Transcript 04. antiparkinsonism.ppt

Muhammad Ali
Life with Parkinson's Disease
He began boxing at the age of 12, winning
various Golden Glove titles, both locally
and nationally
As Muhammad Ali's boxing career started
to wind down in the early 80's, he began to
show signs of a neurological disorder.
He had evident signs of decreasing motor
skills during a fight against Larry Holmes in
1980.
Parkinson's disease was diagnosed soon
after, and it was noted that his illness was
probably brought on by repetitive head
trauma.
In more recent years, Ali has lost his ability
to speak.
What is Parkinson's Disease??
Parkinson's disease (PD) is a slowly progressive, chronic neurological
condition that affects a small area of cells in the mid brain known as
the substantia nigra. Gradual degeneration of these cells causes a
reduction in a vital chemical known as "dopamine".
Dopamine in BG
Acetylcholine in BG
In most cases,protein deposits called Lewy bodies appear
in dead or dying dopamine-producing neurons
Parkinsonism
symptoms of
Parkinson's disease
Primary
parkinsonism
Parkinson’s disease
Secondary
parkinsonism
Viral encephalitis
Other degenerative disorders
Structural brain disorders
Head injury
Cerebral atherosclerosis
Drugs
Toxins
Signs and Symptoms
Resting tremor
Stiffness of limbs (rigidity)
~flexion attitude
~lead pipe rigidity
~cog wheel rigidity
Generalized slowness of
movement (bradykinesia)
Gait or balance problems
(postural dysfunction)
~shuffling gait
Masked face
Mood changes
Salivation
Dementia
Other Symptoms
Small cramped handwriting
(micrographia)
Lack of arm swing on the affected
side
Decreased facial expression
(hypomimia)
Lowered voice volume (dysarthria)
Feelings of depression or anxiety
Episodes of feeling "stuck in place"
when initiating a step (freezing)
Slight foot drag on the affected
side
Increase in dandruff or oily skin
Less frequent blinking and
swallowing
Insomnia
urinary hesitancy
orthostatic hypotension
Antiparkinsonian Drugs
Anticholinergic drugs
Dopaminergic drug
Atropine or hyoscine
Amantidine
Synthetic atropine
subtitutes
Bromocryptine
Drugs with
anticholinergic and
antihistaminic effect.
Selegiline
L-Dopa
These are principally anticholinergic:
Dry mouth
Blurred vision
Cognitive changes
Constipation
Urinary retention
Tachycadia
Aneroxia
Psychosis(an overdose situation)
Reduce tremors ,decrease rigidity and excessive salivation
Tolerance occurs after prolonged use, increase the dose will increase
the side effect
SIDE EFFECT AND OVERDOSE:
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ventricular fibrillation
supraventricular or ventricular tachycardia
dizziness, nausea
blurred vision
loss of balance
dilated pupils
photophobia
• notably in the elderly, extreme confusion, hallucinations, and
excitation.
These latter effects are due to the fact that atropine is able to
cross the blood-brain barrier.
Decrease tremor and rigidity
Decrease side effect
BENZTROPINE ( cogentine)
centrally acting anticholinergic agent with antihistaminic
properties resulting from the combination of the tropine and the
benzohydryl (portion of diphenhydramine).
MECHANISM OF ACTION:
antagonises the effect of acetylcholine
decreasing the imbalance between the neurotransmitters
acetylcholine and dopamine
which may improve the symptoms of early Parkinson's disease
Benzatropine improves tremors but NOT rigidity.Thus, it also
sometimes used for the treatment of dystonia ( disorder that causes
abnormal muscle contraction, resulting in twisting postures of
limbs, trunk, or face)
TRIHEXPHENIDYL(benzhexol)
Adjunct in the treatment of all forms of parkinsonism
(postencephalitic, arteriosclerotic and idiopathic)
often useful as adjuvant therapy with levadopa
Additionally, it is indicated for the control of extrapyramidal
disorders caused by central nervous system drugs such as the
phenothiazines and butyrophenones.
