Anticonvulsant Parkinson 2013
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Transcript of Anticonvulsant Parkinson 2013
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Anti-epilepsy AgentsPrajogo Wibowo
Chief of Pharmacologic Department
School of Medicine – Hang Tuah University
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Aims To describe the pathophysiology of epilepsy
To determine the pharmacological agents used
Mechanism of action Contra-indications
Adverse effects
Patient management
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Introduction 1 person in 20 ill have an epileptic sei!ure at some
time in their life
"pilepsy is diagnosed on the basis of to or moreepileptic sei!ures#
Around $%0&000 people in the '( have epilepsy )$0million people orldide*
A sei!ure is triggered by a sudden interruption in the brain+s highly comple, electro-chemical activity
)ational .ociety for "pilepsy '(*
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Age/Incidence
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rain
100 billion neurons
Control centre temperature
sensory input
motor control emotion
thought
body functionsTa3en from 4'P Illustration 5esource& 2002
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6ross anatomy
Front part of the brain;
involved in planning, organizing, problem solving,
selective attention, personality
and a variety of "higher cognitive functions"
including behavior and emotions#
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6ross anatomyThe parietal lobes contain the primary
sensory cortex which controls
sensation (touch, pressure)
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6ross anatomy
!egion in the bac of the
brain which processes
visual information
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6ross anatomy
These lobes allow a person to
distinguish smells and are
believed to be responsible
for short#term memory
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.tructure
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Action Potential
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.ynapse Activity
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.ei!ures are a symptom of an underlying C.
dysfunction
It is an abnormal& uncontrolled electricaldischarge from neurons
Cell membrane disruptions )permeability*
Altered ion distributions )chemical balance* 7ecreased neurotransmitters )Ach and 6AA*
"veryone has sei!ure threshold
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Classification of .ei!ures $artial%
.imple partial sei!ures )no loss of consciousness*
8ith motor symptoms 8ith sensory symptoms
8ith autonomic symptoms
4nly involve 1 hemisphere
Comple, partial )loss of consciousness* .imple folloed by loss of consciousness
Impaired at the onset
&ependant on which
area of the brain
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'nclassified Classification not possible to problems ith
diagnosis 9 suspected
6eneralised )affect hole brain ith loss ofconsciousness* Clonic& tonic )1min* or tonic-clonic )2-$min*
muscle spasm )e,tensors*& respiration stops&defecation& salivation& violent :er3s
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Myoclonic sei!ures of a muscle or group of
muscles
Absence Abrupt loss of aareness ofsurroundings& little motor disturbance& mostly
children
Atonic loss of muscle tone/strength
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Pathological asis Abnormal electrical discharge in the brain
Coordinated activity among neurons depends on acontrolled balance beteen e,citation and inhibition
Any local imbalance ill lead to a sei!ure
Imbalances occur beteen glutamate-mediatede,citatory neurotransmission and gamma-
aminobutyric acid )6AA* mediated inhibitoryneurotransmission 6eneralised epilepsy is characterised by disruption of
large scale neuro-netor3s in the higher centres#
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Any defect causes the neuron to be closer to
the all or none threshold for an AP = HYPEREXCITABLE STATE #
?eading to instability beteen e,citation andinhibition => "pilepsy
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4ther possible causes
Inherited mutations of proteins involved in
the ion channels
5eduction in the activity of homeostatic
ATPase pumps ithin neuron cell membranes
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asis of Pharmacological 5,
Most anti-epileptic agents act either by bloc3ade
of depolarisation channels )a; and Ca;;*
'!
