Introduction to Cholinergic Pharmacology PDF

Introduction to Autonomic Pharmacology Cholinergic Drugs Part I Dr. Arlene Williams-Persad Department of Para Clinical Sciences, Pharmacology Unit Department of Clinical Surgical Sciences, Op...

Introduction to Autonomic Pharmacology Cholinergic Drugs Part I Dr. Arlene Williams-Persad Department of Para Clinical Sciences, Pharmacology Unit Department of Clinical Surgical Sciences, Optometry Unit Faculty of Medical Sciences The University of the West Indies St. Augustine, Trinidad and Tobago, W.I. Review of the Nervous System Nervous System PNS CNS Brain and Sensory Motor Spinal cord Somatic Autonomic SNS PSNS Enteric NS Autonomic Nervous System Divisions https://images.app.goo.gl/nuJvyjsS6szhy7kq9  Autonomic Nervous System Divisions Cholinergic fibers -ACh Adrenergic fibers - NE or E All preganglionic neurons are Cholinergic both SNS PSNS. Postganglionic nerves of the Sympathetic NS are adrenergic, except postganglionic fibers to the: Sweat glands, piloerector muscle and a few blood vessels are cholinergic. https://images.app.goo.gl/nuJvyjsS6szhy7kq9 Characteristics of ANS  How are the following organ systems innervated by the PSNS: Eye Heart Points to Lungs Blood Vessels Note Sweat glands Piloerector muscles Note the receptor subtypes, the muscles innervated and the action on the organ. Synthesis, Storage and Transmission  Acetylcholine (ACh) Structure and Synthesis  Cholinergic Receptors Two types of cholinergic receptors: Muscarinic: 5 sub-types (M1, M2, M3, M4, M5) (M1, 3 + 5 coupled to Gq proteins) G-protein coupled (M2 + 4 coupled to Gi proteins) Nicotinic: 2 major types (Nm, Nn) ligand-activated ion channels (open in response to binding to ACh, allowing influx of cations and generating EPSP) muscarinic are slower, longer lasting effects; nicotinic are fast synaptic transmission Muscarinic Receptors Muscarinic receptors M1 M3 M5 endocrine gland, CNS and gastric lachrymal and CNS heart (SA, AV). CNS glands smooth muscle Muscarinic Receptors M1 and M3 receptors generally mediate excitatory responses in effector cells. M1 - promote depolarization of postganglionic autonomic nerves, and (decrease heart rate and contractility) M2 - generally mediate heart contractility and vagal nerve. (parasymp responses to reduce CO) M3 - mediate contraction of all smooth muscles and increased secretion in glands. M5 - stimulate endothelium of blood vessels to release endothelium-derived relaxing factor (EDRF) and increase blood flow (primarily NO, leading to vasodilation) Nicotinic Receptors Nicotinic receptors Ligand-gated: stimulation allows Na+ ion move into the cell. Subtypes are located: Nm – NMJ (Nerve endings of skeletal muscle) Nn – CNS and autonomic ganglia both sympathetic and parasympathetic divisions Motor end plates (somatic targets) The effect of ACh binding to nicotinic receptors is always stimulatory *  Termination of Acetylcholine (slow process compared to enzymatic breakdown) ACh is an ester that is hydrolyzed spontaneously in alkaline solutions into acetate and choline. ACh is hydrolyzed by the enzyme cholinesterase Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues: (found only in neuronal tissue) acetylcholinesterases (AChEs) and butyryl- or pseudo-cholinesterases (found in plasma, liver and non-neuronal tissues, less specific to ACh compared to AChE)  Termination of Acetylcholine Acetyl (true) Cholinesterase: relatively specific for ACh and methacholine a membrane-bound enzyme all cholinergic synapses and red blood cells destroys ACh, terminating transmission Plasma (pseudo- or butyryl-) Cholinesterase: Non-specific substrate Widely distributed in plasma, liver, kidney, GIT hydrolyzing ACh in the circulation. Focus tips What is Vesamicol used for? - inhibits vesicular ACh transporter (VAChT) Discuss the type of Cholinergic receptors, their location in the body and the effect on the heart, lungs and eyes? How is methacholine useful? - cholinergic agonist used in diagnostic testing for asthma...stimulates muscarinic receptors and causes bronchoconstriction How is pseudo- or butryl-cholinesterase useful? - drug metabolism and safe administration of certain medications  Cholinergic Agonists Cholinergic Direct Acting Drugs Indirect acting Reversible Irreversible Direct acting agonists Quaternary Acetylcholine: Tertiary Alkaloid Amine Ophthalmic IV: Muscarine Nicotine miosis Low GIT Pilocarpine Reduces absorption Lobeline (cardiac output, Toxic when Well absorbed heart rate BP) ingested broken down by cholinesterase in the blood  Pilocarpine Pilocarpus microphyllus leaves contain the 3°-alkaloid. Prominent M3 actions Dilates blood vessels causes hypotension. On Eyes: Miosis by contraction of ciliary muscle: Spasm of accommodation Fixes for near vision Increased outflow of aqueous humor Lowers intraocular pressure (IOP) in glaucoma when applied topically (drops). Useful in acute glaucoma attack.  