Transcript L10-Parkinsonism

ILOs
At the end of this lecture
you will be able to:Revew the symptoms and
pathophysiology of
parkinsonism.
Detail on the
pharmacology of drugs
used for treatment of
parkinsonism.
Quiz?
•
Neurological presentations
of Parkinsonism EXCEPT:
A- rigidity
B- hyperkinesia
C- tremor
D- postural disturbances.
E- poor balance
Replacement of
dopamine by levodopa.
Levodopa is used with
dopa decarboxylase
inhibitors e.g.
carbidopa ,
benserazide
or COMT inhibitor e.g.
entacapone.
Drugs that mimic the effects of dopamine
at D2 & D3-receptors e.g. bromocriptine,
pergolide.
MAO-B inhibitors
e.g. selegiline
Drugs that release
dopamine e.g.
amantadine
Muscarinic
acetylcholine antagonists e.g.
benzatropine,trihexphenidyl.
Combined with peripheral dopa
decarboxylase inhibitor.
Absorbed from the small
intestine by active transport,
t½=2h
All types of parkinsonism
except those associated with
antipsychotic drug therapy.
Motor Complications of L-dopa
Wearing-off effect.
On-off effect.
→progression of the disease and the loss of
striatal dopamine nerve terminals.
dyskinesias. [Occur in 40 to 90% of patients].
→ fluctuating plasma levels of levodopa and the
presence of hypersensitive dopamine receptors.
The dyskinesias can be reduced by lowering the
dosage; however, the symptoms of parkinsonism
may then reappear.
ADRs:Peripheral side effects are anorexia,
nausea, and vomiting (due to stimulation
of the CTZ).
Orthostatic hypotension ,Cardiac
arrhythmias occur in some patients.
CNS adverse effects of levodopa
therapy include vivid dreams,
delusions, hallucinations, confusion
and sleep disturbances.
Interactions:Proteins ingested
with meals.
Nonselective
MAO inhibitors
(phenelzine,
tranylcypromine).
Pharmacologic
doses of
pyridoxine.
Psychotic patient.
Angle closure glaucoma.
With caution to patients with active
ulcer.
Patients with history of melanoma.
Quiz?
• Carbidopa is useful in treatment of
Parkinson’s disease because:(A) Is a precursor of levodopa
(B) Is a dopamine receptor agonist
(C) Prevents peripheral
biotransformation of L-dopa
(D) Prevents a breakdown of
dopamine
(E) Promotes a decreased
concentration of L-dopa in the
nigrostriatum
Dopamine receptor agonists
long duration of action , less likely to cause
dyskinesias than levodopa.
As monotherapy, the dopamine agonists
are less effective than levodopa.
When used as an adjunct to levodopa
in advanced stages, they may
contribute to clinical improvement and
reduce levodopa dosage needs.
Example ,bromocriptine, pergolide
Bromocriptine, an ergot
derivative, is an agonist at
the D2-receptors and a
partial D1-antagonist.
Bromocriptine is absorbed to a
variable extent from the GIT ;
peak plasma levels are
reached within 1–2 hours after
an oral dose.
It is excreted in the bile and feces.
ADRs:Postural hypotension, nausea,
somnolence
Dyskinesias.
Confusion, hallucinations, delusions,
In order to minimize adverse effects, the
dose is built up slowly over 2 or 3 months.
Used for hyperprolactinemia.
In patients with a history of psychotic
illness .
Recent myocardial infarction,
Active peptic ulceration.
The ergot-derived dopamine agonists are
best avoided in patients with peripheral
vascular disease.
Quiz?
• Which one of the following statements about
bromocriptine is accurate?
(A) It should not be administered to patients taking
antimuscarinic drugs
(B) Effectiveness in Parkinson's disease requires its
metabolic conversion to an active metabolite
(C) The drug is contraindicated in patients with a history
of psychosis
(D) The drug should not be administered to patients
already taking levodopa
(E) Mental disturbances occur more commonly with
levodopa than with bromocriptine.
Amantadine
Originally introduced as
an antiviral.
Modestly effective in
treating symptoms of
parkinsonism.
Useful in the early stages
of parkinsonism or as an
adjunct to levodopa
therapy.
Amantadine affects dopamine release
and reuptake.
antagonist at muscarinic and NMDA
receptors.
Peak plasma concentrations of
amantidine are reached 1–4 hours after
an oral dose.
t½=2-4h, most of the drug being
excreted unchanged in the urine.
Adverse effects include:Nausea, dizziness, insomnia,
confusion, hallucinations,
Ankle edema, and livedo reticularis.
Amantadine and the anticholinergics
may exert additive effects on mental
functioning.
Should be used with caution in patients
with a history of seizures or heart
failure.
Selegiline is an
irreversible inhibitor of
MAO-B, an important
enzyme in the
metabolism of
dopamine.
Blockade of dopamine
metabolism makes
more dopamine
available for stimulation
of its receptors.
Selegiline, as monotherapy, may be
effective in the newly diagnosed
patient with parkinsonism.
It enhances the actions of
endogenous dopamine.
Selegiline is also used in conjunction
with levodopa–carbidopa in laterstage parkinsonism to:reduce levodopa dosage
requirements
and to minimize or delay the onset of
dyskinesias and motor fluctuations
that usually accompany long-term
treatment with levodopa.
Selegiline may slow the progression
of the disease by reducing the
formation of toxic free radicals
produced during the metabolism of
dopamine.
Metabolized to desmethylselegiline,
Which is antiapoptotic.
ADR:-at higher doses
Selegiline may inhibit MAO-A.
Selegiline may cause insomnia
when taken later during the
day.
The adverse effects of
levodopa may be increased by
selegiline.
Selegiline should not be
coadministered with TCA,
meperidine or SSRIs. (may
cause hyperpyrexia, agitation,
delirium, coma).
Anticholinergic Drugs
The efficacy of anticholinergic drugs in
parkinsonism is due to their ability to block
muscarinic receptors in the striatum.
They exert only modest antiparkinsonian
actions , used during the early stages of
the disease or as an adjunct to levodopa
therapy.
Anticholinergics can provide benefit in
drug- induced parkinsonism.
e.g. Benztropine, Trihexyphenidyl.
ADR- cycloplegia, dry
mouth, urinary retention,
and constipation.
Confusion, delirium, and
hallucinations may occur at
higher doses.
Trihexyphenidyl may cause
withdrawal symptoms in
patients receiving large
doses.
Quiz?
• Great caution must be
exercised in the use of this drug
in parkinsonian patients who
have prostatic hypertrophy :•
(A) Benztropine
•
(B) Carbidopa
•
(C) Levodopa
•
(D) Bromocriptine
•
(E) Selegiline
Quiz?
• A drug that is used in the
treatment of parkinsonism
and will also attenuate
reversible extrapyramidal
side effects of neuroleptics
is
•
(A) Amantadine
•
(B) Levodopa
•
(C) Pergolide
•
(D) Selegiline
•
(E) Trihexyphenidyl
M. S. is a 60-year old architect who designs
buildings. His drawings are very detailed and they
must be drawn to a specific scale. During the past
month he has developed a slight tremor in his right
hand that causes some embarrassment but does
not interfere with function. He has, however,
noticed that his writing and drawing have gotten
much smaller, causing problems with his work. His
primary care physician has referred him to a
neurologist for evaluation. On examination, the
neurologist notes some motor rigidity in the right
arm. He also observes a slight slowing in the
patient’s walk and a reduction in the swing of his
arms as he walks. What is the diagnosis, and how
should the patient be treated?