"nhancing the activity of 6AA
)neurotransmission inhibition*
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% Categories of Anti-epileptic 7rugs
All classifications are based upon chemistry
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Pharmaco3inetics
.loly absorbed from gut& use a slo I@ if rapid
action is reuired Avoid IM 9 muscle damage
"liminated by hepatic biotransformation
Can measure amount of free agent in the saliva
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autions% hepatic impairment& pregnancy& breast-feedingB avoid sudden ithdraalB lood or s3in disorders
dverse effects% nausea& vomiting& mental confusion& di!!iness& headache& tremor& transientnervousness& insomnia occur commonlyB rarely dys3inesias& peripheral neuropathyB ata,ia& slurred
speech& nystagmus and blurred vision are signs of overdosageB rashes )discontinueB if mild re-introduce cautiously but discontinue immediately if recurrence*& gingival hypertrophy andtenderness& coarse facies& acne and hirsutism& fever and hepatitisB lupus erythematosus& .tevens-ohnson syndrome& to,ic epidermal necrolysis& polyarteritis nodosaB lymphadenopathyB rarelyhaematological effects& including megaloblastic anaemia )may be treated ith folic acid*&leucopenia& thrombocytopenia& agranulocytosis& and aplastic anaemiaB plasma-calciumconcentration may be loered )ric3ets and osteomalacia*
&ose% y mouth& initially D9$ mg/3g daily or 1%09D00 mg daily )as a single dose or in 2 divided doses*
increased gradually as necessary )ith plasma-phenytoin concentration monitoring*B usual dose 2009 %00 mg daily )e,ceptionally& higher doses may be used*B child initially % mg/3g daily in 2 divided doses&usual dose range $9E mg/3g daily )ma,# D00 mg*
ontraindications% increases metabolism of the contraceptive pill& anti-coagulants& and pethidine
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.uccinimides 9 "thosu,imide )Farontin*
'se for pts ith Absence sei!ures
Acts by antagonising Ca;; channels in thethalamocortical relay neurons => prevention
of synchronised neuronal firing => raising AP
threshold
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Pharmaco3inetics
Almost complete absorption from the gut
",tensive metabolism in the liver ith a longhalf-life )2-D days*
Plasma and salivary concentrations correlate ell
for monitoring purposes
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autions% hepatic and renal impairmentB pregnancy and breast-feedingB avoid sudden ithdraal lood disorders )revie*
dverse effects% gastro-intestinal disturbances& eight loss& drosiness&di!!iness& ata,ia& dys3inesia& hiccup& photophobia& headache& depression& and mild
euphoria# Psychotic states& rashes& hepatic and renal changes )see Cautions*& andhaematological disorders such as agranulocytosis and aplastic anaemia occurrarely )blood counts reuired if signs or symptoms of infection*B systemic lupuserythematosus and erythema multiforme ).tevens-ohnson syndrome* reportedBother side-effects reported include gum hypertrophy& selling of tongue&irritability& hyperactivity& sleep disturbances& night terrors& inability to concentrate&aggressiveness& increased libido& myopia& vaginal bleeding
&ose% adult and child over G years initially& %00 mg daily& increased by 2%0 mg at intervals of
$9H days to usual dose of 191#% g dailyB occasionally up to 2 g daily may be neededBchild up to G years initially 2%0 mg daily& increased gradually to usual dose of 20 mg/3gdaily
ontraindications% may ma3e tonic-clonic sei!ures orse
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ensodia!epines 9 Clora!epam
)(lonopin*& 7ia!epam )@alium* Act by potentiating the actions of 6AA
causing neurotransmission inhibition
)primarily in the C.*
Can be used to induce sleep )high dose*&
anticonvulsant therapy and reduction inmuscle tone#
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Pharmaco3inetics
8ell absorbed from the gut
?ipid soluble to ensure ready prentration of the blood brain barrier
Metabolised in the liver to create active agents
)prolonged therapeutic action*
.lo elimination from body
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Clona!epam autions% elderly and debilitated& respiratory disease& spinal or cerebellar ata,iaB history of
alcohol or drug abuse& depression or suicidal ideationB myasthenia gravisB porphyriaB hepaticimpairmentB renal impairmentB pregnancyB breast-feeding
ontra#indications% respiratory depressionB acute pulmonary insufficiencyB sleep apnoeasyndromeB mar3ed neuromuscular respiratory ea3ness including unstable myastheniagravis
dverse effects% drosiness& fatigue& di!!iness& muscle hypotonia& co-ordinationdisturbancesB also poor concentration& restlessness& confusion& amnesia& dependence& andithdraalB salivary or bronchial hypersecretion in infants and small childrenBrarely gastro-intestinal symptoms& respiratory depression& headache& parado,ical effects includingaggression and an,iety& se,ual dysfunction& urinary incontinence& urticaria& pruritus&reversible hair loss& s3in pigmentation changesB dysarthria& and visual disturbances on long-term treatmentB blood disorders reportedB overdosage%
