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Muscarinics
Lecture 10: muscarinic agonists and antagonists
| Question | Answer |
|---|---|
| where are muscarinic acetylcholine receptors typically found? | In peripheral nervous system (usually autonomic effector cells); also present in autonomic ganglia and some cells (e.g. vascular endothelium) that receive little/no cholinergic innervation |
| * * ALL of the actions of ACH and its congeners at muscarinic receptors can be blocked by ___ | atropine |
| Is acetylcholine a muscarinic agonist or antagonist? | agonist |
| Is bethanecol a muscarinic agonist or antagonist? | agonist |
| Is carbachol a muscarinic agonist or antagonist? | agonist |
| Is methacholine a muscarinic agonist or antagonist? | agonist |
| Is atropine a muscarinic agonist or antagonist? | THE antagonist (blocks all muscarinic effects) |
| Is scopolamine a muscarinic agonist or antagonist? | antagonist |
| Is glycopyrrolate a muscarinic agonist or antagonist? | antagonist |
| Is ipratropium a muscarinic agonist or antagonist? | antagonist |
| Is tropicamide a muscarinic agonist or antagonist? | antagonist |
| Is tolterodine a muscarinic agonist or antagonist? | antagonist |
| Is Donnatal a muscarinic agonist or antagonist? | antagonist |
| What subtype is richly expressed in the brain areas involved in cognition? What does stimulation cause? | M1; too much stimulation causes seizures |
| What muscarinic receptor is associated with tremor , hypothermia, and antinociception? | M2 |
| A mutation in M3 receptors (especially in the hypothalamus) would be expected to have what symptoms? | Dimished appetite, dimished body fat mass |
| What is the mechanism of action of M1 and M3 receptors? | IP3, DAG cascade (Ca++ increase) |
| What is the mechanism of action of M2 and M4 receptors? | Inhibition of cAMP production, activation of K+ channels |
| What are the three major pathways for GI and muscarinic activation of CNS integration? | CN VIII enriched in M1 and H1 receptors (motion detection); CNS inputs from cognition + visual disturbance; vagal and spinal afferents (5HT) respond to GI irritation and distension; stimulate vomiting via vagus |
| What is underlying cause of Alzheimer's disease? How can anticholinesterases help? | Deficiency + degeneration of cholinergic neurons-->anticholinesterase can temporarily improve function (controversial) |
| What does parasympathetic stimulation of the eye do? | contract the pupillary sphincter (miosis) and ciliary muscles (myopia) |
| What is necessary to decrease intraocular pressure in the anterior space? what pharmaceutical intervention might help a patient with wide/open angle glaucoma | Contract the muscles to open space for outflow of aqueous humor-->do so by inhibiting cholinesterase or giving cholinergic agonist (e.g. pilocarpine) |
| What is the result of stimulation of the M2 receptors on the heart? | Vagal slowing down of heart rate (negative chronotropic effect) |
| What is the result of stimulating M3 receptors in the heart? | minor effect; stimulates endothelial NO synthase (eNOS) to increase synthesis and release of vasodilating nitric oxide NO |
| What are the primary physiological/pharmacological stimuli for gsatric contraction? | ACh (muscarinic) and substance P |
| Muscle contraction occurs via ACh binding to ___ receptors, increasing intracellular free calcium and ___ receptors that inhibit cAMP production | M3, M2 |
| Activation of what channels inhibits calcium entry through the voltage calcium channels in the smooth muscle of the gut (and thus limit contraction)? | K+ channels |
| What provides the signals to keep the muscles relaxed downstream of the gut contractions? | NO and vasoactive intestinal peptide (VIP) |
| Giving neostigmine to a person would do what to their intestinal motility? what about atropine? Bethanecol/ | muscarinic agonist-->contractions; would inhibit Muscarinic receptors-->stop contraction; muscarinic agonist as well-->constriction |
| What is the agent responsible for dilating the lower esophageal sphincter? How can you treat spasms in the sphincter? | NO; can treat with botox or antimuscarinics |
| What stimuli causes a sphincter in the GI tract to open? | high level of vagal activity and/or distension of the esophageal wall |
| Parasympathetic ACh and muscarinic agnonists stimulate ___ and ___ in the bladder. | mictruition and urination (contract detrusor, decrease bladder capacity, relax trigone and external sphincter, increase ureteral peristalsis_ |
| What are the main limitations of using muscarinic agonists? | diffuse actions throughout body and high risk of adverse events; limited to local administration (e.g. eye) and limited duration of treatment |
| What is the major clinical use of acetylcholine? | available as opthalmic surgical aid for rapid production of miosis |
| What is the major clinical use of carbachol? | Available use as opthalmic surgical aid for slower onset and more sustained miosis (compared to acetylecholine) |
| What is the major clinical use of pilocarpine? | Available for initial treamtne of open angle glaucoma; drugs targeting adrenergic or prostaglanding regulation, carbonic anhydrase inhibitors, or cholinesterase inhibitors are prefered for long term treatment |
| What is the major clinical use of methacholine? | inhalation challenge used by some to test for asthma or occupational airway hypersensitivity |
| What is the major clinical use of bethanechol? | used for post-operative pseudo-obstruction of gut or urinary bladder (classic indication and rarely used in US) |
