Download - Cholinergic ramesh
CHOLINERGIC DRUGS[PARASYMPATHOMIMETICS]
DR. RAMESH KRISHNANMD,PHARMACOLOGY[2 ND YEAR]
Autonomic Nervous System
Action Potential
Na+
aa
b
ACh
Acetylcholinesterase
Na+
Parasympathetic Ganglionic Synapse
Preganglionic neuron Postganglionic neuron
Receptor
nicotinemuscarine
muscarinicreceptor
The ‘master key’ for both types of ‘lock’
ACh
AC
h
Acknowlegement-Dr.Kumarasingam
M1Location 1) Gastric paracrine glands
2) CNS(Cortex, hippocampus, striatum
3) sympathetic ganglia
Molecularmechanism
Activation of PLC : ↑ IP3 & DAG :↑ Ca2+ & PKC
Functional response
↑ acid secretion↑ cognitive function(learning &memory)↑ depolarisation of autonomic ganglia
Agonists Oxotremorine
Antagonists Pirenzepine,Telenzepine
M2
Location 1)Heart 2)Smooth muscle3)Nerve terminal 4)CNS
Molecularmechanism
(-) of adenyl cyclase – ↓cAMP ,Activation of K+channel
Functional response
HEART -SA node -↓ HR : AV node - ↓ conductionAtria - ↓contraction : Ventricle- ↓ contractionSmooth muscle - ↑contraction
Agonists Methacholine
Antagonists Methoctramine, Tripitramine
M3
Location 1)Glands2)Smooth muscle3) Iris,ciliary muscle4)CNS
Molecularmechanism
Similar to M1
Functional response
Smooth muscle contractionBlood Vessel-relaxationPupil constriction , ciliary contraction
Agonists Bethanechol
Antagonists Darifenacin
M4Location CNS(forebrain)
Molecular mechanism Similar to M2
Functional response Inhibit transmitter releaseAnalgesia
Location Substantia nigra
Molecular mechanism Similar to M1 & 3
Functional response Cerebral vasodilatationFacilitates DA release
M5
Ach actions –Nicotinic
1. Autonomic ganglia:– Both Sympathetic and parasympathetic ganglia are stimulated– After atropine injection Ach causes tachycardia and rise in BP
2. Skeletal muscle– IV injection – no effect– Application causes contraction of skeletal muscle
3. CNS:– Does not penetrate BBB
Classification
Cholinoceptor stimulants
Direct-acting
(receptor agonists)Indirect-acting
(cholinesterase inhibitors)
Muscarinic Nicotinic
Choline esters
Alkaloids
Ganglionic
Neuromuscular
DIRECTLY ACTING CHOLINERGICS
CHOLINE ESTERS
• Acetylcholine
• Bethanechol
• Carbachol
• Methacholine
ALKALOIDS
• Muscarine
• Pilocarpine
• Arecoline
Acetylecholine:-
Is the neurotransmitter of the parasympathetic N.S and cholinergic nerves, it is therapeutically of no importance due to:
• 1. Multiplicity of actions.
• 2. Rapid inactivation by acetyl-cholinesterase.
• 3. Has both muscarinic and nicotinic activity.
