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Has little therapeutic value Has multiple actions Has short t ½ Activates muscarinic & nicotinic receptors 4/9/2017 1 Muscarinic stimulation: On the CVS: -ve chronotropic & inotropic effects Decrease stroke volume & cardiac output Decrease ABP: Stimulation of vascular M3 receptors Increase NO release from endothelium 4/9/2017 2 Eye: Miosis: Contraction of circular muscle of iris Accommodation to near vision: Contraction of ciliary muscle of the eye Decrease IOP( intra-occular pressure) 4/9/2017 3 Exocrine glands & GI secretion: Increase secretion Contraction of intestinal wall & relaxation of sphincters: Defecation Contraction of bladder wall & relaxation of sphincter: Urination 4/9/2017 4 Bronchi: Bronchoconstriction Increase mucosal secretion Penile erection: Increase release of nitric oxide 4/9/2017 5 Nicotinic receptor stimulation: Autonomic ganglia: Stimulation Adrenal medulla: Increase noradrenaline & adrenaline secretion NM Junction transmission: Muscle contraction 4/9/2017 6 Mimic or simulate actions of Ach: Direct-acting Indirect-acting 4/9/2017 7 Activate directly cholinergic receptors: Choline esters: Bethanechol, Carbachol, Methacholine Resist degradation by cholinesterases Have longer duration of action than Ach Natural alkaloid: Pilocarpine Acts directly on end organs like the eye 4/9/2017 9 Derivative of Ach Has: Little nicotinic effects Good muscarinic effects on bladder & GIT Leads to easy urination & defecation Used to treat post-operative or post-labour: Urinary retention or paralytic ileus: the weakness of intestine to push its content causing constipation because of weak peristaltic activity 4/9/2017 13 Derivative of Ach Has muscarinic & nicotinic actions Limited use: Because of nicotinic effects on ganglia & adrenal medulla Used mainly topically as miotic in glaucoma to decrease high intraocular pressure (IOP) 4/9/2017 14 Natural plant alkaloid Resistant to CE enzyme It produces: Miosis (contraction of circular muscle of iris) Contraction of ciliary muscle of the eye Reduction of IOP Used topically in glaucoma 4/9/2017 15 Lowers high IOP in close-angle & open angle chronic glaucoma Improves outflow of aqueous humour: Opens fluid pathway Increase aqueous flow through canal of Schlemm Secondary to contraction of circular muscle of the iris & ciliary muscle Stimulates sweating, lacrimation, salivation 4/9/2017 16 4/9/2017 17 Paralytic ileus (Bethanechol) Urinary retention (Bethanechol) Glaucoma (Pilocarpine & Carbachol topically Xerostomia (dry mouth) of Sjogren’s syndrome (oral pilocarpine) 4/9/2017 19 Excessive sweating, salivation Flushing, hypotension Abdominal colic & diarrhoea Bronchospasm Pilocarpine: Impaired accommodation to far vision & darkness 4/9/2017 21 Bronchial asthma Peptic ulcer 4/9/2017 22 CE is a protein In cholinergic synapses & RBC Metabolizes Ach into choline & acetate Specific for Ach in cholinergic synapses Pseudocholinesterase in plasma & liver Not specific to Ach Metabolizes other drugs (suxamethonium, procaine) 23 Classified into: Reversible cholinesterase inhibitors Irreversible cholinesterase inhibitors 24 Diagnosis of MG (Edrophonium) Treatment of MG (Pyridostigmine) Reversible NMB intoxication (Neostigmine) Alzheimer’s disease (Donepezil) Irreversible CEI: insecticides 25 Autoimmune (autoantibodies to NM in NMJ) Reduction in receptor number Muscle weakness, fatigability,, difficult speaking & swallowing Treatment: Reversible CEI Thymectomy Immunosuppressant 26 Inhibit reversibly CE enzyme Accumulation of Ach Electrostatic bonds Stimulate nicotinic & muscarinic receptors Useful in myasthenia gravis 27 Synthetic CEI, does not cross BBB Duration of action (4 hrs) Mainly in MG & also in: Antidote to competitive NM blocker tubocurarine poisoning Paralytic ileus, urinary retention Given orally, SC 28 Similar to neostigmine Has longer duration of action (6 hrs) Useful orally in myasthenia gravis 29 Over-stimulating of nicotinic receptors can cause muscle weakness and paralysis by the excessive intake ofAnticholinesterases which are (indirect drugs) Over-stimulation of nicotinic receptors will lead to its blockage instead of further activation. Cholinergic crisis can happen to myasthenia gravis patients who are overdosing on anticholinesterases drugs. Similar to neostigmine IV, short duration of action (10-20 min) Useful in diagnosis of MG To differentiate between weakness due to myasthenic crisis or cholinergic crisis: Myasthenic crisis Cholinergic crisis improvement aggravated 31 Excessive salivation Flushing and hypotension Abdominal colic and diarrhoea Bronchospasm 32 Tacrine Reversible CEI used in treatment of Alzheimer’s disease; hepatotoxic Donepezil New selective CEI Once daily Lacks hepatoxicity of tacrine Useful in Alzheimer’s disease 33 Organophosphorous compounds Irreversibly inhibit CE Covalent bond in Enzyme-inhibitor complex Used as insecticides: Parathion, malathion As