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Flashcards in Cholinergic Agonists & Antagonists Deck (31):
1

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

2

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

3

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

4

List the 3 key quaternary analogs of ACh and their pharmacological actions in the body.

1. methacholine - bronchoconstriction
2. carbachol - miosis (pupillary constriction)
3. bethanechol - micturition and GI activation

5

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)

6

Describe the relative susceptibility of the quaternary analog agonists to enzymatic degradation.

resistant to hydrolysis or slower hydrolysis
- longer duration of action

7

List common clinical uses for the 4 muscarinic agonists.

1. methacholine = methacholine challenge test to diagnose asthma
2. carbachol = miosis to treat intraocular pressure of glaucoma, cataract surgery
3. bethanechol = treat urinary retention in postoperation or postpartum; neurogenic atony of bladder
4. pilocarpine = dry mouth, Sjogren's, open/closed-angle glaucoma

8

List 4 key representative reversible cholinesterase inhibitors. Compare their duration of action and their primary clinical applications.

1. neostigmine - DOA = 1hr; more stable than ACh; myasthenia gravis and reverses neuromuscular relaxants
2. edrophonium - short acting; diagnosis of myasthenia gravis, ddx b/w MG and cholinergic crisis
3. physostigmine - DOA = 2hr; anti-delirium due to anticholinergic poisoning
4. donepezil - DOA = 24hr; alzheimer's

9

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

10

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

11

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

12

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

13

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

14

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

15

Describe nicotine.

- Nn receptor agonist
- use: smoking cessation
- toxicity: skin irritation (patch) and dyspepsia (indigestion)

16

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

17

Describe the following for acetylcholine:
- receptor selectivity
- effects
- use
- toxicity
- contraindications

- Nn, Nm, M
- easily hydrolyzed by acetylcholinesterases and plasma cholinesterases
- no therapeutic use

18

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

19

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

20

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

21

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

22

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)

23

List the effects of cholinesterase inhibition or indirect-acting cholinergic agonists.

1. autonomic effects (SM, glands) = increased M activity
2. autonomic ganglia = increased Nn activity
3. striated muscle = increased Nm activity
4. CNS = stimulation or depression = both N and M

24

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

25

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

26

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

27

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

28

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)

29

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

30

Describe the following for echothiophate:
- definition
- effects
- use

def: organophosphate used clinically

EFFECTS - long-term miosis

USE - open angle glaucoma; topical

31

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