**5. Adrenal insufficiency (AI)**

The most common cause of AI is the chronic administration of high doses of GCs. This is called iatrogenic or tertiary AI. Exogenous GCs causes a significant suppression of the hypothalamicpituitary-adrenal axis (HPA) even in small doses for only few days. Consequently, the adrenal cortex loses the ability to produce cortisol in the absence of adrenocorticotrophic hormone (ACTH). When the suppression of ACTH levels prolonges, this situation causes atrophy of the adrenal cortex and secondary adrenal insufficiency. The use of systemic GCs results in higher systemic levels of corticosteroids than in cases of compartmental use, as a result leads to higher percentages of AI. Adrenal suppression is more likely in the following situations: (**1)** longer duration of treatment. The influence of smaller doses over longer durations is highly variable. After long-term systemic therapy with GCs (more than 1 year), AI has to be expected in 100% of the patients. **(2)** Supraphysiologic doses, stronger formulations, and longer acting formulations (**Table 4**). If the patients are taking doses of prednisone of ≥20 mg daily for ≥3 weeks, this situation should be considered as adrenal suppression. AI lasting for more than 4 weeks has been demonstrated after treatment with high-dose dexamethasone for 28 days [57–64].

Adrenal suppression is less likely in the following situations: (1) regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon) and (2) alternate-day dosing of steroids. The possible risk of this side effect is unknown. At the same time, individual responses to GCs may be highly different. The clinical presentation of AI is variable; many of the signs and symptoms are non-specific and can be mistaken for symptoms of intercurrent illness or the underlying condition being treated with GCs. Signs and symptoms of AI

and adrenal crisis are listed in **Table 5**. AI often occurs when the exogenous GCs are withdrawn too rapidly or, in the case of stressful conditions (e.g. surgery and infection), when higher levels of GCs may be required. In addition to AI and adrenal crisis decreased ACTH level related with the suppression of the HPA axis, leads to reduced general steroid-hormone production. This situation favors further side effects, such as hypogonadism and osteoporosis [55, 65–68].

**Dose Definition**

≤7.5 mg prednisone equivalent/day

>100 mg prednisone equivalent/day

Prednisone or prenisolone 5 mg≈/hydrocortisone 20 mg≈/dexamethasone 0.75 mg.

Adrenal suppression •Weakness/fatigue

Adrenal crisis • Hypotension

>7.5 mg but ≤30 mg prednisone equivalent/day >30 mg but ≤100 mg prednisone equivalent/day

**Table 4.** The supraphysiologic dosing and interconversion of SGCs (adapted from [66, 67, 69]).

• Malaise • Nausea • Vomiting • Diarrhea • Abdominal pain

• Fever

• Myalgia • Arthralgia

• Lethargy

**Table 5.** Signs and symptoms of adrenal insufficiency and adrenal crisis (adapted from [72]).

• Hyponatremia • Seizure • Coma

• Anorexia/weight loss

• Psychiatric symptoms

• Decreased consciousness

• Unexplained hypoglycemia

• Poor linear growth in children • Poor weight gain in children • Clinical signs of Cushing syndrome

≥250 mg prednisone equivalent/day for 1 day or a few days

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• Headache (usually in the morning)

Low dose Medium High Very high Pulse therapy


**Table 4.** The supraphysiologic dosing and interconversion of SGCs (adapted from [66, 67, 69]).

or the other medications. GCs associated side effects are dependent on both the average dose and the duration of therapy. Overall, it can be stated that prolonged application is a high-risk factor, whereas total dose is of secondary importance. Even in low-dose therapy, GCs could lead to serious side effects. The severity ranges from more cosmetic aspects (e.g. teleangiectasia, hypertrichosis) to serious disabling and even life-threatening situations (e.g. gastric hemorrhage). Single or multiple side effects can occur [12, 54, 55]. The side effects of GCs are the major limiting factor for the use of these agents. An overview of the most common and serious side effects of GCs is

• Growth retardation • Osteoporosis • Skin atrophy

• Pseudotumor cerebri

• Psychosis

The most common cause of AI is the chronic administration of high doses of GCs. This is called iatrogenic or tertiary AI. Exogenous GCs causes a significant suppression of the hypothalamicpituitary-adrenal axis (HPA) even in small doses for only few days. Consequently, the adrenal cortex loses the ability to produce cortisol in the absence of adrenocorticotrophic hormone (ACTH). When the suppression of ACTH levels prolonges, this situation causes atrophy of the adrenal cortex and secondary adrenal insufficiency. The use of systemic GCs results in higher systemic levels of corticosteroids than in cases of compartmental use, as a result leads to higher percentages of AI. Adrenal suppression is more likely in the following situations: (**1)** longer duration of treatment. The influence of smaller doses over longer durations is highly variable. After long-term systemic therapy with GCs (more than 1 year), AI has to be expected in 100% of the patients. **(2)** Supraphysiologic doses, stronger formulations, and longer acting formulations (**Table 4**). If the patients are taking doses of prednisone of ≥20 mg daily for ≥3 weeks, this situation should be considered as adrenal suppression. AI lasting for more than 4 weeks has

been demonstrated after treatment with high-dose dexamethasone for 28 days [57–64].

