154882837 Blok BMS 2013 Pharmacology of Extrapyramidal Disorders Ppt

8/11/2019 154882837 Blok BMS 2013 Pharmacology of Extrapyramidal Disorders Ppt

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Pharmacology of drugs in

extrapyramidal disorders

D.r Datten Bangun,MSc,SpFK

Dr.Sake Juli Martina,SpFKDept.Farmakologi & Therapeutik

Fak.Kedokteran,USU

M E D A N


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Definition:

Neurologic syndromes in which abnormal

movement occur due to:

= a disturbance of fluency and speed of voluntarymovement; or :

= the presence of unintended extra movements

Extrapyramidal syndrome


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Dopamine Pathways


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Dopamine functions

Motor control - nigrostriatal system

Deficiency results in rigidity, tremor and difficultyinitiating movement

Behavioural effects - mesolimbic system

Overactivity in rats leads to abnormal behavior

Endocrine control - tubero-infundibular system Dopamine and dopamine agonists suppressprolactin release, dopamine antagonists maystimulate it


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Dopamine synthesis


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in normal conditions

acetylcholine release from the striatum (cholinergic

neurons) is strongly inhibited by dopamine

(depleted from the nigrostriatal neurons).Joint GABA-ergic neurons then opposite excitatory

function of glutamate neurones connected to the

motor cortex.

Acetylcholine = excitatory

Dopamine = inhibitory

GABA = inhibitory


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Parkinsons Disease Acetylcholine = excitatory Dopamine = inhibitory

GABA = inhibitor

Neurodegeneration of the dopaminergic neurons

(Subs.nigra)

+ loss of dopamine (the striatum) leads to bothhyperactivity of these cholinergic striatal neurons

+ blockade of GABA-ergic cells(Subst.nigra).

The result is an increase in excitatory activity of

glutamate + the motor cortexPARKINSON


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Clinical Presentation

Altered body image(depression)

Poor balance

Bradykinesia (slow

movement) Bradyphrenia (slowness

of thought)

Constipation

Dribbling/drooling

Dyskinesias (involuntary

movements)

Dysphagia (difficulty

swallowing

Dystonia (pain spasms)

Excessive sweating(impaired

thermoregulation)

Festinating gait

Hullucinations (visual) Postural hypotension

Restless leg syndrome

(leg aches, tingle, or

burn)

Rigidity

Sleep disturbance

Slurring/slowing of

speech

Tremor


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Pathophysiologic ApproachAdams et al (2006)

Parkinson disease

reduced

dopamine

cholinergic

overactivity

Substantia

nigra

Corpus

striatum

L-DOPA

dopamine

D2

receptors

Adenylyl

cyclase

IP3Cyclic

AMP

Ca2+

channel

Intracellular

Ca2+

Firing of striatal

cholinergic nerves

inhibits

closes

inhibits

restores balance


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Drug treatment:

generally starts when the patient is

functionally impaired.

If so, either levodopa or a dopamine agonist is

started, depending on the patients age and

the severity of symptoms.

With increasing severity, other drugs can be

added, and when those fail to control

symptoms, surgery should be considered.


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Levodopa:

The most effective drug, until it wears off.


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Pathogenesis

Results from dysfunction of the extrapyramidal system

Basal ganglioncaudate, putamen, globus pallidus,

subthalamic nucleus, and substantia nigra

motor area of cortex--> basal ganglion(organizingmovement commands)

# affects the size and speed of movements

# selection of components of movements or thesequencing of multi-step movements


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What is Parkinsons?

