Cholinergic agonist Flashcards
Cholinomimetics - what are they and the two types
agents that activate ACh receptors either directly or indirectly
direct - agonist
indirect - ACh esterase inhibitor
Where is ACh released
all preganglionic nerve fibers + all postganglionic parasympathetic nerve fibers
predominant autonomic tone -> parasymp
exceptions of where parasym isn’t involved
vasculature - no parasympathetic input
sweat glands -> cholinergic sympathetic fibers
synthesis and release ACh
Acetyl CoA + choline = ACh { ChAT = choline acetyl transferase}
- acetyl CoA is an intermediate in glucose metabolism
- choline is present in all cells
- ChAT present in cytosol
- newly synthesized ACh -> synaptic vesicles
- ACh released from nerve ending by exocytosis degraded by acetylcholinesterase which is present in synaptic cleft
degradation of ACh
ACh= choline + acetate [ AChE = acetylcholinesterase]
acetylcholine receptors ( 2)
muscarinic and nicotinic
nicotinic - location and type of receptor
ligand gated ion channels
- in muscle, autonomic ganglia, adrenal chromaffin cells and brain
- neuronal nAChRs -> not in muscle can be distingushed pharmacologically
- pentamers
muscarinic - type and location
gtp- binding protein linked receptors
upon activation alter second messenger pathways
Nicotinic muscle ( tissue and action)
NMJ and transient depolarization ( increase Na and K)
Neuronal Nicotinic ( tissue and action_
autonomic ganglia -> transient depolarization
adrenal medulla, CNS-> increase internal Ca
Muscarinic ( M2)
tissue and action
Cardiac - hyperpolarization : increase K and decrease rate of contraction
CNS ; presynaptic terminals -> decrease cAMP
Muscarinic (M3)
tissue and action
smooth muscle -> PI turnover and increase Ca
secretory glands -> increase cAMP
smooth muscle contraction
Muscarinic (M1)
tissue and action
autonomic ganglia , CNS PI turnover increase Ca and increase cAMP
Muscarinic (M4)
tissue and action
CNS decreases cAMP
Muscarinic (M5)
tissue and action
PI turnover; increase Ca and increase cAMP
All muscarinic receptors are selectively blocked by
ATROPINE - no receptor subtype agonist exists that is clinically useful
Nm and Nn are selectively blocked by
curare and mecamylamine respectively
Effect of ACh on muscarinic receptors on
- vasculature
- bronchi
- eye iris
- ciliary muscle
- salivary glands
- lacrimal glands
- sweat glands
- GI tracts
- urinary bladder
- heart
- vasculature -> vasodilation, release of EDRF decrease in bp
- bronchi -> constriction, increase in mucosal secretions
- eye iris- contraction and miosis
- ciliary muscle - contraction- lens accommodations for near vision
- salivary glands- secretion - thin and watery
- lacrimal glands - secretion
- sweat glands - diaphoresis
- GI tracts - increase tone ( motility) relaxation at sphincters
- urinary bladder - contraction of detrusor, relax sphincters
- heart - bradycardia and decrease in conductions
ACh effect on nicotinic receptors
all gang- genral stimulation, predominate tone depends of tissue
adrenal medulla - release of epi
skeletal muscle - contraction/ relaxation
vasculature and effect of Ach
blood vessels contain no cholinergic input but endothelium with in the vessels have muscarinic
ACh receptors and upon stimulation NO is released -> vasodilation
- low dose of ACh -> decrease in BP followed by baroreceptor induced tachy
- if pretreated with atropine ( m antagonist) bp doesnt drop as much
ACh and the brain
ACH and related choline esters are all permanently charged, quaternary amines and dont penetrate into the CNS
but adrenal medulla is effected -> epi
uses of acetylcholine
rapidly hydrolyzed by cholinesterases
limited clinical use
- intraocularly to produce miosis after lens extraction
- used during diagnostic coronary angiography where intracoronary injection causes vasodilation
methacholine
agonist at mAChRs
may be used for diagnosis of bronchial hyperactivity and asthmatic conditions very carefully
- not very susceptible to AChE (+)
no effect at muscarinic receptors
Carbachol
agonist at all AChRs
used for wide angle glaucome, only when other cholinomimetics are no longer effective
cholinesterase -negligible
mus ++
nic +++
Bethanechol
Agonist at GI mAChRs used postop after abdominal surgery and postpartum to decrease badder distention -promotes salvations - cholinersterase - negligible mus ++ nic - none
BBB- bethanechol, bowel and bladder
Side effects of choline esters
all related to muscarinic stim Diarrhea urination miosis bradycardia emesis lacrimation lethargy salivation ( decrease in night vision, trouble focusing on distant objects)
contraindications for use of choline esters
- asthma-> may precipitate attack due to muscarinic mediated bronchial contraction
- urinary obstruction
- acid-peptic disease- may induce gastric acid secretion
plant alkaloids (3)
- pilocarpine
- muscarine
- nicotine
pilocarpine
agonist at mAChRs
- miotic agent ( lasts 1 daY)
-wide angle glaucoma
- AChE inhibitor for emergency narrow angle glaucoma
-oral to overcome xerostomia ( decrease salvation)
-side effects - dumbells
chronic use-> decrease in night vision and focusing on distant objects
muscarine
agonist of mAChRs
muscarine poisoning ; rapidly developing symptoms (30-60 min) revered with atropine
- salvation, lacrimation nausea , vomiting, visual disturbances, bronchospasm, bradycardia and hypotension, shock
