k.14 newbms 2011,pharmacology of extrapyramidal disorders

7/27/2019 K.14 NewBMS 2011,Pharmacology of Extrapyramidal Disorders

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Pharmacology of drugs in

extrapyramidal disorders

Prof.Aznan Lelo,dr,PhD,SpFK

&dr Datten Bangun,MSc,SpFK



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



Dopamine Pathways



Dopamine functions

• Motor control - nigrostriatal system

– Deficiency results in rigidity, tremor and difficulty initiating movement

• Behavioural effects - mesolimbic system

– Overactivity in rats leads to abnormal behavior

•

Endocrine control - tubero-infundibular system – Dopamine and dopamine agonists suppress

prolactin release, dopamine antagonists may stimulate it



Dopamine synthesis



Pathogenesis

• Results from dysfunction of the extrapyramidal system

• Basal ganglion：caudate, putamen, globus pallidus,

subthalamic nucleus, and substantia nigra

• motor area of cortex--> basal gangalion(organizing

movement commands)

# affects the size and speed of movements

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



Drug-induced EPS(1)

• EPS secondary to pharmacologic 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



Drug-induced EPS (2)

Five classes of drugs are known to affect central

dopaminergic systems

• Central stimulants：act as indirect dopamine agonist ex.

Amphetamine• Levodopa：a precursor of dopamine

• Direct dopamine agonist：ex. Bromocriptine

•Presynaptic dopamine antagonists： ex. Reserpine

• Antagonize or block central dopamine receptors：

neuroleptics, metoclopramide〈primperam〉



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

* 1960’s chemical difference in

brain were identified

* 2000 – Michael 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



What is Parkinson’s Disease?

• movement disorder

• slowly progressive

• tremor at rest

• Akinesia: inability to

move

• Bradykinesia: slow

movements• postural reflex

impairment

• affects over 1 million

Americans

• Avg. age of onset: 58

• 40% of PD patients

are under age 60

• Decrease in

neurotransmitterdopamine



Pathophysiology

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

• Parkinson's results from the degeneration of dopamine-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



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 of dopamine that is availableto the brain for use.

http://en.wikipedia.org/wiki/File:Dopamine2.svg



13



What are the Symptoms of

Parkinsons?

The clinical appearance of Parkinsons is marked by

four cardinal, signs:

• Tremor (or trembling) atrest

• Akinesia and Bradykinesia

• Rigidity

• Postural Instability



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



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 of cholinergic and glutaminergic neurons?

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS



Disease Modifying Drugs Overview




Levodopa (L-DOPA) the first-line drug

Levodopa dopamine

Dopamine does not penetrate the blood-brain barrier.

DOPA conversion to dopamine in the periphery, which

would cause troublesome adverse effects …… is largely

prevented by the decarboxylase inhibitor.

Since the inhibitor does not penetrate the blood-brain

barrier, decarboxylation occurs rapidly within the brain

(95% of the levodopa dose).

Dopa decarboxylase

(1) dopamine precursors (replacement of dopamine)



• 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 doesn’t get converted to dopamine before itcrosses the BBB.The inhibitor commonly used is carbidopa, which does not crossthe BBB itself.




Levodopa (L-DOPA)

• About 80% of parkinsonian patients show initialimprovement with levodopa, particularly of rigidity 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: the natural progress of disease

+

receptor down-regulation



Levodopa

• A natural amino acid that the brain converts into

dopamine (replacement therapy) used since the

1960’s

• This is an example of a “prodrug”, that is, amolecule that is a precursor to the drug and is

converted to the actual drug at an appropriate

place in the body.

To make it slow release, combined with benserazide

(an enzyme inhibitor) to create co-beneldopa or co-

careldopa (Sinemet)

•

Dose = 50, 100 or 200mg (12.5, 25 or 50mg)



Levodopa (L-DOPA)

• Pharmacokinetics:

– Absorbed by the small intestine by an activetransport system

–Decarboxylation occurs in peripheral tissues (gutwall, liver and kidney

• decrease amount available for distribution – 1% of anoral dose

•

Extracerebral dopamine amounts causing unwantedeffects (benserazide)

– Short half-life



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-off ’ effect – rapid 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)




INCREASE IN DOPAMINERGIC ACTIVITY


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

(4) blockade of amine neuronal reuptake

(5) dopamine receptors agonists




H t t t d fi it f d i ?




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:= completely absorption, short half-life

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

transient dizziness; insomnia, confusion andhallucinations

Early stage – prescribed on it is own to delay need for levodopa and there is good evidence for its slowing

down of PD progression




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




INCREASE IN DOPAMINERGIC ACTIVITY


(2) MAO-B blockade

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

(5) dopamine receptors agonists



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




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



Dopamine receptor agonists

• Apomorphine (APO-go):

– SC administration

– Rescue therapy – rapid 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



Dopamine receptor agonists

• Adverse effects:

– Use gradual dose titration

– Nausea+ Vomitting (particularly Apomorphine)

– Dyskinesia

– Hallucinations and confusion

– Peripheral vasospasm (Raynaunds)

– Respiratory depression (Apomorphine



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®)



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 combination – Levodopa/carbidopa/entacapone (Stalevo) as 1

tablet (50, 100, 150mg



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 i f i f h li i



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

A ti i i /A ti h li i D



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



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



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!



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 “



Thank you

k.14 newbms 2011,pharmacology of extrapyramidal disorders

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