3.

3 THE CHOLINERGIC BLOCKING AGENTS:

The chemicals that have high affinity for the acetylcholine receptor but
have no intrinsic activity and may decrease the number of available free
receptors and thus the efficacy of the endogenous neurotransmitter. These
include parasympathetic postganglionic blocking agents, ganglion blocking
agents, and neuromuscular blocking agents.

They block the various types of cholinergic receptors.

Antimuscarinic Drugs (parasympathetic postganglionic blocking agents):
They block the action of Acetylcholine at muscarinic receptors and also effects
of parasympathetic nerve stimulation.
Ganglion blocking drugs:
They block the action of Acetylcholine at autonomic ganglia. (Nicotinic
receptors).
Neuromuscular blocking drugs:
They block the effect of Acetylcholine at Neuromuscular junction.

3.3.1 Antimuscarinic Drugs

They are also called ‘Parasympatholytic drugs’ or Anticholinergics’.
They reduce or abolish (block) the muscarinic receptor mediated effects of
parasympathetic nervous system. The dosed required to block the responses to
parasympathetic stimulation are greater than those required to block effects of
exogenously administered drugs. It is due to the fact that by nerve stimulation
the acetylcholine is liberated very close to the receptors, where higher
concentrations of antagonist are required.

• The peripheral cholinergic synapses (other than neuromuscular endplates)

are muscarinic.
• Drugs that inhibit the interaction of ACh with the ACh receptor are
considered cholinergic blocking agents.
• It is important to that these not be confused with ganglionic and
neuromuscular blocking agents which act on the nicotinic receptors.
General Properties of Interest:
✔ Decrease secretion of saliva and gastric juice
✔ Decrease gastrointestinal and urinary tract peristalsis
✔ Dilate pupils
✔ Based on these activities, they are used therapeutically for the following:
✔ Treatment of gastrointestinal diseases (peptic ulcer)
✔ Ophthalmology
✔ Treatment of Parkinson’s (control of cholinergic hyperactivity)
Antimuscarinic drugs include naturally occuring Belladonna Alkaloids
(Atropine, Hyoscine) and a large number of semi synthetic and synthetic drugs.

3.3.1.1 Classification of Antimuscarinic drugs:

Chemical classification:
The major chemical types include:
1. Solanaceous alkaloids and synthetic analogues
2. Synthetic aminoalcohol esters
3. Aminoalcohol ethers
4. Aminoalcohols
5. Aminoamides
6. Miscellaneous
7. Papaveraceous

Antimuscarinic drugs can be classified as

Natural alkaloids:
Atropine
Hyoscine
Semi synthetic compounds:
Atropine methonitrate
Hyoscine methobromide
Hyoscine butylbromide
Homatropine methylbromide
Synthetic compounds:
Mydriatic and Cycloplegics:
Cyclopentolate
Tropicamide
Homatropine
Spasmolytics (antispasmodics)
Propantheline
Isopropamide
Ipratropium (anti asthmatics)
Glycopyrrolate
Pirenzepine
Dicyclomine
Anti-Parkinsonism Agents:
Trihexyphenidyl
Benztropine
Biperiden
 Atropine is prototype, which is (±)-hyoscyamine, obtained from Atropa
bellabonna, Hyoscyamus nigar, and Datura stramonium. The circled portion of
atropine resembling acetylcholine:

3.3.1.2 Structure-Activity Relationships of Muscarinic antagonist:

Antichlolinergic compounds may be considered chemicals structurally
resembling ACh but containing additional substituents that enhance their
binding to the cholinergic receptor.

● An anticholinergic agent may contain a quaternary ammonium function

or a 3o amine that is protonated biologically to cationic species
● N is separated from the central C atom by a chain (ester, ether, or
hydrocarbon)
● Groups A & B contain at least one aromatic ring capable of van der
Waal’s interactions to receptor and one cycloaliphatic or other
hydrocarbon to cause hydrophobic interactions
● C may be hydroxyl, or carboxamide to undergo hydrogen bonding with
receptor
THE CATIONIC HEAD
The cationic head is the primary point of interaction with the receptor, the
nature of the substituent on this head is critical. Steric factors that cause
diffusion of the onium charge or produce a less than-optimal drug-receptor
interaction result in decrease in parasympathomimetic (cholinergic) activity and
allow the drug to be antagonist. The hydrophobicity may also play an important
role.
THE HYDROXYL GROUP
A suitably placed OH group enhances the binding strength possibly
through the hydrogen bonding with the electron-rich site of the receptor and
thus the potency. The position of OH relative to N is critical, diameter of
receptive area estimated to be ~2-3 Å.
THE ESTERATIC GROUP
This may be contributing feature for effective bunding however, is not
essential as many antagonists do not possess such a group (ethers,
amnioalcohols).
CYCLIC SUBSTITUTION
At least one cyclic substituent (phenyl, thienyl, other) is a common
feature in almost all anticholinergic molecules. Mimetic molecules are richly
endowed with polar grouping for some effective binding, but flat, nonpolar
groups (e.g., aromatic ring) are required for hydrophobic binding to achive
compounds with high affinity without intrinsic activity, and thus antagonists.
THE SOLANACEOUS ALKALOIDS (Strucrural Considerations)
Represented by (-)-hyoscyamine, atropine [(±)-hyoscymine], and
scopolamine (hyoscine), obtained principally from henbane (Hyoscyamus
niger), deadly nightshade (Atropa belladonna), and jimson weed (Datura
stramonium). These are isosteres of bicyclic aminoalcohol 3-hydroxytropane or
related aminoalcohols.

