Antimuscarinic Drugs Self-learning

‫من أول هنا‬

They block the M receptors at the smooth muscle of GIT, UT, and glands (have high affinity with no intrinsic activity).

Effects & Uses

1. ↓ secretion of saliva and GIT secretion & HCl → antiulcer. 3. Dilation of eye pupils (Mydriatic) → ophthalmic examination
2. ↓ motility of GIT & UT by relaxation of s.m. → shut down GIT 4. ttt of parkinsonism
during surgery

SAR: ‫هاااام‬
1) R1, R2 = carbocyclic or heterocyclic; Extra-binding with receptor (hydrophobic binding)
generally one is aromatic & the other ▪ R1, R2 may fuse together (tricyclic system) .
is aromatic or alicyclic. ▪ may be separated .
▪ When R1= R2 = naphthalene → inactive compound due to steric hindrance.
2) R3 = H, OH, CH2OH, CONH2 → these groups ↑ D-R binding (H-bonding)
3) X = COO (Aminoalcohol Ester deriv.), -O- (Aminoalcohol ether deriv.) or absent
(Aminoalcohols).
4) N = ▪ 4ry ammonium salt or
▪ 3ry amine
Alkyl group may be methyl, ethyl, propyl or isopropyl
5) The distance n = 2 – 4 atoms.

1) Natural Solanaceous alkaloids & semisynthetic drugs

1. Atropine (prototype)
It is the first compound that blocks the effects of muscarinic receptors.

SAR notes:
1- The intact ester of tropine and tropic acid is essential for the action of atropine, since neither the free acid
nor the base exhibits significant
activity.
2- The presence of a free OH group in the acid portion of the ester also is important for activity.
3- The tropic acid part has an asymmetrical carbon atom. Atropine is racemized during extraction and consists of
a mixture of equal parts of (+)- and (-)-hyoscyamine, but antimuscarinic activity is almost wholly due to the naturally occurring (-) form.
4- Substitution of other aromatic acids for tropic acid modifies but does not necessarily abolish the antimuscarinic activity.
s Cholinergic & SL 1
 5- The intact amino-alcohol tropine is not necessary; only a tertiary N, which is two carbons away from the ester group.
6- It is a tertiary amine, so it has central effects.
7- When given parenterally, quaternary ammonium derivatives of atropine and scopolamine are, in general, more potent than their parent compounds in
both muscarinic receptor (and ganglionic blocking activity); they lack CNS activity because of poor penetration into the brain. Given orally, they are
poorly absorbed, as are other quaternary ammonium compounds.

Its main clinical uses:

1- Treatment of bradycardia.
2- As preoperative agent to decrease secretions before surgery
3- In ophthalmic examination as it causes mydriasis.

C/Is: in glaucoma as it increases the intraocular pressure during mydriasis.

2. Homatropine ‫ هااام‬3. Scopolamine (Hyoscine) 4. Ipratropium bromide

Aminoalcohol Ester derivative.‫هام‬
Homatropine → mydriatic cycloplegic
preparation, while Homatropine methyl
bromide is the quaternary derivative →
available in some combination products intended
for relief of gastrointestinal spasm.
• having CNS depressant activity, contrast for inhalation therapy in ttt of acute
atropine that has some CNS stimulant action. asthma → bronchodilation
• Uses: transdermal patch for ttt of motion
sickness that is applied to the skin behind the
ear → well-absorbed percutaneously

