3. Movement Disorders
• Several types of abnormal movements are recognized.
•Tremor
•Chores
•Tics
•Huntington’s disease
•Parkinsonism
4. Movement Disorders
• Movement disorders have been attributed to
disturbances of the basal ganglia.
• The basic circuitry of the basal ganglia involves three
interacting neuronal loops that include the cortex and
thalamus as well as the basal ganglia.
5. Tremor
• Rhythmic oscillatory movements around a joint
• Tremor at rest is a characteristic of parkinsonism.
• It associates with rigidity and an impairment of voluntary
activity.
• Also may occur during maintenance of sustained posture
(postural tremor) or during movement (interior tremor)
• Intention tremor occurs in patients with a lesion of the
brain stem or cerebellum.
• Also occur as a manifestation of toxicity from alcohol or
certain other drugs.
MovementDisorders
6. Chorea
• Irregular, unpredictable, involuntary muscle jerks that
occurs in different parts of the body.
• Impaired voluntary activity.
• Mostly affected proximal muscles of the limb.
(Abnormal movements at this site is called as the term
ballismus)
• Occur due to hereditary effects and as a complication
of number of medical disorders.
MovementDisorders
7. Tics
• Sudden coordinated abnormal movements.
• Occur repetitively.
• In face and head, specially in children.
• Can be suppressed voluntarily for short periods of time.
• Repetitive sniffing and shoulder shrugging.
• May be transient or chronic.
• Gilles de la Tourette’s syndrome is characterized by chronic
multiple tics.
MovementDisorders
8. Huntingon’s Disease
• Autosomal dominant inherited disorder caused by an
abnormality of the huntingtin gene on chromosome 04.
• Characterized by progressive chorea and dementia.
MovementDisorders
10. Parkinsonism
• Characterized by a combination of rigidity, bradykinesia,
tremor and postural instability.
• Cognitive decline occur in many patients when disease
advance.
• Pathophysiological basis is to exposure to some
unrecognized neurotoxin or to oxidation reaction with the
generation of the free radicals.
• Mutations in parkin gene may cause early onset, autosomal
recessive, familial parkinsonism, or spodiac juvenile onset
parkinsonism.
MovementDisorders
11. Parkinsonism
• Generally progressive, leading to increasing disability unless
effective treatment is provided.
• In parkinsonism, high concentration of dopamine in the basal
ganglia of the brain is reduced.
• Pharmacological attempts to restore dopaminergic activity with
levodopa and dopamine agonists alleviate many of the motor
features.
• Antimuscarinic drugs also gives effect in alleviating motor
features.
• Drugs that induce parkinsonism are dopamine receptor
antagonist (Ex:- Antipsychotics) or lead to the destruction of
dopaminergic nigrostriatal neurons.
MovementDisorders
12. Levodopa
• Dopamine itself does not cross the blood brain barrier.
• Therefore Levodopa is the immediate metabolite of
dopamine, which can cross the blood brain barrier.
• In brain it decarboxylated back in to dopamine.
• Levodopa is the levorotary stereoisomer of DOPA.
• DOPA is the amino acid precursor of dopamine and
norepinephrine.
14. Levodopa – Mechanism of Action
• Dopaminergic neurons originating in the substantia nigra
normally inhibit the GABAergic out put from the straitum ,
whereas cholinergic neurons exert an excitatory effect.
• In parkinsonism, there is a selective loss of dopaminergic
neurons.
• Therefore, dopamine/ Levodopa is covering the loss of
dopamine effectiveness.
15. Levodopa - Pharmacokinetic
• Rapidly absorbed from the small intestine, but absorption
is depend on gastric emptying and the pH of the gastric
contents.
• Ingestion of food delays the appearance of levodopa in the
plasma.
• Certain amino acid in foods may compete with levodopa.
• Peak plasma concentration 1-2 hours after oral dose.
• Plasma half life is 1-3 hours.
• About 2/3 of drug appears as urine metabolites within
8hours of an oral dose.
16. Levodopa - Pharmacokinetic
• Actually 1-3% of administered levodopa enters the
brain unaltered, remainder metabolized
extracerebrally, by decarboxylation of dopamine.
• Levodopa should give high dose when given alone.
• Best is combination with a dopa decarboxylase
inhibitor that not penetrates the BBB.
• Combination decrease metabolism and increase
higher percentage of absorption.
18. Levodopa – Clinical Use
• Best results in first few years of treatment when
use alone.
• Because the daily dose should reduce time to time
to avoid side effects.
• However early initiation lowers the mortality rate.
• But long term therapy lead to problems.
• Generally Levodopa is given with Carbidopa one of
dopa carboxylase inhibitor. (Sinemet)
19. Levodopa – Clinical Use
• Sinemet firstly given 25/100 mg (Carbidopa 25mg
& Levodopa 100 mg) tds.
• It should take 30-60 minutes before meals.
• Ultimately may require Sinemet 25/250.
• At present CR dosage form also available.
• Parcopa is one of best finding which disintegrate in
the mouth and is swallowed with saliva.
• Parcopa should take 1 hour before meals.
20. Levodopa – Adverse Effects
Gastrointestinal effects:
• Anorexia, Nausea & Vomiting (Occur about 80%
patients)
• These can minimized by take drug in divided doses
with or immediately after meals.
• Antacid 30-60 minutes before meals is also
prescribed.