Adrenal suppression is less likely in the following situations: (1) regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon) and (2) alternate-day dosing of steroids. The possible risk of this side effect is unknown. At the same time, individual responses to GCs may be highly different. The clinical presentation of AI is variable; many of the signs and symptoms are non-specific and can be mistaken for symptoms of intercurrent illness or the underlying condition being treated with GCs. Signs and symptoms of AI

summarized in **Table 3**.

• Atherosclerosis • Cataracts • Fatty liver

**Rare and unpredictable**

• Glaucoma • Pancreatitis

**5. Adrenal insufficiency (AI)**

**Delayed and insidious, probably dependent on cumulative dose**

100 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

**Table 3.** The most common and serious side effects of GCs (adapted from [56]).


**Table 5.** Signs and symptoms of adrenal insufficiency and adrenal crisis (adapted from [72]).

and adrenal crisis are listed in **Table 5**. AI often occurs when the exogenous GCs are withdrawn too rapidly or, in the case of stressful conditions (e.g. surgery and infection), when higher levels of GCs may be required. In addition to AI and adrenal crisis decreased ACTH level related with the suppression of the HPA axis, leads to reduced general steroid-hormone production. This situation favors further side effects, such as hypogonadism and osteoporosis [55, 65–68].

### **5.1. Steroid withdrawal or adrenal insufficiency?**

When GCs are tapered and their effects decline, patients might experience lethargy, myalgias, nausea, vomiting, and postural hypotension. In this situation, increasing the dose of GCs to prevent AI may delay recovery of the adrenal function. The treatment plan should be made by evaluating the risk/benefit ratio. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation. Maximal caution is advised with any taper. Fortunately, the adrenal cortex repairs the ability to secrete sufficient amounts of cortisol for some period of time. Repair of endogenous cortisol secretion is expected after stopping the exogenous GCs. But the recovery time may vary among patients. The inhibition of the HPA axis function induced by exogenous GCs may persist for 6–12 months after treatment is withdrawn. In conclusion, all patients using GCs are at risk for AI. Clinicians should inform patients about the risk, signs, and symptoms of AI; and consider testing patients after cessation of high dose or long-term treatment with GCs [68].

first 2 months of therapy with GCs. These side effects are dependent on both the dose and duration of GCs. The risk of weight gain increases from the use of 5 to 7.5 mg per day of prednisone (or an equivalent). The risk of these side effects are higher in younger patients, females, those with a higher baseline body mass index, those with a higher initial caloric intake (>30 kcal/kg/ day), and those with a baseline higher leptin and lower resistin levels. More importantly, these side effects are related with high blood pressure, blood glucose and triglyceride levels, and low high-density lipoprotein cholesterol levels (cardiovascular risk factors). Therefore, treatment with GCs increases the risk of coronary heart disease, cardiac insufficiency, and stroke [70–74].

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GCs have complex, and often conflicting, influences on cardiovascular disease (CVD) and cardiovascular risk. Patients chronically using exogenous GCs are at higher risk of CVD, such as coronary artery disease, heart failure, and stroke. In patients with rheumatoid arthritis, chronic obstructive pulmonary disease, and other conditions who were exposed to chronic exogenous GCs, a case-control study found a dose-response relationship between daily glucocorticoid dose and the risk of heart failure. The risk of ischemic heart disease was also increased. Patients taking ≥7.5 mg of prednisone per day or the equivalent had a significantly higher mixed risk of myocardial infarction, angina, coronary revascularization, hospitalization for heart failure, transient ischemic attack, and stroke. Exposure to GCs within the preceding 6 months was related with increased cardiovascular risks. The risks were higher with continuous use than intermittent use. The relationship between cardiovascular risk and GCs is confounded by the underlying inflammatory disease (e.g. rheumatoid arthritis and systemic lupus erythematosus). Because of chronic inflammation and treatment with higher doses of GCs, chronic inflammatory conditions may further increase the incidence of CVD. This increased risk is cumulative and dose-dependent, is mainly observed during the first month of treatment and is reduced when treatment is interrupted. In patients with inflammatory arthritis, increased mortality from heart disease has been established. Moreover, an association between GCs and the risk for atrial fibrillation and flutter has been established by several studies. Pulse GCs are additionally related with CVD. Sudden death caused by pulse dose GCs has been reported. But this tends to occur in patients with underlying CVD. Therefore, patients with underlying severe cardiac and

renal disease should be closely monitored during pulse therapy with GCs [75–78].

Cardiovascular side effects of GCs can be explained by two mechanisms: (1) direct influence on the function of the heart and vasculature and (2) increasing cardiovascular risk factors. Glucocorticoid receptor is known to be expressed in the heart. By this way GCs exert direct effects on cardiomyocytes. The interaction of GCs with the vascular wall is impaired in CVD. Some well-known cardiovascular risk factors, such as hypertension, insulin resistance, hyperglycemia, and dyslipidemia are more commonly observed in glucocorticoid exposed people. The main effects of GCs on cardiovascular risk are likely due to interaction with the kidney, liver, adipose tissue, and central nervous system. The effects of GCs on homeostasis are presumably due to renal sodium retention and intravascular volume overload. There is also evidence for additional, non-renal mechanisms. This confirms that GCs can interact directly with the cells of the heart and vascular wall. By this way, GCs may alter their function and structure. In patients with

**7. Cardiovascular disease**
