Drugs acting in Cholinergic system Asmah Nasser, M.D.
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
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)
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
Direct acting Cholinergic agonists They act by binding directly to cholinoceptors • Acetylcholine (Synthetic analogue of ACH) • Carbachol • Bethanechol • Pilocarpine (naturally occurring alkaloid)
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
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
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
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.
Indirect Cholingeric Agonists • Cholinesterase inhibitors. Can be reversible or irreversible. • Reversable: • Neostigmine • Physostigmine • Edrophonium • Tacrin • Danopezil • Irreversible • Malathion and Parathion • Sarin • Ecothiopate
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
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
Treatment of Myasthenia gravis • Immunosuppressant drugs • Thymectomy • Acetyl Cholinesterase inhibitors • Neostigmine • Pyridostigmine • Ambenonium • Edrophonium • Other supportive measures
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 )
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.
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
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
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
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.
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)
Ecothiophate • Irreversible cholinesterate inhibitor. • LONG acting • Used in Glaucoma
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
Features of toxicity of cholinergic drugs (organophosphorus poisoning ) In brief …. • Miosis • Excessive salivation • Bradycardia • Bronchospasm • Abdominal cramps, vomiting, diarrhea, urination • Sweating
Glaucoma Asmah Nasser, M.D.
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
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
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).
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
Open angle glaucoma • Excessive β adrenergic receptor mediated production and secretion of aqueous humor from the ciliary body epithelium. • Best treated with betablockers
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