2 OTH EDITION
`
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`
`and Editor
`
`JANSSEN EXHIBIT 2026
`
`JANSSEN EXHIBIT 2026
`Mylan v. Janssen IPR2016-01332
`
`

`

`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`\
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewedfor
`current information, including contraindications, dosages and precautions,
`Printed in the United States ofAmerica
`Entered according to Act ofCongress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress,at Washington DC
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`Copyright 1926, 1936, by the Joseph P Remington Estate
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`All Rights Reserved
`Library of Congress Catalog Card Informationis available
`ISBN 0-683-306472
`
`Thepublishers have made every effort to trace the copyright holders for borrowed
`material. Ifthey have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Namesis by permission of The USP Convention. The Convention is not respon-
`sible for any inaccuracy contained herein.
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event ofany difference or discrep-
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations ofthem herein, the
`context and effect of the official compendia shall prevail.
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers
`should call (301) 714-2324,
`a
`
`*.¢ 00 01°02 03 04
`12345678910
`
`

`

`HORMONES AND HORMONE ANTAGONISTS
`
`1363
`
`The plasma half-life is 10 to 20 min. However, the effect of an
`intramuscular injection lasts from 2 to 8 hr. From 10 to 15% is excreted
`unchanged. Vasopressin tannate is also available as a longer-acting
`preparation.
`
`
`THE ADRENOCORTICAL STEROIDS
`
`and L-arginine at position 8 has been replaced by the p-enantiomer.
`Helv Chim Acta 1966; 49:695.
`Description—White fluffy powder; pK, (gly-NH,) 4.8.
`Solubility—Soluble in alcohol or water.
`Comments—Usedin the treatmentof central (neurogenic) diabetes
`insipidus. It also is used to test the ability of the kidney to concentrate
`urine. Since the hormone can raise the plasma levels of Factor VIII
`(antihemophilic factor), it is sometimes used to treat Factor VIII bleed-
`ing disorders and to increase Factor VIII levels prior to surgery. It may
`be used alone or as an adjunct for some refractory cases of primary
`nocturnal enuresis.
`Headache, mild hypertension, nasal congestion, mild abdominal
`cramping, water intoxication, and vulval pain sometimes occur. Chlor-
`propamide and clofibrate potentiate, and glyburide inhibits, antidi-
`uretic action.
`
`LYPRESSIN
`
`The steroid hormoneproducts of the adrenal cortex are grouped
`into two classes: the corticosteroids (glucocorticoids and min-
`eralocorticoids), which have 21 carbons, and the androgens,
`which have 19. Adrenal corticosteroids differ in their relative
`glucocorticoid (carbohydrate-regulating) and mineralocorticoid
`(electrolyte-regulating) activities. In humans hydrocortisone
`(cortisol) is the main glucocorticoid and aldosteroneis the main
`mineralocorticoid. The cortex, or outer portion, of the adrenal
`Vasopressin, 8-1-lysine-, Diapid
`gland is one of the endocrine structures most vital for normal
`feafodeeaoll
`Cys-Tyr-Phe-Gin-Asn-Cys-Pro-Lys-Gly —NH.
`metabolic function. Whileit is possiblefor life to continue in the
`ee ee Pee 7
`complete absenceof adrenal cortical function, serious metabolic
`derangements ensue, and the capacity of the organism to respond
`to physiological or environmental stress is lost completely.
`PHYSIOLOGICAL ACTIONS—Adrenocortical
`steroids
`have diverse effects that include alterations in carbohydrate,
`protein, and lipid metabolism; maintenanceof fluid andelec-
`trolyte balance; and preservation of normal function of the
`cardiovascular system, the immune system, the kidney, skele-
`tal muscle, the endocrine system, and the nervous system. One
`of the major pharmacological usesof this class of drugs is based
`on their anti-inflammatory and immunosuppressive actions. A
`protective role for cortisol is apparent in the physiological re-
`sponse to severe stress that can increase daily production over
`10-fold. Furthermore, many immune mediators associated with
`the inflammatory response can lead to decreased vascular tone
`and cardiovascular collapse if unopposed by adrenal corticoste-
`roids. The relative or complete absence of adrenocortical func-
`tion, known as Addison’s disease, is accompanied by loss of
`sodium chloride and water, retention of potassium, lowering of
`blood-glucose and liver-glycogen levels, increased sensitivity to
`insulin, nitrogen retention, and lymphocytosis. The disturbances
`in electrolyte metabolism are the cause of morbidity and mortality
`in most cases of severe adrenal insufficiency. All of these disorders
`may be corrected by administration of adrenal cortical extract or
`the pure adrenal cortical steroids now available.
