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Muscarinic Receptors and Directly Acting Cholinomimetics When your eyes hurt, you cant pee, and your GI tract turns off.

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Presentation on theme: "Muscarinic Receptors and Directly Acting Cholinomimetics When your eyes hurt, you cant pee, and your GI tract turns off."— Presentation transcript:

1 Muscarinic Receptors and Directly Acting Cholinomimetics When your eyes hurt, you cant pee, and your GI tract turns off

2 Drug List Acetylcholine Acetylcholine –Has lots of muscarinic activity but also nicotinic activity (of course, as it is the physiologic nicotinic and muscarinic agonist). Very suceptible to acetylcholinesterase. Methacoline Methacoline –Choline ester with effects similar to acetylcholine and no nicotinic activity. Not used due to CV effects. Somewhat resistant to acetylcholinesterase. Carbachol Carbachol –Choline eseter with some nicotinic activity, used for glaucoma. Bethanecol Bethanecol –Choline ester with Muscarinic effects with less CV effects and no nicotinic activity, totally resistant to AChEsterase, used for GI and bladder problems and antimuscarinic poisoning Pilocarpine Pilocarpine –Alkaloid used to reduce intraocular pressure. Has some nicotinic activity Muscarine Muscarine –Pure muscarinic agonist, clinically useless. More on these drugs later… More on these drugs later…

3 By the end of this lecture you should be able to… Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. List the therapeutic uses and adverse side effects of cholinomimetics List the therapeutic uses and adverse side effects of cholinomimetics

4 M-1 Receptor Location Location –Nerves G Protein G Protein –GPCR G q/11- linked Second Messenger Second Messenger –PLC, IP3, DAG –Blocks voltage gated M-type K+ channels. Primary ANS Effects Primary ANS Effects –Critical for muscarinic effect in the sympathetic ganglion and the parasympathetic myenteric plexus innervation. CNS Effects CNS Effects –Highly expressed in the CNS and may be involved in epilepsy.

5 M-2 Receptor Location Location –Heart, nerves, smooth muscle G Protein G Protein –GPCR G i/o- linked Second Messenger Second Messenger –Decreases cAMP and activates K+ channels Primary ANS Effects Primary ANS Effects –Heart- decreases pacemaker current velocity and decreases heart rate by activating K+ channels (GIRKs) (aka is a negative chronotrope) –Smooth muscle- works with M3 to contract –Autoreceptors- presynaptic receptors inhibit the release of Ach Dysfunction of M2 autoreceptors may cause airway problems. –Heteroreceptors-a mixture of M2 and non-M2 receptors, these receptors lie on sympathetic nerve terminals and inhibit NE release. CNS Effects CNS Effects –Is the prominent receptor in the spinal chord and thusly is critical in muscarinic agonist-induced analgesia, whatever that means. –Serves as an autoreceptor in the brain, which might make it important for learning and memory.

6 M-3 Receptor Location Location –Glands, smooth muschle, endothelium G Protein G Protein –GPCR G q/11- linked Second Messenger Second Messenger –PLC, IP3, DAG Primary ANS Effects Primary ANS Effects –Sweat glands- secretion through the sympathetic pathway Designed to make your life difficult and be an exception Designed to make your life difficult and be an exception –Smooth muscle- most important receptor for contraction (GI tract, airway, bladder, uterus, and eye smooth muscle) –Salivary Glands- M3 receptors play a major role in mACHRs-mediated stimulation of salivary secretion CNS Effects CNS Effects –Poorly understood. M3 knockout mice are lean due to reduced food intake. So maybe hypothalamic M3s are important for eating behavior.

7 M-4 Receptor Location Location –CNS –Elsewhere (see effects below) G Protein G Protein –GPCR G i/o- linked Second Messenger Second Messenger –Decreased cAMP Primary Effects Primary Effects –Similar to M2 in the CNS as autoreceptors –Autoreceptor in atrial and bladder parasympathetic nerve terminals (works with M2) –May also play a role as heteroreceptors (NE release blockers) in sympathetic nerve terminals.

8 M-5 Receptor Location Location –CNS G Protein G Protein –GPCR G q/11- linked Second Messenger Second Messenger –PLC, IP3, DAG Primary Effects Primary Effects –May be involved in reward circuitry of the brain –Mediate ACh-induced dilation of cerebral arteries/arterioles –Effects outside CNS are unknown

9 By the end of this lecture you should be able to… Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. List the therapeutic uses and adverse side effects of cholinomimetics List the therapeutic uses and adverse side effects of cholinomimetics

