Intro To Cholinergic Agonists And Antagonists Flashcards
Parasympathetics:
- Neurotransmitters
- Receptors
- Locations
- NT: ACh
- Rec: nAChR, mAChR
- Loc: cardiac and smooth muscle, gland cells, nerve terminals
Sympathetic:
- NT
- Receptors
- Locations
- NT: NE>Epi (DA); ACh
- Rec: alpha, beta, (D), nAChR, mAChR
- Loc: sweat glands (ACh, M); cardiac and smooth muscle, gland cells, nerve terminals (NE, alpha/beta); renal vascular smooth muscle (D, D1)
Cholinergic nerve terminal:
- ACh synthesis
- ACh storage
- ACh release
- ACh destruction
- Synthesized in cytoplasm: AcCoA + Choline
- Stored in vesicle
- Released into synaptic terminal to bind to mAChR and nAChR in other cell
- Destroyed into choline and acetate
Adrenergic nerve terminal:
- Synthesis
- Storage
- Release
- Reuptake
- Synthesized in cytoplasm from tyrosine to dopa to dopamine
- Stored in vesicle as DA and converted in vesicle to NE
- Released as NE into synaptic cleft to bind to alpha/beta receptors
- Reuptake as NE
Sympathetic effects and receptors on heart
beta1>beta2
Increase in heart rate, contractility, conduction velocity, automaticity, rate of idioventricular pacemakers
Parasympathetic effects and receptors of heart
M2>M3
Decrease in heart rate, contractility, conduction velocity
shortened AP duration
AV block
Sympathetic effects and receptors on blood vessels
Coronary: constriction, dilation. alpha1/2, beta2
Skin and mucosa: constriction. Alpha1/2
skeletal muscle: constriction, dilation. Alpha1, beta2
Cerebral: constriction (slight). Alpha1
Pulmonary: constriction, dilation. Alpha1, beta2
Abdominal viscera: constriction, dilation. Alpha1, beta2
Salivary glands: constriction: alpha1, beta2
Renal: constriction, dilation. Alpha1/2, beta1/2
Veins: constriction, dilation. Alpha1/2, beta2
Parasympathetic effects and receptors on blood vessels
Salivary glands: dilation, M3
Rest: no innervation
Sympathetic effects and receptors on lung
Tracheal/bronchial smooth muscle: relaxation, beta2
Bronchial glands: decreased/increased secretion, alpha1, beta2
Parasympathetic effects and receptors on lung
Tracheal/bronchial smooth muscle: contraction, M2=M3
Bronchial glands: stimulation, M3, M2
Sympathetic effects and receptors on stomach/intestine
Motility and tone: decrease, alpha1/2, beta1/2
Sphincters: contraction, alpha1
Secretion: Inhibition, alpha2
Parasympathetic effects and receptors on stomach/intestine
Motility and tone: increase, M2=M3
Sphincters: Relaxation, M3, M2
Secretion: Stimulation, M3, M2
Sympathetic effects and receptors on gallbladder
Relaxation, beta2
Parasympathetic effects and receptors on gallbladder
Contraction, M
Sympathetic effects and receptors on renin secretion
Parasympathetic?
Symp: decrease, increase, alpha1, beta1
Para: no innervation
Sympathetic effects and receptors on urinary bladder
Detrusor: relaxation, beta2
Trigone and sphincter: contraction, alpha1
Parasympathetic effects and receptors of urinary bladder
Detrusor: contraction, M3>M2
Trigone and sphincter: relaxation, M3>M2
Sympathetic effect and receptors on uterus
Pregnant contraction: alpha1
Pregnant relaxation: beta2
Nonpregnant relaxation: beta2
Sympathetic and parasympathetic effects and receptors of male sex organs
Sympathetic: ejaculation, alpha1
Para: erection, M3
Sympathetic effects and receptors of skin
Pilomotor muscles: contraction, alpha1
Sweat glands: localized/generalized secretion: alpha1
Location, structural features, mech of M1
Nerves
GPCR, Gq/11
IP3, DAG
Location, structural features, mech of M2
Heart, nerves, smooth muscle
GPCR, Gi
Inhibition of cAMP production, activation of K+ channels
Location, structural features, mech of M3
Glands, smooth muscle, endothelium
GPCR, Gq
IP3, DAG
Location, structural features, mech of M4
CNS
GPCR, Gi
Inhibition of cAMP production
Location, structural features, mech of M5
CNS
GPCR, Gq
IP3, DAG
Describe direct-acting cholinergic agonists: choline esters
MOA: agonists at cholinergic receptors Choline esters permanently charged Poor absorption and distribution to CNS Metabolized by acetylcholinesterase ACh>methacholine>carbachol=bethanecol
Describe direct-acting cholinergic agonists: alkaloids
MOA: agonists at cholinergic receptors
Uncharged tertiary amines -> well absorbed (nicotine patch)
Muscarine is charged but can cross BBB and is highly toxic when ingested (mushrooms)
MAChR: muscarine and pilocarpine
nAChR: nicotine, lobeline
What are the 3 groups of AChE inhibitors?
