Chapter 11: Drugs Used to Treat Neuromuscular Disorders
Case Study from 6th Edition
ST is a 68 yo female who traded in her stressful job as an academic administrator at a
major academic health center for the relaxed life of Southern California. Heading to
“wine country” with her cats, retirement funds and a few family heirlooms, she
purposefully sought a new life, making new friends and doing the things she loves most.
She’s been very politically and culturally active in her community, and thoroughly enjoys
her job as the social events planner at a small, family-owned winery that is just now
beginning to gain regional notoriety. Attendance at her nightly “wine and cheese”
gatherings have increased dramatically over the past year, giving ST a chance to network
with clients and showcase the high quality of her employer’s “vino”.
Life seemed perfect until a diagnosis of Parkinson’s disease was made three months ago.
ST’s symptoms are characteristic of this dopamine deficiency disorder, and include
rigidity, difficulty speaking and slowed movements. She is still able to function at work,
but obviously worried about what the future holds. She began levodopa therapy
immediately (400 mg twice a day) but is struggling to cope with drug-induced nausea and
vomiting severe enough to limit her usually passionate involvement with a local
Parkinson’s research advocacy group. In addition, while previously normotensive, she
has experienced an increase in blood pressure that is now being treated with a thiazide
diuretic.
You meet up with ST at a wine-tasting event at the vineyard and, in a private moment,
she asks for your professional advice and counsel. Consider the structure of the
compounds drawn below and decide which might benefit this patient.
Cl
NH 2
CH2
CH2 NH
NH2
HO
C
CH2
COOH
HO
OH
CH2
CH
Levodopa
CH2
NH2
CH2
O
HO
C 3H 7
3
N
2
H
CH2
+
H3 C
1
N
CH 2
-
N
H
+
N
C 3H 7
Cl
-
CH3
4
OH
5
C
CH 3
COOH
Identify the therapeutic problem(s) where the pharmacist's intervention may benefit the
patient.
ST is facing a chronic and debilitating disease for which there is currently no known
cure. She is on the “gold standard” anti-Parkinson’s therapy, levodopa, but
experiencing side effects at a level sufficient to interfere with her quality of life.
ST is on dopamine replacement monotherapy. The current standard of care attempts
to maximize central dopamine augmentation by inhibiting premature degradation of its
biochemical precursor, levodopa, in the periphery. This is done through combination
therapy with levodopa and a dopa decarboxylase inhibitor. Levodopa, rather than
dopamine, is the neurotransmitter replacement drug of choice because of its lower pKa
(which translates into a higher u/i ratio at pH 7.4) and its ability to take advantage of
amino acid transporting proteins for entry into the CNS. Dopamine cannot effectively
cross the blood brain barrier if administered peripherally.
Identify and prioritize the patient specific factors that must be considered to achieve the
desired therapeutic outcomes.
ST is experiencing significant nausea and vomiting from her levodopa therapy.
Dopamine liberated from levodopa by peripheral dopa decarboxylase enzymes is
stimulating the chemoreceptor trigger zone (CTZ) in the brainstem and directly
irritating the GI tract.
ST’s blood pressure is elevated as a result of peripherally-generated dopamine
interacting with adrenoceptors in blood vessels (1, leading to vasoconstriction) and
heart (1, leading to an increase in heart rate and force of contraction).
ST’s job involves the consumption of wine and, often, cheese.
ST is only 68 years old and theoretically has many years of life ahead of her. It is
important to make those years of the highest possible quality by appropriately
managing her Parkinson’s disease.
Conduct a thorough and mechanistically oriented structure-activity analysis of all
structures provided in the case.
Levodopa is administered with the intent that it distribute intact to the brain where it
can undergo decarboxylation to dopamine by central dopamine decarboxylase
enzymes. Only after biotransformation to dopamine is this drug able to stimulate the
central dopamine receptors that have been deprived of endogenous transmitter through
the disease-induced destruction of dopaminergic nerve terminals. Dopa decarboxylase
enzymes are also plentiful in the periphery and prematurely convert a large percentage
of the levodopa dose to dopamine before it ever has a chance to reach central sites of
action. As previously noted, dopamine generated in the periphery is unable to
distribute to the CNS and the therapeutic effect in the treatment of Parkinson’s disease
will be lost. Unless peripheral decarboxylase enzymes are inhibited, large doses of
levodopa must be administered to ensure that therapeutic concentrations are achieved
in brain. The high levels of dopamine generated in the periphery as a result of these
augmented doses are responsible for the side effects experienced by ST (nausea,
vomiting, hypertension).
