Transcript Cholinomimetic agents: Cholinoceptor activating and

Cholinomimetic agents:
Cholinoceptor activating
and Cholinesterase
inhibitors
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)
Objectives
• นิ สติ มีความรูค้ วามเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัช
จลนศาสตร์ การใช้ประโยชน์ทางคลินิก อาการไม่พงึ ประสงค์ ข้อควร
ระวังการใช้ยาของยาที่ออกฤทธิ์กระตุน้ ระบบประสาทพาราซิมพาเทติก
และยาที่ออกฤทธิ์ยบั ยัง้ เอนไซม์โคลินเอสเตอร์เรส
Cholinomimetic agents
o Parasympathomimetic = Action like
Parasympathetic nervous system
stimulation
o Alkaloid … “Muscarine”
o Stimulate effector organ receptor
o Muscarinic receptor
o Alkaloid … “Nicotine”
o Stimulate autonomic ganglia &
neuromuscular junction (NMJ)
o Nicotinic receptor
o ACh >>> Stimulate both muscarinic &
nicotinic receptor
Cholinoceptor
o Receptor of ACh and other cholinoceptor activating
agents
o Muscarinic receptor
o GPCR
o Effector organ … heart, exocrine gland, presynaptic
nerve, endothelial cell (no nerve innervation)
o Effector organ which is innervated by cholinergic
sympathetic nerve
o CNS
o Nicotinic receptor
o Ion channel linked receptor
o Autonomic ganglia (both sym & parasym),
Neuromuscular junction (NMJ) [skeletal muscle;
somatic nerve innervation]
o CNS
Mode of action of
cholinomimetic drugs
o Direct acting agents
o Cholinoceptor activating drugs [Agonist]
o Directly bind to cholinoceptor
o Indirect acting agents
o Cholinesterase inhibiting agents
[AChE Inhibitors]
o Anti-cholinesterase
o Inhibit ACh hydrolysis
o Increase endogenous ACh
Basic pharmacology of direct
acting cholinoceptor stimulants
o Choline ester
o Ester of acetic acid:
Acetylcholine (ACh),
Methacholine
o Ester of carbamic acid:
Carbachol, Bethanechol
o Alkaloids
o Muscarine, Nicotine
o Derivative: Pilocarpine,
Lobeline, Oxotremorine
Organ system effects
• Direct effect … Parasympathetic stimulation –
like effect
Organ
Eye
Sphincter muscle of iris
Ciliary muscle
Heart
Sinoatrial node
Atria
Atrioventricular node
Ventricles
Responses
Contraction (miosis)
Contraction for near vision
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
Blood vessels
Arteries
Veins
Lung
Bronchial muscle
Bronchial gland
Gastrointestinal tract
Motility
Sphincter
Secretion
Dilation (via
Constriction
effect)
Dilation (via
Constriction
effect)
EDRF)
(high dose direct
EDRF)
(high dose direct
Contraction
(bronchoconstriction)
Stimulation
Increase
Relaxation
Stimulation
Urinary bladder
Detrusor
Trigone and sphincter
Glands
Sweat, salivary, lacrimal,
nasopharyngeal
Contraction
Relaxation
Secretion
Peripheral nervous system
o Autonomic ganglia >>> Nicotinic receptor
o Nicotine
o High affinity to neuronal nicotinic RC
o Affect both sym & parasym ganglia
o CVS … Sympathetic … Hypertension
o GI, Urinary sys … Parasympathetic …
nausea, vomiting, diarrhea, voiding
o Can cause “depolarizing blockade”
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)
Basic Pharmacology of AChE inhibitors
o
o
o
o
o
o
Acetylcholinesterase enzyme (AChE)
Hydrolysis of ACh
MW ~320,000
Mostly found at cholinergic synapse
AChE inhibitors
Bind at active site … Inhibit AChE
action
o Increase endogenous ACh
o Reversible
o Simple alcohol
o Carbamic acid ester
o Irreversible
o Organophosphates
Carbamate
Organophosphate
Irreversible
Dealkylation
Clinical Pharmacology
• Glaucoma
• Accommodative Estropia
• Postoperative atony, Neurogenic bladder,
Postpartum
• NMJ disease (Myasthenis gravis)
• Antimuscarinic drug intoxication
• Alzheimer’s disease
• Supraventricular tachyarrhythmia
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, Anticonvulsant
– Long term effect of nicotine from cigarette smoke
• Vascular disease
• Sudden coronary death
• Peptic ulcer recurrence
Toxicity & ADRs
o AChE inhibitors esp. Insecticide
o Acute toxic effect ~ Direct
cholinomimetics
o Emergency treatment of insecticide
intoxication
o Miosis, salivation, sweating,
bronchoconstriction, vomiting, diarrhea,
CNS effect, depolarizing NM blockade
o Maintain vital sign
o Decontamination
o Atropine … control muscarinic excess
o Pralidoxime … AChE regerator
o Chronic exposure … Demyelination of
neuron … Neuropathy