1. Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)
Cholinomimetic agents: Cholinoceptor activating and Cholinesterase inhibitors
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)

2. Objectives
นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์ การใช้ประโยชน์ทางคลินิก อาการไม่พึงประสงค์ ข้อควรระวังการใช้ยาของยาที่ออกฤทธิ์กระตุ้นระบบประสาทพาราซิมพาเทติกและยาที่ออกฤทธิ์ยับยั้งเอนไซม์โคลินเอสเตอร์เรส

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 >>> 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]

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)
Lung
Bronchial muscle
Bronchial gland
Contraction (bronchoconstriction)
Stimulation
Gastrointestinal tract
Motility
Sphincter
Secretion
Increase
Relaxation

9. Urinary bladder
Detrusor
Trigone and sphincter
Contraction
Relaxation
Glands
Sweat, salivary, lacrimal, nasopharyngeal
Secretion

10. Peripheral nervous system
Autonomic ganglia >>> 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 >>> 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
Alzheimer’s 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