Drugs For Parkinson’s

  1. Background
  2. Approximately 1.5 million cases of Parkinson’s in US (more common in elderly)
  3. Neurodegenerative disease
  4. Motor impairement due to loss of nigostriatal dopamine neurons
  5. Causes of PD
  6. Majority- unknown/idiopathic
  7. Small % of patients have familial parkinsonism with an autosomal dominant pattern of inheritance
  8. Some forms of parkinsonism may be due to viral inflammation, brain trauma, stroke, poisoning form manganese, CO, pesticide or MPTP. MPTP was a byproduct of the illegal synthesis of Meperidine (Demerol). When patients took this drug they had Parkinson-like syndrome.
  9. Drug induced- antipsychotics- which lead to a decrease in dopamine
  10. Pathophysiology of PD
  11. Dopamine deficiency in specific area of the brain called substantia nigra. Also have loss of dopamine in neostriatum in presence of intracellular Lewy bodies
  12. Imbalance between dopamine and acetylcholine (decreased dopamine, Increased ACH)
  13. Imbalance of two neurotransmitters leads to tremor, rigidity, and bradykinesia (most disabling symptom of Parkinsonism)
  14. Summary of Treatment of PD- No cure
  15. Increase dopaminergic activity

  1. Increase dopamine levels (levodopa)
  2. Dopamine receptor agonists
  3. MAO inhibitors
  4. COMT inhibitors
  5. Amantadine (Symmetrel)

  1. Decrease Acetylcholine activity
  2. Anticholinergics
  1. Drugs Used for PD
  2. Levodopa (L-Dopa)
  3. Most reliable and effective drug used for PD
  4. It is the biochemical precursor to dopamine- dopamine cannot cross BBB but levodopa can.
  5. Transmitted into brain by amino acid transport systems, gets converted to dopamine and can exert its therapeutic benefit
  6. If given alone, metabolized peripherally by dopa-decarboxylase enzyme to dopamine. To avoid this- levodopa given in combo with Carbidopa (peripheral decarboxylase inhibitor)
  7. Carbidopa/Levodopa (Sinemet)
  8. Indications: can be used for all types of parkinsonism except if associated with antipsychotic drug therapy
  9. As disease progresses patient may get
  10. Wearing off effect: duration of benefit from each dose decreases. Causes hypomobility
  11. On-Off effect: sudden, unpredictable fluctuations between mobility and immobility
  12. Precautions- narrow angle glaucoma, CVD, asthma, PUD
  13. MOA- increases dopamine levels in CNS via mechanisms previously discussed
  14. ADRs
  15. CVS: orthostatic hypotension, arrhythmias
  16. CNS: vivid dreams, hallucinations, confusion, sleep disturbances
  17. GI: N,V,D, anorexia
  18. Motor function: dyskinesia (abnormal movements of limbs, hands, trunks, and tongue). Can occur in 40-90% of patients
  19. DDI
  20. Nonselective MAO-I- contraindicated; hypertensive crisis
  21. Pyridoxine (Vit B6)-cofactor for dopa-decarboxylase, so may enhance the peripheral metabolism of levodopa
  22. Antipsychotics, BDZ, phenytoin may inhibit antiparkinsonism effects
  23. Food-drug interaction
  24. high protein meals may compete with amino acid transport of levodopa across BBB
  25. Dosage forms
  26. Available PO as immediate release or sustained release. Dose provided as mg of Carbidopa/mg of Levodopa. (Ex.- Sinemet 10/100 is 10mg of Carbidopa and 100mg of Levodopa)
  27. Also available as orally disintegrating tablet (Parcopa)
  28. Dopamine Agonists
  29. My be preferred to levodopa because have longer DOA and less likely to cause dyskinesia
  30. Less effective than levodopa as monotherapy
  31. Examples in this category include:
  32. Bromocriptine (Parledel) (B)
  33. MOA- dopamine receptor agonist at D2 receptor and partial D1 antagonist and ergot alkaloid
  34. Uses- PD, amenorrhea, infertility, hypogonadism, prolactin-secreting adenomas and acromegaly
  35. Contraindications- uncontrolled HTN, IHD, PVD
  36. Warnings- renal and hepatic dysfunction, psychosis, CVD
  37. ADRs- start with low dose and titrate upward due to CNS effects
  38. CNS: h/a, dizziness, sedation, somnolence, hallucinations
  39. GI: nausea, constipation
  40. CVS: orthostatic hypotension
  41. DDI- CYP3A4 substrate and inhibitor
  42. Pergolide (Permax) (B)
  43. MOA- dopamine receptor agonist at both D1 and D2 receptor and ergot alkaloid
  44. Uses- PD only
  45. Contraindications/Warnings- same as bromocriptine
  46. ADRs- same as bromocriptine
  47. DDIs- CYP2A6 and 3A4 inhibitor
  48. Pramipexole (Mirapex) (B)
  49. MOA- selective D2 receptor agonist. Not ergot derivative
  50. Uses- PD only, non-FDA for depression
  51. Warnings- renal insufficiency
  52. ADRs- similar to bromocriptine, but less severe and frequent. Amy also cause dyskinesia. Excessive sedation
  53. DDI- CNS depressants
  54. Ropinrole (Requip) (C)
  55. MOA- selective D2 and D3 receptor agonist. NOT ergot derivative
  56. Uses- PD only
  57. Warnings- same as Mirapex
  58. ADRs- same as Mirapex
  59. DDIs- CNS depressants, CYP450 substrate and inhibitor
  60. MAO Inhibitors
  61. Selegiline (Eldepryl) (C)
  62. MOA- irreversible inhibitor of MAO-B, an enzyme which metabolizes dopamine. Little effect on MAO-A; drugs that are MAO-A inhibitors cause hypertensive crisis with tyramine containing foods
  63. Uses- PD. Good to use in combo with levodopa and other agents because decreases the dose needed and therefore the ADRs (especially motor fluctuations, dyskinesias, sedation and OH)
  64. Contraindications- use with meperidine, TCAs and SSRIs due to increased risk of serotonin syndrome
  65. ADRs-

