,
`
`Review Article
`
`Drugs 16: 238-255 (l978)
`e ADIS Press 1978
`
`Sum mary
`
`Corticosteroids: Clinical Pharmacology
`and Therapeutic Use
`
`Stephen L. Swartz and Robert G. Dluhy
`
`Peter Bent Brigham Hospital , HaNard Medical School. ac etcn , Massachusotts
`
`The widespread use of contcosterotds in clinical practice emphasises the need for a
`thorough undersla nding of {hei, me tabolic effeas. In general, the actions 0/ corticosteroids on
`carbohydrate, protein, and lipid metabolism result
`in increased hepatic capacity fo r
`gluconeogenesis and enhanced catabolic actions upon muscle. sk in. lymphoid. adipose and con(cid:173)
`nec/ive tissues , Becau se of the morbidity associated lI'ilh steroid therapy. the clinician must
`carefully consider in each case the gains that can reasonably be expected from corticosteroid
`therapy versus the Inevitable undesirable side ~({ecls of prolonged therapy. Thus, it is importa nt
`to remember that lhe enhanced anti- inflammatory activity qfthe various synthetic analogues of
`cortisol is not dissociated from Ihe expected catabolic actions of glucocorticoid hormones.
`Replacement therapy ....ith physiological doses of cortisol in primary or secondary adrenal
`insuf ficiency is intended to simulate the normal daily secretion of cortisol. S hort term. high
`dose suppressive glucocorticoid therapy is indicaled in the treatment of medical emergencies
`such as necrotizing vasculitis, status asthmaticus and anaphylactic shack . Wilh improvement
`of the underlying disorder. the steroid dosage con be rapidly tapered and then discontin ued over
`a 2 to 3 day period. Long term. high dose suppressive therapy is often commonly used to treat
`certain diseases (see sections 4. 7.2 and 4.7.3). In this selling . suppression of the hypotha lamic(cid:173)
`pilui lory -adrenol axis may persiSIfor as long as 9 to / 2 monthslollo....ing steroid ....ithdra....at if
`steroid doses are adminis tered in the supraphys iological range for longer than 2 It'ft'Ks , In
`general , higher doses, longer dura tion of usage, and f reque nt daily administration are all cor(cid:173)
`relaled ....ith the severity of pituitary ACTH suppression.
`When steroid therapy is to be ....ithd ra....n. graduallapering of the dosage is necessary. the
`steroid dosage should also be given as a single morning dose if iosstbte. Rapid or total ....ith (cid:173)
`dra wal of Ihe steroid therapy may be assaciated ....ith exacerbation ofthe underlying disease or
`....ith a steroid withdra lt'al sy ndrome. An additional important point to remember in any with (cid:173)
`drawal programme is thai the steroid dosoge should be appropriately increased fo r an exa cer(cid:173)
`bation of the underlying disease or for intercurrent mator stress. Alternate day Iherapy is
`recommended as a steroid maintenance programme for patients requiring high dose glucocor·
`ticoid therapy over a prolonged period oflime. Thus. i l is usually employed to maintain a thera (cid:173)
`peutic benefit "",'hich had previously been established by doily steroid treatment ,
`Complications resulting f rom corticosteroid therapy include: (J) proximal muscle ....eakness:
`(]) oueopen to, (J) unmasking of latent diabetes mellitus ; (4) sodium retention and/ or elevation
`of mean arterial blood pressure; (5) adverse psychia tric reactions; (6)dnelopment of glaucoma ;
`and (7) reactivation of latent infections (such as tuberculosis ).
`
`JANSSEN EXHIBIT 2068
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`Corticos teroid s: Clinical Pharmacology a'l d Therapeutic Use
`
`239
`
`The w idespread use of corticosteroids in clinical
`practi ce emphasises the need for a th orou gh under(cid:173)
`standing of their metabolic effects if optimum effec(cid:173)
`tiveness is to be obtained with a min imum of un(cid:173)
`desirable side effects . Before instituting corticosteroid
`therapy, it is necessary to carefully consider the gains
`that can be reasonably expected versus the potentia lly
`undesirable metabolic actions of large doses of cor(cid:173)
`ticosteroids. The increased incidence of hyperte nsion,
`chronic infectiou s diseases , osteoporosis and impa ired
`glucose toleran ce as metabolic sequelae of lar ge doses
`of steroids m ust be carefully considered before em(cid:173)
`bar king on a programme of steroid adm inistration.
`The chemical and physiological properties of cortiso l
`and its synthetic analogues will be reviewed in order
`to demonstrate how a kn owledge of the clinical phar(cid:173)
`macology of corticosteroids can aid in their rational
`therapeutic use.
`
`I . S tru cture ofCortiso/ and its
`Sy nthetic Analogues
`
`The basic chem ical structure of adrenal cortico(cid:173)
`steroids cons ists of a 17 carbon skeleton w ith three 6
`carbon hexane rings and a one 5 carbon pentane ring
`(fig.
`I). Cort isol (hydrocort isone) and other ant i-in-
`
`flammatory stero ids are referred to as C 21 stero ids
`(fig. I) because they have a 2 carbon cha in attached at
`position 17, and in addition , have meth yl gro ups at
`C I8 and C 19. C2 1 steroids that also have a hydroxy
`group at position
`17 are called 17-hydroxycor(cid:173)
`ticostero jds. or
`17-hydroxycorticoids . Those C2 1
`steroids which ha ve predominant actions on inter(cid:173)
`mediary metabolism are referred to as glucocor (cid:173)
`ticoids . For the remainder of th is discussion the term
`17-hydroxycorucosteroids
`(or
`cort icosteroids) and
`glucocorticoids will be used interchangeably.
`Th e functional integrity of th e steroi d molecule is
`dependent upon certai n critical arrangements of hy(cid:173)
`drogen, carbon, hydroxyl and oxygen groups around
`the basic steroid nucleus. Those areas wh ich are
`circled in figure 2 are essential for the preservation of
`the biological action of all corticosteroids, and altera (cid:173)
`tion in anyone of them will result in complete loss of
`glucocortico id activity. Th is is illustrated by the ob(cid:173)
`servation th at the adm inistration of cortisone (with
`an oxygen radical at position I I) is relative ly inactive
`in patients with severe liver disease due to impaired
`hepatic conversi on to the active naturally occurring
`compound cortisol (w ith a hydroxyl group at position
`I I) (Peterson, 197 1) jfig. 3). The importance of these
`substituents on the molecule is also illustrated by the
`biological inactivation of cortiso l by the liver. In this
`
`,C
`
`CHZOH (2 1)
`=O ( 20)
`OH li n
`
`"
`
`"
`
`( I I ) HO
`
`0 "
`l J )
`
`l 4)
`
`Steroid 'luc leus
`
`C2 1 Steroid
`
`Fig. t , Basicsteroid stru cture.
`
`

