Pharmacology Lecture 4 PDF

PPT301 Pharmacology Cholinergic agonists Ahmed F. El-Yazbi, BPSc, PhD, BCPS References: - Goodman & Gillman’s: The Pharmacological Basis of Therapeutics Cholinergic transmission In the autonomic nervous system ACh mediates neurotransmission at 2 disparate sites: Gang...

PPT301 Pharmacology Cholinergic agonists Ahmed F. El-Yazbi, BPSc, PhD, BCPS References: - Goodman & Gillman’s: The Pharmacological Basis of Therapeutics Cholinergic transmission In the autonomic nervous system ACh mediates neurotransmission at 2 disparate sites: Ganglia: Neuronal nicotinic receptors (NN) Parasympathetic nerve endings: Muscarinic receptors (M1-5) Presynaptic receptors auto-and cross-regulation Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics Nicotinic ACh receptors Ligand-gated cation channels (Na and Ca permeable) Activation causes rapid depolarization They are further classified into two categories: Neuronal nicotinic receptors (NN) Muscular nicotinic receptors (NM) Location??  Molecular composition First isolated from the electric organ of Torpedo spp. (40% of the cell membrane surface) Strong non-covalent binding to α-toxins in snake venoms Five homologous transmembrane protein subunits surrounding a central ion pore (α, β, γ, and δ in the ration 2:1:1:1 in muscle) Each subunit has four transmembrane domains, Pacific electric ray transmembrane domain 2 forms the inner surface of the channel Several isoforms of the subunits exist providing different possible receptor structures with different permeabilities to Na and Ca α subunit homomers exist in the CNS Ligand binding sites in muscular nicotinic receipts exist at the αγ and αδ interface Both binding and gating in response to the two Bangarus spp sites show positive cooperativity Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics Muscarinic ACh receptors Five distinct sub-types exist Different subtypes exist in the same organ M3 is mostly present peripherally Might be present in locations without parasympathetic innervation (blood vessels) All muscarinic receptors are GPCRs (M1,3,5 are Gq- coupled, M2,4 are Gi/o coupled) No highly selective agonists or antagonists exist GPCR signalling? Neumann E et al., Nat Rev Rheumatol 2014 De Smet et al. Nat Biotech, 2014 Compared to muscarinic receptors, different sub-types of nicotinic receptors have selective agonists and antagonists. A. True B. False 11/23/2018 Table 8–3 Characteristics of Muscarinic Acetylcholine Receptor (mAChRs) Subtypes CELLULAR FUNCTIONAL DISEASE RECEPTOR CELLULAR AND TISSUE LOCATIONa RESPONSEb RESPONSEc RELEVANCE M1 CNS; most abundant in cerebral Couples by Gq/11 Increased cognitive Alzheimer cortex, hippocampus, striatum, and to activate function (learning and disease thalamus PLC-IP3-Ca2+-PKC memory) Cognitive Autonomic ganglia pathway Increased seizure dysfunction Glands (gastric and salivary) Depolarization activity Schizophrenia Enteric nerves and excitation ( Decrease in dopamine sEPSP) release and locomotion Activation of Increase in PLD2, PLA2; AA depolarization of autonomic ganglia Increase in secretions M2 Widely expressed in CNS, hindbrain, Couples by Gi/Go Heart: Alzheimer Antagonist: Pirenzepine thalamus, cerebral cortex, (PTX sensitive) SA node: slowed disease hippocampus, striatum, heart, Inhibition of AC, spontaneous Cognitive smooth muscle, autonomic nerve cAMP depolarization; dysfunction terminals Activation of hyperpolarization, HR Pain  sEPSP) release and locomotion Characteristics of Muscarinic Acetylcholine Receptor (mAChRs) Subtypes Activation of Increase in PLD2, PLA2; AA depolarization of CELLULAR FUNCTIONAL autonomic ganglia DISEASE RECEPTOR CELLULAR AND TISSUE LOCATIONa RESPONSEb