`In its biosynthesis of the steroid hormones, the adrenal
`cortex uses cholesterol, which is present in large amounts in
`the gland; during periods of secretory activity it also consumes
`large quantities of ascorbic acid, which is likewise present in
`high concentration. The synthesis andsecretion of the glucocor-
`ticoids (essentially hydrocortisone) takes place in the zona fas-
`ciculata. Corticotropin (ACTH)is the primary stimulus to hy-
`drocortisone secretion. ACTH is released in response to the
`hypothalamic hormone CRH (see page 1359). Glucocorticoid
`secretion, then, is regulated through suprahypothalamic and
`hypothalamic nuclei, which integrate responses to sensory,
`emotional, and chemical inputs, including the glucocorticoids
`themselves, and the basophilic cells of the adenohypophysis,
`release from which is suppressed by circulating glucocorticoids.
`Physical (injury, surgery, etc) and emotional stress and hypo-
`glycemia increase secretion. Synthesis in the zona fasciculata
`can be altered by drugs that inhibit specific enzymes involved.
`CRH, ACTH, and glucocorticoid release follows a circadian
`rhythm such that blood concentrations of hydrocortisone are
`highest between 6 and 8 am and lowest around midnight.
`The synthesis and release of the mineralocorticoid aldoste-
`rone takes place in the zona glomerulosa. ACTH has only a
`slight effect on secretion. Rather, angiotensins II and III are
`the primary stimulants, although hyperkalemiais also an im-
`portant stimulus. The production of the angiotensins is under
`renal, CNS, and sympathetic nervous system control. In the
`kidney, the macula densa around the juxtaglomerular distal
`tubules monitors Na* and Cl concentrations and luminal
`osmolarity. Low Na* and osmolarity or high Cl” causessignals
`
`[50-57-7] C,,;HgsN j30,052 (1056.22).
`Preparation—Isolated from hog pituitaries and prepared synthet-
`ically (J Biol Chem 1956; 222:951; J Am Chem Soc 1960; 32:3195). One
`commercial synthetic method concludes by reacting the protected tri-
`peptide N-tosyl-S-benzyl-L-cysteinyl-L-tyrosyl-L-phenylalanylhydrazide
`with the protected hexapeptide L-glutaminyl-L-asparaginyl-S-benzyl-1-
`cysteinyl-L-prolyl-N-tosyl-L-lysyl-glycinamide and then splits off the
`protecting groups with metallic sodium.
`One milligram of lypressin is stated to be equivalent to 270 USP
`Posterior Pituitary Units (1 Unit is equivalent to 3.7 yg).
`Comments—Hasstrong antidiuretic but weak pressor activity. It
`is used only in the control or prevention of mild-to-moderate neurogenic
`diabetes insipidus. When the condition is severe, it does not give suffi-
`cient control because of its brief duration of action; even in moderate
`diabetes insipidus, control is only periodic,
`in accordance with the
`dosage regimen. In the severe condition, vasopressin tannate is used,
`although this hormone may be used as an adjunct betweeninjections of
`the tannate.
`Diabetes insipidus from renal disordersis not affected. After nasal
`application, antidiuresis peaks within 1/2 to 2 hr andlasts 3 to 8 hr. The
`half-life is about 15 min.
