upr
`
`{The Medical Journal
`ofAustralia February 3, 1986
`
`Vol. 144, No. 3
`
`JOURNAL OF THE AUSTRALIAN MEDICAL ASSOCIATION
`
` E‘I EALTI‘I SC i El“. {7 33 Li C PIA {I ‘r’
`
`
`
`LEADING ARTICLESUnit-“arcing oi t-‘l'PAGEsin
`
`THERAPEUTICS
`Relinquishing mum; Dr,
`It'llr'n'ii‘ilj'rm Wis.
`
`
`l
`l
`Gordon Parker
`Single-dose therapy in the
`
`a3
`
`Compliance with asthma ‘t e
`
`management of urinary tract
`infections. Judith A. Whitworth_136
`in paediatric practice.
`t
`:
`
`Side-effects of corticosteroid
`David Ft. Lines
`-113 .
`
`Bicycle accidents.
`'
`agents. J. Paul Seale.
`
`139
`_ Mark Fl. Compton
`-
`Douglas Cohen -
`-
`.. 7114- -
`Informational needs for the
`' effective prevention of accidents
`in childhood. Graham Vimpani.
`John Pearn, Jerry Moller____115
`
`LETTERS TO THE EDITOR;__163
`_.
`..
`_.
`.
`__.
`..
`“.
`_._.
`
`gnsrereo oil AUEI'EIIEI Post F'uciltzai-z-n Ht. NBC [HEB-3'
`
`
`JANSSEN EXHIBIT 2069
`
`Wockhardt v. Janssen IPR2016—01582
`
`
`
`I
`.
`
`-
`
`i
`
`.
`5
`
`ORIGINAL ARTICLES
`Psychological disability in women
`who relinquish a baby for
`adoption. John T. Condon ___117
`Effects of intervention on
`medication compliance in children
`with asthma. Nerida A. Smith,
`J. Paul Seale. Philip Ley, John Shaw,
`Peter U. Bracs_____119
`Intrapulmonary coin lesions: the
`changing patterns.
`David B. Francis.
`Paul V. Zimmerman ______122
`Glucagon and ureteric calculi.
`David R. Webb. Ian N. Nunn.
`'
`Donald McOmish, William SC. Here 124
`Effective palliation of melanoma
`with procarbazine and radio-
`therapy given by a low-dose
`fractionation schedule.
`P. Grantley Gill, Richard L. Abbott.
`
`Ash Ahmad. Joan Zeicmanis
`, Major hepatic resection for
`--.
`neoplasia: the Concord Hospital
`"3
`experience. Patrick C. Cregan,
`'
`John W. Hollinshead. David J. Gillett 128
`
`.
`I
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`.
`;,'
`:.
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`_
`j
`'
`
`.
`
`126
`
`POINT OF VIEW
`Psychiatry, compensation and
`rehabilitation. Fiona K, Judd,
`' Graham D. Burrows_____131
`
`'.
`
`l
`
`i
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`-
`
`MEDICAL MISCELLANY
`Frederick III of Germany.
`James H. Leavesley_____143
`
`CASE REPORTS
`Child cyclist iniuries: a
`prospective study.
`Christopher J. Armson.
`Clifford W. Pollard_____144
`Pathological rupture of the spleen
`in transforming non-Hodgkin’s
`lymphoma. James D. Griffiths,
`Jue Chong Ding. Surender K. Juneja.
`Robert JS. Thomas. John J. Martin.
`
`Ian A. Cooper
`A case of uridine diphosphate
`galactose-4-epimerase
`deficiency detected by neonatal
`screening for galactosaemia.
`Francis G. Bowling,
`David KB. Fraser. Alan E. Clague,
`Alan Hayes. Darryl J. Morris___150
`Acute, severe hepatitis due to
`Coxiella burned infection.
`Raymond P. Kelly, David J. Byrnes,
`Jennifer Turner_____151
`
`146
`
`T'IT'
`
`i-igfiikflflvfiiw
`.l. HWY 135
`
`
`
`
`154
`NOticeJquml. "IT Irv-2r
`.
