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Steroidal Anti-inflammatory Drugs (SAIDs). Hypothalamic-Pituitary Adrenal (HPA) Axis. Negative Feedback control of ACTH Production. Suppression of HPA STRESS: Overrides the neg. feedback mechanism . Adrenal cortex Produces 30 steroid hormones Major divisions include:

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hypothalamic pituitary adrenal hpa axis
Hypothalamic-Pituitary Adrenal (HPA) Axis

Negative Feedback control

of ACTH Production.

Suppression of HPA

STRESS: Overrides the

neg. feedback mechanism.

Adrenal cortex

Produces 30 steroid hormones

Major divisions include:

Glucocorticoids

Mineralocorticoids

Adrenal Sex steroids

biosynthesis of glucocorticoids gcs
Biosynthesis of Glucocorticoids (GCs)

Glucocorticoids

Cortisol (95%)

Corticostrone

Cortisone

90% bound to plasma proteins

Circadian release

Of GCs; highest in

the early morning

and lowest in the

evening.

mechanism of action for anti inflammatory steroids1
Mechanism of Action for Anti-Inflammatory Steroids
  • Suppress T-cell activation and cytokine production.
  • Suppress mast cell degranulation.
  • Decrease capillary permeability indirectly by inhibiting mast cells and basophils.
  • Reduce the expression of cyclooxygenase II and prostaglandin synthesis.
  • Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A2 activity.
routes of administration for gc
Routes of Administration for GC
  • Local(Preferred)
    • Intra-articular, IA
    • Intrabursal, IB
    • Intralesional, IL
    • Intrasynovial, IS
    • Soft tissue, ST
    • Intrarectal, IR
    • Topical
    • Nasal
    • Inhaled
  • Systemic
    • Oral, PO
    • Intramuscular, IM
    • Intravenous, IV
    • Subcutaneous, SC
pharmacokinetics of gc
Pharmacokinetics of GC
  • Daily administration of corticosteroids at physiological concentrations for at least 2 weeks suppresses the HPA resulting in decreased production of endogenous hormones. Recovery may take up to 9-12 months.
  • Hepatic Metabolism:
    • The liver is the primary site of GC inactivation. GCs are metabolized by cytochrome P450 3A4 enzymes
    • 25% of GCs are excreted in bile and feces.
  • Renal Clearance
    • 75 % of GC metabolites are excreted in the urine.
differences in individual corticosteroids
Differences in Individual Corticosteroids
  • Biological Half life
  • Mineralocorticoid potency
  • Glucocorticoid (anti-inflammatory) potency
slide13

Mineralocorticoid actvity

Corticosteroids control symptoms and DO NOT stop progression (cure) of the disease

hydrocortisone
Hydrocortisone
  • Prototype corticosteroid for anti-inflammatory activit
  • Short acting GC
  • Clinical uses: Localized inflammatory conditions, i.e. Ulcerative colitis & dermatitis
  • Relative anti-inflammatory potency is 1
  • Plasma half-life is 30 min
  • Biological half-life is 8-12 hrs.
  • Administration: Oral, injectable, topical (creams and ointments) and IR (foam).
  • Contraindications (IR): Systemic fungal infection, recent ileocolostomy, intestinal anatomoses and abscess.
  • Cortisone
prednisone
Prednisone
  • Intermediate acting GC
  • Clinical uses: Adjunct therapy for arthritis (short term admin), asthma, COPD; Ulcerative colitis and Crohn’s disease.; Rheumatic and dermatologic disorders.
  • Relative anti-inflammatory potency is 4; It is 4x more potent than cortisol.
  • Inactive on its own. It must be metabolized in the liver to an active metabolite.
  • Plasma half-life is 60 min
  • Biological half-life is 18-36 hrs
  • Administration: Oral only.
slide18
Anti-inflammatory Drugs
    • Glucocorticoids
      • Inhaled
        • Beclomethasone
        • Budesonide
        • Flunisolide
        • Fluticasone propionate
        • Triamcinoloneacetonide
      • Oral (Quick relief of asthmatic symptoms)
        • Prednisone
        • Prednisolone
        • * Unresponsive to 2 agonists

