Drugs acting in Cholinergic system

1. Drugs acting in Cholinergic system Asmah Nasser, M.D.

4. Whats ahead? • Classification and examples of direct and indirect acting Cholinergic agonists • Brief discussion of few of the above examples • Pathophysiology, diagnosis, and Management of • Myasthenia gravis and tensilon test • Glaucoma • Alzheimer's disease • Organo Phosphorus compound poisoning

5. Pharmac.Actions, Adverse effects and Over dose signs of all Cholinergic drugs • Heart: Cardiac suppressant…Bradycardia, hypotension, • Eye: Miosis, cycloplegia, facilitates aqueous humour drainage, lacrimation • Bronchospasm • Excess secretion from glands….salivary, bronchial, lacrimal glands etc….. • GIT /bladder… smooth muscle contraction and relaxation of sphincters…, increased motility, diarrhea, vomiting , increased micturation (urinary urgency)

6. Cholinergic agonists • Often called parasympathomimetic drugs, because their action mimics the action of the PSNS commonly • Also called as Cholinergic drugs or cholinomimetric Cholinergic agonists are two types : • Direct acting • Indirect acting

7. Direct acting Cholinergic agonists They act by binding directly to cholinoceptors • Acetylcholine (Synthetic analogue of ACH) • Carbachol • Bethanechol • Pilocarpine (naturally occurring alkaloid)

8. Indirect acting Cholinergic agonists • They act through inhibition of Acetyl cholinesterase enzyme….so increases Acetylcholine level in the synapse • Reversible: • Neostigmine • Physostigmine • Pyridostigmine • Edrophonium • Tacrine • Danopezil • Irreversible : • Ecothiophate • Malathion • Parathion • Sarin

9. Direct agonists

10. Acetylcholine • It is a quaternary ammonium compound so Cannot penetrate the membrane • Does not have any therapeutic importance, because of multiplicity of actions & rapid inactivation by acetylcholinesterases • It has both Muscarinic & Nicotinic actions • Neurotransmitter for pre-ganglionic neuron

11. Bethanechol • Not hydrolyzed by acetylcholinesterases • It has strong Muscarinic action & no Nicotinic action • Actions • Directly stimulates M receptors causing increased intestinal motility & tone • It stimulates detrusor muscle of the bladder while trigone & sphincters are relaxed causing expulsion of urine • Therapeutic Uses: • Paralytic ileus • Urinary retentions

12. Pilocarpine An alkaloid, lipid soluble & is stable to hydrolysis by cholinsterases It has Muscarinic activity only . Actions- When applied locally to cornea Produces rapid moisis & contraction of ciliary muscle produces of spasm of accommodation & vision is fixed at particular distance making it impossible to focus for far situated objects Therapeutic Use : In Glaucoma It opens trabecular meshwork around schlemm’s canal ∴ causes drainage of aqueous humor ∴ IOP immediately decreases.

13. Indirect Cholingeric Agonists • Cholinesterase inhibitors. Can be reversible or irreversible. • Reversable: • Neostigmine • Physostigmine • Edrophonium • Tacrin • Danopezil • Irreversible • Malathion and Parathion • Sarin • Ecothiopate

14. Uses of Indirect Cholinergic agonists • Neostigmine in M.gravis • Physostigmine in Glaucoma, atropine overdose • Ecothiopate in glaucoma • Edrophonium in M.gravis to test • Tacrin, Danopezil in Alzheimer's • Malathion, Parathion as insecticides

15. Myasthenia gravis • An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptors on the postjunctional end plates. • Frequent findings are • Double vision…. diplopia, • Drooping of eyelids…. ptosis, • Dysarthria ……Difficulty in speaking • Dysphagia …..difficulty swallowing, • Difficult in Daily routines • Day passes, limb weakness increases. • Difficulty in respiration Severe disease may affect all the muscles, including those necessary for respiration. • Death

16. Treatment of Myasthenia gravis • Immunosuppressant drugs • Thymectomy • Acetyl Cholinesterase inhibitors • Neostigmine • Pyridostigmine • Ambenonium • Edrophonium • Other supportive measures

18. Treatment of Myasthenia Gravis • NeostigmineHas a strong influence at the neuromuscular junction • Pyridostigmine: Has a longer duration of action than neostigmine • Ambenonium :Available only in oral form; cannot be used if patient is unable to swallow tablets • Edrophonium: Diagnostic agent for myasthenia gravis and to diffrentiatemyasthenic and cholinergic crisis (Tensilon test )

19. Tensilon test in brief • Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholinergic crisis) usually occur in very ill myasthenic patients • If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. • Small doses of edrophonium (1–2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. • On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage may be indicated.

