6. Glucocorticoids for oral and parenteral use 7. Mineralocorticoids. Topically applied glucocorticoids Flashcards
Glucocorticoids for sytemic use
short acting: 8- 12h
1. hydrocortisone (cortisol)
(cortisone (mineralocorticoid effect))
intermediate acting: 12- 36h
- Prednisolone (drug of choice)
- Methylprednisolone
- Prednisone (prodrug)
- Triamcinolone (topical)
long acting: 36- 72h
1. Dexamethasone
(Betamethasone)
oral and parenteral
Glucocorticoids for topical use
- Fluocinolone
- Budesonide
- Mometazone
- Fluticasone
for: IBD, Asthma, Rhinitis, Conjunctivitis, Arthritis, Dermatology
Mineralocorticoids
Aldosterone (very short)
Fludrocortisone (short)
Mineralocorticoid receptor antagonist
Spironolactone ( also weak androgen-R antagonist)
Eplerenone
Glucocorticoid receptor antagonist
Mifepristone
- medical abortion with misoprostol
- also progestin-R antagonist (potent)
- cushings disease
synthesis inhibitors
17-alpha-hydroxylase: ketoconazole
inhibits conversion of cholesterol to pregnenolone: Aminoglutethemide
Inhibits 11-ß-hydroxylase: METYRAPONE, prevents synthesis of cortisol, ->diagnostic test for adrenal function
inhibits 11-ß-hydroxylase: (Etonidate)-> severe cushing
Glucocorticoids in general
Pharmacokinetics:
- High bioavailability (good oral absorption)
- Transport in blood: 90% corticosteroid-binding globulin (CBG),
5-10% free form
- T1/2 60-90 min’
- Metabolism: 80% hepatic, 20% renal and/or other
MOA as anti-inflammatory and immunosuppressive agent:
- Leukocyte migration ↓
- Lysosomal membrane stabilization → phagocytosis ↓
- Capillary permeability ↓
- PLA2 inhibition → prostaglandins and leukotrienes ↓
- COX-2 expression ↓
- Platelet-activating factor (PAF) ↓
- Interleukins (ex. IL-2) ↓
- Inhibition of NF-κB pathway (TNF-α, IL-2 ↓)
- Induction of apoptosis in lymphocytes through activation of caspase enzymes
Side effects:
- Growth inhibition
- Glucose intolerance, diabetes
- Muscle wasting
- Visceral fat deposition (central adiposity)
- Thinning of the skin, striae, bruising
- Impaired wound healing
- Osteoporosis
- Salt and fluid retention
- Hypertension
- Psychosis (hypomania, hallucination, confusion)
- Hypokalemia
- Aseptic necrosis of the hip
- Increased intraocular pressure (glaucoma)
- Adrenal atrophy (with chronic use) → risk of ‘Addisonian crisis’ in
case of abrupt withdrawal of treatment
- Reactivation of latent infections (due to extensive immunosuppression)
- Iatrogenic Cushing’s syndrome
- Demargination of WBC may cause artificial leukocytosis (WBC count ↑)
Clinical indications for glucocorticoids (systemic)
- Allergic reactions
- Angioneurotic edema
- Asthma
- Bee stings
- Contact dermatitis
- Adverse drug reactions
- Allergic rhinitis
- Serum sickness
- Urticaria - Collagen-vascular disorders
- Giant cell arteritis
- Systemic Lupus erythematosus
- Mixed connective tissue
syndrome
- Polymyositis
- Polymyalgia rheumatica
- Rheumatoid arthritis
- Temporal arteritis - Eye diseases
- Acute uveitis
- Allergic conjunctivitis
- Choroiditis
- Optic neuritis - Pulmonary diseases
- Aspiration pneumonia
- Bronchial asthma
- Sarcoidosis
- Prenatal prevention of infant respiratory distress syndrome (IRDS) - Gastrointestinal diseases
- Inflammatory bowel disease - Hematologic disorders
- Hemolytic anemia
- Acute allergic purpura
- Leukemia
- Lymphoma
- Idiopathic thrombocytopenic purpura
- Multiple myeloma - Skin abnormalities
- Atopic dermatitis
- Dermatoses
- Lichen simplex chronicum
(localized neurodermatitis)
- Mycosis fungoides
- Pemphigus
- Psoriasis
- Seborrheic dermatitis - Neurologic disorders
- Cerebral edema
- Multiple sclerosis
Further indications:
- Systemic inflammation
- Infections, sepsis
- Inflammatory conditions of bones and joints (ex. gout)
- Nausea and vomiting – chemotherapy-induced nausea
- Organ transplantation
- Autoimmune disorders
- Renal disorders
- Thyroid disorders – thyrotoxicosis
- Mountain sickness
- Diagnostics – dexamethasone suppression test (adrenal adenoma vs. ectopic ACTH production)
Hydrocortisone (cortisol)
Short (8-12 h’)
low anti-inflammatory activity
Drug of choice for replacement therapy (acute/chronic adrenocortical insufficiency)
Cortisone
not on the list
Short
little less anti-inflammatory effect than hydrocortisone (low)
Prodrug;
used for replacement therapy, not used as anti-inflammatory because of mineralocorticoid effects
Prednisolone
Methylprednisolone
Intermediate (12-36 h’)
which one is oral which one parenteral?
