Transcript PARKINSON`S DISEASE

PARKINSON’S
DISEASE
ETIOLOGY
1)
2)
Idiopathic
Exposure to :
neurotoxin
Oxidative stress
Drugs
3)Genetic factors.
Pathology &Principal
treatment

1)
The normally high concentration
of dopamine in the basal ganglia is
reduced and attempts to restore
dopaminergic activity with levodopa
and dopamine agonist.
2)
Restore the normal balance of
cholinergic and dopaminergic influences
on the basal ganglia with antimuscarinic
drugs .
DRUGS AFFECTING
DOPAMINERGIC
NEUROTRANSMISSION
Drugs
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LEVODOPA
Metabolic precursor of dopamine
Pharmacokinetics
Half –life= 1-2 hrs
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Rapidly absorbed from small intestine.
 Food delay absorption.
 Certain amino acids from ingested food compete
for absorption & drug transport from blood to
brain.
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Pharmacokinetics
Main metabolic products: HVA & DOPAC 
Only 1-3% of given dose enters the brain . 
Given with dopa decarboxylase inhibitor 
( CARBIDOPA). Combination Called Sinemet 
1- Reduce peripheral biotransformation of 
levodopa
2- Increase plasma level & half-life of levodopa 
3- Reduce daily requirement of levodopa ( 75%) 
Excreted by kidneys 
Clinical Benefits of levodopa
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Can ameliorate all of the clinical
symptoms of parkinsonism
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It is mainly effective in relieving
bradykinesia
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Other drugs can be added to
levodopa
Clinical considerations
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“ON” and “OFF” Phenomenon
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Tolerance to therapeutic response
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It does not arrest disease progress
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Only effective in the first few years
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Taking drug in divided doses to reduce gastric
symptoms.
Sudden withdrawal causes severe akinetic state.
Clinical Consideration
Postural hypotension is common , so 
patient should take care when he stand
up.
Dyskinesias occur up to 80% ( 
uncontrollable muscle jerks)
Adv. Effects of Levodopa
1.
G.I.T : Nausea, vomiting, and anorexia
2.
Cardiovascular:
- Tachycardia
- Ventricular extrasystoles
- Atrial fibrillation (rare)
- Postural hypotension
- Hypertension
Dyskinesias ( with chronic treatment)
3.
Side effects con’d
4- Behavioral effects are more
common in patients taking
levodopa in combination with
carbidopa
- Depression
- Anxiety
- Agitation
- Confusion
- Hallucinations
Adverse Effects ( cont.)
5- Fluctuations in response
6- Miscellaneous 
Mydriasis ( an attack of acute glaucoma) 
Hemolysis ( +v Coombs test ) 
Gout 
Abnormal of smell or taste 
Brownish discoloration of saliva, urine or 
vaginal secretions
Priapism
Levodopa- Drug Interactions
1.
Pyridoxine- Enhances peripheral
metabolism of levodopa
2. Non selective MOAI –Hypertensive
crises
Contraindications
Psychotic patients
 Glaucoma
 Cardiac patients
 Peptic ulcer
 In patients with history of melanoma or
undiagnosed skin lesions.
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Advantages for the use of
dopamine agonist in parkinsonism
1-They do not require metabolic 
conversion to an active product.
2- Circulating plasma amino acids do not 
compete with dopa agonist for absorption
or transportation.
3-They have long plasma half-life as 
compared to levodopa
4- They do not undergo oxidative 
metabolism & no generation of free
radicals & the associated oxidative stress.