`When used as recommended, its untoward effects are infrequent
`and mild; they include nasal irritation and congestion, rhinorrhea,
`nasal pruritus, nasal ulceration, conjunctivitis, and headache. Overdos-
`age may cause heartburn from postnasal drip, abdominal cramps, bowel
`hypermotility, and fluid retention. Inhalation of the spray can result in
`asthma-like tightness in the chest, dyspnea, and coughing. Thusfar,
`allergic responses have not been reported. Because the marketed sub-
`stance is synthetic and thus free of traces of foreign proteins, it may
`possibly lack allergenicity, even though its composition differs slightly
`from that of the human hormone.
`
`VASOPRESSIN
`
`Beta-Hypophamine; Pitressin
`Lys—Tyr—Phe—Glu—Asp—Cya—Pro—Arg—Gly NH,
`,
`=
`30hUM4
`§
`B6
`Ff
`a8
`4
`("in pig vewoprewwen, Argis Lys)
`
`8-.-Lysine (or arginine) vasopressin: Lysine form-[50-57-7] C,,H,.-N,,0,.5.
`(1056.22); Arginine form-[113-79-1] C,,.H,.N,,0,.5. (1084.23),
`Comments—Its actions are discussed on page 1362.It is employed
`for its antidiuretic effect in central diabetes insipidus and to dispel gas
`shadows in bowel roentgenography and pyelography. It should not be
`used as a pressor agent.
`Untoward effects related to overdosage include water intoxication
`(with headache, nausea and vomiting, confusion, lethargy, coma, and
`convulsions), especially when patients drink excessive amounts of wa-
`ter or are given intravenousfluids, and stimulation of vascular, uterine,
`and intestinal smooth muscle, which mayresult in pallor, hypertension,
`coronary constriction (with anginal chest pain, electrocardiographic
`changes, and occasional myocardial infarction), uterine cramps, men-
`orrhagia, and nausea, vomiting, diarrhea, and abdominal cramps. Hy-
`persensitivity occasionally occurs; manifestations include urticaria,
`neurodermatitis, flushing, fever, wheezing, dyspnea, and rare anaphy-
`lactic shock. Large doses are oxytocic and also cause milk ejection.
`Alcohol, heparin, demeclocycline, lithium, and large doses of epineph-
`rine antagonizeit; carbamazepine, chlorpropamide, clofibrate, glucocor-
`ticoids, and urea potentiate it.
`
`

`

`1364
`
`CHAPTER 77
`
`to be sent to the juxtaglomerular (JG) cells in the afferent
`arterioles, which then release renin. Renin secretion also is
`increased by low blood pressure at the JG cells and by sympa-
`thetic impulses, which work through £,-adrenoreceptors. Re-
`nin then cleaves angiotensin I from angiotensinogen, both lo-
`cally and in the blood. Angiotensin I is converted to angiotensin
`II by a converting enzyme (CE or kininase II), mainly in the
`lung. (Angiotensin ITI is a metabolite of II.) Thus, a variety of
`electrolyte, emotional, cardiovascular, and drug factors can
`affect aldosterone secretion indirectly.
`STRUCTURE-ACTIVITY RELATIONSHIP—Clinical ex-
`perience has indicated that the anti-inflammatory activity of
`adrenal cortical steroids in man correlates well with their glu-
`cocorticoid activity. The undesirable side effects of sodium re-
`tention and edema are associated with mineralocorticoid actiy-
`ity. Synthetic steroids possessing higher glucocorticoid and
`lower mineralocorticoid activity than cortisone or cortisol have
`been prepared and marketed. A comparison of some commonly
`used systemic corticosteroids is included in Table 77-2.
`All adrenal corticoids require the 3-keto group and 4,5 un-
`saturation. Additional unsaturation in Ring A enhances the
`anti-inflammatory properties while at the same time reducing
`the sodium-retaining effect. The presence of oxygen at position
`11 is necessary for significant glucocorticoid activity; the 11p-
`hydroxy group is more potent than the 11-keto group; the
`11-keto group is converted to the active B-hydroxy group in the
`body. The 17w-hydroxy group also is important to glucocorticoid
`activity. Introduction of either a methyl or hydroxyl group at
`position 16 markedly reduces mineralocorticoid activity but
`only slightly decreases glucocorticoid and anti-inflammatory
`activity. The 9a-fluoro group enhances both glucocorticoid and
`mineralocorticoid activities, but the effects of substituents at
`the 6 and 16 positions override this effect.