`

`Corticosteroids : Clinical Pharmacology and Therapeuti c Use
`
`,<0
`
`enha nced anti- inflamm atory and dim inished sodium
`retaining properties (on a mg for mg basis com pared
`with cort isol). Fludrocortisone (9·fluorohydrocor·
`tisone) has marked enhancement of mineralocorticoid
`activity.
`The anti-inflammatory and mineralocort icoid pro(cid:173)
`perties of cortisol can there fore be altered by modify(cid:173)
`ing the basic steroid nucleus. It must be remem bered,
`however, that
`the enhanced anti-inflammatory ac(cid:173)
`tivities or these synt hetic analogues is not dissociated
`from the normal catabolic actions of glucocorticoid
`hormones. Thus, equipote nt doses of cortisol and its
`analogues have similar propensities for producing the
`undesirable actions of glucocorticoids.
`
`Fig. 2. Gfoups essent ial to anti- inflamma tory act ivity .
`
`process, reduction of the double bond at the ] -4 posi(cid:173)
`tion renders the compound biologically inactive.
`Anal ogues of cort isol have been synthesised w hich
`have substitutions adjacent
`to cr itical sites on the
`steroid nucleus. Th is results in enha ncement of cer(cid:173)
`tain properties, such as anti-inflammatory activity,
`and diminuti on of other actions, such as mineralocor(cid:173)
`ticoid activity. For example,
`intr oduction of a 1,2
`double bond produced prednisolone which has a 4(cid:173)
`fold enhancement of anti-inflamma tory activity (fig.
`4). Dexamethasone (with a methyl group at carbon
`16, and a fluoride grou p at carbon 9) has mark edly
`
`2. Transport and Metabolism o/ Cortisol
`and Synthetic Analogues
`
`Approximately 10 to 12mg of cortisol per m?
`body su rface area is produced by the adrenal cortex in
`a normal adult each day. Although cortisol is secreted
`in a pulsatile or episodic fashion, the mean plasma
`concentration of cortisol varies predictably over a 24
`hour period, with highest concentrations in the early
`morn ing and lowest
`levels at midnight (circadian
`rhyth m). T he nor mal plasma concentration at Sa.m.
`is 10 to 15]Jg/ dl.
`
`CHZOH
`O
`
`IC
`
`OH
`
`H O
`
`Hydrocortisone
`
`Cort isone
`
`Fig. 3. Reversible oxidation·reduction reaction of cortisol (hydrocortisone) and cortisone by hepatic microsomal enzvrnes.
`
`

