Cholinergic Agonists and Antagonists

Question 1

Steps in cholinergic transmission

Answer 1

ACh synthesis

ACh storage

ACh release

ACh destruction

Question 2

Steps in Adrenergic Transmission

Answer 2

Synthesis

Storage

Release

Reuptake (destruction)

Question 3

Organs and mAChR Receptors

Answer 3

In most organs, M3 is predominant (or receptor abundance is equal)

M2 predominant in the heart

Smooth muscle – M3, M2

Question 4

What structural features are associated with the subtypes of muscarinic AChRs

Answer 4

M1- Gq
M2- Gi
M3- Gq
M4-Gi
M5- Gq

Question 5

Where are the nicotinic receptors found?

Answer 5

Nm - skeletal muscle, neuromuscular junction

Nn- Postganglionic cell body, dendrites, CNS

Question 6

Nicotinic receptor mechanism

Answer 6

sodium, potassium depolarizing ion channel

Question 7

direct vs indirect cholinergic agonists

Answer 7

Direct-acting
Limited use due to poor absorption and distribution
Some are also rapidly hydrolyzed by AChE

Indirect-acting
Acetylcholinesterase (AChE) inhibitors
Utility determined by pharmacokinetics

Question 8

Types of cholinergic antagonists

Answer 8

Antinicotinic Agents
Neuromuscular Blockers
Ganglion Blockers

Antimuscarinic Agents
Prototype: atropine
Many other compounds; utility determined by pharmacokinetics and receptor selectivity

Question 9

Cholinergic Agonists

Answer 9

Mimic the actions of ACh on nAChRs and mAChRs
Classified based on their mechanism of action

choline esthers, alkaloids

Actions: pupillary constriction, near vision, salivation, bronchial constriction and secretion, slowed heart rate, gastric secretion, diarrhea, voiding of urine

SLUDGE- salivation, lacrimation, urination, defecation, GI, emesis

Question 10

Choline Esters and examples

Answer 10

MOA: agonists at cholinergic receptors
Permanently charged (poor absorption and distribution)

Quaternary amines

Acetylcholine- susceptible to cholinesterse
Methacholine- somewhat suceptible to cholinesterase
Carbachol
Bethanechol

Question 11

Cholinomimetic Alkaloids

Answer 11

MOA: agonists at cholinergic receptors
Uncharged tertiary amines that are well absorbed (e.g., nicotine patch)

Muscarine is charged but can cross the BBB and is highly toxic when ingested (e.g., mushrooms)

Pilocarpine (used for xerostomia)- think of eating a pile of carp and getting so thirsty

Nicotine
Lobeline

Question 12

Major Clinical Uses of Direct-Acting Cholinergic Agonists

Answer 12

Diseases of the eye,

GI/ GU disorders

Question 13

Muscarinic agonists in the eye

Answer 13

Iris sphincter and ciliary muscle contraction cause increased aqueous humor outflow into the canal of Schlemm (drains the anterior chamber)

Clinical relevance:

• Glaucoma (replaced by β-blockers, prostaglandins)
• Accommodative esotropia: misalignment of the eyes caused by hypermetropic accommodative error (farsightedness)

Question 14

Muscarinic agonists in GI/ GU smooth muscle

Answer 14

M3 activation is excitatory (signaling pathway)
M2 activation is inhibitory (signaling pathway)
BOTH cause smooth muscle contraction

Functional effects:
Increased motility and tone
Increased secretions from salivary and gastric glands&raquo_space; pancreas and small intestinal glands

Clinical relevance
Postoperative ileus
Congenital megacolon
Esophageal reflux
Neurogenic bladder
Xerostomia (Sjögren’s syndrome)

Question 15

Direct-Acting Cholinergic Agonists and their uses

Answer 15

• Acetylcholine
  Approved for intraocular use during surgery and causes miosis (reduction in pupil size)
• Bethanechol
  Selective mAChR agonist that primarily affects the urinary and GU tracts
  Can be used to treat patients with neurogenic bladder and urinary retention
  Little cardiovascular stimulation
  May produce urinary tract infection if sphincter fails to relax
• Carbachol
  Nonspecific cholinergic agonist that is used for the treatment of glaucoma or to produce miosis during surgery or ophthalmic examination
• Methacholine
  Selective and potent mAChR agonist used in diagnosis of bronchial airway hyperreactivity
• Pilocarpine
  Approved for xerostomia (Sjögren’s syndrome or head and neck cancer treatment related), miosis during ophthalmic procedures (topical), and for glaucoma (topical)
  Pure mAChR agonist