&ose% 1 mg )elderly %00 micrograms* initially at night for $ nights& increased according to response over
29$ ee3s to usual maintenance dose of $9E mg daily in D9$ divided dosesB may be given as asingle daily dose in the evening once maintenance dose establishedB ma,# 20 mg dailyB child up to1 year& initially 2%0 micrograms increased as above to usual maintenance dose of 0#%91 mg& 19%years& initially 2%0 micrograms increased as above to 19D mg& %912 years& initially %00 microgramsincreased as above to D9G mg
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arbiturates 9 Phenobarbital )?uminal*
'sed for tonic-clonic se!iures#
Act by increasing the duration of Cl- ion channelopening by activating neuronal 6AAa receptors
Causing hyperpolarisation of the AP& ma3ing it less
li3ely to fire again
"ssentially& acts li3e 6AA and can even potentiate
the effects of 6AA hen present#
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Adverse effects C. effects )sedation and fatigue*
5estlessness/
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Pharmaco3inetics .lo and incomplete absorption
Metabolised in the liver 9 creates an e,po,ide metabolite
that can have a ea3 therapeutic effect
5elatively long half-life )1-2 days*
Potency decreases overtime therefore need to increase
dose to ensure adeuate control of sei!ures
Plasma and salivary concentrations correlate ell to
clinical effectiveness
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.odium @alproate
'se in all forms of epilepsy& as it suppresses
the initial sei!ure discharge and its spread#
Clinical actions are Antagonism of a; and Ca;; channels
Potentiation of 6AA
Attenuation of 6lutamate Can be fast acting due to a; MoA& although
the full 5, effect usually ta3es ee3s#
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Pharmaco3inetics
8ell absorbed from gut )should be ta3en ith
food to counteract gastric irritation* ",tensively metabolised in the liver
5apidly transported across the blood brain barrier
Monitor plasma concentration for patient
compliance only
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Adverse effects 6I upset )ausea& vomiting& anore,ia& abdominal pain and diarrhoea*
8eight gain )appetite stimulation*
Transient hair loss
Tremor
Coma )rare*
Thrombocyptopenia )platelets*
4edema
.evere hepatoto,icity )liver damage*
Contraindications People ith liver damage or a historyhepatic dysfunction
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@igabatrin
4nly used in con:unction ith other agents hen pt becomes resistant )due to tolerance* or poorlytolerates
"ffective in partial epilepsy but ith restricted useddue to severe adverse effects )vision*
MoA completely different to other agents as it is astructural analogue of 6AA that the en!yme that
normally inactivates 6AA ill degrade instead of6AA# More 6AA available to inhibit neuron transmission
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Pharmaco3inetics
5apidly absorbed from the gut
'nchanged by renal processes Intermediate half-life )hrs*
lood concentrations are of no value#
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Adverse effects
.edation& fatigue& di!!iness& nervousness&
irritability& depression& impaired concentration#tremor )C. effects*
Psychotic reactions )chec3 pt history*
@isual defects after prolonged use
8eight gain and oedema
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?amotrigine )?amictal*
'sed for partial sei!ures in adults only
Acts by the inhibition )antagonism* of neuronal
a; channels but is highly selective )onluneurons that synthesise glutamate and aspartate*
Additionally& decrease glutamate release
Pharmaco3inetics ell absorbed& e,tensivelymetabolised in the liver and has a long half-life#
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Adverse effects Jever& influen!a-li3e symptoms
.3in irritation 6I disturbances )vomiting& diarrhoea*
C. effects )drosiness& headache& di!!iness&double vision*
Contraindications Pts ith hepaticimpairment
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6abapentin )euronitin*
'sed for partial sei!ures in adults
7esigned to be a structural analogue of
6AA but it does not mimic 6AA in the brain#
Acts via
Increased synthesis and release of 6AA 7ecrease degradation of 6AA
Inhibition of Ca;; channels
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Pharmaco3inetics Incompletely absorbed in the gut ",creted unchanged via 3idney processes
.hort half-life Adverse effects
C. effects )di!!y& drosy& fatigue& headache& doublevisions*
ausea and vomiting
Contraindication be careful ith sudden ithdraalin the elderly due to 3idney effects and alterations inacid-base balance#
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Anti-Par3inson 7rugs
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Aims
To revie pathogenesis of Par3inson+s