`
`
`meetings .‘.
`--
`.-
`“ P 155
`Obituarie .
`-
`158
`_‘
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`Book Revl s_____159
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`JANSSEN EXHIBIT 2069
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`139
`Therapeutics
`l986
`HE MEDICAL lOlJRNAL OF AUSTRALIA Vol. 144 February 3.
`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Side-effects of corticosteroid agents*
`
`
`cortico—
`ABSTRACT Anti—inflammatory
`tcroid drugs are powerful therapeutic agents
`tor a wide range of disorders. l-loweVer, they
`to have recognized side—effects. most of
`which are related to the dose and the duration
`-..t therapy. Thus. short courses of even high
`rinses of corticosteroid drugs have very few
`adverse effects. A detailed knowledge of the
`long-term side-effects of corticosteroid agents
`and their incidence will assist the physician
`1 making informed iudgements on the mien—
`tial benefits of treatment with these drugs.
`(Med l Aust
`'IQBEI: H4: 139-142)
`
`he development ofcorticostcroid agents
`represented a major advance in the
`treatment of numerous inflammatory
`diseases of varying causes: regrettably.
`their
`widespread use must be tempered by an
`appreciation of their side-effects. which occur
`.ommonly. As with any potent
`therapeutic
`agents. the prescribing of corticostcrt'iid therapy
`should be guided by a careful consideration of
`its perceived benefits and potential risks. This
`article will
`review the unwanted effects of
`systemically administered anti-inflammatory
`corticosteroid agents.
`the complications of
`In general.
`any of
`corticosteroid agents are related to the dose and
`the duration oftherapy.1 Thus. most of the well
`known problems will arise only during long—
`tcrm treatment. On the other hand. remarkably
`few. adverse effects are associated with short
`courses of corticosteroid drugs.
`even
`in
`relatively high doses.’
`In view of this clear
`distinction. short—term and long—term treatments
`will he considered separately.
`'-
`Since prcdnisonc. prcdnisolonc
`and
`mctltylprcdnisolone are the most commonly
`used corticosteroid agents. most of the available
`:linical data on side-effects concern these drugs.
`Sound reasons exist for the administration of one
`
`oftliesc agents in preference to the more potent
`corticosteroid drugs. such as dcxmnethas‘one and
`netarnethasonc. Prcdnisone. prcdnisolone and
`its methyl analogue have less mincralocorticoid
`.tctivity than does cortisol. so their propensity
`to retain sodium and water will be less than that
`of cortisol. In addition. their biological half-lives
`are of intennediate duration (12—36 hours).
`allowing a once—a-day dosage
`rcgimcn.‘
`Furthermore, a patient's daily requirements can
`easily be obtained from the range of the available
`tablets and this facilitates the pn'iceSs of titratirrg
`dosage against disease to find the minimum dose
`
`
`the disease.that will control In contrast.
`'Ftltb cuticle in an occasional scrim on therapy with
`corticosteroid agents.
`Department of Pharmacology, The University
`of Sydney. NSW 2006.
`.'. Paul Scale. PhD.
`l-RACP, Associate I’rols-sstir in
`l. ltnical Pharmacology
`Mark R. Compton. BSr, Ruse-arch Assistant
`l‘ll"]‘|'ll'll:~ will not be available front the authors. The
`wires of arltcles on corltroslcroid therapy will be
`published later in booklet form.
`
`J. Paul Scale and Mark R. Compton
`
`although dcxamcthttsone and betamcthasonc are
`virtually devoid of mincralt'icorticoid activity,
`they have much longer biological half-lives
`(36—54 hours) which are responsible for their
`profound suppression of the hypothalamic—
`pituitary—adrenal axis. Also. the available tablet
`strengths do not allow for the same line titration
`of minimal daily dosage that is possible with
`prednisonc and prcdnisolonc.