Parkinsons is a brain disorder Occurs when neurons in a part of the brain called

the substantia niagra die or become impaired

These neurons produce dopamine

Use to be called shaking palsy

* Dr. James Parkinson first

discovered the disease in 1817

* 1960s chemical difference in

brain were identified

* 2000Michael J. Fox

Foundation
http://images.google.co.uk/imgres?imgurl=http://images.scotsman.com/2002/04/09/0904foxb.jpg&imgrefurl=http://news.scotsman.com/topics.cfm%3Ftid%3D296%26id%3D379542002&h=250&w=255&sz=8&tbnid=cDTHbrqHklaciM:&tbnh=103&tbnw=106&hl=en&start=12&prev=/images%3Fq%3Dparkinson%2527s%2Bdisease%26svnum%3D10%26hl%3Den%26lr%3D%26sa%3DG


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Pathophysiology

Normally Dopamine & Ach neurotransmitters worktogether to enable motor neurons to refinevoluntary movement

Parkinson's results from the degeneration ofdopamine-producing nerve cells in the brain,specifically in the substantia nigra and locuscoeruleus

Clients have lost 80% or more of their dopamine-producing cells by the time symptoms appear


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Dopamine

Neurochemical thatsupports fine motor activity,blood pressure, focus,inspiration, intuition,enthusiasm, and joy, amongother functions.

Dopamine Agonist: Drugs

that copy the effects of thebrain chemical dopamineand increase the amount ofdopamine that is availableto the brain for use.
http://en.wikipedia.org/wiki/File:Dopamine2.svg


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In normal conditions

acetylcholine release from the striatum (cholinergic

neurons)is strongly inhibited by dopamine (depleted from

the nigrostriatal neurons).

Joint GABA-ergic neurons then opposite excitatory

function of glutamate neurones connected to the motor

cortex

Neurodegeneration of the dopaminergic neurons

(Subs.nigra)+ loss of dopamine (the striatum) leads to

both hyperactivity of these cholinergic striatal neurons+ blockade of GABA-ergic cells (Subst.nigra). The result is

an increase in excitatory activity of glutamate + the motor

cortex

muscle rigidity, tremor, hypokinesia


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How to treat deficit of dopamine?

A.INCREASE IN DOPAMINERGIC ACTIVITY(1) dopamine precursors (replacement of dopamine)

(2) MAO-B blockade

(3) increase in dopamine release

(4) blockade of amine neuronal reuptake(5) dopamine receptors agonists

B.

How to treat excitatory function ofcholinergic and glutaminergic neurons?

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS


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Disease Modifying Drugs Overview


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L-DOPA is transported across the BBB by an amino acid transportsystem (same one used for tyrosine and phenylalanine)

Once across, L-DOPA is decarboxylated to dopamine by Dopa

Decarboxylase (DDC).In actual practice, L-DOPA is almost always coadminsteredtogether with an inhibitor of aromatic L-amino aciddecarboxylase, so it doesnt get converted to dopamine before itcrosses the BBB.The inhibitor commonly used is carbidopa, which does not crossthe BBB itself.


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Levodopa (L-DOPA)

About 80% of parkinsonian patients show initialimprovement with levodopa, particularly ofrigidity and hypokinesia, and about 20% arerestored virtually to normal motor function. Somesymptoms (cognitive decline, dysphagia) are notimproved.

W i t h t i m e the effectiveness of levodopagradually declines:

= it reflects:

1.the natural progress of disease, +

2. receptor down-regulation


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Levodopa (L-DOPA)

Pharmacokinetics:

Absorbed by the small intestine by an active transport

system

Decarboxylation occurs in peripheral tissues (gut wall,

liver and kidney) decrease amount available for distribution1% of

an oral dose

Extracerebral dopamine amounts causing

unwanted effects (benserazide) Short half-life

Levodopa reserved for later treatment of Parkinsons

as bod y develops to lerance and loses effect iveness

over t ime.


