Drugs Acting on the Parasympathetic Nervous System PDF

Drugs acting on the parasympathetic nervous Parasympathetic nervous system system Dr Kinga Sałaciak...

Drugs acting on the parasympathetic nervous Parasympathetic nervous system system Dr Kinga Sałaciak Department of Pharmacodynamics Jagiellonian University Medical College, Kraków, Poland Autonomic nervous system What is the response of effector to parasympathetic nerve impulses? Pupil ? https://www.news-medical.net/health/What-is-the-Nervous-System-(French).aspx What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Pupil Lens Miosis (constriction of the pupil) ? What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Lens Heart Contraction for near vision ? What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Heart Salivary glands Negative chronotropic e ect (decrease in heart rate) Negative inotropic e ect (decrease in myocardial contractility) ? Negative dromotropic e ect (decrease conduction velocity) What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Salivary glands Lungs increased ow of saliva that is more watery in composition ? fl ff ff ff What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Lungs Gastrointestinal system contraction of bronchial smooth muscle stimulation of bronchial glands ? What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Gastrointestinal system Liver Increased motility Relaxation of sphincters ? Increased secretion What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Liver Kidneys Decreased gluconeogenesis Increased glycogenesis ? What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Kidneys Bladder Increased ltration rate ? fi What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Bladder Male genitalia Contraction of the detrusor muscle Relaxation of the sphincter ? muscle What is the response of effector to parasympathetic What is the response of effector to parasympathetic nerve impulses? nerve impulses? Male genitalia Vascular smooth muscles Tricky! Erection ? What is the response of effector to parasympathetic Acetylcholine nerve impulses? Vascular smooth muscles Relaxation Acetylcholine - location Receptors at the parasympathetic innervated organs in the preganglionic sympathetic and parasympathetic neurons MUSCARINIC RECEPTORS NICOTINIC RECEPTORS at the adrenal medulla at neuromuscular junctions mAChRs nAChRs within central nervous system G protein-coupled receptors ligand-gated ion channel  Receptors M1 M2 M3 M4 M5 Heart CNS Autonomic nerve Smooth muscle Salivary glands CNS CNS terminals Endocrine glands Parietal cells Smooth muscle ↑ smooth muscle Inhibition of Facilitates ↑ cognitive function ↓ heart rate contractions receptor-mediated dopamine ↑ secretions ↑ smooth muscle ↑ vasodilation transmitter release release (gastric acid) contractions ↑ glandular secretion Wess, J., Eglen, R. & Gautam, D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 6, 721–733 (2007). Parasympathomimetics and parasympatholytics Parasympathomimetics activate the parasympathetic nervous system by mimicking or modifying the e ects of acetylcholine Parasympathomimetics and parasympatholytics Parasympatholytics oppose the e ects of the parasympathetic nervous system through anticholinergic action – i.e., they prevent ACh from acting as a neurotransmitter at muscarinic receptors ff ff Parasympathomimetics Parasympatholytics ↓ heart rate, ↑ heart rate, miosis ↑ gland secretion constriction mydriasis ↓ gland secretion relaxation blood pressure blood pressure Which group of drugs are used in the treatment of: Which group of drugs are used in the treatment of: Alzheimer’s disease? atonic bladder? Dysfunction/degeneration of acetylcholine containing neurons in the brain condition where patients are unable to spontaneously urinate (urine retention) contributes substantially to the cognitive decline observed in those with due to insu cient detrusor muscle contraction advanced age and Alzheimer's disease ffi Which group of drugs are used in the treatment of: Which group of drugs are used in the treatment of: chronic obstructive pulmonary disease (COPD)? Sjögren's syndrome? disease characterized by progressive air ow limitation and tissue destruction, autoimmune disease that damages the moisture-producing glands resulting in associated with structural lung changes due to chronic in ammation decreased tears and saliva production Which group of drugs are used in the treatment of: Which group of drugs are used in the treatment of: overactive bladder (urinary incontinence)? myasthenia gravis? urinary urgency, typically accompanied by frequency and nocturia, with and autoimmune disorder in which antibodies form against nicotinic acetylcholine without urge urinary incontinence. The detrusor muscle contracts when the postsynaptic receptors at the neuromuscular junction of the skeletal