| What are the toxic effects of using muscarinic agonists? What drug can undo all these effects? | Increased secretions (cold clammy skin), nausea, vomiting, abdominal colic, diarrhea, miosis, myopia, headache, visual disturbances, bronchospasm, bronchial congestion, bradycardia, hypotension, shock-->can all be blocked by atropine |
| What class of drugs cause the following symptoms: "red as a beet, dry as bone, blind as a bat, mad as a hatter" | Muscarinic receptor antagonists |
| What is the advantage of using tropicamide compared to other drugs in its class? | It is an antimuscarenic, but has a shorter duration than atropine |
| What is Ipratropium commonly prescribed for? | Antimuscarenic prescribed for lung obstructive disease; quaternized and does NOT cross BBB |
| What is tolterodine used for? | Antimuscarenic; prescribed for urinary incontinence |
| What are the effects of atropine on the CNS? | uncharged, able to cross the CNS; vagal excitation by stimulating medulla and higher cerebral centers; restlessness, irritability, disorientation, hallucinations, delirium, stim followed by depression, circulatory collapse, resp. fail, paralysis, coma |
| What are the effects of scopolamine on the CNS? | uncharged-->crosses BBB; causes CNS depression-->drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM sleep; some euphoria; can diminish sea seasickness (vestibular apparatus) |
| How do antihistamines act on muscarinic receptors? | effects of drowsiness and motion disturbances are predominantly antimuscarinic |
| What would an antimuscarenic do when applied topically/systemically to the eye? | mydriasis (pupils dilate), accomodation paralyzed (cycloplegia), hyperopia, photophobia |
| What drug would you prescribe for short term paralysis of the eye muscles? | tropicamide (4-8 hours); avoid atropine, as it lasts for a week |
| What is the effect of using muscarinic antagonists on the cardiovascular system? | Bradycardia (low dose), followed by tachycardia (blocking M2) |
| Why is atropine useful in hear surgery? | Blocks vagal tone and reflex bradycardia by releasing the parasympathetic control of the sympathetic effects on the heart |
| What drugs are useful in limiting the cardiovascular effecs of neostigmine when reversing neuromuscular blockage? | Atropine and glycopyrrolate |
| What effect does atropine have on the skin? | Inhibits sweat glands-->may be the source of the vasodilation (red as a beet, dry as bone) |
| What effect do atropine and muscarinic antagonists have on the lung? | decrease submucosal glandural secretions, reduce bronchial smooth muscle contraction (antiasthmatic properties); dry secretions but also run risk of making mucus plugs (paralize mucocilliary clearance) |
| What is glycopyrrolate used for in the lungs? | charged (no neural receptor access), reduces secretions |
| What is ipratropium useful for in the lungs? | Charged; when inhaled, has little effect on mucociliary clearance-->used in inhalers for chronic obstructive disease |
| Why are muscarinic of limited use in GI effects? | atropine modestly inhibits GI motility and acid secretions since there are other non-cholinergic regulators; use limited due to adverse effects of drug |
| What is donnatal? What is it used for? | combination of belladona alkaloids and combination with sedatives; used to a wide variety of conditions known or supposed to involve IBS; dose difficult to titrate wihtout causing dry mouth or loss of urinattion |
| What is Pirenzepine used for? | Antimuscarenic selective for M3 (somewhat)-->used in other countries for peptic disorders |
| What is atropine and glycopyrrolate used for (in GI symptoms)? | Synthetic qarternary amine substitute; effective in reducing excessive salivation; glycopyrrolate preffered to reduce secretions in prep for surgery |
| What is atropine and glypyrrolate used for in GI? | Limits GI effects of neostigmine when used to reverse neuromuscular blockage |
| What are antihistamines used for in context of GI? | Effects on secretions and motion disturbances are predominantly anticholinergic |
| What is scopolamine used of in GI? | patches or antihistamines used for motion disorders |
| What do antimuscarinics do the bladder? | urinary retention (block signal to the detrusor muscle); good for incontinence |
| What are contraindications of antimuscarinics when used to treat bladder symptoms? | Don't use if urinary tract or GI obstructured; will NOT help stress-induced incontinence; avoid in patients using antifungal agents (metabolized by CYP3A4) |
| What is tolterodine prescribed for? | Potent muscarinic antagonist that shows selectivity for urinary bladder |
| What receptor do you want to target in incontinence? | M3 receptor |
| Why is trospium chloride helpful in treating urinary symptoms? | charged molecule with limited CNS penetrance; actions throughout GI tract |
| In cases where antimuscarinics contraindicated for bladder symptoms, what other drug can be used? | Botox |
| What is a limitation of using atropine in treating anticholinesterase activity? | blocks all muscarinic actions, but leaves nicotinic receptors alone |
| What are muscarinic antagonists used for in surgery? | Reduce systemic effects of carbamate neuromuscular blockers (neostigmine) |
| What drug can you give to reduce CNS toxicity of physostigmine or Alzheimer's drugs? | muscarinic antagonists (atropine) |
| How should you treat toxicity from antimuscarinics? | Confirm with reversible AChE inhibitor (physostigmine); physostigmine can be used to reverse CNS effects (delirium, coma); benzos for sedation + convulsions; neostigmine for peripheral effects (and cardiovascular collapse); support respiration and temp |
Created by:
karkis77
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