In this presentation we will discuss Parkinsonism and other movement disorders, Pathophysiology of parkinsonism and its types, drugs used in Parkinsonism and their pharmacology and briefly discuss the drugs used to treat other movement disorders like tourettes syndrome, Huntington chorea etc.

1. AND OTHER MOVEMENT DISORDERS

2. PARKINSON DISEASE
HUNTINGTON’S CHOREA
GILLES DE LA TOURETTE’S
SYNDROME
WILSON’S DISEASE

3. ATHETOSIS
CHOREA
DYSKINESIA
DYSTONIA
TICS
TREMORS

4.  progressive neurologic disease involving Basal
Ganglia;
 Characterised by:
1. Rigidity of Skeletal Muscles
2. Akinesia(OR Bradykinesia)
3. Flat Facies
4. Resting Tremors
 Divided into two types:
1. Naturally occuring Parkinsonism
2. Drug induced Parkinsonism

6.  Naturally occuring Parkinsonism
 Uncertain origin
 Frequency: Mostly sixth or fifth decade of life
 Characterised by:
1. Decrease Dopamine or degeneration
dopaminergic neurons in the nigrostriatal tract.
AND
2. excessive excitatory actions of cholinergic
neurons on striatal GABAergic(D2 subclass)
neurons
3. Which leads to imbalance between dopamine
and acetylcholine activities.

8.  Drug-Induced Parkisonism
 A small number of diagnosed with Parkinsonism
have developed symptoms following treatment with
certain medications;
1. Antipsychotic drugs: which block brain dopamine
receptors ; butyrophenone (Haloperidol) and
phenothiazine (chlorpromazine)
2. Adrenergic blocking agent; reserpine
3. MPTP (1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine); through destruction of
dopaminergic neurons in the nigrostriatal tract.

9. Treatment Strategies include:
Increasing dopamine activity(D2
receptor subtype) in the brain,
Decreasing muscarinic activity OR
Both

11. a) DOPAMINE PRECURSORS; levo-DOPA
b) DOPAMINE AGONISTS; bromocriptine
c) MAO INHIBITORS; selegiline
d) COMT INHIBITORS; entacapone
e) AMANTADINE
f) MUSCARINIC ANTAGONIST;
benztropine

12. Mechanism of action
 Dopamine precursor
 Readily cross blood-brain Barrier
 Converted to dopamine by enzyme Dopa
Decarboxylase
 Given alongwith Carbidopa; which itself does not cross
blood-brain barrier and
 Inhibits peripheral Dopa Decarboxylase
 Inc. half life and Dec. peripheral side effects

13. Improves the signs of Parkinsonism BUT
Does not cure them
Response to drug may gradually decreases
Motor control fluctuations may occur LIKE
Off-periods of Akinesia alternates with On-
period of improved symptoms WHICH
Can be cured by adding drugs like
Apomorphine or COMT inhibitors

14. Absorption: small intestine (when empty
of food)
Bio-availability: 30%
Metabolism: L- Amino Acid
Decarboxylase
Half Life: 1-2 hours
Excretion: renal 80-90 percent

15. Peripheral Effects:
Anorexia, Nausea and Vomiting(activation of
chemoreceptor trigger zone of Medulla)
Tachycardia and Ventricular Extrasystoles
(Cardiac dopamenergic effect)
Mydriasis
Blood Dyscrasias
Brown Discoloration of Saliva and Urine

16. CNS effects: mostly due inc. activity of
dopaminergic receptors in Basal Ganglia;
 Depression, Mood changes, Psychosis and
Anxiety
Visual and Auditory Hallucinations
Abnormal Involuntary Movements(Dyskinesia)

17. Vit B6(Pyridoxine) inc. peripheral
breakdown of Levo-Dopa
When taken alongwith Phenelzine can
cause Hypertensive crises.
Should be used in caution in Pts
having psychotic illnesses, glaucoma
and Cardiac diseases.

18. Selegiline and Rasagiline
Selective inhibitors of Monoamine Oxidase
type B
Metabolism of Selegiline results in the
formation of Demethylselegiline and
Amphethamine
Rasagiline does not metabolized to any
Amphetamine like substance.

19.  Selegiline has minimal efficacy when given
alone than given in combination with L-Dopa
Due to selective blocking of MAO inhibitor
type B enzyme, selegiline has less potential for
causing Hypertensive crises when given in
LOW DOSES
Rasagiline is five times more potent and have
desirable effects when given alone

20.  Insomnia (as selegiline metabolized to
amphetamines like metabolites)
 Mood changes
 Dyskinesia
 Hypertensive crises (when given in large doses)
 When given with meperidine; can cause agitation,
delirium, and mortality.
 Can involve in serotonin syndrome when given with
SSRIs.

21. Entacapone and Tolcapone
SeIectively and reversibly inhibit
Catechol-O-methyltransferase (COMT)
which converts L-DOPA to 3-O-
methyldopa (3OMD).
That leads to increase amount of
Dopamine in the CNS

22. In Patients taking Levodopa-Carbidopa
combination, significant conc. of 3-O-methyldopa
can be built in periphery due to decrease activity
of DOPA decarboxylase WHICH
Competes with Levo-Dopa for active transport in
CNS
Entacapone and Tolcapone inhibits COMT ,
decrease conc. of 3OMD and increase central
uptake of Levodopa.

