The side effects of corticosteroids

					                 The side effects of corticosteroids

                                           Bernard Becker




C,   'orticosteroids are of enormous value
in the suppression of the ocular inflamma-
                                                          and with competent observations for recog-
                                                          nized side effects. It is important to re-
tory reaction to various injurious agents.                emphasize that steroid therapy is not a
The administration of corticosteroids alters              cure for inflammatory disease, but is often
the metabolism of carbohydrates, proteins,                a very important adjunct to other more
and lipids, as well as affecting almost all               specific therapies. Steroids are most valu-
other endocrine secretions, salt and water                able in the short-term treatment of self-
balance, and a large number of enzymatic                  limited inflammatory processes. In ophthal-
reactions. Therefore, it is not at all surpris-           mology the alleviation of inflammatory re-
ing that corticosteroids have side effects.               actions often becomes of major importance.
   For the intelligent use of any hormone                 Properly used, steroids can prevent opaci-
or drug, the clinician must be familiar not               fication of the ocular media, avoid destruc-
only with its beneficial effects, but also                tion of critical visual elements, and de-
with its other actions. Knowledge of the                  crease damage to aqueous humor outflow
various undesirable changes permits the                   channels.
clinician to recognize their early occurrence
in the individual patient and to alter his                Choice of therapy
therapy accordingly. Such information                        Corticosteroids differ in their relative
should not lead the competent and con-                    potency per milligram, but all available
scientious physician to abandon the use of                steroids are essentially the same as to their
life-saving or sight-preserving corticoste-               effects and side effects at the doses neces-
roids when they are indicated. On the con-                sary for suppressing inflammation. The
trary, an understanding of side effects per-              outstanding exception is the greater elec-
mits him to weigh carefully and continu-                  trolyte-retaining effects of hydrocortisone
ously the relative merits against the                     and cortisone than of the newer and more
potential risks of the prescribed therapy.                potent anti-inflammatory corticosteroids.
   As with other potent drugs, corticoste-                In Table I are presented the relative po-
roids should be used only when indicated,                 tency, size of the tablet for systemic use,
for the minimum amount of time necessary,                 and available concentrations of topical
                                                          preparations for most of the currently avail-
                                                          able steroids. The clinician needs this in-
From the Department of Ophthalmology and the              formation because some patients tolerate
  Oscar Johnson Institute, Washington University          one steroid better than another.
  School of Medicine, St. Louis, Mo.
This investigation was supported in part by a Re-         Systemic side effect of steroids
  search Grant B-621 from the National Institute
  of Neurological Diseases and Blindness, Na-               In Table II are listed the common sys-
  tional Institutes of Health, Bethesda, Md.              temic side effects which may follow the
                                                    492
Volume 3                                                                   Side effects of corticosteroids 493
Number 5




administration of any of the corticosteroids.                   by suitable regulation of diet and insulin.
Most of these become prominent problems                         The retention of sodium and fluid, although
only with prolonged administration and are                      somewhat less prominent with newer
avoided with short-term use (less than 3                        steroids, still remains a problem. It may be
to 4 weeks). When clinically feasible,                          partially avoided by salt restriction or over-
ophthalmologists can avoid many of the                          come by the use of diuretics. Osteoporosis,
systemic effects by the use of topical or                       fractures, and mental and emotional symp-
subconjunctival medications.                                    toms are much more difficult to manage,
   The Cushingoid state with moon facies,                       and often require cessation of steroid
weight gain with typical distribution, in-                      therapy.
creased fat pads, striae, ecchymoses, acne,                        The increased susceptibility to infection
hirsutism, and hypertension is seen fre-                        and the possible dissemination of tubercu-
quently after systemic corticosteroids and                      losis and fungal agents are important com-
is difficult to avoid or manage. Activation                     plications of systemic steroids. Where pos-
of peptic ulcers, occasionally with massive                     sible the use of specific antibiotic therapy
hemorrhage, is a distressful and sometimes                      can be most helpful. In individuals with
serious side effect. Although the use of                        evidence of tuberculosis, it is common
antacids will patrially alleviate some of the                   practice to use isoniazid and para-amino
symptoms, it does not always prevent the                        salicylic acid when steroid therapy is un-
reactivation. Another serious side effect                       dertaken. Adrenal atrophy and insufficiency
is the precipitation or aggravation of a dia-                   are induced in all patients who are treated
betic state. This can usually be managed                        with systemic steroids for prolonged peri-


Table I. Corticosteroid preparations and potency

             Generic name                          Relative                          Dose form
             (trade name)                          potency       Systemic (nig.) \          To^ncal (%)
Hydrocortisone                                        1               20              0.5 and 2.5
  (Cortef, Hydrocortone)
Cortisone                                              0.8           25               0.5 and 2.5
  (Cortone)
                                                       4
                                                                      in




