Classification and SAR of cholinergic drugs

1. Parasympathomimetic Drugs
Classification, SAR and Pharmacological actions
Lecture 2
Dr. Jasmine Chaudhary
Associate Professor
MMCP

2. Cholinergic Drugs/ Parasympathomimetic Drugs
Drugs which mimics/ resembles the action of acetyl choline are
called cholinergic drugs/cholinomimetic.
• Stimulate parasympathetic nervous system in same manner as
does acetylcholine
• May stimulate cholinergic receptors directly or slow acetylcholine
metabolism at synapses (by affecting enzyme acetylcholinesterase)
Depending on which Cholinergic agonists are two types :
1.Direct acting
2.Indirect acting

3. 

Direct acting (act directly on receptors)
Choline esters: Acetyl choline, Methacholine,
Bethanechol
Carbachol,
 Choline alkaloids
 Natural
 Pilocarpine, Arecholine (Muscarnic);
 Nicotine, Lobeline (Nicotinic)
 Synthetic
 Oxotremorine (Muscarinic), Areclidine,
Dimethylphenylpiperazinium(DMPP) (Nicotinic)

4.  Indirect acting (anticholinesterase inhibitors)
 Reversible: Physostigmine, Neostigmine,
Pyridostigmine, Edrophonium, Tacrine
 Irreversible: Ecothiophate, Organic phosphorus
compounds like parathion, malathion

5. Direct acting cholinomimetics
They act by binding directly to cholinoceptors.
Direct acting cholinergics are lipid insoluble.
• Do not readily enter the CNS so effects are peripheral.
• Resistant to metabolism by acetylcholinesterase.
• Effects are longer acting than with acetylcholine.
Indirect acting cholinomimetics
Inhibit the enzyme “cholinesterase” due to which metabolism of
acetyl choline is inhibited leading to availability of more Ach at
the receptors. These are of 2 types:
REVERSIBLE:
Bind to cholinesterase for a period of minute to hours.
IRREVERSIBLE:
Bind to cholinesterase and form a permanent covalent bond.
The body must make new cholinesterases.

6. Acetylcholine
• One of the main neurotransmitters of the ANS is acetylcholine
• Acetylcholine is released at preganglionic fibers of both the
sympathetic and parasympathetic nervous system
• Also released from postganglionic sympathetic neurons that
innervate the sweat glands and from motor neurons that innervate
the skeletal muscles
• It is a quaternary ammonium compound so cannot penetrate the
membrane.
• Does not have any therapeutic importance, because rapid
inactivation by acetylcholinesterases.
• It has both Muscarinic & Nicotinic actions .

7. C H 3
O
C O C H 2 C H 2 N +
C H 3
C H 3
C H 3
A c e t y l c h o l i n e
A c e t y l o x y E t h y l e n e Q u a t e r n a r y N i t r o g e n
B r i d g e
Acetyloxy group
If, Acetyl group is replaced with higher homologs( propionyl or
butyryl groups) Activity decreases
 Replacement of CH3 by aromatic groups or high molecular
weight compounds gives cholinergic antagonist.
Replacement of ester group with ether or ketone group gives
equipotent compounds which suggest that presence of ester group is
not essential for activity.

8.  Replacement of easily hydrolyzable methyl group by less
easily hydrolysable groups like amine leads to compound
with more duration of action. E.g. Carbhachol has more
duration of action than acetyl choline.
 Replacement of O by S decreases the activity.
2
H N
O
N
O
C a r b a c o l

9. Ethylene Bridge
 Increase in chain length of ethylene bridge will give inactive
compounds.
Replacement of H of ethylene chain by CH3 gives compounds
with equipotent activity but higher replacements like C2H5 , C3H7,
gives less active compounds.
Substitution by CH3 group at alpha or beta position gives
different action like methyl group at α-carbon → increase nicotinic
activity whereas introduction of methyl group at β-carbon →
compounds with greater muscarinic activity than nicotinic, and
greater stability / resist hydrolysis (long duration)

10. Quartenary Nitrogen atom


Amine is a Quaternary nitrogen (Trimethylammonium
group) is essential for activity. Its isosteric replacement with
S or As, P, Se → gives less active compounds.
Only those compounds which posses +ve charge on the
atom in place of nitrogen are active
 Replacement of methyl group by ethyl or higher homolog
gives less active compounds.
RULE OF FIVE: Ing postulated that there should not be more
than 5 atoms between nitrogen and terminal hydrogen atom
for maximal activity.

12. Uses
 Used in treatment of glaucoma (Physostigmine, Pilocarpine)
by reducing intraoccular pressure.
Used in Alzheimer’s disease (Tacrine)
Used in treatment of myasthenia gravis (Neostigmine and
Pyridostigmine)
Used to test myasthenia gravis (Edrophonium)
 In Belladona poisoning (Physostigmine)

13. Effects of cholinergic drugs
DUMBBELL (to remember)
D- Diaphoresis (Sweating)
U- Urination
M- Miosis
B- Bronchoconstriction
B- Bradycardia
E- Emesis (Vomiting)
L- Lacrimation
L-Loose store

14. Question Bank
•Classify cholinergic drugs with examples.
• Give pharmacological actions and uses of cholinergic drugs.
•Give SAR of parasympathomimetic drugs.
•Differentiate between direct acting and indirect acting
cholinergic drugs.
•What are anticholinesterase drugs. Give examples.