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Neuropharmacology I Parkinson’s Disease and Movement Disorders: Revision

Standaert 1 
March 2005 
Neuropharmacology I 
Parkinson’s 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. 
• Parkinson’s disease is by far the most common disorder of movement, 
affecting >3% of individuals over the age of 65. 
• Other common movement disorders include: 
¾ Tremor - rest, postural or intention 
¾ Chorea - typified by Huntington’s chorea, an autosomal 
dominant disorder 
¾ Dystonia 
¾ Tic disorders - Tourette’s syndrome 
Pharmacological Approaches to Treatment of Parkinson’s Disease 
• Symptomatic treatments 
¾ most are based on dopamine augmentation 
• “Neuroprotective” treatments 
¾ none presently proven 
¾ most current studies are based on “oxidative stress 
hypothesis” 
Parkinson’s disease 
• Cardinal signs of PD are: 
¾ rest tremor 
¾ bradykinesia 
¾ rigidity 
¾ 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 Parkinson’s disease is unknown. Rare 
families with genetic mutations causing Parkinson’s 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 
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. David StandaertStandaert 2 
March 2005 
Biochemistry of Dopamine: 
• Synthesis, storage and release 
¾ synthesized from tyrosine by tyrosine hydroxylase 
¾ stored in presynaptic vesicles by active transport mechanism 
(blocked by reserpine) 
¾ Released by calcium ion-dependent exocytosis 
• Termination of action and catabolism 
¾ reuptake (blocked by cocaine, amphetamine) 
¾ catabolism - COMT and MAO 
¾ catabolic process may lead to the production of toxic free 
radicals 
• Dopamine receptors 
¾ Pharmacological classification - based on effect on 
intracellular cAMP - D1 stimulates, D2 inhibits 
¾ 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 
¾ d1 and d2 are abundant in striatum
¾ 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). 
¾ Essential feature is the differential effect of DA on the output of 
striatal neurons Standaert 3 
March 2005 
¾ Cholinergic interneurons have an important regulatory role 
D1
SP
GABA
D2
ENK
GABA
Ach
NOS
Direct
Pathway
Indirect
Pathway
Striatum
DA
SNpc
The “Oxidative Stress” hypothesis 
Dopamine + O2
 + H2
O DOPAC + NH2
 +H2
O2
MAO
• 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 Parkinson’s 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: 
¾ peripheral: 
ƒ nausea and vomiting 
ƒ hypotension 
ƒ reduced by carbidopa 
¾ central: 
ƒ 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: 
¾ older drugs: ergot derivatives 
ƒ bromocriptine - d2,3,4 agonist, partial d1/d5 antagonist 
ƒ pergolide - d1-d5 agonist 
¾ newer drugs: non-ergots 
ƒ pramipexole - selective d2/d3 agonist 
ƒ ropinerol - selective d2/d3 agonist 
¾ Newer drugs are much better tolerated than older agents, and 
have expanded the use of this category of medications. 
• Adverse effects 
¾ Most adverse effects related to dopaminergic actions and 
similar to levodopa 
¾ Pramipexole and Ropinirole produce less nausea 
¾ Both ergot and non-ergot drugs can lower blood pressure and 
cause peripheral edema. 
¾ Pergolide recently linked to cardiac valve fibrosis. 
¾ All of the agonists, as well as levodopa, can cause 
somnolence. 
• Dopamine agonists vs. levodopa/carbidopa – which to use? 
¾ Recent evidence suggests that use of an agonist rather than 
levodopa leads to a reduced incidence of wearing off and 
dyskinesias 
¾ But this comes at a price – increased side effects 
(somnolence, hallucinations, peripheral edema). 
¾ 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 
L-DOPA
DA
AADC
DA
3MT
COMT
Periphery Brain
COMT
3-O-MD
L-DOPA
MAO
DOPAC
AADC
carbidopa
entacapone
tolcapone X
X
• Tolcapone 
¾ First agent released 
¾ Favorable kinetics – relatively long half life, both central and 
peripheral inhibition of COMT 
¾ After released to market, associated with 3 fatal cases of 
fulminant hepatic failure – use now limited to patients not 
responding to other treatments. 
• Entacapone 
¾ No effect unless administered together with levodopa 
¾ Less favorable kinetics- short half life, does not cross blood 
brain barrier 
¾ 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 Parkinson’s 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. 
¾ More than a dozen members of this family are marketed. 
¾ They are distinguished by their potency at dopaminergic 
blockade, and the degree of sedation which they produce. 
Examples of antipsychotics 
trade name typical daily
dose 
extrapyramidal 
effects 
sedation 
chlorpromazine Thorazine 200-800 + +++
thioridizine Mellaril 150-600 + +++
thiothixine Navane 5-30 ++ ++
haloperidol Haldol 2-20 +++ +Standaert 7 
March 2005 
¾ Primary clinical use is treatment of psychotic illness. 
¾ Also used for nausea, GI disorders (metaclopramide, 
prochlorperazine). 
¾ They can produce a variety of movement disorders: 
¾ All are capable of producing Parkinsonism or akathisia (a 
feeling of restlesness) 
¾ 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. 
¾ 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. 
¾ 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 
Striatum
(Caudate and putamen)
SNpc
GPe STN
GPi / SNpr
Thalamus
Cerebral Cortex
Glu +
Glu +
Glu +
GABA -
GABA -
GABA -
GABA -
DA
Basal Ganglia in Parkinson’s Disease. Dark lines reflect increased activity, 
while grey lines reflect decreased activity. 
Striatum
(Caudate and putamen)
SNpc
GPe STN
GPi / SNpr
Thalamus
Cerebral Cortex
Glu +
Glu +
Glu +
GABA -
GABA -
GABA -
GABA -
DA