A7-8: Cholinomimetics, Muscarinic Receptor Blocking Drugs Flashcards
What are the two major categories of cholinomimetic drugs + subcategories?
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Direct:
- Choline esters (acetylcholine, metacholine, carbachol, betanechol)
- Alkaloids (muscarin, pilocarpine, nicotine)
- Synthetic Compounds (cevimeline, varenicline)
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Indirect:
- Acetylcholinesterase inhibitors (reversible and irreverisible)
What are the typical important systemic effects of acetylcholine as a result of muscarinic stimulation?
[For the cholinomimetic drugs, remember these either as side effects or as a reason to give the drug in order to cause one of these effects]
- Decreased heart rate/ cardiac output: mimics vagal stimulation. Can cause bradycardia or AV block.
- Decreased blood pressure: both from lower cardiac output + M3 receptors -> NO synthesis -> vasodilation
- Bronchoconstriction: similar to asthma
- Increased secretions: sweating, saliva, urination, GI secretions, stomach acid, diarrhea, nausea/emesis
- Ocular changes: iris sphincter constriction (miosis) + ciliary muscle contraction for near vision
What are some important effects of different muscarinic receptor activation?
(i.e. what does M1R do?)
M2 and M3 are the most important receptors
- M1 Gq increases gastric acid secretion. Agonists are bad for peptic ulcer disease. M1R also important in CNS.
- M2 Gi inhibits cardiac activity. Muscarinic agonists can cause AV block.
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M3 Gq works to contract smooth muscle in the glands, eyes, and bronchioles.
- Muscarinic agonists can trigger asthma-like symptoms from bronchoconstriction.
- M3 receptors on blood vessels make NO -> vasodilation. However there is no parasympathetic innervation of blood vessels, so indirect-acting agonists don’t vasodilate this way.
What are the direct-acting choline ester drugs?
- Acetylcholine: not given systemically because it is immediately metabolized. Can be given in ophthalmology to cause pupilary constriction. Of course targets both nicotinic and muscarinic receptors.
- Methacholine: only affects muscarinic receptors. Metabolized quickly, similar to acetylcholine. Maybe used in bronchial challenge to test for asthma.
- Bethanechol: only affects muscarinic receptors. Longer-lasting. Used in some countries to promote intestinal movement in non-obstructive paralytic ileus or urinary retention.
- Carbachol: agonist of both muscarinic and nicotinic receptors, longer lasting than Ach. Also used as an eyedrop for glaucoma, especially in patients who are resistant to pilocarpine.
What are the alkaloid direct-acting cholinomimetic drugs?
Nitrogen-containing plant-derived particles which activate muscarinic or nicotinic receptors
- Muscarine: poison from Amanita muscaria mushroom. Obviously muscarinic receptor agonist.
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Pilocarpine: muscarinic receptor agonist.
- Used in topical eye drops for glaucoma. Opens up Schlemm canal -> lower intraocular pressure
- Used systemically for xerostomia in Sjogren syndrome
- Arekolin: muscarinic receptor agonist in betel nut. Causes salivation + some euphoria. Usually mixed with calcium carbonate (chalk) to bind saliva
- Nicotine: obviously nicotinic receptor agonist. Lipid soluble, can penetrate through skin. In high doses it eventually becomes a nicotinic receptor antagonist, causing weakness and paralysis. High doses in CNS can cause seizures.
What are two synthetic direct-acting cholinomimetic drugs?
[Probably the least important direct-acting cholinomimetics to know]
- Cevimeline: muscarinic agonist for autoimmune xerostomia
- Varenicline (brand name Chantix): partial nicotinic agonist (neuronal subtype), particuarly in the parts of the brain related to reward mechanisms. Theoretically should help smokers quit, but it’s not been very successful. Might increase the risk for suicide.
What are the reversible indirect-acting cholinomimetic drugs?
[has a very long answer card, but I think it’s better to link them all together to keep the details in order]
All are acetylcholinesterase inhibitors.
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Competitive: Edrophonium: binds AchE in place of Ach. Acts for ~15 minutes.
- Use to diagnose myasthenia gravis (myasthenia crisis), or to test if they are being overdosed with neostigmine (cholinergic crisis).
- Formerly used as anti-arrhythmic (treated PSVT)
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Non-Competitive: Carbamates: bind AchE as substrate, but cause carbamoyl group to remain bound until continuosly hydrolyzed. Lasts ~2 hours
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Tertiary Carbamates: uncharged (lipid soluble) -> can cross BBB
- Rivastigmine: used in Alzheimers bc cholinergic neurons are dying, may improve memory
- Physostigmine: for glaucoma or anticholinergic (i.e. atropine) overdose
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Quaternary Carbamates: charged (water soluble) -> don’t cross BBB
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Neostigmine: parenteral administration
- Mainly used for myasthenia gravis
- Also for smooth muscle problems like paralytic ileus, but not to be used as laxative with an obstruction (-> bowel rupture). Can displace anesthesia meds (curare) + combine with atropine so you don’t overstimulate muscarinic receptors.
- Others: Pyridostigmine, Distigmin, Ambenonium
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Neostigmine: parenteral administration
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Tertiary Carbamates: uncharged (lipid soluble) -> can cross BBB
What are the irreversible indirect-acting cholinomimetic drugs?
Irreversible AchE inhibitors are mostly organophosphates (the phosphorylation is irreversible). High Ach levels -> desensitization, skeletal muscle relaxation, respiratory depression, loss of vasomotor tone.
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Insecticides: at least for older pesticides. Mostly talking about organophosphates, but some are carbamates.