`
`Short-term therapy
`Doses of up to 1th] mg of prednisone a day may
`be taken for three weeks or lcss without any
`great risk of the occurrence of adverse effects.
`Occasionally. patients may notice weight gain.
`mild fluid retention. insomnia or mood changes
`(euphoria. depression or.
`rarely. psychosis).
`Adverse psychiatric reactions are more likely to
`occur in patients with tire—existing psychological
`actions of
`problems} The metabolic
`corticosteroid drugs may
`lead to hyper-
`glycaetnia.
`Io kctottcidosis in diabetic indi—
`viduals
`and to hypoltttlacmia. Superficial
`punctuate ulcerations of the gastric mucosa and
`associated haemorrhage may
`also occur.I
`However. these effects are reversed when the
`drugs an: discontinued. A rare bttt serious
`complication ofthe intravenous administration
`of corticosteroid drugs in asthmatic patients is
`the development of anaphylactoid reactions:
`these may be difficult to differentiate from an
`exacerbation of asthma.3
`Short courses of high—dose corticosteroid
`agents may produce transient abnormalities of
`thc hypothalttmic—pituitary—adrenal axis such as
`reduced basal plasma concentrations of cortisol.
`diminished adrenal gland responses to udreno—
`corticotrt'iphin [ACTH]: and blunted responses
`to insulin-induced hypoglycaernia." Two days
`after the administration of prcdrtisolonc :25 mg
`twice a day for five days). the cortisol responses
`of [0 normal men to both the induction of hypo-
`glycactrtia and the administration of synthetic
`ACTH were reduced to about onc~half their
`
`previous levels:‘ In a study of seven patients with
`chronic airflow obstruction. who were given
`prednisolone (20 mg twice a day for
`three
`weeks). basal plasma cortisol and plasma ACTH
`concentrations were suppressed at
`the com—
`pletion of treatment but returned to normal
`values within four days.S Thus. it is evident that
`corticosteroid therapy can affect hypothalarnic—
`pituitary—adrenal function within a few days of
`its commencement, even though the dysfunction
`usually disappears rapidly once treatment has
`been ceased.
`that patients
`Since these findings suggest
`theoretically may be at risk if they encounter
`stress within a few days of the abrupt discon—
`tinuation of corticosteroid therapy.
`it may be
`preferable to withdraw an agent gradually over
`five to seven days. For some inflammatory
`disorders.
`it may be necessary to reduce the
`
`dosage of a corticosteroid drug over a longer
`period oftirnc to prevent recrudescence of the
`disease. Wltetcver possible.
`once~a—da_v
`regimens should be prescribed. since they are
`more likely to restllt in rapid recovery of the
`hypothtt|antic—pituitary-adrcnal
`axis whcn
`Corticosteroid therapy is ceased}-
`Awareness of the transient disturbances which
`may occur with short—term courses of cortico—
`steroid agents will ensure that these potent drugs
`are used safely and eff'ectively.
`
`Long-term therapy
`It is with prolonged treatment that the unwanted
`effects. well known both to mcdi 'al practitioners
`and to the lay public. are likely to be encouns
`tered.
`lrt general. the lower the maintenance
`dose ofa corticosteroid agent. the less the risk
`of side-effects.
`
`In adults. it is likely that daily doses in excess
`of [0 mg of prednisonc will eventually lead to
`some side—effects? It
`is probable that even
`smaller daily doses- [for example.
`'15 mg of
`prcdnisoriet.
`if taken in the long term. are
`associated with complications in the elderly.“
`Thus. it is not possible to stipulate a daily dose
`at which the risk of side-cl'lccts is non-existent.
`
`Hypertension
`salt~retaining properties of
`Although the
`prcdnisone and prcdnisolonc are less than those
`of cortisol. these synthetic corticosteroid agents
`may still cause hypcrnatraemia. fluid retention
`and hypertension, In addition. other mechan—
`isms. such as the enhancement of thc vasocon—
`stricter effects of endogenous substances and
`increased concentrations of renin substrate“ have
`been postulated as contributing to the hyper-
`tensive effects of glacocorticoid hormones.
