Parkinson's disease and Alzheimer’s disease drugs

• Parkinsonism


  Characterized by combination of rigidity, bradykinesia, tremor and postural instability that can occur for a reasons but usually is idiopathic (Parkinson's disease or paralysis agitans)
• Parkinsonism


  • motor symptoms + Cognitive decline + non-motor symptoms (affective disorders-anxiety or depression, personality changes, abnormalities of automatic function-sphincter or sexual functions, choking, sweating abnormalities and disturbances in blood pressure regulation, sleep disorders, and sensory complaints or pain)
• Parkinsonism: Pathogenesis


  1. Impaired degradation of proteins

  2. Intracellular protein accumulation and aggregation

  3. Oxidative stress

  4. Mitochondrial damage

  5. Inflammatory cascades

  6. Apoptosis
• Genetic factors


  Relevant when the disease occurs at age below 50
• Genetic factors associated with Parkinson's disease


  • Mutations of α-synuclein gene at 4q21
  • Duplication and triplication of normal synuclein gene
  • Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen and the UCHLI gene - autosomal dominant parkinsonism
  • Mutations in the parkin gene - early onset, sporadic juvenile-onset parkinsonism
• Environmental or endogenous factors associated with Parkinson's disease


  • Cigarette smoking (protective)
  • Coffee (protective)
  • Anti-inflammatory drug use (protective)
  • High serum uric acid levels (protective)
  • Working in teaching, health care, or farming
  • Lead or manganese exposure
  • Vitamin D deficiency
• Lewis bodies


  Intracellular inclusion bodies containing alpha-synuclein in fetal dopaminergic cells transplanted into the brain of parkinsonian patients
• Stages of Braak scale for Parkinson's disease pathology

  1. Stage 1: Initially developing pathology at olfactory nucleus and lower brainstem

  2. Stage 2: Higher brainstem

  3. Stage 3: Substantia nigra

  4. Stage 4: Mesocortex and thalamus

  5. Stage 5: Entire neocortex
• Motor features of Parkinson's disease develop at Stage 3 of the Braak scale
• Substantia nigra


  Part of the extrapyramidal system that is the source of dopaminergic neurons that terminate in the neostriatum
• Neostriatum


  Connected to the substantia nigra by neurons that secreted GABA at their termini and the cells of the substantia nigra send neurons back to the neostriatum secreting the inhibitory neurotransmitter dopamine at their termini
• In Parkinson's disease, destruction of cells in the substantia nigra leads to degeneration of the nerve terminals that secrete dopamine in the neostriatum, resulting in decreased inhibitory influence of dopamine on cholinergic neurons and overactivity of acetylcholine by stimulatory neurons, leading to loss of control of muscle movements
• Secondary parkinsonism


  • Phenothiazine and Haloperidol

  Caused by phenothiazine and haloperidol, which block dopamine receptors and produce parkinsonian symptoms (called pseudoparkinsonism)
• Strategy of treatment for Parkinson's disease


  1. Restore dopamine in the basal ganglia

  2. Antagonize the excitatory effect of cholinergic neurons to re-establish correct dopamine/acetylcholine balance
• Levodopa


  Immediate metabolic precursor of Dopamine, can enter the brain via the L-amino acid transporter (LAT) where it can be decarboxylated to Dopamine
• Dopamine cannot cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism
• Metabolic products of Levodopa


  1. methoxy-4-hydroxyphenyl acetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC)
• Levodopa drug holiday


  Discontinuance of drug for 3-21 days to improve responsiveness to Levodopa and alleviate some of its adverse effects, but with risks of aspiration pneumonia, venous thrombosis, pulmonary embolism and depression
• Carbidopa


  Dopamine decarboxylase inhibitor that diminishes the metabolism of Levodopa in the periphery, increasing the availability of Levodopa in the CNS
• Dopamine receptor agonists


  Act directly on post-synaptic dopamine receptors, have beneficial effect in addition to that of Levodopa, do not require enzymatic conversion to an active metabolite, have no potentially toxic metabolites and do not compete with other substances for active transport into the blood and across the BBB
• Older dopamine agonists


  • Bromocriptine
  • Pergolide
• Newer dopamine agonists


  • Pramipexole
  • Ropinirole
• Bromocriptine


  D2 agonist that may commonly cause hallucinations, confusion, delirium, nausea and orthostatic hypotension, and worsen mental condition in psychiatric illness

  • used with caution in patients with history of MI or peripheral vascular disesase
  • may also cause pulmonary and retroperitoneal fibrosis
• Pergolide


  Directly stimulates both D1 and D2 receptors, no longer available since it has been associated with the development of valvular heart disease
• Pramipexole


  Not an ergot derivative, preferential affinity for the D3 family of receptors

  • monotherapy for mild parkinsonism and helful in patients with advanced disease
• Ropinirole


  Relatively pure D2 receptor agonist effective as monotherapy in patients with mild disease and as means of smoothing the response to Levodopa in patients with more advanced disease and response fluctuations

  • metabolism can be affected by fluoroquinolone antibiotics and other inhibitors of CYP 450 1A2 isoenzyme
• Apomorphine


  Injectable (SQ) for acute management of the hypomobility "off" phenomenon in advanced Parkinson's disease, may cause nausea on initiation of therapy addressed by pre-treatment with an anti-emetic Trimethobenzamide for 3 days before starting
• Rotigotine


  Delivered daily through a skin patch, approved for early Parkinson's disease
• Amantadine


  Antiviral drug that can also be used for treating influenza and has anti-parkinsonian action
• MAOIs


  Selegiline/Deprenyl is a selective irreversible inhibitor of MAO B at normal doses and at high dose can also inhibit MAO A, retarding breakdown of Dopamine and enhancing and prolonging anti-parkinsonism effect of Levodopa, Rasagiline is more potent than Selegiline and for MPTP induced parkinsonism, not metabolized to an amphetamine-like substance
• Catechol-O-methyltransferase inhibitors


  Tolcapone and Entacapone prolong action of Levodopa by diminishing its peripheral metabolism, selectively and reversibly inhibit COMT
• • Tolcapone may cause an abnormal liver function test results and has a long duration of action
  • Entacapone requires more frequent dosing
• Symptoms of Parkinson's disease

  A) Parkinsonian gait

  B) slowed

  C) reduced

  D) rigidity

  E) freezing

  F) shuffling

  G) instability

  H) asymmetric

  I) mask

  
• Levodopa should be given in large amount when used alone because only 1-3% administered Levodopa actually enters the brain unaltered
• When Levodopa is given in combination with a dopa decarboxylase inhibitor --> peripheral metabolism is reduced, plasma levels are higher, plasma half life is longer and more dopa available for entry to the brain
• Levodopa interactions with Vit B6

  
  

  • increases peripheral breakdown of Levodopa and diminishes its effectiveness
• Levodopa interactions with MAOIs


  produce hypertensive crisis due to enhanced catecholamine production
• Levodopa interactions with Psychotic patients


  exacerbation of symptoms
• Levodopa interactions with cardiac patients


  possible development of arrhythmias
• Levodopa interactions with Antipsychotic drugs


  CI in Parkinson’s disease --> augment parkinsonism symptoms however low dose atypical antipsychotics are used to treat levodopa-induced psychotic symptoms