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432 Chapter 16 Epilepsy
24) Which drug used for treating absence seizures is the neurologist referring to, and what is its
mechanism of action?
Ambreen has not returned to North Stradbroke Island in all this time—she is nervous about not
being close to the hospital. However, she now feels stable enough to leave Brisbane, and
decides to stay with Pavitar and help him with his pharmacy.
After4yearsonlamotrigineAmbreenisseizurefree,andsheplanstodiscussdiscontinuingher
medication with her doctor.
25) Can antiepileptic drug treatment be discontinued? How?
Pavitar and Ambreen stay together during this time. One thing troubles her—she would like to
have children but is afraid that there may be a chance she will pass her epilepsy on to them.
She thinks that perhaps her problems reside in her genes. Pavitar tells her there is nothing to
worry about; there is no danger that epilepsy can be passed on to her children.
26) Has Pavitar given her the right information? What would you say if you were her pharmacist?
Ambreen is also anxious about the dangers to the developing child if she had to take
antiepileptic medication during pregnancy.
27) How would you counsel Ambreen if you were her pharmacist?
Chapter 17
Neurodegenerative diseases
Useful terms for this topic
Bradykinesia: Slow or limited movement.
Dyskinesia: Impairment of voluntary movement
resulting in jerky or fragmented motion.
Lewy bodies: Spherical aggregates of proteins in
neuronal cell bodies in the substantia nigra.
Particularly abundant in brains of Parkinson’s disease
patients.
Nigrostriatal pathway: Neuronal pathway in brain
composed of dopamine-releasing neurons. Innervates
the striatum which is responsible for control of
movement. Death of these neurons is central to the
pathology of Parkinson’s disease.
Plaques and tangles: Protein aggregates that
accumulate in sufferers of Alzheimer’s disease—
thought to be involved in destroying brain function.
Tardive dyskinesia: Involuntary movements of the
tongue, jaw, and lips.
Substantia nigra: Area of brain containing cell bodies
of neurons in the nigrostriatal pathway.
Gerald, a smartly dressed 75-year-old man, sits in his
front room. He tries to get up when you enter. It is clear
that getting out of his chair unaided would be a struggle,
so you gesture to him to remain seated. He talks quietly,
in a monotone, and you move closer to hear what he has
to say. His facial expression is rigid—no movement, little
attempt at eye contact. He makes small ineectual waving
movements with his arms. You hand him his medication,
and he stiy, slowly, takes his pill, and just manages to
swallow it down with some water. You wonder how he
manages to keep his life together.
strength and intonation in his voice, turning to look at you
with a positive and lively expression on his face. He says:
‘I think I can try and get up now’. Pushing himself from the
chair with his hands he is perhaps a little sti, but he
quickly stands, straightens, and smiles. You see now that
he is a tall slender man, looking almost athletic, despite
his age. A moment’s hesitation and he takes several steps
forward, each more condent than the last: ‘I think I can
turn’. He makes a waving movement with one arm, as if to
get himself going, turns on the spot to face you, steps
forward, and reaches out to shake your hand. His
handshake is rm, and he squeezes very hard. When you
inch he makes a small laugh, as if to say, ‘See, I still have
strength, I am OK’.
Looking at Gerald you have to remind yourself that this
is the same person who a short while ago was almost
immobilized in his chair. You know that a particular
cluster of cells in his brain have died, and will never
come back, meaning (as explained below) that he is
lacking sufficient dopamine in the part of his brain
required for control of movement. You know that when
he took his pill he was getting a compound into his
brain that would be turned into dopamine, restoring
levels of this neurotransmitter for a while, and so
restoring his control of movement. As you talk, he tells
you what will happen to him in the hours ahead, how
he has a period of normality, then with the drug effect
reaching its peak he will start to have movements he
doesn’t want—some bobbing and ducking and
weaving. As the drug effect wears off, his immobility
and stiffness will return, and once again he will be the
434 Chapter 17 Neurodegenerative diseases
disabled man you saw sitting in his chair when you
entered.
is man has Parkinson’s disease, which is the second
most common neurodegenerative disorder—the most
common being Alzheimer’s disease. Parkinson’s disease
is mainly a disease with late onset, aecting
approximately 1% of the population over 65 years of age.