20. Alzheimer’s Disease • A progressive disorder involving neural degeneration in the cortex • Leads to a marked loss of memory and of the ability to carry on activities of daily living • Cause of the disease is not yet known • ?????? There is a progressive loss of ACh-producing neurons and their target neurons

21. Drugs Used to Treat Alzheimer’s Disease • Tacrine • Side effect: HepatoToxicity • First drug to treat Alzheimer’s dementia • Rivastigmine • Available in solution for swallowing ease • Donepezil • Has once-a-day dosing advantage

22. Irreversible cholinestarse inhibitors • Only Ecothipate is used clinically in Glaucoma. This is the long acting drug used in glaucoma • Rest of the drugs are used as pesticides or war gases or poisons: Malathion and Parathion

23. Acute toxic effects of irreversible cholinesterase inhibitors (OP poisoning ) • The dominant initial signs are those of muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. • Central nervous system involvement usually follows rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular blockade.

24. Treatment of OP poisoning (1) maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent further absorption—this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays; and (3) Atropine parenterally in large doses, given as often as required to control signs of muscarinic excess stimulation . (4)Therapy often also includes treatment with pralidoxime (Acetylcholinesterase reactivator)

25. Ecothiophate • Irreversible cholinesterate inhibitor. • LONG acting • Used in Glaucoma

26. Summary…. • Direct/indirect acting cholinergic drugs actions, adverse effects, toxicity features of OP poisoning • In OP poisoning atropine used to reverse only the muscarinic effects.. • Pralidoxime used to reactivate the enzyme

27. Features of toxicity of cholinergic drugs (organophosphorus poisoning ) In brief …. • Miosis • Excessive salivation • Bradycardia • Bronchospasm • Abdominal cramps, vomiting, diarrhea, urination • Sweating

28. Glaucoma Asmah Nasser, M.D.

29. Epidemiology of Glaucoma • About 70 million people are affected Worldwide • 10% of these (~7 million) are blind from glaucoma • US data: > 40 yrs of age, 3 million • about 120, 000 Americans are blind from it. Most common cause of blindness among Black-Americans. • 50% of all patients, are not aware they have it, until late

30. Two types of Glaucoma Types of Glaucoma: 1. Open Angle Glaucoma – Excessive production of Aqueous Humour 2. Closed Angle Glaucoma – Outflow obstruction of Aqueous Humour Two Therapy aimed at: 1. Reduce (Production, Synthesis or Secretion) Dorzolamide, Acetazolamide, Timolol, Betoxolol and Apraclonidine 2.Facilitate the drainage: Pilocarpine, Carbachol, Ecothiopate ,Mannitol and Latanoprost

31. Courtesy : Katzung

32. Reduction of aqueous humor production • Mannitol • reduces IOP by reducing vitreous volume by inhibiting the enzyme carbonic anhydrase • Reduces the secretion/synethesis • Timololtopical eye drops Non-selective β blockade • Betaxolol eye drops Selective β1 blockade • Reduces the synthesis • Acetazolamide (oral), Dorzolamide(topical ) : reduces the synthesis of aqueous humour, inhibits the enzyme carbonic anhydrase • α2 receptor agonist (apraclonidine 1%, topical drops).

33. Increased outflow of aqueous humor • Pilocarpine, Carbachol, Ecothiopate and Physostigmine :Causes Ciliary muscle contraction, increases Irido-corneal angle and open trabecular meshwork. • Prostaglandins : Latanoprost : increase the outflow through uveoscleral meshwork

34. Open angle glaucoma • Excessive β adrenergic receptor mediated production and secretion of aqueous humor from the ciliary body epithelium. • Best treated with betablockers

35. Closed angle glaucoma • Results from obstruction of canal of Schlemm through which aqueous humor was supposed to be filtrated out . • Caused by • Mydriatics : Anti-cholinergic drugs • Antidepressants : SSRI drugs Treatment: Pilocarpine, Carbachol , ecothiopate and physostigmine