• Tolerance may develop in many patients.
22. Levodopa – Adverse Effects
Other effects:
• Dyskinesia
• Depression
• Anxiety
• Insomnia
• Confusion
• Hallucinations
•Euphoria
• Mydriasis
•Precipitation of gout
• Brownish discolouration of
saliva
23. Levodopa – Drug Interactions
• Pyridoxine (Vit B6) enhances the extracerebral
metabolism of levodopa.
• Levodopa should not given to patients taking MAO A
inhibitors or within 2 weeks of their discontinuance.
25. Dopamine Receptor Agonists
• Drugs acting directly on dopamine receptors – MoA
• Not require enzymatic conversions.
• No potentially toxic metabolites.
• Not compete food or other substances.
• Limited adverse effects than Levodopa.
• First line therapy drugs for parkinsonism.
• Sinemet firstly add and then introduces DRA.
26. DRA - Bromocriptine
• D2 receptor agonist.
• Now rarely used.
• Peak plasma level 1-2 hours after oral dose.
• Excreted in bile and feces.
• Daily dose between 7.5mg and 30mg.
• To minimize adverse effects the dose is built up slowly over
2-3 months from starting 1.25mg bd pc, then increased by
2.5 mg every 2 weeks depending on response.
27. DRA - Pergolide
• D1 & D2 receptor agonists.
• Widely used for parkinsonism.
• No longer used due to development of valvular heart
disease.
28. DRA - Pramipexole
• D3 receptor agonists.
• Monotherapy for mild parkinsonism.
• Rapidly absorbed after oral administration.
• Peak plasma level 2 hours.
• Excreted largely unchanged in the urine.
• Start at dosage of 0.125mg tds, doubled after 1week and
again after another week.
• Renal insufficiency may occur.
29. DRA - Ropinirole
• Pure D2 receptor agonists.
• Effective in monotherapy.
• Introduced at 0.25mg tds, and the total daily dose is
then increased by 0.75mg at weekly intervals until the
fourth week and by 1.5mg thereafter.
30. DRA - Rotigotine
• Delivered daily through a skin patch.
• More continuous dopaminergic stimulation than oral
medication..
• This product was recalled in 2008 because of crystal
formation on the patches.
33. Monoamine Oxidase Inhibitors
•Monoamine oxidase A metabolizes norepinephrine,
serotonin and dopamine.
•Monoamine oxidase B metabolizes dopamine
selectively.
•Combination with Levodopa should avoid as it may
cause hypertensive crisis.
34. MOIs - Selegiline
• Selective irreversible inhibitor of MABO at normal
doses. (Higher – MAAOI)
• Enhances and prolong antiparkinsonism effect of
Levodopa.
• Used as an adjunctive therapy.
• 5mg c. breakfast & 5mg c. lunch
• May cause insomnia when taken later during the day.
35. MOIs - Rasagiline
• MAO B inhibitor.
• Used for early symptomatic treatment.
• Start dose 1mg/d.
• Used as an adjunctive therapy.
• Neither selegiline nor rasagiline should be taken by
patients receiving meperidine, TCAs, Serotonin
reuptake inhibitors because the risk of acute toxic
interactions.
36. Catechol-O- Methyl Transferase Inhibitors
(COMT)
• Inhibition of dopa decarboxylase is associated with
compensatory activation of other pathways of
levodopa metabolism, as COMT.
• It increases plasma levels of 3-O- metyldopa (OMD).
• Elevated levels of 3-OMD cause poor therapeutic
response to Levodopa.
• There are selective inhibitors of COMT such as
Tolcapone & Entacapone.
38. Acetylcholine Blocking Drugs
• Antimuscarinic drugs.
• Improve the tremor and rigidity of parkinsonism.
• Little effect of dyskinesia.
• Started with lower doses, then gradually being
increased.
• But may occur dyskinesia.
41. Apomorphine
• Subcutaneous injection of apomorphine hydrochloride (Apokyn),
a potent dopamine agonist.
• Effective in temporary relief of off periods of akinesia in patients
on optimized dopaminergic therapy.
• Rapidly taken into blood then brain.
• Clinical benefit begins about 10 minutes of injection and persists
up to 2 hours.
• Most patients need 3-6 mg tds.
• Adverse Effects – Dyskinesia, drowsiness, chest pain, sweating,
hypotension
42. Amantadine
• An antiviral agent.
• Has Antiparkinsonism activity.
• MoA is unclear, but it may potentiate dopaminergic function.
• Peak plasma level 1-4 hours after an oral dose.
• Plasma half life between 2-4 hours.
• Excreted unchanged in the urine.
• Standard dose is 100mg orally bd/tds.
43. Amantadine
• An antiviral agent.
• Has Antiparkinsonism activity.
• MoA is unclear, but it may potentiate dopaminergic function.
• Peak plasma level 1-4 hours after an oral dose.
• Plasma half life between 2-4 hours.
• Excreted unchanged in the urine.
• Standard dose is 100mg orally bd/tds.
44. Neuroprotective Therapy
• Number of compounds are under investigation as
potential neuroprotective agents that may slow disease
progression.
• Ex:- Antioxidants, Glutamate antagonists, Creatine,
Antiinflammatory Drugs
45. Gene Therapy
• Safety trial of gene therapy for Parkinson’s disorder have
now been completed in USA.
• Phase II trials are now planned and in progress.
