Download Pharmacology Ch 9 110-126 Cholinergic Pharmacology

Pharmacology Ch 9 110-126
Cholinergic Pharmacology
Acetylcholine is involved in neuromuscular junction (NMJ), ANS, and CNS
-Cholinergic receptors are divided into two classes:
1. Muscarinic Cholinergic Receptors – G protein linked receptors on ALL parasympathetic
postganglionic fibers (few sympathetic), and in CNS
2. Nicotinic Cholinergic Receptors – ligand-gated ion channels at excitatory autonomic
synapses and in CNS presynpatics
-Acetylcholinesterase (AChE) – enzyme that degrades acetylcholine
Synthesis of Acetylcholine – synthesized in 1 step from coline + Acetyl CoA by choline
acetyltransferase (ChAT)
-50% of choline generated by acetylcholinasterase in synaptic cleft is transported back into axon
terminal where it comprises 50% of choline used in ACh synthesis
-choline is stored in phospholipids as phosphorylcholine
-acetyl-coA is generated mainly from glycolysis and is produced by pyruvate dehydrogenase
-rate limiting step of ACh synthesis is mediated by availability of choline, which depends on
uptake of choline into the neuron
-choline is taken into the neuron through facilitated diffusion and a Na-dependent transporter
found in cholinergic nerve terminals
Storage and Release of ACh – ACh transported into synaptic vesicles for storage after synthesis
-an ATPase pumping protons into vesicle provides energy for process; then (protons out = ACh
in) through ACh-H antiport channel
-antiport channel is a target of vesamicol, acts to cause deficit of ACh storage and release
-cholinergic vesicles also contain ATP and heparan sulfate proteoglycans which serve as counter
ions to neutralize the positive charge of ACh and disperse electrostatic forces that prevent
dense packing of ACh within vesicle
-Release of ACh occurs through fusion of synaptic vesicle with membrane; dependent on
opening of voltage-dependent Ca channels
-increase in intracellular Ca facilitates binding of synpatotagmin to SNARE complex to mediate
attachment of fusion of vesicle and release of transmitters into synaptic cleft
-Two stores of ACh play distrinct roles in process of release
1. depot pool – vesicles positioned near plasma membrane of axon terminal; axonal
depolarization cause vesicles to release ACh rapidly
2. reserve pool – refill the depot pool as it is being used
Muscarinic Receptors – mainly at autonomic ganglia, at end organs innervated by
parasympathetics, and in CNS; they are GTP binding G proteins; several mechanisms:
1. Inhibition of adenylyl cyclase via Gi and stimulation of phospholipase C mediated by
alpha subunit
2. Also influences ion channels via second messenger molecules; predominantly increases
opening of specific potassium (K) channels to hyperpolarize the cells mediated by
beta/gamma subunits of the G protein
-5 different muscarinic receptors exist labeled M1-5 (M1,3,5 stimulate phospholipase C, M2,4
open K channels to hyperpolarize cell)
-M1 is expressed in cortical neurons/autonomic ganglia, M2 in cardiac muscle, M3 in smooth
muscle and glandular tissue
-M1, 3, 5 EXCITE Cell
-M2, 4 INHIBIT Cell
Nicotinic Receptors – causes direct ligand-gated conductance. Two ACh molecules bind to one
receptor to elicit a conformational change to create monovalent cation-selective pore that is
equally permeable to Na and K ions (Na is predominant due to Nernst potential)
-these can depolarize the cell immediately
-ACh rapidly dissociates from receptor and is degraded by AChE so stimulation is brief
-structure in NMJ is α2βεδ form, while in embryo it is α2βγδ
-besides opening and closing, nicotinic receptors also modulate responses to concentrations of
ACh
-continuous ACh stimulation causes desensitization of receptor in which it is closed
-nicotinic receptors at autonomic ganglia and CNS are termed (N2 or NN) are similar to the ones
at NMJ (N1 or NM)
Degradation of Acetylcholine – cholinesterases degrade acetylcholine; type types of