`

`Cc-nccsteroos: ClinIcal Pharmacology and Therapeutic Use
`
`24'
`
`o
`
`Pred nisolonll
`
`0
`
`16a-Met hyl-9,,- fluoropredn isolone
`(dexamet hasone)
`
`Fig. 4. Three synlhetic analogues of cortisol (hydroconisone).
`
`9a -Fluoroconisol (f1udrocort isone)
`
`2.1 Half-life and Duration of Action
`
`glucocorticoids with 36 to 54 hour biological half(cid:173)
`lives <table n
`
`The plasma half-life of cortisol, defined as the time
`it takes for the plasma level of the horm one to fall to
`50 % of its initial concentration, is approximately 90
`minutes. However, the biological half-life of cortisol,
`defined as the time it takes for a measured metabolic
`activity (e.g . anti-inflammatory effect) of the hormone
`to fall to a half of its initial level, lasts from 8 to I 2
`hours. Since the anti-inflammatory potency of syn(cid:173)
`thetic or natu ral glucocorticoids and their suppression
`of the hypothalamic-pituitary -adrenal axis, parallel
`each other in terms of degree and duration, biological
`half-lives are usually determ ined by the duration of
`suppression of
`the hypothalam ic-pituitary-adrenal
`axis. Thus, hydrocortisone and cortisone are defined
`as short acting glucocorticoids on the basis of their 8
`to 12 hour biological half-Jives; prednisone, pred(cid:173)
`nisolone, methylprednisolone and triam cinolone as
`intermediate acting glucocorticoids, with 18 to 36
`hour biological half-Jives; and paramethasone, be(cid:173)
`tamelhaso ne and dexamethasone as
`long acting
`
`2.2 Protein Binding
`
`Normally, approximately 90 % of the cortisol is
`reversibly bound to plasma proteins (10% to albumin
`and 80 % to a high affinity. Jow capacity oy-glo bulin.
`transcort in or corticosteroid binding globulin); 10 %
`circulates free or unbound . This free fraction , esti(cid:173)
`mated to range between 0.7 and 1.0pg/d l, probably
`determines the biological activity of the hormo ne,
`with the bound fraction serving as a reservoir. The
`binding capacity of transcortin is approximately 20 to
`25pg of cort isol per dl plasma. With cortisol levels
`greater than 25pg/ dl. binding sites on transcortin
`will be saturated, and the binding of cortisol will be
`largely to albumin, a low affinity, high capacity recep(cid:173)
`tor (25 % unbound and 75 % bound). Since the un(cid:173)
`bound fraction is filtered by the glomerulus and ex(cid:173)
`creted into the urine, patients with Cushing's syn-
`
`

