2. mineralocorticoids
               a. sodium retaining
               b. potassium depleting

 B. Epinephrine– part of the ANS Sympathetic nervous system
 

II. Corticosteroid Therapy and Considerations
 A. Corticosteroids refer to all secretions of adrenal cortex, but usually refers mainly to the glucocorticoids
  1. cortisol –95% of secretions, 15-25mg daily
  2. corticosterone – 1.5 to 4mg daily
  3. cortisone secreted in very small quantities

 B. Cyclic secretions– larger amounts in the morning, smaller amounts in evening
 C. Effect On carbohydrate metabolism:
  1. stimulate formation of glucose through breakdown of protein
  2. moderate decrease in cell use of glucose
  –net effect of these two actions is to cause hyperglycemia
 D. On protein metabolism
  1. increased breakdown of protein into amino acids
  2. decrease in production of new proteins–protein depletion results; glycogen stores increase
 F. On lipid metabolism:
  1. increased breakdown of adipose tissue into fatty acids
  2. stimulated oxidation of fatty acids within body cells
 G. On inflammatory and immune response
  1. suppressed inflammatory response
  2. suppressed immune response
 H. On the CNS:  -- at physiologic levels, maintains normal nerve conductivity; excess causes decrease in conduction, altered brain wave patterns
 I. On muscle:
  1. maintains muscle strength
  2. inhibits bone formation and growth; increased bone breakdown
 J. On respiratory system:
  1. maintains open airways
  2. stabilizes mast cells to inhibit inflammation
 K. On the GI system:
  –decrease in mucous production
 L. On fluids and electrolytes:
  1. retention of sodium and water
  2. excretion of potassium and calcium

NOTE: these same effects can occur with the administration of “exogenous” corticosteroids.  Consider what adverse effects these actions could represent.  Oral doses need to always be administered with food.

III. Giving exogenous corticosteroids
 A. Indications
  1. allergic disorders
  2. collagen disorders (SLE, scleroderma)
  3. dermatologic disorders
  4. endocrine insufficiency (Addison’s Disease)
  5. Neurologic disorders
  6. ophthalmic
  7. Organ or tissue transplants or grafts
  8. GI disorders (Crohn’s enteritis)
  9. Hematologic disorders (ideopathic thromocytopenic purpurea)
  10. Liver disorders– cirrhosis, ascites
  11. Neoplastic disease (acute and chronic leukemias, Hodgkin’s disease, multiple myeloma) –suppression of lymphocytes and lymphoid tissue
  12. Renal disorders– nephrotic syndrome and its edema
  13. Respiratory– asthma, COPD (increase in beta-adrenergic receptors)
  14. Rheumatic disorders
  15. Shock from adrenocortical insufficiency

 B. Contraindications
  1. systemic fungal infections
  2. hypersensitivity
  3. infection or risk of infection present
  4. diabetes
  5. GI ulcers
  6. hypertension
  7. inflammatory bowel disorders
  8. CHF
  9. renal insufficiency

IV. Preferred drug selection
 A. Insufficiency disorders (Addison’s)-- hydrocortisone or cortisone
 B. non-endocrine disorders – (antiinflammatory, antiallergic) – prednisone or methylprednisolone (the “Medrol Dosepak”)
 C. Respiratory disorders– inhalers, many on the market
  1. beclomethasone (Vanceril)
  2. flunisolide (Aerobid)
  3. triamcinolone (Azmacort)
 D. Cerebral edema– dexamethasone (IV or po)
 E. Acute, life threatening disorders– hydrocortisone, dexamethasone, methylprednisolone– look for an IV form
 
V.  Scheduling considerations

 A. Short term
  1. can be given in relatively large doses for 48-72 hours
  2. short term therapy is 10 days or less
 B. Long term
  1. for replacement therapy
  2. chronic conditions
  --consider alternate day treatment once patient is stable
  3. physical changes with long term treatment
   fat mobilization promoted, most often to the back, causing  two unusual conditions known as:

   a. “moon face” (accumulation of fat on the face, giving it a rounded appearance)

   b. “buffalo hump” (accumulation of fat on the back)
 
  4. impair growth in children
  5. even topical doses can cause problems

VI. Specific drugs
 A. Dexamethasone (Decadron)
  1. 0.75-9mg daily
  2. doses in higher ranges used for leukemia
 B. Hydrocortisone (Cortef, Hydrocortone, et al)
  1. topical, oral, injection
  2. po, 10-20mg daily in 3-4 doses for insufficiency therapy
  3. enema therapy usually runs 21 days
 C. Methylprednisolone (Medrol)
  1. injection, oral
  2. the 4mg “Dosepak” is a 6 day course of therapy with total administration of 21 tablets
  3. 4-80mg as injection
 D. Prednisolone
  1. 5-60mg daily
  2. po and injection
 E. Prednisone (Deltasone), 5-60mg daily
 F. Triamcinolone (Aristocort, Kenalog)
  1. topical, IM, inhalation
  2. 2.5-60mg daily IM

