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CHOLINERGIC AGONISTS
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DIRECT ACTING Acetyl choline Bethanecol Carbachol cevimeline pilocarpine
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INDIRECT ACTING ( reversible)
Ambenomium Donepezil Edrophonium Galantamine Neostigmine Physostigmine Pyridostigmine Rivastigmine tacrine
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INDIRECT ACTING (irreversible)
Ecothiophate isoflurophate
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REACTIVATION OF ACETYLCHOLINEESTERASE
pralidoxime ( PAM )
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CHOLINERGIC AGONISTS Neurotransmission at cholinergic neurons
Synthesis, storage, release, and binding of acetyl choline. Synthesis—choline cotransport system involving sodium. Storage in vesicles.—contains ach & ATP. Release—opening of ca channels. Binding—ach binds to either of two receptors muscarinic or nicotinic.
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Degradation-acetylcholine esterace cleaves acetyl choline to choline and acetate in synaptic cleft.
Recycling- choline recaptured by sodium and gets transported back to the neuron.
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Muscarinic receptors – decreased HR, increased glandular secretory activity, stimulation of smooth muscle contractions.M1,M2,M3,M4 & M5 Nicotinic receptors – increased B.P (peripheral vasoconstriction), contraction of skeletal muscle. NM, NN.
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Location of muscarinic receptors
Ganglia of pns Autonomic effector organs—heart, smooth muscle, brain and exocrine glands. Location of nicotinic receptors Cns, adrenal medulla, neuro muscular junction.
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Cholinergic agonists Direct acting Indirect acting
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Direct acting Choline esters Acetylcholine Bethanechol Carbachol
Methacholine Alkaloids Muscarine Pilocarpine
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Acetyl choline —both muscarinic and nicotinic activities.
Actions---decrease in heart rate & cardiac output. Mimics effects of vagal stimulation. Decrease in blood pressure—due to vasodilatation.---rise in intracellular calcium. Increases salivary, intestinal, bronchial secretion.
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ACH – both muscarinic (M) and nicotinic (N) receptors
Bethanechol – strong M and low or no N Carbachol – both (Strong N) Pilocarpine – more M
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Gastrointestinal & Genitourinary Bethanechol GI smooth muscle stimulant >> postoperative abdominal distention >> paralytic ileus >>esophageal reflux; (promotes increased esophageal motility) Urinary bladder stimulant post-operative; post-partum urinary retention Carbachol not used due to more prominent nicotinic receptor activation Methacholine used for diagnostic purposes. testing for bronchial hyper reactivity and asthma
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Opthalmological Uses Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery Carbachol may be used also in treatment of glaucoma. Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the closed-angle form. effective even in open angle type. Opens the trab mesh work around schlemm canal. Sequential administration of atropine (mydriatic) and Pilocarpine (miotic) is used to break iris-lens adhesions
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Major contraindication to the use of muscarinic agonists Asthma Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced. Hyperthyroidism Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients. Peptic ulcer Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms. Coronary vascular disease Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow.
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Adverse Effects: Muscarinic Agonists salivation diaphoresis colic GI hyperactivity headache loss of accommodation
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Indirect acting thru enzyme
Reversible inhibitors Irreversible inhibitors
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Reversible" Anticholinesterases Used Clinically
Edrophonium Pyridostigmine - Used in treatment of myasthenia gravis Neostigmine Physostigmine Demecarium Ambenonium - Used in treatment of myasthenia gravis
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Physostigmine Actions – muscarinic and nicotinic actions. Miosis and spasm of accomodation. Decreases iop. High doses can cause convulsions
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Neostigmine Has a quarternary nitrogen. there fore it does not enter the cns. Use – antidote for tubocurarine & treatment of myasthenia gravis.
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Acetylcholinesterase Inhibitors ("Irreversible") Soman Parathion Malathion Isoflurophate Echothiophate
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Organo phosphate poisoning
Reactivation of acetylcholine esterase Pralidoxime (PAM) (Pyridine – 2 aldoxime chloride)
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Drugs affecting the release:
· Drugs which increase Ach release (mainly venom toxins) · b bungarotoxin · Banded krait venom · Black widow spider venom · These toxins cause a massive release of Ach which results in fasciculations of muscle followed by paralysis as all of the Ach is drained from the nerve terminal
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Drugs which decrease Ach release
· Botulinum toxin · Produced by the Clostridium botulinum · This bacterium lives in unsterilised canned foods. Drug that interfere with the synthesis Choline uptake inhibition · Hemicholinium
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Prepare botox Trigeminal neuralgia Bio weapon—1 pound---entire human population
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Glaucoma Myasthenia gravis
a disease of the eye marked by increased pressure within the eyeball that can result in damage to the optic disk and gradual loss of vision. Myasthenia gravis a disease characterized by progressive weakness and exhaustibility of voluntary muscles without atrophy or sensory disturbance and caused by an autoimmune attack on acetylcholine receptors at neuromuscular junctions.
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