`

`CortIcosteroids: Clinical Pharm acology and The rapeutic Use
`
`2"
`
`Table I. Ad renal cortic o steroid preparat ion s
`
`O~g
`
`Equivalent
`Anti-
`inflammatory potency'
`(mg)
`po tency '
`
`Sodi um
`retainir.g
`potency
`
`Daily dose (mg) above
`which HPA axis
`suppression possible "
`
`Plasma
`half.life
`{min)
`
`Biological
`half -life
`Ihl
`
`Cortiso l
`(hydrocortisone)
`Cortisone
`Prednisone
`Prednisolone
`M ethylprednisolone
`Triamcinolooe
`Parametha sone
`Betamethasone
`Dexamethasone
`
`0 8
`3.5
`
`•
`
`5
`5
`10
`25
`30
`
`20
`
`25
`5
`5
`
`•
`•
`
`2
`0. '
`0.75
`
`males
`
`20 -30
`
`25- 35
`7.5- 10
`7.5- 10
`7.5- 10
`7.5- 10
`2.5-5
`1-1. 5
`1- 1.5
`
`females
`
`15-2 5
`
`90
`
`20- 30
`7.5
`75
`7.5
`7.5
`2.5- 5
`1_1.5
`1- 1.5
`
`90
`200 or >
`2DO~ >
`200 or >
`2DO~ >
`300~ >
`300 ~ >
`300 ~ >
`
`8- 12
`
`8- 12
`18-36
`18-3 6
`18-36
`18-3 6
`36-5 4
`36- 54
`36-54
`
`2 .
`
`,.
`
`I.
`H
`0
`0
`0
`0
`0
`
`1 Potency is defined as a mg for mg ll'Quivalence w ith hydrocortisone.
`2 Intended as a g uide only. The dose in an individual depends on total body surface area. The figures quoted are tMse wh ich
`apply in genefal .
`
`drom e (endogenous hypercorticolisrnl will have ele(cid:173)
`vated urinary free cortisol (unmetabolised) levels. On
`the other hand. synthetic analogues of cortisol bind
`less efficiently to transcortin (approximately 70 % )
`and diffuse more completely into the tissues. in part
`explaining their propensity to produce Cushingoid
`low doses (Dfuhy et al.. 1975).
`side effects at
`Similarly. serum albumin depletion. with consequent
`diminution in storage capacity for steroids can also.
`with high dose therapy. lead to unusually high levels
`of free drug and an enhanced susceptibility to steroid
`side effects (Lewis er al.. 1971).
`
`2.3 Elimination
`
`Cort isol disappears rapidly from the circulation
`via hepatic metabolism. The liver converts cortisol to
`inactive acidic compounds by reduction and then con(cid:173)
`jugation with glucuronic acid. These water soluble
`polar compounds are more easily excreted by the
`kidney. Synthetic analogues of cortisol are meta(cid:173)
`bolised in the liver more slowly than cortisol because
`
`of alterations of the steroid molecule. with the net
`result being a prolongation of plasma half-life.
`W hereas it takes approximately 90 minutes for the
`circulating level of cortisol to be reduced to half its
`initial value. methylprednisolone or dexamethaso ne
`have plasma half-lives of 200 minutes or longer.
`
`2.4 Duration of Action and Selection of a Steroid
`
`Since analogues with long plasma half-lives also
`have long biological half-lives (table Il and since the
`biological half-lives of the glucocorticoid horm ones
`represent their dura lion of metabolic activity at the
`tissue level (section 2.1). long acting analogues are
`more likely 10 produce Cushingoid side effects
`because of their continuous stimulation of peripheral
`tissues. Th is concept is important in choosing which
`steroid hormone is best suited for different treatment
`regimens. For instance. in replacement therapy. the
`twice daily adm inistration of cortisol. with an 8 to 12
`hour biological half-life. simulates normal daily secre(cid:173)
`tion of the endogenous horm one. In alternate day
`
`

`

`Corti cost eroids: Clinical Pharmacology and TherapeutIC Use
`
`243
`
`therapy . the 18 to 36 hour biological half-life of pred(cid:173)
`nisone allows for persistence of anti-inflammato ry ac(cid:173)
`tivity throug h the first half of the 'off day. while
`allowing for recovery of the hypothalamic-pituitary
`axis durin g the latter part of the 'off day.
`
`3. Metabolic Actions of Corticosteroids
`
`the metabolism of most
`Corticosteroids affect
`tissues. by either influencing specific functions. such
`as synthesis of specific hepatic enzymes. or as a conse(cid:173)
`quence of a generalised response. such as inhibition of
`glucose uptake and increased degradation of proteins .
`RNA . and DNA (Baxter and Forsham. 1972). In
`either case. a specific hormone receptor system (fig. 5)
`in the cytoplasm of the target tissue appears to be
`necessary for initiation of glucocorticoid action (Feld·
`man et al.. 1972). After dissociation from its plasma
`carrier protein. cortisol penetrates the cell membrane
`of
`the cort icosteroid-responsive
`tissues. Specific
`
`receptor proteins for cortisol are located in the
`cytoplasm of these responsive tissues. After interac(cid:173)
`tion between cortisol and this receptor protein. the
`steroid-receptor complex leaves the cytoplasm and
`binds to specific sites on the chromatin of the cell
`nucleus. This resuns in stimulation by an unknown
`mechanism of new transcription of messenger
`ribonucleic acid (mRNA) and ribosomal ribonucleic
`acid (rR !'\A). which results in translation of specific
`induced proteins and mediation of the physiological
`effects by these induced proteins.
`
`3. 1 Effect on Intermediary Metabolism
`
`In general. the actions of glucocorticoids on car(cid:173)
`bohydrate. protein and lipid metabolism result in in(cid:173)
`creased hepatic capacity for gluconeogenesis and
`enhanced catabolic actions in muscle. skin. lymphoid.
`adipose and connective tissue. The general pattern of
`glucocorticoid action results in stimulation and induc-
`
`~Q)
`L:J ~
`
`~ +
`
`...... Cytoplasmic recep tor pro tein
`
`Jh~
`R
`
`Ribosome
`<,
`
`. \S~
`R
`
`Transcortin ~
`
`Induced
`. proteins
`
`/Glucocorticoid
`
`~-~
`
`TranSlat ion
`
`Transcription
`
`Fig. 5. Schematic representatio n of the mec hanism of action of glucocorticoids.
`
`

