Exam 2: Lecture X, Corticosteroids Flashcards
Corticosteroids are….
steroid hormones produced by adrenal cortex (homeostatic organ responding to stress)
3 major groups:
Glucocorticoids
Mineralocorticoids
Sex Steroid
Adrenal Gland production by layer….
Cortex: steroid hormones
Medulla = Epi/NE
Glucocorticoids role in…
metabolic, immunity and inflammation
Mineralcorticoids role in…
electrolyte-regulating
Regulation fo Cortisol Secretion
- Regulated by hypothalamus-pituitary-adrenal cortex axis
- Corticotropin-releasing hormone
(CRH)»ACTH»»cortisol- CRH produced in hypothalamus H1
- ACTH produced in anterior pituitary H2
- Cortisol is secreted from adrenal cortex H3
- Cortisol secretion is regulated by negative feedback system
The most potent stimulus of cortisol secretion is stress
Corticosteroids Pharmacokinetics
almost 90% bound to protein
Absorption is rapid
Metabolized in liver
excreted by kidney
Spironolactone (Aldactone, CarboSpir)
Diuretic! (Mineralocorticoid Antagonist)
Aldosterone antagonist at its receptor
Reverses many manifestations of aldosteronism
Also useful in preparing patients for surgery
May reduce the incidence of cardiac arrhythmia
Also used to treat heart failure
Fludrocortisone (Florinef Acetate)
Partial replacement for adrenocortical insufficiency and for hypotension treatment
Has significant glucocorticoid activity
Effective safe medication
Major Mineralcorticoids in humans?
Aldosterone
v important in regulation of blood volume and blood pressure
little glucocorticoid activity, MOA same as glucocorticoid tho
Secretion of aldosterone regulated by….
ACTH and RAA system
Glucocorticoid antagonist/Steroid Synthesis inhibitors
Ketoconazole (Nizoral)
Mifepristone (RU 486)(Mifeoprex)
Mitotane (Lysodren)
Mitotane (Lysodren)
Related to DDT insecticide
A non-selective cytotoxic action upon adrenal cortex
Reduces tumor mass in 1/3 of patients
Serious toxicity- available on compassionate basis
Mifepristone (RU 486)(Mifeoprex)
Abortifacient drug
Inhibits glucocorticoid and progesterone receptors
Ketoconazole (Nizoral)
Antifungal drug
Inhibits P450 system enzymes required for steroid hormone synthesis
Reduces steroid levels
Used for Cushing’s syndrome hirsutism and breast cancer.
List of Aerosolized Corticosteroids
Dexamethasone Triamcinolone Beclomethasone Flunisolide Budenoside Fluticasone
Aerosolized corticosteroids info
In asthma and similar respiratory conditions, corticosteroids have a significant affect upon large mucous membrane of the trachea-bronchial tree.
However, systemic effects have to be avoided.
Special glucocorticoids were developed for use in asthma.
Formulations readily penetrate the airway mucosa, however, systemic effects and toxicity are significantly reduced.
Dexamethasone (Decadron)
Very potent and no salt-retaining actions
Very good in cerebral edema (no water retention)
Triamcinolone (Kenalog)
Severe asthma
Local injections into the inflamed joints
Prednisolone (Delta-cortef)
widely given orally for inflammation and allergies
Cortisone (Cortone Acetate)
Orally – as a replacement therapy
Intravenously in shock and status asthmatics
Topically in eczema, enema in ulcerative colitis
Natural Glucocorticoid
Cortisol (Hydrocortisone)
Synthetic Glucocorticoids
Prednisolone
Betamethasone
Triamcinolone
Glucocorticoids-Immunisuppressive effects…
decreased antibody production
Glucocorticoids anti-inflammatory effect
ARACHIDONIC ACID METABOLITES INHIBITION
INFLAMMATORY RESPONSE IS DECREASED
NEUTROPHIL FUNCTION IS DEPRESSED
MACROPHAGE FUNCTION IS DEPRESSED
Corticosterone
- Lipophilic
- Bind to intracellular cytosolic receptors
- Transported into the nucleus
- Affect the nucleus of the cell
- Bind with glucocorticoid response element (GRE)
- Induce gene expression within the cells
- Induce gene expression for lipocortin/inhibits PLA2
- Induce gene expression for antiinflammatory proteins
- Suppress gene expression for proinflammatory proteins
- Inhibit cytokines production
Glucocorticoids Physiological Effects 1
Increase number/affinity of β-receptors
Facilitate conversion of protein to glycogen
Stimulate hepatic gluconeogenesis and liver storage of glucose as glycogen
Peripheral glucose uptake is inhibited
Net effect - rise of blood sugar (can cause hyperglycemia and diabetes mellitus)
Glucocorticoids Physiological Effects 2
Catabolism of muscle proteins to aminoacids
Connective tissue, fat, and skin wasting
Catabolic effect upon bone can lead to osteoporosis
In children growth is inhibited
Stimulation of insulin secretion
Increased lipolysis
CNS effects – at times including euphoria
Corticosteroids Clinical Use
Preserve life in patients with cortical insufficiency (Addison’s disease)
Acute adrenal deficiency associated with shock, infection, or trauma.
Asthma
Severe inflammatory conditions (eye, skin)
Organ transplant rejection
Collagen disease
Leukemia (to suppress lymphopoiesis)
Neurological disorders
Vomiting induced by chemotherapy
Hypercalcemia
Corticosteroids Adverse effects
Corticosteroids are characterized by severe toxicity!
Toxicity limits the use of these agents!
Because of systemic toxicity, oral/intravenous agents are used as a last resort!!!
Glucocorticoids Adverse effects
MOON FACE
FAT REDISTRIBUTION
HYPERGLYCEMIA
OSTEOPOROSIS
FLUID RETENTION - HYPERTENSION
ADRENAL SUPPRESSION – INSUFFICIENCY OF HORMONE PRODUCTION
NECROSIS OF BONES
PEPTIC ULCERATION
DEPRESSION
RECURRENCE OF ALLERGIC INFLAMMATION
OROPHYARYNGEAL FUNGAL INFECTIONS
CHANGES IN VOICE
BRONCHOCONSTRICTION
CATARACTS/GLAUCOMA
TUBERCULOSIS
Methods to minimize glucocorticoid toxicity
Local applications
Aerosols (asthma)
Alternate day therapy
Tapering the dose after achieving a good response
Synthetic glucocorticoids are used to reduce toxicity
- higher affinity for receptors
- little or no salt retaining properties
Chronic Adrenal Excess….
Cushing’s disease – polycythemia, lymphocytopenia, Decreased lymphoid mass Neurosis, psychoses Hypertension Moon face with red cheeks Cataracts Buffalo hump + increased abdominal fat Thin legs/arms -muscle wasting Easy bruising/poor wound healing
Chronic Adrenal Insufficiency….
Addison’s disease –anemia, lymphocytosis, increased lymphoid mass
Apathy, depression, irritability, psychoses
Hypotension
Muscle weakness, fatigue, weight loss
Hyperpigmentation
Hypoglycemia (during fasting)
Sodium loss, hypotension
Minor stress/trauma can trigger acute insufficiency – shock/death
Strongest to Weakest Corticosteroids
Dexamethasone (36h)
Triamcinolone (24h)
Prednisolone (24h)
Cortisone (12h)
