ANNALS O F CLIN ICA L AND LABORATORY S C IEN C E, Vol. 19, No.

2
Copyright © 1989, Institute for Clinical Science, Inc.

Hematologic Side Effects of Drugs

M IC H A E L M. LUBRAN, M .D ., P h .D .

Harbor-UCLA Medical Center,

Department o f Pathology,
Torrance, CA 90509

ABSTRACT

Bone m arrow and peripheral blood cells may be adversely affected by

drugs. Although the risk from m ost drugs is very small, m any cases are
rep o rted because of the millions of doses of drugs taken each year by the
population. N eutropenia, throm bocytopenia, hem olytic anem ia, aplastic
anem ia, and macrocytic anem ia are the com m onest effects, in that order.
Aplastic anem ia is rare, b u t very serious w hen it does occur. A dverse
effects may be produced by a direct toxic action of th e drug or its m etabo­
lites on th e bone m arrow or, less often, on circulating cells. Antineoplastic
drugs and ch lo ram p h en ico l are exam ples. M ost drugs p ro d u ce th e ir
adverse effects through an immunological m echanism . The drug m ay act
as a hapten or may affect the im m une system leading to the production of
an tid ru g antibodies and som etim es autoantibodies. H em olytic anem ia
may result. Penicillins may behave in this m anner. Some drugs act on
erythrocytes w ith enzym e defects, e.g. glucose-6-phosphate dehydroge­
nase (G-6-PD) abnorm alities, to produce hemolysis. In m any cases, the
m echanism underlying the adverse effect is unknown. The paper lists the
drugs re p o rte d to have caused som e hem atological adverse effect and
describes the m echanism s in those cases w here they are known.

Introduction related, and the affected cells retu rn to

Many drugs may adversely affect the
h e m a to p o ie tic system and p e rip h e ra l
blo o d cells. T h e p rin c ip a l effects, in
o rd e r o f fre q u e n c y , a re n e u tro p e n ia ,
th ro m b o cy to p en ia, hem olytic anem ia,
aplastic anem ia (and pancytopenia), and
macrocytic (or megaloblastic) anemia. In
a d d itio n , o th e r ty p es o f an e m ia m ay
occur and also m ethem oglobinem ia and
coagulation defects. A drug may cause
m ore than one adverse reaction and may
act b y tw o or m o re d iffe re n t m ec h a ­
nisms. Often, the effect is dose and tim e
114
0091-7370/89/0300-01X4 $01.20 © Institute for Clinical Science, Inc.
norm al after th e drug is discontinued;
h o w ev er, in som e cases th e a d v e rse
effect is irreversible, and the patient may
die. Serious adverse effects are uncom ­
m on, w h en view ed against th e b ack ­
ground of the millions of doses of drugs
taken daily in the total population. Tran­
s ie n t effects are co m m o n er a n d pass
unnoticed for the m ost part unless dis­
covered during som e clinical exam ina­
tion. The frequency of adverse reactions
to drugs is thus difficult to determ in e.
M uch of our knowledge is derived from
reports in the literature describing one
 HEMATOLOGIC SIDE EFFECTS OF DRUGS
or a sm all n u m b e r o f cases. M any of
th e se re p o rts are an ecd o tal, and it is
som etim es difficult to be sure th at the
effect described was caused by the drug
and not by th e illness for which it was
given, or by some o th er drug. However,
a few large scale studies have been p u b ­
lished,5,816,17 and the m odes of action of
som e drugs on th e blood system have
b een studied. M any countries now col­
lec t system atically a d v erse d ru g rea c ­
tions of all types re p o rte d to th em by
physicians, and th ere are several books
detailing adverse reactions.9,11,15,22 This
paper will describe th e adverse hem ato­
logical reactions (excluding coagulation)
attributed to drugs, gleaned from the lit­
e ra tu re an d , w h e n e v e r p o ssib le , th e
m echanism s underly in g th e reactions.
O nly drugs used in th e U nited States
will be considered.
