Uses for Steroids

  A.   Uses                 

 arthritis 

ulcerative colitis      

asthma 

dermatological conditions 

rhinitis  

ophthalmic conditions  

cancer 

lupus erythematosus 

infections  

organ transplantation

trauma  

shock

Mechanism of Action

   1. Corticosteroids bind to glucocorticoid or

  mineralocorticoid   receptors, the steroid-receptor   complex then regulates gene transcription.

2. Example for anti-inflammatory properties:

   glucocorticoids increase lipocortin transcription

↓

 lipocortin inhibits phospholipase A2

↓

decreased arachidonic acid and eicosanoids

Brief Overview of Physiology

Glucocorticoid physiology:

Increase blood glucose

Fat redistribution and lipolysis

Mineralocorticoid physiology:

  Increase sodium reabsorption

  Increase potassium excretion

 Structure-Activity Relationship (SAR)

1. Required for activity: ketone at 3 position;

     4=5 double bond

2. Small modifications in the basic corticosteroid structure alter:

  a.   carbohydrate-potency

  b.   sodium-retaining potency

  c.   antiinflammatory potency

  d.   drug half-life

  e.  transcortin binding

  1. Glucocorticoid potencies  

Very High:   dexamethasone ,methylprenisolone 

triamcinolone

High: Prendisone

Very Low: fludrocortisone, betamethasone

  2. Mineralocorticoid potencies

  Very High:  Fludrocortisone

 High: Prednisolone , Methylprensiolone

Very Low: dexamethasone, triamcinolone, betamethasone

Pharmacokinetics : Route of Administration 

1.  Routes of administration

Systemic

  a.   oral (systemic, long-term therapy)

  b.  i.m. or  i.v. (emergency)

Local

  c.   topical (eyes and skin)

  d.   intra-articular injection (arthritic joints)

  e.   inhalation (asthma)

  Corticosteroid metabolism (liver)

  a.  reduction of double bond at 4=5 position to yield   inactive metabolite

  b.  conjugation of inactive metabolite

   c.   excretion

  Liver disease affects steroid metabolism.

  prednisone--------> prednisolone

  (inactive)       (active)

 Half-lives of some corticosteroids  

Short Acting(8-12 hrs): Hydrocortisone, Cortisone

Intermediate Acting(12-36): prednisolone, prendisone,triamcinolone, methylprednisolone

  fludrocortisone

Long Acting (36-54) : betamethasone, dexamethasone

Side Effects and Toxicity

  1.   General considerations

  a.  route of administration: systemic vs. local

  b.   dosage

  c.   length of therapy

  2.    Short-term systemic

Long Term Systemic

  a.   Cushingoid features (fat redistribution)

  b.   sodium retention (edema, heart failure, hypertension)

  c.   potassium loss (muscle weakness)

  d.   glucose intolerance (glycosuria/overt diabetes mellitus)

   e.   weight gain

  f.    loss of skin collagen

  g.   osteoporosis*

  h.   peptic ulcers

  i.    HPA axis suppression

  j.    CNS effects (psychosis, insomnia, nervousness, euphoria,   depression)

  k.   susceptibility to infection

  l.    triamcinolone-weight loss and sedation

  m.  masking of symptoms of other diseases

Local Use

  a. inhaled steroids- candidal infection of the mouth,       throat irritation, dysphonia

  b. nasal steroids -nasal irritation, headache, dry       nose, nosebleed  

  c. topical- epidermal atrophy

Minimizing Side Effects

a. use smallest acceptable dose

  b. goal is palliative therapy not total remission

c.  shortest possible therapy (fewer side effects)

  d. alternate day therapy for long-term administration

  (intermediate-acting, 2X daily dose every other day in AM)

  e. administer locally if possible

 GlucocorticoidWithdrawal

    G. Glucocorticoid Withdrawal

  1. General considerations

  a. dose

  b. treatment length

  c. steroid half-life

    2. Withdrawal protocol

  a. use short or intermediating-acting steroids

  b. gradually taper dose (over several months)

Withdrawal Symptoms 

Drug Interactions

  1. Drugs that decrease steroid effectiveness

  a.  hepatic enzyme inducers

  b.  cholestyramine

  2. Drugs that increase steroid effectiveness

  a. certain antibiotics (erythromycin)

  b. oral contraceptives

  c. ketoconazole

Drugs affected by steroid administration

       a. anticoagulants (dosage increase needed)

       b. antihypertensives (dosage increase needed)

       c. hypoglycemics (dosage increase needed)

       d. sympathomimetics (dosage decrease needed)