Pilocarpine Reverse mydriatic effect of Atropine (acute pilocarpine poisoning). Breaks adhesion between iris and cornea/lens alternated with mydriatic - synechia (atropine constricts the pypils, breaking adhesion) Resistant to acetylcholinesterase - remains active even when AChE inhibitors are used, which can prolong its effects Toxic in systemic use. Systemic Toxicity – Excess parasympathetic effect, Profuse salivation, lacrimation, sweating (diaphoresis), urination, GI upset (diarrhea), emesis, bronchospasm in asthmatics, hypotension. mitigate sever parasymp effects Muscarine Amantia muscaria – the fly agaric, contains muscarine Clitocybe and Inocybe species (little brown and white mushroom) (therefore muscarine poisoning can lead to prolonged and severe effects Poor absorption through GIT, crosses the BBB Resistant to acetylcholinesterase, long acting Clinically useless. Alkaloid responsible mushroom poisoning Treatment - muscarinic antagonist. - muscarinic agonist...leading to overstimulation of parasymp pathways - profuse salivation, lacrimation, sweating, urination, GI distress, bronchospasm, hypotension Lobeline Amine derivative similar to nicotine. Lobelia inflata (Indian Tobacco) leaves Mechanism of action: nicotine evoked dopamine release Clinical use: Smoking cessation (reducing cravings and withdrawal symptoms associated with tobacco use)  Methacholine synthetic choline ester non-selective muscarinic receptor agonist with some effect on N-Ach Resistant to AChE breakdown than ACh Uses: airway hyperresponsiveness (AHR) diagnosis of COPD and asthma, medications are working Methacholine challenge test. (used to diagnose AHR, conditions like COPD and asthma) Bethanechol Activates M1 and 3 receptors in all peripheral tissue Negligible effect on Nicotinic receptors More resistant to AChE Effects: Selectively stimulates urinary and GI tracts. Administered orally (po) or subcutaneously (sc). Treat urinary retention, Postoperative/neurogenic ileus. (paralysis of muscles that trigger peristalsis) Other Systemic effects: Bronchospasms in asthmatics Additive effects co-administered with other parasympathomimetic drugs.  Carbachol - synthetic analogue of ACh; acts on both muscarinic and nicotinic receptors (carbon copy of ACh) Resistant to AChE (prolonged action) m-Ach and n-Ach active Reduces IOP Glaucoma (mimics ACh and stimulates muscarinic receptors in the eye)  Indirect acting Agonists: Cholinesterase Inhibitors Reversible Edrophonium Neostigmine Pyridostigmine Ambenonium Physostigmine  Edrophonium Quaternary ammonium alcohol (leading to increased ACh levels and enhanced parasymp activity) Mechanism of action: reversible inhibition of AChE. Effect: amplifies ACh - ⤊ Parasympathetic activity and Somatic NMJ transmission. Clinical applications: Diagnosis of myasthenia gravis. Curare antidote because of its short duration of action (5-15mins) curare-indued muscle paralysis  Myasthenia Gravis - antibodies target ACh or receptors leading to muscle weakness Autoimmune – antibodies to ACh or to its receptor. Characterized- droopy eyes, muscle weakness, etc. Diagnostic tests: (temporarily improves muscle action) Edrophonium test. Treatments: anticholinesterase agents Pyridostigmine bromide Ambenonium chloride Neostigmine bromide (enhance neuromuscular transmission)  Neostigmine Synthetic Structure Quaternary ammonium compound has poor penetration hence topical application is not effective. Mechanism of Covalently binds AChE (released by Action Intermediate hydrolysis) - inhibiting action Effects amplifies ACh - ⤊ Parasympathetic acting AChEIs activity and Somatic NMJ transmission. Clinical uses Myastenia gravis, Stimulates bladder, GIT and reverse effects of NMJ blocker for anesthesia post surgery. - used in anaesthesia to reverse neuromuscular blockade  - similar to neostigmine but longer-acting Pyridostigmine Structure Quaternary amine has poor