Transcript Drugs for Parkinson`s disease

Drugs for Parkinson’s
disease
Pathogenesis of Parkinson’s
disease
Parkinson’s disease (PD) is a
progressive disorder of movement
that occurs mainly in the elderly. The
chief symptoms are:
H ypokinesia
R igidity
T remors
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Parkinson’s Disease
A degenerative and progressive disorder
Associated with neurological consequences of
decreased dopamine levels produced by the
basal ganglia (substantia nigra)
Dopamine is a neurotransmitter found in the
neural synapses in the brain
Normally, neurones from the SN supply
dopamine to the corpus striatum (controls
unconscious muscle control)
Initiates movement, speech and self-expression
Balance, posture, muscle tone and involuntary
movement depends on the roles of dopamine
(inhibitory) and acetylcholine (Ach: excitatory)
Basis to exploit by drugs:


Restore dopamine function
Inhibit Ach within corpus striatum
Consequences of dopamine
reductions
Tremors – hands and head develop involuntary
movements when at rest; pin-rolling sign (finger
and thumb)
Muscle rigidity – arthritis-like stiffness, difficulty
in bending or moving limbs; poker face
Bradykinesia – problems chewing, swallowing
or speaking; difficulty in initiating movements
and controlling fine movements; walking
becomes difficult (shuffle feet)
Postural instability – humped over
appearance, prone to falls
Clinical Presentation
Altered body image
(depression)
Poor balance
Bradykinesia (slow movement)
Bradyphrenia (slowness of
thought)
Constipation
Dribbling/drooling
Dyskinesias (involuntary
movements)
Dysphagia (difficulty
swallowing
Dystonia (pain spasms)
Excessive sweating (impaired
thermoregulation)
Festinating gait
Hallucinations (visual)
Postural hypotension
Restless leg syndrome (leg
aches, tingle, or burn)
Rigidity
Sleep disturbance
Slurring/slowing of speech
Tremor
Causes
number of factors:
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Environmental – toxins
Free Radicals – there is a increase in postmortem brain sections
Aging – age related decline in dopamine
production
Genetic – genes encode for
-α-synuclein
-Carboxy terminal hydroxylase of parkin &
ubiquitin
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Action of MPTP
1-methyl 4-phenyl 1,2,3,6tetrahydropyridine (MPTP) causes
irreversible destruction of nigrostriatal
dopaminergic neurons in various
species, and produces a PD-like state in
primates.
MPP is taken up by the
+
MPTP
MAO-B
inhibit
Selegiline
MPP+
dopaminergic neurons, selective
in destroying nigrostriatal
neurons. It inhibits
mitochondrial oxidation
reactions, producing oxidative
stress.
Medication Rational
Replace depleted levels of dopamine
Stimulate the nerve receptors enabling
neurotransmission
Increase the effect of dopamine on nerve
receptors (agonist)
Counteract the imbalance of Ach and
Dopamine
The Drugs:

Dopaminergic drugs (improving dopamine
functioning)
Levodopa
Dopamine receptor agonists
Amantadine
Selective monoamine oxidase B inhibitors
Catechol-O-methyltransferase inhibitors

