ANTIPARKINSONIAN AGENTS

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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 Society Brain 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 Parkinsons
  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 (110 or 14)
• 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 !!!