Presentation on theme: "Muscarinic Receptors and Directly Acting Cholinomimetics"— Presentation transcript:
1 Muscarinic Receptors and Directly Acting Cholinomimetics When your eyes hurt, you can’t pee, and your GI tract turns off
2 Drug List Acetylcholine Methacoline Carbachol Bethanecol Pilocarpine Has lots of muscarinic activity but also nicotinic activity (of course, as it is the physiologic nicotinic and muscarinic agonist). Very suceptible to acetylcholinesterase.MethacolineCholine ester with effects similar to acetylcholine and no nicotinic activity. Not used due to CV effects. Somewhat resistant to acetylcholinesterase.CarbacholCholine eseter with some nicotinic activity, used for glaucoma.BethanecolCholine ester with Muscarinic effects with less CV effects and no nicotinic activity, totally resistant to AChEsterase, used for GI and bladder problems and antimuscarinic poisoningPilocarpineAlkaloid used to reduce intraocular pressure. Has some nicotinic activityMuscarinePure muscarinic agonist, clinically useless.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 the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics.List the therapeutic uses and adverse side effects of cholinomimetics
4 M-1 Receptor Location G Protein Second Messenger Primary ANS Effects NervesG ProteinGPCR Gq/11-linkedSecond MessengerPLC, IP3, DAGBlocks voltage gated M-type K+ channels.Primary ANS EffectsCritical for muscarinic effect in the sympathetic ganglion and the parasympathetic myenteric plexus innervation.CNS EffectsHighly expressed in the CNS and may be involved in epilepsy.
5 M-2 Receptor Location G Protein Second Messenger Primary ANS Effects Heart, nerves, smooth muscleG ProteinGPCR Gi/o-linkedSecond MessengerDecreases cAMP and activates K+ channelsPrimary ANS EffectsHeart- decreases pacemaker current velocity and decreases heart rate by activating K+ channels (GIRKs) (aka is a negative chronotrope)Smooth muscle- works with M3 to contractAutoreceptors- 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 EffectsIs 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 G Protein Second Messenger Primary ANS Effects Glands, smooth muschle, endotheliumG ProteinGPCR Gq/11-linkedSecond MessengerPLC, IP3, DAGPrimary ANS EffectsSweat glands- secretion through the sympathetic pathwayDesigned to make your life difficult and be an exceptionSmooth 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 EffectsPoorly 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 G Protein Second Messenger Primary Effects CNS Elsewhere (see effects below)G ProteinGPCR Gi/o-linkedSecond MessengerDecreased cAMPPrimary EffectsSimilar to M2 in the CNS as autoreceptorsAutoreceptor 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 G Protein Second Messenger Primary Effects CNS GPCR Gq/11-linkedSecond MessengerPLC, IP3, DAGPrimary EffectsMay be involved in reward circuitry of the brainMediate ACh-induced dilation of cerebral arteries/arteriolesEffects 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 the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics.List the therapeutic uses and adverse side effects of cholinomimetics
10 Muscarinic Agonists: Choline Esters ChemistryAre structural modifications of Acetylcholine.1) addition of a carbon-methacholine2) change a C to an N -Carbamoylcholine/carbachol3) or do both- BethanecholAre less susciptible than ACh to acetylcholinesterase, thus have a longer duration of action.Work by stimulating ACh receptors (of course)Absorption, Distribution, and MetabolismHydrophilicPoorly absorbed in GI tractDo not cross the blood brain barrier readilyMetabolized by acetylcholinesterase
11 Muscarinic Agonists: Natural Alkaloids ChemistryMuscarine- Quaternary ammonium compoundPilocarpin- Tertiary amineProduce effects by binding to and stimulating ACh receptorsAbsorption, Distribution, and MetabolismTertiary amines are well absorbed, while quaternary amines are less well absorbed in the GI tractBoth cross the blood brain barrier wellEliminated by kidneysExcretion 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?VasodilationWhat effect does stimulation of M3 receptors on vascular smooth muscle cells have at high concentrations of agonist, primarily during injury or disease?VasoconstrictionWhat effect do the various Muscarinic receptors have on airways?M1- bronchoconstriction and secretionM2- bronchoconstriction by antagonizing Beta adrenergicsM3- increases secretion of bronchial glandsWhat muscarinic receptors are most prominent in the myenteric plexus?M1What 3 effects do muscarinics have on the eyes?Contraction of the iris sphincter causing miosisContraction of the ciliary muscle for accomodationDraining of the anterior chamberWhich muscarinic drugs cause cortical arousal?Muscarine and pilocarpineWhich 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 the pharmacologic properties of the two classes of directly acting muscarinic cholinomimetics.List the therapeutic uses and adverse side effects of cholinomimetics