BROMOCRIPTINE
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A synthetic ergot derivative
directly stimulate D2 receptors
Used in hyperprolactinemia
Best for patients
Who show akinesia
With “ON” and “OFF” phenomenon
Who are refractory to levodopa
Can be combined with
Levodopa
Amantadine
Anticholinergics
Pharmacokinetics of
Bromocriptine
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Given orally
The dose must be built up slowly
Plasma ½ life =12-16 hrs
Excreted in bile & feces
Clinical Considerations
- Produces less dyskinesia than levodopa
- It has more psychiatric adverse effects
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Adverse effects of
Bromocriptine
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G.I.T: nausea, vomiting and anorexia,
G.I .T bleeding
Cardiovascular:
- Postural hypotension
- Cardiac arrhythmias
- Painless digital vasospasm
CNS: Dyskinesia, Confusion,hallucination
and psychiatric disturbances
Headache .
Miscellenious :Nasal congestion,
erythromelalgia
Rarely pulmonary fibrosis.
Contraindications to
Bromocriptine
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History of psychiatric disease
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Myocardial infarction
History of peptic ulcer
 Peripheral vascular disease
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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
Widely used now
Ha a high affinity for the D3 receptors.
Is effective as monotherapy in mild case of
Parkinson’s disease
In advanced cases is given with levodopa 
( reducing the dose & fluctuation response
of levodopa).
Has a neuroprotective effect ( antioxident 
activity).
Rapidly absorbed & excreted mostly 
unchanged by the kidneys.
Renal insufficiency may necessitate dosage
adjustment.
2. Ropinirole:
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D2 receptor agonist
Effective as monotherapy in patients
with mild disease
Can be combined with levodopa to smooth
its response and prevent fluctuations
in advanced diseases
It is metabolized by CYP1A2 hepatic
enzymes
Adverse Effects of
Pramipexole and Ropinirole
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Anorexia ,nausea ,vomiting and constipation
Excessive day time somnolence has been reported (
uncontrollable tendency to fall asleep that can result in
car accident
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Postural hypotension
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Cardiac arrhythmias
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Peripheral edema
Dyskinesias 
Mental Disturbance 
Are more common & severe than with
levodopa
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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
1.
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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
DEPRENYL (SELEGILINE)
Used in patients who do not respond
well to carbidopa-levodopa
combination
 Mechanism of action
 A) it traps free radicals and other
toxins that degrade the neurons.
 B) As a MAO- B inhibitor ,it may retard
the break-down and destruction of
dopamine by MAO-B ,thus freeing
more DA to interact with its
receptors in substantia nigra.
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MAO-B INHIBITORS
(SELEGILINE)
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Lacks the cheese reaction( dietary amines)
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Reduces “ON” -“OFF” phenomena
Enhances & prolongs the antiparkinsonism effect
of levodopa.
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Reduces Neuronal damage by toxic free radicals
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1.
It retards DA metabolism allowing for
reduction of levodopa dosage
Can be combined with other drugs
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
Contraindications
Should not be taken with: 
Meperidine 
Tricyclic antidepressants 
Serotonin reuptake inhibitors 
( Risk of acute toxic interactions) 
ANTIMUSCARINIC AGENTS
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Benztropine
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Trihexyphenidyl
Procyclidine
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Centrally acting antimuscarinic
drugs.
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Block CNS muscarinic receptors
and reduce cholinergic
transmission in Corpus Striatum
CLINICAL CONSIDERATIONS
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Starts with small doses- gradually
increase.
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Improve best tremor and rigidity
with little effect on bradykinesia.
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Can be combined with : levodopa to Rx
severe forms
*Withdrawal should be gradually to 
prevent acute exacerbation of
parkinsonism.
*Benztropine is used mainly in reserpine
induced parkinsonism.
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Side effects of antimuscarinic
agents
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Peripheral:
Dry mouth,
constipation, tachycardia, increased
intraocular
pressure, blurred
vision, urinary retention,increased
skin temperature
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CNS:
Drowsiness, mental
slowness, delusions, mood changes,
confusion.
Side Effects ( cont.)
 Prolonged
use of trihexyphenidyl produces
involuntary movements & dependence
Contra-indications of
antimuscarinic agents
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Prostatic Hypertrophy
Obstructive G.I.T disease( paralytic
ileus)
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Glaucoma
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Combination with TCA or certain
antihistamines