cholinergic drugs

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  • 1. Cholinergic drugs
  • 2.  Also called Cholinomimetic or parasympathomimetic drugs.  Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces.  This class of drugs includes agents that act directly as agonists at cholinoreceptors and agents that act indirectly by inhibiting the enzymatic destruction of endogenous Ach.
  • 3.  The directly acting cholinomimetics can be subdivided into  Agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuroeffector junctions (parasympathomimetic drugs) and  Agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction.
  • 4. Pharmacological Effects of Muscarinic Stimulation  CARDIOVASCULAR SYSTEM:  ACh has four primary effects on the cardiovascular system:  Vasodilation,  Decrease in cardiac rate (the negative chronotropic effect),  Decrease in the rate of conduction in the specialized tissues of the SA and atrioventricular (AV) nodes (the negative dromotropic effect), and  Decrease in the force of cardiac contraction (the negative inotropiceffect).  The last effect is of lesser significance in ventricular than in atrial muscle.  Certain of the above responses can be obscured by baroreceptor and other reflexes that dampen or counteract the direct responses to ACh.
  • 5. GASTROINTESTINAL AND URINARY TRACTS  Although stimulation of vagal input to the gastrointestinal (GI) tract increases tone, amplitude of contraction, and secretory activity of the stomach and intestine.  such responses are inconsistently seen with administered ACh.  Poor perfusion of visceral organs and rapid hydrolysis by plasma butyrylcholinesterase limit access of systemically administered ACh to visceral muscarinic receptors.  Parasympathetic sacral innervation causes detrusor muscle contraction, increased voiding pressure, and ureter peristalsis, but for similar reasons these responses are not evident with administered ACh.
  • 6. MISCELLANEOUS EFFECTS  ACh and its analogs stimulate secretion by all glands that receive parasympathetic innervation, including the lacrimal, tracheobronchial, salivary, and digestive glands.  The effects on the respiratory system, in addition to increased tracheobronchial secretion, include bronchoconstriction and stimulation of the chemoreceptors of the carotid and aortic bodies.  When instilled into the eye, muscarinic agonists produce miosis.
  • 7. Cholinergic drugs  Cholinergic receptor agonists can be divided into two groups:  (1) ACh and several synthetic choline esters, and  (2) The naturally occurring cholinomimetic alkaloids
  • 8. Classification : 1. Choline esters : Acetylcholine, Methacholine, Carbachol, Bethanechol 2. Alkaloids : Muscarine, Pilocarpine, Arecoline
  • 9.  The therapeutic usefulness of ACh is limited by  (1) its lack of selectivity as an agonist for different types of cholinoreceptors and  (2) its rapid degradation by cholinesterases.  These limitations have been circumvented in part by the development of three choline ester derivatives of ACh:  Methacholine ,  Carbachol and  Bethanechol.
  • 10.  Methacholine differs from ACh only in the addition of a methyl group at the beta-carbon of ACh.  This modification greatly increases its selectivity for muscarinic receptors relative to nicotinic receptors.  It renders methacholine resistant to the pseudo-ChE in the plasma and decreases its susceptibility to AChE, thereby increasing its potency and duration of action compared to those of ACh.
  • 11.  Carbachol differs from ACh only in the substitution of a carbamoyl group for the terminal methyl group of ACh.  This substitution makes carbachol completely resistant to degradation by cholinesterases but does not improve its selectivity for muscarinic versus nicotinic receptors.  Bethanechol combines the addition of the methyl group and the substitution of the terminal carbamoyl group, producing a drug that is a selective agonist of muscarinic receptors and is resistant to degradation by cholinesterases.
  • 12. Clinical Uses  Glaucoma  Cholinomimetic drugs are useful for treating glaucoma because they can decrease the resistance to the movement of fluid (aqueous humor) out of the eye, thereby reducing the intraocular pressure.  Surgery of the Eye  Cataract surgery sometimes requires the use of acetylcholine to constrict the pupil rapidly.  Urinary Retention  Postpartum and postoperative non obstructive urinary retention or urinary retention caused by neurogenic bladder. ( Bethanicol )  XEROSTOMIA  Pilocarpine is administered orally in 5–10-mg doses given three times daily for the treatment of xerostomia
  • 13. Adverse Effects  Potentially severe adverse effects can result from systemic administration of cholinomimetic drugs,and none should be administered by intramuscular or intravenous injection.  If significant amounts of these drugs enter the circulation:  Nausea , abdominal cramps, diarrhea, salivation, hypotension with reflex tachycardia, cutaneous vasodilation, sweating, and broncho constriction can result.
  • 14. Indirect Acting Cholinomimetic Drugs Cholinesterase inhibitors:  Reversible Cholinesterase inhibitors:  Physostigmine, neostigmine, pyridostigmine, edrophonium, Tacrine  Irreversible Cholinesterase inhibitors:  Echothiophate, di-isopropylflurophosphate (organo- phosphate compounds, malathion, parathion, diazinon)
  • 15. Basic Pharmacology  Inhibition of AChE potentiates and prolongs the stimulation of cholinoreceptors resulting from ACh released at cholinergic synapses.  These synapses found at the skeletal neuromuscular junction, adrenal medulla, autonomic ganglia, and cholinergic synapses in the CNS.  Inhibition of AChE can increase the stimulation of both muscarinic and nicotinic receptors produced by synaptically released ACh.  several AChE inhibitors also inhibit the pseudo-ChE in plasma. This can permit plasma concentrations of ACh to rise markedly and activate endothelial muscarinic receptors.
  • 16. Physostigmine Action • Inhibits the breakdown of acetylcholine so that it accumulates and has a prolonged effect. Result is generalized cholinergic response, including : - › Miosis. › Increased tone of intestinal and skeletal musculature. › Bronchial and ureteral constriction. › Bradycardia. › Increased salivation. › Lacrimation. › Sweating. › CNS stimulation.
  • 17. Pharmacokinetics  Absorption: Readily absorbed from subcut and IM sites.  Distribution: Widely distributed; crosses the blood-brain barrier.  Half-life: 1–2 hours.
  • 18. Classifications  Therapeutic Classification: antidotes  Pharmacologic Classification: cholinergics, anticholinesterases Availability • Injection: 1 mg/ml in 2-ml ampules
  • 19. Clinical Uses  Myasthenia Gravis  Smooth Muscle Atony  Antimuscarinic Toxicity ( Atropine )  Alzheimer’s Disease (Tacrine, Rivastigmine)  Reversal of Neuromuscular Blockade  Anticholinesterase agents are widely used in anesthesiology to reverse the neuromuscular blockade caused by nondepolarizing muscle relaxants.
  • 20. Adv. Reactions/Side Effects  CNS: seizures , restlessness  EENT: lacrimation, miosis.  Resp: bronchospasm, excess respiratory secretions.  CV: bradycardia, hypotension .  GI: abdominal cramps, diarrhea , nausea, vomiting, excess salivation .