Cholinomimetic agents: Cholinoceptor activating and Cholinesterase inhibitors

1
Cholinomimetic agents Cholinoceptor activating
and Cholinesterase inhibitors

• Pawitra Pulbutr
• M.Sc. In Pharm (Pharmacology)

2
Objectives

• ?????????????????????????????????????
  ??????????????? ?????????????? ???????????????????
  ???? ?????????????????? ??????????????????????????
  ??????????????????????????????????????????????????
  ????????????????????????????????????

3
Cholinomimetic agents

• Parasympathomimetic Action like Parasympathetic
  nervous system stimulation
• Alkaloid Muscarine
• Stimulate effector organ receptor
• Muscarinic receptor
• Alkaloid Nicotine
• Stimulate autonomic ganglia neuromuscular
  junction (NMJ)
• Nicotinic receptor
• ACh gtgtgt Stimulate both muscarinic nicotinic
  receptor

4
Cholinoceptor

• Receptor of ACh and other cholinoceptor
  activating agents
• Muscarinic receptor
• GPCR
• Effector organ heart, exocrine gland,
  presynaptic nerve, endothelial cell (no nerve
  innervation)
• Effector organ which is innervated by cholinergic
  sympathetic nerve
• CNS
• Nicotinic receptor
• Ion channel linked receptor
• Autonomic ganglia (both sym parasym),
  Neuromuscular junction (NMJ) skeletal muscle
  somatic nerve innervation
• CNS

5
Mode of action of cholinomimetic drugs

• Direct acting agents
• Cholinoceptor activating drugs Agonist
• Directly bind to cholinoceptor
• Indirect acting agents
• Cholinesterase inhibiting agents
  AChE Inhibitors
• Anti-cholinesterase
• Inhibit ACh hydrolysis
• Increase endogenous ACh

6
Basic pharmacology of direct acting cholinoceptor
stimulants

• Choline ester
• Ester of acetic acid Acetylcholine (ACh),
  Methacholine
• Ester of carbamic acid Carbachol, Bethanechol
• Alkaloids
• Muscarine, Nicotine
• Derivative Pilocarpine, Lobeline, Oxotremorine

7
Organ system effects

• Direct effect Parasympathetic stimulation
  like effect

Organ Responses
Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision
Heart Sinoatrial node Atria Atrioventricular node Ventricles Decrease in rate (negative chronotropic) Decrease in contractile strength (negative inotropic) Decrease in refractory period Decrease in conduction velocity (negative dromotropy) Increase in refractory period Small decrease in contractile strength
8
Blood vessels Arteries Veins Dilation (via EDRF) Constriction (high dose direct effect) Dilation (via EDRF) Constriction (high dose direct effect)
Lung Bronchial muscle Bronchial gland Contraction (bronchoconstriction) Stimulation
Gastrointestinal tract Motility Sphincter Secretion Increase Relaxation Stimulation
9
Urinary bladder Detrusor Trigone and sphincter Contraction Relaxation
Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion
10
Peripheral nervous system

• Autonomic ganglia gtgtgt Nicotinic receptor
• Nicotine
• High affinity to neuronal nicotinic RC
• Affect both sym parasym ganglia
• CVS Sympathetic Hypertension
• GI, Urinary sys Parasympathetic nausea,
  vomiting, diarrhea, voiding
• Can cause depolarizing blockade

11
Neuromuscular junction (NMJ)

• Nicotinic receptor
• Immediate depolarization of motor end plate
• Increase Na/K permeability
• Disorganized fasciculation gtgtgt Strong contraction
  of muscle
• Depolarization blockade .Muscle weakness
  (Flaccid paralysis)

12
Basic Pharmacology of AChE inhibitors

• Acetylcholinesterase enzyme (AChE)
• Hydrolysis of ACh
• MW 320,000
• Mostly found at cholinergic synapse
• AChE inhibitors
• Bind at active site Inhibit AChE action
• Increase endogenous ACh
• Reversible
• Simple alcohol
• Carbamic acid ester
• Irreversible
• Organophosphates

13
Carbamate
Organophosphate
Irreversible
Dealkylation
14
Clinical Pharmacology

• Glaucoma
• Accommodative Estropia
• Postoperative atony, Neurogenic bladder,
  Postpartum
• NMJ disease (Myasthenis gravis)
• Antimuscarinic drug intoxication
• Alzheimers disease
• Supraventricular tachyarrhythmia

15
Toxicity ADRs

• Direct acting muscarinic stimulant
• n/v, diarrhea, salivation, sweating, cutaneous
  vasodilation, bronchoconstriction
• Inhibited by Atropine
• Direct acting nicotinic stimulant
• Central stimulant action convulsion, coma,
  respiratory depression
• Skeletal muscle end plate depolarization muscle
  weakness, respiratory paralysis (Not response to
  AChE inhibitor)
• Hypertension, cardiac arrhythmia
• Symptomatic treatment Atropine, Anti-convulsant
• Long term effect of nicotine from cigarette smoke
• Vascular disease
• Sudden coronary death
• Peptic ulcer recurrence

16
Toxicity ADRs

• AChE inhibitors esp. Insecticide
• Acute toxic effect Direct cholinomimetics
• Emergency treatment of insecticide intoxication
• Miosis, salivation, sweating, bronchoconstriction,
  vomiting, diarrhea, CNS effect, depolarizing NM
  blockade
• Maintain vital sign
• Decontamination
• Atropine control muscarinic excess
• Pralidoxime AChE regerator
• Chronic exposure Demyelination of neuron
  Neuropathy

17
Q A