penetration, BUT longer acting than neostigmine Mechanism of Covalently binds AChE (released by hydrolysis) Intermediate Action acting AChEIs Effects amplifies ACh - ⤊ Parasympathetic activity and Somatic NMJ transmission. Can’t cross BBB. Clinical uses Similar to Neostigmine  Physostigmine Natural alkaloids 3° amine esters - Physostigma venenosum Structure Tertiary amine, good tissue distribution, effective by topical application (longer acting than neostigmine) Intermediate Mechanism of Action Covalently binds AChE (released by hydrolysis) acting AChEIs Effects amplifies ACh - ⤊ Parasympathetic activity and Somatic NMJ transmission. Crosses BBB. Clinical uses Glaucoma treatment Atropine antidote (Antidote for anticholinergic toxicity) - more profound effect on CNS than other AChEIs - anticholinergic toxicity results from competitive antagonism of ACh at central and peripheral muscarinic receptors Chemical structure of intermediate acting cholinesterase inhibitors Clinical uses diagnose or treatment Myasthenia Gravis Physostigmine more commonly used to treat glaucoma. Antidote Datura stramonium and Atropa belladonna poisoning Datura contains a list of anticholinergics such as: atropane alkaloids atropine, hyoscyamine, and scopolamine. Other AChEIs used to ease the symptoms of Alzheimer's Donepezil - palliative care in Alzheimer’s These agents are orally active have adequate Rivastigmine penetration to the CNS and are much less toxic Galantamine than tacrine (THA). Reversible, competitive Increase cognitive function brought inhibitor of about by increase in cholinergic activity. acetylcholinesterase (AChE) Adverse effects - nausea, vomiting , diarrhea and other peripheral cholinomimetic effects.  Summary or cholinesterase inhibitors Pharmacological Action - increase cholinergic activity, which can have broad effects on the parasymp NS, somatic NMJ transmission, and cognition depending on lipophilicity and ability to cross BBB Qualitatively similar to direct acting cholinergic agents, but quantitatively different: (cross BBB) Lipid soluble (Physostigmine) – more muscarinic and CNS effects (stimulate ganglia) – less skeletal muscle effect Lipid insoluble like Neostigmine – more skeletal muscle effect but less muscarinic effect CNS.  DFP- irreversibly inhibits AChE, leading to excessive ACh accumulation at synapses Parathion- metabolised in body to active form (paraxon) which irreversibly inhibits AChE Insecticides: Diisopropyl fluorophosphates (DFP) Parathion Indirect acting Agonists Ocular hypertension and Cholinesterase accommodative esotropia Inhibitors Echothiopate irreversible - topical AChE inhibitor...parasymp effects and somatic NMJ - toxicity- headache, uveitis, blurred vision Poison Sarin  Organic derivatives of phosphoric acid Covalently binds AChE Echothiophate Amplifies ACh - ⤊ Parasympathetic activity and Somatic NMJ transmission. Clinical uses: still considered in glaucoma therapy Topical only. Toxicity: headache, uveitis and blurred vision (inflammation inside eye) Irreversible - Sarin poisoning - toxic accumulation of ACh at synapses Vomiting Sweating, Loss of Bronchoconstriction Miosis Nausea consciousness Salivation Lacrimation Abdominal pain What are the effects of Sarin? URL: [https://youtu.be/ynBHl5SJf5c]  Pesticides & Poisons Thiophates Malathion: Relatively safe to mammals and birds because it is metabolised to inactive products. – carboxylase p/w Parathion: Thiophosphate insecticide like Malathion but is not metabolised or detoxified in the system - leads to higher toxicity  The eye Muscarinic stimulants and AChEIs reduce IOP by contraction of the ciliary muscles to facilitate outflow of aqueous humour and by reducing the rate of secretion. Also used in the reversal of (inward turning of one or both accommodative esotropia. eyes that occurs with activation of the accommodative reflex) Gastrointestinal and urinary tract Clinical Uses of Post operative ileus Cholinomimetics Urinary retention – causes post-op, post (cholinergic drugs) partum or secondary to spinal injury bethanechol administered subcutaneously, neostigmine subcutaneous or orally in both instances complete monitoring to avoid exacerbation of the problem. Increase tone of the oesophageal sphincter muscle in patients with reflux esophagitis. Dry mouth associated with Sjögren’s syndrome – use pilocarpine or newer agent Cevimeline.  Heart Edrophonium – supraventricular tachyarrhythmias Now replaced by adenosine and calcium channel blockers, verapamil and diltiazem NMJ Clinical Uses of Effect on skeletal muscle to treat Cholinomimetics Myasthenia gravis CNS Slowing progression od Alzheimer’s disease by improving behavioural and neuropsychiatric symptoms. Antidote Atropine intoxication, tricyclic antidepressant overdose (reversing anticholinergic effects) Reference Text [email protected] Autonomic Pharmacology: Cholinergic Drugs II Dr. Arlene Williams-Persad Department of Para Clinical Sciences, Pharmacology Unit Department of Clinical Surgical Sciences, Optometry Unit Faculty of Medical Sciences The University of the West Indies St. Augustine, Trinidad and Tobago, W.I.  We looked at: the structure and function of the ANS regarding the Cholinergic responses. Drugs affecting the synthesis and transmission of ACh. Hemicholinium (-) CHT - inhibits choline transporter (CHT); responsible for uptake of choline in nerve terminals Vesamicol - inhibits the uptake of ACh into vesicles by Vesicle associated transporter (VAT) is used in the treatment of adenocarcinomas in the lung. (cancer that starts in the glands that line organs) Botulinum toxin -(SNAP-25) inhibits release of ACh from presynaptic terminals; cleaves proteins involved in vesicle fusion - medically treat muscle spasticity, chronic migraine, Drugs affecting the Receptors OAB, hyperhidrosis, cosmetic procedures Two classes of Cholinergic agonists: Direct acting Indirect acting Reversible Irreversible Flowchart Cholinergic Blockers M- selective Anti-muscarinic Non-selective (atropine) Anticholinergic drugs Ganglionic blockers (hexamethonium) Anti-nicotinic Neuromuscular blockers (tubocurarine) Cholinesterase Oximes regenerators (pradiloxime) The eyes M3 receptors 1. Mydriasis 2. Cycloplegia 3. Reduced lacrimal secretion 1. relaxation of sphincter pupillae muscle causes pupil to dilate 2. inhibition of ciliary muscle causes paralysis, resulting in inability to focus on near objects (loss of accommodation) 3. decreases tear production leading to dry eyes  Anticholinergic agents Atropine Tertiary amine alkaloid ester of tropic acid Pharmacokinetic: Well absorbed from gut and conjunctival membrane Competitive reversible blocking agents. (antagonist) Non-selective muscarinic receptors (not nicotinic) Effect: mydriasis, cycloplegia Clinical uses: antidote, retinal exam, prevents synechiae. (adhesion btw iris and lens) Toxicity: ↑IOP (worsen glaucoma) Contraindications: interacts with other antimuscarinics. Atropa belladonna Deadly night shade  Antimuscarinic agents Anti uveitis agents: Dilate pupils to prevent synechia E.g. Homatropine, cyclopentolate or atropine. (muscarinic antagonists that block M3 receptors, causing pupil dilation and paralysis of α1-adrenoceptors To break synechia accommodation) 1. Initial use of cyclopentolate, phenylephrine or tropicamide drops. (muscarinic antagonist used for short acting mydriasis and cycloplegia) (causing constriction of blood vessels (mydriasis), added benefit in breaking synechiae) 2. Resistant synechia use subconjunctival mydriatics. (when standard eye drops fail to induce sufficient pupil dilation) Ocular effects mydriasis and cycloplegia  Scopolamine (blocks muscarinic receptors in CNS, prevention stimulation that causes symptoms like nauseas and vomiting) Reduces vertigo, postoperative nausea prevents motion sickness transdermal patch IM inj. postoperative use Hyoscyanus niger Black Herbane Toxicity: somnolence (drowsiness), (hyoscine) tachycardia, blurred vision, xerostomia. (dry mouth) Cardiac Effect M2 and M4 are Gi coupled...decrease in AC, reduces cAMP, PKA activity M2 and M4 receptors are Gi GCPRs ACh stimulates an inhibitory response leading to a decrease in AC, cAMP and PKA activity Leads to prolonged K+ channel opening. Implications: Increased Heart Rate. - antimuscarinic agents like scopolamine and atropine block these effects Atropine on the SA node, - leads to increased HR by reducing vagal tone atrioventricular node Gastrointestinal effects - M3 receptors in GI tract mediate smooth muscle contraction and secretions - scopolamine block M3 receptors Blocking M3 salivation, speed of micturition, heart rate and accommodation - decreased salivation, reduced GI motility, increased HR - side effects: dry mouth, blurred vision, urinary retention, constipation Antimuscarinic agents Dicyclomine (Bentyl) blocks