`

`Cortico steroid s: CIiJlical Pharmaco1ogy arid Therapeutic Use
`
`244
`
`non of protein synthesis in the liver and inhibition of
`peripheral tissue protein synthesis and glucose uptake
`and utilisation. The catabolic effects on muscle, lym(cid:173)
`phoid tissue. skin and adipose tissue appear to be
`mediated through inhibition of glucose uptake
`(Munck. 1971l. These catabolic actions of glucoccr(cid:173)
`ticoids result in increased degradation of protein and
`RNA,
`and
`provide
`amino acids
`for
`hepatic
`gluconeogenesis.
`
`3.1.1 Enhanced Gluconeogenesis
`In the liver. the enzymes involved in gluconeo(cid:173)
`genesis and glycogen deposition are stimulated.
`Among these enzymes are glucose-S-phosphatase.
`phosphoenol-pyruvate(cid:173)
`fructose- Le -diphosphatase.
`carboxykinase,
`tyrosine
`amino-transferase,
`tryp(cid:173)
`tophan
`pyrrolase.
`and glycogen synthetase A
`(Feigelson et al., 1971). This increased synthesis of
`specific hepatic enzymes plus the increased amounts
`of amino acid substrate (resulting from inhibition of
`peripheral protein synthesis) explain in part the in(cid:173)
`crease in hepatic glucose production which results
`from glucocorticoid administration. It is also possible
`that the enhanced gluconeogenesis seen after glUCO(cid:173)
`corticoid administration results from an increase in
`glucagon secretion. However. this may not be a direct
`stimulatory effect of the corticosteroids. but rather a
`result of the hyperaminoacidaemia which accom(cid:173)
`panies steroid administrat ion (Cahill. 1973; Marco et
`al., 1973). In addition , glucocorticoids cause. by some
`unknown mechanism. a decrease in the activity of
`insulin receptors in insulin sensitive tissues. This pro(cid:173)
`vides at least a partial explanation for the decrease in
`peripheral glucose utilisation seen in patients treated
`with high dose glucocort jceids (Kahn et al., 197 3).
`
`glucose in muscle tissue relative to the existing hy(cid:173)
`perinsulinaemia and hyperglycaemia appears de(cid:173)
`creased (Munck. 197Jl. Similar to the differential
`adipose tissue sensitivities to gjucocorticoids. there
`are varying sensitivities of protein tissues to steroids.
`as manifested by the wasting of osseous protein
`matrix in the vertebrae. but not in the long bones.
`
`3.1.3 Enhanced Lipol ysis
`Glucocorticoids inhibit long chain fatty acid syn(cid:173)
`thesis and are necessary for the activity of lipolytic
`hormo nes. such as catecholamines. glucagon and
`growt h hormone (Rudman and DiGirolarno. 197 1).
`The mechanism for
`this permissive action is
`unknow n. but the increase in lipolysis results in the
`release of free fatty acids and glycerol. Glycerol may
`be utilised as a substrate for hepatic gluconeogenesis.
`while the free fatty acids inhibit peripheral glucose
`uptake (Randall effect) and serve as an alternative
`energy source. Dur ing normal homeostasis,
`the
`release of insulin counteracts these lipolytic and anti(cid:173)
`lipogenic actions of glucocorticolds. resulting in a
`balance between lipolysis
`and lipogenesis. The
`redistribution of fat with excessive levels of glucccor(cid:173)
`ticoids results in a centripetal, or truncal. pattern with
`diminut ion of peripheral fat stores. This may be due
`to the differential sensitivities of the fat cells in
`various areas of the body. Subcutaneous fat cells in
`the extremities appear to be more sensitive to the fat(cid:173)
`mobilising action of lipolytic hormo nes. whereas in
`the adipose tissue of the abdomen and dorsal fat pad.
`the insulin (lipogenic) response predominates.
`
`3.2 Anti-inflammatory
`Effects
`
`3 .1.2 Enha nced Catabolism
`The catabolic actions of glucocorticoids on muscle
`result in muscle wasting and myopathy. There is evi(cid:173)
`dence for both a decreased incorporat ion of labeled
`amino acids into muscle proteins. and an increased
`egress of amino acids into the circulation from
`muscle (Cahill. 197 1). Furth ermore . the uptake of
`
`Cort icosteroids impair each stage of the inflam(cid:173)
`mato ry response (fig. 6l. The degree of anti-inflam(cid:173)
`matory activity appears to be quantitatively related to
`the concentra tion of horm onally active steroid present
`at the site of inflammation (Melby. 1974).
`Steroids decrease the initial inflammatory reaction
`by blocking the increase in capillary permeability in-
`
`