muscles, bladder is not full, often randomly causing muscle weakness and rapid muscle fatigue fl Which group of drugs are used in the treatment of: biliary colic? pain in the abdomen, due to obstruction usually by stones in the cystic duct or common bile duct of the biliary tree. It typically occurs after eating a large, fatty meal that causes contraction of the gallbladder Parasympathomimetics Parasympathomimetics Parasympathomimetics acetylcholine - not used as a drug due to: Direct parasympathomimetics (bind and activate muscarinic ACh receptors) rapid inactivation by acetylcholinesterase Indirect parasympathomimetics (inhibit acetylcholinesterase → ↑ synaptic levels of ACh) lack of receptor speci city chemical instability (easily hydrolyzed) poor absorption across lipid membranes fi  Direct parasympathomimetics carbachol bethanechol Direct parasympathomimetics pilocarpine Increased selectivity for mAChRs cevimeline Direct parasympathomimetics Drug: pilocarpine, cevimeline Mechanism of action: activation of muscarinic receptors Indications: glaucoma, atonic bowel, atonic bladder, xerostomia, Sjögren Indirect parasympathomimetics syndrome, antidote in poisoning with parasympatholytics Side e ects: nausea, vomiting, diarrhea, abdominal cramps, urinary urgency, diaphoresis, salivation, bronchoconstriction, and hypotension ff  Indirect parasympathomimetics REVERSIBLE IRREVERSIBLE Physostigmine Organophosphates Neostygmine Color Atlas of Pharmacology 4e. Autor: Heinz Luellmann, Klaus Mohr, Lutz Hein Indirect parasympathomimetics Poisoning - muscarinic effects Diarrhea Compounds: organophosphates Urination Miosis Mechanism of action: irreversible inhibition of acetylcholinesterase → ↑ Bradycardia concentration of acetylcholine at receptors of cholinergic synapses Bronchospasm Indications: insecticides (not used as drugs) Emesis Lacrimation Salivation Sweating Poisoning - nicotinic effects Antidotes Monday = Mydriasis Atropine (cholinolytic) → counterbalancing the peripheral muscarinic e ects of Tuesday = Tachycardia organophosphate poisoning Wednesday = Weakness Pralidoxime (reactivator) → reactivating the phosphorylated AChE by binding to Thursday = Hypertension the organophosphate Friday = Fasciculations Indirect parasympathomimetics Reversible inhibitors of acetylcholinesterase Drugs: physostigmine, neostigmine Neostigmine Mechanism of action: reversible inhibition of acetylcholinesterase → ↑ Physostigmine Cross blood brain barrier concentration of acetylcholine at receptors of cholinergic synapses Pyridostigmine Indications: postoperative bowel or bladder atony, glaucoma, myasthenia gravis, reversal of neuromuscular blockade caused by non depolarizing muscle relaxants, antidote in poisoning with parasympatholytics Indirect parasympathomimetics Reversible inhibitors of acetylcholinesterase Drugs: donepezil Tacrine Mechanism of action: reversible inhibition of acetylcholinesterase → ↑ Rivastigmine Increased selectivity for AChE concentration of acetylcholine at receptors of cholinergic synapses Galantamine Donepezil Indications: Alzheimer’s disease Atropine Parasympatholytics Color Atlas of Pharmacology 4e. Autor: Heinz Luellmann, Klaus Mohr, Lutz Hein Atropine overdose Parasympatholytics Hot as a hare Inhibition of glandular secretion: Blind as a bat pilocarpine or physostigmine Bronchial secretion - premedication before anesthesia to avoid mucus Dry as a bone hypersecretion (atropine) (antidotes) Red as a beet Gastric secretion - peptic ulcers (pirenzepine) Mad as a hatter Parasympatholytics Treatment of COPD Relaxation of smooth muscles: Ipratropium Chronic obstructive pulmonary disease (ipratropium, umeclidinium) Tiotropium Increased selectivity for M3 receptors Biliary or renal colic (N-butylscopolamine) Glicopyrronium Umeclidinium Diagnostic - mydriatic e ect (tropicamide) Urinary incontinence (solifenacin) ff Treatment of overactive bladder Parasympatholytics Cardioacceleration: Tolterodine Bradycardia, AV blocks (ipratropium) Oxybutynin Increased selectivity for M3 receptors Solifenacin Prevention of cardiac arrest (atropine) Side e ects Peripheral: tachycardia, dry mouth, hyperthermia, constipation Central: disorientation, hallucinations, motor restlessness Nicotine ff Nicotinic receptors Effects of nicotine on body function ionotropic receptors motor type vs neuronal type Color Atlas of Pharmacology 4e. Autor: Heinz Luellmann, Klaus Mohr, Lutz Hein Color Atlas of Pharmacology 4e. Autor: Heinz Luellmann, Klaus Mohr, Lutz Hein Withdrawal symptoms Smoking cessation increased nervousness Inhalers / chewing gums / patches with nicotine lack of concentration Bupropion - dopamine and noradrenaline reuptake inhibitor irritability Varenicline - partial nicotine receptors agonist impatience dysphoria Color Atlas of Pharmacology 4e. Autor: Heinz Luellmann, Klaus Mohr, Lutz Hein Thank you