A dverse Effects o f D rugs
D ru g s m ay p ro d u c e th e ir a d v e rs e
effects through toxicity, by an im m uno­
logical process, by inhibiting the action
of im portant enzym es, by decreasing the
a b so rp tio n of su b stan ces essen tial for
n o rm a l h e m a to p o ie s is , o r b y as y e t
unknow n m echanism s. A w ell-studied
drug, now not often used, is chloram ­
ph en ico l.23 This d ru g s bin d s to m ito ­
chondria, in h ib itin g th e form ation of
inner m em brane enzym es by inhibiting
p e p tid y ltran sfe ra se , n ecessary for the
form ation of p e p tid e bonds. The toxic
effects of chloram phenicol are caused by
its action on m itochondria. Bone marrow
a p la s ia o c c u rs in a b o u t 1 :1 9 ,0 0 0 to
1 :200,000 c o u rse s o f th e ra p y . M ost
patients develop a dose-related revers­
ible e ry th ro id su p p ressio n , caused by
in h ib itio n of ferro ch elatase, an in n e r
m em brane enzyme.
The toxic effect of drugs may be delib­
erately sought to suppress abnorm al cell
activity, as in the use of chem otherapeu­
tic agents, or it m ay b e an u n w an ted
115
side-effect of a drug. In the form er case,
the toxic effect is dose and tim e d ep en ­
dent; in th e la tte r case, it is often not
dose dependent. Imm unological m echa­
nism s r e q u ir e p rio r ex p o su re to th e
drug. S ubsequent adm inistration of the
drug results in antibody formation, lead­
ing to dam age of blood cells. E nzym e
inhibition may be a property of the drug
and occur in all subjects receiving it (as,
for example, w ith m any chem otherapeu­
tic agents), or th e drug may act on cells
g e n e tic a lly d e fic ie n t in an e s s e n tia l
e n z y m e ( e .g ., g lu c o s e - 6 -p h o s p h a te
dehydrogenase). A few drugs decrease
ab so rp tio n of folate o r B12, causing a
m acrocytic anem ia or m egaloblastosis.
A lth o u g h th e a d v e rs e e ffe c t can b e
ex p lained in som e cases, th e cause is
u n k n o w n fo r th e m a jo rity o f d ru g s.
These idiosyncratic effects are unpredic­
ta b le , c a n n o t b e d e d u c e d fro m th e
known pharm acological properties of the
d r u g a n d m ay o r m ay n o t b e d o se
related. T hey m ay be related to som e
genetic feature of the patient, e.g., the
patient may be a slow acetylator, b u t in
m ost cases no cause can be found. Idio­
syncratic drug reactions affecting blood
c e lls a re u n c o m m o n ; n e v e r th e le s s ,
b e c a u se o f th e en o rm o u s n u m b e r of
doses of drugs given to the population,
they will occur almost inevitably, even
w ith th e s a fe s t d ru g s . M o st o f th e
re p o rted adverse d rug effects rela te to
the idiosyncratic behavior of the drug in
one or a very few subjects. H ow ever,
th e re are som e drugs w hich p ro d u c e
adverse effects in an appreciable n u m b er
of subjects. The following sections will
describe the various adverse hem atologi­
cal effects and the drugs causing them .
Aplastic Anem ia
Aplastic anem ia is an occasional com ­
plication of the chem otherapy of cancer.
Antineoplastic drugs are usually used in
com bination to treat cancers and hem a­
116 LUBRAN
tological m alig n a n c ies by in te rfe rin g
w ith cell g row th a n d division. In th e
doses used, rapidly dividing norm al cells
are also affected, including those in the
bone marrow. A selective anemia, n eu ­
tropenia, throm bocytopenia, or combi­
nation of these occur regularly d epend­
ing on the dose, duration of treatm ent,
and susceptibility of th e p atien t. Less
commonly, aplastic anem ia or pancyto­
penia may develop.
Alkylating agents act on DNA, cross-
linking its strands or breaking them . All
phases of th e cell cycle are affected and
all bone m arrow cells may be involved.
Alkylating agents include busulfan, car-
m ustine, chloram bucil, cisplatin, cyclo­
phospham ide, dacarbazine, lom ustine,
m echloretham ine, m elphalan, pipobro-
man, thiotepa, and uracil m ustard.