- In insects, the reaction “ages” and becomes irreversible quickly, but it takes longer to become irreversible in humans. So, with accidental exposure, there is some chance at recovery
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Nerve gas / chemical weapons (Sarin, VX, Soman, Tabun)
- In humans, the reaction “ages” within about 2 minutes and so it rapidly becomes irreversible without treatment.
- Echothiophate: weak, stable organophosphate sometimes used as eyedrops for glaucoma (sounds like there are some much better options though)
What is meant by “aging” when it comes to organophosphates?
What can be used to treat people exposed to organophosphates?
- There are 2 phases of phosphorylation, and the second phase is stable and irreversible. When the second phase is complete, the reaction has “aged”
- If it has not yet aged, administration of oximes such as pralidoxime (2-PAM) can reactivate the enzyme by binding the phosphate group, but it cannot cross the BBB and won’t help the CNS. Atropine should be given to reverse muscarinic effects, and diazepam can be used if there are seizures.
- Prophylactically, some soldiers at risk of chemical attack have been given Pyridostigmine to inactivate a fraction of the person’s AchE, making it inaccessible to the organophosphate acutely during exposure. This could save some fraction of AchE to be available again once the organophosphate has been removed from the circulation.
What are the muscarinic receptor blockers?
What are there 2 categories?
Muscarinic Antagonists aka Parasympatholytic drugs. Usually they are more specific for certain receptors than muscarinic agonists. The model muscarinic antagonist is Atropine. Divided into Tropeins and non-Tropeins
- Tropeins: including the natural plant alkyloid atropine + similar drugs that usually contain some aspect of the word atropine (homatropine, benztropine…)
- Non-Tropeins: synthetic drugs, usually used to treat overactive bladders, or maybe to decrease secretions
What are the peripheral effects of atropine?
(generally these will be side effects for all the other muscarinic antagonists too)
- Eye: pupil dilation (midriasis) + loss off accomodation (double vision; blurry).
- Mouth: xerostomia (dry mouth), no salivation
- Lungs: bronchodilation, decreased bronchial secretions
- Heart: tachycardia, increased CO (although at low doses there is a slight decrease in heart rate, Lippincott p. 67 to see why)
- Stomach: inhibits gastric acid secretion (but PPIs are much better drugs)
- GI and urinary muscles: relaxes smooth muscle + constricts sphincters -> constipation, dysuria
- Skin: perspiration inhibited -> impaired thermoregulation (Adults will have compensate with vasodilation -> red dry skin. Children won’t compensate -> “atropine fever”)
Peripheral effects can be seen after administration of 0.5mg atropine.
What are the CNS effects of atropine?
- At low doses it prevents nausea and so it could be used for sea sickness (but more typically use scopolamine)
- As dose increases, see higher alertness first, then extrapyramidal dyskinesia (shaking hands/tremors), then “raging” and hallucinations. May have convulsions.
- Finally at very high doses, atropine starts to have depressive actions -> coma, possibly death.
- [May happen in people who have consumed the relatively common nightshade plant Jimson Weed / Datura stromonium, either by accident or intentionally]
What are the therapeutic uses of atropine?
- Ophthalmic: Topical atropine for iris cyclitis. However, atropine lasts too long to be practical (effect can be 5-6 days)
- Bradycardia and first degree AV block: possibly used to speed up heart rate. Up until recently it was given during resuscitation from cardiac arrest.
- Antispasmodic: relaxes GI tract
- Antisecretory: can prevent secretions in surgery (prevent aspiration during anesthesia), or in some conditions with excessive drooling
- Antidote for cholinergic agonist poisoning: e.g. organophosphate poisoning. Atropine is especially important because it can cross the blood brain barrier.
Other than atropine, what are the tropein antimuscarinic agents?
[Just names, will have other detailed cards]
- Scopolamine
- Homatropine
- Benztropine
- Butyl-scopolamine
- Ipatropium
- Tiotropium
What is the indication for use of Scopolamine?
- Preferred for treating sea sickness / motion sickness over atropine because it similarly prevents nausea at low doses, but the CNS effects are the opposite (i.e. causes sedation).
- Often given with transdermal patch that lasts for up to 3 days.
- Also has been used to block short-term memory, and sometimes even used as “truth serum”
What can Homatropine be used for?
Ophthalmology uses similar to atropine, e.g. synechia (adhesion) formation in uveitis and iritis
It’s shorter acting than atropine, but still maybe for a day
[probably not too important to know this one]
What are the indications for Ipratropium and Tiotropium?
Used as bronchodilators in COPD. Tiotropium can be administered once daily, whereas ipatropium has to be given 4 times a day.
Ipratropium also used for asthma for bronchospasm (often in conjunction with salbutamol ß2 agonist)
Inhaled locally, but poorly absorbed due to positive charges (so the effects stay in the lungs)
Tiotropium antagonizes more selectively on M3 receptors
What are some of the Non-Tropein antimuscarinics used for treating overactive bladder?
Oxybutynin (cheaper, available as transdermal patch -> less side effects than oral formulas)
Tolterodine, Fesoterodine
M3-selective antagonists: Solifenacine, Olarifenacine
(Overall the effecacies are similar)
What non-tropein antimuscarinics are used to treat Parkinson’s disease?
Procyclidine
Biperidin
These drugs are centrally acting / can cross the blood brain barrier. They are similar but some patients respond better to one than the other.
Antimuscarinics may improve tremor and rigidity of parkinsonism but have little effect on bradykinesia. Blockage of cholinergic transmission corrects the imbalance between the dopamine/acetylcholine ratio
What is/are the indication(s) for Pirenzepine?
Inhibit gastric acid secretion (i.e. peptic ulcer)
Can also be to reduce GI motility / muscle spasm.
This is an M1-selective antagonist
[Not as likely to be used as PPIs like omeprazole, but has less side effects than the other antimuscarinics due to M1 selectivity]