23. Intake: Oral
Bioavailabiliy: 35%-65%
Protein Binding: >98% (binds to serum
albumin)
Metabolism: Hepatic
Excretion: both feces and urine
Tolcapone has longer half life than
entacapone
Entacapone acts only in periphery

24. Mostly related to increase levels of levo-Dopa ;
Dyskinesias
GI distress
Hallucinations
Postural hypotension
However most serious adverse effect is
associated with Tolcapone; Acute Hepatic
Failure

25.  Ergot derivative ;Bromocriptine
 Non Ergot drugs
1. Pramipexole
2. Ropinirole
3. Apomorphine
4. Rotigotine

26.  Ergot Alkaloid
 Partial agonist of D2 receptor
 Inc. functional activity of Dopaminergic receptors
 Adverse effects include;
 Anorexia, nausea and vomiting, dyskinesia and
postural hypotension.
 Behavioral effects like Hallucinations and delusions
 Ergot- related effects like erythromelalgia and
pulmonary infiltrates

27.  Drugs include Pramipixole, ropinirole, Apomorphine
and rotigotine.
 Newer group of drugs
 These agents may delay the need to use Levodopa in
early Parkinson disease
 Pramipixole: high affinity for the dopamine
D3 receptor; Half life 8 hours.
 Given orally 3 times a day
 Neuroprotective; acts as scavenger of H2O2

28.  excreted largely unchanged in the urine.
 Should be given in reduced dose in patients with
renal failure
 Adverse Effects; anorexia, nausea and vomiting,
postural hypotension, dyskinesias and Mental
disturbances (confusion, delusions,
hallucinations,impulsivity).
 Drug Interaction; cimetidine which inhibits renal
tubular secretion of organic bases inc. its half life.

29.  Ropinirole: non ergot, having high affinity for D2 receptors
 Monotherapy as well as in combination with Levodopa to
smooth out response fluctuations .
 Unlike Pramipixole, it is metabolized by hepatic CYP1A2
enzyme
 Half Life is 6 hours
 Adverse effects are similar to those of Pramipixole
 Inhibitors of CYP1A2 like fluoroquinolones and other drugs
metabolized by this isoform(eg, caffeine, warfarin) may
reduce its clearance.

30.  Apomorphine and Rotigotine are newer drugs
available in Injectable and transdermal delivery
system respectively.
 Apomorphine is meant to be used in the treatment
of “Hypomobility Off phenomenon”.
 Because of severe nausea, pretreatment for 3 days
with antiemetics (eg, trimethobenzamide) is
necessary.
 Adverse effects include dyskinesias, hypotension,
drowsiness, and sweating.

31.  Antiviral Drug; effective in the treatment of Influenza.
 MOA: unknown mechanisms that may involving increasing
synthesis or release of dopamine, blockading cholinergic
receptors and inhibit NMDA type of glutamate receptors
 may improve bradykinesia, rigidity, and tremor but is usually
effective for only a few weeks.
 Adverse Effects include behavioral effects, dermatologic
reactions (Livedo reticularis) and peripheral edema(which
response to diuretics).

32.  Drugs include benztropine, biperiden, orphenadrine etc
 MOA: decrease the excitatory actions of cholinergic
neurons on cells in the striatum by blocking muscarinic
receptors.
 Effects: improves tremors and rigidity ; little effect on
bradykinesia and minimize the reversible
extrapyramidal symptoms caused by antipsychotic
drugs.
 Toxicity: CNS toxicity(hallucinations, delusions etc)
and peripheral effects similar to that of atropine.

33.  Inherited disease; progressive breakdown of nerve cells
in the brain.
 Symptoms starts appearing around second decade of life.
 Results from neurotransmitter imbalance i-e GABA
functions are diminished and dopaminergic functions are
enhanced OR
 cholinergic deficit because choline acetyltransferase is
decreased in the basal ganglia of patients.
 Drug therapy; amine-depleting drugs (eg, reserpine,
tetrabenazine) or Dopamine receptor antagonists (eg,
haloperidol, perphenazine).

34.  disorder of unknown origin; childhood onset.
 characterized by repetitive, stereotyped,
involuntary movements and vocalizations
called tics.
Drug of choice ; Haloperidol
other dopamine D2 receptor blockers eg
pimozide can be used.
Less frequently; antihypertensive i-e
agents clonidine and guanfacine, TCAs and
SSRIs.

35.  Inherited; disorder of copper metabolism
 Results in accumulation of copper salts in
Brain(specifically basal ganglia), Liver and other
tissues
 Drug of choice: Penicillamine (dimethylcysteine);
chelator and removes excess copper.
 Adverse Effects: gastrointestinal distress,
myasthenia, optic neuropathy, and blood dyscrasias.
 Other drugs: Trientine and Tetrathiomolybdate.

36.  also called Willis-Ekbom Disease; causes unpleasant
or uncomfortable sensations in the legs and an
irresistible urge to move them.
 common in pregnant women and in uremic
and diabetic patients
 Treatment: Dopaminergic Agonists(drug of choice),
Opoid analgesics, benzodiazepines etc.

37.  Acute Dystonia: Injectible Muscarinic
Blockers(Benztropine)
 Levodopa and Other Dopaminergic agonists are not
useful.
 Tardive dyskinesias is a side effect of antipsychotic
medications ; causes stiff, jerky movements of your
face and body that you can't control.
 Not reversed; no specific treatment.

38.  characterized by postural tremor
 enhanced by anxiety, fatigue, and certain drugs,
including
 bronchodilators, tricyclic antidepressants, and
lithium.
 Treatment: Beta-Blockers i.e. Proparanolol,
Antiepileptic drugs including gabapentin, primidone,
topiramate OR Botulinum toxin(I/M)