Transcript 06_Parkinson`s

Pharmacology
Section 13.
Treatment of motor disorders
Treatment of Alzheimer’s disease
Marta Jóźwiak-Bębenista
Department of Pharmacology
Medical University of Lodz
[email protected]
Parkinson's Disease
» PD belongs to a group
of conditions called
motor system disorders
» progressive neurologic
disorder that affects
neurons in the part of
the brain controlling
muscle movement.
» 1-2% of population
suffer from this
condition
normal, AD,
PD,
PD+dementia
Symptoms of PD
Primary symptoms of PD:
» Tremor
» Muscle rigidity (stiffness
or inflexibility)
» Bradykinesia (slowing of
voluntary movement )
» Postural and gait
abnormalities
Causes of PD
» DA-ergic neurons in substantia
nigra and corpus striatum
(nigrostriatal DA-ergic tract)
are destroyed
» nigrostriatal DA-ergic tract part of the extrapyramidal
system, responsible for motor
control
» 80% of DA-eric neurons are
damaged, the symptoms of
Parkinson disease appear.
Causes of PD
DA
ACh
» The striatum, is also
rich in excitatory
cholinergic neurons that
counteract the action of
dopamine.
» This is the dopamineacetylocholine balance
» the dopaminergic
system inhibits the
acetylocholinergic
system.
In Parkinson`s disease
dopaminergic neurons degenerate
in nigro-striatal dopaminergic tract
and the inhibitory influence of
dopamine on the striatum is
diminished, resulting in increased
activity of excitatory cholinergic
neurons.
Causes of PD
» Parkinson's disease may result from a
combination of genetic and environmental
factors.
» Certain toxins, diseases (viral encephalitis,
small vascular lesions) and drugs may also
cause symptoms similar to those of PD.
- haloperidol (Haldol)
- chlorpromazine (Thorazine)
- metoclopramide (Reglan)
- prochlorperazine (Compazine)
- valproate (Depacon)
Risk factors
• Age - PD usually affects people over the
age of 50
• Genetic factors / Heredity
• Sex - Men are more likely to develop
Parkinson's disease than women are.
• Exposure to pesticides and herbicides
• Reduced estrogen levels
• Reduced folate levels
Treatment of PD
» There is no cure for
PD, but a variety of
medications provide
dramatic relief from
the symptoms!
» The strategy of treatment
of PD rests on:
1. dopamine levels in
nigro-striatal
dopaminergic tract
2. restoring the correct
dopamine-acetylocholine
balance (through
antagonizing the
excitatory effect of
cholinergic neurons)
Drugs used in PD
» Drugs, which restore the dopamine levels in nigrostriatal dopaminergic tract:
 Levodopa (L-dopa) and carbidopa
 COMT inhibitors
 Dopamine agonists
 Amantadine
 Selegiline
» Drugs, which restore the dopamine-acetylocholine
balance:
 Anticholinergics
Levodopa
» the most effective medication for Parkinson`s
disease.
» 70-80% of treated Parkinson`s patients are
on levodopa therapy.
» Standard release preparations:
- levodopa/carbidopa (Sinemet or Atamet)
- levodopa/benserazide (Madopar)
» Prolonged release preparations:
- levodopa/carbiopa (Sinemet CR)
- levodopa/benserazide (Madopar HBS)
Levodopa
» Mechanism of actions:
dopamine doesn't cross
the BBB!
Levodopa – metabolic
precursor of DA easily
penetrate the BBB into
the CNS.
DOPA-decarboxylase
Levodopa
Dopamine
DOPA decarboxylase inhibitors
» Levodopa combined with DOPA decarboxylase
inhibitors represent a significant improvement in the
treatment of PD.
Carbidopa
Benserazide
» a smaller dose of levodopa is needed to treat
symptoms
» nausea and vomiting often associated with levodopa
treatment are greatly reduced by the presence of
DOPA decrboxylase inhibitors.
Levodopa
» Actions:
Levodopa reduces akinesia and
rigidity, in smallest degree
decreases tremor.
» Pharmacokinetics:
- well absorbed upon oral
administration.
- should be taken on empty
stomach, 45 minutes before a
meal. Foods inhibit the
absorption from the gut of
levodopa and it`s transport into
the CNS.
» Interactions:
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Vit. B6
MAOIs
Antidepressants
Neuroleptics
Hypotensive drugs
Levodopa loses therapeutic
efficacy after a long time of
treatment. This means that
the length of time that each
dose is effective begins to
decrease, leading to more
frequent doses.
