Has little therapeutic value. Has multiple actions. Has short t ½ Activates muscarinic & nicotinic receptors. 10/17/2017 2

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2 Has little therapeutic value. Has multiple actions. Has short t ½ Activates muscarinic & nicotinic receptors. 10/17/2017 2

3 Muscarinic stimulation: On the CVS: -ve chronotropic & inotropic effects. Decrease stroke volume & cardiac output. Decrease ABP: Stimulation of vascular M 3 receptors Increase NO release from endothelium 10/17/2017 3

4 Eye: Miosis: Contraction of circular muscle of iris. Accommodation to near vision: Contraction of ciliary muscle of the eye Decrease IOP( intra-occular pressure) 10/17/2017 4

5 Exocrine glands & GI secretion: Increase secretion. Contraction of intestinal wall & relaxation of sphincters: Defecation Contraction of bladder wall & relaxation of sphincter: Urination 10/17/2017 5

6 Bronchi: Bronchoconstriction. Increase mucosal secretion. Penile erection: Increase release of nitric oxide. 10/17/2017 6

7 Nicotinic receptor stimulation: Autonomic ganglia: Stimulation Adrenal medulla: Increase noradrenaline & adrenaline secretion NM Junction transmission: Muscle contraction 10/17/2017 7

8 Mimic or simulate actions of Ach: Direct-acting. Indirect-acting. 10/17/2017 8

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10 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. 10/17/

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13 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 10/17/

14 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) 10/17/

15 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 10/17/

16 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 10/17/

17 10/17/

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19 Paralytic ileus (Bethanechol) Urinary retention (Bethanechol) Glaucoma (Pilocarpine & Carbachol topically Xerostomia (dry mouth) of Sjogren s syndrome (oral pilocarpine) 10/17/

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21 Excessive sweating, salivation Flushing, hypotension Abdominal colic & diarrhoea Bronchospasm Pilocarpine: Impaired accommodation to far vision & darkness 10/17/

22 Bronchial asthma Peptic ulcer 10/17/

23 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

24 Classified into: Reversible cholinesterase inhibitors Irreversible cholinesterase inhibitors 24

25 Diagnosis of MG (Edrophonium) Treatment of MG (Pyridostigmine) Reversible NMB intoxication (Neostigmine) Alzheimer s disease (Donepezil) Irreversible CEI: insecticides 25

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27 Autoimmune (autoantibodies to N M in NMJ) Reduction in receptor number Muscle weakness, fatigability,, difficult speaking & swallowing Treatment: Reversible CEI Thymectomy Immunosuppressant 27

28 Inhibit reversibly CE enzyme Accumulation of Ach Electrostatic bonds Stimulate nicotinic & muscarinic receptors Useful in myasthenia gravis 28

29 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 29

30 Similar to neostigmine Has longer duration of action (6 hrs) Useful orally in myasthenia gravis 30

31 Over-stimulating of nicotinic receptors can cause muscle weakness and paralysis by the excessive intake of Anticholinesterases which are (indirect drugs) Over-stimulation of nicotinic receptors will lead to its blockage instead of further activation.

32 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 32 improvement

33 Excessive salivation Flushing and hypotension Abdominal colic and diarrhoea Bronchospasm 3 3

34 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 34

35 Organophosphorous (OP) compounds. Irreversibly inhibit CE. Covalent bond in Enzyme-inhibitor complex. Used as insecticides: Parathion, malathion As nerve gases in chemical warfare: Tabun, Sarin, Soman 35

36 OP compound. Irreversibly inhibits CE. Insecticide. Toxicity: excessive cholinergic stimulation. May be used topically in glaucoma. Duration of action about a week. 36

37 New agent. Similar to isoflurophate. Long duration of action (week). 37

38 Actions on receptors: Direct Indirect Pharmacodynamic effects: Similar Central effects with indirect: Cross BBB 38

39 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 39

40 General measures. High doses atropine IV or IM. Mechanical ventilation. Diazepam for convulsions. Enzyme reactivation by pralidoxime IM. 40

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