the muscarinic (M1 and M4) receptors in the enteric plexus and on smooth muscles. (associated with IBS) Extremely useful for the relief of abdominal spasm. Low dose minimal ANS effects Higher doses: anticholinergic effects, dry mouth, blurred vision, urinary retention and constipation. –IBS inhibits- by blocking M1 and M4 muscarinic receptors, reduces smooth muscle spasm, and glandular secretion in the gut, helping to relieve discomfort from IBS  HYOSCYAMINE - muscarinic receptor antagonist Isomer of atropine Precursor for the synthesis of scopolamine. Action are similar to scopolamine and atropine antagonist of muscarinic acetylcholine receptors Uses: IBS (reduce cramping and manage GI disorders) Side Effects: drowsiness, dry mouth. Longer duration of action to Dicyclomine  Respiratory tract Blocking M2 salivation, speed of micturition, heart rate and accommodation M2 muscarinic receptors regulate parasymp activity Immunopathogenesis of asthma. (upon first synthesis of IgE exposure to allergen) Re-exposure to allergens , antigen- antibody interaction on mast cells mediators of anaphylaxis: histamine, tryptase, PGD2, leukotrienes, PAF to contract airway smooth muscle (leading to bronchoconstriction...contribute to airway inflammation and mucus hypersecretion) - asthma management focuses on preventing mast cell degranulation...reducing airway smooth muscle contraction Respiratory tract (Ipratropium SAMA- comp inhibits M1, 2, 3 receptors, reducing bronchoconstriction and airway resistance) (block M1, 2, 3 ro reduce parasymp mediated bronchoconstriction and mucus secretion) Antimuscarinics Datura stramonium (atropine) (bronchodilator effect) Ipratropium (depends on conc relative to ACh) Competitive inhibition Mechanisms of response to inhaled irritants - antimuscarinics prevent reflex bronchoconstriction triggered by irritants by:. blocking vagal nerve-mediated pathways. inhibiting ACh release (which stimulates airway smooth muscle contraction)  Inhaled antimuscarinics Ipratropium (M1,2,3), Tiotropium (M1,2,3), Aclidinium (M1-5): Synthetic analogs of atropine Tiotropium and Aclidinium have longer bronchodilator action than Ipratropium Used: tiotropium aclidinium, umeclidinium, and glycopyrrolate are approved for maintenance therapy of COPD asthma - not primary therapy. (block muscarinic receptors; prevents ACh mediated AE: xerostomia (dry mouth) and cough bronchoconstriction and reduces mucus secretion)  Antimuscarinics, selective Tolterodine Darifenacin - primarily M3 receptor antagonists designed for targeted inhibition of smooth muscle contraction, particularly in the bladder Fesoterodine Solifenacin (new) approved antagonists with greater selectivity to M3 receptors. Uses: Urinary incontinence Oral doses (to minimise side effects while optimising therapeutic benefits) Toxicities: heightened effects (anticholinergic syndrome)  OXYBUTYNIN M-ACh receptor antagonist (partially selective M3). Used: Relieves bladder spasm after urologic surgery (prostatectomy). (inhibits detrusor muscle overactivity, reducing bladder spasms and increasing bladder capacity) Darifenacin, Solifenacin and tolterodine are tertiary amines like oxybutynin with greater M3 affinity. (reduced CNS penetration with fewer central side effects) SE: blurred vision, dilates pupils Trospium - overactive bladder (less selective). (suitable for patients where CNS effects are a concern- elderly) Benztropine M-ACh receptor antagonist (partial selectivity M1) (reduces cholinergic overactivity in the striatum, helping to restore balance btw dopamine and acetylcholine in Parkinson's disease) CNS disorders – second line - Parkinson’s disease sometimes used together with levodopa. - for synergistic effects  Selective Antimuscarinic Pirenzepine Telenzepine (highly selective M1 muscarinic receptors) antagonists -selectivity to M1 receptors. - lower gastric acid secretion and promote ulcer healing Uses: Peptic ulcer disease (not available in the USA) Toxicity: heightened effects (dry mouth and blurred vision ) - due to blockade of M1 receptors in salivary glands - anticholinergic effects on ciliary muscles - fewer systemic effects than non-selective antimuscarinics  Nicotinic ganglionic antagonists Selectively blocks ganglionic nicotinic receptors (Nn) - competitively - some block the pore of the (further reducing transmission) receptor. (inhibiting both symp and parasymp neurotransmission) First