To revie clinical presentation
To identify treatment drugs
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Prevalence
1#% million in '.A and 120&000 in the '( 9accounts for about 10 of all acute hospitaladmissions
"ffects 2 in 1&000 peopleB aged E0; incidence is 1 in%0#
Mainly affects adults in later life .lightly more common in men& Afro-Caribbean+s and
people from the Indian subcontinent Affects the uality of life of about %00&000 )family&
carers etc*
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Causes
'nclear& but is a number of factors
"nvironmental 9 to,ins
Jree 5adicals 9 there is a increase in post-mortem brain sections
Aging 9 age related decline in dopamine
production
6enetic 9 possible& no single gene identified
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Par3insonLs 7isease
A degenerative and progressive disorder
Associated ith neurological conseuences ofdecreased dopamine levels produced by the basal
ganglia )substantia nigra* 7opamine is a neurotransmitter found in the neural
synapses in the brain ormally& neurones from the . supply dopamine to
the corpus striatum )controls unconscious musclecontrol*
Initiates movement& speech and self-e,pression
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alance& posture& muscle tone and involuntary
movement depends on the roles of dopamine
)inhibitory* and acetylcholine )Ach e,citatory*
If dopamine missing& Ach produces more of an effect
on muscles
asis to e,ploit by drugs 5estore dopamine function
Inhibit Ach ithin corpus striatum
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Conseuences of dopamine reductions
Tremors 9 hands and head develop involuntarymovements hen at restB pin-rolling sign )finger andthumb*
-uscle rigidity 9 arthritis-li3e stiffness& difficulty in bending or moving limbsB po3er face .randyinesia 9 problems cheing& salloing or
spea3ingB difficulty in initiating movements andcontrolling fine movementsB al3ing becomesdifficult )shuffle feet*
$ostural instability 9 humped over appearance& prone to falls
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Additional symptomology
An,iety
7epression
.leep disturbance 7ementia
7isturbance of A. )difficulty in urinating*
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Clinical Presentation Altered body image )depression* Poor balance rady3inesia )slo movement* radyphrenia )sloness of
thought* Constipation
7ribbling/drooling
7ys3inesias )involuntarymovements*
7ysphagia )difficultysalloing
7ystonia )pain spasms*
",cessive seating )impairedthermoregulation*
Jestinating gait
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Treatment )maintenance stage*
.peech therapist is prophylactic and deals ith
salloing problems )recommend e,ercises etc*
Impaired thermoregulation 9 use beta-bloc3ers
7isturbance in sleep 9 can be side effects of
medicationB change time of inta3e or use a controlled
release drug delivery system
Continued health education and liaison ith other professionals
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Treatment )comple, stage*
Junction has deteriorates to such a level a
combination of drugs are prescribed
7ys3inesias and 7ystonia 9 can be associated ith
long-term ?evodopa use and it can be difficult to
manage these effects 9 co-agent is co-beneldopa
5estless-leg 9 dopamine agonists
An,iety 9 rela,ation& distraction& CT 7epression 9 alterations in dose of anti-par3insonLs
drugs
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Cognitive problems 9 referral to clinical
psychologist and prescription of anti-dementia
agents
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Medication 5ational
5eplace depleted levels of dopamine
.timulate the nerve receptors enabling
neurotransmission Increase the effect of dopamine on nerve
receptors )agonist*
Counteract the imbalance of Ach and7opamine
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The 7rugs
7opaminergic drugs )improving dopamine
functioning* ?evodopa
7opamine receptor agonists
Amantadine
.elective monoamine o,idase inhibitors Catechol-4-methyltransferase inhibitors
Antimuscarinic drugs )Ach inhibitors*
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?evodopa )or ?evodopamine*
Can not administer dopamine directly& as it does not
cross the blood brain barrier
A natural amino acid that the brain converts into
dopamine )replacement therapy* used since the
1G0Ls
To ma3e it slo release& combined ith bensera!ide
)an en!yme inhibitor* to create co-beneldopa or co-careldopa ).inemet*
7ose = %0& 100 or 200mg )12#%& 2% or %0mg*
/umber% Adams et al )200G* Pharmacology for urses
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/umber% Adams et al )200G*# Pharmacology for urses 9
A Pathophysiologic Approach# Prentice
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Pharmaco3inetics Absorbed by the small intestine by an active
transport system
7ecarbo,ylation occurs in peripheral tissues )gutall& liver and 3idney decrease amount available for distribution 9 1 of an