`

`Corticosteroids: Clinical Pharmacology and Therapeuti c Use
`
`'"
`
`1\
`
`Blood Vessel
`
`l ysosome
`
`PMNP 0
`~:(&~
`
`MIF -+
`CD Ctlemot a~ic tecto-
`
`Capillary
`
`1 1
`
`~~
`
`\
`
`)® Ih'< (
`~
`
`I
`
`rW~
`(
`
`/
`
`+
`• Ag
`
`o T'm_v" /
`/
`
`[1] Sensitised
`
`T lymphocyte
`
`rr:
`
`l/Y -i T.xJJ
`
`Increase ifl cepillary permllability wi th leakage of kinins arid
`prot oolytic enevrres. and exudation of leucocyteS and macrophages into
`the inflamed area
`
`Fig. 6. Sch8matic representation of the inflammatory reaction. Corticosteroids (1) antagot'lise the action of MIF arid chema(cid:173)
`ta ~ic fac tor. resulting in inhibition of endothelial sticking of
`IeUCOCytllS and macrophages: (2) int erfere with antigen-processing
`function s of macro phages: (3) stabilise lysosomal rremcraree: arid (4) block the increase in capillarv permeability.
`MIF
`Migratory inhibiting fact or
`PMN
`Polymorphon uclear cell
`= Macrophage.
`Ag
`K An tigen
`M
`
`duced by acute inflammation. Since capillary integrity
`is increased. there is less leakage of proteins and fluids
`in the areas of injury, and therefore less oedema for(cid:173)
`mation. Since less plasma proteins leak into the in(cid:173)
`flammatory area, less vasoactive kinins are released
`which would further promot e the inflammatory res(cid:173)
`ponse. Exudation of macrophages and polymorpho(cid:173)
`nuclear cells into the inflamed area is reduced because
`steroids inh ibit endothelial sticking of leucocytes and
`their diapedesis through the capillary wall. Th is
`reduced adherence of rnacrophages and leucocytes to
`vascular endothelium is probably secondary to
`
`glucocorticoid antagonism of the action of migratory
`inhibiting factor, a substance released by sensitised
`lymphocytes
`following interaction with antigens
`(David et al., 1964). Corticosteroids also interfere
`with the phagocytosis of antigens by macrophages.
`and their subsequent intracellular digestion and pro(cid:173)
`In high doses, corticosteroids
`stabilise
`cessing.
`lysosomal membranes. This prevents tissue damage
`because rupt ure of Iysosomes after cellular injury
`releases a variety of enzymes (acid hydrclases) which
`digest cell contents and thereby perpetuate the inflam(cid:173)
`matory response.
`
`