`BIOLOGICAL ACTIVITY—tThe glucocorticoids appear to
`affect all cells, although not all in the same way. Clinical
`interest primarily focuses on their anti-inflammatory and im-
`munosuppressanteffects. They prevent release of various lytic
`enzymes that extend tissue damage during inflammation and
`generate leukotactic substances. Glucocorticoids decrease
`phagocytosis by macrophages. Anti-inflammatory effects in-
`clude the retardation of the migration of polymorphonuclear
`leukocytes, suppression of repair and granulation, reduction in
`the erythrocyte sedimentation rate, decreased fibrinogenesis,
`and diminished elaboration of C-reactive protein. Glucocorti-
`coids suppress the production of cytokines (eg, IL-1,IL-6, inter-
`feron gamma, TNF-alpha, and others) by inflammatory cells
`(eg, monocytes, macrophages, and lymphocytes) that recruit
`eosinophils. They also decrease lipid eicosanoid and prosta-
`glandin production by inhibiting the production of cytokines
`that induce cyclooxygenase-II in inflammatory cells. The im-
`
`munosuppressant effects may be partly the result of the sup-
`pression of phagocytosis, gene expression of cytokines and a
`decrease in the number of eosinophils and lymphocytes, sup-
`pression of delayed hypersensitivity reactions, decrease in tis-
`sue reaction to antigen-antibody interactions, and reduction in
`plasma immunoglobulins.
`Effects on carbohydrate, fat, and protein metabolism are
`responsible for both beneficial and untoward effects. These
`hormones increase hepatic gluconeogenesis and glycogen dep-
`osition, both lipolysis and lipogenesis (but increase fat deposi-
`tion at only a few specialized sites), and protein catabolism in
`various tissues (especially skeletal muscle).
`In addition to the above-mentioned changes broughtabout
`by glucocorticoids are the so-called permissive effects. In these,
`the steroids do not themselves cause change but physiological
`amounts are required for certain organs or structures to re-
`spond to stimuli. For example, neither the kidney can respond
`to a water load nor the arterioles to epinephrine in the absence
`of adequate levels of glucocorticoids.
`Once a glucocorticoid hormone has permeated a cell mem-
`brane, it combines with a cytosolic glucocorticoid receptor that
`is inactive because it is bound to somespecific proteins, includ-
`ing some heat shock proteins that prevent them from reaching
`the nucleus and binding to DNA. The glucocorticoid-receptor
`complex undergoes conformational changes that allow dissoci-
`ation from the heat shock proteins and other immunomodula-
`tory proteins, then it is translocated to the cell nucleus, where
`it attaches to glucocorticoid receptor elements in the DNA. The
`result is an enhancementor reduction of the gene transcription
`that leads to an increased or decreased synthesis of certain
`proteins. Other transcription factors also interact at the same
`DNAbinding sites. The protein produced is determined, in
`part, by the glucocorticoid receptor, of which there is more than
`one kind within the cell. There are estimated to be from 10 to
`100 glucocorticoid target genes percell, but not all of them are
`expressed in every cell. Tissue selectivity for different steroid
`hormones seems to be considerably determined by steroid-
`metabolizing enzymes that differentially alter intracellular ste-
`roids that upon transport to the nucleus bind to specific hor-
`mone response elements in the DNA.
