Muscarinic Receptors and Directly Acting Cholinomimetics When your eyes hurt, you can’t pee, and your GI tract turns off

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. Methacoline Choline ester with effects similar to acetylcholine and no nicotinic activity. Not used due to CV effects. Somewhat resistant to acetylcholinesterase. Carbachol Choline eseter with some nicotinic activity, used for glaucoma. 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 Alkaloid used to reduce intraocular pressure. Has some nicotinic activity Muscarine Pure muscarinic agonist, clinically useless. More on these drugs later…

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

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

M-2 Receptor Location G Protein Second Messenger Primary ANS Effects Heart, nerves, smooth muscle G Protein GPCR Gi/o-linked Second Messenger Decreases cAMP and activates K+ channels 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 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.

M-3 Receptor Location G Protein Second Messenger Primary ANS Effects Glands, smooth muschle, endothelium G Protein GPCR Gq/11-linked Second Messenger PLC, IP3, DAG Primary ANS Effects Sweat glands- secretion through the sympathetic pathway 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 Poorly understood. M3 knockout mice are lean due to reduced food intake. So maybe hypothalamic M3s are important for eating behavior.

M-4 Receptor Location G Protein Second Messenger Primary Effects CNS Elsewhere (see effects below) G Protein GPCR Gi/o-linked Second Messenger Decreased cAMP 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.

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

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

Muscarinic Agonists: Choline Esters Chemistry Are structural modifications of Acetylcholine. 1) addition of a carbon-methacholine 2) change a C to an N -Carbamoylcholine/carbachol 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 Hydrophilic Poorly absorbed in GI tract Do not cross the blood brain barrier readily Metabolized by acetylcholinesterase

Muscarinic Agonists: Natural Alkaloids Chemistry Muscarine- Quaternary ammonium compound Pilocarpin- Tertiary amine Produce effects by binding to and stimulating ACh receptors 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 (Testable and emphasized Concept)

Strange Muscarinic Effects 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? Vasoconstriction 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? M1 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? Muscarine and pilocarpine Which muscarinic receptor is must important in: A) epileptogenesis? B) spinal chord? C) food intake (hypothalamus) A) M1, B) M2 C)M3

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

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

Carbachol (Carbamoylcholine) 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 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

Bethanechol Pharmacologic Action Clinical Use Drug interactions Similar muscarinic effect to carbachol, but without the nicotinic effect Completely resistant to acetylcholinesterase 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 Quinidine and procainamide antagonize it Serotonin reducing drugs (e.g. reserpine) with Bethanechol cause profound hypothermia

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

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

Muscarinic Blockers When you can’t breathe, your stomach is bleeding, you wet the bed, and you have tremors and motion sickness 9/26/07

Drug List Atropine, Scopolamine Tropicamide Dicyclomine Glycopyrrolate Belladonna alkaloids, oldest antimuscarinics Tropicamide Used opthalmically to produce mydriasis and cycloplegia Dicyclomine Historically used to decrease spasm in GI tract, replacedby Oxybutynin and others Glycopyrrolate Decreases GI motility. Used parenterally in surgery. Propantheline Ganglionic and NMJ blocker, widely used for ulcers Oxybutynin, Tolterodine, Solifenacin Used Urologically (for bladder spasm etc.), Solifenacin is a selective M3 blocker and is the best and newest treatment 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

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

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

Atropine and Scopolamine: Effects 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 Mydriasis (pupil dilation) Cycloplegia, photophobia, blurred vision Reduced aqueous outflow 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 Bronchodilation and reduced secretions (M3) Blocking M2 autoreceptors increases Ach release Better bronchodilation in patients with COPD Digestive system Inhibits salivation (strongly), causes dry mouth at very low dose Reduces gastric, pancreatic,intestinal and biliary secretions at higher doses Urinary Reduced tone and amplitude of contractions Sweat Glands Inhibits sweating at low doses, increases body temp at higher doses (especially in children)

Atropine dose dependency 0.5 mg Slight cardiac slowing, some dry mouth, inhibition of sweating 1 mg Dry mouth, thirst, accelerated heart rate sometimes preceded by slowing, mild pupillary dilation 2 mg Rapid heart rate, palpitation, marked dryness of mouth, dilated pupils, blurring of near vision 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 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

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

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

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

Clinical Uses: Opthalmology 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 Tropicamide is used because it is the only one listed with a short enough duration of effect to be practical

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

Urologic Uses Clinicology Oxybutynin Tolterodine Solifenacin 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 Tertiary amine, non-selective antagonist Tolterodine Tertiary amine with slight preference for M2 Solifenacin Tertiary amine with preference for M3, newest and most useful

Digestive Tract Uses: adjunct ony 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 M1 preferring (and M4) antagonist used in Europe

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 contraindicated Motion Sickness May block cholinergic sites investibular nuclei and the reticular formation Scopalamine is used; available in dermal patch to be placed behind the ear

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

Anesthesiology uses As Premedication With AChE 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 Also used to prevent excess muscarinic effects when acetylcholinesterase agents are used to treat competitive neuromuscular blockade

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

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

Anticholinesterase poisoning Natural causes Ingestion of plants in Solanacae family: deadly nightshade, jimson weed, stinkweed (with names like that who wouldn’t eat them) Most sensitive patients Children Presentation Peripheral effects seen at lower doses, CNS effects at high doses (emphasized in class) Diagnosis Based on symptoms; can use methacholine injection Treatment Gastric lavae, respiratory assistance, physostigmine, benzodiazepines (if delirious or convulsive), and monitor body temp

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.