Asmah Nasser, M.D.

M1Secretory glands salivation, stomach acid, sweating, lacrimation M2HeartDecreases heart rate  bradycardia M3Smooth muscle (GI/GU/Resp) Contraction of smooth muscles (some)  diarrhea, bronchospasm, urination M3Pupil and ciliary muscle Contracts  Miosis Increased flow of aqueous humor NmSkeletal muscle end plate Contraction of skeletal muscle NnAutonomic ganglia, Adrenal Medulla Secretion of Epinephrine Controls ANS

 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

 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)

 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 : 1. Direct acting 2. Indirect acting

They act by binding directly to cholinoceptors  Acetylcholine (Synthetic analogue of ACH)  Carbachol  Bethanechol  Pilocarpine (naturally occurring alkaloid)

 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

 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

 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

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.

 Cholinesterase inhibitors. Can be reversible or irreversible.  Reversable: ◦ Neostigmine ◦ Physostigmine ◦ Edrophonium ◦ Tacrin ◦ Danopezil  Irreversible ◦ Malathion and Parathion ◦ Sarin ◦ Ecothiopate ◦

 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

 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

 Immunosuppressant drugs  Thymectomy  Acetyl Cholinesterase inhibitors ◦ Neostigmine ◦ Pyridostigmine ◦ Ambenonium ◦ Edrophonium  Other supportive measures

 Neostigmine Has 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 diffrentiate myasthenic and cholinergic crisis (Tensilon test )

 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.

 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

 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

 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

 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.

(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)

 Irreversible cholinesterate inhibitor.  LONG acting  Used in Glaucoma

 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

 Miosis  Excessive salivation  Bradycardia  Bronchospasm  Abdominal cramps, vomiting, diarrhea, urination  Sweating

Asmah Nasser, M.D.

 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

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

Courtesy : Katzung

 Mannitol ◦ reduces IOP by reducing vitreous volume by inhibiting the enzyme carbonic anhydrase  Reduces the secretion/synethesis ◦ Timolol topical 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).

1. Pilocarpine, Carbachol, Ecothiopate and Physostigmine :Causes Ciliary muscle contraction, increases Irido-corneal angle and open trabecular meshwork. 2. Prostaglandins : Latanoprost : increase the outflow through uveoscleral meshwork

 Excessive β adrenergic receptor mediated production and secretion of aqueous humor from the ciliary body epithelium.  Best treated with betablockers

 Results from obstruction of canal of Schlemm through which aqueous humor was supposed to be filtrated out.  Caused by 1.Mydriatics : Anti-cholinergic drugs 2.Antidepressants : SSRI drugs Treatment: Pilocarpine, Carbachol, ecothiopate and physostigmine