Autonomic Nervous System Drugs: Introduction and Parasympathomimetics PDF

#Module 3 Pharmacology Autonomic Nervous System Drugs: Introduction and Parasympathomimetics Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry,...

#Module 3 Pharmacology Autonomic Nervous System Drugs: Introduction and Parasympathomimetics Siti Zawanah Binti Halim Master in Pharmacology and Toxicology (UPM) Faculty of Dentistry, AIMST University Learning objectives Describe briefly cholinergic transmission (synthesis, release & storage of ACh). List out the types and locations of cholinoceptors. Classify cholinergic drugs. Discuss the pharmacology & uses of alkaloids & choline esters anticholinesterases. Classify anticholinesterase drugs & discuss their mechanism of action. Discuss the pharmacology & uses of anticholinesterase agents. Discuss myasthenia gravis & the treatment options. Nervous System Central nervous system (CNS) CNS consists of: a) Spinal cord b) Brain Peripheral nervous system (PNS) PNS consists of: a) Sensory neurons running from stimulus receptors that inform the CNS of the stimuli. b) Motor neurons running from the CNS to the muscles and glands - called effectors - that take action. Peripheral Nervous System (PNS) Acetylcholine biosynthesis Cholinergic drugs / cholinomimetic drugs / parasympathomimetics Drugs which produces actions similar to acetylcholine (ACh) or mimic the actions of ACh. Two types: A. Directly-acting: act on ACh receptor stimulants B. Indirectly-acting: act on cholinesterase inhibitors Directly acting means drug directly binds and activate the muscarinic and nicotinic receptors & produce the effects. Indirectly acting means drug act by binding with the enzyme and thereby increase local concentration of ACh. Cholinergic drugs Directly acting: 1. Choline esters Acetylcholine Bethanichol 2. Alkaloid Pilocarpine Indirectly acting: Anticholinesterases (AntiChEs) 1. Reversible (Carbamates) ▪ Physostigmine ▪ Neostigmine ▪ Pyridostigmine ▪ Edrophonium 2. Irreversible (Organophosphates) ▪ Echothiophate ▪ Malathion ▪ Diazinon Cholinergic receptors Muscarinic receptors (M): G-protein coupled receptor. M1 M2 M3 Location Autonomic ganglia, GIT, CNS Heart, cholinergic Smooth muscles (vessels, resp. nerve endings tract, bladder), exocrine glands Mechanism Antagonist Selectively blocked by atropine. Cholinergic receptors ▪ Nicotinic receptors (N): Ion-channel linked receptor. Nicotinic – skeletal Nicotinic – nerve muscle (NM-receptor) (NN- receptors) Location Neuromuscular junction Autonomic ganglia & adrenal medulla Antagonist Tubocurarine Hexamethonium Therapeutic value of ACh Acetylcholine: Therapeutically not using due to: Diffuse action (nonselective action) – stimulates both M & N receptors - can produce more adverse effects. Rapidly hydrolyzed by AChEs - very short duration of action (few seconds). Cholinergic drugs – direct acting ACh的药理作⽤（muscarinic） 1. Pharmacological actions (muscarinic) of ACh; Eye: 瞳孔反射 ❑ Contraction of circular muscle of iris –miosis. ❑ Accommodation for near vision (cyclospasm): ❑ vision is fixed for near objects. ❑ reduces intraocular pressure (esp. in glaucomatous patients). 降低眼压（特别是青光眼患者）。 Smooth muscle - contracted: ❑ ↑ GI motility & secretions. ❑ Respiratory tract (M3 receptors): Constriction of bronchial smooth muscles (bronchospasm). Increases the tracheobronchial mucus secretions.  Cholinergic drugs – direct acting Urinary bladder: Causes contraction of detrusor muscle and relaxation of trigone & sphincter. Facilitate the micturition (urination). CVS: ↓PVR (pulmonary vascular resistance), HR & FOC (atria). Blood vessels (M3 receptors): Vasodilatation - ↓ BP Glands: Causes increased secretion of: I. Sweat (thermoregulatory) II. Saliva from salivary glands III. Tears from lacrimal gland Cholinergic drugs – direct acting 2. Pharmacological actions (nicotinic) of ACh; Autonomic ganglia (NN): a. Sympathetic stimulation: increase HR & BP. b. Parasympathetic stimulation: ◦ decrease HR & BP. ◦ increase GIT motility & secretion. ◦ increase frequency of micturition. Adrenal medulla (NN): Secretion of epinephrine and norepinephrine. Skeletal muscle (NM): Contraction (twitching). Cholinergic drugs – direct acting Adverse effects: Sweating, salivation Flushing, decrease HR & BP Nausea, abdominal pain, diarrhea Bronchospasm Cholinergic drugs – direct acting Pilocarpine - An alkaloid (a tertiary amine), stimulates only muscarinic receptors: it causes severe salivations. decreases intraocular pressure (IOP) – by miosis and increases drainage of aqueous humor. Uses of Pilocarpine ◦ As mitotics - rapidly reduces IOP. ◦ Treatment of glaucoma. ◦ Sjögren's syndrome (an autoimmune disease that causes dryness of the mouth, eyes and other places). ◦ Xerostomia – used to induce salivation after irradiation of head and neck. Adverse effects - sweating and salivation. Cholinergic drugs – indirect acting Acetylcholinesterase inhibitors or Anticholinesterases Drugs which inhibit the breakdown of acetylcholine. Cholinesterase inhibitors are widely utilized as pesticides and, if misused, can produce toxic responses in mammals and man.  ▪ Physostigmine Neostigmine Reversible anticholinesterases Pyridostigmine Edrophonium Traits Physostigmine Neostigmine Source Natural alkaloid Synthetic Chemistry Tertiary amine derivative Quaternary amonium compound Good Oral absorption Poor Present CNS Action Absent Postganglionic Site parasympathetic junction Neuromuscular junction (NMJ) More prominent, so used in glaucoma Action on eye Less or no Antidote to atropine Antidote Antidote to gallamine Cholinergic drugs – indirect acting Irreversible anticholinesterases Organophosphorus compounds: 有机磷化合物： therapeutically not useful. important as poisonous substances. used as insecticides in agriculture fields - ▪ enter the body either through skin or by inhalation route. also commonly used as suicidal & homicidal poison. Toxicity of AChE inhibitors/ Organophosphorus Poisoning Excessive muscarinic and nicotinic stimulations - Muscarinic effects: remember DUMBBELSS ❑ Diarrhea, vomiting ❑ Urination ❑ Miosis, pin point pupil ❑ Bradycardia ❑ Bronchoconstriction ❑ Excitation (CNS and muscle) ❑ Lacrimation ❑ Salivation ❑ Sweating Nicotinic effects: ❑ Skeletal muscle – depolarizing neuromuscular blockade, excitation followed by depolarizing paralysis. ❑ CNS stimulation – convulsions (an abnormal, involuntary contraction of the muscles most typically seen with certain seizure disorders), coma. Management – Maintenance of respiration All muscarinic effects are blocked by atropine (antidote for overdose of cholinergic drugs), i.v. inj. in large doses. Reactivation of AChE with Pralidoxime (PAM). PAM should be initiated as soon as possible, prior to beginning of aging. Overall Uses of Cholinergic Drugs: ❑ Open / Wide angle glaucoma: Pilocarpine, Physostigmine ❑ Myasthenia gravis: Neostigmine, Pyridostigmine ❑ Post-operative urinary retention: Neostigmine, Pyridostigmine, Bethanechol ❑ Post operative parlytic ileus /congenital megacolon: Neostigmine, Pyridostigmine, Bethanechol ❑ Drug poisoning – Atropine: Physostigmine Myasthenia gravis ❑ Myasthenia gravis (MG) is a chronic autoimmune disorder in which antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles. ❑ Myasthenia gravis affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat and limbs. ❑ The disease can strike anyone at any age but is more frequently seen in young women (age 20 and 30) and men aged 50 and older. ❑ A myasthenia gravis crisis can involve difficulty in swallowing or breathing. ❑ The cause of myasthenia gravis is unknown and there is no cure, but early detection and prompt medical management can help people live longer, more functional lives. Symptoms of myasthenia gravis Drooping of one or both eyelids (ptosis) Double vision (diplopia) Altered speaking Difficulty swallowing Problems chewing Limited facial expressions Waddling gait, head drop and difficulty performing physical tasks such as lifting Symptoms of myasthenia gravis Difficulty in: 1. rising from sitting to standing 2. climbing stairs 3. brushing teeth (particularly with the repetitive action involved) 4. washing hair 5. physical activity often leads to tiredness Treatment Acetylcholinesterase inhibitors (pyridostigmine) or immunosuppressants (azathioprine etc). In selected cases thymectomy (surgical removal of the thymus gland). Recommended reading Katzung Bertram G. (2018) Basic & Clinical pharmacology, (14th Edition), Mcgraw Hill. Whalen,K., Finkel, R. (2019 )Lippincott Illustrated Reviews: Pharmacology (7th Edition), Wolters Kluwer. Rang HP, (2020)Dale’s Pharmacology, (9th Edition), Elsevier,. Brunton. L.L., Hilal-Dandan. R., Knollmann. B.C., (2018) Goodman & Gilman's: The Pharmacological Basis of Therapeutics, (13th Edition), Mcgraw Hill. Tripati, K.D. (2016) Essentials of Pharmacology for Dentistry, (3rd edition) Jaypee Brothers. Tripati, K.D. (2019) Essentials of Medical Pharmacology, (8th Edition) Jaypee Brothers. Rang, H.P., M.M and Ritter, J.M.(1999) Pharmacology (4th Edition), Churchill Livingstone. Katjung B.G. (2000) Basic and Clinical Pharmacology, (8th Edition), Appleton and Lange. Page, C.P., Curtis, M.J., Sutter, M.C., Walker, M.J.A and Hoffman, B.B. (2002) Integrated Pharmacology. (2nd Edition), Mosby. Seymour.R, John G. Meechan and Yates. M., Pharmacology and Dental Therapeutics (3rd edition) Oxford publication. Question 1. Correct pair of cholinoreceptor with its locations is a) muscarinic – neuromuscular junction. b) muscarinic – heart. c) nicotinic – exocrine glands. d) nicotinic – cholinergic nerve endings. Question 2. Pilocarpine is classified as a) indirectly acting cholinergic drugs. b) reversible directly acting cholinergic drugs. c) directly acting cholinergic drugs. d) irreversible indirectly acting cholinergic drugs. Question 3. Uses of pilocarpine listed below are correct, except a) treatment of glaucoma. b) for Sjögren's syndrome. c) to induce salivation after irradiation of head and neck. d) increase intraocular pressure (IOP). Question 4. Inhibition of the breakdown of acetylcholine is the mechanism of action of a) pilocarpine. b) anticholinesterase drugs. c) choline esters. d) atropine. Question 5. Statements listed below are correct about myasthenia gravis, except a) can be treated with acetylcholinesterase-inhibitors or immunosuppressants. b) in selected cases patient need for thymectomy. c) chronic autoimmune disorder in which antibodies destroy the communication between nerves and muscle, resulting in weakness of the skeletal muscles. d) improvement in the ability to chew and swallow is one of its symptoms.