Clinical Endocrinology (1995) 42,95-99
Case report
Pseudo-phaeochromocytoma after multiple drug
interactions involving the selective monoamine oxidase
inhibitor selegiline
H. Lefebvre, C. Noblet*, N. Moore* and L. M. Wolf
Departments of Endocrinology and 'Pharmacology,
Centre Hospitalo-Universitaire de Rouen, France
(Received 18 April 1994; returned for revision 6 June 1994;
finally revised 24 June 1994; accepted 19 July 1994)
Summary
A patlent presented wlth paroxysmal hypertenrlon and
typical cllnlml features of phaeochromocytoma, but with
a normal adrenal computed tomographic scan and much
hlgher plasma noradrenaline than adrenaline concenba-
tlonr. Urlnary vanlllylmandelk acld concentratlons were
only moderately elevated. Thls syndrome probably arose
as a consequence of an interaction belwean the mono-
amlne oxldase lnhlbltor seleglllne, the sympathomlmetk
agent ephedrlne, and a trlcycllc antldepressant The
mechanlsm of the interaction Is thought to be related to
Increased sympathetlc release of noradrenailne by
ephedrlne, lnhlbltlon of catabolism by seleglllne, and
lnhlbltlon of reuptake of noradrenallne by the trlcyclk.
Although newer selectlve monoamlne oxldaro Inhibitors
are considered to be safer than earller non-seeledlve
Inhlbltors, they can also contribute to drug lntersctlons
mlmkklng phaeochromocytoma.
Phaeochromocytomas are associated with paroxysmal
hypertension and symptoms (tachycardia, headache,
sweating) that reflect the effects of catecholamine excess.
Similar clinical features can also be produced by interactions
between non-selective monoamine oxidase inhibitors
(MAOIs) and sympathomimetic agents or food-derived
amines (Blackwell & Simon, 1988; Baldessarini, 1990). The
earlier MAOIs are non-selective in that they irreversibly
inactivate both isoenzymes (A and B) of monoamine oxidase
(MAO) (Pare, 1985). The resulting inhibition of biogenic
amine metabolism, especially when combined with drugs
increasing release or decreasing recapture of the amines, may
be responsible for severe hypertension or serotonin syn-
dromes (Baldessarini, 1990). These interactions, often
Correspondence:Dr H. Lefebvre, Clinique MCdicale et
Endocrinologique, CHU de Rouen, HBpital de Bois-Guillaume,
147, avenue du Marichal Juin, BP 100,76233 Bois-Guillaume
Cedex, France.
unpredictable, have limited the therapeutic use of these
MAOIs. During the last decade, the synthesis of new
inhibitors, selective for one of the two forms of the MAO,
caused renewed interest in MAOIs. Because of their
selectivity, these compounds seem to be relatively free of
sigmficant drug interactions (Strolin Benedetti & Dorstert,
1985; Dingemanse, 1993). Selegiline is a selective inhibitor of
MAO-B (MAOI-B) employed as an adjunct in the treatment
of Parkinson's disease (Knoll et al., 1978; Golbe, 1988). As
dopamine is catabolized by MAO-B, selegihne allows the use
of lower doses of L-dopa. It was originally postulated that
selegiline would not induce hypertensivecrisis in association
with tyramine or sympathomimetic agents since adrenaline,
noradrenaline and the other related amines involved are
mainly inactivated by MAO-A (Fowler & Callingham, 1978).
In fact, only one case report has mentioned a tyramine
reaction during selegiline treatmenti (McGrath et al., 1989).
The concurrent administration 08 selegiline and sympatho-
mimetics or tricyclic antidepressants might in theory be
reasonable. However, the selectivity of selegdine for MAO-B
is partial and observed only at low concentrations (Golbe,
1988; Sandler er al., 1980). At therapeutic doses (from 5 to
10mg/day), selepsline may inhibit both isoforms of MA0 and
the risk of hypertensive crisis with drug or tyramine ingestion
may be not negligible, at least in patients who are unusually
sensitive to selegiline's effkcts (Sunderland et al., 1985;
McGrath er al., 1989). To illustrate this, we report a
patient, treated with selegiline, ephedrine (a sympathomi-
metic agent) and maprotiline (a tricyclic antidepressant), who
developed clinical features suggestive of an extremely active
secreting phaeochromocytoma. The diagnosis of pseudo-
phaeochromocytoma was based on plasma catecholamine
concentrations and uneventful recovery after the treatments
were stopped.
Case history
A 57-year-old Caucasian man was hospitalized for
evaluation of paroxysmal hypertensive crises. The patient
had a history of Parkinson's disease, depression and chronic
bronchitis with bronchospasm treated long term with
selegiline 10mg, levodopa 300 mg plus carbidopa 30 mg,
lisuride 0.5 mg, maprotiline 75 mg, and since 1990 also with
theophylline 180mg plus ephedrine 32mg, all daily.
95
96 H . Lefebvre e t a / . Clinical Endocrinology (1995) 42