Our patient Gerald is typical. However, about 5% of cases
are diagnosed in patients under 40, as is the case with
Andreas, the ctional patient in Workbook 14. Parkinson’s
disease is a progressive disorder, meaning that cells
continue to die, the patient’s condition deteriorates, and
the response to therapy becomes less and less
satisfactory. On average, however, life expectancy is
normal and patients generally die with Parkinson’s
disease, rather than as a result of it. You will already have
gathered that the drug treatments have a truly enormous
benecial eect in maintaining and restoring function
and quality of life, but as the years go by they become, for
many patients, deeply inadequate. is is an example of
therapy where there will be a sequence of drug
treatments, complicated by potentially bewildering
combinations of agents that will change over the years.
Understanding how these drugs work, and the science
underlying therapeutic strategies, will enable us to help
these patients live relatively normal lives.
In this chapter we consider both Parkinson’s and
Alzheimer’s disease—both neurodegenerative
disorders, both mainly but not exclusively diseases of
the elderly, and both named after long-dead physicians.
e Englishman James Parkinson rst described
Parkinson’s disease in an essay in 1817, and the German
Alois Alzheimer wrote of this condition in 1907. Only a
very small part of the current chapter is devoted to
Alzheimer’s disease. is does not reect the
signicance of the disease, the suering it causes, and
the challenge it poses to healthcare. It is the most
prevalent neurodegenerative disorder, and imposes an
enormous and increasing burden on families, society,
and the provision and distribution of medical resources.
e way dierent societies handle this burgeoning
challenge will be one of their dening characteristics in
the future. e reason we spend so little of this chapter
on Alzheimer’s disease is simply because its drug
treatment is very limited and so the pharmacological
basis of Alzheimer’s therapy is not, at the present time
anyway, an extensive subject.
In addition to these two chronic and slowly developing
conditions, neuronal function in a specic locus can be
lost acutely due to a stroke. is is most usually
associated with ischaemia (reduced blood, and hence
oxygen supply), or more rarely with haemorrhage
(bursting of an artery in the brain). Eective drug
treatment for stroke patients is extremely limited,
despite stroke being a leading cause of death, and the
commonest cause of long-term disability in the UK.
Since there are no pharmacological agents that
specically target the neurodegeneration resulting from
stroke, it is not considered further here; the thrombotic
process underlying ischaemic stroke is detailed in
Chapter 4.
17.1 Symptoms and diagnosis of Parkinson’s disease
A diagnosis of Parkinson’s disease is based on presenting
symptoms and is supported by a characteristic response to
medication. Core symptoms can be put into four categories:
• tremor (particularly of the hands when rested on a
support)
• rigidity (in limbs, overall posture, and face)
• bradykinesia (slow or limited movement)
• posture—assuming a bent/hunched/stooped position
when standing and postural instability (as when
walking, leading to danger of falling).
Diagnosis may be conrmed and progression of the
disease monitored by functional imaging (e.g. positron
emission tomography (PET) scan). is is a brain scan
used to examine the functional state of the dopaminergic
systems in the brain, monitor their decline as time passes,
and perhaps assess changes in response to treatment.
Diagnosis may also be established with a positive
response to a dose of a drug (e.g. levodopa; see Section
17.3.2) that restores dopamine activity to the brain.
Non-motor symptoms. ese are symptoms other than
diculties with movement, for example issues such as
depression, sleep problems, and cognitive decits (lack
of understanding, or diculty in making sense of
day-to-day occurrences). Some further discussion of
non-motor symptoms is given in Box 17.1.
17.2 Neurodegeneration: selective death of brain neurons 435
17.2 Neurodegeneration: selective death of brain neurons
In Parkinson’s disease we know that there is a major loss
of dopaminergic inuence in the striatum (caudate/
putamen), the part of the brain concerned with the
control of movement. Dopamine pathways are also
implicated in schizophrenia. is condition is covered in
Chapter 18, where we consider the notion that here the
problem arises from an inappropriately high level of
dopamine inuence in the cortico-limbic brain regions
(parts of the brain related to higher function and
emotion). e dopamine pathways in the brain are
illustrated in Chapter 18, Figure 18.3.