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Levodopa

(Madopar & Sinemet)

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)on-off effect

rapid fluctuation in clinial state where

hypokinesia and rigidity suddenly worsen (for

anything from a few minutes to a few hours) and

then improve again (probably the fluctuations

reflect the changing plasma levodopa

concentration)


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Levodopa (L-DOPA)

Adverse effects (type A)Dyskinesia

- involuntary writhing movements develop in the majority

of patients within 2 years of starting levodopa therapy :

affect the face and limbs are dose-dependent (disappear if the dose is reduced)

Others:

nausea and anorexia, hypotension,

by increase dopamine activity in the brain----schizophrenia-like syndrome with delusions and

hallucinations

confusion, disorientation, insomnia (in 20% of patients)


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Levodopa (L-DOPA)

Adverse effects (type A)

= dyskinesia- involuntary writhing movements develop in themajority of patients within 2 years of starting levodopatherapy :

affect the face and limbs

are dose-dependent (disappear if the dose is reduced)

= on-offeffectrapid fluctuation in clinial state ,where

hypokinesia and rigidity suddenly worsen (for anything froma few minutes to a few hours) and then improve again(probably the fluctuations reflect the changing plasma

levodopa concentration)= Others:

nausea and anorexia, hypotension,

by increase dopamine activity in the brain----schizophrenia-like syndrome with delusions and hallucinations

confusion, disorientation, insomnia (in 20% of patients)


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INCREASE IN DOPAMINERGIC ACTIVITY

(1) dopamine precursors (replacement of dopamine)

(2) MAO-B blockade(3) increase in dopamine release

(4) blockade of amine neuronal reuptake

(5) dopamine receptors agonists


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Ad.2 MAO-B blockade Dopamine is oxidized by monoamine oxidase B

(MAO-B).

MoA: prolongs the effects of levodopa as MAO-Bdegrades dopamine

Pharmacokinetics:= complete absorption, short half-life

Adverse effects:= N, V, Dia, Constipation; dry mouth, sore throat;

transient dizziness; insomnia, confusion andhallucinations

Early stageprescribed on it is own to delay need forlevodopa and there is good evidence for its slowing

down of PD progression


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Ad.2 MAO-B blockade

MAO-B inhibition:

protects dopamine from intraneuronal degradation

lacks the adverse peripheral effects of non-selective MAO -

Inhibitors used to treat depression does not provoke the cheese reaction

Selegiline

a selective inhibitor for MAO-B, which predominates in

dopamine containing regions in the CNS

Combination of levodopa + selegilin is more effective

in relieving symptoms and prolonging life


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INCREASE IN DOPAMINERGIC ACTIVITY

(1) dopamine precursors (replacement of dopamine)

(2) MAO-B blockade

(3) increase in dopamine release(4) blockade of amine neuronal reuptake

(5) dopamine receptors agonists


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ad. dopamine receptors agonists-

a.increase in dopamine release-b. blockade of amine neuronal reuptake

potent agonists at dopamine D2 receptors in the CNS:

= bromocriptine derived from the ergot alkaloids

- lisuride and pergolide

= amantadine :

- increases dopamine release,

- activates D2 receptors

- less active, more tolerated



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Dopamine receptor Agonists

Dopamine agonists mimic dopamine's function in

the brain.

They are used primarily as adjuncts to

levodopa/carbidopa therapy.

They can be used as monotherapy but are generallyless effective in controlling symptoms, with Side

effects similar to those produced by levodopa

- Bromocriptine (Parlodel)- Pergolide (Permax)- Pramipexole (Mirapex)-Ropinirole (Requip)-Apomorphine


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Dopamine receptor agonists

Apomorphine (APO-go):

SC administration

Rescue therapyrapid onset with a short

duration of action (~50mins) Bromocriptine (Parlodel); Pergolide (Celance);

Ropinirole (Requip)

Direct agonists of dopamine receptors in thebrain

?longer lasting therapeutic effects that Levodopa


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Dopamine receptor agonists

Adverse effects:

Use gradual dose titration

Nausea+ Vomitting (particularly Apomorphine)

Dyskinesia

Hallucinations and confusion

Peripheral vasospasm (Raynaunds)

Respiratory depression (Apomorphine


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COMT (Catechol-O-Methyl Transferase Inhibitors )

These new class of Parkinson's medications

augment levodopa therapy by inhibiting the COMT

enzyme, which metabolizes levodopa before it

reaches the brain.

