PARASYMPATHOMIMETIC DRUGS Classification and SAR.pptx

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) C hol i n e e s t er s : A c e t y l c h o lin e, M e th a cho l in e , Bethanechol C a r b ac h ol ,  Choline alkaloids  Natural  Pilocarpine, Arecholine (Muscarnic);  Nicotine, Lobeline (Nicotinic)  Synthetic  Oxotremorine (Muscarinic), A r e c lid i n e , Dimethylphenylpiperazinium(DMPP) (Nicotinic)

4.  Indirect acting ( anticholinesterase inhibitors) R e v e r s i b l e : Ph y s o s tig m ine, Neos ti g m in e , 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. CH 3 O C O CH 2 CH 2 N + CH 3 CH 3 CH 3 Acetylcholine Acetyloxy Ethylene Quaternary Nitrogen Bridge Acetyloxy group If, Acetyl group is replaced with higher homologs( propionyl or butyryl groups) Activity decreases Replacement of CH 3 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 CH 3 gives compounds with equipotent activity but higher replacements like C 2 H 5 , C 3 H 7, gives less active compounds.  Substitution by CH 3 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.

11. 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 )

12. 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

13. 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.