Steroids: Review and Update

CHAPTER 3O Steroids: Review And Update

Raymond G. Caualiere, D.PM,

Cortisone and related cofiicosteroids owe their This may include ectopic sources (i.e., non- popularity to their anti-inflammatory effect, there- pituitary production of ACTH by cancers, and the fore, they have become widely used and often therapeutic administration of large doses of abused in medicine. The following paper is synthetic, anti-inflammatory glucocorticoids). The intended to offer a review of the physiologic and converse to Cushing's syndrome, Addison's disease, described by Addison in the mid 19th cen- pharmacologic basis of corticosteroids, as well as tury, includes primary failure of the adrenal cortex information on current steroids used in podiatric as well as loss of both glucocorticoid and medicine, their side effects, indications, and mineralocorticoid secretory capaciqr . contraindications. principal products The secretory of the HISTORY OF ADRENAL STEROIDS adrenal cortex in humans are the steroid hormones; Cortisol, Aldosterone and Androgens. A milestone in the history of the adrenal steroids Cholesterol is the precursor of all the adrenocorti- was the reporl of Hench and coworkers on the cal steroid hormones, and itself derived from effectiveness of cortisone and adrenocotticotrophic circulating low-density lipoproteins (LDL) (Fig. 1). hormone (ACTH) in rheumatoid afthritis. Clinical Cortisol, a glucocorticoid, is responsible for regu- trials in rheumatoid arthritis were dramatic with lating hepatic gluconeogenesis and other actions. cortisone, which also provided symptomatic relief Aldosterone, a mineralocorticoid, is responsible for in many other disease conditions. It was recog- sodium and potassium homeostasis, while the nized at that time that cortisone was not a cure, androgens are the sex hormones that regulate however, it seemed to provide the susceptible tis- one's reproductive and behavi oral characteristics. sues with a shield-like buffer against the irritant. Subsequent research on the glucocorticoids "cH,oH 1ed to the development of a variery of newer steroids that have significantly greater anti-inflam- ,of: o matory potency than cortisone, although their influence on carbohydrate metabolism generally parallels their anti-inflammatory activity. A signifi- cant advantage of the newer steroids, such as Prednisone, Methylprednisolone (Medrol), Triamcinolone (Aristocort, Kenalog), and Dexamethasone (Decadron), is that these anti- inflammatory steroids exert little effect on renal sodium reabsorption, while stil1 possessing potent

anti-infl amm atory acl| ity .

Figufe 1. The structure of Cortisone. Note the cholesterol infrastruc- ture. Other steroids are derived from changes at the various number PTIARMACOLOGIC EFFECTS positions. Cortisol, which is the major natural glucocorticoid A change in the balance of hormones in the produced by the adrenal cortex, exerts three body can have detrimental effects. One example, accurately-measurable effects and numerous Cushing's refers picture syndrome, to the clinical of miscellaneous effects. The three maior effects are: hypercortisolism, regardless of the pathogenesis. I5O CHAPTER 30

