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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 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) 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 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 • 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 • 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 • Biological Half life • Mineralocorticoid potency • Glucocorticoid (anti-inflammatory) potency
Mineralocorticoid actvity Corticosteroids control symptoms and DO NOT stop progression (cure) of the disease
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 • 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.
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 • 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 • 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 • 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 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 • 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 • 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 • 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 • 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