Antim etabolites affect DNA synthesis
by enzym e inhibition or by blocking the
synthesis of p urine or pyrim idine com ­
ponents. A zathioprine, m ercaptopurine,
th io g u a n in e a re p u r in e a n ta g o n ists;
cytarahine, floxuridine, fluorouracil are
p y rim id in e a n ta g o n ists; m e th o tre x a te
b in d s to d ih y d ro fo la te re d u c ta s e and
h y d ro x y u re a in h ib its rib o n u c le o tid e
reductase. A ntim etabolites may act d u r­
ing th e e n tire cell cycle b u t are m ost
effective in the S phase (DNA synthesis).
M ethotrexate inhibits folic acid synthesis
and may cause megaloblastosis.
Antibiotic antineoplastic agents affect
DNA and RNA synthesis. Dactinom ycin
and daunorubicin depress all cell types
o f th e bone m arrow ; dexorubicin may
cause agranulocytosis; m ithram ycin and
m itom ycin pro d u ce throm bocytopenia;
bleom ycin does n o t d e p re ss th e bone
marrow.
O th e r antineoplastic agents: Procar­
bazine inhibits DNA, RNA and protein
synthesis and may cause leukopenia and
a n e m ia . A m in o g lu te th im id e , w h ic h
in h ib its th e synthesis of som e stero id
horm ones, causes a transient leukopenia
b u t m ay give a se v ere pancytopenia.
Tam oxifen, an estrogen antagonist, may
cause leukopenia or throm bocytopenia.
Vinca alkaloids (vinblastine, vincristine,
vindesine) and podophyllin derivatives
(etoposide, teniposide) arrest mitosis in
m etaphase and stop cell division. T he
podophyllin drugs may severely depress
th e bo n e m arrow ; th e vinca drugs are
less toxic, causing usually a transient leu­
kopenia and throm bocytopenia. Asparag­
inase may cause a leukopenia.
A p la s tic a n e m ia is an u n c o m m o n
result of o th er drugs. Various estim ates
exist for th e risk of developing it follow­
ing use of certain classes of drugs. The
incidence of aplastic anem ia among sub­
jects taking th era p eu tic drugs is about
2.2:1,000,000. M ore than half of th ese
cases result from drugs and the m ortality
is high. F o r in d om ethacin th e risk of
aplastic anem ia is about 1:100,000, for
p h e n y lb u ta z o n e a b o u t 1:300,000 a n d
m uch lower for o th er analgesics. The risk
is also v ery low for som e a n tith y ro id
drugs.
D rugs w ith a relatively high risk for
ap la stic a n e m ia in c lu d e a llo p u rin o l,
ampicillin, chloramphenicol, gold salts,
in d o m e th a c in , m e clo fen a m a te, m efe-
namic acid, m ephenytoin, oxyphenbuta-
zone, param ethadione, phenobarbital,
phenylbutazone, phenytoin, quinacrine,
trim ethadione. P henytoin toxicity may
be related to a transient antibody forma­
tion and production of abnorm al T-sup-
pressor cells.10 Phenytoin and carbamaz-
e p in e g iv e ris e to toxic a re n e -o x id e
in te rm e d ia te m etab o lites, w hich b in d
covalently to m acrom olecules of stem
cells in th e m arrow and lym phocytes.13
A bout 70 p e rc e n t of p atients on long­
te rm p h e n y to in th e ra p y have m ild to
severe abnorm alities of the im m une sys­
tem .
Low risk drugs, reported in the litera­
tu re once o r a few tim es include acet­
am inophen, acetazolam ide, acetohexa-
m id e , a s p irin , b e n d ro flu m e th ia zid e ,
benthiazide, captopril, carbamazepine,
 HEMATOLOGIC SIDE EFFECTS OF DRUGS
carbim azole, chlordiazepoxide, chloro-
quine, chlorothiazide, chlorpromazine,
chlorpropam ide, chlorthalidone, chlor-
tetracycline, cim etidine, colchicine, co-
trimoxazole, cyclothiazide, dichlorphen-
a m id e , e th o s u x im id e , e th o to in ,
e th o x z o la m id e , h y d r o c h lo r o th ia z id e ,
hydroxychloroquine, isoniazid, m epro­
b a m a te , m e th a m a z o le , m e th a r b ita l,
m ethazolam ide, m ethim azole, methsuxi-
m id e , m e th y c lo th ia z id e , m eto la zo n e,
oxytetracycline, penicillin, phenacemide,
p h e n s u x im id e , p o ly th ia z id e , p r im a ­
q u in e , p r im id o n e , p ro c h lo rp e ra zin e ,
prom azine, propylthiouracil, pyrim eth­
amine, quinethazone, salicylate, strepto­
m ycin, sulfacytine, sulfadiazine, sulfa-
merazine, sulf amethizole ,
sulfamethoxazole, sulfapyridine, sulfasa­
lazine, sulfisoxazole, sulindac, tolaza­
m ide, tolbutam ide, trichlorm ethiazide,
tr im e th a d io n e , tr ip e le n n a m in e , v a l­
proate.
