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ANTIPARKINSONIAN AGENTS

ANTIPARKINSONIAN AGENTS. MA. LENY ALDA G. JUSAYAN, MD DEPARTMENT OF PHARMACOLOGY. PARKINSONISM. Tremors are present even at rest Rigidity & impairment of voluntary movements Postural tremor, intention tremors. The UK Parkinson's Disease Society Brain Bank Criteria For Clinical Diagnosis:.

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ANTIPARKINSONIAN AGENTS

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  1. ANTIPARKINSONIAN AGENTS MA. LENY ALDA G. JUSAYAN, MD DEPARTMENT OF PHARMACOLOGY

  2. PARKINSONISM • Tremors are present even at rest • Rigidity & impairment of voluntary movements • Postural tremor, intention tremors

  3. The UK Parkinson's Disease SocietyBrain Bank Criteria For Clinical Diagnosis: • Bradykinesia plus one of rigidity, tremor, or postural instability • At least three of rest tremor, progressive symptoms, unilateral onset, early response to levodopa, revodopa-induced dyskinesia • No identifiable cause for the parkinsonism.

  4. Motor Symptoms: • Tremor: • 70% of patients suffer resting tremor • pill rolling quality • can affect all of the limbs as well as the face, neck, head and jaw. • Rigidity: • increased tone or stiffness in the muscles • mask-like face and clog-like release of muscles. • Bradykinesia • difficulty initiating and continuing movement.

  5. Postural Instability • Forward flexion of neck, hips, knees and elbows leads to poor balance. • Gait disorders • Shuffling, small steps described as festination, reduced arm swing and sudden freezing spells lead to problems walking • Swallowing (dysphagia) and Speech disorders (dysarthria) • Handwriting: Micrographia

  6. Nonmotor Symptoms: • Depression: • 20-90% major depressive episode, reactive or endogenous • Dementia: • 20% of patients will become demented (have impairments of 3 of the following in the presence of clear consciousness: language, memory, visuospatial skills, emotionality, personality and cognition

  7. Sleep disturbances: • Problems with sleep fragmentation, sleep initiation, early morning awakening, excessive daytime somnolence and parasomnias. • Sexual dysfunction • Ability to drive a car • Ability to gain employment • Constipation

  8. CHOREA • Irregular, unpredictable involuntary jerks • Impaired voluntary activity • ballismus

  9. ATHETOSIS • Slow & writhing movements • Abnormal postures (dystonia)

  10. TICS • Sudden coordinated abnormal movements • Repetitive sniffing • shoulder shrugging • face & head movement

  11. PATHOGENESIS: • Idiopathic • Exposure to unrecognized neurotoxins • Oxidation reaction with generation of free radicals • Reduced level of dopamine in the basal ganglia

  12. Pyramidal System: begins in the primary motor cortex descends through the corticospinal and corticobulbar tracts affects the lower motor neurones in the brain stem and spinal cord.

  13. Extrapyramidal System: • basal ganglia and their cortical connection • basal ganglia are made up of the: • Caudate Nucleus • Putamen (Striatum) • Globus Pallidus interna (Gpi) • Globus Pallidus externa (Gpe) • Subthalamic Nucleus • Substantia Nigra • main outputs of this system are the Substantia Nigra and the Gpi, both of which feed to the ventrolateral thalamus.

  14. The main Pathological feature of Parkinson’s disease is the loss of the dopaminergic nigrostriatal pathway • 80% of the Dopamine producing cells must be lost before symptoms begin to show

  15. GOALS OF TREATMENT: • Pharmacologic attempt to restore dopaminergic activity with levodopa and dopamine agonists • Restore normal balance of cholinergic & dopaminergic influences on the basal ganglia

  16. PATHOPHYSIOLOGIC BASIS OF TREATMENT: • Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost

  17. LEVODOPA • (-) -3-(3-4 dihydroxyphenyl) L- alanine • Immediate metabolic precursor of dopamine • Levorotatory stereoisomer of dopamine

  18. PHARMACOKINETICS: • Rapidly absorbed from the SI • Food delays absorption • Amino acids in food competes with drug • Peak plasma concentration: 1-2 hrs • Plasma t ½ : 1-3 hrs • HVA, DOPAC (dihydroxyphenylacetic acid) are main metabolites