Question 16

Cevimeline

Answer 16

Synthetic muscarinic agonist
Selective for M3 receptors
Oral tablet used to treat dry mouth (xerostomia) in patients with Sjögren’s syndrome
Common AEs include excessive sweating, nausea, blurred vision

Question 17

Varenicline (Chantix)

Answer 17

FDA approved for smoking cessation
Partial agonist that binds with high affinity and selectivity to α4β2 nAChRs (NN)
MOA: stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation
Adverse effects: nausea and insomnia
Serious AEs (warrants discontinuation): neuropsychiatric symptoms, including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide

Question 18

Toxicity of Direct-Acting Cholinergic Agonists: Muscarinic stimulants

Answer 18

Muscarinic stimulants
Nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction/wheezing, increase in glandular secretion (SLUDGE)
Contraindicated in patients who have asthma, hyperthyroidism, coronary insufficiency, acid-peptic disease

Treatment
Antimuscarinic (atropine

Question 19

Toxicity of Direct-Acting Cholinergic Agonists: Nicotinic stimulants

Answer 19

Nicotinic stimulants
Nicotine poisoning: from cigarettes and insecticides
Acute toxicity includes CNS stimulation, skeletal muscle end plate depolarization, respiratory paralysis, hypertension, cardiac arrhythmias
Also muscarinic signs (vomiting, diarrhea, bronchorrhea, salivation, wheezing)

Treatment
Atropine for muscarinic effects
Parenteral anticonvulsants (diazepam) for seizures
Intubation and ventilation may be required to support respiration

Question 20

Chemical Classes of AChE Inhibitors

Answer 20

Three chemical groups
Alcohols – charged, reversible
Carbamates – charged or uncharged, reversible
Organophosphates – mostly uncharged, irreversible, highly lipid soluble

Chemistry dictates PK profile
Charged vs. uncharged
Lipid soluble or insoluble
Reversible or irreversible binding

Question 21

Properties of AChE Inhibitors

Answer 21

Charged agents: Edrophonium, Neostigmine, Pyridostigmine, Echothiophate (100 hours action)

Insoluble in lipids
Do not cross the blood-brain barrier
Poor PO absorption

Uncharged agents: Physostigmine
Lipid soluble
Cross the BBB
Readily absorbed

Question 22

AChE Inhibitor Pharmacodynamics

Answer 22

Bind to AChE (also BuChE) and block its enzymatic activity
Increases the concentration of ACh
Causes stimulation of both nAChRs and mAChRs
Consequences can be therapeutic or deadly (organophosphates, others at high concentrations)

Question 23

AChE Inhibitor Clinical (and other) Uses

Answer 23

Myasthenia gravis
Reversal of neuromuscular blockade during anesthesia
Dementia associated with Alzheimer or Parkinson disease
Antidote for anticholinergic poisoning
Symptoms of anticholinergic poisoning reflect sympathetic nervous system activation (fight or flight)
Pretreatment of Soman nerve gas exposure
High concentrations of long-acting agents are used as chemical warfare (e.g., soman gas)

Question 24

AChE Inhibitor Toxicity

Answer 24

Acute intoxication (parasympathetic effects): SLUDGE
Salivation, Lacrimation, Urination, Defecation, Gastrointestinal, Emesis
Also NMJ effects: muscle fasciculations followed by paralysis
Treatment includes atropine, maintenance of vital signs, decontamination, pralidoxime (cholinesterase regenerator)

Question 25

Introduction to Cholinergic Antagonists

Answer 25

Muscarinic and nicotinic subgroups Antinicotinic agents Neuromuscular junction (skeletal muscle relaxants) Ganglia (rarely used) Antimuscarinic agents CNS, nerves, heart, smooth muscle, glands, endothelium Block the effects of parasympathetic autonomic discharge The most clinically useful cholinergic antagonists Prototype antimuscarinic agent: atropine

Question 26

Antimuscarinic Drugs used for motion sickness

Answer 26

scopolomine

Question 27

Antimuscarinic Drugs used for respiratory disorders

Answer 27

Ipratropium | Tiotropium

Question 28

Antimuscarinic Drugs for gastrointestinal disorders

Answer 28

Atropine Dicyclomine Glycopyrrolate Hyoscyamine

Question 29

Antimuscarinic Drugs used for movement disorders

Answer 29

``` Benztropine Biperiden Orphenadrine Procyclidine Trihexyphenidyl ```

Question 30

Antimuscarinic Drugs used in ophthalmology

Answer 30