`

`ccmccs reroos: Clinical Pharmacology and Therapeutic Use
`
`,<6
`
`The re are 2 kinds of lymphocytes present in peri(cid:173)
`pheral blood -
`the B and T lymphocytes. The B lym(cid:173)
`phocytes. derived from bone marrow stem cells. bear
`specific immunoglobulins on their surface membrane
`which interact with antigens. T his results in a differ(cid:173)
`entiat ion of the B lymphocytes into plasma cells
`which secrete humoral antibod ies. The T lym(cid:173)
`phocytes, derived from bone marrow precursor cells
`which are processed in the thymus, are responsible
`for cell-mediated immunity and do not produce anti(cid:173)
`bodies. T lymphocytes are more susceptible to the
`cytolytic effects of steroids than are the B lym(cid:173)
`phocytes. Thus. steroid adm inistration rarely signifi(cid:173)
`cantly reduces antibody production. unless very high
`doses of glucocort icoids are used. whereas cell medi(cid:173)
`ated-immunity is inhibited at
`lower corticosteroid
`concentrations.
`Finally, formation of granulation tissue is sup(cid:173)
`pressed by the inhibitory action of glucocorticoids on
`fibrob lasts and collagen formation (Green. 1965).
`T his negative effect on fibrous scar formation leads to
`incomplete healing of surg ical incisions and allows
`for the danger of wound dehiscence.
`
`3.3 Effect on Blood Elements
`
`Glucocorticoid admi nistratio n leads to an increase
`in neutrophils. platelets and red cell mass (David et
`al., 1970). The increase in neutrophils declines after
`approximately 4 hours. but may be prolonged by long
`term treatment. This granulocytosis results from an
`increased influx of cells from the bone marrow. as
`well as a decrease in the rate of egress of cells from
`the blood.
`Glu cocorticoids cause a rapid decrease in the num(cid:173)
`bers of circulating eosinophils, probably reflecting in(cid:173)
`creased destruction and decreased formatio n of these
`cells (Nelson et al., 1952). The decrease in lym(cid:173)
`phocytes noted after glucocort icoid administration
`may be the result of steroid induced inhibition of
`glucose uptake in lymphoid cells. result ing in cell
`lysis. However, as mentioned in section 3.2. variable
`sensitivit ies of the Band T lymphocytes (possibly
`
`reflecting differing numbers of specific cytoplasmic
`receptors) is seen with steroid administration.
`
`3.4 Effect on Skeleton and Bone
`
`Long term administration of glucoccrticoids is
`associated with osteoporosis in adults and reduced
`skeletal growth in children. Steroids cause inhibition
`of both linear bone growth and epiphyseal closure, so
`that with high dose glucocorticoid administration in
`children one sees an inhibition or cessation of normal
`growth. Fort unately. permanent growth retardation
`in children is unusual and accelerated growth (usually
`back to the child's height percentile) occurs if steroid
`administration can be discontinued. T his is due to
`steroid inhibition of epiphyseal closure. which allows
`for further growth once the steroid is discontinued.
`This is contrasted to androgen admi nistration where
`epiphyseal closure is accelerated and furthe r growth
`potential is severely curtailed.
`The negative calcium and nitrogen balance associ(cid:173)
`ated wit h glucocorticoid admi nistration results from:
`(I) reduced intestinal absorption of calcium. possibly
`related
`to
`inhibition
`of
`the
`activation
`of
`cholecalciferol
`to 25-hydroxycholecalciferol
`in the
`(Klein et al., 197n (2)
`increased urinary
`liver
`calcium loss as a result of increased glome rular filtra(cid:173)
`tion rates and direct
`tubular inhibition of calcium
`reabsorpt ion; 0) secondary hyperparathyroidism as a
`means of compensation for this reduced availability
`of calcium; (4) tissue catabolism in the bone matrix
`which decreases the surface on which bone mineral
`can be deposited; (5) a decrease in the rate of bone for(cid:173)
`mation. generally attr ibuted to a direct inhibition of
`osteoblast function by glucocorticoids. and (6) impai r(cid:173)
`ment of release of growth hormone.
`
`3.5 Miscellaneous Effects
`
`Glucocorticoid hormones act in a permissive man(cid:173)
`ner to enhance periphera l vascular respons iveness to
`endogenous vasoconstrictors. This permissive role of
`
`

