Flashcards in Cholinergic System Deck (95):
What is the MOA of Tetrodotoxin and Saxitoxin?
Blocks Na Channels and Action Potentials
What is the MOA for Hemicholinium?
Blocks choline uptake (blocks ACh synthesis!)
What is the MOA for Black Widow Spider Venom?
Stimulates ACh release (cholinomimetic)
What is the MOA for Bolutinus Toxin?
Prevents ACh release (anticholinergic)
What is the MOA for Bethanechol?
Cholinomimetic at Muscarinic Receptors
What is the MOA for Nicotine?
Cholinomimetic at Nicotinic Receptors
What is the MOA for Atropine?
Blocks the Muscarinic effects of ACh
What is the MOA for Mecamylamine?
Blocks Ganglionic nicotinic receptors
What is the MOA for Curare?
Blocks muscular nicotinic receptors -- skeletal muscle relaxation
What is MOA for Physostigmine and DFP?
Inhibits AChE - (cholinomimetic)
What are the cardiovascular effects of Muscarinic Receptor Activation? (Parasympathomimetic)
DEC AV Node Conduction
What are the GI effects of Muscarinic Receptor Activation? (parasympathomimetic)
INC Gastric Secretions
What are the urinary effects of Muscarinic Receptor Activation? (parasympathomimetic)
INC Urination (micturition)
What are the respiratory effects of Muscarinic Receptor Activation? (parasympathomimetic)
INC Respiratory Secretions
What are the eye effects of Muscarinic Receptor Activation (parasympathomimetic)
Miosis -- contracted iris sphincter
Loss of Far Vision -- contracted ciliary muscle
What are the sweat gland effects of Muscarinic Receptor Activation? (sympathetic)
Nicotinic-Neural (Nn) Receptor Effects (para or symp) (8)
1. Vasoconstriction (s)
2. Bradycardia (p)
3. Miosis + Near Vision (p)
4. GI tract (p)
5. Salivary Gland Secretion (p)
6. Sweat gland secretion (s)
7. Micturition (p)
8. Release of NE and EPI at adrenal cells (s)
Muscle Nicotinic (Nm) Receptor Effect
Selective muscarinic receptor AGONISTS have what actions?
ACTIVATE Muscarinic Receptors
Selective muscarinic receptor ANTAGONISTS have what actions?
INHIBIT Muscarinic Receptors
What are the different cardiovascular effects of a LOW dose vs. HIGH dose of a muscarinic receptor AGONIST?
Low: Hypotension, Vasodilation, INC HR
High: Hypotension, Vasodilation, DEC HR, DEC AV Node Conduction, DEC Contractility
SLUD(E) + BBB (muscarinic receptor agonist actions)
Bradycardia (at high doses)
Blurred Vision (ciliary muscle spasm)
What are the 3 uses for Bethanechol?
1. Reverse GI stasis and urinary retention
2. Reverse postoperative abdominal distention
3. Reverse gastric atony following bilateral vagotomy
What are Carbachol and Pilocarpine used for?
Treatment of wide angle glaucoma
Also acute narrow angle glaucoma (surgery indicated for long-term treatment)
Adverse Effects of Muscarinic Receptor Agonists (2)
1. Stimulate excessive SLUD(E) +BBB
2. Mushrooms (Inocybe and Ciltocybe families) contain high levels of muscarine and when ingested will induce rapid onset muscarine poisoning that can be treated (reversed) by Atropine.
Contraindications for Muscarinic Receptor Agonists (5)
1. Asthma/COPD (bronchoconstriction)
2. Hyperthyroidism (A Fib)
3. Cardiovascular Disease (bradycardia, hypotension)
4. Coronary Insufficiency (DEC coronary blood flow)
5. PUD (INC acid secretion)
Cardiovascular effects of Muscarinic Receptor ANTAGONISTS
Low doses: DEC HR (CNS effect)
High doses: INC HR (direct cardiac effect)
Toxic doses: dilation of cutaneous blood vessels
GI Effects of Muscarinic Receptor ANTAGONISTS
Urinary effects of Muscarinic Receptor ANTAGONISTS
Respiratory effects of Muscarinic Receptor ANTAGONISTS
Eye effects of Muscarinic Receptor ANTAGONISTS
Cycloplegia (relaxed ciliary muscle)
Mydriasis (relaxed sphincter muscle)
Skin effects of Muscarinic Receptor ANTAGONISTS
DEC Sweating (could cause hyperpyrexia)
CNS effects of Muscarinic Receptor ANTAGONISTS (atropine, scopolamine)
1. Atropine -- toxic doses will cause CNS stimulation, even higher doses will cause CNS depression
2. Scopolamine -- therapeutic doses = CNS depression
Uses of Homatropine, Cyclopentolate, and Tropicamide (3)
1. Ophthalmologic exam
2. Mydriatic effects promote exam of retina and optic disk
3. Cycloplegia effects allow measurement of refractive errors
Use of Glycopyrrolate
Reverses muscarinic effects of anticholinesterases that are used to reverse neuromuscular blockade
MOA of Glycopyrrolate
Inhibits ACh action at muscarinic receptors
What do we use Atropine for?