  1. CVS: orthostatic hypotension
  2. CNS: hallucinations, dizziness, sedation
  3. GI: n,v, constipation, dry mouth
  4. GU: sexual dysfunction

  1. DDIs- CYP450 substrate and inhibitor
  1. COMT inhibitors
  2. MOA- inhibit the COMT enzyme in PNS and CNS increased levodopa available to cross BBB and increase levodopa and dopamine concentration in CNS
  3. Uses- adjunct with Carbidopa/levodopa for PD
  4. ADRs- similar to other PD drugs
  5. DDI- CYP450 inhibitor, CNS depressants, cardiac drugs metabolized by COMT
  6. Examples in this category include:
  7. Tolcapone (Tasmar) (C)
  8. Warning: can cause severe hepatic toxicity. Last line agent; informed consent to patient
  9. Entacapone (Comtan) (C)
  10. Iron chelator- separate dosing
  11. Causes brown-orange urine discoloration
  12. New combo product Stalevo contains Carbidopa, levodopa, and entacapone
  13. Amantadine (Symmetrel) (C)
  14. MOA- exact MOA for PD is unknown. It may affect dopamine release and uptake
  15. Uses- in early stage PD in combo with Sinemet, also for influenzae A (only)
  16. Warnings: renal and liver disease, seizure disorder
  17. ADRs: orthostatic hypotension, CNS effects, N, V, constipation
  18. DDI: anticholinergics may potentiate CNS side effects
  19. Anticholinergics
  20. MOA- blocks muscarinic receptors in striatum, reducing cholinergic activity and improving dopamine/ACH balance
  21. Use- moderate antiparkinsonian activity. Used in early stages of disease or as adjunct to levodopa/Carbidopa therapy. Also used to treat drug-induced parkinsonism from anti-psychotic therapy
  22. ADRs- anticholinergic side effects. Sedation, blurred vision, dry mouth, constipation, urinary retention. Confusion, delirium and hallucinations with higher doses
  23. Examples in this category include

  1. Trihexyphenidyl (Artane) (C)
  2. Benztropine mesylate (Cogentin) (B)
  3. Procyclidine (Kemadrin) (C)
  4. Diphenhydramine (Benadryl) (B)

  1. Apomorphine (Apokyn)
  2. New SC injectable drug released in 2004
  3. MOA- dopamine agonist. Chemically related to morphine, but does not relive pain and is not addictive; will treat symptoms for up to 90 minutes
  4. Uses: treat acute episodes of hypomobility, also used sublingually for erectile dysfunction
  5. ADRs: severe N/V, must be taken in combo with an antiemetics (NOT 5HT3 antagonists because of DDI), sedation, flushing, dyskinesias
  6. Other treatments for PD- used to affect progression of disease by stopping neuronal death
  7. CEP-1347: oral kinase apoptosis inhibitor. May enhance survival of neurons that produce dopamine; prevent progression of disease; stop neuronal cell death
  8. Glial-derived neurotrophic factor (GDNF) infusion- neuroprotective agent
  9. Nasoduodenal infusion of levodopa/Carbidopa gel- improve motor fluctuations
  10. High frequency brain stimulation