CHOLINERGIC DRUGS Flashcards
2 types of cholinergic agonists
- Direct-acting: some are selective for muscarinic or for the nicotinic receptor or both —> most therapeutically useful drugs preferentially activate MUSCARINIC receptors
I. Choline esters
II. Alkaloids - Indirect-acting: Acetylcholinesterase inhibitors
Direct effects of Acetylcholine
- Vasodilation (M3)
- Decrease in cardiac rate, rate of conduction in SA and AV nodes, and in force of contraction (M2)
Cardiovascular affect - Low dose ACh
Fall in BP d/t vasodilation (M3), usually accompanied by REFLEX TACHYCARDIA
Cardiovascular effect- High dose ACh
Hypotension (M3) and BRADYCARDIA (M2)
ACh effect on VASCULATURE
Release of NO and vasodilation = decreased BP
ACh effect on IRIS
Miosis
ACh effect on CILIARY MUSCLE
Accommodation of lens to near vision
ACh effect on SALIVARY/SWEAT/LACRIMAL GLANDS
Inc. secretions
ACh effect on BRONCHI
Bronchoconstriction; inc. secretions
ACh effect on HEART
Dec HR; dec conduction velocity
ACh effect on GI TRACT
Inc. secretions, peristaltic activity, and tone; relaxation of sphincters
ACh effect on URINARY BLADDER
Constriction of detrusor muscle; relaxation of sphincter
Acetylcholine
- Choline ester
- No systemic therapeutic application d/t multiplicity of actions, and rapid hydrolysis by acetylcholinesterase and plasma butyrylcholinesterase
Uses: to obtain rapid myosin after delivery of lens in cataract surgery and other anterior procedures
Bethanechol
MUSCARINIC agonist (no nicotine activity) Resistant to AChE
Uses: -postoperative and postpartum urinary retention Postoperative ileus Neurogenic ileus - atony of urinary bladder
*ileus- lack of movement somewhere in the intestines that leads to possible obstruction
Carbachol
Both muscarinic and nicotinic agonist
Uses:
- Open angle glaucoma: constricts pupil and relieves IOP
- Dec. IOP after cataract surgery
- Miosis during surgery
Methacholine
Muscarinic agonist
Uses: Challenge test for diagnosis of asthma
Pilocarpine
- Naturally occurring Alkaloid
- Partial muscarinic agonist
- tertiary amine
Uses: -open and closed angle glaucoma -Xerostomia (Sjogren syndrome) -potent stimulator of sweat, tears, and saliva “You cry, drool and sweat on your PILOw”
Low dose Nicotinic effects
CVS: mainly sympathometic effects - inc. HR and BP d/t catecholamine release from adrenal medulla
GI and urinary tracts: largely parasympathomimetic - N/V, diarrhea, and voiding of urine.
Initial stimulation of salivary and bronchial secretions
High dose Nicotinic effects
Causes ganglionic blockade d/t prolonged depolarization
Neuromuscular blackade
Edrophonium
Binds reversibly to the active site of acetylcholinesterase
Short lived (2-10 min)
Quaternary ammonium
Uses:
- Dx of myasthenia gravis
- Used to reverse the neuromuscular block produced by non-depolarizing muscular blockers
Carbamates
Form a covalent bond with AChE
Bond spontaneously hydrolyzes w/in 30 minutes - 6 hrs
Physostigmine, neostigmine, pyridostigmine
Organophosphates
Form a covalent phosphorous-enzyme bond at the active site of AChE.
Extremely stable bond.
The phosphorylated-enzyme complex may undergo a process called ageing which further strengthens the bond.
Cause DUMBBELSS: Diarrhea Urination Miosis Bronchospasm Bradycardia Excitation of skeletal muscle Lacrimation Sweating Salivation
Echothiophate, Thiophosphate insecticides (malathion & parathion), Nerve agents (Tabun, Sarin, Soman)
*organophosphate-insecticide poisoning: to regenerate cholinesterase, administer pralidoxime (able to split phosphorous-enzyme bond if given before ageing process has occurred)
Neostigmine
Quaternary ammonium
Uses:
- reversal of effects of non-depolarizing neuromuscular blockers after surgery.
- treatment of myasthenia gravis (although pyridostigmine is most commonly used).
- prevention/treatment of postoperative distention and urinary retention.
Adverse effects:
-salivation, flushing, low bp, nausea, abd pain, diarrhea
Pyridostigmine
Quaternary ammonium
Uses:
-treatment of myasthenia gravis (most commonly used anticholinesterase for this indication)
“Pyridostigmine get rid of myasthenia gravis”
Physostigmine
-tertiary amine
Uses:
-treatment of overdose of anticholinergic drugs
“Physostigmine “PHYxes” atropine overdose”
Note: should not be given to a pt w/ suspected TCA overdose b/c it can aggravate depression of cardiac conduction.
Adverse effects:
- effects on CNS may lead to convulsions at high doses
- bradycardia
- accumulation of ACh at NMJ, causing skeletal muscle paralysis
Echothiophate
Organophosphate (AChE inhibitor)
Used for chronic open-angle, subacute it chronic closure-angle glaucoma after iridectomy
Malathion and Parathion
Thiophosphate insecticides (organophosphates)
Activated in body by conversion to oxygen analogs.
