Autonomic nervous pharmacology 2

Acetylcholine Has little therapeutic value. Has multiple actions. Has short t ½ Activates muscarinic & nicotinic receptors. 9/21/2018

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   9/21/2018

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) 9/21/2018

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 9/21/2018

Pharmacodynamics of Ach Bronchi: Bronchoconstriction. Increase mucosal secretion. Penile erection: Increase release of nitric oxide. 9/21/2018

Pharmacodynamics of Ach Nicotinic receptor stimulation: Autonomic ganglia: Stimulation Adrenal medulla: Increase noradrenaline & adrenaline secretion NM Junction transmission: Muscle contraction 9/21/2018

Cholinomimetics Direct-acting. Indirect-acting. Mimic or simulate actions of Ach: Direct-acting. Indirect-acting. 9/21/2018

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. 9/21/2018

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 9/21/2018

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) 9/21/2018

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 9/21/2018

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 9/21/2018

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Indications of direct cholinomimetics Paralytic ileus (Bethanechol) Urinary retention (Bethanechol) Glaucoma (Pilocarpine & Carbachol topically Xerostomia (dry mouth) of Sjogren’s syndrome (oral pilocarpine) 9/21/2018

Adverse effects of direct cholinomimetics Excessive sweating, salivation Flushing, hypotension Abdominal colic & diarrhoea Bronchospasm Pilocarpine: Impaired accommodation to far vision & darkness 9/21/2018

Contraindications of cholinomimetics Bronchial asthma Peptic ulcer 9/21/2018

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)

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

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

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

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

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  

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

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.

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

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

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

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

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

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

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

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

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