Pharmacology - Muscarinic Receptor Agonists and Antagonists PDF

Pharmacology ACETYLCHOLINE & ITS MUSCARINIC RECEPTOR TARGET MUSCARINIC Receptors in the PNS: ACETYLCHOLINE ➔ found on autonomic effector cells innervated by postganglionic parasympathetic nerves Receptors in the CNS: ➔ found in...

Pharmacology ACETYLCHOLINE & ITS MUSCARINIC RECEPTOR TARGET MUSCARINIC Receptors in the PNS: ACETYLCHOLINE ➔ found on autonomic effector cells innervated by postganglionic parasympathetic nerves Receptors in the CNS: ➔ found in the hippocampus, cortex, or thalamus Muscarinic agonists ▪ mimic the effects of ACh at these sites (alkaloid muscarine acts selectively and produces the same qualitative effects as ACh) ▪ typically are longer-acting PROPERTIES AND All are G protein-coupled receptors (GPCRs) that couple to various cellular effectors SUBTYPES OF Subtypes: MUSCARINIC RECEPTORS M1, M3, and M5 ▪ activate the Gq-PLC pathway ▪ causes hydrolysis of polyphosphoinositides and mobilization of intracellular Ca2+ ▪ result to a variety of Ca2+-mediated responses M2 and M4 ▪ inhibit adenylyl cyclase ▪ regulate specific ion channels via their coupling to the pertussis toxin-sensitive G proteins (Gi and Go) o important in modulation of nicotinic cholinergic transmission in the ganglia M1 o predominant subtype in the cholinergic control of the heart M2 o predominant in the control of smooth muscle secretory glands and the eye M3 3 PHARMACOLOGICAL IN THE CARDIOVASCULAR SYSTEM EFFECTS OF ACETYLCHOLINE Acetylcholine has four primary effects: (1) Vasodilation ▪ due to stimulation of muscarinic receptors (primarily M3) located on vascular endothelial cells ▪ activates Gq-PLC-IP3 pathway → Ca2+-calmodulin-dependent activation of endothelial eNOS → production of NO → diffuses to vascular smooth muscle cells → relaxation ▪ produces transient fall in BP (2) Decrease in heart rate ▪ negative chronotropic effect ▪ due to decrease in the rate of spontaneous depolarization ▪ attainment of threshold potential and the succeeding events in the cardiac cycle are delayed (3) Decrease in conduction velocity in the AV node ▪ negative dromotropic effect ▪ due to increase in refractory period because it inhibits Ca2+ channels from opening (4) Decrease in the force of cardiac contraction ▪ negative inotropic effect ▪ In the atria: hyperpolarization and decrease in action potential (d/t increase in K+ channel opening) ▪ Also inhibits cAMP formation and release of NE IN THE RESPIRATORY TRACT (1) Bronchoconstriction (2) Increased tracheobronchial secretion (3) Stimulation of the chemoreceptors of the carotid and aortic bodies These effects are mediated by M3 muscarinic receptors on bronchial and tracheal smooth muscle. MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS Karrel C.  Pharmacology IN THE URINARY TRACT (1) Detrusor muscle (bladder) contraction ▪ Mediated by multiple muscarinic receptor subtypes, but primarily by M3 receptors ▪ M2 receptors: small contribution; indirectly reverse receptor-cyclic AMP-mediated relaxation of detrusor muscle (2) Increased voiding pressure (3) Ureteral peristalsis IN THE GASTROINTESTINAL TRACT (1) Increased tone (2) Amplitude of contractions (3) Secretory activity of stomach and intestine M3 receptors are primarily responsible for mediating cholinergic control of GI motility, but M 2 receptors also contribute to the activity OTHER EFFECTS (1) In the lacrimal, nasopharyngeal, salivary, and sweat glands ▪ Increased secretions ▪ via M3 receptors (2) In the eye: ▪ causes miosis by contracting the pupillary sphincter muscle ▪ accommodation for near vision by contracting ciliary muscle (3) In the central nervous system ▪ Muscarinic agonists crossing the BBB can cause arousal or activation response MUSCARINIC RECEPTOR AGONISTS 2 GROUPS OF RECEPTOR CHOLINE ESTERS CHOLINOMIMETIC ALKALOIDS AGONISTS Methacholine Muscarine β-methyl analog of ACh with added methyl group Acts almost exclusively at muscarinic receptors Increased resistance to cholinesterases → greater duration of action Arecoline May also act on nicotinic receptors Carbachol and its β-methyl analog (Betanechol) unsubstituted carbamoyl esters Pilocarpine almost completely resistant to hydrolysis by Dominant muscarinic effect but is only partial agonist cholinesterases Sweat glands are particularly sensitive ADME of receptor agonists: Quaternary amines Tertiary amines - poorly absorbed and does not cross BBB - readily absorbed and can cross BBB - resistant to hydrolysis but with short half-life - include arecoline and pilocarpine d/t kidney elimination - include choline esters and muscarine THERAPEUTIC USES Muscarinic agonists are currently used in: (1) the treatment of urinary bladder disorders (2) the treatment of xerostomia (3) the diagnosis of bronchial hyperreactivity MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS Karrel C.  Pharmacology Acetylcholine Used topically for induction of miosis during ophthalmologic surgery Methacholine Diagnosis of bronchial airway hyperreactivity in patients who do not have clinically apparent asthma Bethanechol Urinary tract: treatment of urinary retention and inadequate emptying of the bladder GIT: stimulation of peristalsis, increase motility, increase resting lower esophageal sphincter pressure Carbachol Treatment of glaucoma Induction of miosis during surgery Pilocarpine Treatment of xerostomia that follows head and neck radiation treatment or Sjogren syndrome Enhance salivary secretion, ease of swallowing, and subjective improvement in oral cavity hydration Cevimeline Preferentially activate M1 and M3 on lacrimal and salivary gland epithelia Long-lasting sialagogic action Fewer side effects than pilocarpine CONTRAINDICATIONS (1) Asthma (2) Chronic obstructive pulmonary disease (3) Urinary or GIT obstructions (4) Acid-peptic diseases (5) CVD with bradycardia (6) Hypotension (7) Hyperthyroidism MUSCARINIC RECEPTOR ANTAGONISTS WHAT ARE THE (1) the naturally occurring alkaloids (atropine and scopolamine) MUSCARINIC (2) semisynthetic derivatives of these alkaloids → differ from the parent compounds in their disposition in the ANTAGONISTS? body or their duration of action (3) synthetic derivatives → show limited degree of selectivity for certain receptor subtypes PHARMACOLOGICAL IN THE CARDIOVASCULAR SYSTEM EFFECTS OF ▪ Dominant response: tachycardia ATROPINE ▪ Average clinical dose (0.4-0.6 mg) - usually slows HR because it blocks M1 receptors on SA node, which normally inhibits ACh release - ACh = bradycardia while inhibition of ACh = tachycardia → block inhibition = bradycardia ▪ Larger doses - tachycardia because it blocks M2 receptors on SA node, thus inhibiting parasympathetic activity IN THE RESPIRATORY SYSTEM ▪ Effect is most significant in patients with respiratory disease ▪ Atropine can inhibit bronchoconstriction caused by histamine, bradykinin, and eicosanoids ▪ Stops secretions of the nose, mouth, pharynx, and bronchi ▪ Dries the mucus membranes of the respiratory tract EYES ▪ Dilate the pupil (mydriasis) and paralyze accommodation (cycloplegia) ▪ Lead to: a) Photophobia b) Lens fixed for far vision, near objects are blurred, and objects may appear smaller than they are c) Normal pupillary reflex constriction to light or convergence of the eyes is abolished IN THE GASTROINTESTINAL TRACT ▪ Atropine only incompletely inhibits GI responses to vagal stimulation ▪ GI tract has other synapses and plexuses that is non-cholinergic in origin ▪ Gastric secretions are also mediated by gastrin-releasing peptides ▪ Parietal cells also secrete acid in response to 3 hormones: gastrin, histamine, ACh ▪ Salivary secretion is sensitive to muscarinic antagonists → can completely abolish watery secretion, making it hard to swallow MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS Karrel C.  Pharmacology SWEAT GLANDS AND TEMPERATURE ▪ Inhibit the activity of sweat glands ▪ Skin becomes hot and dry CENTRAL NERVOUS SYSTEM (1) Atropine ▪ Minimal effects ▪ Toxic dose leads to restlessness, irritability, disorientation ▪ Larger doses = depression, circulatory collapse, respiratory failure, period of paralysis and coma (2) Scopolamine ▪ Prominent effects ▪ Therapeutic doses: drowsiness, amnesia, fatigue, dreamless sleep, and decreased REM ▪ Effective in preventing motion sickness by blocking neural pathways in the vestibular apparatus of the inner ear ADME OF Tertiary antagonists Quaternary antagonists MUSCARINIC ANTAGONISTS - belladonna alkaloids and other synthetic and - systemic absorption of inhaled or orally semisynthetic derivatives ingested antagonists is limited - absorbed rapidly from GIT and enter circulation - penetrate the conjunctiva of the eye less when applied locally to mucosal surfaces readily - absorption in intact skin is limited - lack central effects d/t not crossing the BBB ➔ Ipratropium, tiotropium, aclidinium, and umeclidinium - used exclusively for their effects on respiratory tract - Ipratropium: administered as an aerosol or solution for inhalation - Tiotropium: administered as dry powder THERAPEUTIC ▪ ipratropium, tiotropium Respiratory tract EFFECTS ▪ inhaled metered doses or dry powder inhaler for respiratory problems (COPD) ▪ for overactive urinary bladder Genitourinary tract ▪ lower intravesicular pressure, increase capacity, reduce frequency of contractions ▪ treat enuresis in children ▪ can be used for diarrhea with irritation of the lower bowel (diarrheal IBS) Gastrointestinal tract ▪ was once widely used for treating peptic ulcer ▪ side effects (photophobia, cycloplegia, xerostomia) decreases patient compliance Eye ▪ topical administration for mydriasis (thorough examination of retina and optic disc) ▪ therapy for iridocyclitis and keratitis Cardiovascular system ▪ atropine for excessive vagal tone (sinus bradycardia) Central nervous system ▪ Scopolamine for motion sickness ▪ Atropine is commonly given to block responses to vagal reflexes induced by Anesthesia surgical manipulation of visceral organ ▪ Atropine or glycopyrrolate are also used to block the parasympathomimetic effects of neostigmine when it is administered to reverse skeletal muscle relaxation after surgery. ▪ The use of atropine in large doses for the treatment of poisoning by Anticholinesterase anticholinesterase organophosphorus insecticides poisoning ▪ Also used to antagonize the parasympathomimetic effects of pyridostigmine or other anticholinesterases administered in the treatment of myasthenia gravis ADVERSE EFFECTS & Adverse effects Contraindications CONTRAINDICATIONS (1) Xerostomia (1) Urinary tract obstruction (2) Constipation (2) GI obstruction (3) Blurred vision (3) Uncontrolled angle-closure glaucoma (4) Dyspepsia (4) BPH (5) Cognitive impairment MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS Karrel C.  Pharmacology MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS Karrel C.