Drugs Used to Treat Parkinson’s

Disease
 Parkinson’s Disease
• Parkinson’s disease – is a
disorder caracterized by:

• Resting tremor
• Skeletal muscle rigidity
• Bradikinesia (poverty of
movement)
 Parkinson’s Disease
subtypes
• Idiopathic Parkinson’s disease –
Primary (unknown origin)

•Parkinsonism – Secondary (known

origin) – drugs, stroke, trauma

•Familial – (genetic origin)

Subclinical hypodopaminergic state - loss
of 80-90% of DA neurons before
symptoms present (roughly 20 years)
DA neuronal loss not from Basal Ganglia -
loss of dopaminergic input to Striatum
Neuronal death observed in Substantia Nigra
(Pars Compacta) and the Nigrastriatal bundle
A9 DA System
DA content decrease in extra pyramidal
motor areas of basal ganglia
Caudate and putamen
Pat
Pathology of Parkinson’s Disease

Midbrain (substantianigra
Midbrain(substantia nigra)
Midbrain (substantia nigra)
Substantia Nigra, Normal. Pigment Loss Is S
• 1 % Prevalence in Adult Population- Age
65 and Older
• As many as 10% aged 60 and older may
have undiagnosed early stages of the
disease
• Increased onset due to
– Transitory Ischemic Attacks (TIA)
– Brain Damage
– Drug Abuse

• 1 ½ times more prevalent in women

Cardinal Symptoms
Bradykinesia - Slowness and
poverty of movement
Muscle “Cogwheel” rigidity
Resting tremor
Abates during voluntary
movement
Shuffling gait
Impairment of postural balance
Posture disturbance in
Parkinson‘s disease
Secondary Symptoms
Dementia
Visuospatial deficits, impaired
attention and executive function
Anxiety
Sleep disturbances
Sexual dysfunction
Abnormal theromregulation
Sites of Action of
Parkinson’s Disease Drugs
Drugs Treatment of Parkinson’s
Disease
Drugs that replace dopamine (e.g. levodopa, usually used
concomitantly with peripherally acting dopa decarboxylase
inhibitor, e.g. Carbidopa, benserazide)

Drugs that mimic the action of dopamine (e.g. bromocriptine,

pergolide, ropinirole) and others in development)
MAO-B inhibitors (e.g. selegiline)
Drugs that release dopamine (e.g. amantadine)
Acetylcholine antagonists (e.g. artane)
COMT Inhibitors - Entacapone (Comtan®), Tolcapone (Tasmar®)
Pharmacotherapy of PD
Levodopa preparations:
Carbidopa/levodopa
Sinemet®
Sinemet CR®
Parcopa™
Stalevo®
Dopamine agonists
Apomorphine (Apokyn®)
Pramipexole (Mirapex®)
Ropinirole (Requip®)
Rotigitine (Neupro®)
Parlodel (Bromocriptine®)*
Pergolide (Permax®)*
Pharmacotherapy of PD
NMDA Antagonists
Amantadine (Symmetryl®)
MAO-B Inhibitors
Selegeline (Eldepryl® or Deprenyl)
Zydis Selegeline (Zelapar®)
Rasagiline (Azilect®)
Carbidopa
Anticholinergic agents
Benztropine (Cogentin®)
Trihexyphenidyl (Artane®)
COMT Inhibitors
Entacapone (Comtan®)
Tolcapone (Tasmar®)
 Therapy