Agranulocytosis and N eutropenia
Agranulocytosis may arise through the
toxic action of th e drug on bone m arrow
precursors6,7 or by destruction of cells by
circulating neutrophil antibodies. Some
dru g s d e p re ss su p p re sso r T-cells and
allow th e p ro d u c tio n of au to im m u n e
antibodies by the B-cells.25 Anti thyroid
drugs may behave in this way. In m ost
cases, th e m echanism is unknow n and
presum ed to be idiosyncratic.
N eutropenia and agranulocytosis may
b e p ro d u c e d by th e drugs listed p r e ­
viously causing aplastic anem ia. A nti­
n e o p la stic d ru g s a re re sp o n sib le for
m any o f th e cases o f n e u tro p e n ia ;1 in
fact, a selectiv e n e u tro p e n ia is m uch
c o m m o n e r th a n a p la s tic a n e m ia o r
agranulocytosis. Throm bocytopenia may
or may not occur as well. O th er drugs
producing neutropenia, which may prog­
ress to agranulocytosis, include aceto-
p h e n a zin e , a m itrip tylin e , am oxapine,
brom pheniram ine, carphenazine, chlor-
117
prothixene, clem astine, dapsone, desi-
pram ine, doxepin, ethacrynate, flu p h en -
a z in e , f u r a z o l i d o n e , g r is e o fu lv in ,
ib u p r o fe n , im ip ra m in e , lev a m iso le,
maprotiline, m ercaptom erin, mesorida-
zine, m ethotrim eprazine, m ethysergide,
metronidazole, nifedipine, nortriptyline,
novobiocin, para-am inosalicylic acid,
penicillamine, perphenazine, piperaceta-
zine, procainam ide, protriptyline, quini-
dine, quinine, thiethylperazine, thiorid­
azine, thiothixene, tocainide, trifluoper­
a zin e, triflu p ro m a zin e , trim e p ra zin e ,
trim ipram ine, tybam ate. D rugs usually
p r o d u c in g a s e le c tiv e n e u tr o p e n ia
include amoxicillin, ampicillin, bacampi-
cillin, capreom ycin, carbenicillin, cefa­
clor, cefadroxil, cefamandole, cefazolin,
cefotaxime, cefoxitin, cephalexin, cepha-
log lycin , c e p h a lo rid in e , c e p h a lo th in ,
cephapirin, cephradine, chlorphenira­
m ine, clindam ycin, clofibrate, cyclacil-
lin, dantrolene, dem eclocycline, diaze­
pam , diazoxide, doxycycline, flucytosine,
haloperidol, hetacillin, levodopa, linco-
m ycin, loxapine, methacycline, methyl-
dopa, mezlocillin, molindone, moxalac-
tam, nafcillin, oxacillin, oxy tetracycline,
p e n ic illin G, p e n ic illin V, p y r im e th ­
amine, rifam pin, tetracycline, ticarcillin,
trim ethoprim , valproate, vidarabine,
H em olytic Anem ia
D rug-induced hem olytic anem ia may
occur as a result of a direct toxic effect on
norm al circulating erythrocytes, on cells
w ith ce rtain enzym e defects, on cells
w ith som e u n s ta b le h e m o g lo b in s, or
through an im m une m echanism .