10 Muscarinic Agonists: Choline Esters Chemistry Chemistry –Are structural modifications of Acetylcholine. 1) addition of a carbon-methacholine 1) addition of a carbon-methacholine 2) change a C to an N -Carbamoylcholine/carbachol 2) change a C to an N -Carbamoylcholine/carbachol 3) or do both- Bethanechol 3) or do both- Bethanechol –Are less susciptible than ACh to acetylcholinesterase, thus have a longer duration of action. –Work by stimulating ACh receptors (of course) Absorption, Distribution, and Metabolism Absorption, Distribution, and Metabolism –Hydrophilic –Poorly absorbed in GI tract –Do not cross the blood brain barrier readily –Metabolized by acetylcholinesterase

11 Muscarinic Agonists: Natural Alkaloids Chemistry Chemistry –Muscarine- Quaternary ammonium compound –Pilocarpin- Tertiary amine –Produce effects by binding to and stimulating ACh receptors Absorption, Distribution, and Metabolism Absorption, Distribution, and Metabolism –Tertiary amines are well absorbed, while quaternary amines are less well absorbed in the GI tract –Both cross the blood brain barrier well –Eliminated by kidneys Excretion can be accelarated by acidification of urine Excretion can be accelarated by acidification of urine (Testable and emphasized Concept)

12 Strange Muscarinic Effects What effect does stimulation of M3 receptors on arteries and veins have under normal conditions and at low concentrations of agonist? What effect does stimulation of M3 receptors on arteries and veins have under normal conditions and at low concentrations of agonist? –Vasodilation What effect does stimulation of M3 receptors on vascular smooth muscle cells have at high concentrations of agonist, primarily during injury or disease? What effect does stimulation of M3 receptors on vascular smooth muscle cells have at high concentrations of agonist, primarily during injury or disease? –Vasoconstriction What effect do the various Muscarinic receptors have on airways? What effect do the various Muscarinic receptors have on airways? –M1- bronchoconstriction and secretion –M2- bronchoconstriction by antagonizing Beta adrenergics –M3- increases secretion of bronchial glands What muscarinic receptors are most prominent in the myenteric plexus? What muscarinic receptors are most prominent in the myenteric plexus? –M1 What 3 effects do muscarinics have on the eyes? What 3 effects do muscarinics have on the eyes? –Contraction of the iris sphincter causing miosis –Contraction of the ciliary muscle for accomodation –Draining of the anterior chamber Which muscarinic drugs cause cortical arousal? Which muscarinic drugs cause cortical arousal? –Muscarine and pilocarpine Which muscarinic receptor is must important in: A) epileptogenesis? B) spinal chord? C) food intake (hypothalamus) Which muscarinic receptor is must important in: A) epileptogenesis? B) spinal chord? C) food intake (hypothalamus) –A) M1, B) M2 C)M3

13 By the end of this lecture you should be able to… Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe in detail the physiologic effects of muscarinic receptor activation in both the ANS and the CNS. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. Describe the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics. List the therapeutic uses and adverse side effects of cholinomimetics List the therapeutic uses and adverse side effects of cholinomimetics

14 Methacholine Pharmacologic action Pharmacologic action –Similar to Ach given IV; no nicotinic effects –Longer duration with some resistance to acetylcholinesterase Clinical use Clinical use –No longer used due to side effects, particularly cardiovascular –Historically used to diagnose atropine poisoning and to treat peripheral vascular disease

15 Carbachol (Carbamoylcholine) Pharmacologic Action Pharmacologic Action –Some nicotinic effect –More pronounced muscarinic effect in the GI tract, urinary bladder, and iris. –Less effective on cardiovascular system –Resistant to acetylcholinesterase Clinical Use Clinical Use –Used only as opthalmic solution, primarily because of nicotinic effects of systemic administration –Used for wide angle glaucoma and to produce miosis during eye surgery –Side effects include pupillary constriction, accomodative spasm, headache, and conjunctival hyperemia

16 Bethanechol Pharmacologic Action Pharmacologic Action –Similar muscarinic effect to carbachol, but without the nicotinic effect –Completely resistant to acetylcholinesterase Clinical Use Clinical Use –Primarily used as a treatment for urinary retention (postoperative or neurogenic) –Also used for postoperative abdominal distension and (rarely) for antimuscarinic intoxication –Given orally or subcutaneously –Contraindicated in peptic ulcer, asthma, coronary insufficiency, bradycardia, hypotension –While cardiovascular side effects are not common, overdose can cause cardiac arrest. –other side effects are consistent with muscarinic activation Drug interactions Drug interactions –Quinidine and procainamide antagonize it –Serotonin reducing drugs (e.g. reserpine) with Bethanechol cause profound hypothermia

17 Muscarine Pharmacologic action Pharmacologic action –No nicotinic activity. The reason muscarinic receptors are called muscarinic –Absorbed from GI tract, crosses BBB. –Resistant to acetylcholinesterase, long acting Clinical Relevance Clinical Relevance –Not used –Is the alkaloid responsible for Inocybe type mushroom poisoning Treatment for muscarine poisoning is Atropine Treatment for muscarine poisoning is Atropine

