Cholinergic Agonists & Antagonists Flashcards
Distinguish nicotinic and muscarinic receptors regarding the following characteristics:
- structure
- function
- signaling mechanisms
- location in ANS
MUSCARINIC
- GPCR
- found on smooth muscle, cardiac muscle, exocrine glands, sweat glands, CNS, vascular beds
NICOTINIC
- ligand gated ion channel with 5 TM subunits
- cation channel selective for Na and K
- Nm = postganglionic, membranes of muscle cells
- Nn = postganglionic cell membranes of autonomic system; brain
Describe the difference between parasympathetic and nicotinic effects in the body.
- nicotinic receptors are found on postganglionic cells of both parasympathetic and sympathetic neurons
=> thus, nicotinic agonists activate BOTH simultaneously - parasympathetic effects are mostly through muscarinic receptors of the effector organs and also affected by nicotinic receptor activity
Describe the difference in MOA of direct and indirect cholinergic agonists.
- direct = binds to the receptor and causes action
- indirect = inhibits cholinesterases to increase activity of ACh (reversible or irreversible
List the 3 key quaternary analogs of ACh and their pharmacological actions in the body.
- methacholine - bronchoconstriction
- carbachol - miosis (pupillary constriction)
- bethanechol - micturition and GI activation
List the prototype tertiary amine muscarinic agonist and describe the major chemical feature that distinguishes it from the quaternary analogs. How does feature affect the drug’s clinical effects?
prototype = muscarine
- no ester domain
- resistant to hydrolysis by acetylcholinesterases or plasma cholinesterases
- can have profound parasympathetic activation when ingested in wild mushrooms (muscarine poisoning)
- treated with atropine (M antagonist)
Describe the relative susceptibility of the quaternary analog agonists to enzymatic degradation.
resistant to hydrolysis or slower hydrolysis
- longer duration of action
List common clinical uses for the 4 muscarinic agonists.
- methacholine = methacholine challenge test to diagnose asthma
- carbachol = miosis to treat intraocular pressure of glaucoma, cataract surgery
- bethanechol = treat urinary retention in postoperation or postpartum; neurogenic atony of bladder
- pilocarpine = dry mouth, Sjogren’s, open/closed-angle glaucoma
List 4 key representative reversible cholinesterase inhibitors. Compare their duration of action and their primary clinical applications.
- neostigmine - DOA = 1hr; more stable than ACh; myasthenia gravis and reverses neuromuscular relaxants
- edrophonium - short acting; diagnosis of myasthenia gravis, ddx b/w MG and cholinergic crisis
- physostigmine - DOA = 2hr; anti-delirium due to anticholinergic poisoning
- donepezil - DOA = 24hr; alzheimer’s
Describe the MOA of the irreversible cholinesterase inhibitors. What does it cause?
MOA of irreversible cholinesterases = phosphorylation of AChE, which over time creates a stable compound; irreversibly bound
- causes cholinergic crisis
Describe the pharmacologic effects and the treatment for organophosphate toxicity.
D - diarrhea, delirium U - urinary frequency, incontinence M - miosis, muscle weakness B - bronchorrhea (increased bronchial secretions) B - bradycardia B - bronchoconstriction E - emesis L - lacrimation L - lethargy S - salivation, sweat
List uses of atropine.
def: competitive inhibition of muscarinic receptors (reversible); at high doses, can block Nn activity
USES
- relieve frequency and urgency of urination during UTI
- relieve hypermotility of colon
- relieve hypertonicity of SI
- treat cholinergic crisis due to AChE inhibitor poisoning
- induce mydriasis and cycloplegia (paralysis of ciliary muscle)
- reverse bradycardia of vagal origin
Describe the symptoms of atropine poisoning and its treatment.
PNS Symptoms
- dry mouth
- difficulty swallowing
- marked thirst
- hot, flushed skin
- dilated pupils
- blurred vision and photophobia
- tachycardia
- increased BP
- difficulty urinating
- respiratory collapse
CNS Symptoms
- nervousness
- confusion
- hallucinations
- muscular incoordination and weakness
- inappropriate laughter
- psychosis
TX
- gastric lavage
- support maintenance of circulation and respiration
- cold sponge to lower body temperature
- catheterization for bladder
- myosis agents and dark room
- barbiturates for sedation
- IV physostigmine
Describe how, when, and why glycopyrrolate is used during recovery from anesthesia.
when - after surgery, in combination with cholinesterase inhibitors
why - prevent stimulation of the gut during reversal of neuromuscular blockade
Describe the signaling mechanisms and functions of M1, M2, and M3 receptors.
M1 - Gaq => IP3/DAG => Ca2+
- activates myenteric plexus in GI
M2 (found in heart)
- opens K channels => decreased heart rate and contractility, decreased CO
- Gi => inhibits AC => reduced cAMP => reduced Ca2+
==> inhibits NE release from sympathetic nerve terminals
M3 - Gaq => IP3/DAG => Ca2+
- contracts circular pupillary muscle = pupillary constriction
- contracts pupillary muscle = pupillary accommodation
- contracts bronchiole, GI, uterine, and detrusor (micturition)
- relaxes vascular smooth muscle via NO
- stimulates secretions of GI tract, eccrine sweat, tear, salivary, pancreas, and liver bile
Describe nicotine.
- Nn receptor agonist
- use: smoking cessation
- toxicity: skin irritation (patch) and dyspepsia (indigestion)
Describe succinylcholine.