1) influence of carbohydrate, protein and fat com.ulsive threshold, while prolonged use of glu- metabolism, 2) mineralocorticoid effect, and 3) cocorticoids can cause proximal muscle wasting anti-inflammatory effect. Structural modifications of and weakness. Cortisol can lead to a dissociation of the carbohy- The effects of corticosteroid treatment on drate effects from the mineralocorticoid effects, infection are quite complex. Very large doses in thus sodium retention does not parallel the carbo- animal experiments suggest an adverse effect on hydrate or anti-inflammatory effects in Cortisol infection course, especially in fungal diseases. Vith derivatives. Some of the miscellaneous effects reasonable doses, antibody production is not include alterations of the immune system, changes decreased, opsonins remain normal, and leuko- in vascular permeability, and loss of muscle integrity. cytes ingest and destroy microorganisms. Cortisol stimulates gluconeogenesis and also Adverse effects of excessive doses of gluco- tends to inhibit peripheral glucose utilization. It corticoids after prolonged administration include: also causes marked accumulation of glycogen in Cushing's disease, moon face, hirsutism, acne, the liver and can produce hyperglycemia and gly- amenorrhea, osteoporosis, muscle wasting, cosuria. Therefore, Cortisol carr aggrayate diabetes varrable hypernatremia and hypokalemia, hyper- and may bring out an insulin-resistant disturbance tension, aggravalion of diabetes mellitus, of carbohydrate metabolism in latent diabetics. necrotizing afteritis in rheumatoid patients, aggra- Cortisol promotes protein breakdown and vation of peptic ulcer disease, psychotic also inhibits its synthesis. Large doses administered manifestations, and adrenal atrophy (Tables 1, 2). to children and young animals will cause failure to grow and slow healing of wounds. This failure to Table 1 grow is secondary to epiphyseal growth center disturbance. Little is known about the basic action of SYSTEM-SPECIFIC SIDE EFFECTS Cortisol on fat metabolism. Unusual accumulation OF A]\TI-INIFIAMMATORY of fat (buffalo hump) occurs in patients treated with glucocorticoids. Glucocorticoids also have effects CORTICOSTEROID THERAPY on water metabolism and electrol),tes. Cortisone administration will result in increased sodium reten- Endocrine-Metabolic tion, increased potassium excretion, and hypokalemic Hyperglycemia, including hyperosmolar acidosis in patients on prolonged treatment. non-ketotic stupor/coma and, rarely, Calcium metabolism is also affected by Cortisol. it diabetic ketoacidosis promotes renal excretion of calcium, and may Truncal obesity, enlargement of ceruical, reduce calcium absorption from the intestine. supraclavicular, and mediastinal fat pads Most of the clinical uses of the corticosteroids Retarded somatic growth (pediatric centers around their ability to inhibit the inflamma- patient population) tory process. The mechanism of the anti- Acne inflammatory action of the glucocorticoids remains Hirsutism unknown, but multiple theories persist: 1) sup- Negative nitrogen and calcium balances pression of migration of polymorphonuclear Sodium retention (except with synthetic 75 leukocytes, 2) suppression of reparative processes substituted, 9 alpha-fluorinated and function of fibroblasts, and 3) reversal of corticosteroids) enhanced caprllary permeability and lysosomal sta- Cardiovascular System bilization. Cortisonelike steroids also exefi a Hypefiension striking effect on the number of circulating Gastrointestinal Tract eosinophils. They may disappear from the blood Pancreatitis following glucocorticoid administration. In addi- Peptic ulcer disease tion, cortisone produces a marked decrease in Musculoskeletal System circulating lymphocyes and an involution of lym- Osteoporosis phoid tissue. There are central nervous system Aseptic necrosis of femoral and effects such as euphoria and other behavioral humeral heads abnormalities. Glucocorticoid treatment may lower Myopathy CI]APTER 30 t5l

Nervous System around tendons of the foot and ankle, and it is rec- Pseudotumor cerebri ommended that a period of casting be employed Mood disorders, including both euphoria after their use. Intra-articular steroids can have and depressive states detrimental effects on articular cartilage with Psychosis prolonged use. Soluble steroids (phosphate Host Defenses Against Infectious Agents solution, i.e. Decadron phosphate) are perhaps bet- Increased susceptibility to opportunistic ter utilized in this area, as opposed to non-soluble infections, owing to impaired cellular alternatives (acetate suspension, i.e. Kenalog). and humoral responses Eye CLINICAL USES OF STEROIDS Posterior subcapsula r cataract Orally, steroids are rapidly and completely absorbed from the GI tract. After oral administra- The ultimate pharmacologic effect of glucocorti- tion, maximal plasma concentrations are reached coids is dependent on the dose of the agent, type in one to rwo hours. Hepatic degradation leads to of disease to be treated, clinical status of the a fairly rapid fall in plasma levels, so that after eight (age, patient gender, renal and hepatic function), hours only 25o/o of the peak value can be demon- and the interaction of these factors with the spe- strated, and the active drugs disappear completely cific steroid administered. in about 12 hours. Oral therapy can be useful Additional local effects of injected steroids for hypersensitivity or allergic type reactions. include telangiectasias, hypopigmentation of the Methylprednisolone is available in a convenient skin (sometimes resolving spontaneously), corli- dosing package, as Medrol Dosepak, and delivers costeroid-induced avascular necrosis of bone, as methylprednisolone in a dally decreasing dose. well as local tissue atrophy. These changes can be Steroids such as Hydrocortisone, Methyl- detrimental within the foot. Injection of a steroid prednisolone, Prednisolone, and Dexamethasone, within the foot should therefore be deep within the which are formulated as sodium phosphate or tissues being treated, except in cases of scar treat- sodium succinate salts, exhibit rapid rates of ment to promote fibrinolysis. Steroids injected in or absorption owing to increased water solubility. around tendons can be responsible for weakening They are used when a raprd effect is desirable. The of the tendon, ultimately resulting in rupture. glucocorticoids that are conjugated with acetate Steroids should generally be used with caution (Prednisolone, Methylprednisolone, Cortisone,

Table 2 INCIDENCE OF MAJOR SIDE EFFECTS OF Ai\TI-INIFI-{MMAIORY CORTICOSTEROID THERAPY Duration of Minimal daily Therapy Prior Dose Reported Incidence To Appearance To Result Complication Range (o/o) of Complication in Complication Reversibility

