Drugs acting in Cholinergic system
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Transcript of Drugs acting in Cholinergic system
Asmah Nasser, M.D.
M1 Secretory glands
salivation, stomach acid, sweating, lacrimation
M2 Heart Decreases heart rate bradycardia
M3 Smooth muscle (GI/GU/Resp)
Contraction of smooth muscles (some) diarrhea, bronchospasm, urination
M3 Pupil and ciliary muscle
Contracts Miosis
Increased flow of aqueous humor
Nm Skeletal muscle end plate
Contraction of skeletal muscle
Nn Autonomic 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 GlaucomaIt 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 Humour2. 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 by1. Mydriatics : Anti-cholinergic drugs2. Antidepressants : SSRI drugs
Treatment: Pilocarpine, Carbachol , ecothiopate and physostigmine