`These effects are probably related to the dose
`since long—tam] low-dose therapy does not carry
`any appreciable risk. Ina study of 129 patients
`with chronic airflow obstruction who were tak-
`ing prednisone or prednisolone (mean daily dose
`1— SD. 6.? i 3.3 mg for 9.7 i 5.5 years) and
`66 patients with rheumatoid arthritis who were
`taking prednisone or prcdnisolone (8.4 i- 23’ mg
`for 8.4 i 2.7 years).
`there was
`a
`small.
`statistically significant increase in systolic blood
`pressure without
`a
`significant
`increase
`in
`diastolic blood pressure!“ However, multiple
`regression analysis showed that an increased
`systolic blood pressure level correlated with age
`and blood pressure before therapy. which
`suggested that
`these factors were the main
`determinants of increases in systolic blood
`pressure.
`It was concluded that low doses of
`prednisonc or prcdnisolonc an: not important
`causes of hypertension.
`in the elderly. the incidence ofelcvated blood
`pressure may be higher. Fifteen of IOU patients
`(aged 69 years or more) who were taking pred-
`nisolone {12.5 mg a day or less) for an average
`of 4.8 years developed hypertension (defined as
`
`

`

`140 Therapeutics
`Febt'Lto ry
`3.
`l‘JBEI Vol. 14-4 THE MEDICAL JOURNAL OF AUSTRALIA
`
`than
`It diastolic blood pressure of greater
`Ilfi mmHg or a systolic blood pressure ol’ureIlcr
`titan ISU IttntHgl LontptIred with three of lllll
`age matched and sex— matched controls}1 the
`precise mechanisms by which elderly patients
`develop hypertension, and other side-effects ol"
`corticosteroid therapy. such as osteoporIJsis.
`more
`readily than others
`have
`not been
`elucidated. (Jae possible contributory factor may
`be
`the increased plasma concentration ol‘
`unbound corticosteroid drug due to the lower
`serum albttntin level
`in the elderly."
`Electrolyte disturbances
`Since prednisone and [.trcdnisolone retain some
`ntineralt'tcorticoid activity.
`they increase the
`distal renal tubular reabsotption of sodium in
`exchange
`for potassium. hydrogen and
`Itnttniiniuttt ions which may lead to hypernnt—
`memin and ltypokalaentia in some individuals.'1
`In large doses. conicosteroid drugs may cause
`hypokalacrttic alkalosis. However. alkalosis may
`develop in some patients without any evidence
`ol'pttassium depletion. suggesting that increases
`in scrurtt bicarbonate levels may be a direct
`effect of corticosteroid therapy.”
`Osteoporosis
`Patients who receive prolonged therapy with
`greater than physiological doses ol‘ corticosteroid
`agents tend to develop some degree ol' osteo—
`porosis. Glucocorticoid agents decrease bone
`limitation :‘twing to a direct inhibition ol‘osteo-
`blastic activity and they
`increase bone
`resorption. which leads to loss of bone —
`preferentially that ol' trubccnlar bone in the spine
`and ribs.m Bone
`resorption occurs
`as
`a
`consequence of secondary hypeiparathyroidisnt.
`wltich is caused by corticostcroid—induced
`hypercnlcittria and inhibition ot'enteral calcium
`absorption." Not all patients develop osteo—
`porosis. but postmenopausal women and elderly
`or immobilized patients are at high risk Iiithis
`complication. Since curtcnt pharmacological
`approaches at best halt. rather than reverse.
`corticoste mid-induced osteopt'trosis. one should
`aim to detect
`this problem before serious
`complications such as compression fractures of
`the vertebral column have occurred. While the
`reliable detection of early changes requires
`sophisticated techniques
`such as photon
`absorptiotttetry. plain IL—ray films of the spine
`may also provide useful
`information. Once
`patients at risk have been identified. prophylaxis
`vvith vitamin D and calcium supplements. or
`vitamin D and hydrochlorotltiazide therapy it'
`hypercalciuria
`is
`prLsertt.