`Mineralocorticoids act on the distal tubules and collecting
`ducts of the kidney to increase the expression of genes that
`encode for proteins that enhance reabsorption of Na” from the
`tubularfluid. The effects on electrolytes are associated with an
`increase in the numberof open Na* and K* channels in the
`luminal membrane tubularcells, and they increase the activity
`of basolateral membrane Na‘/K*-activated ATPase. The net
`result is a return of Na* to the systemic circulation in exchange
`for K*. Similar electrolyte effects are promoted by mineralo-
`
`Table 77-2. Major Adrenal Corticosteroids”
`
` DRUG
`
`RELATIVE ACTIVITY
`
`ANTI-INFLAM
`TOPICAL
`
`Na + RET
`
`DOSAGE FORM
`
`Short- to medium-acting glucocorticoids
`Hydrocortisone (Cortisol)
`Cortisone
`Prednisone
`Prednisolone
`Methylprednisolone
`Intermediate-acting glucocorticoids
`Triamcinolone
`Fluprednisolone
`Long-acting glucocorticoids
`Betamethasone
`Dexamethasone
`Mineralocorticoids
`Oral, Inj, Top
`250
`10
`10
`Fludrocortisone
`
`Desoxycorticosterone acetate Inj, pellets 0 0 20
`
`
`
`”" Legend: Relative activity, potency relative to hydrocortisone; anti-inflammatory, anti-inflam; sodium retention, Na + Ret; Injection, Inj; topical, Top,
`
`1
`0.8
`0.3
`0.3
`0
`
`0
`0
`
`0
`0
`
`Oral, Inj, Top
`Oral, Inj, Top
`Oral
`Oral, Inj, Top
`Oral, Inj, Top
`
`Oral, Inj, Top
`Oral
`
`Oral, Inj, Top
`Oral, Inj, Top
`
`1
`0.8
`4
`5
`5
`
`5
`15
`
`25-40
`30
`
`1
`0
`0)
`4
`5
`
`5-100
`7
`
`10
`10-40
`
`

`

`corticoids in other tissues (eg, colon, salivary glands, and sweat
`glands).
`Glucocorticoids also inhibit membranelipid peroxidation,
`which possibly contributes to the salutary effects in brain
`edema; the effect appears to be one of decreasing the activity
`of membrane-bound, superoxide radical-generating mixed-
`function enzymes. Possibly related is an action to block
`phospholipase-A2, which prevents the release of arachidonic
`acid from membrane phospholipids and its subsequent conver-
`sion to eicosanoids. This inhibitory effect results from the pro-
`duction of an inhibitory protein, lipocortin, in leukocytes.
`The primary effects of mineralocorticoids are on cortical
`collecting tubule cells in the kidney to increase sodium reab-
`sorption and potassium secretion. Thus, elevated aldosterone
`titers cause sodium retention and potassium depletion with
`accompanying volume expansion and weight gain, hyperten-
`sion, and metabolic alkalosis.
`SIDE EFFECTS—Certain side effects may appear during
`the first week of treatment with glucocorticoids; they include
`euphoria anda rare paradoxical suicidal depression, psychoses
`(especially with high doses), hypertension (rare), anorexia, oc-
`casional hyperglycemia, colonic ulceration (rare), increased
`susceptibility to infections (especially viral infections, fungal
`infections, tuberculosis), and acne. After 7 to 10 days oftreat-
`ment, the pituitary release of ACTH is suppressed, and the
`adrenal! secretion of cortisol is temporarily inadequate once
`glucocorticoid administration ceases. In the case of a medical
`emergency,
`the depressed pituitary-adrenal response may
`make the patient unable to respond to stress. Additional exog-
`enous corticosteroid is given in a dosage and for a duration
`appropriate for the severity of the stress. Consequently, pa-
`tients on high-dose or long-term treatment should carry iden-
`tification stating that they are under treatment with cortico-
`steroids. Withdrawalof corticosteroids should be slow.
`From the first week through thefirst year of therapy, addi-
`tional side effects may appear, namely, fat redistribution to the
`nape of the neck (bujfalo hump) and lower abdomen,diabetes
`mellitus and hyperglycemia, moon face and other edematous
`states, and renal potassium loss (from mineralocorticoid activ-
`ity), alkalosis, additional infections (including tuberculosis),
`papilledema,glaucoma, posterior subcapsular cataracts, diplo-
`pia, 6th nerve palsies, osteoporosis, myopathy, ecchymoses and
`purpura, and cutaneousstriae. After prolonged suppression of
`the anterior pituitary secretion of ACTH, there may be a per-
`manent defect in pituitary-adrenal function. Continuous or
`repetitive use of glucocorticoids may cause painless joint de-
`struction, especially if the drug is given intra-articularly. Af-
`ter prolonged glucocorticoid therapy, additional untoward
`effects include bone fractures and vertebral collapse (from
`marked osteoporosis), hyperlipidemia, and possible premature
`atherosclerosis.