Levodopa (L-dopa)
Remains the most effective drug for PD
Used since the 1960s
Must be actively transported across gut and
blood brain barrier
Rapidly decarboxylated to dopamine in the
periphery
Pulsatile receptor stimulation (due to short
half-life) implicated in possible long term
motor complications
 Therapy
Levodopa (L-dopa)
Rapid oral absorption – 95%
converted to DA in plasma
DA doesn’t cross BBB from plasma
into CNS
Precursor L-dopa does cross BBB
via active transport system
(about 5%)
Most effective current treatment
Problems Associated with L-
Dopa
Decrease high levels of DA in
periphery that can cause nausea
by inhibiting dopa decarboxylase
which converts dopa to DA
Carbidopa, Benserazide – Peripheral
decarboxylase inhibitor
Carbidopa/ levodopa combo reduces
the amount necessary for therapeutic
level of L-Dopa by 75%
Problems Associated with L-
Dopa
Even with carbidopa, much of L-Dopa converted
by COMT (in GI tract and Liver) to inactive
metabolic by-product
Recent addition of peripheral COMT inhibitors
to standard treatment – Talcapone and
Entacapone
Increase the half-life and prolong the
effects of L-Dopa
– A few cases of serious liver toxicity
attributed to Talcapone (1998) –
Entacapone too new to say (2000)
 L-dopa – side effects
Becose the peripheraly dopamine
generation
Nausea, vomiting
Vasodilation
Effects arising from excessive central
dopamine generation
Diskinetic involuntary movements
(face, neck)
Akatisia (restlessness)
Psychological disturbance –
hallucinations, confusion
 Limitations to L-dopa
Therapy
Becomes less effective as time goes on
“on-off”/ “wearing off” effect
between 1-5 yrs patients on L-dopa therapy
gradually become less responsive
Results in hypermovement, then hypomovement,
then no movement (akinesia)
Taking doses more often, or taking large doses
results in dyskinesias (uncontrolled movements)
and may result in psychiatric complications.
On-off effect possibly related to DA neurons inability
to synthesize and store DA
 DA Receptor Agonists
Bind to postsynaptic striatal neurons
Possible use for early and late stages
Four currently available
Bromocriptine (1978) and Pergolide (1989)
Derived from lysergic acid, structurally similar
to DA
– Marginally effective with numerous side
effects
– Affinity for D2 receptors (Inhibitory)
 DA Receptor Agonists
Pramipexole, and Ropinirole (1997)
Affinity for D2, D3 receptors (Inhibitory)
Indicated for use in early onset
Increased safety and efficacy over older agonists
(although risk of sleep attacks)
Long half lives may partially explain reduction in
on-off effect
Side effects:
hallucinations,
insomnia,
nausea,
somnolence and dizziness.
Long term use of DA agonists results in increased
sensitivity of DA receptors (sensitization)
 DA Releasers
AMANTADINE
Stimulate release og dopamine stored
in nerve terminals
Reduce reuptake of released dopamine
intzo the presinaptic neuron

Well absorbed from the gut

Variable but long half-life
Excreted unchanged by the kidney
 DA Releasers
AMANTADINE
Side effects:
– Ankle oedema
– Postural hypotension
– Insomnia or hallucinations – high
dose
– Livedo reticularis (skin
vasoconstriction caused by local
catecolamine release)
SELECTIVE MONOAMINE OXIDASE B
INHIBITORS
SELEGILINE
Selectively inhibits MAO-B (preferential
affinity for DA neurons) – responseble for
the intraneural degradation
Prolongs the duration of action of levodopa
and reduses the levodopa dosage
requirement bu 1/3
Used in newly diagnosed, younger patients
Appears to slow disease progression and
delay need for L-Dopa
SELECTIVE MONOAMINE OXIDASE B
INHIBITORS
SELEGILINE
Completely absorbed from the gut
Has a short half-life
Metabolized to several by-products, including
amphetamine and methamphetamine
In combo with L-Dopa, may result in increased
morbidity after 5 years
Side effects:
Transient nausea
Diyyisness, lightheadedness
Agitation, confusion, hallucination (amphetamine
metabolites)
 CATECOL – O – METHYL
TRANSFERASE INHIBITORS
ENTACAPONE
COMT – responsable for break down of
between 10-30% of levodopa
Inhibition of COMT in conjunction with a
dopamine decarboxylase inhibitors –
doubles the half-life of levodopa
Entacapone does not cross the blood-brain
barrier
Rapidely absorbed from the gut
Metabolized in liver
Has a short half-life
Side effects: nausea, diarrhoea,
halluciantion, dyskinesia
Muscarinic Receptor
Antagonists
TRIHEXIPHENIDYL
ORPHENADRYL
PROCYCLIDINE
Block central muscarinic receptors –
restore the balance between
cholinergic and dopaminergic
activity by reducind the former
Have little effect on bradikinesia
Less effective than levodopa for
treating tremor and rigidity
Muscarinic Receptor
Antagonists
Pharmacokinetics
Oral absorbtion is moderate
Most of these drugs undergo
extensive hepatic metabolism with
intermediate to long half-life
High lipid solubility ensures ready
transfere across the blood-brain
barrier
Side effects: reduce saliva
production, confusion (in elderly)
 DRUGS USED IN
SPASTICYTY DISORDERS
SPASTICYTY– sustained muscle tone or tension
which is often associated with an increase in stretch
reflexes
The increase in muscle tone can arise from continued
spinal reflex activity in the absence of inhibitory
input from motor cortex – stroke or multiple sclerosis
Is often associated with partial or complete loss of
voluntary movement and can produce painful and
deforming contracture
Primary site of action of drugs for sparticity are:
Spinal reflexes
The release of Ca’’ in the muscle fibers
 DRUGS USED IN
SPASTICYTY DISORDERS

DIAZEPAM
Inhances spinal inhibitory
pathways by facilitating GABA –
mediated opening of Cl-
channels
Sides effects: sedation –
inhibitori activity in higher
centres
 DRUGS USED IN
SPASTICYTY DISORDERS
BACLOFEN
Inhibits excitatory activity at mono
- and polisynaptic reflexes at the
spinal level
Agonist at GABA –B receptors
Reduces presynaptic Ca++ influx -
reducing excitatory
neurotransmitter release
Inhibition of the release of
substance P – analgezic effect
 DRUGS USED IN
SPASTICYTY DISORDERS
BACLOFEN - Pharmacokinetics
Absorbed rapidly from the gastro-intestinal
tract
It has a short half-life
Is eliminated largely in the urine in the
unchanged form
It can be given by intratraheal injection if
severe spasticity is resistant to oral therapy
Side effects: sedation, drowsiness, nausea,
confusion, dizziness, headache, hallucination
 DRUGS USED IN
SPASTICYTY DISORDERS
DANTROLENE -
Inhibits the release of Ca++ from
sarcoplasmatic reticulum of skeletal
muscle – impaire activations of the
contractile apparatus and relaxes the
muscle
In patients with spasticity may improve
functional capacity
Used for the tratment of malignant
hyperthermia
Adjuvant in neuroleptic malignant
syndrom
 DRUGS USED IN
SPASTICYTY DISORDERS
DANTROLENE – Pharmacokinetics
Well absorbed from the gut
Can also be given intravenously
It is metabolised in the liver
It has a variable and unpredictable half
life

Side effects: drowsiness, dizzines,

weakness, malais, hepatitis,
diarrhoea
 DRUGS USED IN
SPASTICYTY DISORDERS
TIZANIDINE
It is an alfa 2 – adrenoceptor agonist -
increase in excitatory amino acid and increase
presynaptic inhibitory of motor neurons
Inhibition is greatest in polysinaptic rather than
monosynaptic pathway
Inhibits the imidazoline receptors
Its action are both spinal and supraspinal
It inhibits descending noradrenergic pathways
but has anly 10% of antihypertensive activity of
clonidine
 DRUGS USED IN
SPASTICYTY DISORDERS
TIZANIDINE – Pharmacokinetics
Well absorbed from the gut
Undergoes extensive first-pass
methabolism
It has a short half life

Side effects: dry mounth,

drowsiness, tiredness, dizziness