  19. CLINICAL USE: • Responsiveness may be lost secondary to disappearance of dopaminergic nigostriatal nerve terminals • Early use lowers mortality rate • Combined with Carbidopa & Benseraside • Sinemet – dopa preparation containing levodopa in fixed proportion (1:10 or 1:4) • Sinemet 25/100 TID • 30 -60 minutes before meals

  20. ADVERSE EFFECTS: • GIT effects • Cardiovascular • Dyskinesias • Behavioral effects • Fluctuations in response • Misc: mydriasis, blood dyscrasias, hot flushes, gout, brownish discoloration of the urine, abnormal smell

  21. DRUG INTERACTIONS: • Vitamin B6 enhance extracerebral metabolism of levodopa • MAO – A inhibitors

  22. CONTRAINDICATIONS: • Psychoses • Angle closure glaucoma • Cardiac dysrhythmia • PUD • Melanoma or suspicious undiagnosed skin lesions

  23. DOPAMINE AGONISTS • Do not require enzymatic conversion for an active metabolite • No potential toxic metabolites • Do not compete with other substances for an active transport • First line in parkinsonism • End of dose akinesia to levodopa • On & off phenomenon refractory to levodopa

  24. ERGOT ALKALOIDS: • BROMOCRIPTINE • D2 agonists • Endocrinologic disorders (hyperprolactinemia) • Absorbed variably in GIT • Peak plasma levels: 1-2 hrs

  25. ERGOT ALKALOID: • PERGOLIDE • Stimulates both D1 and D2 • More effective than bromocriptine

  26. CLINICAL USE: BROMOCRIPTINE: • 7.5 mg & 30 mg • 1. 25 mg BID after meals X 2-3 months and increase 2.5 mg q 2 wks PERGOLIDE: - 3 mg daily - 0.05 mg starter dose

  27. ADVERSE EFFECTS: • GIT • Cardiovascular • Dyskinesias • Mental disturbances • Misc: erythromelalgia

  28. NON-ERGOT DOPAMINE AGONISTS: • PRAMIPEZOLE • Preferential affinity to D3 • Monotherapy is effective • Neuroprotective (H scavenger) • Enhance neurotrophic activity • Rapidly absorbed • Peak plasma concentration: 2 hrs • 0.125 mg TID then doubled after 1 wk • Increments of 0.75 mg at weekly intervals

  29. NON-ERGOT ALKALOIDS: • ROPINIROLE • Pure D2 receptor agonists • 0.25 mg TID then total daily dose is increased by 0.75 mg at weekly intervals until the 4th wk & increased by 1.5 mg thereafter

  30. SIDE EFFECTS: • Postural hypotension • Fatigue • Somnolence • Peripheral edema • Nausea • Constipation • Dyskinesias • Confusion

  31. MONOAMINE OXIDASE INHIBITORS • MAO – A: metabolizes NE & serotonin • MAO – B: metabolizes dopamine

  32. SELEGILINE (Deprenyl) • Selective inhibitor of MAO-B • Retards breakdown of dopamine • Adjunct in fluctuating response to levodopa • 5 mg with breakfast & lunch • Cause insomnia when taken during the day • Not to be taken with meperidine, TCAs, SSRIs • Increase adverse effects of levodopa

  33. RASAGILINE • MAO-B inhibitor • Potent than selegiline • CI with levodopa – HPN crisis

  34. CATHECOL-O-METHYLTRANSFERASE INHIBITORS: • TOLCAPONE- central & peripheral metabolism • ENTACAPONE • peripheral metabolism • Prolong the duration of levodopa by decreasing its peripheral metabolism • Helpful in patients receiving levodopa who have fluctuations • t ½ = 2 hrs

  35. AMANTADINE • Antiviral agent • Potentiates dopaminergic function by influencing the synthesis, release, reuptake of dopamine PHARMACOKINETICS: • peak plasma concentration: 1-4 hrs after oral dose • Plasma t ½ = 2-4 hrs

  36. CLINICAL USE: • Less potent than levodopa and benefits are short-lived • 100 mg BID-TID ADVERSE REACTIONS: • Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations & confusion • Livedo reticularis

  37. CONTRAINDICATIONS: • History of seizures • Heart failure

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