`should
`be
`considered .' " Since no proof yet exists that such
`a programme ol' prophylaxis is effective. therapy
`should be embarked upon in preference to
`witnessing the
`relentless progression of
`osteoporosis
`in
`susceptible
`individuals.
`Alternate-day treatment. which reduces the
`incidence of
`smite of
`the
`side—effects
`ot‘
`corticosteroid drugs. would appear to have no
`advantage over daily use in terms of
`the
`development ol' osteopeniu.bl
`Calm-Icons effects
`Easy bruising. pnrput‘a and ecchyn'toses. which
`are quite common in older patients on long—term
`
`corticosteroid treatment. typically involve the
`lace and neck. the extensor surliiccs ot' the arms
`and the hands and the areas below the knees.
`Although the mechanism is not clearly under—
`stood.
`it
`is
`thought
`to be related to the
`diminished pltagt1IL3-tttsis ol' estravnsatcd blood
`and changes in connective tissue.” Hirsutistn has
`been reported in approximately 109-? of patients
`and depends on the duration of treatment.“
`Acneitbrm lesions that affect the lace and upper
`trunk may occur in It minority of patients on
`long—to rm the rapy.‘ -‘
`Gran-1th hupt‘tirtttcttt
`in children.
`long—term use of corticosteroid
`agents inhibits linear bone growth and epi—
`pltyscal closure. reducing skeletal growth. To
`facilitate the early detection ol'growth retarda—
`tion it is essential that regular measurements of
`height and weight are plotted on percentile
`clturts. Fortunately accelerated growthbackto
`the childs height percentile usually follows the
`cessation of corticosteroid therapy as the ad-
`ministration of corticosteroid drugs also inhibits
`epiphyseal closure. However. this growth catch—
`up may not occur after long-term use Itl‘ high-
`dose corticosteroid llterapy.
`leaving the child
`permanently stunted.
`ll
`single doses of
`prednisone or prednisolone. which have a
`relatively short biological half-lite. are taken in
`the morning. this regimen is least likely to aft'ect
`the maximal secretion ol'gntwtlt hormdnc in the
`early hours of the morninglfi
`Glucose intolerance
`impair carbohydrate
`Glueocorticoid agents
`metabolism by increasing hepatic glueonco-
`genesis and by decreasing the utilization of
`glucose by various tissues.” Fasting blood
`glucose concentrations are within normal ranges
`in most patients who are taking corticosteroid
`drugs but usually some reduction in the ability
`to respond to a glucose load is present. with a
`pattern in a glucose tolerance test
`that
`is
`indicative of insulin resistance. This impairment
`ot'glucose tolerance isgreatest vthen cortico—
`steroid ttcatment begins and the response
`improves considerably during long— te rm
`lherapy.” The development (It overt diabetes is
`unusual except in individuals with pre—misting
`abnormal results ol :1 glucose tolerance test.
`Corticosteroid—induced diabetesis usually mild
`and can be managed along convctttional lines
`by dietary measures. the administration oforal
`hypoglycttemic agents and the judicious use of
`insulin. ifneeessary, It is frequently reversible
`on cessation ofcorticosteroid therapy. although
`[he reversal ut'the diabetic state may take several
`months.“1
`
`Aseptic necrosis of the femoral head
`The use of cI'Irlicosteroid agents is one of many
`Factors which may predispose patients to the
`development of aseptic necrosis ofthe femoral
`head. Among the numerous theories that are
`advanced as a basis tor this unusual complica-
`tion of corticosteroid therapy.
`the currently
`lavonted explanation is that
`fat nticroemboli
`occlude subchrondtal end-arterioles and lead to
`bone—cell death.” The typical
`radiological
`appearance is that ol'n lucent area between the
`
`collapsed bone and the overlying cartilage.