Prednisone
  (Meticorten, Deltasone)
                                                       4
                                                                      in




Prednisolone                                                                          0.12, 0.2, 0.5, and 1.0
   (Meticortelone, Sterone)
Methylprednisolone                                     5               4               o
   (Medrol)
Triamcinolone                                          5               4              0.1
   (Aristocort, Kenacort)
Paramethasone                                         10               2              0.1
   (Haldrone)
Fluprednisolone                                       13               1.5
   (Alphadrol)
Fludrocortisone                                      20                 t             0.1
   (Florinef)
Dexamethasone                                        28                0.75           0.1
  (Decadron, Maxidex, Hexadrol, Gam-
    macorten)
Betamethasone                                        33                0.6            0.1
  (Celestone)
°Depo Medrol, 20 mg. and 40 mg. per milliliter for injection,
f Marked mineralocorticoid effects.
494 Becker                                                                       Investigative Ophthalmology
                                                                                                October 1964




Table II. Systemic side effects of                        prednisone or equivalent), 30 to 40 per
corticosteroids                                           cent are found to have posterior subcap-
                                                          sular cataracts. With high doses (over 15
1.   Cushingoid state
2.   Activation of peptic ulcer
                                                          mg. of prednisone) and long-term therapy
3.   Precipitation of diabetes                            (over 4 years), the incidence of cataracts
4.   Retention of sodium and fluid                        approaches 80 to 100 per cent. Steroid-
5.   Osteoporosis                                         induced cataracts are also described in
6.   Acute interstitial pancreatitis
7.   Mental and emotional symptoms                        patients with lupus erythematosus, ne-
8.   Increased susceptibility to infection                phrotic syndromes, sarcoid, scleroderma,
9.   Iatrogenic adrenal insufficiency                     asthma, pemphigus, and lymphoma. The
                                                          fact that the lens changes relate to the dose
                                                          and time of administration, as well as their
Table III. Ocular side effects of                         occurrence in very young individuals, lends
corticosteroids                                           credence to the belief that the cataracts are
                                                          steroid induced. The failure of some ob-
Systemic                                                  servers to note lens changes suggests varia-
  Cataracts                                               tions in different populations. Such marked
  Papilledema
                                                          differences in individual susceptibility to
Topical                                                   lens opacification may reflect genetic fac-
  Keratitis: viral, bacterial, fungal                     tors.
  Glaucoma
  Other: mydriasis, blurred vision,          refractive      Fortunately, most of the lens changes
          change, ptosis, lens opacities                  that follow steroid therapy do not markedly
                                                          impair visual acuity. Thus, in various series,
                                                          less than 10 per cent of patients on long-
ods of time. It is important to appreciate                term steroids had vision reduced to less
this and to taper gradually rather than to                than 20/60. The management of patients
discontinue systemic steroid therapy ab-                  with cataracts induced by systemic steroids
ruptly. Some recommend stimulation of the                 must depend on the early observation of
adrenal by ACTH preparations. Supple-                     the lens alterations, re-evaluation of the
mental steroids may be needed during ma-                  needs of the patient for steroids, and the
jor diseases or for general anesthesia and                degree of visual impairment. If steroids
surgical procedures within a year after                   can be given for short periods of time,
cessation of steroid therapy.                             cataracts are not a significant problem. If
   For those clinicians who attempt to de-                long-term steroids are necessary for the
termine by skin-testing the "etiologic" basis             maintenance of life or for permitting the
of such diseases as uveitis, it is important              patient to continue as a productive indi-
to realize that large systemic doses of cor-              vidual, then they may be continued in spite
ticosteroids can suppress skin reactions.                 of increasing lens changes. If lens changes
                                                          occur which are of sufficient magnitude to
Ocular side effects of systemic steroids                  impair visual acuity, cataract surgery may
   The major ocular side effect of systemic               be necessary. The question as to whether
steroid therapy is the development of pos-                the less frequent (e.g., weekly) adminis-
terior subcapsular cataracts (Table III).                 tration of steroids in very large doses will
Without steroids posterior subcapsular                    reduce the incidence of cataracts is not yet
cataracts are described in 0 to 8 per cent                resolved.
of individuals with rheumatoid arthritis,                    Papilledema is a rare complication that
and in 0 to 4 per cent of normal individuals.             occurs after prolonged systemic adminis-
In patients with rheumatoid arthritis sub-                tration of triamcinolone or prednisone to
jected to steroids, after long-term use (over              children. Unless a careful history is taken
2 years) at moderate doses (10 mg. of                      and due consideration given to this cause
Volume 3                                                 Side effects of corticosteroids 495
Number 5