s Cholinergic & SL 2

1. Glycopyrrolate
• Uses: for peptic ulcer & as
Antispasmodic.
• presence of quaternary
ammonium group facilitates the
prolonged existence of the drug
inside GIT → ↓its absorption.
4. Procyclidine
Uses: 3ry amine (lipophilic) → Aminoalcohol Ester derivative ‫هام‬
cross BBB → for treatment of
Parkinson’s disease ‫هام‬
s Cholinergic & SL
2) Synthetic atropine derivatives
2. Propantheline
Xanthene derivative
Uses: for gastritis, hypermotility, bladder irritability,
cholinergic spasm, pancreatitis, and peptic ulcer.
Synthesis:
5. Oxybutynin 6. Benztropine
• a tertiary amine → access
CNS
• Uses: used in ttt of
Parkinson’s disease
3. Orphenadrine
‫ج‬
• structurally related to diphenhydramine,
but with lower antihistaminic activity.
• It has central inhibitory action →
↓voluntary muscle spasm
• Uses: 3ry amine (lipophilic) → cross BBB →
for treatment of Parkinson’s disease ‫هام‬
7. Pirenzepine & Telenzepine
Selective M1-muscarinic antagonist
Uses: as anti-ulcer drug with minimal effects on
salivary glands, heart & eye.
3
 Nicotinic antagonists
(1) Ganglionic blockers (N1-blockers)
Classification: Examples:
1- Depolarizing Ganglionic blockers E.g. mecamylamine, trimethaphan, hexamethonium
2- Non-Depolarizing Competitive Ganglionic blockers

(2) N2-blockers (Neuromuscular blockers) (Skeletal muscle relaxants)

• They block the action of ACh at the motor endplate.
• Used mainly as adjuvant in surgical anesthesia to obtain relaxation of skeletal muscles.
• Called curarimimetics in reference to the original representative of the class that was obtained from curare (active principle is tubocurarine).

• They are subdivided into:

1. Non-depolarizing blocking agents. 2. Depolarizing blocking agents.

Tubocurarine Metocurine

• It is the active ingredient of the curare mixture

that has been known as arrow poison cause of its
paralysis effect.
• It is the prototype of this class and has long duration.
• Isoquinoline derivative
• Presence of 2 quaternary nitrogens separated by a
distance of 10 atoms (1.4 nm) allow the blocking of Nm-receptors. ‫هام‬

Design of synthetic neuromuscular blockers:

s Cholinergic & SL 4
 1. Design of compounds 2. Molecular simplification of
have 2 positively charged nitrogens separated by steroidal spacer as tubocurarine to give compounds like decamethonium, succinyl choline & gallamine
Pancuronium (distance 1.1 nm)

(Non-depolarizing neuromuscular blockers) (Depolarizing neuromuscular blockers)

They compete with ACh for the nicotinic receptor at the motor These drugs lead to sustained depolarization → receptor site become insensitive to ACh.
endplate.
1-Pancuronium bromide & Vecuronium bromide 1. Decamethonium bromide 2. Succinyl choline chloride
Dexamethylene bis
(trimethylammonium) Dibromide

• One of the bis-quaternary • Stereochemistry: The active form is the

ammonium compounds with a
number of methylene groups
separating the N-atoms.
• The maximal neuromuscular
• The steroid nucleus used as a spacer. blockade occurred with 10 to
• They are long acting agents with higher activity 12 unsubstituted methylene
than Tubocurarine. Why? They are activated in vivo to groups. ‫هام‬
the hydroxy metabolite
• The first can cause ↑BP & HR → cautions must be N.B. Compare with
taken with patients with coronary artery diseases Hexamethonium??????
while the second is devoid of this side effect.
staggered (trans) conformation. ‫هام‬
• Metabolism: rapidly hydrolyzed to inactive forms
(Succinic acid & choline) [short duration] ‫هام‬
• So it is frequently used for the rapid induction
of neuromuscular blockade of short duration of
action such as endotracheal incubation or
endoscopic procedures.

2-Atracurium Besylate & Mivacurium

Review the next page

Note: Antidote → neostgmine

s Cholinergic & SL 5
 Atracurium Besylate

• It is non-depolarizing neuromuscular blocker in

which the quaternary ammonium groups are
located in 2 substituted tetrahydroisoquinoline
rings separated by aliphatic diester.
• It is not metabolized in the liver, it undergoes
hydrolysis of the ester functional groups (safe for
patients with liver & kidney disease)
• It also undergoes Hofmann elimination which is
non-enzymatic , base catalysed decomposition to
yield Laudanosine

Mivacurium

Doesn’t undergo Hofmann elimination

s Cholinergic & SL 6