Diabetes Mellitus 2-28 Days to months 7.5 mg prednisone Yes Redistribution of body fat 73 2 months 4-12 mg triamcinolone Variable Hypefiension 4-25 2 weeks 7.5 mg prednisone Yes Peptic ulcer disease 0-74 1 month Yes Aseptic necrosis of bone 1-10 6 weeks 5-20 mg prednisone No Myopathy 10 1 week 10 mg prednisone Yes Psychiatric disorders 1-18 Days 60 mg hydrocortisone Yes Cataract 4 2 months 5 mg prednisone No 152 CHAPTER 30

Dexamethasone, and Hydrocortisone) or absorption) on the inflamed joint space. This Acetonide Esters (Triamcinolone), demonstrate an depends on whether crystalline or non-crystalline enhanced lipid solubility resulting in a slower rate suspensions are used. Long-term steroid utilization of absorption and prolonged duration of action. within joints can result in articular cartrlage dam- For example, a single intramuscular injection of age. Intra-articular use of the longer acting steroids Triamcinolone Acetonide (Kenalog,40) is absorbed is probably best avoided due to their lack of warer slowly with effects lasting a few weeks. Lipid solu- solubility. ble Ester formulations are inappropriate steroid Table 3 lists a comparison of the pharmacoki- selections when a rapid clinical response is netics and potencies of a variety of corticosteroids required following steroid injection. Celestone commonly used. This table will allow one to Soluspan, a mixture of betamethasone sodium understand relative potency in terms of glucocorti- phosphate and betamethasone acetate is an exam- coid and mineralocorticoid activity, plasma and ple of a long and shoft acting steroid combination. tissue half life, as well as equivalent dosing. It Dexamethasone, a commonly used injectable should be noted that equivalent dosages ate steroid is available as the short acting steroid, approximate and apply only to oral or intravenous Decadron injectable, or as a long acting steroid, administration. Potency will vary significantly Decadron-LA. when agents are administrated intramusculaiy or Intra-articular steroid use can deliver a tem- into a joint space. porary or prolonged effect (with delayed systemic

Table 3 COMPARISON OF PTIARMACOKINETICS AND POTENCIES OF CORTICOSTEROIDS

Relative Potency

I I Plasma Tissue Glucocorticoid Mineralocorticoid Equivalant Corticosteroid (minutes) (hours) Activity Activity Dose (mg)

Cortisol 90 8-72 20 (hydrocortisone) Cortisone 30 B-72 0.8 0.8 25

(1 1 -dehydrocortisol) Prednisone 50 12-36 4 0.8 5 Prednisolone 200 12-35 4 0.8 5 6 alpha-methylpred- 180 72-36 5 0.5 4 nisolone Fludrocortisone 200 B-72 10 725 (9 alpha-fluorocortisol) Triamcinolone 300 12-36 0 (9 alpha-fluoro-16 alpha- hydroxyprednisolone) Betamethasone (9 alpha-fluoro-15 100-300 35-54 )< 0.75 beta-methylprednisolone) Dexamethasone (9 alpha-fluoro-75 alpha- 100-300 36-54 25 0.75 methylprednisolone) CHAPTER 30 I53

CONTRAINDICATIONS pharmacokinetics will enhance their effective use, TO THE USE OF STEROIDS and help avoid potential complications. Steroids require close monitoring, and the smallest dose Relative contraindications to high-dose anti- should be used over the shortest amount of time inflammatory steroid use are the presence of bac- to avoid potential toxicity. Armed with this infor- terial infection, poorly-controlled diabetes mellitus, mation, the physician is able to make more and advanced demineralizing bone disease. peptic intelligent choices when utilizing a steroid within ulcer disease would also be considered to be a the clinical practice. relative contraindication. BIBLIOGRAPTIY CONCLUSION Goodman and Gillman: The Pharmacological Basis of Therapeutics, Steroids have a variety of uses within foot Sth Ed, Elmsford, NY, Pergmon Press, 1990. the Hench PS, Shocumb CH, Barnes AR, Smith HL, Polley HL, Kendall EC: and ankle. Their use centers mainly around their The Effects of Adrenal Cortical Hormone 17-Hydroxy-11- (Compound phase potent anti-inflammatory effects and their use Dehydro=Corticosterone E) On the Acute of Rheumatic Fever, Mayo Clinic Proceedings +24:277, L949 as fibrinolltics. There are rnany potential side Hench PS: Introduction: Cortisone and ACTH in Clinical Medicine, effects, which cafl affect many body systems. Mayo Clinic Proceedings *25: 474,7950 Goth A: Medical Pharmacology, 9th Ed, Sr. Louis, Mo, Mosby An understanding of steroid administration and Yearbook, 1978.