D irect toxic effects are dose related,
have a slow onset, and occur in all sub­
jec ts. Few drugs are know n to cause
hem olytic anem ia in this way. The best
known are phenacetin (which also acts on
enzym e-defective cells) and th e sulfones
used in the treatm en t of leprosy, espe­
cially dapsone. This drug causes hem o­
lysis in all subjects, m ethem oglobinem ia
118 LUBRAN
in m any and hem olytic anem ia in a few
on prolonged treatm en t. D rugs which
may b e toxic to erythrocytes, b u t may
also act by o th e r m echanism s, include
cep h a lo th in , ch lo rp ro m a zin e, clem as­
tin e, ethoxzolam ide, h y d ro ch lo ro th ia ­
zid e , in d o m e th a c in , m e fa n a m ic acid,
m eta xo lo n e, m e th a zo la m id e , m e th y l-
dopa, oxyphenbutazone, phenazopyri-
d in e, p h e n y lb u ta z o n e , s tr e p to m y c in ,
sulfam ethazine.
E n z y m e d e f e c ts : T h e p rin c ip a l
enzym e involved in hem olytic anem ia is
g lu c o s e - 6 - p h o s p h a te d e h y d ro g e n a s e
(G- 6 -PD). These drugs give rise to acute
episodes of hem olytic anem ia which may
b e dose related, w hen adm inistered to
G - 6 -P D d e fic ie n t p a tie n ts . In som e
cases, the condition is self-limiting and
disap p ears in a b o u t seven days, even
though drug adm inistration is continued.
This occurs w hen existing G- 6 -PD defi­
cient cells have been destroyed and the
newly form ed cells have becom e resis­
ta n t to th e drug. T h e e ry th ro cy te s in
drug-induced hem olytic anem ia caused
by enzym e deficiency usually show baso­
philic stippling and may contain H einz
bodies. D rugs include chloram phenicol,
chloroquine, dapsone, dimercaprol, f u r ­
azolidone, isoniazid, m enadione, nali­
dixic acid, nitro fu ra n to in , phenacetin,
phytonadione, prim aquine, probenecid,
quinidine, quinine, sulfapyridine, sulfi-
soxazole, sulfoxone.
H em olytic anem ia is seldom caused by
d ru g s in th e c a se o f o th e r r e d c e ll
enzym e deficiencies, b u t existing anem ia
m ay b e e x a c e rb a te d . S u lfo x o n e m ay
cause hem olytic anem ia in glutathione
reductase deficiency.
U nstable hem oglobins: E xacerbation
of existing hem olytic anem ia m ay occur
in subjects w ith some unstable hem oglo­
bins, e .g ., H b-Z urich, w hen given the
drugs causing hemolysis in G- 6 -PD defi­
ciency.
D rug-induced im m une hem olytic ane­
m ia : A ntibodies w hich re a c t w ith re d
cells to activate com plem ent and p ro ­
duce lysis may be form ed by two differ­
e n t m e c h a n ism s. I n th e h a p te n -c e ll
m echanism , certain drugs given in large
doses b in d to p ro te in s o f th e re d cell
m em brane and act as haptens. Cephalo­
sp o rin s an d p e n ic illin s m ay p ro d u c e
these antibodies. Penicillin is p resent on
th e surface of re d cells of all p a tie n ts
receiving the drug. A bout th ree percent
of p atients on high doses of penicillin
have IgG antibodies, and a small n um ber
of these patients go on to develop hem o­
lytic anemia.
In the im m une complex mechanism,
the drugs bind to a serum protein and
com bine w ith th e resulting antibody to
form an im m une complex. This adsorbs
to the surface of the red cell and to other
cells, e.g., throm bocytes and leukocytes,
b in d s c o m p le m e n t a n d c a u se s c e ll
destruction. T he antibody is usually IgM
in type. Q uinidine and rifam pin produce
im m une complexes.
An a u to -im m u n e hem olytic anem ia
may be drug-induced. It is believed that
the drug binds to one o f the blood group
antigens on the red cell surface, usually
an Rh antigen. The resulting antibody is
directed against the blood group antigen;
occasionally, an anti-drug antibody coex­
ists . 14 A bout 15 p e rc e n t o f p atients on
m ethyldopa and about nine percent on
lev o d o p a h av e d e m o n s tra b le a u to im ­
m une antibodies in th eir sera after treat­
m ent for th re e m onths to a year; about
one in ten thousand develop hemolytic
anem ia. An a lte rn a tiv e to th e h a p te n
m echanism is th e suppression of T-cell
function through an increase of c-AMP in
lym phocytes, leading to an unregulated
production of autoantibodies by B-cells.
