Parkinson

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Drugs used in Parkinsons disease
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"Parkinson's disease" (Parkinsonism, PD) is a
progressive neurodegenerative brain disorder that
was first described by Dr. James Parkinson in
1817.
The disease occurs mainly in the elderly (above
the age of 65) and affects the "extrapyramidal
system" at the level of the "corpus striatum"
"substantia nigra" (parts of the brain "basal
ganglia").
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In the basal ganglia, the 2 neurotransmitters
"dopamine" "acetylcholine" co-exist in a normal
balance, where dopaminergic neurons exert an
inhibitory effect on excitatory cholinergic
neurons.
DA
ACh
In Parkinsons disease, the "nigrostriatal
dopaminergic neurons" are degenerated (damaged)
while cholinergic neurons are intact, resulting
in a marked decrease in dopamine content
(dopamine deficiency syndrome) and a relative
predominance of cholinergic activity.
Therefore, the strategy for treatment of
Parkinsonism is to restore the normal balance
between dopaminergic cholinergic tones in the
basal ganglia.
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Pathophysiology of PD Disease
Cortex
Caudate nucleus
Corpus striatum
Putamen
Thalamus
Globus pallidus
Loss of dopaminergic input to striatum
Disrupted signaling between basal ganglia,
cortex, and thalamus
Midbrain
Degeneration of neurons in substantia nigra pars
compacta
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Symptoms of Parkinsonism
The symptoms of Parkinsonism appear only when
dopamine depletion exceeds 80. It is
characterized by
Tremors at rest (especially in hands) which
diminish during voluntary movements. Muscle
rigidity and resistance to passive
movements. Bradykinesia (i.e. slowness of
movements) where the motor activity is difficult
to be initiated or stopped. Diagnosis requires 2
of 3 symptoms - bradykinesia, - rigidity, -
resting tremor
Abnormalities of posture and gait (shuffling
gait). Mask-like facial expressions, impaired
speech skilled acts such as writing and eating.
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Pharmacotherapy of PD

• Levodopa preparations
• Carbidopa/levodopa
• Sinemet
• Sinemet CR
• Parcopa
• Stalevo

• Dopamine agonists
• Apomorphine (Apokyn)
• Pramipexole (Mirapex)
• Ropinirole (Requip)
• Rotigitine (Neupro)
• Parlodel (Bromocriptine)
• Pergolide (Permax)

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Pharmacotherapy of PD

• Anticholinergic agents
• Benztropine (Cogentin)
• Trihexyphenidyl (Artane)
• COMT Inhibitors
• Entacapone (Comtan)
• Tolcapone (Tasmar)

• NMDA Antagonists
• Amantadine (Symmetryl)
• MAO-B Inhibitors
• Selegeline (Eldepryl or Deprenyl)
• Zydis Selegeline (Zelapar)
• Rasagiline (Azilect)
• Carbidopa

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Treatment of Parkinsonism


D2





D2



Tyrosine
DOPA
DA







D2



MAO-B


D2

Dopaminergic Nerve terminal
Postsynaptic receptors
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Drugs used to treat Parkinsonism do not stop the
progression of the disease but they can only
ameliorate the symptoms. Parkinsonism could be
managed by
A. Enhancing dopaminergic activity using

1. Reducing cholinergic activity by the use of
   anticholinergic drugs (benzatropine)
2. Neurotransplantation (which is still in
   experimental phase).
3. Physical therapy regular exercise.

1. drugs that replace dopamine (levodopa)
2. drugs that release dopamine from its stores
   (amantadine)
3. drugs that prolong the action of dopamine by
   preventing its metabolism (seligiline)
4. drugs that mimic the action of dopamine
   (dopaminergic agonists)

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Levodopa
"Levodopa" is the first line treatment of
Parkinsonism. Dopamine itself has no therapeutic
effect in Parkinsonism as it is not lipid soluble
and therefore is not absorbed from the GIT and
cannot cross the blood brain barrier. However,
"levodopa" (which is the immediate precursor of
dopamine) is well absorbed from the GIT and can
cross the blood brain barrier, where it is taken
up by dopaminergic neurons and converted to
dopamine by the action of the enzyme "dopa
decarboxylase".
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In patients with early Parkinsonism, the number
of residual dopaminergic neurons in the
substantia nigra (about 20 of normal) is still
enough to convert levodopa to dopamine. However,
when the disease progresses, a fewer number of
neurons are capable to take up levodopa and
convert it to dopamine resulting in a declined
effectiveness of levodopa. This indicates that
the effect of levodopa depends on the presence of
"functional dopaminergic neurons".
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Major disadvantage of levodopa Only 5 of an
oral dose of levodopa can reach the brain because
95 of the dose undergoes decarboxylation to
dopamine in the gut peripheral tissues
producing peripheral side effects.
decarboxylation
L-dopa
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CNS
Peripheral sites
BBB
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This problem was solved by the concomitant
administration of levodopa with an inhibitor of
dopa decarboxylase that does not cross the BBB
(peripheral dopa decarboxylase inhibitor). Example
of peripheral dopa decarboxylase inhibitors
carbidopa or benzerazide. Carbidopa or
benzerazide inhibit the peripheral
decarboxylation of levodopa allowing it to reach
its desired site of action (i.e. the
nigrostriatal system) in a greater proportion.
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SINEMET(CARBIDOPA-LEVODOPA)DESCRIPTIONSINEMET
(Carbidopa-Levodopa) is a combination of
carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
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Combing levodopa with the peripheral dopa
decarboxylase inhibitors "carbidopa" or
"benzerazide" has the following advantages