cholinesterases are AChE and butyrylcholinesterase (BuChE); BuChE plays a secondary role in
ACh degradation and can play a role in early neural development as coregulator of ACh
Neuromuscular Junction – ACh is neurotransmitter at neuromuscular junction; binding of ACh
released by alpha motor neurons to nicotinic receptors in muscle cell membrane results in
motor end-plate depolarization
-extent of depolarization depends on quantity of ACh released into synaptic cleft
-each quantum of ACh is a single synaptic vesicle and elicits a small depolarization in motor endplate termed miniature end-plate potential (MEPP)
-large depolarization of end-plate is called end-plate potential (EPP) triggers AP in muscle fiber
-ACh depolarizes muscle AND modulates its own action at this site
-presynaptic cholinergic receptors on axon terminal of motor neuron respond to ACh binding by
FACILITATING mobilization of synaptic vesicles from reserve pool to the depot pool
-only when 50% or more of postsynaptic receptors are desensitized is decline in muscle tension
observed during tetanic stimulation (known as tetanic fade)
-blockade of moldulatory presynaptic cholinergic receptors by antagonists such as
hexamethonium prevents facilitation and causes rapid tetanic fade to occur
Autonomic Effects – primary event in postsynaptic ganglionic response is rapid depolarization
mediated by nicotinic ACh receptors on postganglionic neuron similar to that of NMJ in that
inward current elicits immediate EPSP; 3 other events remaining that modulate primary signal:
-known as slow EPSP, IPSP, and late/slow EPSP
Slow EPSP – occurs after a latency of 1s and is mediated by M1 muscarinic ACh receptors
IPSP – product of catecholamine (dopamine and norepinephrine) stimulation of dopaminergic
and alpha-adrenergic receptors, but some by M2 muscarinic receptors)
Late/Slow EPSP – mediated by decrease in K conductance induced by stimulation of receptors
for peptide transmitters, angiotensin, substance P, LHRH; plays a role in long-term regulation of
postsynaptic neuron sensitivity to repetitive stimulation
-drugs against slow EPSP, IPSP, and late/slow IPSP cannot eliminate ganglionic transmission, but
instead only alter efficiency of transmission; methacholine, a muscarinic receptor agonist,
resembles stimulation of slow EPSPs
-overall effect of ganglionic blockade is complex and depends on relative predominance of
sympathetic and parasympathetic tone at various end organs
-heart influenced primarily by parasympathetic system whose tonic effect is a slowing of heart
rate, so blockade of autonomic ganglia that innervates the heart by moderate to high doses of
atropine results in blockade of vagal slowing of SA node  tachycardia
-blood vessels influenced by sympathetic system; and sympathetic stimulation causes
vasoconstriction. Ganglionic blockade results in VASODILATION
CNS Effects – CNS functions of ACh include modulation of sleep, wakefulness, learning, memory,
suppression of pain at spinal cord, neural plasticity, early neural development,
immunosuppression, and epilepsy
-as part of the ascending reticular activating system – cholinergic neurons play a role in arousal
and attention and levels of ACh in brain INCREASE during wakefulness and REM and decrease
during inattentive states and non-REM/slow-wave sleep
-acetylcholine potentiates excitatory effects of other inputs to its cortical target cells without
affecting the baseline activity of neurons; modulates excitatory neurotransmitter release
-during awake states, ACh prevents interference in hippocampus during initial learning by
suppressing retrieval of stored memories, but release of this suppression is necessary to allow
consolidation of new memories
-acetylcholine plays a role in pain modulation through inhibition of spinal nociception
Pharmacologic Agents and Drugs – there are many variations of cholinergic drugs used for
various diseases.