14 Methacholine Pharmacologic action Clinical use Similar to Ach given IV; no nicotinic effectsLonger duration with some resistance to acetylcholinesteraseClinical useNo longer used due to side effects, particularly cardiovascularHistorically used to diagnose atropine poisoning and to treat peripheral vascular disease
15 Carbachol (Carbamoylcholine) Pharmacologic ActionSome nicotinic effectMore pronounced muscarinic effect in the GI tract, urinary bladder, and iris.Less effective on cardiovascular systemResistant to acetylcholinesteraseClinical UseUsed only as opthalmic solution, primarily because of nicotinic effects of systemic administrationUsed for wide angle glaucoma and to produce miosis during eye surgerySide effects include pupillary constriction, accomodative spasm, headache, and conjunctival hyperemia
16 Bethanechol Pharmacologic Action Clinical Use Drug interactions Similar muscarinic effect to carbachol, but without the nicotinic effectCompletely resistant to acetylcholinesteraseClinical UsePrimarily used as a treatment for urinary retention (postoperative or neurogenic)Also used for postoperative abdominal distension and (rarely) for antimuscarinic intoxicationGiven orally or subcutaneouslyContraindicated in peptic ulcer, asthma, coronary insufficiency, bradycardia, hypotensionWhile cardiovascular side effects are not common, overdose can cause cardiac arrest.other side effects are consistent with muscarinic activationDrug interactionsQuinidine and procainamide antagonize itSerotonin reducing drugs (e.g. reserpine) with Bethanechol cause profound hypothermia
17 Muscarine Pharmacologic action Clinical Relevance No nicotinic activity. The reason muscarinic receptors are called muscarinicAbsorbed from GI tract, crosses BBB.Resistant to acetylcholinesterase, long actingClinical RelevanceNot usedIs the alkaloid responsible for Inocybe type mushroom poisoningTreatment for muscarine poisoning is Atropine
18 Pilocarpine Pharmacologic Action Clinical Use Side Effects Mostly muscarinic but some nicotinic activityFew cardiovascular effectsClinical UseOnly as opthalmic solution or Ocusert, to reduce intraocular pressureSide EffectsCiliary spasm, conjunctival vascular congestion, headache, and reduced visual acuity
19 Muscarinic BlockersWhen you can’t breathe, your stomach is bleeding, you wet the bed, and you have tremors and motion sickness9/26/07
20 Drug List Atropine, Scopolamine Tropicamide Dicyclomine Glycopyrrolate Belladonna alkaloids, oldest antimuscarinicsTropicamideUsed opthalmically to produce mydriasis and cycloplegiaDicyclomineHistorically used to decrease spasm in GI tract, replacedby Oxybutynin and othersGlycopyrrolateDecreases GI motility. Used parenterally in surgery.PropanthelineGanglionic and NMJ blocker, widely used for ulcersOxybutynin, Tolterodine, SolifenacinUsed Urologically (for bladder spasm etc.), Solifenacin is a selective M3 blocker and is the best and newest treatmentIpratropium, TriatropiumQuaternary 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, atropineDescribe the pharmacological properties of muscarinic blockers that are used clinicallyList the therapeutic uses for and adverse side effects of muscarinic blockers
22 Atropine and Scopolamine: Chemo-pharmacology ChemistryTertiary amines, levos are activePharmacologic actionCompetitive antagonists of muscarinic receptors (bind to receptors but elicit no response)Do not effect nicotinic receptors
23 Atropine and Scopolamine: Effects CNSAtropine at therapeutic doses produces few effectsScopolamine at therapeutic dose and atropine at high dose causes: drowsiness, amnesia, fatigue, REM disturbancesHigher and higher doses make confusion, hallucination, convulsion, paralysis, coma, respiratory failure, and ciruculatory collapseEyeMydriasis (pupil dilation)Cycloplegia, photophobia, blurred visionReduced aqueous outflowCardiovascularTransient decrease in HRHigh dose produces tachycardia (M2 at SA node), no change in BPNo vascular effect at therapeutic level, flushing at toxic doseRespiratory systemBronchodilation and reduced secretions (M3)Blocking M2 autoreceptors increases Ach releaseBetter bronchodilation in patients with COPDDigestive systemInhibits salivation (strongly), causes dry mouth at very low doseReduces gastric, pancreatic,intestinal and biliary secretions at higher dosesUrinaryReduced tone and amplitude of contractionsSweat GlandsInhibits sweating at low doses, increases body temp at higher doses (especially in children)