Tabla 1 Biochemical results on admission

Plasma assays Urinary assays

NA A Renin Aldo NA A M VMA

(nmol/l) (nmol/l) (ng.1) @mol/l) (nmol/day) (nmol/l) (nmol/day) (pmol/day)

Normal values
15-3.3 0.3-0.9 7-19 40-405 <SO0 <lo0 <SO00 < 40
Patient values
15.1 0.95 39 1313 NM NM NM 48

Biochemical results on NA, noradrenaline; A, adrenaline; Aldo, aldosterone; M, metane-

phrines; VMA, vanillylmandelic acid; NM, not measurable.

Hypertension was diagnosed a few months after the
introduction of the latter treatment and controlled with
nicardipine 100mg/day. Two weeks before admission, the
doses of theophylline and ephedrine were increased to 270
and 48 mg/day, respectively. Hypertensive crises appeared
within 2 days of this adjustment. On admission to hospital,
examination revealed episodes of intense vasoconstriction,
confusion, abdominal pain, sweating, hypertension up to
300/150mmHg and tachycardia (110 per min). Electro-
encephalography, performed during a crisis associated with
confusion, showed no sign of epilepsy. Hypertensive
encephalopathy was excluded by a normal cerebral CT
scan. A diagnosis of phaeochromocytoma was considered
and endocrine evaluation was performed. Plasma and urine
catecholamineswere assayed using high performance liquid
chromatography coupled to electrochemical detection
(HPLC-ECD). We observed a dramatic increase in plasma
noradrenaline contrasting with near normal adrenaline
(15.1 and 0.95 nmol/l, respectively; normal values < 3.3
and c 0.9). Urinary catecholamines and metanephrines
were not evaluable because of drug interferences. Urinary
*Or I
2 I t
vanillylmandelic acid (VMA) was only moderately elevated
(48 pmollday; normal values < 40). Supine plasma renin
and aldosterone were also increased (Table 1). CT scan of
the adrenals was normal.
The results of all the tests, and the potential interaction
risk of the patients treatment, led us to suspect that the
disorder was drug induced. All the treatments were stopped
and the hypertensive crises were controlled by intravenous
nicardipine. No further attacks occurred and plasma
catecholamine levels returned to normal within 3 weeks
(Fig. 1). The patient recovered uneventfully and has had no
symptoms since. All catecholamine, renin and aldosterone
assays remain normal.
Dlscusslon
The clinical features of our patient were compatible with the
presence of a phaeochromocytoma.During the hypertensive
crises, the vasoconstriction was probably severe enough to
cause cerebral ischaemia, as previously described in
phaeochromocytoma (Lefebvre et al., 1992), resulting in
mental confusion and/or sluggishness. However, the patient
had been taking selegiline, a selective inhibitor of the MAO-
B, associated with maprotiline (a tricyclic antidepressant)
and ephedrine (a sympathomimetic agent) which are known
to cause hypertension in combination with non-selective
MAOIs (Baldessarini, 1990). Furthermore, hypertensive
crises appeared after the dose of ephedrine was increased.
No new paroxysm occurred after the drugs were stopped.
The diagnosis of a drug related pseudo-phaeochromo-
cytoma was also supported by the following observations:

.,
(i) plasma catecholamines returned to normal after the
drugs were stopped; (ii) the CT scan of the adrenals was
Time (days) normal; (iii) in addition, the very low plasma adrenaline/
noradrenaline ratio (0.06) was more in favour of sym-
Fig. 1 Plasma 0, noradrenaline and adrenaline levels after
cessation of treatments (arrow). The upper limits of normal pathetic presynaptic release rather than adrenomedullary
ranges are indicated by dashed tines. secretion of catecholamines. In phaeochromocytoma, this
Clinical Endocrinology (1995) 42 Drug-induced pseudo-phaeochromocytoma 97

