1. Autonomic nervous pharmacology 2

2. Acetylcholine Has little therapeutic value. Has multiple actions.
Has short t ½
Activates muscarinic & nicotinic receptors.
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3. Pharmacodynamics of Ach
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  
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4. 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)
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5. 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
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6. Pharmacodynamics of Ach
Bronchi:
Bronchoconstriction.
Increase mucosal secretion.
Penile erection:
Increase release of nitric oxide.
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7. Pharmacodynamics of Ach
Nicotinic receptor stimulation:
Autonomic ganglia:
Stimulation
Adrenal medulla:
Increase noradrenaline & adrenaline secretion
NM Junction transmission:
Muscle contraction
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8. Cholinomimetics Direct-acting. Indirect-acting.
Mimic or simulate actions of Ach:
Direct-acting.
Indirect-acting.
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10. Direct acting cholinomimetics
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.
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13. Bethanechol 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
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14. 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)
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15. 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
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16. 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
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17. 9/21/2018

19. Indications of direct cholinomimetics
Paralytic ileus (Bethanechol)
Urinary retention (Bethanechol)
Glaucoma (Pilocarpine & Carbachol topically
Xerostomia (dry mouth) of Sjogren’s syndrome (oral pilocarpine)
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21. Adverse effects of direct cholinomimetics
Excessive sweating, salivation
Flushing, hypotension
Abdominal colic & diarrhoea
Bronchospasm
Pilocarpine:
Impaired accommodation to far vision & darkness
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22. Contraindications of cholinomimetics
Bronchial asthma
Peptic ulcer
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23. 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)

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

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

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

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

29. 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  

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

31. Cholinergic Crisis:
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.
Cholinergic crisis can happen to myasthenia gravis patients who are overdosing on anticholinesterases drugs.

32. 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

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

34. 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

35. Irreversible CE Inhibitors
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

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

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

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

39. 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

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