`

`Cortic osteroids: Clinical Pharma colog y and Thera peut ;c Use
`
`steroids in vascular responsiveness may explain its
`possible effectiveness in various shock states by
`restoring circulatory competence. It is also possible
`that the therapeuti c effect of glucocorticoids in treat(cid:173)
`ing shock may be related to its direct effect on heart
`muscle. with improv ement in left ventricular work
`index (David et al., 1970). Although much contro(cid:173)
`versy exists concern ing the aetiology of hypertension
`in Cushing 's disease, a contr ibutin g factor may be the
`steroid induced enhancement of hepatic production of
`angiotensinogen, which ultimatel y leads to increased
`levels of angiotensi n II.
`Glucocorticolds are importa nt in maintaining nor(cid:173)
`mal
`internal water distribution. They prevent se(cid:173)
`questration of water intracellularty with swelling and
`destruction of cells. Steroids also facilitate the norm al
`excret ion of a water load.
`Glu cocorticoids may produce peptic ulcer disease
`by ( I) increasing acid secretion in basal and stimu(cid:173)
`lated states, and (2) disr upting the protective gastr ic
`mucus which lines the mucosa , making this layer
`more vulnerable to Ulceration. However,
`recent
`retrospective ana lyses of the association of steroid
`therapy with peptic ulcer diathesis fail to detect an in(cid:173)
`creased incidence of peptic ulcers with glucocorticoid
`use, except in cirrhotic and nephr otic patients (Conn
`and Blitzer, 1976).
`
`4. Principles of S teroid Therapy
`
`There are many clinical situations in which a deci(cid:173)
`sion to admini ster glucocort icoid hormones arises.
`
`4. 1 Basic Considerations
`
`The use of replacement steroid doses (that is. doses
`which approximate the normal daily amount of cor(cid:173)
`tisol produced by the adrenal cortex) in proven prim(cid:173)
`ary or secondary adrenal
`insufficiency is straight(cid:173)
`forward. Similar ly. the short
`term , high dose ad(cid:173)
`ministrat ion of steroid therapy for life threate ning
`
`vascufuis. status asth maticus. or anaphylactic shock
`requires little hesitation . However. prolonged sup(cid:173)
`pressive steroid therapy in doses which exceed the
`nor mal physiological levels (table n in order to take
`advantage of the anti-inflammatory activity of the
`steroid.
`requires careful consideration. One must
`assess the severity of the under lying disorder and the
`gains that can be reasonably expected from cortico(cid:173)
`steroid therapy versus the inevitable undesirable side
`effects of prolonged therapy.
`It is first necessa ry to establish a firm diagnosis of
`the disorder with which the patient presents. and to
`understand its natural course. complications. and the
`results of therapy with other types of agents.
`Then, if the decision to administer steroid therapy
`is made, it is importan t to decide in advance which
`signs, symptoms or laboratory tests can be used to in(cid:173)
`dicate whether benefit has occurred. There are some
`signs wh ich are too nonspecific to be useful. T hese in(cid:173)
`clude the disappearance of malaise. improvement in
`sense of well-being. or a fall in temperature since
`these nonspecific changes occur as a result of steroid
`therapy in the majority of patients. Therefore, signs
`and symptoms more specifically related to the disease
`being treated should be decided upon before steroid
`therapy is initiated. For example. when steroids are
`used to treat lupus nephritis, a fall in urinary protein
`excretion or a change in complement levels are useful
`parameters to follow as signs of a positive therapeutic
`response.
`If no recognisable impro vement has occurred
`within 7 to 10 days. the follow ing possibilities should
`be considered:
`I) The disorder may not be responsive to steroid
`therapy.
`implying an incorrect initial clinical diag(cid:173)
`nosis.
`2) The dosage may be insufficient (this can be
`tested by increasing the dose).
`J) Absorption of the steroid may be incomplete
`(this can be tested by measuring plasma cort isol levels
`or changing to another steroid prepara tion). and
`4) An
`unrecognised.
`concurrent problem is
`becoming worse either because of the therapy or
`unrelated to it (e.g. reactivation of tuberculosis).
`
`

`

`Cortl cooteroids; Clinical Pharmacology and TherapeutI c Use
`
`'"
`
`4.2 Mode of Adm inistration
`
`The mode of admi nistrat ion of stero id hor mone
`has a significant effect on its clinical efficacy. For ex(cid:173)
`ample. in the treatment of acute adrenal insufficiency
`with decreased peripheral perfusion. intramuscular
`administration of stero id preparat ions may be ineffec(cid:173)
`tive. In this setting . approp riate therapy would be an
`intravenous bolus of the water soluble hemisuccinate
`or phosphate ester of cortisol
`(or
`its synthetic
`equivalent> followed by a continuous intravenous in(cid:173)
`fusion. On the other hand, the acetates of cortisol and
`its synthetic analogues are relatively insoluble in
`water and are injected as suspensions which are
`slowly absorbed from the intramuscular site. thus
`prolonging the duration of effectiveness. The prin(cid:173)
`cipal use of this type of repository corticosteroid pre(cid:173)
`paration is in the patient who requires short term.
`continuous therapy and for whom oral administra(cid:173)
`tion is either inconvenient or undesirable.
`
`4.3 C hoice between ACTH
`and Oral Steroids
`
`The choice between ACT H therapy and oral
`steroid therapy must take into account several factors:
`I ) ACfH therapy consists of costly daily injec(cid:173)
`tions which are difficult to taper as compa red with
`the relatively inexpensive and convenient oral steroid
`medication. which can be regulated more accurately .
`2) ACT H administration provides natural andro(cid:173)
`gens as well as glucocort icoids. whereas exogenous
`steroid therapy actually results in inhibition of endo(cid:173)
`genous androg