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7/22/2019 7. Cholinergic Drugs
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Asmah Nasser, M.D.
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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
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Classification and examples of direct and
indirect acting Cholinergic agonists Brief discussion of few of the above
examples
Pathophysiology, diagnosis, andManagement of Myasthenia gravis and tensilon test
Glaucoma
Alzheimer's disease
Organo Phosphorus compound poisoning
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Heart: Cardiac suppressantBradycardia,
hypotension,
Eye: Miosis, cycloplegia, facilitates aqueoushumour drainage, lacrimation
Bronchospasm
Excess secretion from glands.salivary, bronchial,lacrimal glands etc..
GIT /bladder smooth muscle contraction andrelaxation of sphincters, increased motility,
diarrhea, vomiting , increased micturation (urinaryurgency)
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Often called parasympathomimetic drugs,
because their action mimics the action of thePSNS commonly
Also called as Cholinergic drugs or
cholinomimetricCholinergic agonists are two types :
1.Direct acting
2.Indirect acting
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They act by binding directly to cholinoceptors
Acetylcholine (Synthetic analogue of ACH)
Carbachol
Bethanechol
Pilocarpine(naturally occurring alkaloid)
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They act through inhibition of Acetyl
cholinesterase enzyme.so increasesAcetylcholine level in the synapse
Reversible: Neostigmine Physostigmine Pyridostigmine Edrophonium Tacrine
Danopezil
Irreversible :
Ecothiophate
Malathion
Parathion
Sarin
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It is a quaternary ammonium compound soCannot 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
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Not hydrolyzed by acetylcholinesterases
It has strong Muscarinic action & no Nicotinic action Actions
Directly stimulates M receptors causing increasedintestinal motility & tone
It stimulates detrusor muscle of the bladder whiletrigone & sphincters are relaxed causing expulsion ofurine
Therapeutic Uses:
Paralytic ileus Urinary retentions
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An alkaloid, lipid soluble & is stable to hydrolysis by
cholinsterases It has Muscarinic activity only .ActionsWhen applied locally to cornea Produces rapidmoisis & contraction of ciliary muscle produces ofspasm of accommodation & vision is fixed at
particular distance making it impossible to focusfor far situated objectsTherapeutic Use: In GlaucomaIt opens trabecular meshwork around schlemms
canal
causes drainage of aqueous humor IOP immediately decreases.
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Cholinesterase inhibitors. Can be reversibleor irreversible.
Reversable: Neostigmine
Physostigmine
Edrophonium
Tacrin
Danopezil
Irreversible Malathion and Parathion
Sarin
Ecothiopate
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Neostigmine in M.gravis Physostigminein Glaucoma, atropine overdose
Ecothiopate in glaucoma
Edrophonium in M.gravis to test
Tacrin, Danopezil in Alzheimer's
Malathion, Parathion as insecticides
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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
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Immunosuppressantdrugs
Thymectomy
Acetyl Cholinesterase inhibitors Neostigmine
Pyridostigmine
Ambenonium
Edrophonium
Other supportive measures
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NeostigmineHas a strong influence at theneuromuscular junction
Pyridostigmine:Has a longer duration of actionthan neostigmine
Ambenonium :Available only in oral form;cannot be used if patient is unable to swallowtablets
Edrophonium: Diagnostic agent for myastheniagravis and to diffrentiate myasthenic andcholinergic crisis ( ensilon test)
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Clinical situations in which severe myasthenia
(myasthenic crisis) must be distinguished fromexcessive drug therapy (cholinergic crisis) usuallyoccur in very ill myasthenic patients
If excessive amounts of cholinesterase inhibitorhave been used, patients may become
paradoxically weak because of nicotinicdepolarizing blockade of the motor end plate.
Small doses of edrophonium (12 mgintravenously) will produce no relief or even worsenweakness if the patient is receiving excessivecholinesterase inhibitor therapy.
On the other hand, if the patient improves withedrophonium, an increase in cholinesteraseinhibitor dosage may be indicated.
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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
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Tacrine Side effect: HepatoToxicity First drug to treat Alzheimers dementia
Rivastigmine Available in solution for swallowing ease
Donepezil Has once-a-day dosing advantage
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Only Ecothipate is used clinically inGlaucoma. This is the long acting drug usedin glaucoma
Rest of the drugs are used as pesticides or war
gases or poisons: Malathion and Parathion
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The dominant initial signs are those of
muscarinic excess: miosis, salivation, sweating,
bronchial constriction, vomiting, and diarrhea.
Central nervous system involvement usuallyfollows rapidly, accompanied by peripheral
nicotinic effects, especially depolarizing
neuromuscular blockade.
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(1) maintenance of vital signsrespiration in particular may be
impaired;
(2) decontamination to prevent further absorptionthis 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)
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Irreversible cholinesterate inhibitor. LONG acting
Used in Glaucoma
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Direct/indirect acting cholinergic drugsactions, adverse effects, toxicity features ofOP poisoning
In OP poisoning atropine used to reverseonly the muscarinic effects..
Pralidoxime used to reactivate the enzyme
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Miosis Excessive salivation
Bradycardia
Bronchospasm Abdominal cramps, vomiting, diarrhea,
urination
Sweating
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Asmah Nasser, M.D.
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About 70 million people are affectedWorldwide 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 amongBlack-Americans.
50% of all patients, are not awarethey have it,until late
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Types of Glaucoma:1. Open Angle Glaucoma Excessive production ofAqueous Humour2. Closed Angle Glaucoma Outflow obstruction ofAqueous Humour
Two Therapy aimed at:1. Reduce (Production, Synthesis or Secretion)
Dorzolamide, Acetazolamide, Timolol, Betoxolol andApraclonidine
2.Facilitate the drainage: Pilocarpine, Carbachol,
Ecothiopate ,Mannitol and Latanoprost
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Courtesy : Katzung
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Mannitol
reduces IOP by reducing vitreous volume byinhibiting the enzyme carbonic anhydrase
Reduces the secretion/synethesis
Timolol topical eye drops Non-selective blockade
Betaxolol eye drops Selective 1 blockade
Reduces the synthesis
Acetazolamide (oral), Dorzolamide (topical):
reduces the synthesis of aqueous humour,inhibits the enzyme carbonic anhydrase
2 receptor agonist (apraclonidine1%, topical
drops).
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1. Pilocarpine, Carbachol, Ecothiopateand
Physostigmine :Causes Ciliary muscle contraction,
increases Irido-corneal angle and open trabecularmeshwork.
2. Prostaglandins : Latanoprost: increase the outflow
through uveoscleral meshwork
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Excessive adrenergic receptor mediatedproduction and secretion of aqueous humorfrom the ciliary body epithelium.
Best treated with betablockers
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Results from obstruction of canal ofSchlemmthrough which aqueous humorwas supposed to be filtrated out .
Caused by1. Mydriatics : Anti-cholinergic drugs
2. Antidepressants : SSRI drugs
Treatment: Pilocarpine, Carbachol , ecothiopateand physostigmine