`Adverse effects of glucocorticoids applied to the skin include
`stinging or burning sensations, itching,irritation, dryness, sca-
`liness, vasoconstriction, folliculitis, acne, bacterial or yeast in-
`fections, hypopigmentation, atrophy, and striae, Systemic ef-
`fects also can occur, especially if occlusive dressings are used.
`Topical ophthalmological glucocorticoids not only may cause
`serious exacerbations of viral, fungal, and bacterial infections
`of the eye but also glaucoma. From all of the above, it can be
`seen that glucocorticoids are drugs that have numerous and
`potentially serious side effects.
`Because the mineralocorticoids are used mainly in physio-
`logical doses for replacement therapy, untoward effects are
`usually infrequent and mild. Sodium and water retention (with
`moon face), potassium loss, alkalosis, and hypertension can
`occur with excessive doses.
`DRUG INTERACTIONS—Glucocorticoids decrease the
`hypoglycemic activity of insulin and oral hypoglycemics,so that
`a changein dose of the antidiabetic drugs may be necessitated.
`In high doses, glucocorticoids also decrease the response to
`somatotropin. The usual doses of mineralocorticoids and large
`doses of some glucocorticoids cause hypokalemia and may ex-
`
`HORMONES AND HORMONE ANTAGONISTS
`
`1365
`
`aggerate the hypokalemic effects of thiazide and high-ceiling
`diuretics. In combination with amphotericin B they also may
`cause hypokalemia. Glucocorticoids appear to enhance the ul-
`cerogenic effects of nonsteroidal anti-inflammatory drugs
`(NSAIDs), They decrease the plasma levels of salicylates, and
`salicylism mayoccur on discontinuing steroids. Glucocorticoids
`may increase or decrease the effects of prothrombopenic anti-
`coagulants. Estrogens, phenobarbital, phenytoin, and rifampin
`increase the metabolic clearance of adrenal corticosteroids and
`hence necessitate dose adjustments.
`PRECAUTIONS AND CONTRAINDICATIONS—Both
`glucocorticoids and mineralocorticoids must be used cautiously
`in congestive heart failure, hypertension, liver failure, renal
`failure, or nephrolithiasis. When glucocorticoids are used in
`persons with emotional instability or psychotic tendencies, hy-
`perlipidemia, diabetes mellitus, hypothyroidism, myasthenia
`gravis, osteoporosis, peptic ulcer, ulcerative colitis, chronic in-
`fections (especially tuberculosis or a positive test), or a history
`of herpetic infections, patients should be monitored frequently
`for untoward effects. Topical application to the eye is absolutely
`contraindicated in the presence of ophthalmological infections.
`PHARMACOKINETICS—Most corticosteroids are ab-
`sorbed rapidly and completely from the GI tract. Somecortico-
`steroids (hydrocortisone and someinhaled congeners including
`beclomethasone and budesonide) are rapidly inactivated by
`metabolism as they pass through the liver. Thus, some corti-
`costeroids must be given parenterally for systemic effects. Es-
`terification with large hydrophobic organic acids decreasessol-
`ubility and therefore slows systemic absorption from sites of
`injection. Esterification with water-soluble acids, such as phos-
`phoric or succinic, increases the rate of absorption from injec-
`tion sites and even may permit intravenous administration. All
`of the glucocorticoids are absorbed from the skin, but some
`slowly enough that metabolic destruction can limit systemic
`accumulation. Many glucocorticoids also are metabolized in the
`skin. Fluorination at the 9-position and various substituents at
`the 17-position make glucocorticoids resistant to local destruc-
`tion and hence make these derivatives more likely to cause
`systemic effects.