of papilledema, the patient, parents, and        mal lesions requires further study. The oc-
physician may suffer unnecessarily. There        currence of herpetic keratitis in a patient
are also reports of keratitis or impaired out-   who is taking topical steroids for other
flow facility after systemic corticosteroids,    purposes is best managed by discontinuing
but of lesser magnitude than follow topical      the steroids and probably instituting IDU
administration.                                  therapy.
                                                    Other viral and bacterial infections. It
Ocular side effects of topical or                is not yet clear as to how many other viral
subconjunctival corticosteroids                  diseases of the cornea are aggravated by
   Herpetic keratitis. The incidence of her-     topical steroids. There is suggestive evi-
petic keratitis induced by topical steroids      dence that this may be true for vaccinia.
appears to be very low. The administration       There are also reports of systemic spread
of topical steroids for periods of 6 to 16       of herpes zoster following steroid admin-
weeks to over a thousand individuals with        istration. Trachoma and bacterial infections
normal eyes, with primary open-angle glau-       may also be enhanced by topical steroids
coma, or with suspected glaucoma, failed         even when the clinical picture seems de-
to induce a single instance of herpetic          ceptively improved. The use of specific
keratitis in spite of weekly tonometry and       antibiotics is most important in the man-
tonography. On the other hand, there is          agement of these conditions, and may even
reasonable clinical and experimental evi-        permit the continuation of corticosteroids
dence that herpetic keratitis can be re-         if necessary. It is much better to treat these
activated or made very much worse by the         infections if and when they occur rather
use of topical or subconjunctival cortico-       than to use routine combinations of corti-
steroids. It is the experience of many oph-      costeroids and antibacterial or antiviral
thalmologists that individuals with herpetic     agents. Such admixtures involve unneces-
keratitis too frequently have been con-          sary expense, arbitrary dosage, increased
tinued on topical steroids to the point of       risk of sensitization to the antibiotic, po-
descemetocele and perforation. In spite of       tentiation of development of resistant orga-
considerable publicity and attempts to dis-      nisms, and increased risk of superinfections
seminate this information, most large clin-      with fungi and low-grade pathogens.
ics continue to see herpetic keratitis mis-         Fungal keratitis. Fungal keratitis is an-
treated in this fashion.                         other potential danger of the use of topical
   Although it is generally agreed that          or subconjunctival corticosteroids. The
steroids are contraindicated in superficial      characteristic picture here is of a trivial
dendritic keratitis, there are many who feel     farm injury to the cornea, especially with
that steroids can be of great help in the        vegetable matter. Treatment with corti-
stromal and anterior uveal involvement           costeroids and antibiotics is followed by
which may follow herpetic keratitis. In          the development of a mycotic abscess of
these instances some investigators believe       the cornea. As with herpetic lesions, the
that iodo-deoxyuridine (IDU) may be of           aggravation of fungal keratitis can be
help in attacking the virus while steroids       demonstrated in experimental rabbits as
are reducing the inflammatory reaction in        well as in patients. Management consists
the cornea. In individual instances it does      of avoiding steroids in certain types of in-
prove possible to avoid recurrence of her-       jury, discontinuing steroids promptly, and
petic figures by the use of IDU and suit-        the possible use of such agents as nystatin
able reduction of corticosteroid dose.           or amphotericin. Many of these eyes re-
However, the question of whether IDU             quire corneal transplantation and too many
and corticosteroids used together may po-        are lost.
tentiate the deleterious effects of each on         Corticosteroid glaucoma. Isolated cases
wound repair and healing of corneal stro-        of corticosteroid glaucoma have been
496   Becker                                                             Investigative Ophthalmology
                                                                                        October 1964