-pirenzepine binds M1 receptor (autonomic ganglia) with higher affinity than M2 and M3
-Methacholine – more resistant to degradation by AChE and possesses longer duration of action
-Physostigmine – agent of choice for treating CNS effects of anticholinergic overdose;
penetrates CNS well
Inhibitors of Acetylcholine Synthesis, Storage, and Release
1. Hemicholinium-3 blocks high affinity transporter for choline and prevents uptake of choline
for ACh synthesis
2. Vesamicol – blocks ACh-H antiporter used to transport ACh into vesicles to prevent storage
3. Botulinum Toxin A – degrades SNAP-25 and prevents vesicle fusion to axon terminal, used
to treat torticollis, achalasia, strabismus, and others
Acetylcholinesterase Inhibitors – agents bind and inhibit AChE to elevate concentration of ACh
-all indirect cholinergic agonists interfere AChE by binding to active site of enzyme; three
different classes (alcohols, carbamic acid esters, and organic phosphoric acid derivatives);
pharmacokinetic differences
1. Edrophonium – simple alcohol inhibits AChE by reservible association on active site,
short acting and ideal for diagnostic purposes; helpful in diagnosing competitive AChR
antagonists or myasthenia gravis/Eaton-Lambert Syndrome
2. Neostigmine – carbamic ester blocks AChE but also activates nicotinic AChRs at NMJ
(irreversible)
3. Physostigmine – carbamic ester that is fairly irreversible
-all of these increase increase transmission at NMJ, increase parasympathetic tone, and increase
central cholinergic activity (treats alzheimers disease); TREATS MYASTHENIA GRAVIS
-AChE inhibitors cannot reverse agents that cause paralysis by inducing sustained depolarization
-for chronic myasthenia gravis, use longer-acting AChEs such as pyridostigmine, neostigmine,
and ambenonium
-CNS AChE inhibitors can cause GI symtoms like nausea, vomiting, anorexia, flatulence, diarrhea;
use drug after a meal
Receptor Agonists – cholinergic receptor agonists bind to ACh binding site of cholinergic
receptors; can be divided into muscarinic/nicotinic-selective agents
-muscarinic receptor agonists are used clinically in asthma diagnosis and miotics (pupil constrict)
-nicotinic receptor agonists are used for induction of muscle paralysis
1. Choline Esters:
Methacholine – 3x more resistant to hydrolysis by AChE than ACh and is selective for
cardiovascular muscarinic receptors; little affinity for nicotinic receptors
-use limited for vasodilation (vagomimetic)
-diagnosis of asthma (causes exaggerated bronchoconstriction)
Carbachol – resistant to AChE and has enhanced nicotinic actions, used as a topical miotic agent
in treatment of glaucoma to cause pupillary constriction and decreased intraocular pressure
Bethanechol – selective for muscarinic receptors, promoting GI and urinary motility
2. Alkaloids:
Muscarine – low bioavailability because it is charged
Pilocarpine – miotic agent and a sialagogue (saliva-inducing agent) used to trat xerosotomia
Cevimeline – M1 and M3 agonist treats xerostomia in Sjogren’s syndrome
Nicotinic Receptor Agonists
Succinylcholine – high affinity for nicotinic receptors and is resistant to AChE, used to induce
paralysis during surgery by causing depolarizing blockade; can lead to electrolyte imbalance
-pattern is period of excitation, widespread fasciculations in muscle cells, followed by paralysis
-any nAChR agonist is capable of producing depolarizing blockade
Receptor Antagonists – act by binding directly to agonist site and blocking stimulation
Muscarinic Receptor Antagonists –
1. Atropine – induces mydriasis (pupil dilation), to reverse symptomatic sinus bradycardia,
inhibit excessive salivation and mucus secretion, and counteract muscarinic poisoning
2. Scopolamine – has CNS effects and treats motion sickness, antiemetic, transdermal
patch exists; can ameliorate nausea
3. Methscopolamine and Glycopyrrolate – low CNS penetration used to decrease oral
secretions, treat peptic ulcer disease, decrease GI spasms, and prevent bradycardia
(glycopyrrolate)
4. Pirenzepine – selective for M1 and M4 receptors is an alternative to H2 receptor
antagonists
5. Ipratropium – more effective than B adrenergic agonists in treatment of COPD but less
effective at treating asthma
6. Tiotropium – bronchodilates and treats COPD
-antimuscarinics promote detrusor relaxation and tightening of bladder sphincter; treatment for
overactive bladder are :oxybutynin, propantheline, terodiline, tolterodine, fesoterodine,
trospium, darifenacin, and solifenacin
to treat Parkinson’s disease, people use amantadine, benztropine, procyclidine, and
trihexyphenidyl
-benztropine and trihexyphenidyl also treats symptoms and akathisia associated with
neuroleptics
-antimuscarinic toxicity causes substantial morbidity in geriatric population by causing
bradycardia and sedation
-over the counter drug diphenhydramine is an antihistamine and anticholinergic drug that can
cause morbidity in people older than 65
Nicotinic Receptor Antagonists – produce nondepolarizing (competitive) neuromuscular
blockage during surgical procedures
Tubocurare antagonizes ACh receptor directly to prevent ACh binding and depolarization
-duration of action is important:
d-tubocurarine, pancuronium are LONG LASTING
vecuronium and rocuronium are INTERMEDIATE DURATION
mivacurium is RAPIDLY DEGRADED