1 / 67

Acetylcholine

Acetylcholine. Has little therapeutic value Has multiple actions Has short t ½ Activates muscarinic & nicotinic receptors. Pharmacodynamics of Ach. Muscarinic stimulation: On the CVS: - ve chronotropic & inotropic effects Decrease stroke volume & cardiac output   Decrease ABP:

Download Presentation

Acetylcholine

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Acetylcholine • Has little therapeutic value • Has multiple actions • Has short t ½ • Activates muscarinic & nicotinic receptors

  2. Pharmacodynamics of Ach • Muscarinic stimulation: • On the CVS: • -vechronotropic & inotropic effects • Decrease stroke volume & cardiac output   • Decrease ABP: • Stimulation of vascular M3 receptors • Increase NO release from endothelium  

  3. Pharmacodynamics of Ach • 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. Pharmacodynamics of Ach • Exocrine glands & GI secretion: • Increase secretion • Contraction of intestinal wall & relaxation of sphincters: • Defecation • Contraction of bladder wall & relaxation of sphincter: • Urination

  5. Pharmacodynamics of Ach • Bronchi: • Bronchoconstriction • Increase mucosal secretion • Penile erection: • Increase release of nitric oxide

  6. Pharmacodynamics of Ach • Nicotinic receptor stimulation: • Autonomic ganglia: • Stimulation • Adrenal medulla: • Increase noradrenaline & adrenaline secretion • NM Junction transmission: • Muscle contraction

  7. Cholinomimetics • Mimic or simulate actions of Ach: • Direct-acting • Indirect-acting

  8. Direct acting cholinomimetics • Activate directly cholinergic receptors: • Cholineesters: • Bethanechol, Carbachol, Methacholine • Resist degradation by cholinesterases • Have longer duration of action than Ach • Naturalalkaloid: • Pilocarpine • Acts directly on end organs like the eye

  9. Bethanechol • Derivative of Ach • Has: • Little nicotinic effects • Good muscarinic effects on bladder & GIT • Leads toeasy 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. Carbachol • 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. Pilocarpine • 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

  12. Pilocarpine • 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

  13. Indications of direct cholinomimetics • Paralytic ileus (Bethanechol) • Urinary retention (Bethanechol) • Glaucoma (Pilocarpine & Carbachol topically • Xerostomia (dry mouth) of Sjogren’s syndrome (oral pilocarpine)

  14. Adverse effects of direct cholinomimetics • Excessive sweating, salivation • Flushing, hypotension • Abdominal colic & diarrhoea • Bronchospasm • Pilocarpine: • Impaired accommodation to far vision & darkness

  15. Contraindications of cholinomimetics • Bronchial asthma • Peptic ulcer

  16. Cholinesterase enzymes • 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)

  17. Classification of indirect-acting cholinomimetics Classified into: • Reversible cholinesterase inhibitors • Irreversible cholinesterase inhibitors

  18. Uses of indirect-acting cholinomimetics • Diagnosis of MG (Edrophonium) • Treatment of MG (Pyridostigmine) • Reversible NMB intoxication (Neostigmine) • Alzheimer’s disease (Donepezil) • Irreversible CEI: insecticides

  19. Myasthenia gravis (MG) • Autoimmune (autoantibodies to NM in NMJ) • Reduction in receptor number • Muscle weakness, fatigability,, difficult speaking & swallowing • Treatment: • Reversible CEI • Thymectomy • Immunosuppressant

  20. Reversible ChE inhibitors • Inhibit reversibly CE enzyme • Accumulation of Ach • Electrostatic bonds • Stimulate nicotinic & muscarinic receptors • Useful in myasthenia gravis

  21. Neostigmine • 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  

  22. Pyridostigmine • Similar to neostigmine • Has longer duration of action (6 hrs) • Useful orally in myasthenia gravis

  23. Cholinergic Crisis: • Over-stimulating of nicotinic receptors can cause muscle weakness and paralysis by the excessive intake ofAnticholinesteraseswhich 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.

  24. Edrophonium • 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

  25. Adverse effects of CEI • Excessive salivation • Flushing and hypotension • Abdominal colic and diarrhoea • Bronchospasm

  26. CEI useful in Alzheimer’s disease • 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

  27. Irreversible CE Inhibitors • 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

  28. Isoflurophate (DFP) • OP compound • Irreversibly inhibits CE • Insecticide • Toxicity: excessive cholinergic stimulation • May be used topically in glaucoma • Duration of action about a week

  29. Echothiophate • New agent • Similar to isoflurophate • Long duration of action (week)

  30. Differences between direct & indirect-acting cholinomimrtics • Actions on receptors: • Direct • Indirect • Pharmacodynamic effects: • Similar • Central effects with indirect: • Cross BBB

  31. Organophosphorous Insecticide Poisoning • 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

  32. Treatment of OPI Poisoning • General measures • High doses atropine IV or IM • Mechanical ventilation • Diazepam for convulsions • Enzyme reactivation by pralidoxime IM

  33. Cholinergic Antagonist Drugs • 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.

  34. Anti-muscarinic anti-cholinergic drugs • Natural agents: • Atropine, Hyoscine • Semi-synthetic • Homatropine • Synthetic • Ipratropium, Pirenzepine, Propantheline

  35. Anti-muscarinic • 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

  36. Clinical pharmacology of anti-muscarinic drugs 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)

  37. Pharmacokinetics • 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 excretedunchanged

  38. Pharmacodynamics • Exocrine glands: at low doses reduced secretions • Salivary • Bronchial • Sweet glands

  39. CNS • 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

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

More Related