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PARKINSONISM DAN ANTICHOLINERGIC
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Parkinsonism
• Parkinsonism is characterized by acombination of rigidity, bradykinesia,tremor, and postural instability thatcan occur for a variety of reasons butis usually idiopathic (Parkinson'sdisease or paralysis agitans).
• Cognitive decline occurs in manypatients as the disease advances
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Top: Dopaminergic neurons (red) originating in the substantia nigranormally inhibit the !"!ergic output from the striatum, #hereas
cholinergic neurons (orange) e$ert an e$citatory e%ect. Bottom: &nparkinsonism, there is a selective loss of dopaminergic neurons
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• Cardinal Features"radykinesiaPostural instability
esting tremor (may have postural andaction components)igidity
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• Motor SymptomsDecreased de$terityDysarthriaDysphagia
estinating gaitle$ed posturereezing at initiation of movementypomimia
ypophonia*icrographia+lo# turning
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• Autonomic Symptoms"ladder and anal sphincter disturbancesConstipation
Diaphoresisrthostatic blood pressure changesParo$ysmal -ushing+e$ual disturbances
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• Mental Status Changes"radyphreniaConfusional state
DementiaPsychosis (paranoia, hallucinosis)+leep disturbance
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• Otheratiguabilityily skin
Pedal edema+eborrheaeight loss
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Common types of gait abnormalities
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eneral algorithm for treating early idiopathic
Parkinson's disease.
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!lgorithm for treating advanced idiopathicParkinson's disease. C, controlled release/ C*0,
catechol11methyltransferase
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!nticholinergic *edications
• !nticholinergic drugs can be e%ectivefor tremor and dystonic features insome patients but rarely sho#substantial bene2t for bradykinesia orother disabilities.
• 0hey can be used as monotherapy orin con3unction #ith otherantiparkinsonian drugs.
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Amantadine• !mantadine is often e%ective for mild symptoms,
especially tremor. &t may also decrease dyskinesia atrelatively high doses (455 mg6day).
• &ts precise mechanism of action is unkno#n but mayinvolve dopaminergic or nondopaminergic mechanismssuch as inhibition of 71methyl1d1aspartate receptors.
• !dverse e%ects include sedation, vivid dreams, dry
mouth, depression, hallucinations, an$iety, dizziness,psychosis, and confusion. 8ivedo reticularis (a di%usemottling of the skin) is a common but reversible sidee%ect
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Levodopa and Carbidopa/Levodopa• 8evodopa, the most e%ective drug
available, is the immediate precursor ofdopamine. &t crosses the blood1brain
barrier, #hereas dopamine does not.• 0he decision to start 81dopa as soon as the
diagnosis is made or only #hen symptomscompromise social, occupational, orpsychological #ell1being hasgenerated controversy
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Cholinergic nerves are sho#n in blue/ noradrenergic in red/ and dopaminergic in green.7ote that some sympathetic postganglionic 2bers release acetylcholine or dopaminerather than norepinephrine. 0he adrenal medulla, a modi2ed sympathetic ganglion,
receives sympathetic preganglionic 2bers and releases epinephrine and norepinephrineinto the blood. !Ch, acetylcholine/ D, dopamine/ 9pi, epinephrine/ *, muscarinic
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Cholinoceptor1!ctivating :Cholinesterase1&nhibiting Drugs
• !cetylcholine1receptor stimulants and cholinesteraseinhibitors together make up a large group of drugsthat mimic acetylcholine (cholinomimetic agents)
• Cholinoceptor stimulants are classi2ed
pharmacologically by their spectrum of action,depending on the type of receptor;muscarinic ornicotinic;that is activated.
• Cholinomimetics are also classi2ed by their
mechanism of action because some bind directly to(and activate) cholinoceptors #hereas others actindirectly by inhibiting the hydrolysis of endogenousacetylcholine
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!nticholinergic
• Cholinergic blocking drugs also arecalled anticholinergics orparasympathomimetic blocking
drugs.
