Cholinergic Drugs

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Bethanechol

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a choline ester (all resistant to breakdown by BuChE, more stable and specific than ACh); muscarinic, resistant to all cholinesterases
Pharm Effects:
CV --> little CV effect
GI --> increased tone and motility
bladder --> contract detrusor
(other choline esters - pupil constriction)
Therapeutic Uses --> stimulant of GI tract and bladder

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Muscarine

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muscarinic agonist (parasympathomimetic - pupillary constriction, bradycardia, vasodilation, increased GI motility and salivation); prototype of group; in poisonous mushrooms

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Pilocarpine

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muscarinic agonist; naturally occuring alkaloid; therapeutic use --> reduction of intraocular pressure in glaucoma (causes contraction of ciliary muscle, loosens trabecular meshwork, allows greater outflow of aqueous humor) and for xerostomia (dry mouth)

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Nicotine

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a nicotinic agonist; clinically relevant insofar as they are capable of blocking transmission (biphasic effect - initial large build up of ACh with facilitation of N synapses, followed by blockade of stimulation as post-syn cell becomes insensitive)
-plant derived, positive nitrogen
-in small doses get pure agonist effects (small increases in HR, BP, RR)
-acutely toxic (but also stimulates emetic center
-clinical use - patches and gum

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Mode of action of Anticholinesterases

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1) block hydrolysis of released ACh in synaptic cleft, thus enhancing transmission at the junction
2) eventually get desensitization blockade at nicotinic junctions, accounting for lethality of drugs

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Properties and Mechanism of Action of Acetylcholinesterase (AChE)

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-associated with postsynaptic membrane
-extremely active (hydrolzying 600,000 molecules of ACh per min)
-BuChE - in blood, glial cells and synapse, prefers butyrylcholiine
Mechanism:
1) carbonyl carbon in acetyl moiety of ACh covalently binds to active center
2) Choline split off
3) Acetylated enzyme hydrolyzed to remove acetyl moiety

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Edrophonium

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truly reversible Anti-ChE; ie - don't need a chemical action to reverse; bind reversibly (no covalent bond) to active center

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Physostigmine (eserine)

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reversible anticholinesterase
a carbamate (longer acting than edrophonium); isolated from Calabar bean; structure = tertiary or quaternary nitrogen attached to carbamyl group by ester linkage (like ACh); Mechanism = reacts with AChE like ACh; reversibility of initial binding poor due to covalent bond; yields a carbamylated enzyme which is only slowly regenerated to original form

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Neostigmine

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also a carbamate, like physostigmine; tertiary or quaternary nitrogen attached to carbamyl group by ester linkage (like ACh); reacts with AChE like ACh but with poorer reversibility of binding
Therapeutic use = atony of GI tract and bladder and myasthenia gravis

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Structure of Irreversible (organophosphorus) Anti-ChEs

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phosphorous double bonded to O, single bonds to 2 hydrocarbon chains, and to 1 X (often a halogen atom)
-taken up into the body and can pass blood-brain barrier easily (very lipid soluble)

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Mechanism of action of Irreversible Anti-ChEs

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1) Phosphorous binds covalently to active center
2) Hydrolysis extremely slow or non-existent
3) Reactivators (like pralidoxime) can pull the drug off the active group

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Pralidoxime

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reactivator of ChE; pulls drug off the active group; regenerates phosphorylated enzyme, unless it is "aged"; nucleophilic oxygen pulls phosphorous away from nucleophilic oxygen of the active center

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Diisopropyl Phosphorofluoridate (DFP)

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irreversible anti-ChE; X = F on general structure; acts at N and M sites with parasympathomimetic actions at autonomic effectors (eye - miosis, decreased HR, increased GI, stimulation of secretory glands); skeletal muscle (stimulation followed by block and death from respiratory failure), CNS (confusion and ataxia), and difficult to predict actions at autonomic ganglia
Treatment for poisoning = atropine for muscarinic effects (M antagonist) and pralidoxime for skeletal muscle paralysis

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Therapeutic uses of Cholinergic Agonists

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1) atony of GI tract and bladder - neostigmine
2) glaucoma - physostigmine
3) myasthenia gravis
4) Alzheimer's disease - maximize function of remaining ACh neurons