17.2.1 Parkinson’s disease is associated
with the death of nigrostriatal
dopaminergic neurons
e nigrostriatal pathway comprises a very dense
collection of cell bodies in a small part of the brain called
the substantia nigra, with axons ascending to provide a
substantial innervation of the much larger striatum. is
pathway is composed of dopaminergic neurons. On post
mortem, when the brain is sectioned, dopamine oxidizes
to a very dark colour, hence the term substantia nigra
(meaning black body). Early observations showed the
loss of this dark patch of tissue in post-mortem brains of
Parkinson’s disease patients; the central pathology of
Parkinson’s disease is death of neurons in this area of the
brain (Figure 17.1). As a result there is a progressive loss
of dopaminergic terminals, and of released dopamine, in
the striatum. e marked loss of striatal dopamine in
Parkinson’s disease is clearly illustrated in the positron
emission tomography (PET) scan images shown in
Figure 17.2. Evidence shows that over half (perhaps up to
80%) of these nigrostriatal neurons will have died even
before the patient is diagnosed with the disease. It is likely
that in most cases the degeneration will have started
several years before, and that the loss will continue,
giving greater movement problems and poorer response
to medication.
Striatum
(Caudateputamen)
The nigrostriatal
pathway
Substantia
nigra
Normal brain Parkinson’s brain
Figure 17.1 Nigrostriatal neurons are lost in the brain of Parkinson’s disease
patients.
In reality dopaminergic neurons in the substantia nigra of a normal human brain number
hundreds of thousands in each hemisphere, and over half (perhaps up to 90%) are lost in
Parkinson’s disease. The diagram shows the loss of extensively branching axons and
their terminals in the ascending pathway. Most of the dopamine in the striatum is located
in storage vesicles within these terminals, and so the result is a critical reduction in the
dopamine available for release and a downregulation of the dopaminergic influence that
can be exerted on striatal function. This imbalance results in the lack of control of
movement seen in Parkinson’s disease.
Box 17.1
Lewy bodies and the involvement of brain systems other than the
nigrostriatal system in non-movement symptoms of Parkinson’s disease
Nigrostriatal neuronal loss is the cardinal feature of
Parkinson’s disease, with associated loss of dopamine
in the striatum, resulting in the main symptoms of this
movement disorder. It is important to note, however,
that the situation is more complex in at least two ways,
both of which may contribute to the spectrum of
symptoms seen in Parkinson’s disease.
• Dopaminergic neurons of the substantia nigra
mainly project to the striatum and related basal
ganglia areas. However, they also contribute, albeit
in a relatively minor way, to dopamine input to
some cortical areas, and this is therefore similarly
downregulated in Parkinson’s disease.
• Non-dopaminergic neurons and pathways are also
aected to varying degrees.
Both of these eects are likely to be involved in the
non-movement symptoms of Parkinson’s disease,
which are typically prominent in the later stages of
the disease. e involvement of non-dopaminergic
neurons is seen in the progressive appearance of
Lewy bodies. ese are spherical aggregates of
intracellular proteins that are found in the cell bodies
of the substantia nigra in Parkinson’s disease; their
accumulation is thought to cause cell death.
Although Lewy bodies are particularly associated
with the substantia nigra, they may appear at an
earlier stage in the olfactory bulb and lower
brainstem. ese regions are associated with sense of
smell and sleep patterns, and are sometimes aected
in advance of the onset of classic Parkinson’s disease
symptoms.
In established Parkinson’s disease the major nonmovement disorder conditions are depression, sleep
problems, and cognitive decits, as well as peripheral
eects associated with autonomic nervous system
dysfunction (e.g. sweating, constipation, and sexual
problems). While some conditions (e.g. depression)
could be exacerbated by the eects of the movement
disorder, it is thought that the major source of these
symptoms is neurodegeneration beyond the
substantia nigra. is includes the death of
cholinergic, noradrenergic, and
5-hydroxytryptaminergic (serotonergic) neurons.
Treatment of such symptoms is very much on an
individual basis, with drugs often able to provide a
degree of relief.
e presence of non-dopaminergic
neurodegeneration provides some indication of the
true nature, and origin, of Parkinson’s disease. It
remains to be established why these neurons die, but
the emerging understanding of the mechanisms of cell
death will hopefully lead to advances in
neuroprotective drugs that slow or halt the
progression of the disease.
17.2.2 Other brain systems are also
important in Parkinson’s disease
e movement disorder symptoms of Parkinson’s disease
result from the degeneration of the nigrostriatal
dopaminergic projection. It is apparent, however, that
neurons in other brain systems are also aected (e.g.
serotonergic (5-hydroxytryptamine, 5-HT) neurons) and
that this contributes to the spectrum of additional
symptoms seen in many cases of Parkinson’s disease. is
is explored further in Box 17.1.
