Drugs%20Used%20for%20Parkinson

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Drugs Used for Parkinsons Disease
Parkinsons Disease

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• ?????????????????
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Parkinsons Disease

• was described in 1817 by Dr. James Parkinson
• Paralysis agitans or Shaking palsy

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4-Major Symptoms of Parkinsons Disease

• Tremor
• Rigidity
• Bradykinesia
• Postural instability

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Other Symptoms

• Depression
• Emotional changes
• Difficulty in swallowing and chewing
• Speech changes
• Urinary problems or constipation
• Skin problems
• Sleep problems

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Etiology

• Idiopathic (no genetic link)
• Known causes
• Age (50-60)
• Cerebral atherosclerosis
• Virus encephalitis
• CO poisoning
• Manganese poisoning
• Drug-induced (flunarizine, cinnarizine, etc.)

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MPTP(1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
)

• by-product of street synthesis of meperidine like
  drug
• non-toxic
• convert to toxic metabolite by MAO-B MPP
  (selectivity destroy DA cells)

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Dopamine pathways
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Extrapyramidal tract
Corpus striatum
Pathway via thalamus
-
Cortex

-
Spinal cord
Substantia nigra
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Parkinsons Disease
Corpus striatum
Pathway via thalamus
-
Cortex

ACh
Dopamine
GABA
-
Spinal cord
Substantia nigra
Parkinsons disease
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Goal of Treatment

• Alleviate symptoms
• Prevent or limit complications
• Slow progression of the disease

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(No Transcript)
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Treatment
Levodopa Amantidine Bromocriptine Deprenyl
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Treatment
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Levodopa

• ???? precursor ??????????????????? dopamine (DA
  ?????????????????????)

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Levodopa

• Distribution

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Levodopa

• Pharmacokinetics
• Absorption from small intestine rapid
• Factors influence absorption
• Gastric emptying time
• pH and enzymes
• Proteins - delay absorption
• Metabolism
• Decarboxylation
• Oxidation by MAO and COMT

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Levodopa

• No effect on muscle tone and movement in normal
  subjects
• Parkinsons disease bradykinesia and rigidity gtgt
  tremor
• CVS effects (stimulation of DA, a, b receptors)
• tachycardia, cardiac arrhythmias, postural
  hypotension
• DA (prolactin-inhibitory hormone) --gt inhibit
  prolactin release from pituitary

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Levodopa

• Adverse reactions
• Emesis (stimulation of CTZ)
• CVS side effects
• Abnormal involuntary movements (dyskinesia)
  twitching, nodding, jerking
• long-term use of high dose
• Treatment lower the dose or use DA antagonists
  ???????

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Levodopa

• Adverse reactions
• Wearing-off effect
• ????????????????????????? ???????????????????????
• On-off phenomenon
• sudden, unpredictable changes in movement, from
  normal to parkinsonian movement
• indicate disease is progressing or patients
  response to the drug is changing

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Levodopa

• Adverse reactions
• ????????????? on-off phenomenon
• Drug holiday
• ?????????????????????????????????????????? DA
  agonists
• ????????????? height-proteins
• ??? controlled-release formulation

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Levodopa

• Adverse reactions
• Psychiatric and behavioral toxicity
• nightmare, psychotic state, hallucinations,
  confusion

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Levodopa

• Drug Interactions
• Vitamin B6 (pyridoxine)
• co-factor for decarboxylase enzyme
• decrease DA level in the CNS
• Antipsychotic drugs
• DA antagonists
• do not for counteract emesis

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Levodopa

• Drug Interactions
• MAOIs
• inhibit DA metabolism
• stop MAOIs at least 2 weeks
• Anticholinergic drugs
• interfere absorption

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Peripheral Decarboxylase Inhibitors (PDI)

• Carbidopa
• Benzerazide
• Sinemet

Levodopa Carbidopa
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Levodopa Carbidopa
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Advantages of PDIs in Combination with Levodopa

• ????????? levodopa
• ???????????????????? periphery
• ???????????? levodopa ???????
• ????? interaction ??? B6
• ?????????????????????? (less variability)
• ???????????????????????? (enhance efficacy)

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PDIs no effect on

• Hypotension
• Abnormal involuntary movements
• Behavioral toxicity

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Amantadine

• Antiviral drug
• Increase DA release
• Efficacy
• LevodopagtAmantadinegtanticholinergics
• decrease within 6-8 weeks
• Livedo reticularis (local release of
  catecholamines)