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Botulinum Toxin

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Blocks release of ACh at NMJ, causing local, long-lasting paralysis when injected into muscle
Therapeutic Uses:
-blepharospasm (involuntary clinching of eyelids)
-strabismus (cross-eye)
-hemifacial spasm (irritation of facial nerve on one side)
-facial wrinkles

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Atropine

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Muscarinic Blocker, block receptor competitively, parasympatholytics
Autonomic effects in order of appearance with increasing dose:
1) decreased salivation and sweating
2) pupil dilation; HR increase
3) inhibition of micturition, decreased gut motility
4) inhibition of gastric secretion
-does not cross blood brain barrier

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Benztropine

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muscarinic antagonist

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Scopolamine

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muscarinic antagonist, block competitively, parasympatholytic; central effects too (causes drowsiness, amnesia in clinical doses)

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Muscarinic Antagonists

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block muscarinic receptors competitively (so can outcompete); toxicology - treat with physostigmine (anti-ChE) to increase the concentration of ACh and outcompete
Pharmacological Actions:
1) Autonomic effects in order of appearance with increasing dose (decreased salivation and sweating, pupil dilation and increased HR, inhibition of micturition and decreased GI motility, inhibition of gastric secretion
2) CNS - scopolamine
3) Subtype - specific drugs may allow lessening of side effects (M1 - autonomic ganglia and brain, M2 - heart and pre-syn feedback inhibition of ACh in brain, M3 - salivation, bladder, GI, blood vessels, M4 - forebrain, movement)
-M1 and M3 - stimulate phospholipase C.
-M2 and M4 inhibit adenylyl cyclase
Therapeutic Uses:
1) Treatment of Parkinsons
2) prevention of motion sickness
3) bronchodilator (M3 in airway)
4) mydriatic
5) reduce nasal and bronchial secretions
6) M1 selective for ulcers
7) overactive bladder

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D-Tubocurarine

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a competitive (stabilizing) nicotinic blocker; natural mix of alkaloids used as arrow poison; blocks at skeletal NMJ with less prominent effects at autonomic ganglia; pharm action = muscle weakness then paralysis, death by respiratory paralysis, small muscles affected first; also - histamine release
-therapeutic use = muscle relaxant for surgery - except has a long duration of action

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Metocurine

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competitive (stabilizing) blocker of nicotinic receptors; a synthetic, more potent derivative of d-tubocurarine

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Pancuronium

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competitive (stabilizing) blocker of nicotinic receptors
therapeutic use = muscle relaxant
-not specific for N receptors, blocks M2 on heart which can lead to CV problems

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Atracurium

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competitive nicotinic blocker; can use as a muscle relaxant with intermediate duration, derivative of d-tubocurarine
-advantages over older drugs = shorter duration of action; less cumulative tendency; less CV effect

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Vecuronium

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competitive (stabilizing) blocker of nicotinic receptors; derivative of pancuronium
advantages over older competitive blockers:
-shoerter duration of action
-less cumulative tendency
-less cardio effect

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Hexamethonium

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competitive (stabilizing) blocker of nicotinic receptors; bis-quaternary amonium series; specific for autonomic ganglia; block sympathetic and parasympathetic ganglia --> at rest, typically a predominant input for each end organ (usually PS)
-example - at the heart, PS- decreases HR, with block, loss of predominant input is most important, so you get tachycardia

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Predominant Tone at Various Effector Sites

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arterioles and veins - symp (adrenergic)
sweat glands - symp (cholinergic)
heart, iris, ciliary muscle, GI, urinary bladder, salivary glands - PS

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Succinylcholine

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depolarizing blocker at nicotinic receptor; act as agonists with a biphasic effect (Na channel inactivation caused by maintained depolarization)
-acts at ganglion and skeletal NMJ (more prominent at NMJ)
-action = muscle fasciculation followed by paralysis
-brief acting muscle relaxant (for tracheal intubation and other brief procedures), fasiciculation can lead to soreness

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Decamethonium

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depolarizing nicotinic receptor blocker; member of the bis-quarternary amonium series
-selective blocker of skeletal NMJ