Malathion is rapidly metabolized in birds and mammals but not insects —> considered safe enough for sale to general public
Parathion is not detoxified in vertebrates and this is more dangerous than malathion —> not available for general public use
Tabun, sarin, soman
Nerve agents
Among the most potent toxic agents known.
AChE inhibitors
Alzheimer’s disease
Pts have reduced cerebral production of choline acetyl transferase —> dec. ACh synthesis
DOC: centrally acting cholinesterase inhibitors to attempt to compensate for the depletion of ACh in the cerebral cortex and hippocampus
Donepezil, rivastigmine, galantamine
—> all orally taken
“Alzheimer’s patients GALlANtly swim DowN the RIVer”
Pralidoxime
Can reactivate inhibited AChE
- unable to reverse the central effects of organophosphate insecticide poisoning b/c it is unable to enter the CNS d/t it’s + charge
Atropine
Muscarinic antagonist Blocks DUMBBeLLS ( doesn’t block excitation of skeletal muscle and CNS as those are mediated by nicotinic receptors)
Uses:
- as an antisialogogue, prior to surgery, when reduction of secretions of the resp. tract are needed
- to inc HR or dec AV block
- as an antidote for overdose of cholinergic drugs
Adverse effects:
- inc body temp d/t dec sweating
- rapid pulse
- dry mouth
- dry, flushed skin
- cycloplegia
- constipation
- disorientation
-in older pts, use may exacerbate an attack of glaucoma as it induces mydriasis and cycloplegia
Tertiary amine
Scopolamine
Produces peripheral effects similar to atropine; greater actions on the CNS and longer duration of action
Uses:
- one of the most effective anti-motion sickness drugs available; administered transdermally via patch
Unusual affect: blocks short term memory
Ipratropium & Tiotropium
Quaternary ammonium muscarinic antagonists
Use: COPD, asthma
“I PRAy I can breathe soon!”
Homatropine & Tropicamide
Tertiary amine muscarinic antagonists
Produce mydriasis and cycloplegia
Benztropine and Trihexyphenidyl
Tertiary amine muscarinic antagonists
Uses:
- Parkinsonism and the extrapyrimidal effects of antipsychotic drugs. “Park my Benz”
- acute dystonia
Glycopyrrolate
Anti muscarinic
Uses:
- inhibit GI motility
- prevent bradycardia during surgical procedures
- reduce airway secretions
Tolterodine
Anti muscarinic
Use: To treat overactive bladder - reduce bladder spasms and urge urinary incontinence
Contraindications of Antimuscarinic Agents
- pts w/ angle-closure glaucoma
- pts w/ BPH
- elderly (should be used w/ caution) —> are very sensitive to cholinergic blockade d/t central cholinergic hypofxn and dysfxn in ageing and dementia, respectively
Mecamylamine & hexamethonium
Nicotinic receptor antagonists
Tubocurarine
Prototype drug for ‘non-depolarizing (competitive) blockers’ of NMJ
MOA: bind to nicotinic receptor & prevent ACh binding thus preventing depolarization of muscle cell membrane and inhibit muscular contraction.
Use: During anasthesia, the IV administration of a nondepolarizing blocker causes skeletal muscles to become totally flaccid and inexcitable to stimulation
PK: given IV (oral absorption is minimal w/ poor membrane penetration and don’t cross BBB)
Adverse: Autonomic- some are moderate muscarinic receptor blockers. Histamine- tubocurarine may cause histamine release.
Action can be overcome by increasing synaptic ACh concentration (ie: w/ neostigmine or edrophonium)
Succinylcholine
Depolarizing neuromuscular blocker
MOA: bond to nicotinic receptor and act like ACh to cause end-plate depolarization —> spread of depolarization to adjacent membranes = disorganized contraction of muscle motor units —> Succinylcholine not metabolized effectively @ synapse so membrane remains depolarized and unresponsive to additional impulses —> flaccid paralysis
PK: given continuous IV. Rapidly hydrolyzed by plasma cholinesterase. Extremely brief duration of action (5-10 min) and rapid onset (1-1.5 min)
Uses: useful for rapid endotracheal intubation. Also used during ECT.
Adverse: malignant hyperthermia- AD disorder of skeletal muscle —> caused by stimulus elicited excessive Ca2+ release from SR. One of the main causes of death in anesthesia. Treated w/ DANTROLENE, which blocks Ca2+ release from SR = reduced heat production and muscle relaxation
Hemicholinium
Inhibitor if ACh synthesis
Blocks transport of choline into presynaptic neuron (CHT1 receptor block)
Only used as a research tool
Vesamicol
Inhibits ACh - H+ antiporter ised to transport of ACh into vesicles for storage
Only used as a research tool
Botulinum Toxin
Protein produced by anaerobic Clostridium botulinum.
Neurotoxin- prevents synaptic vesicle fusion w/ the axon terminal membrane = no ACh release
Use:
- treatment of several diseases associated with increased tone (such as torticollis, achalasia, strabismus, blepharospasm, etc)
- cosmetic use for facial wrinkles
- various headache and pain syndromes