Compound 1 is an aralkylhydrazine that competes with catecholamine-based
neurotransmitters (including dopamine) for access to monoamine oxidase (MAO)
enzymes. MAO inactivates endogenous neurotransmitters and some xenobiotics
through oxidative deamination, the first step of which is hydroxylation of an
unsubstituted (methylene) -carbon to form an unstable carbinolamine. The
carbinolamine intermediate rapidly degrades to release ammonia and an aldehyde
metabolite. Compound 1, being a hydrazine, has no -carbon atom and thus, once
bound to the enzyme through its terminal amine and phenyl ring, cannot be
hydroxylated. Rather, the drug oxidizes to a reactive diazine that loses N2 and
generates a highly destructive benzyl radical which inactivates the enzyme. Potent
MAO inhibition in aralkylhydrazines demands an unsubstituted phenyl ring and a 2-3
carbon chain between phenyl ring and terminal nitrogen. Compound 1 is a nonspecific MAO antagonist, meaning it irreversibly inactivates both MAO-A and MAO-B.
MAO-A is involved in metabolizing monoamines in foodstuffs (e.g., tryamine found in
wine, cheese, beer, herring, etc.), as well as endogenous neurotransmitters like
epinephrine and it nor derivative. MAO-B, on the other hand, metabolizes endogenous
phenethylamines and dopamine, but not vasoactive amines found in foods.
Compound 2 is a -aminopropanol substituted at the  (carbinol) carbon with two
cyclic hydrocarbon substituents. This is one structural prototype for antimuscarinic
action (the others are aminoalkyl ethers and aminoalkyl esters). The amino nitrogen,
in cationic form, anchors the drug to the G-protein coupled muscarinic receptor, and
the “bulky” hydrocarbon ring systems both increase affinity for the receptor protein
over the acetylcholine transmitter (a slender structure with a terminal methyl group)
and provide steric hindrance to competition from the endogenous agonist. The
terminal OH group is also believed to enhance affinity for the muscarinic receptor
through hydrogen bonding. Aminoalcohol antimuscarinics can be either protonated
tertiary amines or quaternary amines. The protonated tertiary amines are in
equilibrium with their unionized free base forms at pH 7.4 and, therefore, have the
ability to penetrate into the CNS. While their efficacy in Parkinson’s disease can be
debated, they are sometimes used to provide a better balance of dopamine and
acetylcholine receptor stimulation in the brains of Parkinson’s patients. The
commonly observed peripheral side effects of dry mouth, blurred vision, urinary
retention and constipation are, at best, annoying while the central effects of sedation,
ataxia and potential hallucinogenic or delusional thinking can be use-limiting.
Quaternary amine antimuscarinics are fully cationic at all pH values and cannot
penetrate the blood brain barrier. They are, however, very effective peripheral agents,
and are often used to treat overactive bladder (antispasmotic) or COPD
(bronchodilation).
Compound 3 has a “phenethylamine” pharmacophore buried in its structure which
provides access to dopamine receptors. The tertiary amine is able to penetrate the
blood brain barrier to reach central sites of action, and dopamine receptor agonism
results. While the unionized amine is required for distribution to the CNS, the cationic
amine is essential for anchoring the drug to the G-protein coupled dopamine receptor.
The dihydroindol-2-one aromatic moiety provides access to the D2 and D3 subtypes but
does not permit stimulation of other catcholaminergic receptors (e.g., , ). As
dopamine agonists, molecules like Compound 3 can directly irritate the GI tract and
stimulate dopamine receptors in the CTZ, leading to significant nausea and vomiting.
Compound 4 is an N-methyl-4-phenyl-tetrahydropyridine structure known as MPTP.
This chemical is a byproduct of the clandestine synthesis of a highly addicting opioid
known chemically as 4-hydroxy-N-methyl-4-phenylpiperidine propionate ester
(MPPP). If this ester hydrolyzes, which happens often during synthesis and work-up,
it forms a tertiary alcohol which readily dehydrates to form this highly neurotoxic
substance. Once transported into the brain, MPTP oxidizes to a quaternary
dihydropyridine structure (N-methyl-4-phenyl-5,6-dihydropyridine or MPP+) that is
trapped in the CNS and destroys dopaminergic neurons in the substantia nigra. The
signs and symptoms of Parkinson’s disease result.