1. The dose of levodopa can be reduced by about 75.
2. The peripheral side effects of levodopa are
   greatly reduced.

• If levodopa is administered alone (i.e. without
  carbidopa), it can interact with pyridoxine
  (vitamin B6) in multivitamin preparations which
  enhances its peripheral metabolism (dopa
  decarboxylase is a pyridoxine-dependent enzyme).
• On the other hand, if levodopa is combined
  with carbidopa, pyridoxine cannot reduce the
  therapeutic effectiveness of levodopa since the
  peripheral decarboxylation of levodopa is already
  inhibited with carbidopa.

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Pharmacological actions of levodopa

• Levodopa restores "dopamine" content in the basal
  ganglia.
• Dopamine then acts on dopaminergic D2 receptors
  in the nigrostriatal pathway to ameliorate the
  symptoms of Parkinsonism and improve the overall
  functional ability of Parkinsonian patients.
• Dopamine can also act on the limbic system,
  tuberohypophyseal system and CTZ producing side
  effects.

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Side effects of levodopa
1. "On-Off" effect This effect results from
fluctuations of the level of levodopa in the
plasma because of its very short t½ (1-2 hours).
The "off" effect can be very sudden so that
patients stop while walking or are unable to rise
from a chair in which they have sat down normally
a few moments earlier. This effect is
counteracted by the combination of levodopa with
an inhibitor of COMT (e.g. entacapone) to inhibit
the degradation of dopamine.

• "Dyskinesia" and induction of abnormal voluntary
  movements.
• "Nausea vomiting" due to stimulation of
  dopamine receptors in the chemoreceptor trigger
  zone (CTZ) in the medulla oblongata.
• This effect is counteracted by the
  co-administration of "food" and peripheral (but
  not central) dopaminergic antagonists (e.g.
  domperidone) with levodopa.

1. Tachycardia resulting from dopamine action on the
   heart.
2. Psychological effects levodopa may lead to an
   over activity of dopamine in the limbic system
   leading to "schizophrenia-like syndrome".
3. Endocrine effects inhibition of prolactin
   secretion due to the effect of DA on the
   tuberohypophyseal system.

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Drug interactions of levodopa

1. "Pyridoxine" (vitamin B6) increases the
   peripheral break down of levodopa and reduces its
   effectiveness.
2. Concomitant administration of levodopa with "MAO
   inhibitors" leads to hypertensive crisis due to
   increased catecholamines (dopamine is a substrate
   for MAO and is also converted to noradrenaline).

• "Antipsychotic drugs" block central dopaminergic
  receptors and can induce parkinsonism-like
  syndrome themselves.
• Therefore they are contraindicated during
  Parkinsonism or levodopa therapy since they can
  reverse the benefits of levodopa.

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Dopamine Agonists

• Pramipexole (Mirapex)
• Ropinirole (Requip)
• Rotigitine (Neupro)
• Apomorphine (Apokyn)
• (cabergoline, lisuride)

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Dopamine Agonists

• May be used as initial therapy for patients with
  mild disease or as add on therapy for patients
  with more severe disease
• May delay need for levodopa therapy in early
  patients
• Later stage patients may be able to decrease
  levodopa dosing if DA added
• Neuroprotective effect?

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Dopamine Agonists

• Directly stimulate dopamine receptors
• No metabolic conversion required
• Longer half-life than levodopa (exception
  apomorphine)
• May delay onset of dykinesias or motor
  fluctuations

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Dopamine agonists

• Advantages over levodopa no need for
  biotransformation no competition with other
  substances across intestine
• Absorption rate decreased in when patient has
  full stomach
• Side effects hallucinations, peripheral edema,
  somnolence, compulsive behavior
• Ergot alkaloid DA no longer used

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Apomorphine

• Structurally similar to dopamine
• First synthesized in 1869 from acidic treatment
  of morphine (but retains no opiate properties)
• Requires parenteral delivery

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Apomorphine

• Indications
• Acute, intermittent treatment of hypomobility,
  off episodes (end-of-dose wearing off and
  unpredictable on/off episodes) associated with
  advanced PD
• As an adjunct to other medications
• Contraindicated
• In patients who have demonstrated
  hypersensitivity to the drug or its ingredients,
  such as its preservative metabisulfite

