04- Cholinergics Flashcards
atropine
cholinergic antagonist that is MUSCARINIC selective
- no selectivity for Muscarinic sub-types
- tertiary amine so easily cross BBB and cause CNS toxicity
- quickly distributed after administration (30-60 min in CNS)
- duration of action 5-10 hours
- most sensitive tissues are salivary, bronchial, and sweat glands
- has LONG-acting topical application used in eyes that elicits mydriasis and cycloplegia, relieves urinary incontinence, may be useful adjunct therapy for Parkinsonism, overcome poisoning by O-P or muscarine mushrooms, and can inhibit some vagal slowing of heart due to MI
homatropine
cholinergic antagonist that is MUSCARINIC selective
- tertiary amine so can cross BBB (mainly used topically so this does not normally occur)
- duration of action 2-4 hours
- has INTERMEDIATE-acting topical application that is useful for eliciting mydriasis and cycloplegia (for eye exams)
scopolamine
cholinergic antagonist that is MUSCARINIC selective
- quickly distributed after admin (30-60 min in CNS)
- duration of action 5-10 hours
- tertiary amine derivative primarily used for CNS effects (CNS depression manifested with drowsiness, amnesia, fatigue, dreamless sleep)
- most effective treatment for motion sickness
- side effects include sedation and dry mouth
methscopolamine (Pamine)
cholinergic antagonist that is MUSCARINIC selective
- duration of action 5-10 hours
- quaternary derivative of scopolamine so only used in PNS and lacks CNS effects
- primarily used for GI diseases
trihexyphenidyl (Artane)
cholinergic antagonist that is MUSCARINIC selective
- tertiary amine that readily crosses BBB and can cause CNS toxicity
- duration of action 3-6 hours
- useful adjunct therapy to dec. uncoordinated movement and excess salivation for Parkinsonism (main use) and extra-pyramidal side effects of anti-psychotics
cyclopentolate (Cyclogyl)
cholinergic antagonist that is MUSCARINIC selective
- short acting (3-6hrs) topical application to induce mydriasis and cycloplegia
- non-specific muscarinic blocker so can exhibit all associated effects of muscarinic blockade
ipratroprium (Atrovent)
cholinergic antagonist that is MUSCARINIC selective
- aerosol, synthetic analog of atropine
- quaternary derivative of atropine
- bronchodilation, tachycardia, decreased salivation
- minimizes mucociliary clearance effect and is useful for patients with airway problems (maintains airway fluidity)
- specifically targeted when used as an inhalant and unable to cross membranes (so will only bronchodilate)
- used for patients with COPD
tiotropium (Spiriva)
cholinergic antagonist that is MUSCARINIC selective
- synthetic analog of atropine
- serves as LONGER ACTING “topical” inhalation application that targets bronchodilation and specifically minimizes mucociliary clearance problems (maintains airway fluidity)
darifenacin (Enablex)
cholinergic antagonist that is M3 selective
- slows micturition
- aids in treatment of urinary urgency due to inflammatory bladder problems
- may alleviate bladder spasm following urologic surgery
- may precipitate urinary retention in men with prostatic hyperplasia
solifenacin (VESIcare)
cholinergic antagonist that is M3 selective
- slows micturition
- aids in treatment of urinary urgency due to inflammatory bladder problems
- may alleviate bladder spasm following urologic surgery
- may precipitate urinary retention in men with prostatic hyperplasia
tolterodine (Detrol)
cholinergic antagonist that is M3 selective
- slows micturition
- aids in treatment of urinary urgency due to inflammatory bladder problems
- may alleviate bladder spasm following urologic surgery
- may precipitate urinary retention in men with prostatic hyperplasia
mecamylamine (Inversine)
cholinergic antagonist that is NICOTINIC selective
- acts as non-depolarizing competitive antagonist
- secondary amine developed to improve absorption from GI tract following oral administration
- Duration of action: 12 hours
- CNS side effects include tremors, confusion, seizures, mania, depression
trimethaphan (Arfonad)
cholinergic antagonist that is NICOTINIC selective
- acts as non-depolarizing competitive antagonist
- sulfonium (positively charged sulfur group) developed for IV use (lasts minutes)
- used during surgery to minimize blood loss in OR
- monitor carefully for excessive hypotension and brain anoxia
succinylcholine
- cholinergic antagonist that is DEPOLARIZING
- non-competitive receptor agonist that opens Na+ channels and mimics effect of ACh
- not substrate for AChE, but activity short because broken down by plasma cholinesterase
- only depolarizing NM blocker
- Phase I block (depolarizing): membrane remains depolarized and unresponsive inducing flaccid paralysis
- Phase II block (desensitizing): membrane repolarizes but receptor is desensitized due to prolonged exposure to Succ.