17.2.3 Cholinergic–dopaminergic balance
in the striatum is lost in Parkinson’s
disease
It remains the case that the dominant pathology of
Parkinson’s disease is death of nigrostriatal neurons,
leading to a decit in dopaminergic input in the striatum
(Figure 17.2). For correct control of movement the
striatum must maintain a balance between the inuence
of cholinergic and dopaminergic neurons. In Parkinson’s
disease the progressive loss of dopamine input reaches
17.3 Drug treatment of Parkinson’s disease 437
Figure 17.2 PET scans highlighting the loss of
dopamine storage capacity in Parkinson’s disease.
In the scan of a disease-free brain made with [18F]-FDOPA PET
(left image), the red and yellow areas show the dopamine
concentration in the normal putamen, a part of the dorsal
striatum in the mid-brain. By comparison, a similar scan of a
Parkinson’s patient (right image) shows marked deficiency in
dopamine in the putamen.
Reprinted by permission of The Feinstein Institute of Medical Research.
the point where the striatum is so imbalanced that the
cholinergic inuence becomes too dominant, leading to
loss of movement control. It is possible therefore to
simply regard the main symptoms of Parkinson’s disease
as being due to an over-dominant cholinergic system
within the striatum (Figure 17.3).
17.3 Drug treatment of Parkinson’s disease
Considering that cholinergic–dopaminergic imbalance in
the striatum underlies Parkinson’s disease,
pharmacological approaches to its treatment could
conceivably involve either anticholinergic therapy or
agents that increase the dopaminergic inuence
(Figure17.3). Essentially, though, most treatments for
Parkinson’s disease are dopamine-enhancing drugs, the
principal one being levodopa. ere is, however, a small
additional role for drugs blocking acetylcholine receptors.
As well as re-establishing motor function by restoring
dopamine inuence, there is also an obvious need for
agents which can slow or halt the loss of neurons; this
remains, however, largely a hope for the future. e
ultimate aim for Parkinson’s disease therapy is to
regenerate the neuronal pathways aected;
neurotransplantation and gene transfer techniques which
address this are in their infancy.
17.3.1 Anticholinergic drugs in the
treatment of movement dysfunction
As shown in Figure 17.3, decreasing the cholinergic
inuence in the brain could address the cholinergic–
dopaminergic imbalance. e receptors for acetylcholine
in the striatum are muscarinic; an antagonist acting at
this receptor type might be expected to be eective.
Antimuscarinic drugs such as benzhexol and
procyclidine are eective against tremor and rigidity, but
disappointingly do not help with the paucity of
movement (i.e. bradykinesia) that characterizes
Parkinson’s disease. Overall, these drugs are less eective
than dopamine-enhancing drugs (see below). is, along
with very unpleasant side eects (e.g. dry mouth,
constipation, and blurred vision), means that they are not
commonly used to treat Parkinson’s disease. ey are,
however, useful in reversing movement dysfunction
produced by antipsychotic medication, as illustrated in
the case of Shaun in Chapter 18. Tardive dyskinesias
(involuntary movements of the tongue, jaw, and lips) are
not improved by antimuscarinic drugs, and may actually
be exacerbated.
17.3.2 Dopaminergic drugs in the
treatment of movement dysfunction
Strategies for increasing dopamine inuence in the
striatum involve:
• directly stimulating the receptor with a drug acting as
an agonist at dopamine receptors
• increasing synthesis of dopamine in the brain by
supplying its precursor
438 Chapter 17 Neurodegenerative diseases
Parkinson’s disease
Normal
Acetylcholine Dopamine
Drug therapy
Increase dopamine
Decrease acetylcholine
Figure 17.3 Dopaminergic–cholinergic balance in the striatum.
In the normal brain, dopamine and acetylcholine are balanced, and the
seesaw is level. A fall in dopaminergic input following the death of
nigrostriatal neurons leads to acetylcholine having a disproportionately
larger weight in the striatum in Parkinson’s disease, and the seesaw tips.
This imbalance contributes to the symptoms of movement disorders, and
both dopamine-enhancing and anticholinergic atropine-like drugs (e.g.
procyclidine) can reduce the symptoms of Parkinson’s disease.
• decreasing breakdown of dopamine by inhibiting one
of the two enzymes involved: catechol-O-
methyltransferase (COMT) and monoamine oxidase B
(MAO-B)
• enhancing dopamine release.
In reality it is common for these dierent approaches to
be used in combination, meaning that most patients will
take more than one drug.