oral dose ",tracerebral dopamine amounts causing unanted
effects )bensera!ide*
.hort half-life
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autions% pulmonary disease& peptic ulceration& cardiovascular disease& diabetesmellitus& osteomalacia& open-angle glaucoma& history of s3in melanoma )ris3 ofactivation*& psychiatric illness )avoid if severe*B arn patients about e,cessivedrosinessB in prolonged therapy& psychiatric& hepatic& haematological& renal& andcardiovascular surveillance is advisableB arn patients to resume normal activitiesgraduallyB avoid abrupt ithdraalB
ontra#indications% closed-angle glaucomaB pregnancy breast-feeding dverse effects% anore,ia& nausea and vomiting& insomnia& agitation& postural
hypotension )rarely labile hypertension*& di!!iness& tachycardia& arrhythmias&reddish discoloration of urine and other body fluids& rarely hypersensitivityBabnormal involuntary movements and psychiatric symptoms hich includehypomania and psychosis may be dose-limitingB depression& drosiness&headache& flushing& seating& gastro-intestinal bleeding& peripheral neuropathy&
taste disturbance& pruritus& rash& and liver en!yme changes also reportedBsyndrome resembling neuroleptic malignant syndrome reported on ithdraal
&ose% Initially 12%9%00 mg daily in divided doses after meals& increased according to
response )but rarely used alone& see notes above*
8
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Adverse effects
As a result of the amount of peripheral dopamine
levels ausea& vomiting
Postural hypotension
As a result of the amount of C. dopamine
levels 7ys3inetic involuntary movements )face K nec3*
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7opamine receptor agonists
Apopmorphine )AP4-go* .C administration
5escue therapy 9 rapid onset ith a short durationof action )N%0mins*
romocriptine )Parlodel*B Pergolide )Celance*B5opinirole )5euip*
7irect agonists of dopamine receptors in the brain longer lasting therapeutic effects that ?evodopa
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.tart a pt on this alone& then combine ithlevodopa to Osmooth outL control hen P7 isgetting progressive )especially young*
Pharmaco3inetics Incompletely abosrbed need e,tensive first-pass
metabolism )biotransformed in liver*
Pergolide K 5opinirole have higher bioavailability )distribution*
.hort to medium half life )Potency*
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Adverse effects
'se gradual dose titration
; @ )particularly Apomorphine* 7ys3inesia
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4ther 7isease Modifying 7rugs
.elective monoamine o,idase inhibitors)selegiline 9 Trade name "ldepryl/Felapar* MoA prolongs the effects of levodopa as MA4-
degrades dopamine Pharmaco3inetics completely absorption& short half-life
Adverse effects & @& 7ia& ConstipationB dry mouth& sorethroatB transient di!!inessB insomnia& confusion andhallucinations
"arly stage 9 prescribed on it is on to delay need forlevodopa and there is good evidence for its sloing donof P7 progression
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Catechol-4-methltransferase inhibitors - C4MT
)entacapone& Trade name Comtess* MoA inhibits the brea3don of levodopa
Pharmaco3inetics variability of absorption& e,tensive
first-pass metabolism& short half-life
Adverse effects dys3inesias& hallucinationsB & @& 7ia
and abdominal pain
e combination 9 ?evodopa/carbidopa/entacapone
).talevo* as 1 tablet )%0& 100& 1%0mg*
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Antimuscarinic/Anticholinergic 7rugs Trihe,yphenidyl )rofle,& Artane& Agitane*B en!tropine
)Cogentin*B 4rphanadrine )7isipal*B Procycline
)(emadrin& Arpicolin* ?ess common drugs but they affect Ach based interactions
MoA bloc3ing cholingeric )Ach* receptors to restore
balance
Pharmaco3inetics fairly ell absorbed& e,tensive hepaticmetabolism& intermediate to long half-lifes
Adverse effects dry mouth and confusion
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7isease Modifying 7rugs 4vervie
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.ymptom Management 7rugs
P7 is multidimensional& therefore there are a
number of clinical presentations that reuiresupplementary agents
7rug-7rug reactions is the problem
Ma:or area is depression
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Antidepressants
Amitriptyline )Trypti!ol*& imipramine )Tofranil*&
ortriptyline )Allegron*& Iofepramine )6amanil*
MoA bloc3 re-upta3e of noradrenaline and
serotonin => .edative actions& can help ith
drooling and loss of appetite
Adverse effects sleepiness& dry mouth& increased
hunger& cardiac arrhythmias and changes in P Can interfere ith the effects of levodopa
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4ther 7rugs to Avoid
0eneric *ame .rand *ame $rescribed for
Prochlorpera!ine .temetil ;@& 7i!!iness
Prephena!ine Triptafen 7epressionJlupenti,ol Jluan,ol/7epi,ol Confusion&
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