used to treat hypertension. (due to non-selectivity + significant side effects) Mecamylamine and trimethaphan oral and parenteral blocks all ANS effects - symp blockade: vasodilation, decreased sweat gland activity (anhidrosis) - parasymp blockade: tachycardia, mydriasis and cyclocplegia (loss of ciliary muscle control), urinary retention, constipation Antinicotinic neuromuscular blockers Non-depolarizing agent d-Tubocurarine Competitive antagonist ACh- nicotinic (n-ACh) receptor in NJM Prevents depolarization by ACh causes flaccid paralysis - blocks ACh binding, preventing depolarization and propagation of action potentials - induces prolonged skeletal muscle relaxation to facilitate surgery or mechanical ventilation - used primary when immobility or muscle relaxation is required  - cholinesterase inhibitors (e.g., neostigmine) used to restore muscle function d-Tubocurarine Used: prolonged relaxation for surgical procedures. PK and Toxicities: Anti-nicotinic renal excretion duration of action 40-60 mins neuromuscular causes initial twitch then blockers persistent depolarization. Non- Adverse effects: Hypotension, Tachycardia, depolarizing Respiratory paralysis, agent Bronchospasm, vomiting. Other agents: Pancuronium, Rocuronium and Vecuronium, Mivacurium.  Pralidoxime Prototype cholinesterase regenerator Oxime groups - very high affinity for organophosphates. Binds at the active site of the enzyme (AChE) and Cholinesterase displaces organophosphate –regenerate AChE. (AChE) Used to treat parathion poisoning, not regenerator carbamates (organophosphate AChEI) Side effects: Muscle weakness. Remember: Atropine and Pralidoxime are antidotes for AChEI poisoning by two different mechanisms. Pralidoxime (PAM) Oximes Regenerator of ACE Organophosphate- cholinesterase complex Diacetylmonoxime (DAM) - similar action to pralidoxime (always used with atropine- blocks muscarinic overstimulation, whole pralidoxime regenerates AChE for broader effect)  Summary Use the flow chart to write in the examples discussed in class and recall the mechanisms and some clinical uses of each drug. M- selective Anti-muscarinic Non-selective (atropine) Anticholinergic drugs Ganglionic blockers (hexamethonium) Anti-nicotinic Neuromuscular blockers (tubocurarine) Cholinesterase Oximes (pradiloxime) regenerators Prepare for the Seminar… (contains atropine, scopolamine, and hyoscyamine- antimuscarinic agents, blocking ACh at M receptors) Deadly nightshade, belladonna, Devil’s cherries (Atropa belladonna) (clinical manifestations- CNS symptoms of delirium, hallucinations, seizures; peripheral symptoms of dry mouth, mydriasis, blurred vision, tachycardia, hyperthermia, decreased sweating and salivation, flushed skin, urinary retention and constipation) Cholinergic Pharmacology Seminar Dr. Arlene Williams-Persad Department of Para Clinical Sciences, Pharmacology Unit Department of Clinical Surgical Sciences Optometry Unit Faculty of Medical Sciences The University of the West Indies St. Augustine, Trinidad and Tobago, W.I. Autonomic Nervous System ACh is secreted at all pre- ganglions. Parasympathetic pathways: Decrease Heart Rate and force GIT increase salivation Eye constricts Contracts bronchial smooth muscles Relaxes bladder.  Autonomic Nervous System E or NE is secreted at the post-ganglions and AM. α and β - receptors Sympathetic pathways: NE released at smooth muscle and cardiac muscle nerve junction E released by adrenal medulla and circulates throughout blood NE and E act in opposition to acetylcholine Generalized Cholinergic Junction Physostigmine Pilocarpine - + Atropine -  Generalized Adrenergic Junction Reserpine Guanethidine - Inhibit monoamine + oxidase, eg tranylcypromine. - + Amphetamine Cocaine and Phenylephrine - tricyclic antidepressants. + Propanolol - Respiratory tract Auto-inhibitory M2 receptors M3 receptors Whatthe Select areanti-muscarinic the agents discussed agent in the last most suitable class to treat patients that arewith asthmafor available and in many with COPD. treatment of respiratory A. Tiotropium conditions? B. Aclindinium C. Ipratropium D. Glycopyrrolate The Eye Ambient Light The effect of ambient light Low light innervates contraction of the pupillary dilator muscles (SNS - ⍺ receptors). High light innervates contraction of the pupillary sphincter muscles (PSNS – M receptors). - low light triggers SNS to activate...contraction of