Pharmacology Section 13. Treatment of motor disorders Treatment of Alzheimer

1
PharmacologySection 13. Treatment of motor
disordersTreatment of Alzheimers disease

• Marta Józwiak-Bebenista
• Department of Pharmacology
• Medical University of Lodz
• martia1_at_tlen.pl

2
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, PDdementia
3
Symptoms of PD

• Primary symptoms of PD
• Tremor
• Muscle rigidity (stiffness or inflexibility)
• Bradykinesia (slowing of voluntary movement )
• Postural and gait abnormalities

4
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.

5
Causes of PD

• The striatum, is also rich in excitatory
  cholinergic neurons that counteract the action of
  dopamine.
• This is the dopamine-acetylocholine balance
• the dopaminergic system inhibits the
  acetylocholinergic system.

DA
ACh
6
In Parkinsons 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.

7
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)

8
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

9
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
• ?dopamine levels in nigro-striatal dopaminergic
  tract
• restoring the correct dopamine-acetylocholine
  balance (through antagonizing the excitatory
  effect of cholinergic neurons)

10
Drugs used in PD

• Drugs, which restore the dopamine levels in
  nigro-striatal dopaminergic tract
• Levodopa (L-dopa) and carbidopa
• COMT inhibitors
• Dopamine agonists
• Amantadine
• Selegiline
• Drugs, which restore the dopamine-acetylocholine
  balance
• Anticholinergics

11
Levodopa

• the most effective medication for Parkinsons
  disease. 
• 70-80 of treated Parkinsons 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)

12
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
13
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. 

14
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 its transport into
• the CNS.

• Interactions
• 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.
15
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.

16
COMT inhibitors

• represent a new class of Parkinson's medications
• they must be taken as an adjunct with
  levodopa/carbidopa! 

Entacapone (Comtan) Tolcapone (Tasmar)
17
COMT inhibitors

• Side effects diarrhea, postural hypotension,
  dyskinesias, insomnia, nausea, hallucinations,
  anorexia, constipation . Tolcapone is hepatotoxic
  
• Interaction MAOIs

• Indication
• Tolcapone- reduces the frequency of the
  on-offperiods (motor fluctuations)
• Entacapone- secondary medication delays wearing
  off by prolonging effectiveness of levodopa
  (Stalevo)

18
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.

19
Amantadine- Symmetrel

• Side effects
• difficulty in concentrating
• confusion, insomnia
• nightmares, agitation
• hallucinations 
• leg swelling
• mottled skin

• 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

for people in the latter stages of Parkinson's
disease, if they have problems with dyskinesia
induced by levodopa
20
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

• Side effects
• heartburn,
• nausea,
• dry mouth,
• dizziness
• risk for severe hypertension (only at high doses
  of drug)

- Eldepryl - Atapryl - Carbex
has a mild antidepressant effect. 
21
Anticholinergics

• the main treatment for Parkinson's disease before
  the introduction of levodopa.
• Mechanism of actions
• the activity of Ach
• Actions
• - used as secondary- adjuvant 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)
22
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.

23
PharmacologySection 13. Treatment of
Alzheimers disease

• Marta Józwiak-Bebenista
• Department of Pharmacology
• Medical University of Lodz
• martia1_at_tlen.pl

24
Alzheimers 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).

25
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
• - wandering

The severity of the symptoms increases over
time. The onset of AD is usually very slow and
gradual.
26
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.
27
Causes of AD

• Age (10 of people over age 65 and 50 of
  those over 85 have AD)
• Genetic factors

• 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.

28
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

• 1. 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)

29
Treatment of AD

• Side effects of tacrine
• abdominal cramps
• nausea
• polyuria
• diarrhea
• hepatotoxic

• 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.

The newer drugs are not effective for everyone,
and their effectiveness is limited to the early
and middle stages of AD.
30
Treatment of AD

• Memantine (Namenda)
• approved to treat moderate to severe AD,
• Its 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.

31
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.
• Benzodiazepines- improve sleeping patterns
• Antidepressants - treat depression.

• Other drugs
• selegiline
• antioxidants (vit. E, koenzym Q10)
• anti-inflammatory drugs indometacin (NSAIDs)

32
Huntingtons disease
33
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

34
Pathophysiology of HD

• Imbalance of dopamine, acetylcholine, GABA
• and perhaps other neurotransmitter in the basal
  ganglia.
• overactivity in dopaminergic nigrostriatal
  pathways
• increased responsiveness of postsynaptic dopamine
  receptors
• deficiency of a neurotransmitter that normally
  antagonizes dopamine.

35
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 Huntingtons
  disease

36

• The symptoms of HD are suppressed by drugs that
  block dopaminergic receptors and worsened by
  drugs that increase basal ganglia dopaminergic
  activity.

37
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.

38
Treatment of HD

• enhance central GABA or Ach activity
• no consistently beneficial response