- blocks nicotinic receptors are neuromuscular junctions (Nm)
- causes depolarization block
- used as a muscle relaxant for intubation or during electroshock therapy
- contraindication: familial hyperthermia, skeletal muscle myopathy
Describe the following for acetylcholine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
- Nn, Nm, M
- easily hydrolyzed by acetylcholinesterases and plasma cholinesterases
- no therapeutic use
Describe the following for methacholine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
RECEPTOR SELECTIVITY
- primarily M agonist activity on smooth muscle (M3), heart (M2), and glands (M3)
- resistant to hydrolysis, longer duration of action than ACh
EFFECTS
- constriction of bronchioles, pupillary, uterine, bladder, GI,
- stimulates gland secretions
- vasorelaxation in vascular beds
- inhibits NE release from sympathetics
USE
- methacholine challenge test to diagnose asthma
=> if asthma is suspected, giving a low dose of methacholine will cause hyperreactivity in the bronchioles => increased constriction => decreased lung function
TOXICITY
- bronchoconstriction
CONTRAINDICATIONS
- pt on beta blockers b/c has M2 agonist effect => slowed conduction exacerbation
Describe the following for carbachol:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
RECEPTOR SELECTIVITY
- both N and M
USE
- miotic agent (pupillary constriction - M3) to relieve intraocular pressure in glaucoma pts or after cataract surgery
TOXICITY
- excessive N and M activity
Describe the following for bethanechol:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
RECEPTOR SELECTIVITY
- selective M agonist
- M1 (GI)
- M3 (bladder)
EFFECTS
- activation of myenteric plexus
- contraction of the detrusor muscle (micturition)
USE
- postoperative nonobstructive urinary retention
- postpartum urinary retention
- neurogenic atony of bladder
TOXICITY
- less than carbachol because no M2 effect
- bradycardia
CONTRAINDICATIONS
- peptic ulcer
- asthma
- bradycardia
Describe the following for pilocarpine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
RECEPTOR SELECTIVITY
- pure muscarinic activity (found in leaf)
- crosses BBB and has CNS effects
- not resistant to enzyme degradation unlike muscarine b/c has an ester
USE
- dry mouth due to head/neck radiotherapy
- Sjogren’s syndrome (autoimmune against lacrimal and salivary glands)
- open and angle-closure glaucoma
CONTRAINDICATIONS/use with care
- pts. on B blockers b/c it will exacerbate slow conduction via M2 agonist activity
Describe the 2 endogenous cholinesterases, where they are found, and what their function is.
ACETYLCHOLINESTERASE (AChE, true, specific)
- found in neurons, motor endplates of skeletal muscle, RBCs
- fxn: hydrolysis of ACh in synaptic clefts or neuroeffectr transmisstion
BUTYRYLCHOLINESTERASE (BuChE, pseudo, nonspecific, plasma)
- found in plasma, glial cells, and liver
- fxn: hydrolysis of certain drugs (like succinylcholine)
List the effects of cholinesterase inhibition or indirect-acting cholinergic agonists.
- autonomic effects (SM, glands) = increased M activity
- autonomic ganglia = increased Nn activity
- striated muscle = increased Nm activity
- CNS = stimulation or depression = both N and M
Describe the following for neostigmine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
- reversible AChE inhibitor; indirect agonist
RECEPTOR SELECTIVITY
- primarily, increases Nm activity
- no BBB access due to quaternary nitrogen
EFFECTS
- reverses neuromuscular blockade
USE
- reverse neuromuscular relaxant therapy
- myasthenia gravis
TOXICITY
- increased peripheral N and M activation
CONTRAINDICATION
- intestinal obstruction
Describe the following for edrophonium:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
- reversible AChE/BuChE inhibitor; indirect agonist
- rapid onset, short DOA
RECEPTOR SELECTIVITY
- Nm
USE
- diagnose myasthenia gravis
- differentiate b/w MG and cholinergic crisis
TOXICITY
- excess dose can cause muscle weakness mistaken for MG
- bradycardia
CONTRAINDICATIONS
- intestinal blockade
- urinary tract obstruction
Describe the following for physostigmine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications
- crosses BBB
- inactivated by plasma ChE, but takes a long time; (DOA = 2 hrs)
USE
- counteracts delirium due to anticholinergic poisoning (when you are given too many cholinergic antagonists, you have very little ACh…need more)
TOX
- increased ACh at N and M
- convulsions
CONTRAINDICATIONS
- asthma
- cardiac insufficiency
- intestinal obstruction
Describe the following for donepezil:
- site of action
- use
- reversible AChE inhibitor in the CNS; indirect-acting agonist
- high bioavailability, long half life
USE
- alzheimer’s disease
Define cholinergic crisis, its causes, symptoms, and treatments.
def = overstimulation of the NMJ due to excess ACh
CAUSE - too much AChE inhibitors => too much ACh => too much stimulation => refractory nicotinic receptors, cannot stimulate contraction
SX - flaccid paralysis, respiratory failure, sweating
DUE TO: nerve gasses, organophosphates, overdose on AChE inhibitors
TX
- mechanical ventilation
- suction of oral secretions
- atropine to protect from systemic M activation
- 2PAM to reactivate sequestered AChE => breakdown of ACh
- physostigmine to reverse delirium (enters BBB)
Describe the following for 2PAM:
- action
- use
ACTION
- reactivates AChE by taking the phosphate on itself
- breakdown of ACh
USE
- tx for cholinergic crisis
- tx for organophosphates
Describe the following for echothiophate:
- definition
- effects
- use
def: organophosphate used clinically
EFFECTS - long-term miosis
USE - open angle glaucoma; topical
Describe the following for scopolamine:
- use
- contraindications
- prototype, natural alkaloid
USE - preparation for surgical anesthesia to minimize secretions
- treatment for N/V associated with motion sickness or chemotherapy
CONTRAINDICATION - narrow angle glaucoma
