Transcript Drugs for Parkison`s disease and Alzheimer`s disease

Drugs for Parkison’s
disease and Alzheimer’s
disease
Department of pharmacology

Part one Antiparkisonian Drugs

Part two Drug for Alzheimer’s
disease
Neurodegenerative disorders
---- Progressive & irreversible loss of neurons from
specific regions of the brain.
Parkinson's
disease
loss of neurons
from structures
of the basal
ganglia results
in abnormalities
in the control of
movement;
Alzheimer's disease, the loss of
hippocampal and cortical
neurons leads to impairment of
memory and cognitive ability
PD
AD
3
Antiparkisonian Drugs



The feature of Parkinsonism
Classification of drugs
Levodopa
Mechanism of Action
Pharmacological effects and therapeutic
application
Pharmacokinetics
Adverse effects
Drug interactions and Contraindications
What’s Parkinson’s disease?
Parkinson’s disease
is a progressive
degenerative disorder
of the central nervous
system.
Parkinson`s disease
Pope John Paul II
Muhammad Ali
Katharine Hepburn
Michael J. Fox
Johnny Cash
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• Neurodegeneration is the umbrella term
for the progressive loss of structure or
function of neurons, including death of
neurons
The architecture of the
neuron
A dying neuron
nigra
caudatum
○
○
(D2R) DA
Ach(MR)
striatum
(-) (+)
motor neurons in anterior horn of spinal cord
skeletal muscle contraction
nigra
caudatum
○
○
(D2R) DA
Ach(MR)
striatum
(+)
(-)
motor neurons in anterior horn of spinal cord
skeletal muscle contraction
The symptoms of Parkinson’s disease
Four Cardinal Signs




T remor
R igidity
A kinesia and bradykinesia
P ostural instability
The feature of Parkinsonism
• Parkinson's disease (PD) is the most
prevalent type (approximately 80%) of
Parkinsonism.
• A clinical syndrome pathologically
characterized by lesions of the basal
ganglia that produce abnormalities in
motor activities.
The feature of Parkinsonism
•
• PD is related to the loss of
neurons in the substantia nigra
that provide dopaminergic
innervation to the striatum
(caudate end putamen )
The feature of Parkinsonism

PD is a progressive neurological
disorder

common symptoms
akinesia
 bradykinesia
 rigidity
 resting tremor
 Poor balance, falls

What`s happening
in PD
Pathophysiology
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NORMAL
Parkinsonism
Degeneration of pigmented,
Dopaminergic neurons of SN
Histochemical staining of SN
Normal
PD
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How to treat PD
A. Pharmacotherapy
Supplement dopamine--levodopa
Directly stimulate dopaminergic receptor
Anticholinergic drugs
B. Surgical treatment
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Drugs Treatment of Parkinson’s
Disease
• Drugs that replace dopamine (e.g.
levodopa, usually used concomitantly
with peripherally acting dopa
decarboxylase inhibitor, e.g. carbidopa)
• Drugs that mimic the action of
dopamine (e.g. bromocriptine,
pergolide and others in development)
Classification of drugs

Levodopa and enhancer

Agonist of dopaminergic receptor

COMT and MAO inhibitors

Anticholinergics of CNS

Amantadine
Antiparkisonian Drugs
• Levodopa
Mechanism of Action
Pharmacological effects and therapeutic
application
Pharmacokinetics
Adverse effects
Drug interactions and Contraindications
Dopamine can be
used to treat PD?
Why ?
Levodopa

Levodopa is the metabolic precursor of
dopamine.

Levodopa is still the gold standard
antiparkinsonian agent.
L-DOPA rescues Parkinsonian
rabbits
Rabbits treated with
reserpine
The same rabbits
15 minutes after
treatment with
L-DOPA
Levodopa Metabolism
Mechanism of Action

Levodopa is the natural precursor
to dopamine in the brain.
Mechanism of Action

Exogenous levodopa, unlike dopamine,
can cross the blood-brain barrier is
converted into dopamine by an
aromatic amino acid decarboxylase
(AAD)
Mechanism of Action
 primarily
within the presynaptic
terminals of dopaminergic
neurons in the striatum.
Levodopa

Alter release, it is either transported
back to dopaminergic terminals by the
presynaptic uptake mechanism or
metabolized by MAO and COMT.
Therapeutic
effects
Blood
GUT
What we
can do?
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Carbidopa
Levodopa + Carbidopa = without emesis
Carbidopa

Carbidopa is an inhibitor of dopa
decarboxylase.

