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Pharm > Cholinergic Agonists and Antagonists > Flashcards

Cholinergic Agonists and Antagonists Flashcards

1
Q

Steps in cholinergic transmission

A

ACh synthesis

ACh storage

ACh release

ACh destruction

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2
Q

Steps in Adrenergic Transmission

A

Synthesis

Storage

Release

Reuptake (destruction)

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3
Q

Organs and mAChR Receptors

A

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

M2 predominant in the heart

Smooth muscle – M3, M2

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4
Q

What structural features are associated with the subtypes of muscarinic AChRs

A 
M1- Gq
M2- Gi
M3- Gq
M4-Gi
M5- Gq
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5
Q

Where are the nicotinic receptors found?

A

Nm - skeletal muscle, neuromuscular junction

Nn- Postganglionic cell body, dendrites, CNS

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6
Q

Nicotinic receptor mechanism

A

sodium, potassium depolarizing ion channel

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7
Q

direct vs indirect cholinergic agonists

A

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

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8
Q

Types of cholinergic antagonists

A

Antinicotinic Agents
Neuromuscular Blockers
Ganglion Blockers

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

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9
Q

Cholinergic Agonists

A

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

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10
Q

Choline Esters and examples

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

Quaternary amines

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

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11
Q

Cholinomimetic Alkaloids

A

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

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12
Q

Major Clinical Uses of Direct-Acting Cholinergic Agonists

A

Diseases of the eye,

GI/ GU disorders

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13
Q

Muscarinic agonists in the eye

A

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)
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14
Q

Muscarinic agonists in GI/ GU smooth muscle

A

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)
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15
Q

Direct-Acting Cholinergic Agonists and their uses

A
  • 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
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16
Q

Cevimeline

A

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

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17
Q

Varenicline (Chantix)

A

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

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18
Q

Toxicity of Direct-Acting Cholinergic Agonists: Muscarinic stimulants

A

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

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19
Q

Toxicity of Direct-Acting Cholinergic Agonists: Nicotinic stimulants

A

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

20
Q

Chemical Classes of AChE Inhibitors

A

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

21
Q

Properties of AChE Inhibitors

A

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

22
Q

AChE Inhibitor Pharmacodynamics

A

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)

23
Q

AChE Inhibitor Clinical (and other) Uses

A

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)

24
Q

AChE Inhibitor Toxicity

A 
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)
25
Q

Introduction to Cholinergic Antagonists

A

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

26
Q

Antimuscarinic Drugs used for motion sickness

A

scopolomine

27
Q

Antimuscarinic Drugs used for respiratory disorders

A

Ipratropium

Tiotropium

28
Q

Antimuscarinic Drugs for gastrointestinal disorders

A

Atropine
Dicyclomine
Glycopyrrolate
Hyoscyamine

29
Q

Antimuscarinic Drugs used for movement disorders

A 
Benztropine 
Biperiden
Orphenadrine 
Procyclidine 
Trihexyphenidyl
30
Q

Antimuscarinic Drugs used in ophthalmology

A 
Atropine
Cyclopentolate
Homatropine
Scopolamine
Tropicamide
31
Q

Antimuscarinic Drugs used for urinary disorders

A 
Darifenacin 
Oxybutynin 
Solifenacin 
Tolterodine 
Trospium

“Oxy dares to hold it in”

32
Q

Antimuscarinic Drugs used for cholinergic poisoning

A

Atropine (+ pralidoxime)

33
Q

CNS Effects of Antimuscarinics

A

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

34
Q

Eye effects of antimuscarinics

A

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

35
Q

CV effecs of antimuscarinics

A

Tachycardia may occur, little effect on blood pressure

36
Q

Respiratory system effects of antimuscarinics

A

Bronchodilation and secretion reduction

37
Q

GI/ GU tract effects of antimuscarinics

A

Reduction in salivation, gastric secretion, prolonged gastric emptying time

Urinary retention

38
Q

Sweat gland effects of antimuscarinics

A

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

39
Q

Antimuscarinics for Parkinson disease

A

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

40
Q

Antimuscarinics for motion sickness

A

Scopolamine – PO, injection, transdermal

41
Q

Antimuscarinics for anesthesia

A

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

42
Q

Antimuscarinics for Ophthalmologic Disorders

A

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

43
Q

Antimuscarinics for Respiratory Disorders

A

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

44
Q

Antimuscarinics for GI Disorders

A

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

45
Q

Antimuscarinics for GU Disorders

A

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

46
Q

Antimuscarinics for Cholinergic Poisoning

A

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

47
Q

Anticholinergics: AEs and Contraindications

A

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

Pharm (14 decks)

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