Metered Dose Inhaler

Also, Dry-powder inhalers

and Nebulizers

prednisolone
Prednisolone
  • Intermediate acting GC
  • Prenisolone acetate/sodium phosphate
  • Clinical uses: Opthalmic disorders, respiratory diseases.
  • Plasma half-life is 60 min
  • Biological half-life is 18-36 hrs.
  • Administration: Oral, Injectable (systemic and local).
methylprednisolone
Methylprednisolone
  • Intermediate acting GC
  • Methylprenisolone acetate/sodium succinate
  • Clinical uses: Rheumatoid arthritis Intra-articular injections
  • , UC,severe alcoholic hepatitis.
  • Plasma half-life is 60 min
  • Biological half-life is 18-36 hrs.
  • Administration: Oral, Injectable (systemic and local).
  • Adverse effects: vertigo, headache, weight gain, sodium/water retention and impaired wound healing.
triamcinolone
Triamcinolone
  • Intermediate acting GC
  • Triamcinoloneacetonide/diacetate/hexacetonide
  • Clinical uses: Similar to prednisone: Opthalmic disorders, respiratory diseases.
  • Plasma half-life is 60 min
  • Biological half-life is 18-36 hrs.
  • Administration: Oral, Injectable (systemic and local).
inhaled glucocorticoids long term control of chronic asthmatic symptoms
Inhaled Glucocorticoids: “Long-term control” of Chronic Asthmatic Symptoms

Taken Daily, over a long period of time

SE: oropharyngeal candidiasis (Thrush), dysphonia (hoarseness), adrenal suppression, bone loss, in children, retarded growth

Reduced risk of toxicity with inhaled preparations

Beclomethasone

Budesonide

Flunisolide

Fluticasone propionate

Triamcinoloneacetonide

Mechanisms of Action:

  • Reduce bronchial hyperreactivity
  • Decreased synthesis and release of inflammatory mediators, e.g, leukotrienes, prostaglandins and histamine
  • Decreased infiltration and activity of inflammatory cells, e.g. eosinophils, leukocytes)
  • Decreased edema of the airway mucosa and mucus production
  • Increase responsiveness to 2 agonists
betamethasone
Betamethasone
  • Long acting GC
  • Betamethasone acetate/sodium phosphate
  • Clinical uses: Respiratory diseases, Respiratory distress syndrome, local inflammatory conditions (similar to prednisone). Life threatening or disabling condition.
  • Relative anti-inflammatory potency is 25.
  • Plasma half-life is 300+ min
  • Biological half-life is 36-54 hrs.
  • Administration: Oral, topical, Injectable (systemic and local).
dexamethasone
Dexamethasone
  • Long acting GC
  • Dexamethasone acetate/sodium phosphate
  • Clinical uses: Lupus and Rheumatoid arthritis.; Life threatening or disabling conditions.
  • Maximal anti-inflammatory action.
  • Relative anti-inflammatory potency is 25.
  • Plasma half-life is 110-210 min
  • Biological half-life is 36-54 hrs.
  • Administration: Oral, topical, Injectable (systemic and local).
adverse effects
Adverse Effects
  • Adrenocortical insufficiency: Suppression of HPA
  • Adrenocortical excess (Cushing’s disease): “Moon face”, “buffalo hump”
  • Diabetes Mellitus
  • CNS effects: psychological and behavioral changes; aggravation of pre-existing psychiatric disorders.
  • Impaired wound healing
  • Musculoskeletal effects: osteoporosis (brittle bones), muscle weakness and atrophy
  • Cardiovascular effects: fluid retention, edema, hypertension.

Glucocorticoid Withdrawal: Should be performed slowly

Withdrawal syndrome: hypotension, hypoglycemia, myalgia and fatigue

drug interactions
Drug Interactions
  • Drugs that Enhance Corticosteroid Effects
    • Estrogens
    • Oral contraceptives
    • Antifungal agents
    • Antibiotics
    • *all of these agents inhibit cytochrome P450 enyzymes
  • Drugs that Reduce Corticisteroid Effects
    • Antacids
    • Cholestyramine
      • *these drugs decrease the absorption of corticosteroids
    • Phenytoin: inhibits cytochrome P450 enyzymes