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Endocrinological Pharmacology > 6. Glucocorticoids for oral and parenteral use 7. Mineralocorticoids. Topically applied glucocorticoids > Flashcards

6. Glucocorticoids for oral and parenteral use 7. Mineralocorticoids. Topically applied glucocorticoids Flashcards

1
Q

Glucocorticoids for sytemic use

A

short acting: 8- 12h
1. hydrocortisone (cortisol)
(cortisone (mineralocorticoid effect))

intermediate acting: 12- 36h

  1. Prednisolone (drug of choice)
  2. Methylprednisolone
  3. Prednisone (prodrug)
  4. Triamcinolone (topical)

long acting: 36- 72h
1. Dexamethasone
(Betamethasone)

oral and parenteral

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2
Q

Glucocorticoids for topical use

A
  1. Fluocinolone
  2. Budesonide
  3. Mometazone
  4. Fluticasone

for: IBD, Asthma, Rhinitis, Conjunctivitis, Arthritis, Dermatology

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3
Q

Mineralocorticoids

A

Aldosterone (very short)

Fludrocortisone (short)

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4
Q

Mineralocorticoid receptor antagonist

A

Spironolactone ( also weak androgen-R antagonist)

Eplerenone

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5
Q

Glucocorticoid receptor antagonist

A

Mifepristone

  • medical abortion with misoprostol
  • also progestin-R antagonist (potent)
  • cushings disease
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6
Q

synthesis inhibitors

A

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

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7
Q

Glucocorticoids in general

A

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 ↑)
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8
Q

Clinical indications for glucocorticoids (systemic)

A
  1. Allergic reactions
    - Angioneurotic edema
    - Asthma
    - Bee stings
    - Contact dermatitis
    - Adverse drug reactions
    - Allergic rhinitis
    - Serum sickness
    - Urticaria
  2. Collagen-vascular disorders
    - Giant cell arteritis
    - Systemic Lupus erythematosus
    - Mixed connective tissue
    syndrome
    - Polymyositis
    - Polymyalgia rheumatica
    - Rheumatoid arthritis
    - Temporal arteritis
  3. Eye diseases
    - Acute uveitis
    - Allergic conjunctivitis
    - Choroiditis
    - Optic neuritis
  4. Pulmonary diseases
    - Aspiration pneumonia
    - Bronchial asthma
    - Sarcoidosis
    - Prenatal prevention of infant respiratory distress syndrome (IRDS)
  5. Gastrointestinal diseases
    - Inflammatory bowel disease
  6. Hematologic disorders
    - Hemolytic anemia
    - Acute allergic purpura
    - Leukemia
    - Lymphoma
    - Idiopathic thrombocytopenic purpura
    - Multiple myeloma
  7. Skin abnormalities
    - Atopic dermatitis
    - Dermatoses
    - Lichen simplex chronicum
    (localized neurodermatitis)
    - Mycosis fungoides
    - Pemphigus
    - Psoriasis
    - Seborrheic dermatitis
  8. Neurologic disorders
    - Cerebral edema
    - Multiple sclerosis

Further indications:

  1. Systemic inflammation
  2. Infections, sepsis
  3. Inflammatory conditions of bones and joints (ex. gout)
  4. Nausea and vomiting – chemotherapy-induced nausea
  5. Organ transplantation
  6. Autoimmune disorders
  7. Renal disorders
  8. Thyroid disorders – thyrotoxicosis
  9. Mountain sickness
  10. Diagnostics – dexamethasone suppression test (adrenal adenoma vs. ectopic ACTH production)
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9
Q

Hydrocortisone (cortisol)

A

Short (8-12 h’)

low anti-inflammatory activity

Drug of choice for replacement therapy (acute/chronic adrenocortical insufficiency)

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10
Q

Cortisone

not on the list

A

Short

little less anti-inflammatory effect than hydrocortisone (low)

Prodrug;
used for replacement therapy, not used as anti-inflammatory because of mineralocorticoid effects

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11
Q

Prednisolone

Methylprednisolone

A

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

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12
Q

Prednisone

not on the list

A

Intermediate

4x anti inflammatory activity of hydrocortisone

Prodrug, no topical activity

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13
Q

Triamcinolone

A

Intermediate

5x anti inflammatory activity of hydrocortisone

(very high topical activity)

Topical applications mainly, increased toxicity compared to other agents

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14
Q

Dexamethasone

Betamethasone

A

Long (36-72 h’)

30x anti inflammatory activity of hydrocortisone

(topically active)

Anti-inflammatory and immunosuppressive; used especially where water retention is undesirable

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15
Q

Glucocorticoids for topical use

A 
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

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16
Q

Aldosterone

A

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
17
Q

Fludrocortisone

A

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
18
Q

Spironolactone

A

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
19
Q

Eplerenone

A

Mineralocorticoid receptor antagonists

  • Oral
  • Similar to spironolactone; more selective for aldosterone receptor (no androgen receptor activity)
20
Q

Mifepristone

A

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
21
Q

Ketoconazole

A
  • 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
22
Q

Aminoglutethimide

not on the list

A
  • Inhibits cholesterol side-chain cleavage enzyme (P450scc) – prevent conversion of cholesterol to pregnenolone
  • Cushing’s syndrome
  • Adrenocortical tumors (in combination with other
    agents)
23
Q

Metyrapone

A
  • Inhibits 11β-hydroxylase – prevent synthesis of cortisol, with no effect on its precursors
  • Diagnostic tests of adrenal function
24
Q

Etomidate

A
  • 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

Endocrinological Pharmacology (6 decks)

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