Because it is unable to penetrate the
blood-brain barrier, it acts to reduce the
peripheral conversion of levodopa to
dopamine.

As a result, when carbidopa and levodopa
are given concomitantly.
Carbidopa
Virtue:
a. It can decrease the dosage of levodopa.
b. It can reduce toxic side effects of levodopa.
c. A shorter latency period precedes the
occurrence of beneficial effects.
Levodopa
Pharmacological effects and therapeutic
application

Levodopa is very effective in
reducing all the signs and symptoms
of PD.
Levodopa
Pharmacological effects and therapeutic
application

When administrated to the early stage
PD patient,
the improvement in tremor, rigidity, and
bradykinesia may be nearly complete.
Levodopa
Pharmacological effects and therapeutic
application

As the disease progresses, dopamine
production diminishes
Levodopa
Pharmacological effects and therapeutic
application

Larger doses of oral levodopa are
needed to produce the same dopamine
Levodopa

In the longer term, the progressive
nature of PD inevitably causes
levodopa to become less effective,

and may give rise to periods where the
clinical symptoms of PD are
inadequately controlled.
Levodopa

Patients may begin to experience
sudden fluctuations in symptom
control: changing from full symptom
control (known as 'on' -time) to periods
of reduced voluntary movement ( 'off' time).
Levodopa
Pharmacokinetics
1.Administered orally, levodopa is rapidly
absorbed from the small bowel by an
active transport system for aromatic
amino acids.
Levodopa
Pharmacokinetics
2. Levodopa short half-life in plasma (l-2
hours).
Ingestion of meals, particularly if high
in protein content, interferes with the
transport of levodopa into CNS.
Pharmacokinetics
3.Some amino acids (such as leucine and
isoleucine) may compete with levodopa
for transporters in small bowel and
blood-brain barrier.
Pharmacokinetics
4. Thus levodopa should be taken on an
empty stomach.
Levodopa
Adverse effects
Stimulation of dopamine receptors in
peripheral system.
 In gastrointestinal system: anorexia,
nausea, and vomiting.
 In cardiovascular system: tachycardia,
ventricular extrasystoles, and
hypotension.
Levodopa
Adverse effects
Stimulation of dopamine receptors in
peripheral system.

For the long term user, involuntary
movements.
Levodopa
Adverse effects
Stimulation of dopamine receptors in
peripheral system.

Psychiatric symptoms : agitation,
anxiety, elation and insomnia,
depression, delusions, hallucinations,
suicidal behavior.
Levodopa
Drug interactions Contraindications

Vitamin B6 increases the peripheral
breakdown and reduces its
effectiveness.
Levodopa
Drug interactions Contraindications

Monoamine oxidase (MAO) inhibitor
can increase conversion of dopamine
to catecholamine thus may cause
hypertensive crisis.
Contraindications




Melanoma
Glaucoma
Severe cardiovascular
Psychotic disorders
Agonist of dopaminergic
receptor
drug
D1
D2
Bromocripine
partial
antagonist
agonist
Ｒopinirole
agonist
Pramipexole
agonist
Pergolide
agonist
agonist
Agonist of dopaminergic
receptor

All the four drugs are well absorbed
orally, and have similar therapeutic
actions.

Ｔhey are particularly effective in the
treatment of on/off phenomena.
Agonist of dopaminergic
receptor

All the drugs may produce hallucinosis，
confusion，orthostatic hypotension.
MAO inhibitors

Selegiline is a selective inhibitor of
MAO isoenzyme, MAO-B.

While both isoenzymes MAO-A and
MAO-B are present in the periphery．
MAO inhibitors

MAO-B is the predominant form in the
striatum and is responsible for the
majority of oxidative metabolism of
dopamine in the striatum.
Selegiline

A selective inhibitor of MAO-B, which
predominates in DA-containing regions
of the CNS and lacks unwanted
peripheral effects of non-selective MAO
inhibitors.


