1. Autonomic Nervous System (ANS) Cholinergic Drugs 4 أ0م0د.وحدة بشير اليوزبكي

2. Objectives At end of this lecture, the students should be able to: 1- Identify myasthenia gravis (pathogenesis, diagnosis & treatment). 2- Enumerate drugs induced disorders of N-M transmission. 3- State clinical indications of the cholinergic drugs (agonists) in general. 4- Discuss adverse reactions of all the cholinergic drugs. - At a level consistence with standards scientific curriculum for the College of Medicine/ University of Mosul.

3. Myasthenia Gravis It is a disease affecting neuromuscular junctions of skeletal muscle. Pathogenesis: - Clinical features of MG are caused by special autoimmune antibodies (Abs), which either block or causes lyses of the Ach receptors. - Cholinoceptors exist for about 7days in normal individuals but for only 1day in MG patient. - The thymus gland is in some way involved in the pathogenesis as 75% of the patients have either thymitis or a thymoma.

4. Symptoms of myasthenia gravis - The characteristic symptoms of weakness and fatigability that decrease with rest and worsen with exercise, may affect any skeletal muscle but most often involve the small muscles of the head, neck, and extremities. - Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing & extremity weakness. - Severe disease may affect all the muscles, including muscles necessary for respiration.

5. myasthenia gravis Diagnosis of - Edrophonium is used as a diagnostic test for MG. 2 mg dose is injected IV after baseline measurements of muscle strength have been obtained. If no response occurs after 45 seconds, an additional 8 mg may be injected. - If the patient has MG an improvement in the strength of muscles last for 15 minutes ( this differentiate MG from cholinergic crisis due to excessive drug therapy in which there will be worsening of the condition).

6. myasthenia gravis Treatment of 1- Chronic long-term therapy of MG is usually accomplished with neostigmine, pyridostigmine. Notes: a- The doses are titrated to optimum levels based on changes in muscle strength. b- These agents are relatively short-acting and therefore require frequent dosing (every 2-4 hours, for neostigmine and every 3-6 hours for pyridostigrnine). ?

7. c- If muscarinic effects of such therapy are prominent, they can be treated by atropine (antimuscarinic drugs) d- Longer-acting cholinesterase inhibitors such as the organophosphorous agents are not used. ?? because the dose requirement in this disease changes too rapidly to permit smooth control with these drugs.

8. myasthenia gravis Treatment of 2- Thymectomy should be done once the clinical state allows and if there is no powerful contraindication to surgery. 3- Adreno corticosteroid, (prednisolone), induce improvement in 80% of cases. 4- Immunosuppressive therapy. Aim is to eliminate Ach. Receptor Abs. Azathioprine may be used as steroid-sparing agent.

9. Drug induced disorders of N-M Transmission 1- Antibiotics: - Ammoglycosides (streptomycin, gentamycin) - polypeptides (colistin, polymyxin B) - polypeptides (colistin, polymyxin B) - Quinolones (ciprofloxacin). 2- C.V.S: - Quinidine, procainamide, lignocaine -B-blockers e.g propranolol; oxprenolol. 3- Other drugs: pencillamine, phenytoin, Lithium.

10. Clinical indications of the cholinergic drugs (agonists) They have 4 main clinical indications: 1. Reduce IOP in patients with glaucoma and during ocular surgery. 2. Treatment of atony of (GIT & bladder). 3. Diagnose & treatment of myasthenia gravis. 4. Minor uses: as antidotes to: a- Neuromuscular blocking agents (muscle relaxants), tubocurarine. b- Drugs with anticholinergic effects such as tricyclic antidepressant, belladonna alkaloid. Note: Tacrine: The newest anticholinesterase agent used for treatment of mild to moderate dementia associated with Alzheimer's disease.

11. Adverse Reactions of all the cholinergic drugs 1. On eye : blurred vision, decrease accommodation and meiosis. 2. On skin : Increase sweating. 3. On GIT : Increase salivation, belching, nausea, vomiting, intestinal cramps (abdominal colic) and diarrhea.

12. 4. On CVS : vasodilatation, decrease heart rate (bradycardia). 5. At motor end plate : hyperpolarization of the skeletal muscle which will reduce contraction. 6. On CNS : irritability, anxiety and fear, some of them causes seizures.