- cannot reverse action of succinylcholine***
curare (d-tubocurarine)
cholinergic antagonist that is NON-DEPOLARIZING
- LONG-acting benzylisoquinoline that competes with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- devoid of vagolytic and ganglionic blocking activity
- may elicit some histamine release
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh at synapse which can compete off antagonist from receptor
atracurium (Tracrium)
cholinergic antagonist that is NON-DEPOLARIZING
- competes with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh at synapse which can compete off antagonist from receptor
cisatracurium (Nimbex)
cholinergic antagonist that is NON-DEPOLARIZING
- INTERMEDIATE-acting benzylisoquinoline that competes with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- devoid of vagolytic and ganglionic blocking activity
- may elicit some histamine release
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh at synapse which can compete off antagonist from receptor
mivacurium (Mivacron)
cholinergic antagonist that is NON-DEPOLARIZING
- SHORT-acting benzylisoquinoline that competes with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- devoid of vagolytic and ganglionic blocking activity
- may elicit some histamine release
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh at synapse which can compete off antagonist from receptor
pancuronium (Pavulon)
cholinergic antagonist that is NON-DEPOLARIZING
- LONG-acting ammonio steroid that causes neuromuscular blockade by competing with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- will have some muscarinic block leading to vagal blockade and tachycardia
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh which can compete off antagonist from receptor
vecuronium (Norcuron)
cholinergic antagonist that is NON-DEPOLARIZING
- INTERMEDIATE-acting ammonio steroid that causes neuromuscular blockade by competing with ACh for binding to N2 receptor sites which prevents depolarization of membrane and flaccid paralysis
- will have some muscarinic block leading to vagal blockade and tachycardia
- poor lipid solubility so cannot cross BBB
- can be reversed by AChE inhibitor which leads to more ACh which can compete off antagonist from receptor
Cholinergic Antagonists
block the effects of ACh and ACh-like agonists from interacting with the various nicotinic and muscarinic receptors and prevent the normal physiological responses caused by these receptors
Anti-Muscarinic (parasympatholytics) Agents
anticholinergic drugs that combine with muscarinic receptors (M1-M3) and prevent physiologic responses to ACh at post-ganglionic parasympathetic transmission sites
- used when both mydriasis and cycloplegia are required
- block vagal slowing of the heart due to antagonism of muscarinic receptors on SA and AV nodes
- elicit bronchodilation and decreased secretions in airway
- decrease smooth muscle motility and secretions in GI tract
- decrease activity of salivary glands and thermoregulatory sweat glands
- relax smooth muscle of genitourinary system
- have anti-parkinson, anti-motion sickness and amnesic properties
Anti-Nicotinic Agents
anticholinergic agents that block nicotinic receptors
- ganglionic blockers (N1)
- NMJ blockers (N2)
Tertiary Amine
nitrogen forming 3 bonds and has a neutral charge
-derivatives can cross mucous membranes and BBB to exert effects on CNS
Quaternary Ammonium
-positively charged nitrogen that forms 4 bonds
derivatives do not cross membrane boundaries due to poor lipid solubility from charged N group
-avoid CNS effects because does not cross BBB
-poor and unreliable oral absorption
-poor absorption across conjuctiva
Why can’t we reverse a neuromuscular block created by succinylcholine (Succ) with neostigmine (Neo)?