O
O
N
C CH2
CH3
C2H2
COOH
hydrolysis
CH3
MPPP ("synthetic heroin")
OH
H2O
N
CH3
dehydration
N
CH3
4
oxidation
N +
CH3
MPP+ (trapped in CNS)
Compound 5 differs from levodopa only by the presence of an -CH3 group. While
this destroys affinity for dopamine receptors, the compound retains high affinity for
peripheral dopa decarboxylase enzymes. With the peripheral dopa decarboxylase
enzymes tightly bound to Compound 5, levodopa can escape their metabolic action,
allowing a greater percentage of the dose to reach the brain and undergo the desired
decarboxylation reaction right at the site of action. Importantly, central dopa
decarboyxlase enzymes are fully operational since Compound 5 does not distrtibute
and is not transported to the CNS.
Evaluate the SAR findings against the patient specific factors and desired therapeutic
outcomes and make a therapeutic decision.
Compound 1 (phenelzine) would be dangerous to use in this patient, particularly with
the likelihood of her consuming wine and cheese on a regular basis. The inhibition of
MAO-B would be desirable, as it would attenuate the inactivating metabolism of
dopamine in central synapses, but the inhibition of MAO-A could lead to a
hypertensive crisis, especially if large amounts of tyramine are consumed. Tyramine is
a highly vasoactive amine and, if it is allowed to persist due to a loss of its inactivating
MAO enzyme, it will increase blood pressure to potentially fatal levels. The half-life of
the endogenous vasopressor neurotransmitter norepinephrine would also be extended
through the inhibition of MAO-A and –B, so the risk of hypertension is significant
even without the added impact of exogenous tyramine. With the consumption of
tyramine-rich foods, pathological hypertension would be essentially guaranteed.
Compound 2 (the quaternary analog of the antimuscarinic trihexyphenidyl) would do
no good in a Parkinson’s patient since it would be unable to cross the blood brain
barrier and, therefore, could not decrease cholinergic activity in the CNS. The tertiary
analog might have had some value, although clinicians debate risk:benefit ratio of
antimuscarinic therapy in Parkinson’s disease.
The value of compound 3 (ropinirole) might also be debated in ST’s case. As a
centrally active dopamine receptor agonist, it could take the place of levodopagenerated dopamine, and might be a good alternative therapy if the extent of
neurodegeneration progresses to where ST can no longer decarboxylate levodopa.
Dopamine agonists like ropinirole are sometimes used in combination with levodopa,
allowing a lower dose of the latter compound with, hopefully, fewer side effects.
However, the levodopa side effects most troubling to ST (nausea and vomiting) are also
commonly experienced with ropinirole. In addition, patients on ropinirole can
experience excessive daytime drowsiness, and can fall asleep without warning while
engaged in normal daytime activities.
Administering compound 4 (MPTP) would be an invitation to a malpractice lawsuit
and a jail sentence. This neurotoxic substance, generated from the clandestine
synthesis of a narcotic, would worsen ST’s Parkinson’s disease, and could prove fatal.
Compound 5 (carbidopa) should be added to ST’s levodopa regimen ASAP. This
peripheral dopa decarboxylase inhibitor would allow for a significant reduction in the
levodopa dose and should decrease the extent and severity of the adverse effects this
patient is experiencing.
Counsel your patient
ST should be told how the actions of carbidopa can help decrease the side effects of
levodopa therapy, and that a single medication is available that contains both drugs in
an appropriate ratio (1:10 carbidopa:levodopa). Carbidopa can also be administered
separately (which permits titration to an optimal patient-specific ratio), but should be
taken at the same time as levodopa. ST should be told to take her first dose of
carbidopa (or the carbidopa:leovopa combination medication) no sooner than 8-12
hours after her last dose of levodopa, and informed that her urine may be darker than
usual.
ST should be warned that she might experience orthostatic hypotension when
carbidopa is added to her regimen. She should take appropriate precautions when
rising from a sitting position until she knows how she will respond to this new therapy.
You may want to decrease the dose of the thiazide as ST begins carbidopa therapy, and
assess need for continued antihypertensive therapy after she has been stabilized on the
new combination antiParkinson’s regimen.
If ropinerole is added to the regimen, ST must be warned about its sedating potential,
and to exercise extreme caution until she knows how she will respond. As noted,
patients fully engaged in the activities of daily living (including driving a car) can fall
asleep without warning. This potential adverse effect is very serious, and can occur
long after therapy is initiated. ST should definitely avoid other CNS depressants,
including alcohol. She should, however, take this medication with food to avoid
potential GI distress.
ST should be asked to monitor the extent of nausea and vomiting she experiences on
this therapy so it can be determined if it is having a beneficial effect. As with
carbidopa, postural hypotension is possible and appropriate precautions should be
taken. She should promptly report any visual, auditory or sensory hallucinations or
worsening of Parkinson’s symptoms to her physician.