`During a
`Ill—year period. sis patients (who
`represented tipprositttately IF»? ot'all patients in
`one study who were receiving corticosteroid
`drugs for pulmonary diseases} developed aseptic
`necrosis olthc femoral head.” Atypical patient
`had been receiving greater than physiological
`doses ot'conicostemid drugs for more than three
`months. and more ofien for years. Recipients
`ol' renal transplants have an increased incidence
`ol' aseptic necrosis of bone. presumably as a
`long term scquela of corticosteroid treatment.
`In a recent Austtulian survey. six 0t 52 Icnal
`transplant Iccipiean who survived tor more than
`10 years developed aseptic necrosis of bone
`which involvccl other joian in addition to the
`hip.m A review ot‘ the literature suggests that
`high doses of corticosteroid agents in the first
`month alter transplantation were associated with
`an increased prevalence of aseptic necrosis.all
`Patients with other disorders such as ltyperuri‘
`caemia. alcoholism. hyperlipidaemia or poly~
`L‘ythaentia. who also take corticosteroid drugs.
`may be at greater risk ol~ developing aseptic
`necrosis than those without these disorders.”
`Peptic ulcettttion
`Support tor the thcoty that conicostetoid drugs
`lead to the development ol peptic ulceration has
`nascd :tnd waned over tltc years. The widely
`accepted clinical notion that
`lhcrc was an
`association was dispelled in l976 by Conn and
`Blitzer. when they reviewed 42 randomired cott-
`trolled trials and found that there was no sig~
`niticant
`telationship between corticostctoid
`therapy and peptic ulceration unless the dtue
`was taken for more tltan 30 days or in large
`doses. 3‘ The burning question has been
`rekindled recently by Messer ct al.. who
`reviewed 71 controlled trials in which patients
`were randomized to receive corticosteroid
`therapy or non-steroidal therapy for at least tour
`days.“ The incidence ol‘pcptic ulcers was l.8 {ii-
`in the corticosteroid—treated group compared
`with 0.3% in control patients.” Thus. current
`evidence suggests a small but signitieant associa~
`tion between corticosteroid therapy and peptic
`ulceration. However.
`in view of this
`low
`incidence it is illogical to institute prophylactic
`therapy — with antacids or with histamine
`til—receptor antagonists — in all patients who
`are receiving corticosteroid drugs. If a patient
`is sufficiently unlucky as to develop an ulcer
`during corticosteroid treatment. he or she should
`be Ittannged with conventional therapy. In the
`absence of eonvincing evidence that “steroid
`ulcers" are resistant to therapy.
`there are no
`compelling reasons to discontinue corticosteroid
`treatment unless life-threatening complications
`of the ulcer have supervened.
`Symptoms of gastmintestinal intolerance such
`as dyspepsia and nausea may occur. in which
`case antacid therapy is useful. It is important
`to choose agents such as aluminium hydroxide.
`magnesium lrisilicate and magnesium hydroxide
`which do not appear to affect the absorption of
`pred ni solone.“
`Hittcreutitis
`
`Acute pancreatilis is a rare but serious compli-
`
`

`

`141
`Therapeutics
`lilfib
`I44 February l,
`l'l'lf: MEDlCAl JOURNAL OF AUSTRALIA Vol.
`
`
`corticosteroid agent on the day of plasma
`sampling. A morning cortisol concentration of
`greater than [1.28 itmolr’l. (It) ugtll'lllmLi
`indi-
`cates that basal hypothalamic- pituitary—adrenal
`function has rccovcred. Adrenal reserve is then
`assessed by a Ictracosaclt’in {ACT H l stimulation
`test. If the morning plasma cortisol level is less
`than 0.28 utttolJL [lL'l pgfltltlmLi.
`then
`corticosteroid treatment should be continued hit
`another one to two months before another
`
`morning plasma sample is collected.
`In most circumstances. a justifiable alternative
`to these diagnostic tests of adrenal function is
`to administer
`supplemental corticosteroid
`therapy during physiological stress {such as
`accidents. surgical procedures. febrile illnesses.