`In the plasma, corticosteroids are bound to both corticoste-
`roid-binding globulin (CBG,transcortin, a,-macroglobulin) and
`albumin, which serve as transport vehicles. The extent of bind-
`ing varies among the steroids. Various drugs and diseases can
`affect the concentration of transport proteins and their capac-
`ities. Corticoids cross the placental barrier and may cause
`congenital malformations. They also appearin breast milk and
`may suppress growth of the infant. The action of a steroid-
`receptor complex at the genes long outlasts significant plasma
`concentrations of the steroid, so that the plasma half-life has
`little relevance to a dosage regimen. Instead, a parameter
`knownasthebiological half-life is the primary determinant of
`dosage intervals.
`THERAPEUTIC USES—tTheadrenal corticosteroids are
`used for replacement therapy in adrenal insufficiency (eg, Ad-
`dison’s disease and congenital adrenal hyperplasia). In this
`use, toxic effects are infrequent, since the aim is to approximate
`the equivalent of physiological body concentrations. Both min-
`eralocorticoids and glucocorticoids may be required. Glucocor-
`ticoids additionally are used to treat rheumatic, inflammatory,
`allergic, neoplastic, and other disorders; the effects are pallia-
`tive only and do not eradicate the underlying disorders. It is
`necessary to use supraphysiological doses, so some untoward
`effects are unavoidable.
`The anti-inflammatory actions of the glucocorticoids are
`employed in the treatment of noninfectious acute ocular in-
`flammation andcertain infectious inflammations, especially in
`combination with antibiotics. Glucocorticoids are of value
`in decreasing somecerebral edemas, eg, vasogenic. Their value
`in the treatment of bacterial meningitis probably accrues to
`decreased permeability of the blood-brain barrier plus inhibi-
`tion of cytokine production, especially tumor necrosis factor
`(TNF-alpha).
`
`

`

`1366
`
`CHAPTER 77
`
`In serious acute allergic disorders, systemic glucocorticoids
`may be indicated; they should not be used chronically in aller-
`gic disorders, except in acute flareups. However, potent topical
`corticosteroids are now regularly used by inhalation for chronic
`treatment of bronchial asthma and intranasally for chronic
`noninfectious rhinitis (see Respiratory Drugs in Chapter 69).
`Similarly, acute bronchial asthma, status asthmaticus, and
`some chronic obstructive pulmonary disease may require sys-
`temic glucocorticoids. These drugs suppress allergic and in-
`flammatory manifestations of trichinosis.
`Topical or systemic glucocorticoids often markedly improve
`certain skin diseases, such as pruritus, psoriasis, dermatitis
`herpetiformis, and eczema; pemphigus, erythema multiforme,
`exfoliative dermatitis, and mycosis fungoides usually require
`systemic treatment, which maybelife-saving.
`Probably the most widely known application of the anti-
`inflammatory actions of the glucocorticoids is in the treatment
`of the arthritic and rheumatic disorders. Immunosuppressant
`actions also may play a role in the treatmentof such disorders.
`These disorders are systemic lupus erythematosus, polyarteri-
`tis nodosa, temporalarteritis, Wegener’s granulomatosis, poly-
`myositis, and polymyalgia rheumatica. Glucocorticoids may be
`indicated in severe cases of rheumatoid arthritis unresponsive to
`other treatment, Still’s disease, mixed connective tissue disease,
`drug-induced lupoid syndromes, and psoriatic arthropathy.
`Rheumatic or arthritic conditions in which glucocorticoids
`may or may not provide temporary relief but are not justified
`chronically because of a high toxicity/benefit ratio are osteoar-
`thritis, systemic ankylosing spondylitis, gout fibrositis, and
`Reiter’s syndrome. Even though the nephrotic syndromeis not
`inflammatory, it may respond to treatment, perhaps as the
`result of immunosuppression. Ulcerative colitis sometimes may
`respond dramatically. The beneficial effects in myasthenia gra-
`vis are probably immunosuppressant. Chronic multiple sclero-
`sis does not respond, but acute relapses may. The incidence and
`severity of the respiratory distress syndrome in premature
`infants can be decreased by glucocorticoid treatment.
