PHA051 LAS#6

RATIONALE
1.Discuss SAR of anticholinergics
A.Substitution at R1 position
- Substituent R1 should be
carbocyclic or heterocyclic ring for
maximal antagonist activity

B.Substitution at R2 position
- Substituent R2 should be a
hydrogen atom, hydroxyl group,
hydroxymethyl group, amide
C. Substitution at X position
The X is mostly Ester in most potent
derivatives but it can be an ether or absent
completely
D. N- substitution
can be both quaternary ammonium/ tertiary amine with different alkyl
groups. Most potent derivatives have quaternary ammonium salt.

The alkyl group is not restricted to only methyl (as in SAR of Ach agonist).
It can be ethyl, propyl or isopropyl
E. Stereochemistry at benzylic carbon
The stereochemistry at the benzylic carbon is critical for
muscarinic antagonist activity.

F. Phenyl ring substitution

The phenyl ring at the R1 position cannot tolerate any
substituent other than F on the p-position without losing its
antagonist activity
2. What are the three predictable and
clinically useful effects of blocking the
muscarinic effects of ACh?
1. Mydriatic effect: dilation of the pupil of the eye; and
cycloplegia, a paralysis of the ciliary structure of the eye,
resulting in a paralysis of accommodation for near vision
2. Antispasmodic effect: lowered tone and motility of
the GI tract and the genitourinary tract
3. Antisecretory effect: reduced salivation
(antisialagogue), reduced perspiration (anhidrotic), and
reduced acid and
gastric secretion
3. Enumerate the different
anticholinergics based on the ff. chemical
classes and give the clinical uses of each
class. (TAKE NOTE OF THEIR
STRUCTURES)

a. Solanaceous alkaloids and synthetic

analogs:
Atropine, Hyoscyamine, Scopolamine,
Homatropine, Ipratropium bromide, Tiotropium
b. Synthetic aminoalcohol esters:

Clidinium, Cyclopentolate, Dicyclomine,

Glycopyrrolate, Eucatropine HCl, Mepenzolate,
Methantheline bromide, Oxyphencyclimine HCl,
Propantheline bromide, Oxybutynin, Trospium
Cl, Solifenacin succinate
C. Aminoalcohol ethers:
Benztropine mesylate, Orphenadrine citrate,

D. Aminoalcohols:
Biperiden, Procyclidine HCl, Tridihexethyl Cl, Trihexyphenidyl HCl,
Tolterodine

E. Aminoamides:
Isopropamide Iodide, Tropicamide, Darifenacin,

F. Miscellaneous:
Diphemanil methylsulfate, Ethopropazine HCl, Papaverine HCl
4. Identify the structure of the
anticholinergics below:
5. Enumerate the adverse effects of atropine.

Expected ‘side effects’ of anticholinergic therapy

include: photophobia, blurriness of near vision,
cycloplegia, dry mouth, tachycardia, difficult
urination, red skin (‘atropine flush’), and increase
in skin temperature, central-sedation or
excitement.
6. Describe the structure of ganglion
blocking drugs.
• They are divided
into 4 subgroups
based on their
chemical structure:
A. Mono quaternary
ammonium
compounds
Tetraethylammonium
bromide
B. Bis quaternary ammonium
compounds

n - count: 5 or 6, active as ganglionic

blockers
n - count: 9 to 12, weak ganglionic blockers
ex. Pentamethonium
Hexamethonium
Decamethonium
Pentamethonium bromide
Hexamethonium
Decamethonium
C. Secondary and tertiary amines

Mecamylamine
- a secondary amine
 D. Quaternary Sulphonium Compounds
• Trimethaphan
camsylate
- a monosulfonium
compound, bears some
similarity to the
quaternary ammonium
types because it, too, is
a completely ionic
compound.
7. Discuss the mechanism of action of
Ganglion blocking drugs.
• Ganglionic blockers inhibit autonomic activity by interfering
with neurotransmission within autonomic ganglia.
• This reduces sympathetic outflow to the heart thereby
decreasing cardiac output by decreasing heart rate and
contractility.
• Reduced sympathetic output to the vasculature decreases
sympathetic vascular tone, which causes vasodilation and
reduced systemic vascular resistance, which decreases
arterial pressure.
• Parasympathetic outflow is also reduced by ganglionic
blockers
8. Describe the structure of
neuromuscular blockers.
• All of the available neuromuscular blocking
drugs bear a structural resemblance to
acetylcholine. For example, succinylcholine
is two acetylcholine molecules linked end-
to-end . In contrast to the single linear
structure of succinylcholine and other
depolarizing drugs, the nondepolarizing
agents (eg, pancuronium) conceal the
“double-acetylcholine” structure in one of
two types of bulky, semirigid ring systems.
Another feature common to all currently
used neuromuscular blockers is the
presence of one or two quaternary
nitrogens, which makes them poorly lipid
soluble and limits entry into the CNS.
• Structural relationship of
succinylcholine, a depolarizing
agent, and pancuronium, a
nondepolarizing agent, to
acetylcholine, the neuromuscular
transmitter:
• Succinylcholine, originally called
diacetylcholine, is simply two
molecules of acetylcholine linked
through the acetate methyl groups.
Pancuronium may be viewed as two
acetylcholine-like fragments
(outlined in color) oriented on a
steroid nucleus.
•Structures of
two isoquinoline
neuromuscular
blocking drugs.
These agents
are
nondepolarizing
muscle relaxants.
• Structures of steroid
neuromuscular
blocking drugs
(steroid nucleus in
color).
• These agents are all
nondepolarizing
muscle relaxants:
9. Differentiate the mechanism of action of
Depolarizing and Non- depolarizing
neuromuscular blockers. Enumerate the drugs
under each class.
• Nondepolaring relaxant drugs:
A. Isoquinoline derivatives: Atracurium, Cisatracurium,
Tubocurarine (prototype)
B. Steroid derivatives: Pancuronium, Rocuronium,
Vecuronium, Pipecuronium
• MOA: Nondepolarizing neuromuscular blockers are competitive
acetylcholine (ACh) antagonists that bind directly to nicotinic
receptors on the postsynaptic membrane, thus blocking the
binding of ACh so the motor endplate cannot depolarize. This
leads to muscle paralysis.
• Depolarizing Relaxant Drug:
Succinylcholine
Mechanism of action:
1. Phase I block (depolarizing)—Succinylcholine is
the only clinically useful depolarizing blocking drug. Its
neuromuscular effects are like those of acetylcholine
except that succinylcholine produces a longer effect at
the myoneural junction. Succinylcholine reacts with the
nicotinic receptor to open the channel and cause
depolarization of the motor end plate, and this in turn
spreads to the adjacent membranes, causing
contractions of muscle motor units.
2. Phase II block (desensitizing)—With
prolonged exposure to succinylcholine, the
initial end plate depolarization decreases and
the membrane becomes repolarized. Despite
this repolarization, the membrane cannot
easily be depolarized again because it is
desensitized
10. Give the clinical uses of
Neuromuscular blockers.
• is clinically useful in producing muscle
relaxation, a requirement for surgical
relaxation, tracheal intubation and control of
ventilation.