``` Atropine Cyclopentolate Homatropine Scopolamine Tropicamide ```

Question 31

Antimuscarinic Drugs used for urinary disorders

Answer 31

``` Darifenacin Oxybutynin Solifenacin Tolterodine Trospium ``` "Oxy dares to hold it in"

Question 32

Antimuscarinic Drugs used for cholinergic poisoning

Answer 32

Atropine (+ pralidoxime)

Question 33

CNS Effects of Antimuscarinics

Answer 33

Sedation, drowsiness, amnesia, hallucinations, tremor reduction Effects vary within class (atropine vs. scopolamine)

Question 34

Eye effects of antimuscarinics

Answer 34

Pupil dilation, cycloplegia (ciliary muscle paralysis), loss of accomodation, secretion reduction

Question 35

CV effecs of antimuscarinics

Answer 35

Tachycardia may occur, little effect on blood pressure

Question 36

Respiratory system effects of antimuscarinics

Answer 36

Bronchodilation and secretion reduction

Question 37

GI/ GU tract effects of antimuscarinics

Answer 37

Reduction in salivation, gastric secretion, prolonged gastric emptying time Urinary retention

Question 38

Sweat gland effects of antimuscarinics

Answer 38

Suppression of thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (no parasympathetic innervation of sweat glands)

Question 39

Antimuscarinics for Parkinson disease

Answer 39

mAChR antagonists can reduce tremors Not as effective as standard dopaminergic therapy (often used in combination) Tertiary amines benztropine, trihexyphenidyl, and procyclidine

Question 40

Antimuscarinics for motion sickness

Answer 40

Scopolamine – PO, injection, transdermal

Question 41

Antimuscarinics for anesthesia

Answer 41

Atropine is given to block responses to vagal reflexes induced by surgical manipulation of visceral organs Atropine or glycopyrrolate is paired with the cholinesterase inhibitor neostigmine to block its parasympathetic effects during reversal of neuromuscular blockade

Question 42

Antimuscarinics for Ophthalmologic Disorders

Answer 42

mAChR antagonists are only used when cycloplegia or prolonged mydriasis is required Refractive eye surgery (LASIK) α-adrenergic receptor agonists are shorter-acting and produce less adverse effects Homatropine and atropine are used to prevent synechia formation in uveitis and iritis (where the iris adheres to either the lens or the cornea) Long-acting agents Mydriasis may last 6 hours to 12 days and cycloplegia persists about 10 hours to 14 days

Question 43

Antimuscarinics for Respiratory Disorders

Answer 43

Asthma and chronic obstructive pulmonary disease (COPD) Ipratropium and tiotropium Inhalation mAChR antagonists Tiotropium has a longer bronchodilator action than ipratropium and can be dosed once daily mAChR antagonists such as atropine and scopolamine were used in preoperative settings to limit airway secretions that were increased by irritant anesthetics (e.g., ether) Now replaced by inhalational anesthetics

Question 44

Antimuscarinics for GI Disorders

Answer 44

mAChR antagonists may be used in the treatment of common traveler’s diarrhea and other mild or self-limited conditions of hypermotility Side effects and alternative therapies limit use Often combined with an opioid antidiarrheal drug to discourage abuse of the opioid agent Example: Lomotil - combination of atropine and diphenoxylate

Question 45

Antimuscarinics for GU Disorders

Answer 45

mAChR antagonists can provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders Agents with selectivity to M3 subtype of mAChR are beneficial due to presence in bladder wall and sphincter smooth muscle Oxybutynin is prototype selective M3 antagonist but has side effects (dry mouth/eyes, dizziness, constipation, blurred vision) Darifenacin, solifenacin, and tolterodine are selective for the M3 subtype and are advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation

Question 46

Antimuscarinics for Cholinergic Poisoning

Answer 46

Medical emergency that can be caused by cholinesterase inhibitor insecticides, wild mushrooms, as well as chemical warfare nerve gases Antimuscarinic agents (atropine) are given to reduce mAChR stimulation No effective treatment at nAChR (pralidoxime) Atropine is useless in delayed-onset mushroom poisoning Characterized by vomiting and nausea 6-12 hrs after ingestion and causes hepatic/renal cellular injury by amatoxins that inhibit RNA polymerase

Question 47

Anticholinergics: AEs and Contraindications

Answer 47

Good for one organ system, bad for another Mydriasis and cycloplegia may be adverse effects of antimuscarinic agents used to reduce GI secretion High systemic concentrations lead to block of parasympathetic function: dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare Treat with AChE inhibitors or symptomatically Contraindications/caution: Glaucoma (closed-angle) Prostatic hyperplasia Acid-peptic disease