• Atropine is the tropic acid ester of racemic tropic acid and is optically
inactive. The natural (-)-hyoscyamine is racemized by refluxing in
chloroform or by treating with cold dilute alkali.
SYNTHETIC CHOLINERGIC BLOCKING AGENTS
The aminoalcohol ester anticholinergics are used primarily as
antispasmodics or mydriatics and aminoalcohol or aminoalcohol ethers as
antiperkinsonian drugs. The synthetic antispasmodics contain quaternary
nitrogen presumably to enhance activity.
The types of synthetic compounds include:
A. Tertiary aminoesters: Ar-COO-R
B. Tertiary aminoalcohol ethers: Ar-O-R
C. Tertiary aminoalcohols: Ar-C(R)-OH
D. Aminoamides and miscellaneous: Ar-C(R)-CONH

3.3.2 NEUROMUSCULAR JUNCTION BLOCKERS:

These compounds act on the nicotinic receptors at the neuromuscular
endplate and are widely used in surgery. The function to relax the abdominal
muscles without the use of deep anesthesia and thus make surgery much easier.
These drugs fall into 2 major categories:

1. Nondepolarizing (competitive) agents (occupy same site as ACh)

Those compete with ACh for the recognition site on nicotinic receptor by
preventing depolarization of the end plate by neurotransmitter
Examples: tubocurarine, dimethyltubocurarine, pancuronium and gallamine
2. Depolarizing agents (mimic the action of ACh but persist at the receptor)
The depolarizing blocking agents that depolarize the membrane of the
muscle end plate in the way similar to ACh and can not repolarize, which
sometimes refer to as desensitizaton
Examples: decamethonium and succinylcholine

3.3.2.1 Nondepolarizing (Competitive) Agents

• These compounds were largely developed through the study of curare
(arrow poison of indigenous South American peoples).
• Crude curare preparations contain various isoquinoline and indole
alkaloids: the best known is tubocurarine.
 • Tubocurarine seems an unlikely candidate to interact with ACh receptors
of the post-junctional membrane (no ester functionality and two
ammonium centers).

✔ Tubocurarine is prototype
✔ Bulky rigid molecules
✔ The principal active alkaloid in curare is tubocurarine .
✔ A closely related trimethylate derivative is metocurine.
✔ Produces competitive blockade at the end plate nicotinic receptor.
Causing flaccid paralysis lasting for 30-60 min.
✔ Other drugs are Pancuronium, Atracurium, vancuronium are short
acting.

Synthetic curariforms
Atracurium

Doxacurium

Gallamine

Mivacurium

Pipecurium
3.3.2.2 Depolarizing Agents.
• These compounds bind strongly and normally to the receptor to initially
trigger the same response as ACh; i.e., a brief contraction of the muscle.
• Once the ACh agonist effect has passed, the drug remains bound and thus
acts as an antagonist by preventing ACh from binding resulting in
muscular paralysis.
• Succinylcholine is a related compound that possesses the same
intra-atomic N+-N+ distance although not all atoms between the charged
centers are carbon. For producing complete muscle relaxation in surgery

Succinylcholine

decamethonium

Summary of Neuromuscular Junction blocker and Ganglion blocker.

Receptor type location Structura Postrecepto

l feature r
mechanism

NM (muscle type,end Skeletal muscle Pentamer Na+,K+

plate receptor) neuromuscular (α2βδγ)2 depolarizing
junction ion channel

NN (Neuronal type, Post ganglionic α and β Na+,K+

ganglion receptor) sell bodies, subunits depolarizing
dendrites only as ion channel
α2β2 or
α3β3
NM antagonists: NN antagonists:
Tetramethylammonium,
Mechamylamine
Hexamethonium,
,
Decamethonium, Trimethaphan.