`repeated vomiting or dehydration) for a year
`after the medication is discontinued. Depending
`upon the clinical urgency. therapy can be given
`parettterally or by mouth in a daily dose that
`is equivalent to 200—100 mg of hydrocartisone.“
`A syndrome called “steroid psettdorheuma-
`tism". which is distinct from simple adrenal
`insufficiency. has been recognized in patients
`who take their corticostert'tid therapy erratically
`or whose dosage is
`reduced abruptly.
`It
`is
`characterized by
`fever. anorexia. malaise.
`myalgia and arthntlgia.‘ These symptoms resolve
`after increasing the dose ofcorticostcroid agent:
`a more gradual reduction ot'corticosteroit'l drugs
`prevents their recurrence.
`
`the onset ol
`therapy.
`cation of cwrticoslet'oitl
`whtch is not related to the dose. duration or type
`of corticosteroid drug that is used. in a review
`of Ill patients with drug—induced pancreatitis.
`cortict'isteroid agents were ll‘tc most common
`til'lcntlcl's. being ititplicatcd in ii cases.—’"
`Mi-‘upttllrt‘
`Corticosteroid inyopatliy presents as weakness
`and wasting iii
`the proximal
`litttb atttl girdle
`musculature. Although the dosage of cortico—
`steroid agent has frequently been high and
`sustained over many months.
`there does not
`tppear to be good correlation between the total
`dose. the duration of treatment. tlte patient‘s age
`at sex and the severity of the myopathy. Since
`the iitcidence is higher with the tluorittated coni-
`_'ostcrnid drugs siteh as triarncinolotte.-'5 such
`agents should not he used iii
`the long term.
`’aticnts usually recover within a few weeks of
`the cessation of the corticosteroid therapy.
`()r'ttft‘tr effects
`-\lthough an increase in intraocular pressure is
`more common with the topical administration
`of corticosteroid preparations. it cart also occur
`with systemic cotticosteroid ageitts bttt only alter
`notiths or years oft ailment?“ The risk. which
`appears to be genetically detertttined. is greatest
`in individuals with myopia or diabetes. The
`proposed mechanism involves increased produc—
`tion of aqueous humour and swelling of the
`collagen in the trabcculur ineshwot'k in the
`drainage angle ol‘the anterior chamber. leading
`to an increased resistance to aqueous outflow.“
`Increases in intraocnltti pressure are usttally
`reversible if corticosteroid therapy is ceased.
`Posterior siibcapsular cataracts have been
`documented in patients who are receiving long—
`tettrt corticosteroid therapy. The usual minimum
`time required for the onset of cataracts is one
`year of
`treatment with at
`least
`10 mg of
`prednisone a day.“ There is some evidence to
`suggest that this complication is more common
`in children and in patients with rheumatoid
`arthritis. In view of these ocular complications.
`it is prudent for all patients who are being treated
`with long-term cotticosteroid therapy to undergo
`regular ophthalmological examinations.
`Raised litttrtcrrtnlttl pressure
`A small proportion ofpatients. usually children
`.ir young women. develop papilloedema and
`signs of raised intracranial pressure when their
`_orticosteroid dosage is being reduced. This
`syndrome has been designated either as "benign
`intracranial hypertension" or as “pseudotumour
`ccrebri". The usual treatment is to increase the
`corticosteroid dose temporarily to relieve the
`symptoms and then to attempt a more gradual
`w i thdrawal .37
`
`Infections
`Corticosteroid drugs impair cell—titediated im—
`munity by decreasing the number of circulating
`lymphocytes and monocytes. by blocking the
`sensitization of lymphocytes to antigen and by
`inhibiting the responsiveness of monoeyles to
`the ehetnotactic factors that are elaborated by
`lymphocytes?a Antibody formation and tumover
`are not affected significantly by corticosteroid
`drugs.