- Alcohols: reversible
- Carbamic acid esters: reversible but longer lasting than alcohols
- Organophosphates: irreversible (covalent)
Describe PK and PD of AChE inhibitors
Chemistry dictates PK
Charged AChE inhibitors are insoluble in lipids
- Do not cross BBB, poor PO absorption
- Quaternary agents (edrophonium, pyridostigmine, neostigmine, echothiophate, ambenoium)
Neutral AChE inhibitors are lipid-soluble
- Can cross BBB and readily absorbed
- Most organophosphates, tertiary agents (physostigmine, donepezil, galantamine, rivastigmine, tacrine)
MOA: inhibition of AChE (also BuChE)
Acetylcholine clinical use
Intraocular use during surgery and causes miosis (reduction in pupil size)
Bethanechol clinical use
Selective mAChr agonist that primarily affects urinary and GU tracts
Used to treat pts with urinary retention and heartburn
Little cardiovascular stimulation
May produce urinary tract infection if sphincter fails to relax
Carbachol clincal use
Nonspecific cholinergic agonist that is used for treatment of glaucoma or to produce miosis during surgery or ophthalmic examination
Cevimeline clinical use
Oral tablet used to treat dry mouth (xerostomia) in patients with Sjogren syndrome
Pilocarpine
Approved for xerostomia treatment in pts with Sjogren syndrome or head and neck cancer treatment related to xerostomia
Miosis during ophthalmic procedures (topical) and for glaucoma (topical)
Pure mAChR agonist
Varenicline (Chantix) clinical use
FDA approved for smoking cessation
Partial agonist that binds with high affinity and selectivity to alpha4beta2 nAChRs (Nn)
MOA: stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation
Nausea most common adverse side effect
Serious adverse side effects: neuropsychiatric symptoms including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide
Describe major uses of direct-acting cholinergic agonists
Diseases of eye:
Glaucoma
Accommodative esotropia: misalignment of eyes caused by hypermetropic accomodative error
GI/GU disorders: Postoperative ileus Congenital megacolon Urinary retention Esophageal reflux Xerostomia, Sjogren syndrome
Describe toxicity of direct-acting cholinergc agonists: muscarinic stimulus
Predictable: nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction, increase in glandular secretion (SLUDGE)
Contracindicated: asthma, hyperthyroidism, coronary insufficiency, acid-peptic disease
Describe toxicity of direct-acting cholinergic agonists: nicotinic stimulants
Nicotine poisoning from cigarettes and insecticides
Acute toxicity includes CNS stimulation, skeletal muscle end plate depolarization, respiratory paralysis, hypertension, cardiac arrhythmias
Treat with atropine and parenteral anticonvulsants (diazepam)
Describe clinical uses of indirect-acting cholinergic agonists
- Glaucoma: stimulation of mAChRs on ciliary body facilitates aqueous humor outflow and reduces intraocular pressure (replaced by beta-blockers, prostaglandins)
- Dementia (Alzheimer and Parkinson): deficiency of intact cholinergic neurons (particularly those extending from subcortical areas such as nucleus basalis of Meynert)
- Antidote to anticholinergic poisoning:
- -from atropine, antihistamines, TCAs, sleep aids, cold preparations
- -symptoms: cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, reduction/elimination of desire to urinate
- Reversal of neuromuscular paralysis
- Myasthenia gravis
Describe AChE inhibitor toxicity
SLUDGE symptoms, effects on NMJ
Treatment: atropine, maintenance of vital signs, decontamination, pralidoxime (cholinesterase regenerator)
Compare/contrast cholinergic agonist vs cholinergic antagonist effects on organ systems
Cholinergic agonist: Eye: pupillary constriction, near vision Salivary glands: salivation Bronchi: constriciton, secretion Heart: Slowing GI tract: gastric secretion increased, colic, diarrhea Bladder: voiding of urine
Cholinergic antagonists: Eye: pupillary dilation, far vision Salivary glands: dry mouth Bronchi: relaxation, sticky dry Heart: acceleration GI tract: gastric secretion reduced, constipation Bladder: retention of urine
