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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

MA. LENY ALDA G. JUSAYAN, MD

DEPARTMENT OF PHARMACOLOGY


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PARKINSONISM

  • Tremors are present even at rest

  • Rigidity & impairment of voluntary movements

  • Postural tremor, intention tremors


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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.


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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.


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  • 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


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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


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  • 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


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CHOREA

  • Irregular, unpredictable involuntary jerks

  • Impaired voluntary activity

  • ballismus


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ATHETOSIS

  • Slow & writhing movements

  • Abnormal postures (dystonia)


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TICS

  • Sudden coordinated abnormal movements

  • Repetitive sniffing

  • shoulder shrugging

  • face & head movement


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PATHOGENESIS:

  • Idiopathic

  • Exposure to unrecognized neurotoxins

  • Oxidation reaction with generation of free radicals

  • Reduced level of dopamine in the basal ganglia


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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.


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  • 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.


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  • 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


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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


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PATHOPHYSIOLOGIC BASIS OF TREATMENT:

  • Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost


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LEVODOPA

  • (-) -3-(3-4 dihydroxyphenyl) L- alanine

  • Immediate metabolic precursor of dopamine

  • Levorotatory stereoisomer of dopamine


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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


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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


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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


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DRUG INTERACTIONS:

  • Vitamin B6 enhance extracerebral metabolism of levodopa

  • MAO – A inhibitors


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CONTRAINDICATIONS:

  • Psychoses

  • Angle closure glaucoma

  • Cardiac dysrhythmia

  • PUD

  • Melanoma or suspicious undiagnosed skin lesions


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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


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ERGOT ALKALOIDS:

  • BROMOCRIPTINE

    • D2 agonists

    • Endocrinologic disorders (hyperprolactinemia)

    • Absorbed variably in GIT

    • Peak plasma levels: 1-2 hrs


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ERGOT ALKALOID:

  • PERGOLIDE

    • Stimulates both D1 and D2

    • More effective than bromocriptine


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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


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ADVERSE EFFECTS:

  • GIT

  • Cardiovascular

  • Dyskinesias

  • Mental disturbances

  • Misc: erythromelalgia


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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


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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


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SIDE EFFECTS:

  • Postural hypotension

  • Fatigue

  • Somnolence

  • Peripheral edema

  • Nausea

  • Constipation

  • Dyskinesias

  • Confusion


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MONOAMINE OXIDASE INHIBITORS

  • MAO – A: metabolizes NE & serotonin

  • MAO – B: metabolizes dopamine


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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


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RASAGILINE

  • MAO-B inhibitor

  • Potent than selegiline

  • CI with levodopa – HPN crisis


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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


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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


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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


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CONTRAINDICATIONS:

  • History of seizures

  • Heart failure


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ACETYLCHOLINE BLOCKING AGENTS:

  • Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia

  • Benztropine mesylate

  • Biperiden

  • Orphenadine

  • Procyclidine

  • Trihexyphenidyl


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ADVERSE EFFECTS:

  • CNS

  • Mydriasis, urinary retention, constipation, tachycardia, tachypnea, increase IOP, palpitations, cardiac arrythmias

  • Acute suppurative parotitis


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CONTRAINDICATIONS:

  • Prostatic hyperplasia

  • Obstructive GI diseases

  • Angle closure glaucoma


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  • The net result of all of these medications is the balancing out of the acetylcholine/dopamine balance and an improvement in movement


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SURGICAL PROCEDURES:

  • Thalamotomy – conspicous tremor

  • Posteroventral pallidotomy


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THANK YOU !!!


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