1. 1  Has little therapeutic value  Has multiple actions  Has short t ½  Activates muscarinic & nicotinic receptors 11/19/2016

2. 2  Muscarinic stimulation:  On the CVS:  -ve chronotropic & inotropic effects  Decrease stroke volume & cardiac output  Decrease stroke volume & cardiac output  Decrease ABP:  Stimulation of vascular M 3 receptors  Increase NO release from endothelium  Increase NO release from endothelium 11/19/2016

3. 3  Eye:  Miosis:  Contraction of circular muscle of iris  Accommodation to near vision:  Contraction of ciliary muscle of the eye  Decrease IOP( intra-occular pressure) 11/19/2016

4. 4  Exocrine glands & GI secretion:  Increase secretion  Contraction of intestinal wall & relaxation of sphincters:  Defecation  Contraction of bladder wall & relaxation of sphincter:  Urination 11/19/2016

5. 5  Bronchi:  Bronchoconstriction  Increase mucosal secretion  Penile erection:  Increase release of nitric oxide 11/19/2016

6. 6  Nicotinic receptor stimulation:  Autonomic ganglia:  Stimulation  Adrenal medulla:  Increase noradrenaline & adrenaline secretion  NM Junction transmission:  Muscle contraction 11/19/2016

7. 7  Mimic or simulate actions of Ach:  Direct-acting  Indirect-acting 11/19/2016

9. 9  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 11/19/2016

13. 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  Urinary retention or paralytic ileus: the weakness of intestine to push its content causing constipation because of weak peristaltic activity 11/19/2016

14. 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) 11/19/2016

15. 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 11/19/2016

16. 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 11/19/2016

17. 1711/19/2016

19. 19  Paralytic ileus (Bethanechol)  Urinary retention (Bethanechol)  Glaucoma ( Pilocarpine & Carbachol topically  Xerostomia (dry mouth) of Sjogren’s syndrome (oral pilocarpine) 11/19/2016

21. 21  Excessive sweating, salivation  Flushing, hypotension  Abdominal colic & diarrhoea  Bronchospasm  Pilocarpine:  Impaired accommodation to far vision & darkness 11/19/2016

22. 22  Bronchial asthma  Peptic ulcer 11/19/2016

23. 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)

24. 24 Classified into:  Reversible cholinesterase inhibitors  Irreversible cholinesterase inhibitors

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

26. 26  Autoimmune (autoantibodies to N M in NMJ)  Reduction in receptor number  Muscle weakness, fatigability,, difficult speaking & swallowing  Treatment:  Reversible CEI  Thymectomy  Immunosuppressant

27. 27  Inhibit reversibly CE enzyme  Accumulation of Ach  Electrostatic bonds  Stimulate nicotinic & muscarinic receptors  Useful in myasthenia gravis

28. 28  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  Given orally, SC

29. 29  Similar to neostigmine  Has longer duration of action (6 hrs)  Useful orally in myasthenia gravis

30.  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.

31. 31  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 improvement  Cholinergic crisis aggravated

32. 32  Excessive salivation  Flushing and hypotension  Abdominal colic and diarrhoea  Bronchospasm

33. 33  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. 34  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

35. 35  OP compound  Irreversibly inhibits CE  Insecticide  Toxicity: excessive cholinergic stimulation  May be used topically in glaucoma  Duration of action about a week

36. 36  New agent  Similar to isoflurophate  Long duration of action (week)

37. 37  Actions on receptors:  Direct  Indirect  Pharmacodynamic effects:  Similar  Central effects with indirect:  Cross BBB

38. 38  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. 39  General measures  High doses atropine IV or IM  Mechanical ventilation  Diazepam for convulsions  Enzyme reactivation by pralidoxime IM

40.  Anti-muscarinic drug: Atropine-like drugs, Hyoscine (Scopolamine)  Anti-nicotinic drugs a) Ganglion blockers: Used in experimental pharmacology. E.g. Nicotine, Trimethapan. b) Neuro-muscular blockers: Used in surgery to produce complete muscle relaxation.

43.  Natural agents: Atropine, Hyoscine  Semi-synthetic Homatropine  Synthetic Ipratropium, Pirenzepine, Propantheline

44.  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 anti- muscarinic effects

45. 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 (M 1,M 2,M 3 )

46.  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

47.  Exocrine glands: at low doses reduced secretions Salivary Bronchial Sweet glands

49.  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

50.  Mydriasis (dilatation of pupil)  Cycloplegia (relaxation of the ciliary muscle) cause: blurred vision and impaired accommodation to near vision  Decreased lacrimation  Increase IOP

52. Depending in the doses  Central effect:  Decrease heart rate  Peripheral effect:  Blockade of vagus nerve and increase heart rate  ABP:  No change

53.  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.

54.  Decrease salivation  Decrease acid secretion  Decrease motility  Delay gastric emptying  Prolong intestinal transit time  Anti-diarrhoeal and anti-spasmodic effects

55.  Relaxation of bladder wall  Useful in inflammatory spasm and pains of the urinary tract  Risky in patients with BPH (Benign Prostatic Hypertrophy)

56. 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, trans- dermal patches

57. 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

58.  Premedication: Hyoscine and Atropine (use as adjunct in anaesthetic procedure)  Bronchial asthma: Ipratropium inh. (produce bronchodilatation) Cardiovascular:  Bradycardia and heart block following AMI: Atropine

59. 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

60.  Cholinergic poisoning as: Irreversible CEI insecticide poisoning Chemical warfare intoxication.  To counteract muscarinic effects  (nicotinic effects can not be reversed)  Atropine IV

62.  Dry mouth  Blurred vision  Tachycardia  Constipation  Hot flushed dry skin & hyperthermia may occur with high doses

63.  Glaucoma Increase IOP  BPH Bladder wall relaxation & sphincter contraction

64.  Hot flushed dry skin & hyperthermia,  Agitation, delirium, hallucination,  Convulsions & coma  Treatment is symptomatic

65.  Atropine  Hyoscine Buscopan  Clidinium Libraxam  Prifinium Riabal

66.  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.

67.  Depolarizing agents  Depolarizing blocking agents work by depolarizing the plasma membrane  of the muscle fiber, similar to the action of ACh.