Increase incsecretions RESPONSE RELEVANCE M12 CNS; most Widely abundant expressed in cerebral in CNS, hindbrain, Couples by Gq/11 i/Go Heart: Increased cognitive Alzheimer thalamus, cortex, cerebral cortex, hippocampus, striatum, and (PTX to sensitive) activate SA node:(learning function slowed and disease hippocampus, striatum, heart, Inhibition 2+ AC, thalamus PLC-IP 3-Caof -PKC spontaneous memory) Cognitive smooth muscle, Autonomic autonomic nerve ganglia cAMP pathway depolarization; Increased seizure dysfunction terminals Glands (gastric and salivary) Activation of Depolarization hyperpolarization, activity HR Schizophrenia Pain Enteric nerves inwardly and excitation ( AV node: decrease Decrease in in dopamine rectifying K+ sEPSP) conduction release and velocity locomotion channels of Activation Atrium: inrefractory Increase Inhibition PLD of 2, PLA2; AA period, contraction depolarization of voltage-gated Ventricle: slight autonomic ganglia Ca2+ channels contraction Increase in secretions Hyperpolarization Smooth muscle: M2 Widely expressed in CNS, hindbrain, Couples by Gi/Go Heart: Alzheimer and inhibition Contraction thalamus, cerebral cortex, (PTX sensitive) SA node: slowed disease Peripheral nerves: hippocampus, striatum, heart, Inhibition of AC, spontaneous Cognitive Neural inhibition via smooth muscle, autonomic nerve cAMP depolarization; dysfunction autoreceptors and terminals Activation of hyperpolarization, HR Pain heteroreceptor inwardly AV node: decrease in Ganglionic rectifying K+ conduction velocity transmission. channels Atrium: refractory CNS: Inhibition of period, contraction Neural inhibition voltage-gated Ventricle: Tremors;slight Ca2+ channels contraction hypothermia; analgesia Hyperpolarization Smooth muscle: and inhibition Contraction 11/23/2018 CELLULAR FUNCTIONAL DISEASE RECEPTOR CELLULAR AND TISSUE LOCATION RESPONSE RESPONSE RELEVANCE M3 Widely expressed in CNS ( other Couples by Gq/11 Smooth muscle: Chronic mAChRs), cerebral cortex, to activate Contraction obstructive hippocampus PLC-IP3/DAG- (predominant in some, pulmonary Abundant in smooth muscle and Ca2+-PKC e.g., bladder) disease glands pathway Glands: (COPD) Heart Depolarization Secretion Urinary and excitation ( (predominant in salivary incontinence sEPSP) gland) Irritable Activation of Increases food intake, bowel disease PLD2, PLA2; AA body weight, fat deposits Inhibition of DA release Synthesis of NO M4 Preferentially expressed in CNS, Couples by Gi/G0 Autoreceptor- and Parkinson particularly forebrain, also striatum, (PTX sensitive) heteroreceptor- disease cerebral cortex, hippocampus Inhibition of AC, mediated inhibition of Schizophrenia cAMP transmitter release in Neuropathic Activation of CNS and periphery pain inwardly Analgesia; cataleptic + rectifying K activity channels Facilitation of DA release Inhibition of voltage-gated Ca2+ channels Hyperpolarization and inhibition M5 Substantia nigra Couples by Gq/11 Mediator of dilation in Drug  rectifying K+ activity channels Facilitation of DA release Inhibition of voltage-gated Ca2+ channels Hyperpolarization and inhibition M5 Substantia nigra Couples by Gq/11 Mediator of dilation in Drug Expressed in low levels in CNS and to activate PLC- cerebral arteries and dependence periphery IP3-Ca2+-PKC arterioles (?) Parkinson Predominant mAchR in neurons in pathway Facilitates DA release disease VTA and substantia nigra Depolarization Augmentation of drug- Schizophrenia and excitation ( seeking behavior and sEPSP) reward (e.g., opiates, Activation of cocaine) PLD2, PLA2; AA a Most organs, tissues, and cells express multiple mAChRs. b 3/4  8/29/2016 Muscarinic receptor agonists Muscarinic receptor agonists Two