Inhibiting COMT increases the amount of levodopa

that enters the brain.

These drugs are only effective when used withlevodopa

- Entacapone (Comtan)- Tolcapone (Tasmar)


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Catechol-O-methltransferase inhibitors

(COMT-I)

MoA: inhibits the breakdown of levodopa

Pharmacokinetics: variability of absorption,

extensive first-pass metabolism, short half-life Adverse effects: dyskinesias, hallucinations; N, V,

Dia and abdominal pain

New combinationLevodopa/carbidopa/entacapone (Stalevo) as 1

tablet (50, 100, 150mg


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Amantadine (Symmetrel)

Originally an antiviral drug, now used as conjunctive therapy fordyskinesis effects produced by Levodopa

MoA:

stimulates/promotes the release of dopamine stored in the

synaptic terminals Reduces reuptake of released dopamine by pre-synaptic

neuron

Pharmacokinetics:

Well absorbed, long half-life, excreted unchanged by thekidney

Adverse effects:

Not many

Ankle oedema, postural hypotension, nervousness,insomnia, hallucinations (high dose)

H t t t it t f ti f h li i


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How to treat excitatory function of cholinergic

and glutaminergic neurons?

Anticholinergics

= reduce the relative overactivity of the

neurotransmitter acetylcholine to balance the

diminished dopamine activity.= This class of drugs is most effective in the

control of tremor, and they are used as adjuncts to

levodopa.

= Side effects associated with anticholinergic

drugs include dry mouth, blurred vision,

constipation, and urinary retention

Antimuscarinic/Anticholinergic Drugs:


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Antimuscarinic/Anticholinergic Drugs:

Trihexyphenidyl (Broflex, Artane, Agitane);

Benztropine (Cogentin); Orphanadrine (Disipal);

Procycline (Kemadrin, Arpicolin)

Less common drugs but they affect Ach basedinteractions

MoA: blocking cholinergic (Ach) receptors to

restore balance

Pharmacokinetics: fairly well absorbed, extensive

hepatic metabolism, intermediate to long half-lifes

Adverse effects: dry mouth and confusion


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Symptom Management Drugs

PD is multidimensional, therefore there are a

number of clinical presentations that require

supplementary agents

Drug-Drug reactions is the problem

Major area is depression


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Antidepressants

Amitriptyline (Tryptizol), imipramine (Tofranil),

Nortriptyline (Allegron), Iofepramine (Gamanil)

MoA: block re-uptake of noradrenaline and

serotonin => Sedative actions, can help withdrooling and loss of appetite

Adverse effects: sleepiness, dry mouth, increased

hunger, cardiac arrhythmias and changes in BP

Can interfere with the effects of levodopa!


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Drug-induced EPS

EPS secondary topharmacologic agents are the

most common.

The risk of developing a drug-induced EPS begins at

the onset of treatment with an offending agent. Acutely: within hours or a few days

Subacutely: over several weeks

Late or delayed onset: six months or longer afterexposure(tardive)

short-term therapy of minimal therapeutic dosages

should be the strategy employed


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Drugs affect EPS

Five classes of drugs are known to affect central

dopaminergic systems

1.Central stimulantsact as indirect dopamine agonist

ex. Amphetamine 2.Levodopaa precursor of dopamine

3.Direct dopamine agonistex. Bromocriptine

4.Presynaptic dopamine antagonists

ex. Reserpine 5.Antagonize or block central dopamine receptors

neuroleptics, metoclopramideprimperan


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Other Drugs to Avoid

Generic Name Brand Name Prescribed for

Prochlorperazine Stemetil N +V, Dizziness

Prephenazine Triptafen Depression

Flupentixol Fluanxol/Depixol Confusion,

Hallucinations

Chlorpromazine Largactil

Pimozide Orap

Sulpiride Dolmatil

Thanks for your attention


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Thanks for your attention

Documents

154882837 Blok BMS 2013 Pharmacology of Extrapyramidal Disorders Ppt