Pharmacological effects: dilator muscles via alpha receptors to cause mydriasis Phenylephrine ⍺-agonist - high light triggers PSNS to Pilocarpine M-agonist activate...contraction of sphincter muscles via M receptors causes miosis. phenylephrine mimics SNS activation by stimulating alpha receptors. pilocarpine mimics PSNS activation by stimulating M receptors Accommodation Accommodation Drugs acting on sympathetic system (Hypotheses testing)  -adrenoreceptor agonist 1. alpha-1 agonist: directly stimulates Phenylephrine: receptors, causing vasoconstriction and pupillary dilation Cocaine: inhibits NE uptake 2. inhibits NE reuptake by blocking NET, increasing NE levels at synapses, increased symp activity (indirect acting agonist ) 3. indirect sympathomimetic, stimulates release of NE and dopamine from Amphetamine: releases NE presynaptic vesicles, inhibits reuptake and increases synaptic concs of NE (indirect acting agonist ) EYE PAIN A 37-year-old man complains of eye pain, pressure and blurred vision in his right eye. (acute angle-closure glaucoma characterised by increase in IOP, eye pain, pressure, blurred vision and potential nerve damage) IOP left eye (46mmHg) and right eye (55 mm/Hg). EYE PAIN 1. What is the drug action Pilocarpine: muscarinic agonist 1. muscarinic agonist stimulates contraction of pupillary sphincter and ciliary muscles, enhancing aqueous humor outflow 2. muscarinic agonist blocks parasymp stimulation causing pupil dilation and potetntially worsening angle-closure by Atropine: muscarinic antagonist further obstructing aqueous humor outflow 3. AChEI increases ACh levels indirectly stimulating muscarinic receptors to induce miosis and facilitate aqueous humor drainage Physostigmine: acetylcholinesterase inhibitor EYE PAIN 2. How will each drug affect the normal eye? Pilocarpine: miosis 1. miosis Atropine: mydriasis 2. mydriasis 3. miosis Physostigmine: miosis  EYE PAIN 3. Explain how the cholinergic drugs would affect the patient’s intraocular pressure. Pilocarpine: decrease IOP 1. decreases IOP 2. increases IOP Atropine: increase IOP 3. decreases IOP Physostigmine: decrease IOP Horner’s syndrome https://www.ophthalmologyreview.org/articles/horne r-syndrome-pharmacologic-diagnosis  Pre-ganglionic Horner’s syndrome - damage occurs to pre-ganglionic symp fibres leading to loss of symp tone Sympathetic nerve traffic and loss of sympathetic tone However, postganglionic sympathetic nerves are still present with releasable NE: Redness (loss of symp-mediated vasoconstriction in facial blood vessels) resting pupillary diameter adjustment is slowed Cocaine test  adaptation to low light. Pupil will dilate Cocaine blocks NE reuptake, increasing NE in synaptic cleft and causing pupil dilation in normal eyes. Oucome: pupil will dilate as post-g symp nerve is intact and capable of releasing NE when stimulated. Pre-ganglionic fibre Post-ganglionic fibre - post-ganglionic fibres remain intact, capable of releasing NE upon stimulation  Post-ganglionic Horner’s syndrome No sympathetic nerve traffic, loss of sympathetic tone Postganglionic sympathetic nerves not present, no releasable NE. Redness, resting pupillary diameter, slowed and adaptation to reduced light. - no NE release from post-g terminals Pre-ganglionic fibre Post-ganglionic fibre - pupil does not dilate (no NE release)  Mr. Brown Has Horner’s syndrome in his left eye. List a few signs and symptoms you would expect: One pupil is smaller than the other -Drooping miosis of the eyelid (ptosis) -Raising ptosis of the lower lid -Anhidrosis facial anhidrosis(lack of sweat on the affected side) -Pupil - slow to dilate heterochromia A lighter color of the iris in the children If administration of cocaine test caused no response. Locate the lesion: Post ganglionic lesion post-g lesion  Micturition reflex: Spinal chord (S2 and S3) mediated by spinal centres at S2, 3 Brain – Pons Pontine storage center and Pontine micturition center. responsible for inhibiting urination (promoting relaxation of detrusor muscle and contraction of internal sphincter) ↑PNS and a ↓SNS facilitates urination by stimulating detrusor muscle to contract, and inhibiting internal sphincter, allowing urine flow PNS ⇒ contraction of the Detrusor SNS ⇒relaxes the internal sphincter. Decrease motor nerve stimulation Relax external sphincter. Urine flow: Pontine micturition centre allows urine flow while the Pontine storage centre