`In spite of the recognized effects of
`
`corticosteroid agents and experimental studies
`that have detttonstrated an increased risk of
`in l'eclioti with
`numerous
`agents
`in
`L‘tll'llCllEilCl'lJILl‘lI'Clllt’Ll animals. it has been more
`difficult to document the degree of increased
`susceptibility in clinical studies?" Nevertheless.
`it is generally agreed that patients who are taking
`it'tttg-tertit corticosteroid dttigs are predisposed
`to bacterial
`t mycol'iacteria.
`staphylococcus.
`Iistcriul. vital lhcrpcs. cylotttegaltiwirttsl. fungal
`(candida.
`cryptoeoccusi
`and parasitic
`llt'tsttplasttta. pneutnocystis) infections.” In the
`case of tuberculosis. preventive measures should
`be taken.
`In patiettls with positive results of
`Mantotis skin tests to intermediate strength
`tuberculin [S TU}. but normal chest radiograph
`films. modest doses of corticosteroid agents
`tltl—lfi tttg ofpredttisolonc a day} do not appear
`to carry an increased risk of tiibcrculosis.—‘"
`Therefore. such individuals do ttot benefit from
`
`prophylactic therapy with isoniazid. However.
`if patients have radiological features that are
`consistent with inactive pulmonary tuberculosis.
`they warrant treatment with two drugs such as
`isoniazid and ethantbtitol or ril".irnpicin.m The
`physician should be alert to the possibility of
`both common and unusual infections in patients
`who are receiving corticosteroid agents. par
`ticularly if these are cottibined with other
`immunosuppressaht drugs.
`Adrenal .t'ttppt‘cs‘siort
`to treating inflammatory diseases with cortico—
`steroid agents. it is common to begin with high
`doses to obtain some measure of control. There-
`fore. the dose is reduced. according to indices
`ofdiscase activity. until a satisfactory mainten—
`ance dose is reached. Ultitnately iI may be
`possible to cease the administration of cortico—
`stentitl therapy altogether. itt which case certain
`guidelines should he observed.
`It
`is generally
`accepted that derangement of adrenal function
`occurs after a few days of high-dose cortico-
`steroid therapy. In contrast to the rapid recovery
`after treatment that is limited to two to three
`weeks.
`long—term daily therapy with cortico—
`steroid drugs may suppress hypothalamic—
`pituitary~ttdrenal function for up to nine months
`after the cessation of treatment.“ Therefore. it
`is important to keep the daily maintenance dose
`as low as possible. or
`to use alternate-day
`therapy.“2 because both of these strategies —
`particularly the latter — minimize the chances
`of blunting the
`stress
`response of
`the
`hypothalnmic—pituitary—adrenal axis.
`Since the recovery ol'the adrenal cortex lags
`behind that ot'the pituitary. one can usually- as—
`sume that full integrity has been restored when
`the adrenal gland can mount an adequate
`secretory response of cortisol
`to synthetic
`ACTH." Therefore. the following approach for
`the withdrawal of corticosteroid therapy is sug~
`gested.“ First. wean the patient
`to “physio—
`logical" doses of a corticosteroid agent tstich
`as 10 mg of hydrocortisone or 5 mg of pred—
`nisone] to be taken for one to two months: then
`halve the dose for the next one to two months:
`and then determine the morning plasma cortisol
`ct'inccntration. omitting the morning dose of
`
`1.
`
`‘JI
`
`ltl.
`
`References
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`l. Melhy
`JL'. Clinical pltitrttiucolugy of
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`Il-SR’Ir
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`(Than CS. Brown 16. Oliver WA. Zimmerman PV.
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`

`

`142 Therapeutics
`
`'I-‘i-‘i THE MEDICAL JOURNAL OF AUSTRALIA
`February 3. 1986 VIII.
`
`iuirniuiie. Lirii'ei NM. 2:
`
`21.
`
`34
`
`liifiZ-liifii.
`IlEiJiIi-riuii. Lunar I‘ifi-l, I:
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`I‘Jl'il.‘ 63': I—ii-lil.
`BU. Maiuany .IF. Slieii AER. Erheredge SH. o