SIDE EFFECT:
dryness of the mouth
Blurred vision
Dependence
Involuntary movements
-DRUG ABUSE AND DEPENDENT:
the possibility of abuse should be borne in mind due to its
stimulant and euphorian properties.
According to a recent news report, it has become a drug of abuse
among Iraqi soldiers and police. The report states that the drug,
taken in high doses, results in an increased sense of well-being
and decreased anxiety.
PRECAUTIONS:
Patients with :
Cardiac and liver diseases
kidney disorders
with hypertension
Since triyhexphenidyl has parasympatholytic activity, it should be
used with caution in patients with:
glaucoma
obstructive disease of the gastrointestinal
genitourinary tracts problems
in elderly males with possible prostatic hypertrophy
Example :diphenhydramine
Mechanism:
works by blocking the effect of histamine at H1
receptor sites. This results in effects such as the
reduction of smooth muscle contraction
→ inhibit reuptake of the neurotransmitter
serotonin. This discovery led to a search for viable
antidepressants like SSRI (fluoxetine)
Function of diphenhydramine
• Decrease tremors and rigidity (atropine like action)
• Antihistaminic effect producing a sedative effect
• Side effects :
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motor impairment (ataxia),
dry mouth and throat,
flushed skin,
tachycardia
blurred vision
Photophobia
mydriasis
urinary retention + constipation
difficulty in concentrating
general contraindication :
• Glaucoma
• Prostate enlargement
DOPAMINE AGONIST
Bromocriptine
• Ergot derivative
• Dopamine receptor (D2) agonist
• Stimulates dopamine receptors in the basal
ganglia
• Inhibits prolactin release (suppresses
lactation)
Clinical uses
• Indicated in the treatment of the signs and
symptoms of idiopathic or postencephalitic
Parkinson’s disease.
• Adjunctive treatment to Levodopa
Bromocriptine ( cont.)
• To minimize its adverse effects , the dose is
built up slowly over 2-3months.
• Addition of bromocriptine to levodopa
permits :
• Reduction of Levodopa dosage
• Reduce the adverse effects of levodopa
(mainly On-Off phenomenon ).
PERGOLIDE
Stimulates both D1 & D2 receptors.
More potent than bromocriptine
Dose must be built up slowly
Has the same side effects &
contraindications of bromocriptine
NON ERGOT DOPAMINE AGONISTS
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1)
PRAMIPEXOLE
a)
is a new DA agonist that is not an ergot
derivative.
b)
it is widely used now
c)
it has high affinity for the D3 receptors.
d)
is effective as monotherapy in mild case of
Parkinson’s disease
2. Ropinirole:
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Is a pure D2 receptor agonist
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Is effective as monotherapy in patients
with mild or early disease
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In advanced cases is given in combination
with levodopa to smooth
its response
and prevent fluctuations
Continue
• has a neuroprotective effect ( antioxident
activity).
• rapidly absorbed & excreted mostly
unchanged by the kidney.
• Renal insufficiency may need dosage
adjustment.
Adverse effects of dopamine agonist
• Gastrointestinal effects ( nausea, vomiting ,
dyspepsia, constipation , reflux esophagitis)
• Cardidovascular effects
Postural hypotension, painless digital
vasospasm( long-term use of ergot
derivatives), cardiac arrhythmias, peripheral
edema
• Dyskinesias
Adverse effects ( continue)
•Mental disturbances
•Miscellaneous
[Headache, nasal congestion, pulmonary
infiltrate ,retroperitoneal fibrosis,
erythromelalgia ( ergot derivatives )
MonoAmine Oxidase B Inhibitors
Selegiline ( Deprenyl )
• Clinical uses :
-Monotherapy in early stage of Parkinson’s
disease
- Adjunctive therapy with levodopa ( enhance
antiparkinsonian effect of levodopa, reduce
doses & side effects of levodopa mainly
fluctuating response)
- Depression
- Senile dementia
Mechanism of action
• Selectively inhibits MAO-B (which metabolizes
dopamine but doesn’t inhibit MAO-A which
metabolizes norepinephrine and serotonin )
Lack cheese reaction
• Has antioxidant effect
Adverse effects of Selegiline
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Dependence upon chronic use (due to
methamphetamine metabolite )
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Nausea
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Sedation
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Skin rashes
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G.I.T irritation
• Insomnia
AMANTADINE
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Mode of action:
Releases DA from CNS neurons
Inhibits the re-uptake of DA
Anticholinergic effect
It affects the bradykinesia more than tremors.