Furthermore, Parkinson’s disease is a progressive disease,
and consequently the response to drugs changes with
time. Medication that is eective early on is likely to
become less satisfactory, drug doses and combinations
will need to be changed, unwanted eects will intrude,
and clinical management will be a changing and
challenging practice over the years.
e limitations and complications of drug therapy were
alluded to at the beginning of this chapter with the patient
Gerald, and are explored further with Andreas in
Workbook 14 at the end of the chapter. We will mention
here three commonly encountered problems, which
present therapeutic challenges to the management of
Parkinson’s disease.
• Peak-dose eects: as the eect of a dose of drug taken
orally reaches its maximum, it creates involuntary
movements.
• Wearing-o: immobility can reoccur as the eect of
one dose declines before the next dose is eective.
Dopamine
Acetylcholine
• On–o phenomenon can result in a rapid switch from
normal mobility to total immobility, a severely
compromising situation. is can occur repeatedly,
and is referred to as ‘yo-yo-ing’.
Direct-acting dopamine agonists
Drugs which stimulate striatal dopamine receptors may
be desirable for rst-line treatment, particularly for
younger patients. ey have the potential to improve
motor performance with fewer unwanted movement
eects compared with levodopa (see below). Using these
drugs for initial treatment allows levodopa therapy to be
reserved for later. Given the limited number of years in
which levodopa gives maximum benet, this is obviously
an important consideration for younger patients.
However, as Parkinson’s disease progresses, dopamine
receptor agonists are seen to be less eective than
levodopa. In addition they are associated with an
enhanced risk of psychiatric side eects (see
Section17.3.3).
Some, particularly older, direct dopamine agonists fall
into a particular chemical class called ergots. Examples
include bromocriptine, pergolide, and cabergoline.
ese have the unfortunate risk of brotic side eects (e.g.
Ergot-derived dopamine receptor agonists are also used
in the treatment of chronic endocrine disorders such as
galactorrhoea (milky secretions from the breast,
17.3 Drug treatment of Parkinson’s disease 439
unassociated with breastfeeding) and gynaecomastia
(male breast enlargement). ese symptoms can also
arise from the use of antipsychotic medication (see
Chapter 18).
Apomorphine is a non-ergot direct-acting D2 dopamine
receptor agonist that is given subcutaneously; it is used
only in dicult cases, for instance when the patient is
unable to swallow pills or there are severe ‘on–o ’
phenomena. It is a strong emetic (i.e. it induces vomiting)
and so must be preceded by the antiemetic D2 antagonist
domperidone. You may wonder how domperidone is
able to counteract the emetic eect of apomorphine
without interfering with its anti-Parkinson’s disease
eect, given that both drugs act at D2 receptors in the
brain. e answer is that while apomorphine distributes
freely around the brain, domperidone cannot pass the
blood–brain barrier and therefore does not reach the
striatum. However, in the vicinity of the chemoreceptor
trigger zone (a part of the vomiting centre), the blood–
brain barrier is very leaky. is allows access to
domperidone, which is thus able to selectively block the
eect of apomorphine in this area, whilst not opposing its
action in the striatum.
ere is a view that the periodic stimulation of striatal
dopamine receptors by short-acting direct agonists
contributes to the risk of unwanted movement eects.
Longer-lasting drugs may therefore decrease peak-dose
and on–o eects. is has led to the development of
drugs with long half-lives, as well as a number of
sustained-release preparations. Pramipexole and
ropinirole are examples of long half-life drugs intended
to provide continuous dopaminergic stimulation.
Rotigotine is a dopamine agonist that can be delivered
slowly via a transdermal patch.
Unwanted movement eects with levodopa therapy
(see below) are often more troublesome with young
patients; Andreas in Workbook 14 has early-onset
Parkinson’s disease and is given pramipexole. is
works well for 3 years until his symptoms re-emerge,
and he is then prescribed levodopa to be taken
concomitantly.
Provision of the dopamine precursor levodopa
e reason why levodopa (also called -dopa) is the
optimal choice for dopamine precursor treatment is
based on a simple neurochemical premise.
e pathway for dopamine synthesis is
Tyrosine
Dopa
decarboxylase
→
hydroxylase
→
Dopamine
- L-dopaL-tyrosine Ldihydroxyphenylalanine( )
e step catalysed by tyrosine hydroxylase is rate
limiting. e dopa-decarboxylase step is not—there is a
lot of this (or equivalent) enzyme around. So when
levodopa is taken, it is freely converted to dopamine,
bypassing the rate-limiting step, and substantially
increasing dopamine availability at its receptors in the
brain.