18 Pilocarpine Pharmacologic Action Pharmacologic Action –Mostly muscarinic but some nicotinic activity –Few cardiovascular effects Clinical Use Clinical Use –Only as opthalmic solution or Ocusert, to reduce intraocular pressure Side Effects Side Effects –Ciliary spasm, conjunctival vascular congestion, headache, and reduced visual acuity

19 Muscarinic Blockers When you cant breathe, your stomach is bleeding, you wet the bed, and you have tremors and motion sickness 9/26/07

20 Drug List Atropine, Scopolamine Atropine, Scopolamine –Belladonna alkaloids, oldest antimuscarinics Tropicamide Tropicamide –Used opthalmically to produce mydriasis and cycloplegia Dicyclomine Dicyclomine –Historically used to decrease spasm in GI tract, replacedby Oxybutynin and others Glycopyrrolate Glycopyrrolate –Decreases GI motility. Used parenterally in surgery. Propantheline Propantheline –Ganglionic and NMJ blocker, widely used for ulcers Oxybutynin, Tolterodine, Solifenacin Oxybutynin, Tolterodine, Solifenacin –Used Urologically (for bladder spasm etc.), Solifenacin is a selective M3 blocker and is the best and newest treatment Ipratropium, Triatropium Ipratropium, Triatropium –Quaternary amines used in aerisolized form to treat COPD. Triatropium preferentially blocks M1 and M3 and has a longer duration, making it slightly better

21 By the end of this session, you should be able to: Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacological properties of muscarinic blockers that are used clinically Describe the pharmacological properties of muscarinic blockers that are used clinically List the therapeutic uses for and adverse side effects of muscarinic blockers List the therapeutic uses for and adverse side effects of muscarinic blockers

22 Atropine and Scopolamine: Chemo-pharmacology Chemistry Chemistry –Tertiary amines, levos are active Pharmacologic action Pharmacologic action –Competitive antagonists of muscarinic receptors (bind to receptors but elicit no response) –Do not effect nicotinic receptors

23 Atropine and Scopolamine: Effects CNS CNS –Atropine at therapeutic doses produces few effects –Scopolamine at therapeutic dose and atropine at high dose causes: drowsiness, amnesia, fatigue, REM disturbances –Higher and higher doses make confusion, hallucination, convulsion, paralysis, coma, respiratory failure, and ciruculatory collapse Eye Eye –Mydriasis (pupil dilation) –Cycloplegia, photophobia, blurred vision –Reduced aqueous outflow Cardiovascular Cardiovascular –Transient decrease in HR –High dose produces tachycardia (M2 at SA node), no change in BP –No vascular effect at therapeutic level, flushing at toxic dose Respiratory system Respiratory system –Bronchodilation and reduced secretions (M3) –Blocking M2 autoreceptors increases Ach release –Better bronchodilation in patients with COPD Digestive system Digestive system –Inhibits salivation (strongly), causes dry mouth at very low dose –Reduces gastric, pancreatic,intestinal and biliary secretions at higher doses Urinary Urinary –Reduced tone and amplitude of contractions Sweat Glands Sweat Glands –Inhibits sweating at low doses, increases body temp at higher doses (especially in children)

24 Atropine dose dependency 0.5 mg 0.5 mg –Slight cardiac slowing, some dry mouth, inhibition of sweating 1 mg 1 mg –Dry mouth, thirst, accelerated heart rate sometimes preceded by slowing, mild pupillary dilation 2 mg 2 mg –Rapid heart rate, palpitation, marked dryness of mouth, dilated pupils, blurring of near vision 5 mg 5 mg –All above and difficulty speaking and swallowing, reslessness and fatigue; headache; dry hot skin; difficulty in micturition; reduced intestinal peristalsis 10 mg or more 10 mg or more –Ave symptoms more marked, pulse rapid and weak, iris practically obliterated, vision very blurred, skin flushed, hot dry and scarlet skin; ataxia, restlessness, excitement, hallucinations, delerium, coma

25 By the end of this session, you should be able to: Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacological properties of muscarinic blockers that are used clinically Describe the pharmacological properties of muscarinic blockers that are used clinically List the therapeutic uses for and adverse side effects of muscarinic blockers List the therapeutic uses for and adverse side effects of muscarinic blockers

26 Muscarinic antagonist chemo-pharmacology Tertiary Amines Tertiary Amines –Well absorbed through the GI tract –Readily cross the blood brain barrier (BBB) Quaternary Amines Quaternary Amines –Poorly absorbed (10-30%) –Do not cross the BBB, so no CNS effects Excretion Excretion –Both are mostly excreted in the urine –Some are metabolized by liver P450 (not specified which)

