L11,12- Cholinergic Agonists & Antagonists PDF

ANS- Cholinergic Agonist Classify & describe cholinergic agonists including actions, therapeutic uses & adverse reactions. Describe myaesthenia gravis & its management Explain Organophosphorous poisoning & treatment A. Autonomic control of Pupil B. Site of action of Mydriatics C....

ANS- Cholinergic Agonist Classify & describe cholinergic agonists including actions, therapeutic uses & adverse reactions. Describe myaesthenia gravis & its management Explain Organophosphorous poisoning & treatment A. Autonomic control of Pupil B. Site of action of Mydriatics C. Site of action of Miotics  Parasympathetic Sympathetic (Muscarinic) (Adrenergic) Origin Cranio-sacral Thoraco-lumbar Ganglia Usually terminal or embedded in Usually paravertebral in the supplied organ the sympathetic chain Preganglionic Long short Postganglionic Short Long innervation Most organs receive dual innervation Control Almost all organs except B.V. Most of blood vessels Usually localized Usually generalized Actions Conserve energy and discharge Stress( fight and flight) (rest , digestion & waste removal) Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA = acetyl coenzyme A. C H O L I N E R G I C R E C E P T O R S M&N  Muscarinic Receptor Activation Cholinergic Receptor Mechanisms  Classification of -cholinergic agonists / Muscarinic Agonist / Parasympathomimmetics- Indirect acting cholinergic Agonist Direct acting cholinergic Agonist Acetylcholinesterase reactivator- Pralidoxime Pralidoxime Indirect-Acting Cholinergic Agonists: Anticholinesterase Agents (Reversible) AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its actions. Inhibitors of AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide cholinergic action by preventing the degradation of ACh. This results in an accumulation of ACh in the synaptic space.Therefore, these drugs can provoke a response at all cholinergic receptors, including both muscarinic (M) and nicotinic (N) receptors of the ANS, as well as at the NMJ and in the brain.  Actions of acetylcholine Muscurinic actions: Heart: it decreases the heart rate and cardiac output. Blood vessels: it causes vasodilatation and decreases BP. GIT: It increases the salivary & intestinal secretion. Increases intestinal motility and relaxes sphincters Respiratory system: bronchoconstriction & Increased secretions. Eyes: it causes: Miosis. Accommodation of near vision. Decrease the IOP due to increase in the out flow of aqueous humor. Genitourinary tract: it causes: Urination. Erection of genital in male. CNS: it causes excitatory effect and effect on the learning, short term memory and arousal. The nicotinic actions: NMJ: contraction of skeletal muscles. Stimulates both sympathetic and parasympathetic ganglia. Stimulates the release of adrenaline from the adrenal medulla and chromoffin. In CNS: stimulates the release of ADH at the hypothalamus. Therapeutic uses: Uses as eye drop to produce rapid and complete miosis after cataract surgery.  BETHANECHOL Not hydrolyzed by acetylcholinesterase but it is hydrolyzed by other esterase. It has no nicotinic actions. It is longer duration of action than acetylcholine. Therapeutic uses: Post operative non-0bstractive urinary retention. Post-operative or Neurogenic ileus. Gastric Atony  PILOCARPINE It is natural alkaloid, not hydrolyzed by acetylcholinesterase. It has marked muscarinic actions. Actions: Eye: loss of accommodation, miosis and lowering the intraocular pressure (IOP) by causing contraction of ciliary muscles & pupillary sphincter of the eye. Other actions: it stimulates the secretary glands and causes sweating, salivation and lacrimation. Therapeutic uses of pilocarpine: In the treatment of GLAUCOMA. Sgogren Syndrome To reverse cycloplagic and mydriatic effect of atropine. Side effects: CNS disturbance because it is crossing the BBB. Sweating and salivation.  