Drugs used in parkinsonism

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Drugs used in parkinsonism
By Prof. Hanan Hagar Pharmacology unit Medical
College
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• ILOs
• At the end of this lecture you will be able to-
• Recognize the symptoms and pathophysiology of
  parkinsonism
• Understand the pharmacology of drugs used for
  treatment of parkinsonism.
• Define pharmacokinetics, pharmacodynamics and
  side effects of different drugs used for the
  treatment of parkinsonism.

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Parkinson's Disease

• A progressive neurological disorder that
  occurs mainly in the elderly.

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• Characters of Parkinson's disease
• Tremors at rest
• Bradykinesia (slowness in initiating and carrying
  out voluntary movements) or Akinesia
• Muscle rigidity
• Postural and gait abnormalities

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Parkinsons disease

• occurs mainly due to reduction of dopamine
• content in substantia nigra corpus striatum
• that are involved in motor control.

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Parkinsons disease
Parkinsons disease

• Deficiency of dopamine
• Predominance of Ach

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• Causes
• Parkinsons disease is an idiopathic disease but
  some causes may be
• Genetic.
• Toxins.
• Head trauma.
• Cerebral anoxia .
• Oxidative stress
• Drug-induced Parkinson's disease e.g.
  antipsychotics like haloperidol.

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Drug Treatment
Drugs to increase dopaminergic activity
Drugs to block cholinergic activity
or/and
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• 1) Drugs that increase dopaminergic activities
• Dopamine precursor (the most widely used)
• L-dopa usually combined with carbidopa
• Dopamine agonists
• Ergot derivatives bromocriptine
• Non ergot derivatives pramipexole
• Dopamine releaser amantadine
• COMT inhibitors entacapone
• MAO-B inhibitors selegiline
• 2) Drugs that decrease cholinergic activity
• Muscarinic antagonists e.g. benzatropine

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• Levodopa (L-dopa)
• First line treatment
• a precursor of dopamine (converted centrally and
  peripherally into dopamine).
• 98-99 is decarboxylated in gut and liver
• 1-2 crosses BBB and dopamine is formed
• given combined with carbidopa

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• Carbidopa
• Is a peripheral dopa decarboxylase inhibitor
• Inhibits peripheral conversion of L-dopa to
• dopamine
• L-dopa
• Dopamine

dopa decarboxylase
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• Why carbidopa is combined with L-dopa?
• decrease metabolism of L-dopa in GIT and
  peripheral tissues (thus increasing t1/2 ).
• increase availability of levodopa.
• reduce dose of levodopa and side effects.

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• Levodopa (L-dopa)
• absorbed from the small intestine (active
  transport)
• High protein meal interferes with its absorption
  and transport into CNS (should be taken on empty
  stomach).
• Short duration of action (t½ 2 h)
• (fluctuation of plasma concentration).
• L-Dopa ameliorates the signs of parkinsonism
  particularly bradykinesia rigidity but does not
  cure the disease.

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• Adverse drug effects
• On-off phenomenon (OffAkinesia or hypomobility).
  
• Wearing-off effect (duration of on states
  becomes shorter).
• Dyskinesia (involuntary movements occurs in 40 to
  90 of patients) due to fluctuating plasma levels
  of levodopa.

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• Adverse drug effects
• Peripheral effects
• anorexia, nausea, vomiting (due to stimulation of
  emetic center).
• mydriasis, orthostatic hypotension, cardiac
  arrhythmias.
• CNS effects
• (Psychological disorders) mainly psychosis,
• delusions, hallucinations, confusion, sleep
• disturbances and depression

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• Drug Interactions-
• Proteins ingested with meals.
• Pyridoxine (Vitamin B6).
• Nonselective MAO inhibitors (phenelzine).

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Contrindications

• Psychotic patient.
• Glaucoma (due to mydriatic effect).
• Patients with history of melanoma Why?
• Note L-dopa is a precursor of melanin

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• Dopamine receptor agonists
• Bromocriptine, pergolide, Pramipexole
• Ergot derivatives Bromocriptine, pergolide
• Non ergot derivatives Pramipexole
• Have longer duration of action than L-dopa (less
  likely to cause dyskinesias than levodopa)
• Dopamine agonists are used in advanced
  Parkinson's disease with fluctuation and
  dyskinesia.