neostigmine is an AchE inhibitor leading to increased Ach in the neuromuscular junction. Succ is a depolarizing neuromuscular blocker which acts as a Nm receptor agonist. Increasing the amount of Ach in the neuromuscular junction will augment and increase the depolarization further.
edrophonium
- Competitive inhibitor of cholinesterase (reversible, short-acting)
- simple alcohol with Quaternary ammonium (binds to active site on AChE)
- Major uses: myasthenia gravis, ileus, arrhthmias
- Duration of action: 5-15 minutes
carbaryl (Sevin)
Organophosphate insecticide. AChE inhibitor
malathion
Organophosphate insecticide. AChE inhibitor
parathion
Organophosphate insecticide. AChE inhibitor
echothiophate
- non-competitive inhibitor of cholinesterase (irreversible, long-acting)
- organophosphate
- major use: glaucoma
- duration of action: 100 hours
sarin
Nerve gas. AChE inhibitor.
soman
Nerve gas. AChE inhibitor
diisopropylfluorophosphate (DFP)
Organophosphate. Noncompetitive AChE inhibitor.
Organophosphate derivatives
Noncompetitive inhibitors of cholinesterase. Insecticides react first with plasma cholinesterase. Nerve gases react more with AChE
edrophonium
- Competitive inhibitor of cholinesterase (reversible, short-acting)
- simple alcohol with Quaternary ammonium
- Major uses: myasthenia gravis, ileus, arrhthmias
- Duration of action: 5-15 minutes
neostigmine
- competitive inhibitor of cholinesterase (reversible, short-acting)
- carbamate
- major uses: myasthenia gravis, ileus
- duration of actionL 0.5-4 hours
physostigmine
- competitive inhibitor of cholinesterase (reversible, short-acting)
- carbamate
- major uses: glaucoma
- duration of action: 0.5-2 hours
pyridostigmine
- competitive inhibitor of cholinesterase (reversible, short-acting)
- carbamate
- major uses: myasthenia gravis
- duration of action: 4-6 hours
diisopropylfluorophosphate (DFP)
- non competitive inhibitor of cholinesterase (irreversible, long-acting)
- organophosphate
ambenonium
- competitive inhibitor of cholinesterase
- carbamate
- major use: myasthenia gravis
- duration of action: 4-8 hours
bethanechol
-cholinergic agonist (synthetic choline ester)
-contains a methyl (CH3) and amine (NH2) group.
+methyl increases specificity for muscarinic receptors
+amine decreases substrate binding to AchE and pseudocholinesterase leading to an increased DOA.
-can be used in combination with neostigmine for post-op ileus.
carbachol (Carbastat)
-cholinergic agonist (synthetic choline ester)
-contains amine group
+amine decreases substrate binding to AchE and pseudocholinesterase leading to an increased DOA.
methacholine (Provocholine)
-cholinergic agonist (synthetic choline ester)
-contains a methyl group
+methyl increases specificity for muscarinic receptor
muscarine
- muscarinic receptor agonist (natural alkaloid)
- found in mushrooms
pilocarpine
- muscarinic receptor agonist (natural alkaloid).
- sweat glands very sensitive to pilocarpine.
- pilocarpine can be combined with an AchE inhibitor to treat acute closed angle glaucoma
- can be used in increase salivation if xerostomia is present.
nicotine
cholinergic agonist that is a natural alkaloid and NICOTINIC selective
Effects: increased HR, vasoconstriction, decreased mucus movement in the lungs, increased endogenous Epi.
-central stimulant effects: convulsions, coma, respiratory arrest, cardiac arrhythmia.
varenicline (Chantix)
- partial cholinergic nicotinic agonist.
- treatment for nicotine addiction
What do we see clinically with parasympathetic stimulation?
- decreased HR
- decreased BP
- bronchial constriction
- increased salivation
- increased GI motility
- bladder relaxation
- miosis