Levodopa is always administered with a peripheral
decarboxylase inhibitor. If levodopa is taken orally on its
own, the majority is metabolized in the gut wall and very
little (less than 1%) gets to the brain. e peripheral
metabolism of levodopa to dopamine is also responsible
for some unwanted side eects, such as nausea, vomiting,
and postural hypotension. For both these reasons the
precursor is given with a peripheral decarboxylase
inhibitor (‘peripheral’ meaning that it distributes around
the body, but does not enter the brain). Two such
inhibitors, carbidopa and benserazide, are available and
are combined with levodopa in a single tablet (co-
careldopa and co-beneldopa, respectively). is
co-administration ensures that more of the drug is
delivered to the brain, so that eective dopamine levels
are achieved with much lower doses of levodopa. In
addition, the reduced production of dopamine in the
periphery lessens some side eects. It is this combination
type of drug which would have produced such an
extraordinary (albeit temporary) alteration in Gerald’s
condition described at the start of this chapter, and is
considered the bedrock of anti-Parkinson’s disease
treatment. e patient Andreas in Workbook 14 is also
treated with co-beneldopa—in his case, however, not
without serious unwanted side eects, both movement
disorder and psychiatric eects (see Section 17.3.3).
e majority of patients show initial improvement with
levodopa, particularly in terms of bradykinesia and
rigidity, but over time its eectiveness reduces,
presumably reecting the continued deterioration in
dopaminergic neurons in this progressive condition.
Prolonged use of levodopa is also associated with the
appearance of dyskinesias, usually aecting the limbs and
face, which can be disabling (as noted for Gerald earlier).
ese are peak-dose eects, which appear in most
patients within 2 years of initiating therapy and limit the
usefulness of the drug. It is well known that these
440 Chapter 17 Neurodegenerative diseases
drug-induced dyskinesias develop earlier in the
treatment of younger suerers of Parkinson’s disease than
in older patients, although the reason for this dierence
remains unknown.
Levodopa has a short half-life (1–3 hours) and so
produces uctuating stimulation of dopamine receptors
in the brain as concentration rises to a peak following
administration, and then falls away. Both co-careldopa
and co-beneldopa are available in modied-release form,
intended to reduce peak-dose and wearing-o eects.
Additional strategies to atten these uctuations include
the combination therapy of levodopa with COMT and
MAO-B inhibitors (see below). e aim is to further
reduce peripheral levodopa metabolism, thus delivering
more to the brain, and also to slow the rate of clearance in
the brain of dopamine produced from the administered
levodopa. Despite its limitations, levodopa remains the
most eective oral treatment for symptoms of Parkinson’s
disease.
MAO-B and COMT inhibitors
One strategy to increase neurotransmitter availability in
the synapse, where it can act on receptors, is to inhibit the
enzymes responsible for its breakdown. In the brain,
dopamine is broken down by two enzymes, MAO and
COMT, and drugs which inhibit these enzymes will
thereby modify dopamine availability (see Box 17.2). Such
drugs have consequently assumed a signicant role in the
management of Parkinson’s disease.
Monoamine oxidase enzymes and their inhibitors are
discussed fully in Chapter 19, in particular in Box 19.2
where the two forms, MAO-A and MAO-B, are
introduced. Both forms break down dopamine, but
MAO-B in the astrocytes is the most eective target in the
treatment of Parkinson’s disease, where marked
reduction in dopaminergic terminals is seen. In the
context of this disease, with the loss of 70–80% of
dopamine in the striatum, inhibitors of COMT and
MAO-B can be seen as making the most of the dopamine
that remains.
COMT metabolizes both levodopa and dopamine, and is
found throughout the body. It is particularly abundant in
the liver, and so is involved in the rst-pass metabolism of
levodopa, which limits its delivery to the brain following
administration.
when movement dysfunction is modest and cognitive
impairment is absent. Presumably at this early stage there
is sucient residual dopamine input into the striatum;
this input can be enhanced, meaning that levodopa
treatment can be delayed. However, as the disease
progresses and more dopaminergic neurons die,
levodopa therapy will be introduced. It is logical that
when levodopa is used, MAO-B inhibitors will be a useful
adjunct therapy, enhancing the availability of dopamine
and reducing wearing-o problems.