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Monoamine Oxidase Inhibitors (MAOIs)
As shown above, monoamine oxidase is an enzyme
that catalyzes the destruction of primary amines
(such as dopamine,norepinephrine, seritonin) and
secondary amines. The type B isoform of MAO
(MAO-B) is primarily responsible for metabolism
of dopamine.
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Metabolism of Dopamine via Monoamine Oxidase
(MAO)
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MAO Inhibitors - General

• MAO-B breaks down dopamine within the CNS
• Inhibition of MAO-B increases dopamine levels and
  function
• Because of increase in dopamine activity within
  CNS, potential for increased dopamine side effects

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Inhibitor of MAO-B

• Selegiline (l-deprenyl, Eldepryl or Anipryl
  veterinary) is a drug used for the treatment of
  early-stage Parkinson's disease and senile
  dementia.
• In normal clinical doses it is a selective
  irreversible MAO-B inhibitor.

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• In late stage Parkinsons Disease, Selegiline is
  usually added to levodopa to prolong and enhance
  its effect

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MAO Inhibitors

• Selegeline
• At low doses, remains selective for MAO-B
• At doses gt10 mg, becomes non-selective
• Active amphetamine-like metabolite

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MAO Inhibitors

• Rasagaline
• Precise mechanism of action is unknown thought
  to contribute to increased dopamine levels within
  CNS due to inhibition of MAO
• Although thought to be MAO-B selective, packaged
  with non-selective dietary and drug restrictions

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Metabolism of Dopamine via Catachol-O-Methyl
Transferase(COMT)
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Inhibitors of COMT
Entacapone
Tolcapone
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Inhibitors of COMT

• Entacapone is marketed by Novartis as Comtan in
  the US
• Stalevo is a combination of Levodopa, Carbidopa,
  and Entacapone

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COMT Inhibitors

• In presence of a decarboxylase inhibitor
  (carbidopa), COMT is major metabolizing enzyme of
  levodopa
• Effect of medication thought to be due to
  increased/sustained plasma levels of levodopa
• Entacapone and Tolcapone

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COMT Inhibitors

• General precautions should not be given with
  non-selective MAO inhibitors
• May decrease metabolism of epinephrine,
  isoproterenol, norepinephrine, dobutamine,
  alpha-methyldopa
• Will potentiate side effects of levodopa
• Tolcapone Black box warning liver monitoring
  required

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Amantadine

• Antiviral agent anti-PD effect found
  accidentally
• Effective for tremor, rigidity and dyskinesias
• Actual mechanism of action poorly understood
• perhaps facilitates release of dopamine from
  striatal neurons, inhibits presynaptic reuptake
  of catacholamines, or creates an NMDA receptor
  blockade. Does have weak DA properties
• Decreases glutamatergic output from STN (may
  account for anti-dyskinetic effect)

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Amantadine

• T1/2 is 2-4 hours
• Medication is excreted mostly unchanged in the
  urine
• Side effects may include hypotension,
  hallucinations, sedation, dry mouth
• Rare side effect unique to amantadine is livido
  reticularis patchy discoloration of the skin
  (although unsightly, harmless to patient
  resolves with discontinuation of med)

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Livido reticularis
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Anticholinergic agents

• Trihexiphenidyl (Artane)
• Benztropine mesylate (Cogentin)
• Diphenhydramine (Benadryl)
• ALL
• Potential benefit for tremor, little or no effect
  on rigidity or bradykinesia
• Prominent side effects dry mouth, sedation,
  mood changes, mental slowness, blurred vision,
  increased intraocular pressure
• Contraindicated in patient with prostatic
  enlargement, narrow-angle glaucoma, obstructive
  GI disease

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Anticholinergic drugs are less effective than
levodopa and can diminish mainly the tremors and
to a lesser extent the rigidity and
bradykinesia. Therefore, they are used as
supplemental treatment with levodopa.
Anticholinergic drugs are used "instead of
levodopa" in

1. Parkinsonian patients who cannot tolerate
   levodopa because of its side effects or
   contraindications.

1. Parkinsonian patients who cannot benefit from
   levodopa because of non-functional dopaminergic
   neurons.

1. Parkinsonian patients receiving central
   dopaminergic antagonists (antipsychotic drugs)
   which can nullify the effect of levodopa.

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Side effects of anticholinergic drugs

• Dry mouth
• Blurred vision
• Constipation
• Urine retention
• Glaucoma

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Summary of the Treatment of Parkinsons Disease
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Huntingtons Disease

• Formally described in 1872 by George Huntington
• Occurs in 5 to 10 per 100,000 people
• Inherited as an autosomal dominant disorder
• Caused by trinucletoide repeats in gene IT15
• Disease usually starts in mid-thirties to
  mid-forties
• Personality change and adventitious movement
  develops into chorea , cognitive dysfunction and
  memory loss
• Death usually occurs as a result of secondary
  factors within 10 to 30 years