nerve gases in chemical warfare: Tabun, Sarin, Soman 34 OP compound Irreversibly inhibits CE Insecticide Toxicity: excessive cholinergic stimulation May be used topically in glaucoma Duration of action about a week 35 New agent Similar to isoflurophate Long duration of action (week) 36 Actions on receptors: Direct Indirect Pharmacodynamic effects: Similar Central effects with indirect: Cross BBB 37 Agricultural or industrial accidents Excessive cholinergic manifestations GIT (diarrhoea, colic) Respiratory (dyspnoea, bronchospam) CV (bradycardia, hypotension) Micturition, excessive sweating, M. paralysis Miosis (pin-point pupil), convulsions & death 38 General measures High doses atropine IV or IM Mechanical ventilation Diazepam for convulsions Enzyme reactivation by pralidoxime IM 39 a) b) Anti-muscarinic drug: Atropine-like drugs, Hyoscine (Scopolamine) Anti-nicotinic drugs Ganglion blockers: Used in experimental pharmacology. E.g. Nicotine, Trimethapan. Neuro-muscular blockers: Used in surgery to produce complete muscle relaxation. • • • Natural agents: Atropine, Hyoscine Semi-synthetic Homatropine Synthetic Ipratropium, Pirenzepine, Propantheline Atropine (Hyoscyamine) • Alkaloids obtained from Atropa Belladona, Considered as prototype for parasympatolytics Hyoscine (Scopolamine) • • Obtained from Hyocyamus niger plant (Datura Stramonium) Note: Antihistamines, phenothiazides and some antidepressants have antimuscarinic effects Mechanism of action: Reversible blockade of M receptors Exocrine glands are most sensitive Gastric secretion is the least affected Heart is intermediate Note: Atropine blocks all 3 subtypes receptors (M1,M2,M3) Absorption: Natural and most tertiary amines: good Wide distribution and cross BBB Quaternary amines: poorly absorbed and poor crossing BBB (Ipratropium) Atropine t½: 2hrs Partly metabolized and partly excreted unchanged Exocrine • • • glands: at low doses reduced secretions Salivary Bronchial Sweet glands Central stimulant effects (Atropine) Some may produce sedation (Hyoscine) Hyoscine blocks M receptors in vomiting centre and has anti-emetic effect Toxic doses: hallucination, convulsion, coma Mydriasis (dilatation of pupil) Cycloplegia (relaxation of the ciliary muscle) cause: blurred vision and impaired accommodation to near vision Decreased lacrimation Increase IOP Depending in the doses Central effect: Decrease heart rate Peripheral effect: Blockade of vagus nerve and increase heart rate ABP: No change Bronchodilatation Reduced bronchial secretion Ipratropium (quaternary amine derivate of Atropine) inhalation: ◦ Useful in asthma and chronic obstructive pulmonary disease (COPD), also in patient who are unable to take adrenergic agonists. Decrease salivation Decrease acid secretion Decrease motility Delay gastric emptying Prolong intestinal transit time Anti-diarrhoeal and anti-spasmodic effects Relaxation of bladder wall Useful in inflammatory spasm and pains of the urinary tract Risky in patients with BPH (Benign Prostatic Hypertrophy) CNS disorders: Parkinson’s disease Drug-induced parkinsonism as Phenothiazine (induced acute dystonias: sustained contraction of muscles leading to twisting, distorted postures) Benztropine, Benzhexol: useful Motion sickness: Hyoscine oral, injection, transdermal patches Ocular uses: In eye examination (Tropicamide) produce mydriasis and cycloplegia In iritis (Atropine eye drop) prevent synechia (adhesion of the iris to the lens) Note: Atropine eye drops effects: 7 days Tropicamide eye drops effects: 4-12hrs Premedication: Hyoscine and Atropine (use as adjunct in anaesthetic procedure) Bronchial asthma: Ipratropium inh. (produce bronchodilatation) Cardiovascular: Bradycardia and Atropine heart block following AMI: GI disorders: Anti-diarrhoeal • Lomotil= atropine + diphenoxylate Anti-spasmodics (in intestinal colic, irritable bowel syndrome) • Atropine, hyoscine, clidinium, prifinium. Urinary disorders: Urinary urgency with UTI Renal colic Cholinergic poisoning as: • Irreversible CEI insecticide poisoning • Chemical warfare intoxication. To counteract muscarinic effects (nicotinic effects can not be reversed) Atropine IV Dry mouth Blurred vision Tachycardia Constipation Hot flushed dry skin & hyperthermia may occur with high doses Glaucoma • Increase IOP BPH • Bladder wall relaxation & sphincter contraction Hot flushed dry skin & hyperthermia, Agitation, delirium, hallucination, Convulsions & coma Treatment is symptomatic Atropine Hyoscine • Buscopan Clidinium • Libraxam Prifinium • Riabal Nondepolarizing (competitive) blockers The first drug known to block the skeletal NMJ was curare. Neuromuscular blockers are clinically useful during surgery to facilitate tracheal intubation and provide complete muscle relaxation at lower anesthetic doses, allowing for more rapid recovery from anesthesia and reducing postoperative respiratory depression. Depolarizing agents Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh.