Neuropharmacology Parkinson Disease and Movement Disorders

Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology

Instructor: Dr. David Standaert
Standaert 1
March 2005
Neuropharmacology I
Parkinsons Disease and Movement Disorders
What are movement disorders?
These are a diverse group of neurologic disorders in which the normal
functions of the motor system are impaired.
Parkinsons disease is by far the most common disorder of movement,
affecting >3% of individuals over the age of 65.
Other common movement disorders include:
Tremor - rest, postural or intention
Chorea - typified by Huntingtons chorea, an autosomal
dominant disorder
Dystonia
Tic disorders - Tourettes syndrome
Pharmacological Approaches to Treatment of Parkinsons Disease
Symptomatic treatments
most are based on dopamine augmentation
Neuroprotective treatments
none presently proven
most current studies are based on oxidative stress
hypothesis
Parkinsons disease
Cardinal signs of PD are:
rest tremor
bradykinesia
rigidity
impairment of postural reflexes.
Pathologically, PD is characterized by a loss of dopaminergic neurons
from the substantia pars compacta (SNpc) in the midbrain, with the
presence of Lewy bodies. This results in a loss of dopaminergic
innervation of the striatum (caudate and putamen).
The cause of most cases of Parkinsons disease is unknown. Rare
families with genetic mutations causing Parkinsons have been identified,
but most cases are sporadic. Increasing evidence implicates a) the
protein alpha-synuclein and b) the role of environmental exposures,
including pesticides.
Some other, relatively rare disorders may give rise to similar clinical
features - examples include striatonigral degeneration, progressive
supranuclear palsy, and multiple cerebral infarcts. In general, these do
not respond as well to medication as idiopathic PD
Standaert 2
March 2005
Biochemistry of Dopamine:
Synthesis, storage and release
synthesized from tyrosine by tyrosine hydroxylase
stored in presynaptic vesicles by active transport mechanism
(blocked by reserpine)
Released by calcium ion-dependent exocytosis
Termination of action and catabolism
reuptake (blocked by cocaine, amphetamine)
catabolism - COMT and MAO
catabolic process may lead to the production of toxic free
radicals
Dopamine receptors
Pharmacological classification - based on effect on
intracellular cAMP - D1 stimulates, D2 inhibits
Molecular cloning has revealed that there are 5 DA receptor
proteins. These each have 7 transmembrane domains, and
are part of the superfamily of G-protein coupled receptors
d1 and d2 are abundant in striatum
d5 (D1 type) and d3, d4 (D2 type) are primarily extrastriatal
Dopamine and the etiology of Parkinsonism: (see Reference Section at
the end of the handout).
Essential feature is the differential effect of DA on the output of
striatal neurons
Standaert 3
March 2005
Cholinergic interneurons have an important regulatory role
Striatum
D1
SP
GABA
DA
SNpc
Ach
NOS
Direct
Pathway
D2
ENK
GABA
Indirect
Pathway
The Oxidative Stress hypothesis
Dopamine + O2 + H2O
MAO
DOPAC + NH2 +H2O2
Proposes that dopamine cell death is caused by the reactive free radicals
produced by the catabolism of dopamine
Suggests that treatments which reduce catabolism of dopamine should
slow the progress of the disease
Treatment of Parkinsons disease

Levodopa
Most effective agent for the treatment of the symptoms of PD
Metabolic precursor of dopamine - acts by augmenting the effectiveness
of remaining nigrostriatal neurons.
Converted to dopamine by L-aromatic acid decarboxylase
Almost always administered in combination with carbidopa, an inhibitor of
the decarboxylase which does not cross the blood-brain barrier
Onset of action is rapid - 30 - 60 min - but affected by gastric pH and
emptying. Uptake from GI system and transport into brain by active
mechanism - other aromatic amino acids compete
Duration of action is variable, and is greatly affected by extent of disease.
Declining duration of effect is the primary limitation of long-term levodopa
therapy.
Standaert 4
March 2005
Available in both standard (e.g., Sinemet 10/100, 25/100, 25/250) and

controlled-release formulation (e.g., Sinemet CR 50/200)
Adverse effects:
peripheral:
nausea and vomiting
hypotension
reduced by carbidopa
central:
psychosis
Major limitation of long term use is the induction of motor complications
wearing off and dyskinesia.
Dopamine agonists
Act directly at dopamine receptors. Four currently available:
older drugs: ergot derivatives
bromocriptine - d2,3,4 agonist, partial d1/d5 antagonist
pergolide - d1-d5 agonist
newer drugs: non-ergots
pramipexole - selective d2/d3 agonist
ropinerol - selective d2/d3 agonist
Newer drugs are much better tolerated than older agents, and
have expanded the use of this category of medications.
Adverse effects
Most adverse effects related to dopaminergic actions and
similar to levodopa
Pramipexole and Ropinirole produce less nausea
Both ergot and non-ergot drugs can lower blood pressure and
cause peripheral edema.
Pergolide recently linked to cardiac valve fibrosis.
All of the agonists, as well as levodopa, can cause
somnolence.
Dopamine agonists vs. levodopa/carbidopa which to use?
Recent evidence suggests that use of an agonist rather than
levodopa leads to a reduced incidence of wearing off and
dyskinesias
But this comes at a price increased side effects
(somnolence, hallucinations, peripheral edema).
There is also some recent evidence to suggest that the choice
of drug may have an effect on the rate of progression of the
disease although interpretation of these studies remains
controversial.
COMT inhibitors
New class of drugs which act by inhibiting the breakdown of levodopa.
When given alone have no effect on PD, but when combined with
levodopa increase the duration of action
Standaert 5
March 2005
Periphery
Brain
3-O-MD
entacapone
tolcapone
COMT
MAO
AADC
L-DOPA
carbidopa
DOPAC
AADC
L-DOPA
DA
COMT
3MT
DA
Tolcapone
First agent released
Favorable kinetics relatively long half life, both central and
peripheral inhibition of COMT
After released to market, associated with 3 fatal cases of
fulminant hepatic failure use now limited to patients not
responding to other treatments.
Entacapone
No effect unless administered together with levodopa
Less favorable kinetics- short half life, does not cross blood
brain barrier
A useful and relatively safe treatment for levodopa-associated
wearing off.
Other Agents
Selegiline: Irreversible inhibitor of the enzyme MAO-B, the subtype of
MAO responsible for most central metabolism of dopamine. Symptomatic
benefit arises from reduction in the rate of dopamine breakdown;
magnitude of this effect is modest. Has been proposed that selegiline
might have neuroprotective properties, slowing the death of dopaminergic
neurons by inhibiting the generation of toxic free radicals which are a
byproduct of dopamine catabolism. Despite initial enthusiasm, a recent
multicenter trial (the DATATOP study) did not demonstrate any protective
effect of selegiline. Metabolized to amphetamine and methamphetamine
- may cause insomnia. At doses used for PD (10 mg/day) does not inhibit
MAO-A, and thus does not require dietary restrictions.
Anticholinergics: Trihexyphenidyl is the most widely used agent in this
class; all have similar profile of actions and adverse effects. Rarely
satisfactory as primary therapy for PD, except in mild cases. Used most
Standaert 6
March 2005
often as adjunct to levodopa. Side effects reflect antimuscarinic actions.

Most significant are drowsiness and confusion, which are particularly
prominent in the elderly and those with pre-existing cognitive impairment
Amantadine: Developed as an antiviral; Mechanism uncertain, although
has both anticholinergic and dopamimetic actions
Approach to the treatment of Parkinsons disease

The treatment of early PD is changing rapidly with the availability of new
drugs
Levodopa/carbidopa is very effective, but there is increasing interest in
delaying the use of this drug as long as possible in order to reduce later
complications (wearing off and dyskinesias)
New DA agonists are now used as primary therapy in many patients,
especially younger onset.
When wearing off and dyskinesias develop, both COMT inhibitors and
dopamine agonists are useful
Dopamine receptor antagonists
Several drugs which are antagonists of central dopamine receptors are
widely used clinically. These are often grouped together as
antipsychotics since their principle application is in the treatment of
psychiatric illness.
These drugs may be used to treat some types of movement disorders; in
addition, their use may induce temporary or permanent abnormalities of
movement.
More than a dozen members of this family are marketed.
They are distinguished by their potency at dopaminergic
blockade, and the degree of sedation which they produce.
chlorpromazine
thioridizine
thiothixine
haloperidol
Examples of antipsychotics
trade name
typical daily
extrapyramidal
dose
effects
Thorazine
200-800
+
Mellaril
150-600
+
Navane
5-30
++
Haldol
2-20
+++
sedation
+++
+++
++
+
Standaert 7
March 2005
Primary clinical use is treatment of psychotic illness.

Also used for nausea, GI disorders (metaclopramide,
prochlorperazine).
They can produce a variety of movement disorders:
All are capable of producing Parkinsonism or akathisia (a
feeling of restlesness)
Each of them may cause dystonia (abnormal postures of the
face neck, trunk, or limbs. This effect is usually sudden in
onset and short-lived (hours to days). It often responds to
anticholinergic treatments.
All may also produce tardive dyskinesia, a choreiform disorder
that most often affects the face and mouth and may persist for
years even if the medication is discontinued. This effect is
difficult to treat.
Rarely, they may also cause neuroleptic malignant syndrome
- rigidity, hyperthermia, obtundation, elevated serum CK. This
most often occurs most often with high-potency, long acting
phenothiazines. This may be fatal if untreated - dantrolene,
bromocriptine useful
Atypical antipsychotics New class of drugs which are dopamine antagonists but do not produce
extrapyramidal side effects
clozapine - d4 antagonist, effective in treatment of refractory psychosis.
Numerous adverse effects, including neutropenia (which may be fatal)
and seizures (1-2%). Requires intensive monitoring.
Risperidone, olazepine, quetiapine - newer, less selective, but more
favorable adverse effect profile.
Standaert 8
March 2005
Reference section: A model of the basal ganglia. For more information about
these models, see Albin RL, Young AB, Penney JB (1989) The functional
anatomy of basal ganglia disorders. Trends Neurosci 12:366-375.
Normal Basal Ganglia
Cerebral Cortex
Glu +
Glu +
Striatum
Thalamus
(Caudate and putamen)
GABA DA
GPe
GABA -
STN
GABA -
SNpc
GABA -
Glu +
GPi / SNpr
Basal Ganglia in Parkinsons Disease. Dark lines reflect increased activity,

while grey lines reflect decreased activity.
Cerebral Cortex
Glu +
Glu +
Striatum
Thalamus
(Caudate and putamen)
GABA DA
GPe
GABA -
STN
GABA -
SNpc
GABA -
GPi / SNpr
Glu +

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Harvard-MIT Division of Health Sciences and Technology

HST.151: Principles of Pharmocology

Cholinergic interneurons have an important regulatory role

The Oxidative Stress hypothesis

DOPAC + NH2 +H2O2

Treatment of Parkinsons disease

Available in both standard (e.g., Sinemet 10/100, 25/100, 25/250) and

often as adjunct to levodopa. Side effects reflect antimuscarinic actions.

Approach to the treatment of Parkinsons disease

Primary clinical use is treatment of psychotic illness.

(Caudate and putamen)

Basal Ganglia in Parkinsons Disease. Dark lines reflect increased activity,

(Caudate and putamen)

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