Pharmacology - Parkinsonism

1. Parkinsonism
By: Aditya Arya

2. Parkinsonism:
Definition :
Parkinsonism is a progressive neurological disorder of
muscle movement as a clinical syndrome consisting
of 4 cardinal features:
3) bradykinesia (slowness of movement) and, in
extreme cases, a loss of physical movement
(akinesia)
4)muscular rigidity
5)resting tremor (which usually disappears during
voluntary movement)
6)impairment of postural balance leading to
disturbances of gait and falling

3. Idiopathic Parkinson's disease
•Idiopathic Parkinson's disease - or Parkinson's
- is the most common type of parkinsonism.
Unlike some other forms which have specific
causes it is not known why idiopathic
Parkinson's occurs.
•The main symptoms of idiopatic Parkinson's
are tremor, rigidity and slowness of
movement.
•Symptoms and the rate at which the condition
progresses vary from person to person. This
can make diagnosis difficult.

4. Vascular Parkinsonism:
•Vascular parkinsonism is one of the atypical forms of
parkinsonism.
•The most likely causes of vascular parkinsonism are
hypertension and diabetes. A stroke (cerebrovascular
accident), cardiac disease or carotid artery pathology
(another form of stroke) may also be involved.
•Symptoms of vascular parkinsonism may include
difficulty speaking, making facial expressions or
swallowing.
•Other signs can include problems with memory or
confused thought, cognitive problems and
incontinence.

5. Drug Induced Parkinsonism
•A small number (around 7%) of people diagnosed with parkinsonism have
developed their symptoms following treatment with particular
medications.
•Drugs - known as neuroleptic drugs - used to treat schizophrenia and
other psychotic disorders block dopamine. These drugs are thought to be
the biggest cause of drug-induced parkinsonism.
•Dopamine is a chemical in the brain which allows messages to be sent to
the parts of the brain that co-ordinate movement.
•The symptoms of Parkinson's appear when the level of dopamine falls.
•The symptoms of drug-induced parkinsonism tend to be static. Only in
rare cases do they change in the manner that the symptoms of
Parkinson's do.
•Most people will recover within months, and often within hours or days,
of stopping the drug that caused the dopamine block.

6. Dementia with Lewy bodies:
•Dementia with Lewy bodies is similar, in some ways, to
Parkinson's and Alzheimer's.
•Symptoms differ slightly from Parkinson's and include
problems with memory and concentration, attention,
language and the ability to carry out simple actions.
•People who have dementia with Lewy bodies commonly
experience visual hallucinations and some Parkinson's-type
symptoms, such as slowness of movement, stiffness and
tremor.
•Dementia with Lewy bodies is also a progressive condition,
which means that the symptoms can become worse over
time. Currently, there is no cure or treatment for the
condition.

7. Inherited Parkinson's
•There is no conclusive evidence that Parkinson's is a
hereditary condition that can be passed on within families,
apart from in exceptionally rare cases.
•It is thought that although it is not directly inherited, some
people may have genes that increase the possibility of
developing Parkinson's.
•People who have genes that are prone to Parkinson's may be
more likely to develop the condition when combined with
other factors, such as environmental toxins or viruses.
•At present, it is estimated that up to 5% of people with
Parkinson's may have a genetic cause.
•The role genetics may play in the development of Parkinson's
is currently the subject of much research.

8. Juvenile Parkinson's:
•Juvenile Parkinson's is a term used when the
condition affects people under the age of 20.

9. Causes of parkinsonism:
2)Idiopathic PD:
- Due to loss of dopaminergic neurons of the substantia
nigra
- Progressive loss of dopamine-containing neurons is a
feature of normal aging; however, most people do not lose
the 70% to 80% of dopaminergic neurons required to cause
symptomatic PD
- Death frequently results from complications of immobility,
including aspiration pneumonia or pulmonary embolism
6)Secondary PD:
e.g., following stroke, and intoxication with dopamine-
receptor antagonists as antipsychotics and antiemetics.

