**11. Dyslipidemia**

GCs have a very important role in energy homeostasis and on lipid metabolism. Chronic exposure to exogenous GCs is a secondary cause of dyslipidemia. But the degree of lipid abnormalities in different clinical conditions is quite variable. These variabilities are related with the heterogeneity of the populations treated in terms of age, sex, underlying condition, glucocorticoid dose, and concomitant medications. All possible changes in lipid profile (i.e. isolated increase of triglyceride levels, increase of both cholesterol and triglycerides levels, absence of changes in lipid parameters, and improvement in lipid profile with increased HDL cholesterol) have been reported, excluding organ transplant recipients. Because transplanted patients concomitantly treated with other immunosuppressive drugs with side effects on the lipid metabolism (e.g. cyclosporine), which is a confounding factor. People with glucocorticoid-induced lipodystrophy are more likely to develop an unfavorable lipid profile. But interestingly, findings from the Third National Health and Nutrition Examination Survey suggest that GCs may have a beneficial effect on lipid profile in adults ≥60 years of age. GCs stimulate lipolysis and modulate free fatty acid (FFA) mobilization through various mechanisms. These mechanisms are summarized in **Figure 2**. Stimulation of lipolysis depends on dose and duration. Therefore in patients treated with GCs at high doses or for prolonged periods, regular monitoring of lipid profile is recommended [111–114] (**Figure 3**).

**9.2. Osteonecrosis**

exposure

1. Dose and duration of therapy 2. Intra-articular administration

1. Decreased bone formation

2. Increased bone reabsorbtion

• Inhibition of osteoblasts replication • Inhibition of osteoblastic apoptosis • Inhibition of bone matrix synthesis

• Stimulation of osteoclast synthesis

3. Polymorphisms in VEGF, GR, 11β-HSD2, COL2A1, PAI1, P-glycoprotein

**Table 7.** Effects of glucocorticoids on bone metabolism (adapted from [103]).

**Direct effects Indirect effects**

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

5. Dexamethasone causes greater skeletal complications than prednisone

**Table 8.** Risk factors for glucocorticoid-induced osteonecrosis (adapted from [99]).

shown in **Table 8** [104–106].

**10. Hypertension**

renal Na<sup>+</sup>

The most common joint involved is the hip and GCs are the second most common cause. The incidence of osteonecrosis induced by GCs increase with higher doses and prolonged treatment. But can be seen with short-term exposure to high doses, and without osteoporosis. Osteonecrosis develops in 9–40% of adult patients receiving long-term GCs. Risk factors are

VEGF: vascular endothelial growth factor; GR: glucocorticoid receptor; 11β-HSD2: 11β-hydroxysteroid dehydrogenase type2; COL2A1: collagen type II; PA1: plasminogen activator inhibitor 1; HIV: human immunodeficiency virus.

1. Decrease in net intestinal Ca2+ absorbtion 2. Inhibition of renal Ca2+ re-absorbtion

3. Stimulation of parathyroid hormone secretion 4. Inhibition of growth hormone secretion

4. Underlying disorders: renal insufficiency, transplantation, graft vs. host disease, inflammatory bowel disease, HIV, acute lymphoblastic leukemia, excessive alcohol intake, hypercoagulable states, sickle cell disease, radiation

Glucocorticoid-induced elevation in blood pressure is classified as secondary hypertension and is a major risk factor for cardiovascular diseases. Blood pressure in humans is subjected to tight control by several physiologic systems that have pleiotropic effects and interact together in a complex fashion. GCs can cause hypertension by influencing these systems in different ways. One possible mechanism is the in vitro affinity of the non-selective mineralocorticoid receptor (MR) for the GCs. As a result, stimulation of the MR by exogenous GCs leads to

tone (imbalance between vasoconstriction and vasodilation), centrally mediated mechanisms, renin-angiotensin system activation, cardiac hypercontractility, and endothelial cell dysfunction may also play a role. Enhanced reactive oxygen species and reduced nitric oxide (NO)

retention, volume expansion, and finally to an increase in blood pressure. Vascular



**Figure 3.** Effects of glucocorticoids on adipose tissue and hepatic fatty acid metabolism (adapted from [115]).