It enhances and prolongs the
antiparkinsonism effect of levodopa.
It may reduce mild on-off or wearing-off
phenomena.
Selegiline
 It
enhances and prolongs the
antiparkinsonism effect of levodopa.
 It
may reduce mild on-off or
wearing-off phenomena.
Selegiline

Long-term trials showed that the
combination of selegiline and levodopa
was more effective than levodopa along
in relieving symptoms and prolonging
life.
Anticholinergics of CNS

Imbalance between the dopaminergic
and the cholinergic activity in the
striatum may play an important role in
pathogenesis of PD．
Anticholinergics of CNS

Diminished dopaminergic activity, a
relative overactive cholinergic activity
may contribute to the symptoms in PD
patients.
Anticholinergics of CNS

Thus cholinergic antagonists could be
beneficiary for PD patients by blocking
the cholinergic activity．
Anticholinergics of CNS
Several drugs :Artane, benztropine.
 These anticholinergic drugs are less
efficacious than levodopa and play an
adjuvant role in PD therapy.
Anticholinergics of CNS
Several drugs :Artane, benztropine.

The adverse effects of these drugs are
results of their anticholinergic
properties, similar to those caused by
high dose of atropine
Anticholinergics of CNS
Several drugs :Artane, benztropine.
 They
shouldn't be used in
patients with glaucoma,
prostatic hypertrophy.
Trihexyphenidyl
(Artane)
1.Action mechanism
blocking M receptors in CNS
function of cholinergic nerves in
nigrostriatum
restoring balance
between dopaminergic and cholinergic
neurons.
Trihexyphenidyl
(Artane)
2.Effect:
 Less efficious than levodopa.

More effective on tremor, less effective
on bradykinesia and rigidity.
3.Use

alone for:
mild patients
patients of discontinuation of L-dopa due to
adverse effects, Parkinsonian syndrome
induced by phenothiazides

all Parkinsonian disorders in combination with
L-dopa
4.side effects
similar to those of atropine.
scopolamine
Amantadine

Amantadine is an antiviral drug used
for the treatment of influenza.

It was found later that amantadine has
an antiparkinsonism effect.

Amantadine appears to enhance the
synthesis, release, or re-uptake of
dopamine from the surviving neurons.
Amantadine

It is used an initial therapy of mild PD.

It also may be helpful as an adjunct in
patients on levodopa with dose-related
fluctuations.
Amantadine
Therapeutic uses and mechanism of action
• Amantadine may be more
efficacious than the
anticholinergic atropine
derivatives but is less effective
than levodopa.
• It has been used alone to treat early
PD and as an adjunct in later stages.
Drug for Alzheimer’s disease
ALZHEIMER'S
DISEASE
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What is AD?
Alzheimer’s disease is an
irreversible, progressive
brain disease that slowly
destroys memory and
thinking skills.
Slide 4
What is AD?
Although the risk of developing AD
increases with age – in most people
with AD, symptoms first appear after
age 60 – AD is not a part of normal
aging. It is caused by a fatal disease
that affects the brain.
Slide 5
Alzheimer’s disease
Damage of acetylcholine neurons
Destroys memory and thinking skills
“Cholinergic hypothesis “
A deficiency of acetylcholine is critical in
the genesis of the symptoms of AD
Involving multiple neurotransmitter
systems, including serotonin, glutamate,
and neuropeptides
Neurochemistry
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“Cholinergic hypothesis “
In AD there is destruction of not
only cholinergic neurons but also
the cortical and hippocampal
targets that receive cholinergic
input.
Neurochemistry
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Classification of drugs

Acetylcholinesterase Inhibitors: tacrine

Agonist of M-receptor: xanomeline

Enhancer of growth factor of neurons: ATT
082

Enhancer of Metabolism and protective agent
of neurons: piracetam
Acetylcholinesterase Inhibitor
tacrine
inhibit (block)
Acetylcholinesterase
The concentration of acetylcholine in the brain
Improvement symptoms of Alzheimer's disease
Tacrine
A potent, centrally acting inhibitor of AChE
Oral tacrine in combination with lecithin
produces modest improvement on memory
performance
Side effects (significant and dose-limiting)
Abdominal cramping, anorexia, nausea,
vomiting, and diarrhea (1/3)
Elevations of serum transaminases ( 50% )
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Donepezil
A selective inhibitor of AChE in the
CNS with little effect on AChE in
peripheral tissues.
Produces modest improvements in
cognitive scores in AD patients and
has a long half-life, allowing oncedaily dosing
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Agonist of M-receptor
xanomeline
Improvement symptoms of think
skill and behavior
• TO grasp Levodopa:
Mechanism of Action
Pharmacological effects and
therapeutic application
Pharmacokinetics
Adverse effects
Drug interactions and
Contraindications