A curious issue with selegiline, but not rasagiline, is that it
is metabolized to an amphetamine. Amphetamine-like
drugs release dopamine, which could be helpful in
Parkinson’s disease. A disadvantage is that this approach
can lead to signicant psychostimulant eects, and even
induce psychotic behaviour (see Chapter 18, Box 18.2). It
is always advisable to take this drug in the morning to
avoid this stimulating eect interfering with sleep.
Another issue with MAO-B inhibitors is that they cannot
be given with selective serotonin reuptake inhibitors such
as uoxetine (see Chapter 19 and Workbook 14 at the end
of this chapter). Both drugs enhance, by dierent
mechanisms, the availability of 5-HT at its receptors; the
combined eect presents increased risk of hypertension
and CNS excitation. Considering that the incidence of
depression in patients with Parkinson’s disease is high,
this interaction is clinically signicant. Generally, though,
selective MAO-B inhibitors present less risk of
interactions with foods (e.g. cheese reaction) and other
drugs compared with the non-selective MAO inhibitors
used to treat depression.
COMT inhibitors. e benets of levodopa therapy can
be enhanced by COMT inhibitors. Tolcapone was the
rst such drug to be developed. It is available for
treatment of Parkinson’s disease but is associated with
risk of liver damage, and is only used in severe cases
which are unresponsive to other drug treatment
regimes, and then with monitoring of liver function. e
COMT inhibitor entacapone is mainly given with
levodopa to help resolve wearing-o problems. Unlike
tolcapone, it is unable to cross the blood–brain barrier
and inhibits only peripheral COMT activity. Both drugs
commonly cause gastrointestinal disturbance,
particularly diarrhoea.
Dopamine release
MAO-B inhibitors (rasagiline and selegiline) may be
used alone in the treatment of early Parkinson’s disease
A drug which causes release of dopamine from its storage
vesicles in the nerve terminals will deliver dopamine to
Box 17.2
Inhibition of MAO-B and COMT in the manipulation of brain
dopamine levels
Axon
Tyrosine
Circulation
Tyrosine
L-dopa
L-dopa
Carbidopa
Benserazide
Figure a Role of MAO and COMT in controlling dopamine levels.
On the left are depicted the endothelial cells of the brain’s microvasculature (the blood–brain barrier). Levodopa (l-dopa) in
the circulation is metabolized by DDC and COMT. In the therapeutic use of levodopa, DDC is inhibited in the periphery by
co-administration of a DDC inhibitor that does not enter the brain (carbidopa/benserazide). A COMT inhibitor (e.g.
entacapone/tolcapone) may further reduce the peripheral levodopa breakdown. Dopamine is also a substrate for COMT.
Tolcapone is able to penetrate the blood–brain barrier, and can additionally reduce dopamine breakdown in the large
population of astrocytes. Similarly, the selective MAO-B inhibitors selegiline and rasagiline will reduce dopamine
breakdown in the astrocytes. COMT, catechol-O-methyltransferase; DDC, dopa-decarboxylase; MAO-B, monoamine
oxidase B.
DDC
Dopamine
COMT
Methyl
-dopa
Tolcapone
Entacapone
Astrocyte
Rasagiline
Selegiline
Blood-brain barrier
MAO-A
COMT Tolcapone
MAO-B
MAO
Dopamine
Dopamine
Active uptake
-
t
s
o
P
Dopamine
receptors
e
n
a
r
b
m
e
m
c
i
t
p
a
n
y
s
e role of monoamine oxidase and its two forms,
monoamine oxidase A (MAO-A) and B (MAO-B), are
discussed more extensively in Chapter 19, in
particular in Box 19.2. Both monoamine oxidase B
(MAO-B) and catechol-O-methyltransferase (COMT)
are involved in the metabolism of dopamine in the
brain (see Figure a). When considering the eects of
inhibitory drugs, two points about these enzymes are
worth noting.
• Both COMT and MAO-B are found in the brain, but
are also present in other tissues. Particularly
important here are the high levels of COMT in the
liver.
• COMT metabolizes both dopamine and levodopa
(see Figure a).
ese properties of COMT and MAO-B account for the
consequences of their inhibition using therapeutic
agents.
• When levodopa is swallowed it enters the bloodstream
and is subject to modication by COMT in the liver.
Consequently, co-inhibition of COMT will enable
more levodopa to be delivered to the brain.