24 Atropine dose dependency 0.5 mgSlight cardiac slowing, some dry mouth, inhibition of sweating1 mgDry mouth, thirst, accelerated heart rate sometimes preceded by slowing, mild pupillary dilation2 mgRapid heart rate, palpitation, marked dryness of mouth, dilated pupils, blurring of near vision5 mgAll above and difficulty speaking and swallowing, reslessness and fatigue; headache; dry hot skin; difficulty in micturition; reduced intestinal peristalsis10 mg or moreAve 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, atropineDescribe the pharmacological properties of muscarinic blockers that are used clinicallyList the therapeutic uses for and adverse side effects of muscarinic blockers
26 Muscarinic antagonist chemo-pharmacology Tertiary AminesWell absorbed through the GI tractReadily cross the blood brain barrier (BBB)Quaternary AminesPoorly absorbed (10-30%)Do not cross the BBB, so no CNS effectsExcretionBoth are mostly excreted in the urineSome 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, atropineDescribe the pharmacological properties of muscarinic blockers that are used clinicallyList the therapeutic uses for and adverse side effects of muscarinic blockers
28 Clinical Uses: Opthalmology Opthalmologic UseMuscarinic blockers are useful to produce cycloplegia to study disorders of accomodationProduce mydriasis which enables easy examination of retina and optic discSpecific Drug usedTropicamide is used because it is the only one listed with a short enough duration of effect to be practical
29 Respiratory Uses Limitations Ipratropium Tiotropium Usefulness is somewhat limited because of systemic side effects and the reduced production of respiratory mucousIpratropiumNon selective quaternary amine used as an aerosol for COPDFew systemic effects due to poor absorptionDoes not impede mucociliary transportTiotropiumQuaternary amine preferentially inhibits M1 and M3 over M2Longer duration of action than ipratropiumAlso used for COPD
30 Urologic Uses Clinicology Oxybutynin Tolterodine Solifenacin Used in uninhibited bladder syndrome, bladder spasm, enuresis, and urge incontinenceIncrease functional bladder capacity, reduce pressure and frequency of contractionsSide effects include dry mouth and dry eyeOxybutyninTertiary amine, non-selective antagonistTolterodineTertiary amine with slight preference for M2SolifenacinTertiary amine with preference for M3, newest and most useful
31 Digestive Tract Uses: adjunct ony Muscarinic antagonists are used as an adjunct therapy forPeptic Ulcer- effective at reucing basal and nocturnal acid secretion (not postprandial)Duodenal ulcer- used when initial H2 antagonists and antacids are inadequateIrritable bowel syndromeAcute pancreatitis- if pancreatic ducts are obstructedPirenzepineM1 preferring (and M4) antagonist used in Europe
32 CNS Uses Used in two CNS conditions: Parkinsonism Motion Sickness Tertiary amines are used as an adjunct to L-dopa or in patients for whom L-dopa is contraindicatedMotion SicknessMay block cholinergic sites investibular nuclei and the reticular formationScopalamine is used; available in dermal patch to be placed behind the ear
33 Cardiovascular Use: limited Therapeutic IndexVery lowMyocardial InfarctionAtropine used in patients with severe bradycardia and hypotension to increase heart rate, BP, and COOther UseBradycardia caused by excessive carotid sinus reflex
34 Anesthesiology uses As Premedication With AChE Historically used with diethyl ether to reduce salivary and respiratory secretionsCurrently used to block bradycardia and hypotension from reduced vagal activity during surgeryWith AChEAlso used to prevent excess muscarinic effects when acetylcholinesterase agents are used to treat competitive neuromuscular blockade
35 As Antidote Antidote for 2 poisonings Anticholinesterase poisoning Amanita muscaria mushroom poisoning
36 Random clinical uses of Random drugs (from the last page of the lecture) DicyclomineDecrease spasm in the gi tractReplaced by oxybutyninGlycopyrrolateoral use decreases GI motilityParenterally used during surgeryPropanthelineWidely used for ulcerGanglionic blockerNMJ blockade
37 Anticholinesterase poisoning Natural causesIngestion of plants in Solanacae family: deadly nightshade, jimson weed, stinkweed (with names like that who wouldn’t eat them)Most sensitive patientsChildrenPresentationPeripheral effects seen at lower doses, CNS effects at high doses (emphasized in class)DiagnosisBased on symptoms; can use methacholine injectionTreatmentGastric lavae, respiratory assistance, physostigmine, benzodiazepines (if delirious or convulsive), and monitor body temp
38 The End 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.