Describe antinicotinic and antimuscarinic agents
Antinicotinic agents:
Neuromuscular junction: skeletal muscle relaxants
Ganglia: rarely used
Antimuscarinic agents:
CNS, nerves, heart, smooth muscle, glands, endothelium
Block effects of parasympathetic autonomic discharge
Most clinically useful cholinergic antagonists
Protype: atropine
Drugs used for motion sickness
Scopolamine
Drugs for GI disorders
Atropine
Dicyclomine
Glycopyrrolate
Hyoscyamine
Drugs used in ophthalmology
Atropine Cyclopentolate Homotropine Scopolamine Tropicamide
Drugs used for respiratory disorders
Ipratropium
Tiotropium
Drugs used for urinary disorders
Darifenacin Oxybutynin Solifenacin Tolterodine Trospium
Drugs used for cholinergic poisoning
Atropine (+pralidoxime)
Drugs used for movement disorders
Benztropine Biperiden Orphenadrine Procyclidine Trihexyphenidyl
Describe organ system effects of anticholinergics
(General increase in sympathetic tone)
CNS: sedation, drowsiness, amnesia, hallucinations, tremor reduction. Effects vary with class (atropine vs scopolamine)
Eye: Pupil dilation, cycloplegia (ciliary muscle paralysis), loss of accommodation, secreation reduction
CV system: tachycardia may occur. Little effect on blood pressure
Respiratory system: Bronchodilation and secretion reduction
GI tract: reduction in salivation, gastric secretion, prolonged gastric emptying time
GU tract: urinary retention
Sweat glands: suppression of thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (no parasympathetic innervation of sweat glands)
Describe anticholinergics for CNS disorders
Parkinson:
MAChR antagonists can reduce tremors
Not as effective as standard dopaminergic therapy (often used in combination)
Tertiary amines benztropine, trihexyphenidyl, and procyclidine
Motion sickness:
Scopolamine: PO, injection, transdermal
Anesthesia:
Atropine given to block responses to vagal reflexes induced by surgical manipulation of visceral organs
Atropine or glycopyrrolate is paired with cholinesterase inhibitor neostigmine to block parasympathetic effects
Describe anticholinergics for ophtalmologic disorders
MAChR antagonists only used when cyclopegia or prolonged mydriasis is required
- refractive eye surgery (LASIK)
- alpha-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 iris adheres to either lens or cornea)
- long-acting agents
- mydriasis may last 6 hours to 12 days , and cycloplegia persists about 10 hours to 14 days
Anticholinergics 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
MACH antagonists such as atropine and scopolamine were used in preoperative settings to limit airway secretions that were increased by irritant anestehtics (ether)
-Now replaced by inhalational anesthetics
Describe anticholinergics for GI disorders
MAChR antagonists used in treatment of common traveler’s diarrhea and other mild and self-limited conditions of hypermotility
Side effects and alternative therapies limit use
Often combined with opioid antidiarrheal drug to discourage abuse of opioid agent
Ex: lomotil: combination of atropine and diphenoxylate
Describe anticholinergics for GU disorders
MAChR antagonists can provide symptomatic relief in 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: prototype selective M3 antagonist but has side effects (dry mouth/eyes, dizziness, constipation, blurred vision)
Darifenacin, solifenacin, and tolterodine are selective for M3 subtype and are advantageous because of longer half-lives and reduced incidence of xerostomia and constipation
Describe anticholinergics for cholinergic poisoning
Medical emergency that can be caused by cholinesterase inhibitor insecticides, wild mushrooms, chemical warfare nerve gases
Antimuscarinic agents (atropine) 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
Describe adverse effects and contraindications of anticholinergics
Good for one organ, bad for another
-mydriasis and cycloplegia may be adverse effects if muscarinic 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
Prostatic hyperplasia
Acid-peptic disease