blocks. Parasympathetic response M2 and M3 receptors stimulates M2 and M3 leading to detritus muscle contraction (micturition)  Uninhibited Detrusor muscle Stimulation of the cholinergic receptors along CNS by these drugs would cause the detrusor muscle to be: Acetylcholine stimulated to relax Bethanechol stimulated to relax cholinergic agonist (M2,3)...stimulates detrusor contraction Tolterodine inhibited to constrict antimuscarinic (M2,3 antagonist)...inhibits detrusor contraction Trospium antimuscarinic inhibited to constrict (M2, 3 antagonist)...inhibits detrusor contraction Case bladder trauma: A 20-year-old female sustained injury to the lower back following a motorcycle accident and temporarily lost the ability to void urine.  Case bladder trauma: State the drug action of each agent: Bethanechol muscarinic agonist 1. muscarinic agonist (M2, 3) in detrusor muscle of bladder leading to contraction of detrusor and increased bladder emptying Oxybutynin muscarinic antagonist 2. muscarinic agonist (anticholinergic) inhibits action of acetylcholine on M2, 3 in bladder preventing detrusor muscle contraction Ipratropium muscarinic antagonist 3. muscarinic antagonist, anticholinergic blocking M3 receptors in airways leading to bronchodilation 4. muscarinic antagonist blocks M3 receptors in bladder, inhibiting muscle contraction and preventing involuntary Trospium muscarinic antagonist bladder contractions  Case bladder trauma: Explain how these cholinergic agents will affect the bladder? Bethanechol stimulate urination 1. stimulate urination Oxybutynin stop urination 2. stops urination 3. stops urination Ipratropium stop urination 4. stops urination Trospium stop urination PNS stimulation of Mouse-model What effect would a slow I.V. infused of bethanechol have on the parasympathetic nervous system of the mouse? Increase Urination (stimulates detrusor muscle) Bronchial constriction (stimulates M3 receptors in bronchi) Miosis (stimulates pupillary sphincter muscle in eye) Reduced heart rate (stimulates M2 receptor in heart resulting in bradycardia)  Pesticides & Poisons Thiophates Malathion: Relatively safe to mammals and birds because it is metabolised to inactive products. – carboxylase p/w Parathion: Thiophosphate insecticide like Malathion but is not metabolised or detoxified in the system  Careless Gardner A gardener unable to breathe after inhaling organophosphate compounds present in the pesticide. What could be the mechanism of action of this organophosphate? Irreversible AChEI (accumulation of ACh in synapses, resulting in prolonged stim of cholinergic receptors- bradycardia, bronchoconstriction, miosis, excessive salivation, sweating and lacrimation, diarrhea, urination) Give an example of a drug in this class: Parathion - when inhaled causes irreversible inhibition of AChE, leading to cholinergic toxicity - malathion is detoxified in mammals Hyperhidrosis condition characterised by excessive sweating (blocks M3 on sweat glands, reducing excess sweating) Anti-muscarinic agents Propantheline bromide Incomplete relief due to apocrine rather than eccrine glands involved Glycopyrrolate – study above : suggest that low- dose glycopyrrolate may be a safe and effective method of controlling exertional hyperhidrosis. Hyperhidrosis - Perspi-Guard Ireland Hyperhidrosis A 17-year-old female athlete with the highest sweat rate recorded in the literature (5.8 L/h). Initial TFT and FBS were normal. On examination was previous treatment included: not potent enough, apocrine Aluminium chloride topical treatment (failed), glands less affected, application technique/conc., non- Botulinum toxin A injection (block release of ACh at NMJ and reduce sweating compliance Further considerations: - manage exertional hyperhidrosis Low doses glycopyrrolate in combination… by reducing eccrine sweating  Hyperhidrosis can cause dehydration and exercise intolerance What are agents that may cause secondary hyperhidrosis? Medications that may cause Secondary Hyperhidrosis Cholinergic agonists - stim the parasymp NS, specifically M receptors on sweat glands which increases sweating Pilocarpine - M agonist used to treat dry mouth and glaucoma but increase sweat production Pyridostigmine - AChEI used in MG, increases sweating by prolonging ACh action at M receptors in sweat glands  The end Best of luck in your Pharmac QUIZ! Follow the instructions of the invigilators on the day.