Anticonvulsant Parkinson 2013

8/19/2019 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*

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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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Anticonvulsant Parkinson 2013