27 By the end of this session, you should be able to: Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacologic activities of the prototype muscarinic blocker, atropine Describe the pharmacological properties of muscarinic blockers that are used clinically Describe the pharmacological properties of muscarinic blockers that are used clinically List the therapeutic uses for and adverse side effects of muscarinic blockers List the therapeutic uses for and adverse side effects of muscarinic blockers

28 Clinical Uses: Opthalmology Opthalmologic Use Opthalmologic Use –Muscarinic blockers are useful to produce cycloplegia to study disorders of accomodation –Produce mydriasis which enables easy examination of retina and optic disc Specific Drug used Specific Drug used –Tropicamide is used because it is the only one listed with a short enough duration of effect to be practical

29 Respiratory Uses Limitations Limitations –Usefulness is somewhat limited because of systemic side effects and the reduced production of respiratory mucous Ipratropium Ipratropium –Non selective quaternary amine used as an aerosol for COPD –Few systemic effects due to poor absorption –Does not impede mucociliary transport Tiotropium Tiotropium –Quaternary amine preferentially inhibits M1 and M3 over M2 –Few systemic effects due to poor absorption –Does not impede mucociliary transport –Longer duration of action than ipratropium –Also used for COPD

30 Urologic Uses Clinicology Clinicology –Used in uninhibited bladder syndrome, bladder spasm, enuresis, and urge incontinence –Increase functional bladder capacity, reduce pressure and frequency of contractions –Side effects include dry mouth and dry eye Oxybutynin Oxybutynin –Tertiary amine, non-selective antagonist Tolterodine Tolterodine –Tertiary amine with slight preference for M2 Solifenacin Solifenacin –Tertiary amine with preference for M3, newest and most useful

31 Digestive Tract Uses: adjunct ony Muscarinic antagonists are used as an adjunct therapy for Muscarinic antagonists are used as an adjunct therapy for –Peptic Ulcer- effective at reucing basal and nocturnal acid secretion (not postprandial) –Duodenal ulcer- used when initial H2 antagonists and antacids are inadequate –Irritable bowel syndrome –Acute pancreatitis- if pancreatic ducts are obstructed Pirenzepine Pirenzepine –M1 preferring (and M4) antagonist used in Europe

32 CNS Uses Used in two CNS conditions: Used in two CNS conditions: –Parkinsonism Tertiary amines are used as an adjunct to L-dopa or in patients for whom L-dopa is contraindicated Tertiary amines are used as an adjunct to L-dopa or in patients for whom L-dopa is contraindicated –Motion Sickness May block cholinergic sites investibular nuclei and the reticular formation May block cholinergic sites investibular nuclei and the reticular formation Scopalamine is used; available in dermal patch to be placed behind the ear Scopalamine is used; available in dermal patch to be placed behind the ear

33 Cardiovascular Use: limited Therapeutic Index Therapeutic Index –Very low Myocardial Infarction Myocardial Infarction –Atropine used in patients with severe bradycardia and hypotension to increase heart rate, BP, and CO Other Use Other Use –Bradycardia caused by excessive carotid sinus reflex

34 Anesthesiology uses As Premedication As Premedication –Historically used with diethyl ether to reduce salivary and respiratory secretions –Currently used to block bradycardia and hypotension from reduced vagal activity during surgery With AChE With AChE –Also used to prevent excess muscarinic effects when acetylcholinesterase agents are used to treat competitive neuromuscular blockade

35 As Antidote Antidote for 2 poisonings Antidote for 2 poisonings –Anticholinesterase poisoning –Amanita muscaria mushroom poisoning

36 Random clinical uses of Random drugs (from the last page of the lecture) Dicyclomine Dicyclomine –Decrease spasm in the gi tract –Replaced by oxybutynin Glycopyrrolate Glycopyrrolate –oral use decreases GI motility –Parenterally used during surgery Propantheline Propantheline –Widely used for ulcer –Ganglionic blocker –NMJ blockade

37 Anticholinesterase poisoning Natural causes Natural causes –Ingestion of plants in Solanacae family: deadly nightshade, jimson weed, stinkweed (with names like that who wouldnt eat them) Most sensitive patients Most sensitive patients –Children Presentation Presentation –Peripheral effects seen at lower doses, CNS effects at high doses (emphasized in class) Diagnosis Diagnosis –Based on symptoms; can use methacholine injection Treatment Treatment –Gastric lavae, respiratory assistance, physostigmine, benzodiazepines (if delirious or convulsive), and monitor body temp

38 The End What is a gastric lavage? What is a gastric lavage? – –According to Wikipedia: – –Gastric lavage, also commonly called Stomach pump or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or overdosed on a drug. They may also be used prior to surgery, to clear the contents of the digestive tract before it is opened.lavagestomachpoisonoverdoseddrugsurgerydigestive tract


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