10. Treatment of parkinsonism
•Aim of treatment is to enhance dopaminergic
pathway or inhibit cholinergic pathway in the
brain

13. •Dopamine itself does not cross the
blood-brain barrier and therefore
has no CNS effects. However,
levodopa, as an amino acid, is
transported into the brain by amino
acid transport systems, where It is
converted to dopamine by the
enzyme L-aromatic amino acid
decarboxylase.

14. Drugs used in the treatment of parkinsonism
1- Levodopa (1)
Levodopa is (the most effective drug used in the treatment of
parkinsonism)
Chemistry:
•It is the metabolic precursor of dopamine
Mechanism of action:
• In the brain, levodopa is converted to dopamine by
decarboxylation primarily within the presynaptic terminals of
dopaminergic neurons in the stratium (by action of L-aromatic
amino acid decarboxylase). The dopamine produced is
responsible for the therapeutic effectiveness of the drug in PD;
after release, it is either transported back into dopaminergic
terminals by the presynaptic uptake mechanism or
metabolized by the actions of MAO and catechol-O-
methyltransferase (COMT) .

15. Drugs used in the treatment of parkinsonism
1- Levodopa (2)
• If levodopa is administered alone, the drug is
largely decarboxylated by enzymes in the
peripheral sites so that little unchanged drug
reaches the cerebral circulation.
•In addition, dopamine release into the
circulation by peripheral conversion of
levodopa produces undesirable effects,

16. Drugs used in the treatment of parkinsonism
1- Levodopa (3)
•In practice, levodopa is administered in combination with a
peripherally acting inhibitor of aromatic L-amino acid
decarboxylase, such as carbidopa, that do not penetrate into
the CNS.
• Inhibition of peripheral decarboxylase markedly increases
the fraction of administered levodopa that crosses the
blood-brain barrier and reduces the incidence of peripheral
side effects.
•The most commonly prescribed form of carbidopa/levodopa
is the 25/100 form, containing 25 mg carbidopa and 100 mg
levodopa.

17. Drugs used in the treatment of parkinsonism
1- Levodopa (4)
Adverse effects:
A) Central:
• long-term therapy leads to "wearing off" phenomenon: each
dose of levodopa improves mobility for 1 to 2 hours, but
rigidity and akinesia return at the end of the dosing interval.
Increasing the dose and frequency of administration can
improve this situation, but this often is limited by the
development of dyskinesias (excessive and abnormal
involuntary movements). Patients may fluctuate between
being "off," having no beneficial effects from their
medications, and being "on" but with dyskinesias, a situation
called the on/off phenomenon.

18. Drugs used in the treatment of parkinsonism
1- Levodopa (5)
2) Mental effects
Depression, anxiety, agitation, insomnia,
delusions, hallucinations, euphoria
3) Dyskinesias (excessive and abnormal
involuntary movements) as chorea and tremor

19. Drugs used in the treatment of parkinsonism
1- Levodopa (6)
A.Peripheral:
Due to formation of dopamine peripherally
3.The most common peripheral side effects are
anorexia, nausea, and vomiting (likely due to
dopamine’s stimulation of the chemoreceptor
trigger zone in the medulla oblongata).
4.Cardiovascular side effects in the form of
orthostatic hypotension and cardiac arrhythmias
 Abrupt withdrawal of levodopa may precipitate
the neuroleptic malignant syndrome.

20. Drugs used in the treatment of parkinsonism
1- Levodopa (7)
Drug Interactions:
•Pharmacologic doses of pyridoxine (vitamin B6)
enhance the extracerebral metabolism of levodopa
and prevent its therapeutic effect unless a
peripheral decarboxylase inhibitor is also taken.
•Levodopa should not be given to patients taking
monoamine oxidase A inhibitors or within 2
weeks of their discontinuance, because such a
combination can lead to hypertensive crises.

