaucoma, prostatic hypertrophy in
elderly men, which could lead to urinary retention.
55
2. Cyclopentolate Hydrochloride.
• It quickly produces cycloplegia and
mydriasis locally.
• Used in the management of iritis,
iridocyclitis, keratitis, and choroiditis.
B. Aminoalcohol ethers.
• Used as antiparkinsonian drugs rather than as
conventional anticholinergics.
• In general, they may be considered closely related to
the antihistaminics, and indeed, do possess substantial
antihistaminic properties.
• In turn, the antihistaminics possess anticholinergic
activity have been used as antiparkinsonian agents.
56
• Comparison of orphenadrine with the antihistaminic
diphenhydramine illustrates the close similarity of
structure.

• The use of diphenhydramine in parkinsonism has been

cited previously.

57
1. Benztropine Mesylate.
• It has anticholinergic, antihistam-
inic and local anesthetic properties.
• Used as antiparkinsonian agent.
• It does not produce central stimulation but instead exerts the
characteristic sedative effect of the antihistamines.
• Caution with glaucoma and prostatic hypertrophy.
2. Orphenadrine Citrate.
• It is closely related to diphenhydramine,
but has much lower antihistaminic activity
and much higher anticholinergic action.
• It lacks the sedative effects. Its weak peripherally
anticholinergic, by working centrally, it used for the
symptomatic treatment of parkinson disease.
58
• Orphenadrine citrate is also used as an adjunct to rest,
physiotherapy, and other measures to relieve pain of local
muscle spasm.
C. Aminoalcohols.
1. The presence of the alcohol group seems to substitute
adequately as a prosthetic group for the carboxyl function
in creating an effective parasympatholytic blocking agent.
2. Another common structure is γ-aminopropanol
arrangement, with 3 carbons intervening between the
hydroxyl and amine functions.
3. All used drugs are tertiary amines for centrally effect as
antiparkinsonian agents.
4. Tridihexethyl chloride was quaternized to enhance the
anticholinergic activity to produce an antispasmodic and
antisecretory compound.
59
1. Biperiden.
• It has a strong nicotinolytic action in
terms of its ability to block nicotine-
induced convulsions.
• Used in parkinson syndrome by minimizing side effects.
• Used in all types of parkinson disease (post-encephalitic,
idiopathic, arteriosclerotic).
• It is also used in drug-induced extrapyramidal disorders to
eliminate symptoms and permit continued use of tranquilizers.
• It is contraindicated in all forms of epilepsy.
• The same care should be exercised with anticholinergics when
its administered to patients with glaucoma, tachycardia or
prostatic hypertrophy.
60
2. Tridihexethyl Chloride.
• It possess the antispasmodic and the
antisecretory activities.
• Because of its quaternary character not
used for parkinson syndrome.
3. Trihexyphenidyl Hydrochloride.
• Parkinsonian agent. Relief mental
depression associated with this condition.
D. Aminoamides.
• The polar amide group replaces the corresponding polar
hydroxyl group.
• It retain the same bulky structural features found at one
end of the molecule or the other.
61
• Isopropamide iodide is the only drug of this class
currently in use.

1. Isopropamide Iodide.
• Potent anticholinergic producing
atropine-like effects peripherally.
• Its principal distinguishing feature is its long duration of
action.
• A single dose can provide antispasmodic and antisecretory
effects for as long as 12 hours.

62
3. Miscellaneous.
1. Papaverine Hydrochloride.
• Its natural origin is closely related
to morphine “opium”.
• A spasmolytic on smooth muscle,
acting as a direct, non specific relaxant on vascular, cardiac,
and other smooth muscle.
• Called a nonspecific antagonist.
• It has been used in the treatment of peripheral vascular
disorders, but its use is limited by lack of potency.

63
 References
1. Wilson and Gisvold’s Textbook of Organic Medicinal
and Pharmaceutical Chemistry, 12ed, 2011, John M.
Beale and John H. Block; page: 558-596.

2. An Introduction to Medicinal Chemistry, 5ed, 2013,

Graham L. Patrick; page: 578-608.

3. Foye’s Principles of Medicinal Chemistry, 7ed, 2013,

Thomas L. Lemke, David A. Williams, Victoria F. Roche
and S. William Zito; page: 309-334.
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