• 9$amples of cholinergic blockingdrugs include atropine, scopolamine,
and propantheline
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ACTO!S
• Cholinergic blocking drugs inhibit theactivity of acetylcholine inparasympathetic nerve 2bers
• hen the activity of acetylcholine isinhibited, nerve impulses travelingalong parasympathetic nerve 2bers
cannot pass from the nerve 2ber tothe e%ector organ or structure.
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Sites of actions of cholinergic antagonists
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Sites of actions of cholinergic antagonists
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!ntimuscarinic !gents
!tropine
• a tertiary amine belladonna alkaloid, has ahigh a<nity for muscarinic receptors,
#here it binds competitively, preventingacetylcholine from binding to those sites .
• !tropine acts both centrally and
peripherally.
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Competition o" atropine and scopolamine #ithacetylcholine "or the muscarinic receptor
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Dose1dependent e%ects of atropine
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Pharmacokinetics=
!tropine is readily absorbed, partiallymetabolized by the liver, andeliminated primarily in the urine.
&t has a half1life of about 4 hours.
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0herapeutic uses
– phthalmic= &n the eye, topical atropinee$erts both mydriatic and cycloplegic
e%ects+horter1acting antimuscarinics(cyclopentolante and tropicamide) havelargely replaced atropine due toprolonged mydriasis observed #ithatropine (>1?4 days versus @1A4 hours#ith other agents).
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– !ntispasmodic= !tropine is used as anantispasmodic agent to rela$ the & tract andbladder.
– !ntidote for cholinergic agonists= !tropine is used
for the treatment of overdoses of cholinesteraseinhibitor insecticides and some types of mushroompoisoning (certain mushrooms contain cholinergicsubstances that block cholinesterases).
–
!ntisecretory= 0he drug is sometimes used as anantisecretory agent to block secretions in theupper and lo#er respiratory tracts prior to surgery.
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!dverse e%ects=
• Depending on the dose, atropine maycause dry mouth, blurred vision,tachycardia, and constipation.
•
9%ects on the C7+ include restlessness,confusion, hallucinations, and delirium,#hich may progress to depression, collapseof the circulatory and respiratory systems,and death.
• 8o# doses of cholinesterase inhibitors suchas physostigmine may be used toovercome atropine to$icity.
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• &n older individuals, the use of atropine toinduce mydriasis and cycloplegia is consideredto be too risky, because it may e$acerbate anattack of glaucoma in someone #ith a latent
condition.
• &n other older individuals, atropine may induceurinary retention that is troublesome.
•
Children are sensitive to e%ects of atropine,the rapid increases in body temperature that itmay elicit. 0his may be dangerous in children.
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+copolamine
!ctions=
• +copolamine is one of the moste%ective antimotion sickness drugs .
• +copolamine also has the unusual e%ectof blocking short1term memory.
• &n contrast to atropine, scopolamineproduces sedation, but at higher dosesit can produce e$citement instead.+copolamine may produce euphoria andis sub3ect to abuse
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Pharmacokinetics and adverse e%ects=
• 0hese aspects are similar to those ofatropine
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0ropicamide and cyclopentolate
• 0hese agents are used as ophthalmicsolutions for similar conditions asatropine (mydriasis and cyclopegia).
• Duration of action is shorter thanthat of atropine/ tropicamideproduces mydriasis for @ hours and
cyclopentolate for A4 hours.
$%ects o" the Cholinergic
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$%ects o" the CholinergicBloc&ing
'rugs
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A'($)S$ )$ACTO!S
• Central nervous system—headache, fushing,nervousness, dro#siness, #eakness, insomnia,nasal congestion, fever
B Eyes—blurred vision, mydriasis, photophobia,cycloplegia, increased ocular tension
B Gastrointestinal tract—nausea, vomiting, dicultyin s#allo#ing, heartburn
B Urinary tract—urinary hesitancy and retention,dysuria
B Cardiovascular system—palpitations, bradycardia(after lo# doses of atropine), tachycardia (afterhigher doses of atropine)
B Other—urticaria, anaphylactic shock, other skinmanifestations
!d % l b d i h
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!dverse e%ects commonly observed #ithcholinergic antagonists
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CO!T)A!'CATO!S
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