21. Drugs used in the treatment of parkinsonism
1- Levodopa (7)
Contraindications
2.Psychotic patients
3. Angle-closure glaucoma
4.Cardiac disease
5.Peptic ulcer
6.Melanoma

22. Drugs used in the treatment of parkinsonism
2- Dopamine receptor agonists (1)
•Four orally administered dopamine-receptor
agonists are available for treatment of PD:
•Ergot derivatives: as bromocriptine or
pergolide
•Non ergot derivatives as ropinirole

23. Drugs used in the treatment of parkinsonism
2- Dopamine receptor agonists (2)
Adverse effects:
II.Central:
•Dyskinesias , mental Disturbances
V.Peripheral:
A) Gastrointestinal Effects:
•Anorexia and nausea and vomiting
B) Cardiovascular effects:
9. postural hypotension
10. cardiac arrhythmias
11.peripheral vasospasm (with ergot derivatives)

24. Drugs used in the treatment of parkinsonism
2- Dopamine receptor agonists (3)
Contraindications
2.Psychotic patients
3. Angle-closure glaucoma
4.Cardiac disease
5.Peptic ulcer
6.Peripheral vascular disease (ergot derivatives).

25. Drugs used in the treatment of parkinsonism
3- Monoamine oxidase inhibitors (1)
Two types of monoamine oxidase (MAO) have been distinguished.
Monoamine oxidase (A) metabolizes norepinephrine and serotonin;
monoamine oxidase (B) metabolizes dopamine.
Selegiline:
Mechanism of action:
•Selective inhibitor of monoamine oxidase B (retards the breakdown of
dopamine). Given alone, it has a weak action. It is therefore used as
adjunctive therapy for patients with a declining response to levodopa.
Side effects:
• May cause insomnia when taken later during the day.
Drug interactions:
•It should not be taken by patients receiving tricyclic antidepressants, or
serotonin reuptake inhibitors because of the risk of acute toxic interactions.
•The adverse effects of levodopa may be increased by selegiline.

26. COMT inhibitors
Periphery CNS (striatum)
3-O-
Methyldopa
L-DOPA
Dopamine
L-DOPA Dopamine
DOPAC
3-Methoxy
tyramine
MAO-B
COMT
COMT
AAD
AAD
carbidopa x
tolcapone x
tolcapone x
selegilinex
-

27. Drugs used in the treatment of parkinsonism
3- Catechol O methyl transferase inhibitors (1)
Tolcapone
•Mechanism of action:
• Inhibit catechol O methyl transferase (COMT) which is responsible
for the conversion of dopa into methyl dopa. Elevated levels of
methyldopa decreases the response to levodopa, because
methyldopa competes with levodopa for an active carrier
mechanism that governs its transport across the blood-brain barrier.
•prolong the action of levodopa by diminishing its peripheral
metabolism.
•These agents may be helpful in patients receiving levodopa to
reduce dose and decrease fluctuations in response
•Side effects are similar to levodopa

28. Drugs used in the treatment of parkinsonism
4- Amantadine(1)
Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclear
Clinical Use
•Amantadine is less potent than levodopa and its effects disappear after only a few
weeks of treatment
Adverse Effects
5.Central nervous system effects
6.Peripheral edema
7.headache
8.Heart failure
9.postural hypotension
10.urinary retention
11. gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth).
Contraindications
•Amantadine should be used with caution in patients with a history of seizures or
heart failure.

29. Drugs used in the treatment of parkinsonism
5- Acetylcholine blocking drugs(1)
•Benztropine
Clinical Use
•Antimuscarinic drugs may improve the tremor
and rigidity of parkinsonism but have little
effect on bradykinesia.

30. Adverse Effects
1) Central nervous system effects, including drowsiness,
restlessness, confusion, agitation, hallucinations, and mood
changes. Dyskinesias occur in rare cases
2) Atropine – like actions: dryness of the mouth, blurring of
vision, urinary retention, nausea and vomiting, constipation,
tachycardia, palpitations, and cardiac arrhythmias.
withdrawal should be gradual in order to prevent acute
exacerbation of parkinsonism.
Contraindications
6.Prostatic hyperplasia,
7.Obstructive gastrointestinal disease (eg, paralytic ileus)
8.Angle-closure glaucoma.

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