Levodopa
» The adverse side effects:
CNS:
- visual and auditory hallucinations,
- mood changes (depression, excitation).
With increased dosing and prolonged use of levodopa,
patients experience:
- dyskinesias (spontaneous, involuntary
movements) and "on-off" periods when the
medication will suddenly and unpredictably start or
stop working.
- insomnia and anxiety.
Peripheral:
- nausea, vomiting
- low blood pressure.
COMT inhibitors
» represent a new class
of Parkinson's
medications
» they must be taken as
an adjunct with
levodopa/carbidopa!
Entacapone (Comtan)
Tolcapone (Tasmar)
COMT inhibitors
» Indication:
» Tolcapone- reduces the
frequency of the “onoff”periods (motor
fluctuations)
» Entacaponesecondary medication;
delays wearing off by
prolonging
effectiveness of
levodopa (Stalevo)
» Side effects: diarrhea,
postural hypotension,
dyskinesias, insomnia,
nausea, hallucinations,
anorexia, constipation .
Tolcapone is
hepatotoxic
» Interaction: MAOIs
Dopamine agonists
» They mimic the effects of
dopamine in the brain
» The older used in
combination with levodopa
» The side effects:
similar to those of levodopa,
although they are less likely
to cause involuntary
movements (dyskinesia) and
more likely to cause
hallucinations, confusion,
nausea or orthostatic
hypotension.
» Agonists available in the
United States include:
› bromocriptine (Parlodel)
› pergolide (Permax)
» New drugs:
› pramipexole (Mirapex)
› ropinirole (Requip)
The newer used alone, as the
first-line; side effects similar to
bromocriptine but they are
milder.
Amantadine- Symmetrel
» antiviral drug
» Mechanism of actions:
enhences the syntesis and
release of DA and improve
Dopaminergic neurotransmission.
» Actions:
» less efficacious than levodopa but it
has fewer side effects
» has little effect on tremor but is more
effective than the anticholinergics
against rigitidy and bradykinesia
»
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Side effects:
difficulty in concentrating
confusion, insomnia
nightmares, agitation
hallucinations
leg swelling
mottled skin
for people in the latter
stages of Parkinson's
disease, if they have
problems with dyskinesia
induced by levodopa
Selegiline- Deprenyl
» selective IMAO-B
» an adjunct to levodopa
therapy,
» prevent the break down
of both naturally
occurring DA and DA
formed from levodopa,
resulting in dopamine
levels in the brain
»
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has a mild antidepressant effect.
Side effects:
- Eldepryl
heartburn,
- Atapryl
nausea,
- Carbex
dry mouth,
dizziness
risk for severe
hypertension (only at high
doses of drug)
Anticholinergics
» the main treatment for
Parkinson's disease
before the introduction
of levodopa.
» Mechanism of actions:
 the activity of Ach
» Actions:
- used as secondaryadjuvant medications.
- they help control tremors
in the early stages of
the disease.
» Adverse effects:
• blurred vision, dry mouth,
urinary retention)
• mental problems:
- memory loss,
- confusion
- hallucinations.
» They are not used long-term
due to their side effects.
Biperiden HCL (Akineton), Benztropine mesylate (Cogentin)
Procyclidine (Kemadrin), Trihexyphenidyl (Artane)
Over the counter medications
» Free radicals or reactive
oxygen species may be
harmful to cells and
lead to their death.
» Antioxidants protect
nerve cells from
oxidative damage.
» Neuroprotective
treatments may be most
helpful at an early stage
of PD.
Pharmacology
Section 13.
Treatment of Alzheimer’s disease
Marta Jóźwiak-Bębenista
Department of Pharmacology
Medical University of Lodz
[email protected]
Alzheimer’s disease
» AD it is one of the
dementing disorders, which
are a group of brain
diseases that result in the
loss of mental and physical
functions.
» AD is a progressive
disease of the brain that is
characterized by
impairment of memory and
a disturbance in at least
one other thinking function
(for example, language or
perception of reality).
Symptoms of AD
» Cognitive symptoms:
- memory loss
- disorientation
- confusion
- difficulty with reasoned thought
- loss of language skills.
» Behavioral symptoms:
- agitation/anxiety
- delusions/hallucinations
- depression
- insomnia
The severity of the symptoms increases over
- wandering
time.