classes of muscarinic agonists exist: Two classes of muscarinic agonists exist: Goodman & Gilman's: The Pharmacological Basis of Therapeutics, Choline esters: methacholine, carbachol, and Choline 12e esters: > Muscarinic methacholine, Receptor Agonists andcarbachol, Antagonists and bethanechol bethanechol Figure 9–1. Cholinomimeticalkaloids: Cholinomimetic alkaloids:muscarine, muscarine, pilocarpine, pilocarpine, and arecoline and arecoline Schmiedeberg Source: Source:Goodman Goodman& &Gillman’s: Gillman’s:The Pharmacological The Basis Pharmacological of Therapeutics Basis of Therapeutics Whatundefined What do do you you infer infer about about PK PK andand stability from stability thethe from structure? structure? Copyright © 2016 McGraw-Hill Education. All rights reserved. Which of the following muscarinic agonists will have the highest residual nicotinic activity? A. Muscarine B. Bethanechol C. Pilocarpine D. Carbachol  Actions Actions Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e > Muscarinic Receptor Agonists and Antagonists Table 9-1 Some Pharmacological Properties of Choline Esters and Natural Alkaloids MUSCARINIC ACTIVITY MUSCARINIC SUSCEPTIBILITY TO Urinary Eye Antagonism NICOTINIC Cardiovascular Gastrointestinal AGONIST CHOLINESTERASES Bladder (Topical) by Atropine ACTIVITY Acetylcholine +++ ++ ++ ++ + +++ ++ Methacholine + +++ ++ ++ + +++ + Carbachol − + +++ +++ ++ + +++ Bethanechol – ± +++ +++ ++ +++ − a Muscarine − ++ +++ +++ ++ +++ − Pilocarpine − + +++ +++ ++ +++ − a Not used therapeutically undefined Copyright © 2016 McGraw-Hill Education. All rights reserved. Source:Goodman Source: Goodman && Gillman’s: Gillman’s: The Pharmacological Pharmacological Basis BasisofofTherapeutics Therapeutics General therapeutic uses Urinary bladder disorders Paralytic ileus Xerostomia Miotic drugs for glaucoma Diagnosis of bronchial hyper-reactivity M1 and M4 receptor stimulation is of therapeutic interest for Alzheimer’s dementia and schizophrenia  1% ACh solution Used topically to induce miosis in ophthalmologic surgery  Methacholine Methacholine given by inhalation for the diagnosis of bronchial hyper- reactivity Asthmatic patients respond with intense bronchoconstriction (if symptoms not otherwise clear) Contraindications to methacholine testing: - severe airflow limitation - recent myocardial infarction or stroke - uncontrolled hypertension - pregnancy The response to methacholine is exaggerated if patients use β-blockers  Bethanechol Treatment of urine retention in absence of organic obstruction: - postoperative urinary retention - diabetic autonomic neuropathy - chronic hypotonic, myogenic, or neurogenic bladder Given orally 3-4 times/day on an empty stomach (why?) Previously used to treat postoperative abdominal distention, gastric atony, gastroparesis, adynamic ileus, and gastroesophageal reflux (Stimulates peristalsis, increases motility, and increases resting lower esophageal sphincter pressure)  Carbachol Used topically to treat glaucoma and for induction of miosis during surgery  Pilocarpine Treatment of xerostomia following head and neck radiation or associated with Sjögren's syndrome Lower doses should be used in patients with hepatic impairment Used topically for treatment of glaucoma  Glaucoma Cholinergic agonists produce miosis and increase drainage of aqueous humour Side effects include decreased peripheral and dark visual acuity, poor far vision Currently replaced with agents of a better side effect profile www.grafeyecare.com Contra-indications and side effects Consequences of receptor stimulation?? Treatment of toxicity by plant products containing muscarine, pilocarpine, or arecoline Mushroom poisoning Inocybe mushrooms