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Bromocriptine (PARLODEL)

• Ergot alkaloid (derivative of LSD)
• Potent DA agonist (D2)
• ????????????????? presynaptic neurons
• More selective than levodopa
• Longer duration
• ?? neuroprotective effects ??
• Combination with levodopa for -- reduce abnormal
  involuntary movements and on-off phenomenon
• First-dose phenomenon sudden CV-collapse
• Other use hyperprolactinemia

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Pergolide (CELANCE)

• Ergot derivatives ????? bromocriptine
• More effective than bromocriptine

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Pramipexole (Mirapex)Ropinirole (ReQuip)

• Non-ergot drugs
• Selective D2-R agonists
• Monotherapy for early PD, combined with
  lododopa/carbidopa in latter stages of PD (reduce
  the problems of wear-off and on/off)
• Side effects similar to the other DA agonists
• Pramipexole is now the most frequently prescribed
  DA agonist for PD

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Monoamine Oxidase Enzymes (MAO)

• MAO-A
• inactivate NE, 5-HT, DA and tyramine
• MAO-B
• inactivate DA and tyramine
• is predominant form in the striatum

Catechol-O-Methyltransferase
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Selegiline (Deprenyl)

• Selective MAO-B inhibitor

• Low efficacy ?????????????????????? levodopa
  ??????
• ?????????????????? (young pt. or mild
  parkinsonism-- delay disease progression)
• ?????????? (?)
• ???????????? cheese reactions

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Tolcapone (Tasmar)Entacapone (Comtan)

• inhibitors of COMT (inhibit conversion of
  levodopa to 3-O-methyldopa in gut and liver)
• ----gt a twofold increase in oral bioavailability
  and half-life of levodopa ---gt increase efficacy
  and reduced dose

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Tolcapone (Tasmar)Entacapone (Comtan)

• Tolcarpone ?????? central ??? peripheral effects
  ??? entacapone ??????? peripheral
• Side effects ??? ?????????????????
• ??????? entacapone ?????????????????????????
  hepatotoxicity ???????? tolcapone

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Anticholinergic Drugs
Block the action on striatal cholinergic
interneurones
Tremor gtgt rigidity, posture disturbance

• Benztropine (COGENTIN)
• Biperiden (AKINETON)
• Trihexyphenidyl (ARTANE)
• Diphenhydramine (antihistamine)

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Drugs Therapy of Acute Muscle Spasms

• Spasticity

stiffness or tightness of the muscles and may
interfere with gait, movement, and speech.
condition in which certain muscles are
continuously contracted.
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• ?????????????????????????????????????? spinal
  cord ????????? voluntary movement
• ????????????????????? spinal cord injury,
  multiple sclerosis, cerebral palsy, anoxic brain
  damage, brain trauma, severe head injury, some
  metabolic diseases ???? adrenoleukodystrophy ???
  phenylketonuria

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??????

• ??????????????????????? stretch reflex arc
  ??????????????????????????? upper motor neuron
  lesion ??????????????? hyperexcitability ???
  alpha motorneuron ?? spinal cord
• ????????????? ???????????????????
• ?????? hyperactive stretch reflex arc ?????
  excitatory ???? ????? inhibitory synapse
• excitation-contraction coupling
  ???????????????????

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Drugs Therapy of Acute Muscle Spasms

• Mephenesin, Methocarbamol
• Orphenadrine, Cyclobenzaprine
• Anticholinergic drugs
• Inhibit polysynaptic excitation of motor neurons
  in spinal cord
• Diazepam
• Act on GABA synapses ????????????? spinal cord

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Baclofen

• Site of action ??????? spinal cord
• Structure relate with GABA (GABAB agonist)
• Depress mono- and polysynaptic transmission at
  spinal cord
• Excretion unchanged form in urine
• Side effects drowsiness, insomnia, dizziness,
  confusion
• Drug withdraw hallucination, anxiety, tachycardia

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Dantrolene

• Site of action skeletal muscle
• Direct action on excitation-contraction coupling
  (decrease Ca2 released from sarcoplasmic
  reticulum)
• Oral absorption poor
• Biotransformation metabolized
• Side effects
• Hepatotoxicity
• CNS effects - euphoria, headache, dizziness,
  weakness

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