PHYSOSTIGMINE: It is an alkaloid. Well absorbed and penetrate the BBB. Therapeutic uses: Glaucoma. Atropine poisoning Alzheimer s disease. Side effects: CNS: convulsions. Heart: bradycardia. Paralysis of skeletal muscles which it is rare seen in the therapeutic dose. Lid muscles twitching. NEOSTIGMINE: It is synthetic anticholinerASE drug. It is poorly absorbed. It is polar compound and so that not cross to the CNS. Therapeutic uses: As antidote for tubocurarine poisoning Management of Mysthenia Gravis (MG): MG-is an a autoimmune disorder due to antibodies against Ach receptor, Physostigmine Vs Neostigmine Summary of Cholinergic agonist. Organophosphorous (OP) compounds: OP compounds are highly lipid soluble, so they cross the BBB easily. Irreversible AChE inhibitors (mostly organophosphate compounds) are commonly used as insecticides (malathion), They are frequently used for suicidal and homicidal purposes. Organophosphate nerve gases such as sarin are used as agents of warfare and chemical terrorism. Acute toxicity (organophophorous compound poisoning / Anticholinesterase poisoning) with these agents is manifested as nicotinic and muscarinic signs and symptoms (cholinergic crisis) by inactivate enzyme ACHE enzyme irreversibly and increasing the level of acetylcholine So, they Cause; Muscarinic (DUMBBELLS) Diarrhea Urination Miosis (pupil constriction) Bradycardia Bronchospasm/bronchorrhea Emesis Lacrimation Lethargy Salivation Nicotinic (at very large dose)- Skeletal Muscle paralysis &excitation of CNS Chronic toxicity of organophosphorous compounds causes neuropathy and demyelination of axons.  Treatment of Organophosphorous Poisoning: Maintenance of vital signs: Aspiration of bronchial secretions, endotracheal intubations and artificial respiration. Decontamination: to prevent further absorption, removal of the contaminated clothes and washing the skin, gastric lavage if need. Atropine (mustarinic antagonist- Blocks-DUMBBELLS)- It is Given IV (dose monitored by Heart rate & pupil Size) Cholinesterase reactivator examples: pralidoxime (PAM). Diazepam Other symptomatic treatment Management of myaesthenia gravis Management of myaesthenia gravis(contd.) Summarize…. Further reading; Lippincott’s illustrated pharmacology 7 th edition Essentials of medical pharmacology by K.D. Tripathi- 8th edition Katzung basic & clinical pharmacology 15th edition  Cholinergic Antagonist / Muscarinic Antagonist Objectives Classify & describe cholinergic antagonists Explain actions, therapeutic uses & adverse reactions of cholinergic antagonists Site of antimuscarinic blockers/ Atropine Atropine is a competitive antagonist of Acetyl Choline at muscarinic receptor (Post synaptic parasympathetic Neuro-Effector Junction) Classification of Anticholinergic drugs / Anti-Muscarinic Drugs Actions of antimuscarinic / Atropine Atropine; is a tertiary amine extracted from belladonna alkaloid. It has a high affinity for muscarinic receptors and is competitive antagonist of Ach. Actions of Atropine (Blocks DUMBBELLS) Eye -Atropine blocks muscarinic activity in the eye, resulting in mydriasis (dilation of the pupil), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with angle-closure glaucoma, intraocular pressure may rise dangerously. Gastrointestinal (GI) - Atropine reduces GI motilitity and cause constipation. Atropine can be used as an antispasmodic to reduce activity of the GI tract. Cardiovascular -Atropine cause a progressive increase in heart rate by blocking M2 receptors on the sinoatrial node. Secretions -Atropine blocks muscarinic receptors in the salivary glands, producing dryness of the mouth (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. Respiratory- Decreases secretions & causes bronchodilataion Genito urinary- relaxes detrusor & contracts sphincter leading to retention of urination- CNS- Decreases Muscle rigidity & tremors Uses of Atropine/ Muscarinic antagonist Organophosphorous poisoning Fundoscopic examination of eye- Mydriasis Pre-anaesthetic medication Parkinsons disease Asthma/ COPD Urinary urgency Motion sickness Bradycardia Peptic ulcer disease / IBD Adverse effects of atropine / Muscarinic antagonist Constipation Dryness of mouth Blurring of vision Drowsiness Tachycardia / palpitation Photophobia / decreased accomodation Note: Atropine toxicity is treated with - Physostigmine AntiMuscarinic agents- Uses & Characteristics Summarize…. Further reading; Lippincott’s illustrated pharmacology 7 th edition Essentials of medical pharmacology by K.D. Tripathi- 8th edition Katzung basic & clinical pharmacology 15th edition