The autoantibodies are usually of the Rh
system . 18 The drug does not act as a hap­
te n , b u t p ro d u c e s its effects via th e
im m u n e system . T h e im m u n e system
plays an im p o rta n t ro le in reg u latin g
norm al hem atopoiesis . 21
Drugs giving rise to antibodies include
c e fa m a n d o le , c e fo ta x in e , c e fo x itin e ,
cephalothin, co-trim oxazole, isoniazid,
 HEMATOLOGIC SIDE EFFECTS OF DRUGS
levodopa, m efanam ic acid, m ethicillin,
m ethyldopa, moxalactam, nalidixic acid,
oxacillin, para-aminosalicylic acid, peni­
cillin G, penicillin V, quinidine, quinine,
rifam pin, sulfacytine, sulfadiazine, sul-
fa m e r a zin e , su lfa m e th izo le , su lfa p y ri-
dine, sulfasalazine, ticarcillin, tolmetin.
A utoantibodies are found w ith levodopa,
m ethyldopa and m efanam ic acid.
T hrom bocytopenia
This m ay re s u lt from a d ire c t toxic
effect o f the drug on platelet precursors
in th e bone m arrow or on th e circulating
platelets. D rugs associated w ith aplastic
a n em ia also cause thro m b o cy to p en ia,
th ro u g h action on m egakaryocyte p r e ­
cursors in the marrow. Low risk drugs
may cause a selective throm bocytopenia,
which is often the only indication of sup­
pression of m arrow activity. R istocetin
acts d ire c tly on c irc u la tin g p la te le ts.
L ithium carbonate given for one or m ore
y ears low ers th e p la te le t c o u n t, b u t
rarely causes p u rp u ra . 2
T h ro m b o c y to p e n ia m ay also re s u lt
from an im m une m echanism . D rug and
p la te le t com bine and produce an an ti­
body against the drug. An im m une com ­
plex is form ed w hich is adsorbed non-
specifically on to p la te le ts a n d o th e r
cells. This is referred to as “th e innocent
bystander” hypothesis. As an example,
valproate depresses the platelet count in
about one th ird of th e cases . 3,24 H ow ­
ever, the im m une complex m ay com bine
specifically w ith platelets. The antibody
to quinidine com bines w ith th e m ajor
g lyco p ro tein com plex on th e p la te le t
surface and th e antibody to ticarcillin
com bines w ith a polym orphic p late le t
a n tig e n . 14 D rugs acting by an im m une
m echanism include antim ony potassium
ta rtra te, azatadine, brom pheniram ine,
capreom ycin, captopril, chlorothiazide,
c h lo rp ro m a zin e , ch lo rpropam ide, cle­
m a s tin e , c lin d a m y c in , c lo n a z e p a m ,
deferoxamine, diazoxide, digitoxin, etha-
119
crynate, ethclorvynol, ethinamate, eth­
io n a m id e, flu c y to s in e , flu p h e n a z in e ,
f u r o s e m id e , is o n ia z id , lin c o m y c in ,
m ephobarbital, m eprobam ate, m ethar-
bital, methim azole, para-aminosalicylic
acid, penicillamine, penicillins, phenace-
tin , p h en o b a rb ito n e, p h e n y lb u ta zo n e,
p h e n o th ia z in e , p h e n y to in , p r o c a in a ­
mide, propylthiouracil, quinidine, qui­
nine, rifam pin, salicylates, stre p to m y ­
cin, sulfonamides, ticarcillin, tocainide,
trichlorm ethiazide, trim ethoprim , val­
proate, vidarabine.
M egaloblastic Anem ia
This may result from adm inistration of
drugs interfering w ith the absorption of
folic acid or vitamin B 12 or the m etabolic
functions in w hich th e y are involved.
F rank m egaloblastic anem ia is uncom ­
m on. The usual effect is m acrocytosis,
u n le s s th e p a tie n t is s e v e re ly ill or
u n d e rn o u rish e d and d e fic ie n t in folic
acid or vitamin B12. In many cases, there
is no clinical evidence of folate or B 12
deficiency, b u t th e ir concentrations in
th e blood are low.