CHOLINOMIMETIC ALKALOIDS
PILOCARPINE
• Obtained from leaves of Pilocarpus Microphyllus
• Tertiary amine Crosses BBB
• Dominant – M3 & NN
• Too toxic for systemic use
• ADR –
↑ sweating, salivation & other secretions
• Small doses ↓ BP High doses ↑ BP
USES
1. EYE - Penetrates cornea – Miosis, Ciliary muscle contraction, ↓IOP lasting 4 – 8 hrs
• 3rd line drug - Primary open angle Glaucoma
– S/E : Initial stinging ,
–Painful spasm of accomodation
• To counteract Mydriatics
• Prevent adhesions of Iris with lens/ cornea
2. As SIALOGOGUE
MUSCARINE
• Obtained from poisonous mushrooms
• Amanita muscaria & Inocybe
• Has only muscarinic actions
• No therapeutic indications
• Quarternary alkaloid↓ BBB penetration
ARECOLINE
• Betel nut
• Predominant M + slight N
• Prominent CNS effect
CEVIMELINE
• Direct acting at M3
• Lacrimal & Salivary gland epithelium
• Longer lasting Sialogogue action than pilocarpine
• ↑ lacrimal secretion in Sjogrens syndrome
INDIRECTLY ACTING PARASYMPATHOMIMETICS
ANTI CHOLINE ESTERASES
REVERSIBLE
NATURAL SYNTHETIC
CARBAMATES ACRIDINE
IRREVERSIBLE
OP CARBAMATES
ANTI CHOLINE ESTERASES
NATURAL
• Physostigmine
• Galantamine
SYNTHETIC
CARBAMATES ACRIDINE
Neostigmine TacrinePyridostigmineEdrophoniumDonepezilRivastigmine
REVERSIBLE
IRREVERSIBLE
Organophosphates• Ecothiophate
• Isoflurophate
• Parathion
• Malathion
• Diazinon
NERVE GASES
• Tabun , Sarin , soman
CARBAMATES
• Carbaryl
• Propoxur
ACh is broken by AChE
Mechanism of action :-
• 1.Acetylcholinesterase inhibitors - inhibit the AChE, responsible for breakdown of ACh
• 2.increased cholinergic activity -both nicotinic and muscarinic receptors
Mechanism of action of phosphates:-AchE
+ phosphates
Phosphorylated enzyme
Ageing-Loss of alkyl gp-resistant to hydrolysis(extremely slow reaction)
Mechanism of action of carbamates:-
AchE+ carbamates
Carbamylated enzyme+ H2O
Free enzyme + carbamic acid(slow reaction)
½ life of reactivation - carbamylated enzyme - 30 mins -less than synthesis of fresh enzyme
USES OF ANTICHOLINESTERASE DRUGS
1.MIOTIC A) GLAUCOMA
• ↑ tone of ciliary muscle ( attached to scleral spur) &
• ↑ tone of Sphincter pupillae pull on & improve alignment of trabeculae outflow facility is ↑
• Physostigmine (0.1 %)
B ) TO REVERSE EFFECT OF MYDRIATICS
C ) TO PREVENT ADHESIONS OF IRIS WITH CORNEA / LENS
2. MYASTHENIA GRAVIS
3.POST OPERATIVE PARALYTIC ILEUS / URINARY RETENTION• Neostigmine4.POST OPERATIVE DECURARIZATION• Atropine (Block M) Followed by Neostigmine5.COBRA BITE• Neostigmine + Atropine prevent Respiratory Paralysis
6.ANTI CHOLINERGIC OVERDOSAGE• TCA, Phenothiazine, Anti Histamine – Physostigmine.
7. BELLADONA POSONING
Belladona poisoning
8. ALZHEIMERS’DISEASE :-
Management of OP Poisoning :-
• Termination of further exposure
fresh air, wash the skin & mucosa with soap & water, gastric lavage
• Maintain airway- PPV if its failing
• Supportive measures
– Maintain BP
– Hydration
– control of convulsions -diazepam
1. Atropine
• Highly effective, it counteract Muscarinicsymptoms, higher doses antagonise central effects
• 2 mg IV repeated every 10 minutes till dryness of mouth
• Dilatation of pupil and HR up to 140
• Does not reverse peripheral muscle paralysis
CHOLINE ESTERASE REACTIVATORS
2.OXIMES
• Phosphorylated enzyme reacts very slowly with water
• Hydrolysis occurs a million times faster if more reactive OH groups in the form of oximes are given.
• PRALIDOXIME
• Quarternary N : Attaches to Anionic site – which remains unoccupied in OP poisoning