Cholinergic Agonists and Antagonists Flashcards
Steps in cholinergic transmission
ACh synthesis
ACh storage
ACh release
ACh destruction
Steps in Adrenergic Transmission
Synthesis
Storage
Release
Reuptake (destruction)
Organs and mAChR Receptors
In most organs, M3 is predominant (or receptor abundance is equal)
M2 predominant in the heart
Smooth muscle – M3, M2
What structural features are associated with the subtypes of muscarinic AChRs
M1- Gq M2- Gi M3- Gq M4-Gi M5- Gq
Where are the nicotinic receptors found?
Nm - skeletal muscle, neuromuscular junction
Nn- Postganglionic cell body, dendrites, CNS
Nicotinic receptor mechanism
sodium, potassium depolarizing ion channel
direct vs indirect cholinergic agonists
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
Types of cholinergic antagonists
Antinicotinic Agents
Neuromuscular Blockers
Ganglion Blockers
Antimuscarinic Agents
Prototype: atropine
Many other compounds; utility determined by pharmacokinetics and receptor selectivity
Cholinergic Agonists
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
Choline Esters and examples
MOA: agonists at cholinergic receptors Permanently charged (poor absorption and distribution)
Quaternary amines
Acetylcholine- susceptible to cholinesterse
Methacholine- somewhat suceptible to cholinesterase
Carbachol
Bethanechol
Cholinomimetic Alkaloids
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
Major Clinical Uses of Direct-Acting Cholinergic Agonists
Diseases of the eye,
GI/ GU disorders
Muscarinic agonists in the eye
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)
Muscarinic agonists in GI/ GU smooth muscle
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»_space; pancreas and small intestinal glands
Clinical relevance Postoperative ileus Congenital megacolon Esophageal reflux Neurogenic bladder Xerostomia (Sjögren’s syndrome)
Direct-Acting Cholinergic Agonists and their uses
- 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
Cevimeline
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
Varenicline (Chantix)
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
Toxicity of Direct-Acting Cholinergic Agonists: Muscarinic stimulants
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
Toxicity of Direct-Acting Cholinergic Agonists: Nicotinic stimulants
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
Chemical Classes of AChE Inhibitors
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
Properties of AChE Inhibitors
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
AChE Inhibitor Pharmacodynamics
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)
AChE Inhibitor Clinical (and other) Uses
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)
AChE Inhibitor Toxicity
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)
Introduction to Cholinergic Antagonists
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
Antimuscarinic Drugs used for motion sickness
scopolomine
Antimuscarinic Drugs used for respiratory disorders
Ipratropium
Tiotropium
Antimuscarinic Drugs for gastrointestinal disorders
Atropine
Dicyclomine
Glycopyrrolate
Hyoscyamine
Antimuscarinic Drugs used for movement disorders
Benztropine Biperiden Orphenadrine Procyclidine Trihexyphenidyl
Antimuscarinic Drugs used in ophthalmology
Atropine Cyclopentolate Homatropine Scopolamine Tropicamide
Antimuscarinic Drugs used for urinary disorders
Darifenacin Oxybutynin Solifenacin Tolterodine Trospium
“Oxy dares to hold it in”
Antimuscarinic Drugs used for cholinergic poisoning
Atropine (+ pralidoxime)
CNS Effects of Antimuscarinics
Sedation, drowsiness, amnesia, hallucinations, tremor reduction
Effects vary within class (atropine vs. scopolamine)
Eye effects of antimuscarinics
Pupil dilation, cycloplegia (ciliary muscle paralysis), loss of accomodation, secretion reduction
CV effecs of antimuscarinics
Tachycardia may occur, little effect on blood pressure
Respiratory system effects of antimuscarinics
Bronchodilation and secretion reduction
GI/ GU tract effects of antimuscarinics
Reduction in salivation, gastric secretion, prolonged gastric emptying time
Urinary retention
Sweat gland effects of antimuscarinics
Suppression of thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (no parasympathetic innervation of sweat glands)
Antimuscarinics for Parkinson disease
mAChR antagonists can reduce tremors
Not as effective as standard dopaminergic therapy (often used in combination)
Tertiary amines benztropine, trihexyphenidyl, and procyclidine
Antimuscarinics for motion sickness
Scopolamine – PO, injection, transdermal
Antimuscarinics for anesthesia
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
Antimuscarinics for Ophthalmologic Disorders
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
Antimuscarinics for Respiratory Disorders
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
Antimuscarinics for GI Disorders
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
Antimuscarinics for GU Disorders
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
Antimuscarinics for Cholinergic Poisoning
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
Anticholinergics: AEs and Contraindications
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