ratio is usually around 0.25, though a lower ratio does not

exclude the disease (Plouin et al., 1991). The increased
plasma renin and aldosterone concentrations were likely to
be consequences of the activation of the renin-angiotensin
axis by the catecholamine excess and/or ephedrine as
previously reported (Keeton & Campbell, 1980). Urinary E P ~
assays of catecholamines and their metabolites did not
contribute to the diagnosis since the presence of ephedrine
was responsible for interferences in the HPLC-ECD
analysis, as is well known. In addition, VMA was near
normal, probably because of inhibition of catecholamine
oxidation by selegiline.
Although selegiline is thought to have a low propensity
for producing drug interactions, a series of recent reports
dNorodrenoline - MA0
Metabolites

have described selegiline/fluoxetine,selegiline/pethidineand

selegiline/food-derived tyramine interactions resulting
in severe pseudo-phaeochromocytomas or serotonin
syndromes (McGrath et al., 1989; Suchowersky & de
Vries, 1990; Zornberg et al., 1991; Jermain et al., 1992;
Montastruc et al., 1993). Similar drug interactions were
observed with two selective MAOI-A, toloxatone and
moclobemide (Dingemanse, 1993; Freeman, 1993; Lefebvre
et al., 1993; Neuvonen et al., 1993; Spigset & Mjorndal,
1993).
Considering the pharmacological properties of the drugs
taken by the patient, the following mechanism can be
proposed for their interaction. The powerful sympatho-
mimetic ephedrine probably stimulated the release of
noradrenaline from sympathetic endings through an
activation of presynaptic 8-2 receptors (Nedergaard &
Abrahamsen, 1990). In addition, the degradation and
re-uptake of the released noradrenaline were inhibited by
selegiline and maprotiline respectively, leading to the
dramatic increase in plasma noradrenaline concentrations.
Ephedrinemay have further contributed to vasoconstriction
(Fig. 2).
In conclusion, we have described a severe drug induced,
pseudo-phaeochromocytoma after selegiline/ephedrine/
maprotiline interaction. Considering the multiple drugs
taken by the patient, an interaction should perhaps have
been expected. This observation illustrates the fact that,
despite selectivity, selegiline and newer inhibitors of MAO-
A are not entirely devoid of the usual interactions of less
selective MAOIs. Such an interaction must be considered
when clinical features of phaeochromocytoma occur in a
patient treated with a selective MAOI. The diagnosis of drug
induced phaeochromocytoma is based on recovery after
interruption of treatments, increased plasma noradrenaline
concentrations and absence of tumour on CT scan of the
adrenals. It should be noticed that urinary VMA
concentrations are normal or only moderately elevated in
Hypertension
FIg. 2 Putative mechanism of the drug interaction. Ephedrine
enhances the release of noradrenaline (NA) from sympathetic
nerve endings. Re-uptake and degradation of NA are inhibited by
maprotiline and selegiline, respectively. The resulting increase in
plasma NA levels is responsible for a pseudo-
phaeochromocytoma syndrome which is further aggravated by
the direct sympathomimeticeffect of ephedrine.
this situation, since the oxidative catabolism of catechola-
mines is inhibited by the MAOI. New selective MAOIs,
sympathomimetics and tricyclic antidepressants should be
given together only with extreme caution.
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Commentary
Drug interactions mimicking phaeochromocytoma
D. J. M. Reynolds
University Department of Clinical Pharmacology,
RadcliffeInfirmary, Woodstock Road, Oxford OX2 W E , U K
Adverse drug interactions may cause arterial hypertension
by means of direct or indirect augmentation of the pressor
effects of noradrenaline. This can occur through a variety
of peripheral and central mechanisms, for example, by
increasing noradrenaline synthesis, blocking its degrada-
tion, stimulating release, inhibiting reuptake and mimicking
its effects at adrenergic receptors. The best known example
is the hypertensive reaction associated with the use of non-
selective monoamine oxidase inhibitor antidepressant drugs
in combination with indirect sympathomimetic agents such
as dietary tyramine (Asatoor et al., 1963) or ephedrine.
Clinical Endocrinology (1995) 42
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Lefebvre and colleagues (1994) report a complex drug
interaction which resulted in paroxysmal hypertension and
with features suggesting phaeochromocytoma. The patient
was receiving the monoamine oxidase type B inhibitor
selegiline, the tetracyclic antidepressant maprotiline, the
sympathomimetic ephedrine, levodopa with carbidopa,
theophylline, and the dopamine agonist lisuride. The
trigger to the development of hypertension appears to
have been the introduction of ephedrine for the treatment of
bronchospasm. Ephedrine is a non-selective adrenoceptor
stimulant with direct and indirect sympathomimeticactions.
Its lack of selectivity coupled with the availability of more
selective B2 receptor agonists has rendered it almost
redundant. The combination of drugs used in this patient
carried a high risk for provoking cardiac arrhythmias and