`Glucocorticoids maybe palliative in acute leukemia and also
`in chronic lymphocytic leukemia, and they are components of
`certain curative antineoplastic combinations. They suppress
`the associated autoimmune hemolytic anemia and the nonhe-
`molytic anemia, granulocytopenia, and thrombocytopenia that
`result from encroachment on the bone marrow. Theeffects are
`only temporary, and the patient eventually becomes refractory
`to steroid therapy. Hodgkin’s disease, lymphosarcoma, and
`multiple myeloma also may be suppressed temporarily.
`In the treatment of endotoxin shock, massive doses of glu-
`cocorticoids suppress the vasculotoxic effects of the toxin. In all
`kinds of shock, massive doses decrease peripheral resistance,
`stimulate the heart, and decrease the amount of circulating
`myocardial depressant factor. To be optimally effective they
`must be given as boluses.
`MODALITIES AND REGIMENS OF CORTICOSTE-
`ROID THERAPY—Replacement Therapy—Treatmentofpri-
`mary and secondary adrenal insufficiency requires replace-
`ment of both glucocorticoids
`and mineralocorticoids
`in
`sufficient doses to relieve the signs and symptoms of insuffi-
`ciency. However, when the patient experiences an additional
`stress, supplements of glucocorticoids may be required. The
`dose and dose-interval vary from patient to patient, but the
`doses are small, and complications are infrequent and minimal;
`the most difficult challenge is in the adjustment of dosage in
`response to changesin stress.
`CHRONIC LOW-DOSE SYSTEMIC THERAPYOFDIS-
`EASE—In mild inflammatory or collagen disorders, low doses
`of glucocorticoids often are sufficient to be palliative, and low-
`dose regimens are preferable, since adverse effects usually are
`of low intensity, provided that the therapeutic endpointis only
`amelioration and not elimination of the morbidity. Although
`low-dose therapy may cause some suppression of pituitary-
`adrenal function, the suppression is readily reversible, and
`somereserve exists in the system. However, abrupt withdrawal
`
`of the drug may be followed not only by a return to the previ-
`ous condition but also an acute exacerbation of the disease.
`Pituitary-adrenal suppression and consequent acute flareup
`after withdrawal may be lessened by avoiding round-the-clock
`administration and, instead, giving the drug between 6 and 9
`AM, so that plasma levels and, hence, pituitary-adrenal sup-
`pression are at a minimum during the early morning sleeping
`hours, when pituitary adrenal function is at its diurnal peak.
`Moreover, the selection of a steroid with a short biological
`half-life allows some drug-free time during the day, during
`which pituitary-adrenal recovery can occur.
`CHRONIC HIGH-DOSE SYSTEMIC THERAPY—In se-
`rious chronic inflammatory or immunological disorders or in
`glucocorticoid-responsive neoplasia, large doses of glucocorti-
`coids may be given for long periods of time. Consequently, side
`effects are frequent, and pituitary-adrenal suppression may be
`severe. The suppression may continue for weeks to months
`after cessation of treatment, so withdrawal must be tapered
`slowly to allow the pituitary-adrenal system to recover.
`Abrupt withdrawal will result in adrenal
`insufficiency,
`which may be life-threatening, as well as an acute recrudes-
`cence of the original disorder. Pituitary-adrenal suppression
`and systemic side effects may be less severe if the dose is given
`in the morning, so that nocturnal pituitary-adrenal activity is
`less inhibited. Another device to minimize such adverse sys-
`temic effects is use of alternate-day therapy. Thus, twice the
`usual daily dose is given, but only every other day, which
`permits the hypothalamicopituitary segment of the pituitary-
`adrenal negative feedback system and various undiseased tar-
`get organs time to recover partially between doses. Only glu-
`cocorticoids with an intermediate duration of action (12 to 36
`hr) should be used for alternate drug therapy.
`INTENSIVE SHORT-TERM S