Pharmacology of drugs in extrapyramidal disorders

D.r Datten Bangun,MSc,SpFK Dr.Sake Juli Martina,SpFK Dept.Farmakologi & Therapeutik Fak.Kedokteran,USU MEDAN

Extrapyramidal syndrome Definition: Neurologic syndromes in which abnormal movement occur due to: = a disturbance of fluency and speed of voluntary movement ; or : = the presence of unintended extra movements

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

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

Parkinsons Disease

Acetylcholine = excitatory Dopamine = inhibitory GABA = inhibitory

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 PARKINSON

Parkinson's Disease Hypokinesia Can't initiate movements Stuck in the doorway

Decreased spontaneous movements

Cogwheel rigidity Hyperkinesia

Bradykinesia Poverty of Movements

Parking Brake Rigidity Can't stop movements once started Parkinsons "Quick Boys" Resting tremor Pill Rolling

Destruction of the Dopamine input to the Neostriatum

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

L-DOPA

Pathophysiologic ApproachAdams et al (2006)

dopamine

Parkinson disease

D2 receptors

reduced dopamine

cholinergic overactivity

Adenylyl cyclase

inhibitsIP3

Cyclic AMP

closesCa2+ channel Intracellular Ca2+

Substantia nigra

Corpus striatum

restores balance inhibitsFiring of striatal cholinergic nerves

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.

Levodopa: The most effective drug, until it wears off.

Pathogenesis Results from dysfunction of the extrapyramidal system Basal ganglioncaudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra motor area of cortex--> basal ganglion(organizing movement commands)

# affects the size and speed of movements # selection of components of movements or the sequencing of multi-step movements

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 * 2000 Michael J. Fox Foundation

Pathophysiology Normally Dopamine & Ach neurotransmitters work together to enable motor neurons to refine voluntary movement

Parkinson's results from the degeneration of dopamine-producing nerve cells in the brain, specifically in the substantia nigra and locus coeruleus Clients have lost 80% or more of their dopamineproducing cells by the time symptoms appear

Dopamine Neurochemical that supports fine motor activity, blood pressure, focus, inspiration, intuition, enthusiasm, and joy, among other functions. Dopamine Agonist: Drugs that copy the effects of the brain chemical dopamine and increase the amount of dopamine that is available to the brain for use.

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In normal conditionsacetylcholine 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

Biosynthesis of Catecholamines

How to treat deficit of dopamine?(1) dopamine precursors (replacement of dopamine)

Levodopa (L-DOPA) the first-lineLevodopaDopa decarboxylase

drug

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).

L-DOPA is transported across the BBB by an amino acid transport system (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 coadminstered together with an inhibitor of aromatic L-amino acid decarboxylase, so it doesnt get converted to dopamine before it crosses the BBB. The inhibitor commonly used is carbidopa, which does not cross the BBB itself.

How to treat deficit of dopamine?Levodopa (L-DOPA)

About 80% of parkinsonian patients show initial improvement with levodopa, particularly of rigidity and hypokinesia, and about 20% are restored virtually to normal motor function. Some symptoms (cognitive decline, dysphagia) are not improved.

W i t h t i m e the effectiveness of levodopa gradually declines: = it reflects: 1.the natural progress of disease, + 2. receptor down-regulation

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 distribution 1% of an oral dose Extracerebral dopamine amounts causing unwanted effects (benserazide) Short half-life Levodopa reserved for later treatment of Parkinsons as body develops tolerance and loses effectiveness over time.

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)

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)

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)

= 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) = Others: nausea and anorexia, hypotension, by increase dopamine activity in the brain----schizophrenialike syndrome with delusions and hallucinations confusion, disorientation, insomnia (in 20% of patients)

How to treat deficit of dopamine?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

Disease Modifying Drugs Overview

How to treat deficit of dopamine? 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 and hallucinations Early stage prescribed on it is own to delay need for levodopa and there is good evidence for its slowing down of PD progression

How to treat deficit of dopamine? Ad.2 MAO-B blockadeMAO-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 CNSCombination of levodopa + selegilin is more effective in relieving symptoms and prolonging life

How to treat deficit of dopamine?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

Disease Modifying Drugs Overview

How to treat deficit of dopamine?ad. dopamine receptors agonistsa.increase in dopamine releaseb. 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 generally less 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 the brain ?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 with levodopa- 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 for dyskinesis 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 the kidney Adverse effects: Not many Ankle oedema, postural hypotension, nervousness, insomnia, hallucinations (high dose)

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: Trihexyphenidyl (Broflex, Artane, Agitane); Benztropine (Cogentin); Orphanadrine (Disipal); Procycline (Kemadrin, Arpicolin) Less common drugs but they affect Ach based interactions 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 with drooling and loss of appetite Adverse effects: sleepiness, dry mouth, increased hunger, cardiac arrhythmias and changes in BP Can interfere with the effects of levodopa!

Drug-induced EPS 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 after exposure(tardive) short-term therapy of minimal therapeutic dosages should be the strategy employed

Drugs affect EPSFive 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

Other Drugs to AvoidGeneric NameProchlorperazine Prephenazine Flupentixol

Brand NameStemetil Triptafen Fluanxol/Depixol

Prescribed forN +V, Dizziness Depression Confusion, Hallucinations

Chlorpromazine Pimozide Sulpiride

Largactil Orap Dolmatil

Thanks for your attention