Folic acid: Low serum folate concen­
tratio n s caused by p oor ab so rp tio n of
folate may result from adm inistration of
cycloserine, eth o to in , m e p h o b a rb ita l,
m etharbital, n itro fu ra n to in , phensuxi-
mide, phenytoin, primidone. Megaloblas­
tic anem ia m ay occur in a few cases.
About 50 percen t of patients on ph en y ­
toin have low serum folate co n cen tra­
tions and about 30 percen t have red cell
m acrocytosis a n d e a rly m eg alo b lastic
changes in the bone marrow. A bout one
percen t develop frank m egaloblastic a ne­
m ia . 4 It m ay take m any years o f d ru g
adm inistration for this to occur. It is not
clear why some patients should develop
th is co n d itio n , b u t d ie ta ry in ta k e of
folate may be a contributory factor.
D ihydrofolate reductase is in h ib ited
by methotrexate, triam terene, pyrim eth­
a m in e, tr im e th o p r im . T his is a key
120 LUBRAN
enzym e in folate m etabolism and DNA
sy n th e sis. M egaloblastic a n e m ia w ill
occur if the drug is given for a sufficient
length of tim e, in high enough doses,
b u t in practice it is unusual.
C ytarabine, flo xu rid in e, flu o ru ra c il
(an tim etab o lite antin eo p lastic agents)
in hibit pyrim idine synthesis; h y d ro xy ­
urea inhibits ribonucleotide reductase;
azathioprene, m ercaptopurine, thiogua-
nine in h ib it p u rin e synthesis; su lfo n ­
amides block the synthesis of folic acid.
All o f th e se drugs cause a low seru m
folate and eventually megaloblastic ane­
mia.
V itam in B ,,: Low serum c o n c e n tra ­
tions may result from adm inistration of
colchicine, neomycin, para-aminosalicy-
lic acid, slow release potassium chloride,
which im pair absorption of vitam in B12.
D rug-induced M ethem oglobinem ia
The com m onest cause is self-m edica­
tion w ith pain-relieving drug com bina­
tions c o n ta in in g p h e n a c e tin .20 O th e r
drugs are am yl n itrite, dapsone, prilo-
caine, prim aquine, sulfoxone, trim etho­
prim . Primaquine acts on red cells defi-
c i e n t in N A D H m e t h e m o g l o b i n
reductase. M ethem oglobinem ia is p ro ­
duced by drugs w hich are redox com ­
pounds or form a com plex w ith hem e.
H ydrogen peroxide or peroxide radicals
are form ed, leading to the form ation of
m eth e m o g lo b in . 12 In som e cases, th e
reaction proceeds further, resu ltin g in
H e in z b o d ies a n d h e m o ly tic an em ia.
M ost drugs producing hem olytic anem ia
by direct toxic action on the red cells will
also produce m ethem oglobin in th e early
stages. Som e drugs act by p ro d u cin g
toxic m etabolites in the liver.
A nem ia
Drugs which may cause aplastic ane­
m ia m ay also h a v e le s s e r e ffe c ts, o f
which anem ia is one. O ther drugs, not
asso c ia te d w ith a p la stic a n em ia, m ay
p ro d u ce anem ia by d e p re ssio n o f th e
bone m arrow or by other means. Isonia-
zid increases the severity of the anem ia
in p a tie n ts s u ffe rin g fro m p y rid in e -
responsive hypochrom ic anem ia. Rarely,
it may produce a p u re red cell hypopla­
sia . 19 This co n d itio n m ay also b e p ro ­
du ced by chlorpropam ide, co-trim oxa-
z o le , p e n i c i l l i n , p h e n y l b u t a z o n e ,
p henytoin, tolbutam ide. Indom ethacin
produces an iron-deficiency anem ia and
am photericin B a norm ochrom ic, nor-
mocytic anem ia. O ther drugs which may
produce anem ia, usually hypochrom ic,
include amoxicillin, ampicillin, bacampi-
cillin, cyclacillin, cefadroxil, cefazolin,
cephalexin, cephaloglycin, cephalori-
dine, cephapirin, novobiocin, oleovita­
m in A , vidarabine.
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