Reverse mushroom poisoning (due to excessive muscarine) and the muscarinic effects that can occur as a consequence of anti cholinesterase poisoning
What are Benztropine and Trihexyphenidyl used for?
What is Scopolamine used for?
Prophylactic treatment of motion sickness (as a transdermal patch)
What are Ipratropium and Tiotropium used for?
COPD and asthma
What conditions are contraindications for Muscarinic Receptor Antagonists? (4)
*1. Narrow Angle Glaucoma (angle closure glaucoma) (INC intraocular pressure)
2. Open Angle Glaucoma (use with caution)
3. Cardiac Disease (causes tachycardia)
4. Prostatic Hypertrophy
What drugs have significant antimuscarinic activity but are not in the muscarinic receptor class? (3)
2. H1 Receptor Antagonists
Muscarinic Receptor Antagonist toxicity manifests as (5)
Red as a Beet
Dry as a Bone
Blind as a Bat
Hot as a Firestone
Mad as a Hatter
Antimuscarinic poisoning can be reversed by administering what?
What is the difference between the 2 types of nicotinic receptors?
1. Nn - in peripheral ganglia and the adrenal gland; sympathetic AND parasympathetic
2. Nm - in the NMJ; mediates skeletal muscle contraction
*Both types are activated by ACh and Nicotine
MOA of Non-Depolarizing/Competitive NMJ Blockers
Bind Nm receptor displacing ACh and leading to paralysis
*Non-Depolarizing = they fail to depolarize Nm
What are the 5 long acting Nondepolarizing/Competitive NMJ Blockers?
What are the 3 intermediate acting Nondepolarizing/Competitive NMJ Blockers?
What is the short acting Nondepolarizing/Competitve NMJ Blocker?
What are non depolarizing/competitive NMJ blockers used for therapeutically?
Induce muscle paralysis as an adjunct to anesthetic during surgery
How are non depolarizing/competitive NMJ blockers administered?
Do nondepolarizing/competitive NMJ blockers cause CNS effects?
No because they are quaternary ammonium drugs
Pharmacokinetics of Cisatracurium
Metabolized by plasma esterase
Short duration of action
Adverse Effects of Tubocurarine
Partial ganglionic block which DEC BP and causes tachycardia and stimulates histamine release from mast cells (induces bronchospasm and hypotension)
Pharmacokinetics of Tubocurarine
Pharmacokinetics of Mivacurium
Hydrolyzed by plasma cholinesterase (pseudocholinesterase)
adverse effects of Gallamine
Blocks cardiac vagus nerve --> induces tachycardia and hypertensions (due to INC CO)
What is the overall adverse effect of non depolarizing/competitive NMJ blockers?
Prolonged muscle paralysis/apnea
What is the effect of using an anticholinesterase drug (like neostigmine) along with a non depolarizing/competitive NMJ blocker?
It will reverse the effects of the blocker
What 3 types of drugs will enhance the activity of non depolarizing/competitive NMJ blockers?
1. Halogenated Hydrocarbon Anesthetics
2. Aminoglycoside Antibiotics (inhibits release of ACh)
3. Calcium Channel Blockers
What is Succinylcholine used for?
Induce rapid muscle paralysis for endotracheal intubation
MOA for Succinylcholine
Induces a prolonged depolarization of Nm (stable Nm agonist)
*It is resistant to acetylcholinesterase-mediated hydrolysis so it exhibits prolonged binding to Nm -- this leads to a Phase 1 Depolarizing block causing muscle paralysis.
*Succinylcholine-induced Phase 1 Depolarizing block can progress to phase 2 NON-Depolarizing block if succinylcholine is not metabolized by butrylcholinesterase, or if the dose is too high.
How is succinylcholine metabolized?
By a plasma cholinesterase known as Butyrylcholinesterase (terminating it's action)
Pharmacokinetics of Succinylcholine
Will not cross BBB
Short duration of action
What are the adverse effects of succinylcholine? (4)
1. Prolonged muscle paralysis
2. Prolonged apnea (in pts with low butrylcholinesterase activity)
2. Malignant Hyperthermia
3. Muscle Pain and Hyperkalemia (can lead to cardiac arrest)
What is malignant hyperthermia?