Pharmacokinetics:
- t ½ = 2-4 hrs
- excreted unchanged in urine
- absorbed orally
Clinical considerations
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less potent than levodopa
effective only for a few weeks
can not be used alone
Adverse effects:
- Depression, Agitation, Confusion
- Insomnia
- Psychosis ,Convulsions, C.H.F, urinary
retention, Postural hypotension
- Ankle edema
- Livedo reticularis
Contraindications: - History of seizures
- History of C.H.F
- With antimuscarinic drugs
L-DOPA
( LEVODOPA )
What is L-Dopa?
• Naturally occurring amino acid found in food and made from
L-Tyrosine in the human body.
• It is a precursor of dopamine. So, it is used to
increase dopamine levels for the treatment of
Parkinson's disease.
Dopa decarboxylase enzyme
L-Dopa
Dopamine
How it works ?
How L-Dopa treat parkinsonism?
• L-Dopa can cross the BBB whereas dopamine itself cannot.
Thus, dopamine is not used in treatment of parkinsonism.
• Once L-dopa has entered the CNS, it is metabolized to
dopamine by decarboxylase and increase the dopamine
content in basal ganglia.
• Conversion to dopamine also occurs in peripheral tissue.
Conversion of
given L-Dopa
to dopamine
95%
occur in
peripheral tissue.
Only 5%
in
basal ganglia
• Decrease the antiparkinsonian effect of L-Dopa.
Carbidopa…
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a peripheral DOPA decarboxylase inhibitor, prevent synthesis
of dopamine in peripheral tissue.
• It inhibit only in peripheral tissue because it cannot cross BBB.
So all the given L-Dopa will reach the basal ganglia.
L-Dopa without
decarboxylase
inhibitor
Dopamine
accumulation in
the periphery
Accelerates
extracerebral
decarboxylation
Nausea
&
vomiting
• Give Carbidopa + L-Dopa in 1:10
Sinemet
• This combination therapy is able to;
– decrease the dose of L-Dopa.
– decrease the side effects of L-Dopa.
– increase the efficiency in treatment of parkinsonism.
Drug interactions
L-Dopa
+
•Reduces anti-parkinsonian effect
because it elevates dopa
decarboxylase activity.
Vitamin B6
L-Dopa
+
Anticholinergic d.
L-Dopa
+
MAOA inhibitors
•Synergism
(the effect is greater than the
sum of their individual effects)
•Hypertensive crisis due to
elevated level of catecholamine.
Side effects of levodopa
Peripheral
Gastrointestinal effects
• Increase when levodopa is given without carbidopa
• Anorexia, nausea, vomiting ( 80% )
Cardiovascular effects
• Increase when levodopa is given alone without
carbidopa
• Cardiac arrhythmias, postural hypotension,
hypertension
Side effects ( cont.)
• (Long term use ) :
-Fluctuation in response ( on-off phenomenon
-C.N.S. effects
Increase when levodopa is given with
carbidopa
-drug-induced dyskinesias & dystonia
-mental disturbances
-Miscellaneous :Mydriasis, +ve Coomb test,
gout, brownish of saliva, urine
Priapism
Additional information
Melanin formation
• Both levodopa and its precursor amino acid L-tyrosine are
precursors to the biological pigment melanin.
Contraindications
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Psychotic patients
Glaucoma
Cardiac patients
Peptic ulcer
In patients with history of melanoma or
undiagnosed skin lesions.