described in the literature for many years,      chamber when applied topically, but which
but it is only in the past two or three years    can be very effective in the treatment of
that it has been generally appreciated how       external diseases involving the lids and
frequently topical or subconjunctival ste-       conjunctiva.
roids induce elevations of intraocular pres-        The finding that intraocular pressure can
sure in human eyes. Although the detailed        be elevated by the administration of topical
mechanism of this elevation is not yet           steroids leads many ophthalmologists to
known, it is clear that the pressure eleva-      give up the use of topical steroids com-
tion simulates that of primary open-angle        pletely. This is indeed unfortunate, for
glaucoma. Thus, one sees impaired out-           these agents are extremely valuable com-
flow facility, elevated intraocular pressure     ponents of the pharmacologic armamen-
and, if sustained long enough, characteris-      tarium of the eye physician. It is important
tic glaucomatous cupping of the optic            to know that glaucoma can follow the use
nerve and field loss. The more marked pres-      of topical corticosteroids and this offers a
sure elevations after topical steroids ap-       strong argument against the indiscriminate
pear to be genetically determined. They          administration of these agents for a large
are the rule in patients with primary open-      variety of minor ills. However, since intra-
angle glaucoma and occur in a large per-         ocular pressure can be measured readily,
centage of the close relatives of such pa-       and when corticosteroids are discontinued
tients. In addition, significant pressure ele-   the pressure effects appear to be entirely
vations are noted in some 30 to 50 per cent      reversible, there is every reason for using
of the adult population. In the secondary        topical steroids when they are needed. It
and angle-closure glaucomas, the preva-          can be demonstrated that even the early
lence of pressure elevation more closely         changes in visual fields that follow the in-
resembles that of the normal population          traocular pressure elevation induced by
rather than the primary open-angle glau-         corticosteroids are also reversible after the
coma group.                                      pressure is normalized. However, the pro-
   In addition to genetic determinants, a        longed use of topical steroids can produce
number of other factors contribute to the        extensive cupping and irreversible field loss
pressure rise induced by topical steroids.       which persist even after intraocular pres-
The rise in pressure occurs more frequently      sure and outflow facility return to normal.
in older people. It appears to be related to        It is important to remember that the de-
the potency and dose of the agent used,          gree of pressure elevation as well as the
the frequency of its administration, and         time to return to normal after steroids are
the duration of therapy. The less potent         discontinued relate to the duration of ad-
agents take longer to produce pressure ele-      ministration as well as to the dose and
vation, and the elevation is not as high as      potency of the steroid. For most external
those induced by more potent agents. An-         diseases the problem may be resolved when
other important factor in determining the        corticosteroids become available which are
degree of elevation of intraocular pressure      effective anti-inflammatory agents but do
is the ease with which the steroid pene-         not induce elevations of intraocular pres-
trates into the anterior chamber. There is       sure (because of their poor penetration or
evidence that only those steroids that get       pharmacologic properties). As a reasonable
into the anterior chamber influence out-         rule until then, one should use short-term
flow facility. Poor penetration as well as       administration of an agent just potent
plasma dilution undoubtedly account for          enough and sufficiently frequent to over-
the much lesser effect of systemic steroids      come the inflammatory process. Intraocular
on intraocular pressure. It should therefore     pressure should be measured and eleva-
be possible to find anti-inflammatory ste-       tions anticipated. If there are pressure ele-
roids that fail to penetrate into the anterior   vations and it is felt to be essential to con-
Volume 3                                               Side effects of corticosteroids   497
Number 5




tinue the topical steroid administration,       conditions as well as to the effects of topi-
antiglaucoma medications, such as miotics,      cal steroids. However, except for the lens
topical epinepbrine, and systemic carbonic      changes, these side effects are entirely
anhydrase inhibitors, should be used as         reversible and rarely prove of sufficient
needed. It has been demonstrated re-            magnitude to alter therapy.
peatedly that these antiglaucoma agents
act in steroid-induced glaucoma very much       Conclusion
as they do in primary open-angle glau-             The administration of corticosteroids in-
coma. Ultimately, the effectiveness of the      duces a multiplicity of interrelated altera-
antiglaucoma medication can be evaluated        tions in metabolic processes. As with other
by measurements of intraocular pressure         drugs, only a small per cent of such changes
and outflow facility. It often proves neces-    are beneficial. The remainder is either
sary to continue such antiglaucoma medi-        meaningless or undesirable. The clinician
cation for considerable periods of time         must determine and continue to re-evaluate
 (months) after long-term topical corti-        the needs of the individual patient for cor-
costeroids are discontinued. So far as the      ticosteroids, the choice of dose, route,
side effects of elevated intraocular pressure   agent, duration of therapy, and the relative
are concerned, therefore, the crux of the       therapeutic benefits as compared to the
 use of topical steroids depends upon the       possible harmful effects. In the individual
measurement of intraocular pressure, the        patient this may depend on hereditary fac-
 continuous re-evaluation of need for steroid   tors, the disease process itself, the presence
therapy, and the careful follow-up of the       of other diseases, the nutritional and endo-
individual patient.                             crine status of the patient, and many other
    Other side effects. Other ocular side ef-   factors. The ophthalmologist determines
fects that have been noted following topi-      the nature and severity of the patient's eye
 cal corticosteroid administration include      disease and knows the prognosis without
 slight dilatation of the pupil, unexplained    therapy. It is most important that he have
 blurring of vision, occasional refractive      an awareness of the complications as well
 changes, rare posterior subcapsular lens       as the benefits of the potent agents that are
 opacities, and variable ptosis. All of these   placed at his disposal.
 are confined to the eye receiving steroids
 and have been better delineated in con-        Summary
 trolled series of "normal" individuals in        The systemic and ocular complications
 whom topical steroids have been applied to     of the use of corticosteroids are reviewed
 one eye. The mechanisms of these changes       and suggestions made for their manage-
 are unknown but may provide important          ment.
 clues to the pathogenesis of these ocular

				
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