Rapid onset of muscle rigidity which increases temperature causes hypertensions and tachycardia
What causes malignant hyperthermia?
Genetic susceptibility (congenital myopathies) in combination with halothane anesthetics and succinylcholine
How do we rescue patients with malignant hyperthermia?
DANTROLENE which blocks Calcium release from SR relaxing skeletal muscle
What are the 2 drug interactions with Succinylcholine?
1. Anticholinesterases (like neostigmine) will prolong succinylcholine induced muscle paralysis and apnea
2. Halothane anesthetics with succinylcholine can lead to malignant hyperthermia
MOA of Nicotine
Low doses: stimulates Nn and Nm
High doses: first induce Nn and Nm followed by a depolarization block at Nn and Nm
Peripheral effects of nicotine
Induction of Nn and Nm: Excessive SLUD(E) + bronchoconstriction and blurred vision, tachycardia and hypertension and skeletal muscle fasciculation (Nm)
Depolarization block of Nn and Nm: (if dose is high) paralysis (including respiratory muscles)
CNS effects of Nicotine
Stimulation followed by depression of vital medullary and respiratory centers
Acute Nicotine Poisoning (3)
1. Well absorbed by oral mucosa, lungs, and skin
2. Excessive SLUD(E) + BB, muscle weakness followed by paralysis
3. Death may result from respiratory failure in a few minutes (central inhibition, paralysis of respiratory muscle at NMJ)
What is the treatment for acute nicotine poisoning?
1. vomiting of gastric lavage/wash skin
2. respiratory assistance
3. treatment of shock
4. atropine to control muscarinic effects
How do anticholinesterases work?
They inhibit acetylcholinesterase AND butrylcholinesterase -- this increases the levels of ACh promoting the activation of Nn, Nm, and Muscarinic Receptor
*They can potentially induce a depolarization block at Nm (due to high levels of ACh) resulting in paralysis
What are the 2 reversible inhibitor anticholinesterases and how do they work?
- bind to anionic site
- competes with ACh for anionic site
- fast acting
- short duration
- leads to INC Ach
What are the 2 drugs with a carbamoyl ester linkage anticholinesterases and how do they work?
- they carbamylate the esteratic site
- slow hydrolysis of the carbamylating drug by AChE will lead to increases in ACh
What are the 2 organophosphate inhibitor drugs?
1. Isoflurophate (DFP)
What are the 3 Insecticide organophosphate inhibitors?
What are the 3 nerve gas organophosphate inhibitors?
How do the organophosphate inhibitor anticholinesterases work?
- phosphorylate the esteratic site (essentially irreversible)
- regeneration of the active enzyme requires hours
- the return of AChE activity depends on the synthesis of new enzyme
- stability of phosphorylated enzyme enhanced by "aging"
- aging occurs through the loss of one alkyl or alkoxy group which makes phosphorylated enzyme more stable -- CANNOT be reactivated
Pharmacokinetics of the Anticholinesterases (4)
1. Edrophonium - quaternary ammonium; NO BBB; rapid onset; short duration
2. Neostigmine - quaternary amine; NO BBB
3. Physistigmine - tertiary amine; Crosses BBB (peripheral and CNS effects)
4. Organophosphates - cross BBB
What are neostigmine and physostigmine used for?
Used to reverse atony of smooth muscle of intestine and bladder
What is Echothiophate used for?
-Chronic wide angle glaucoma
-acute angle glaucoma (surgery indicated for long-term treatment)
-Long duration of action (~1 week)
-not a first line therapy
-INC risk for cataract formation with prolonged treatment
What drugs are used for Alzheimer's Disease? (3)
1. Tacrine (hepatotoxicity limits use of this)
What drug is used to reverse treatment intoxication by atropine like drugs?
What drugs will reverse the effects of nondepolarizing/competitive NMJ blockers but NOT succinylcholine? (3)
What is Myasthenia Gravis?
Abs against Nm destroys the Nm at the NMJ reducing muscle strength
How do you differentiated between myasthenia graves and a cholinergic crisis?
MG: INC muscle strength (INC anticholinesterase)
CC: DEC muscle strength (DEC anticholinesterase)
Treatment of Myasthenia Gravis?
Acute Toxic Effects of Anticholinesterases?
*excessive muscarinic receptor activation/ accumulation of ACh at NMJ
*IF Nm depolarization block happens, muscle fasciculation will become muscle paralysis (could lead to resp issues)
Chronic effects of Anticholinesterases
-delayed neurotoxicity unrelated to cholinesterase inhibition
-no specific therapy
What is special about Atropine?
It will reverse muscarinic receptor effects but has NO effect on nicotinic receptors
What is Pralidozime?