5x anti inflammatory activity of hydrocortisone
Drug of choice for systemic anti-inflammatory and immunosuppressive effects
Prednisone
not on the list
Intermediate
4x anti inflammatory activity of hydrocortisone
Prodrug, no topical activity
Triamcinolone
Intermediate
5x anti inflammatory activity of hydrocortisone
(very high topical activity)
Topical applications mainly, increased toxicity compared to other agents
Dexamethasone
Betamethasone
Long (36-72 h’)
30x anti inflammatory activity of hydrocortisone
(topically active)
Anti-inflammatory and immunosuppressive; used especially where water retention is undesirable
Glucocorticoids for topical use
Several agents provide good surface activity on mucus membranes or skin surfaces, where systemic effects are to be avoided. Classified based on potency: class I (very potent), class II (potent), class III (moderate), class IV (mild).
Agents:
- Fluocinolone
- Budesonide
- Mometasone
- Fluticasone
Application examples:
- Asthma (inhaled preparations)
- Dermatology (ointment, gel)
- Allergic rhinitis (nasal spray)
- Allergic conjunctivitis (eye drops)
- Arthritis (intra-articular injection)
- IBD’s (suppository preparations)
*Potential local adverse effects with long-term cutaneous administration → skin atrophy, striae, rosacea, perioral dermatitis, acne, and purpura.
Side effects:
oropharyngeal candidiasis
Aldosterone
Very short (1-2 h’)
no anti-inflammatory activity
500: very high Na+ retaining activity
Endogenous mineralocorticoid
Side effects:
- Salt and fluid retention, electrolyte abnormalities
- Hypertension
- Cardiac remodelling, congestive heart failure
- Signs and symptoms of glucocorticoids excess
Fludrocortisone
Short (8-12 h’)
low antiinflammatory activity (like cortisone
150: Na+ retaining activity
Drug of choice for replacement therapy
(acute/chronic adrenocortical insufficiency, post-adrenalectomy)
Side effects:
- Salt and fluid retention, electrolyte abnormalities
- Hypertension
- Cardiac remodelling, congestive heart failure
- Signs and symptoms of glucocorticoids excess
Spironolactone
Mineralocorticoid receptor antagonists
K+-sparing agents
Competitively inhibit mineralocorticoid (aldosterone) receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention
- Natriuresis (Na+ reabsorption ↓)
- K+ and H+ retention (hyperkalemic metabolic acidosis)
- Oral
- Slow onset and offset of effect
- Duration of action 24-48 h’
- Weak antagonist of androgen receptor
- Hyperaldosteronism (Conn’s syndrome, secondary)
- Hypokalemia caused by K+-wasting diuretics
- Congestive heart failure (also reduce mortality) (2nd line)
- Antiandrogenic effects (female hirsutism, PCOS)
- Side effects: hyperkalemic metabolic acidosis,
anti-androgenic effects (gynecomastia, impotence)
Anti-hypertensive double/triple therapy
- Initial approach →
ACE inhibitor or ARB + Ca2+-channel blocker or diuretic
- If resistant, progress with →
ACE inhibitor or ARB + Ca2+-channel blocker + diuretic
- If resistant, add additional agent →
Spironolactone or β-blocker
HF:
- reduce muscle remodelling
- improve survival
Eplerenone
Mineralocorticoid receptor antagonists
- Oral
- Similar to spironolactone; more selective for aldosterone receptor (no androgen receptor activity)
Mifepristone
Glucocorticoid receptor inhibitor
- Progestin and glucocorticoid receptor antagonist
- Oral
- Potent inhibitor of progesterone receptor
- Cushing’s syndrome (not extensively used)
- Medical abortion (together with misoprostol- PGE1 analogue) can be used up to 49 days after last menstrual period
- Side effects: abdominal pain, GI disturbances (mostly due to coadministration of misoprostol), headache, vaginal bleeding in women atypical infection
Ketoconazole
- Inhibits 17α-hydroxylase (and other enzymes) – prevent mammalian steroid hormone synthesis and fungal ergosterol synthesis
- Oral, topical
- Anti-fungal drug
- Adrenal carcinoma
- Hirsutism
- Breast cancer
- Prostate cancer
- Side effects:
GI symptoms,
hepatotoxicity,
drug-drug interaction due to its wide effects on CYP450
Aminoglutethimide
not on the list
- Inhibits cholesterol side-chain cleavage enzyme (P450scc) – prevent conversion of cholesterol to pregnenolone
- Cushing’s syndrome
- Adrenocortical tumors (in combination with other
agents)
Metyrapone
- Inhibits 11β-hydroxylase – prevent synthesis of cortisol, with no effect on its precursors
- Diagnostic tests of adrenal function
Etomidate
- Inhibits 11β-hydroxylase
- Severe Cushing’s syndrome
Facilitate GABA-mediated inhibition at GABAA receptors
Intravenous anesthetics
- similar to propofol
- IV
- Rapid onset and short-duration of action
- Anesthesia in patients with limited cardiac or respiratory reserves (induction)
Side effects:
- Post-operative nausea
- Adrenal suppression with prolonged administration