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Bromocriptine

• Is an ergot derivative
• D2 agonist
• Is given orally
• Half life 6-8 h
• Uses
• Parkinsons disease
• Hyperprolactinemia (galactorrhea).
• Infertility in women.

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• Adverse drug effects
• Nausea, vomiting, postural hypotension
• Confusion, hallucinations, delusions
• Dyskinesias (less prominent).
• Contraindications
• Psychosis
• Peripheral vascular disease
• Recent myocardial infarction

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Pramipexole

• Non Ergot dopamine agonist
• Used alone or in combination with L-Dopa.
• Side effects similar to L-Dopa, but less
  dyskinesias.
• Has the advantage of being free radicals
  scavenger.

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• Amantadine
• originally introduced as an antiviral.
• Amantadine increases dopamine release.
• acts as an antagonist at muscarinic and NMDA
  (N-methyl-D-aspartate) receptors.
• given orally with short half life
• most of the drug being excreted unchanged in the
  urine

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• Amantadine
• modestly effective in treating symptoms of
  parkinsonism but last only for short period (few
  weeks) and only used for L-Dopa resistance.
• Adverse effects
• Nausea, anxiety, insomnia, confusion,
  hallucinations (dopamine like side effects).
• Dry mouth, urinary retention (anticholinergic
  effects).
• Restlessness and hallucinations (NMDA antagonist).

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• Selegiline
• Selegiline is an irreversible inhibitor of
• MAO-B
• It inhibits dopamine degradation by
• MAO-B in CNS.
• It increases endogenous dopamine available for
  its receptors.

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• Selegiline
• It has antioxidant activity against toxic free
  radicals produced during dopamine metabolism.
• Selegiline is metabolized to desmethylselegiline,
  Which is antiapoptotic.

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• Selegiline
• used for the newly diagnosed patient with
• parkinsonism (as monotherapy).
• Combined with levodopa / carbidopa in
  later-stage parkinsonism to
• reduce the required dose of levodopa
• delay the onset of dyskinesia and motor
  fluctuations that usually accompany long-term
  treatment with levodopa.

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• Adverse drug effects
• At high doses, selegiline may inhibit MAO-A
  (hypertensive crises).
• May cause insomnia when taken later during the
  day.
• Contraindications
• Selegiline should not be co-administered with
  tricyclic antidepressants, or selective serotonin
  reuptake inhibitors (may cause hyperpyrexia,
  agitation, delirium, coma).

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COMT Inhibitors(Catechol-O- methyl transferase)
Inhibitors

• Entacapone
• Acts peripherally and centrally to inhibit COMT
  enzyme required for dopamine degradation
• It is used as adjuvant to L-Dopa to
• Decrease fluctuations
• Improve response
• Prolonged the ON-Time
• Side effects
• L-Dopa side effects.
• Orange discoloration of urine.

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• Anticholinergic Drugs
• Benztropine, Trihexphenidyl
• muscarinic antagonist.
• Has modest anti- parkinsonian actions.
• Tremor is benefited more than rigidity
• used during the early stages of the disease or as
  an adjunct to levodopa therapy.
• Provide benefit in drug-induced parkinsonism (due
  to antipsychotics).

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• Adverse effects
• Cycloplegia, dry mouth, urinary retention,
  constipation.
• Confusion, delirium, and hallucinations may occur
  at higher doses.
• Contraindications
• Prostatic hypertrophy
• Glaucoma
• Intestinal obstruction

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Summary

• In mild cases, selegiline, amantadine or
  anticholinergics can be used.
• Levodopa and carbidopa is the main treatment
• All other medications are adjuncts to levodopa
  therapy
• Other useful drugs include bromocriptine
  (dopamine agonist), selegiline (monoamine
  oxidase-B inhibitor), amantadine (enhances
  dopamine release) and benztropine (muscarinic
  receptor antagonist, used for parkinsonism caused
  by antipsychotic drugs.