Antimuscarinic drugs (Ach inhibitors)
Drugs Treatment of Parkinson’s
Disease
Dopamine precursor –levodopa
Peripherally dopa decarboxylase inhibitor
(carbidopa)
COMT inhibitors ( entacapone, tolcapone)
Drugs that mimic the action of dopamine
( bromocriptine, cabergoline, ropinirole,
pramipexole)
Drugs Treatment of Parkinson’s
Disease
MAO-B inhibitors (e.g. selegiline)
Drugs that release dopamine (e.g.
amantadine)
Centrally acting antimuscarinic
drugs (e.g. trihexyphenidyl,
procyclidine, orphenadrine,
benztropine)
Levodopa
Mechanism:
(1) Because dopamine does not cross the
blood-brain barrier levodopa, the
precursor of dopamine, is given instead.
(2) Levodopa is formed from L-tyrosine
and is an intermediate in the synthesis
of catecholamines.
Levodopa
Mechanism:
(3) Levodopa itself has minimal
pharmacologic activity, in contrast to its
decarboxylated product, dopamine.
(4) Levodopa is rapidly decarboxylated in
the gastrointestinal tract. Prior to the
advent of decarboxylase inhibitors
(carbidopa), large oral doses of levodopa
were required; thus, toxicity from
dopamine was a limiting factor.
Levodopa
Pharmacokinetics:
(1) Levodopa is well absorbed from the small
bowel; however, 95% is rapidly
decarboxylated in periphery.
(2) Peripheral dopamine is metabolized in the
liver to dihydroxyphenylacetic acid
(DOPAC) and homovanillic acid (HVA),
which are then excreted in urine.
Levodopa
Pharmacologic effects:
The effects on bradykinesia and rigidity
are more rapid and complete than the
effects on tremor. Other motor defects in
PD improve. The psychological wellbeing of patient is also improved.
Levodopa
Pharmacologic effects:
Tolerance to both beneficial and adverse
effects occurs with time. Levodopa is
most effective in the first 2-5 years of
treatment.
wearing off effect
On-off phenomenon
Levodopa
Adverse effect:
Principal adverse effects include:
(1) Anorexia, nausea, and vomiting upon
initial administration, which often limit
the initial dosage.
(2) Cardiovascular effects, including
tachycardia, arrhythmias, and
orthostatic hypotension.
Levodopa
Adverse effect:
(3) Mental disturbances, including vivid
dreams, delusions, and hallucination.
(4) Hyperkinesia
(5) On-off phenomena
Levodopa
Adverse effect:
Sudden discontinuation can result in
fever, rigidity, and confusion. The drug
should be withdrawn gradually over 4
days.
Levodopa
Drug interactions:
Vit B6 reduces the beneficial effects of
Levodopa by enhancing its extracerebral
metabolism.
Phenothiazines, reserpine, and
butyrophenones antagonize the effects of
levodopa because they lead to a junctional
blockade of dopamine action.
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.
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
Long-term trials showed that the
combination of selegiline and levodopa
was more effective than levodopa along in
relieving symptoms and prolonging life.
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COMT- inhibitors (entacapone)
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MoA: inhibits the breakdown of levodopa
Pharmacokinetics: variability of absorption, extensive
first-pass metabolism, short half-life
Adverse effects: dyskinesias, hallucinations
Amantadine
Therapeutic uses and mechanism of
action
Amantadine is an antiviral agent used in
the prophylaxis of influenza A2 .
It improve parkinsonian symptoms by
stimulating the release of DA from
dopaminergic nerve terminals in the
nigrostriatum and delaying DA reuptake.
Anticholinergic agents
Mechanism:
Since the deficiency of dopamine in the
striatum augments the excitatory cholinergic
system in the striatum, the blockade of this
system by anticholinergic agents helps to
alleviate the motor dysfunction.
Improvement in the parkinsonian tremor is
more pronounced than improvement in
bradykinesia and rigidity.
Therapeutic uses:
Although not as effectives as levodopa, it
may have an additive therapeutic effect at
any stage of the disease when taken
concurrently.
Adverse effects:
Mental confusion and hallucinations.
It can occur as can peripheral atropine-like
toxicity (e.g. cycloplegia, urinary retention,
constipation)
Huntington’s Chorea
Inherited autosomal dominant disorder
Error in huntingtin gene
Synthesis of huntingtin protein (repeats of
polyglutamine cause excitotoxicity and
apoptosis in cortex and striatum)
Degeneration of GABAergic neurons in the
striatum
Huntington’s Chorea
Huntington’s Chorea
Dance like movements of limbs
Rhythmic movements of tongue and face
Dementia
Progressive brain degeneration
Huntington’s Chorea
Tx
Chlorpromazine
Haloperidol
Olanzapine
Alzheimer’s disease
Progressive memory loss
Disordered cognitive functions
Reduced verbal fluency
Bedridden as disease progresses
Complications of immobility
Alzheimer’s disease
Amyloid plaque (extracellular deposits of
β-amyloid protein)
Intraneuronal neurofibrillary tangles
(aggregates of highly phosphorylated
neuronal protein)
Loss of cholinergic neurons in brain
(originates from nucleus basalis in
forebrain and project to frontal cortex and
hippocampus)
Alzheimer’s disease Tx
Anticholinesterases
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Tacrine (hepatotoxic)
Donepezil
Rivastigmine
Galantamine
Nootropics
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Anti-oxidants
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NMDA antagonist
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Memantine
Piracetam
Vit. A, C,
Zinc, Selenium
Miscellaneous
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Statins
Ibuprofen
Multiple Sclerosis
Demylenation in brain, spinal cord, optic
nerves
autoimmune
Weakness, numbness, spastic
paraparesis, diplopia, sphincter
disturbances
Tx
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Interferon beta-1b
Natalizumab
Baclofen, Diazepam (for spasticity)
Amyotropic Lateral sclerosis
Neurodegenerative dis. of motor neurons
Muscle wasting and atrophy
Defective superoxide dismutase (defective
scavenging of superoxide free radicals)
Defective glutamate uptake (excitotoxicity)
Spontaneous twitching of motor units
Difficulty in chewing & swallowing
Respiratory failure & death within 5 yrs
Tx – Riluzole (↓es glutamate release)
Psychostimulants
Amphetamine & Methylphenidate
(release NA & DA in brain) -ADHD
Modafinilinc alertness & keep awake
CaffeineMigraine, allay fatigue, apnoea in
premature infants
MCQs
Q1. In parkinsonism, Carbidopa acts as:
A. Dopamine agonist
B. Dopamine precursor
C. Peripheral decarboxylase inhibitor
D. Dopamine reuptake blocker
Ans- C
Q2. In parkinsonism, Entacapone acts as:
A. Dopamine agonist
B. Dopamine precursor
C. COMT inhibitor
D. Dopamine reuptake blocker
Ans- C
Q 3.Which one of the following clinical
features of parkinsonism is benefited
more by central anticholinergic drugs?
A. Hypokinesia
B. Rigidity
C. Tremors
D. Festinating gait
Ans C
Q 4.Which one of the following clinical
features of parkinsonism is resolved
first by levodopa?
A. Hypokinesia
B. Rigidity
C. Tremors
D. Festinating gait
Ans
A and B
Q5. Tolcapone is withdrawn due to
A. Cadiotoxicity
B. Nephrotoxicity
C. Carcinogenecity
D. Hepatotoxicity
Ans D
Thank you
Bibliography
Essentials of Medical Pharmacology -7th edition by KD Tripathi
Goodman & Gilman's the Pharmacological Basis of
Therapeutics 12th edition by Laurence Brunton (Editor)
Lippincott's Illustrated Reviews: Pharmacology - 6th edition
by Richard A. Harvey
Basic and Clinical pharmacology 11th edition by Bertram G Katzung
Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
Principles of Pharmacology 2nd edition by HL Sharma and KK
Sharma
Review of Pharmacology by Gobind Sparsh
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