The onset of AD is usually very slow and
gradual.
Causes of AD
» Neuropathologic causes:
- beta-amyloid protein (amyloid plaques)
- degeneration of cholinergic neurons
- atrophy of NA,DA,5-HTergic neurons
- Large amount patologic
proteins: apolipoprotein E,
presenilins
- Inflammation.
- traumatic head injuries
earlier in life.
Causes of AD
» Abnormalities in the
brain's
neurotransmitters,
» ACh is a critical
neurotransmitter in the
process of forming
memories.
» ACh is abundant in the
nerve cells of the
hippocampus and
cerebral cortex, the
regions that are
devastated by AD.
• Age (10 % of
people over age
65 and 50 % of
those over 85
have AD)
• Genetic factors
Treatment of AD
» There is no treatment
that will stop or reverse
the symptoms of AD.
» The used drugs attempt
to slow the progression
of the disease.
» These drugs work to
maintain levels of
neurotransmitters in the
brain!
» To increase the activity
of cholinergic system
we use:
acetylocholine
precursors (lecithin,
choline)
2. ACh-esterase inhibitors
(acetylcholinesterase,
an enzyme responsible
for the destruction of
acetylcholine)
» Tacrine (Cognex),
» Donepezil (Aricept),
» Rivastigmine (Exelon),
» Galantamine
(Razadyne, Reminyl)
1.
Treatment of AD
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Side effects of tacrine:
abdominal cramps
nausea
polyuria
diarrhea
hepatotoxic
The newer drugs are not
effective for everyone, and
their effectiveness is
limited to the early and
middle stages of AD.
» The newer
anticholinesterase
inhibitors: donepezil,
rivastigmine, galantamine
are better tolerated.
» The main side effects are
nausea, vomitimg,
diarrhea.
» The newer
anticholinesterase
inhibitors have proved
beneficial in improving
memory, and have fewer
side effects.
Treatment of AD
Memantine (Namenda)
» approved to treat moderate to severe AD,
» It`s effects are independent of acetylcholine
and acetylcholinesterase.
» by blocking the NMDA receptors and the
effects of glutamate, memantine may protect
nerve cells from excess stimulation by
glutamate.
Treatment of AD
» It is possible to reduce
some of the common
emotional and
behavioral symptoms
associated with AD.
» Tranquilizers- reduce
agitation, anxiety,
unpredictable behavior.
» Benzodiazepinesimprove sleeping
patterns
» Antidepressants - treat
depression.
Other drugs:
» selegiline
» antioxidants (vit. E,
koenzym Q10)
» anti-inflammatory drugs:
indometacin (NSAIDs)
Huntington`s disease
Huntington's disease (HD) =
Huntington disease =
Huntington's chorea = chorea
maior
» movement disorder associated with defects
in the basal ganglia
» inherited neurological disorder
» appears during adult life
» one out of every 10,000 Americans has HD
Pathophysiology of HD
Imbalance of dopamine, acetylcholine,
GABA
and perhaps other neurotransmitter
in the basal ganglia.
» overactivity in dopaminergic nigrostriatal
pathways
1. increased responsiveness of
postsynaptic dopamine receptors
2. deficiency of a neurotransmitter that
normally antagonizes dopamine.
Pathophysiology of HD
» GABA and glutamic acid decarboxylase are
reduced in the basal ganglia of patients with HD.
» Ach and choline acetyltransferase are reduced in
the basal ganglia of patients with HD.
Theses deficiencies reduce the inhibitory influence
on the nigrostriatal dopaminergic neurons and
lead to the dopamainergic hyperactivity
associated with Huntington`s disease
The symptoms of HD are
suppressed by drugs that
block dopaminergic receptors
and worsened by drugs that
increase basal ganglia
dopaminergic activity.
Treatment of HD
Reduction basal ganglia dopaminergic activity
Drugs that deplete central
dopamine stores by blocking
entry into the neuronal
storage vesicles:
 reserpine (small doses of
0.25 mg daily; no longer
used in the UK)
 tetrabenazine
The adverse effects:
hypotension, depression,
sedation, gastrointestinal
disturbances.
Drugs that block the
dopaminergic receptors:
» phenothiazines (e.g.
Perphenazine)
» butyrophenones (e.g.
Haloperidol)
The adverse effects:
restlessness,
parkinsonism.
Treatment of HD
» enhance central GABA or Ach activity
no consistently beneficial response