VII. Warnings
 A. may mask signs of infection
      B. may decrease host resistance to infection
      C. may potentiate fungal infections
      D. ocular effects
         1. secondary infections--especially HERPETIC
  2.. prolonged use may cause
              a. cataracts
             b. glaucoma
 E. fluid/electrolyte imbalance
     F. peptic ulceration
          1. by direct irritation
          2. also, tends to thin the gastric mucosa with prolonged use
         3. give with food or antacids
 G. immunosuppression
           --NO VACCINATIONS (dealing with live or attenuated virii!)
      H. adrenal suppression
          1. can be seen with therapy over 5 days in duration
         2. could be reduced with q.o.d. (every other day) therapy
          3. do not stop taking steroids abruptly; wean off

 I. use in caution in patients with
          1. hypertension
          2. Congestive Heart Failure (CHF)
          3. thromboembolatic tendencies
          4. renal problems
          5. GI problems
         6. severe infections
              --especially fungal or viral

 J. Steroid psychosis
          1. primarily in women, esp. among patients with family history
          2. usually in doses of 40mg or more daily (prednisone equivalents)

 K. menstrual irregularities may occur

First of all, these anabolic steroids are NOT glucocorticoids...

 A. “Rationale” for anabolic steroid use
  1. increase in muscle mass
  2. increase in strength, aggressiveness
  3. decrease “recovery time” during training
 
 B. The problem
  1. The agents are all derivatives of the male sex hormone testosterone
  2. The theory for the “mechanism of action”
   a. increased RNA production, increased protein synthesis
   b. nitrogen retention, therefore an improved use of protein
   c. psychological– euphoria produced makes the potential athlete perform better and train harder; a coupling, perhaps, with endorphin production

  3. The side effects are dangerous
   a. testosterone is considered a stress hormone, producing a profound effect on the cardiovascular system
   b. excessive nitrogen in the system results in hepatitis, liver cancer, and elevation in liver enzymes
   c. the endocrine effects
    i. transient infertility
    ii. gynecomastia
    iii. acne
    iv. masculinization of women
    v. the body detects the presence of exogenous hormones and ceases to produce its own!
  4. And furthermore....
   a. fluid and sodium retention– congestive heart failure
   b. stroke and MI– some patients in their early 20s
   c. dementia, schizophreniform symptoms
   d. premature epiphesial closure in adolescents
   e. AIDS (shared needles)
   f. necrosis of tissue (contaminated needles)
   g. use of veterinary and black market sources
   (quality control there)
   h. clotting in legs, resulting in amputation

 C. Commercial products, all controlled substances
  1. Androderm (topical patch)
  2. Testoderm (topical patch)
  3. Halotestin (tablet)

I. Background Discussion
    A. Histamine
        1. precise function unknown
            a. neurotransmitter/neuromodulator
            b. effects on microcirculation after cellular injury
            c. gastric secretions/mast cells

        2. release of histamine causes
            a. constriction of large veins
            b. dilation of arterioles
            c. increased permeability of vessels

        3. action of "2" results in
            a. blood pooling in small blood vessels
            b. proteins enter tissues, bringing fluids with them
            c. edema and hypotension result
            d. mild form--redness, rash, hives
            e. severest forms--shock
 
        4. on nerves
            a. stimulation--itching and pain
            b. gastric acid secretion
        5. histamine and the allergic response
           a. antigen meets antibody, stimulating histamine release
            b. other substances released as well
                i. prostaglandins and slow-reacting substances (SRS)
                   --involved in bronchoconstriction
               ii. bradykinins
                   --involved in hypotension

[In anaphylaxis, the calamatous results seen are as a result of the extreme form of these mediators and their reaction on the body]
 
            c. causes edema of skin and mucosa
               --definition time--

                i. urticaria-- hives

               ii. angioedema--edematous areas of skin, mucous membranes, or internal organs

 
II. Antihistamines--two types
     A. Receptor-specific
         1. H1 receptors--the "classic" antihistamines work here
             a. chlorpheniramine (Chlortrimeton)
             b. diphenhydramine (Benadryl/Benylin)
             c. promethazine (Phenergan)
             d. meclizine (Bonine/Antivert)
             e. hydroxyzine (Atarax/Vistaril)

         2. H2 receptors--gastric secretion
             the relatively new class of drugs, the H2 antagonists, works here
             a. cimetidine (Tagamet)*
             b. ranitidine (Zantac)*
             c. famotidine (Pepcid)*
       d. nizatidine (Axid)*

III. Antihistamine activity--the H1 antihistamines
     A.  "The Classic Antihistamines"
          1. compete with histamine for the receptor site
          2. no effect on the release of histamine
 
    B. The action of antihistamines
         1. can help counteract the increased permeability of vessels
         2. decrease itch, pain
         3. little effect on reversing vasodilation
         4. other effects
             a. sedative
   diphenhydramine (Benadryl) is the most sedative of all antihistamines
               --while regarded generally as a side effect, this action can be an indication
               –also recall that diphenhydramine injection, with epinephrine, has been used as a local anesthetic for patients allergic to other anesthetic classes

  Astemizole (Hismanal) and terfenadine (Seldane) were withdrawn from the market in the late 90s due to serious drug interactions with erythromycins and antifungal agents

           --both diphenhydramine and hydroxyzine are used as mild "sleepers," especially among asthmatics or among patients who would not benefit from the respiratory depression caused by some of the stronger barbiturate/CNS depressants

             b. reduction of vertigo, motion sickness
               --hydroxyzine especially

             c. reduction of n/v (CTZ inhibition)
               --promethazine (Phenergan), hydroxyzine (Atarax/Vistaril)

             d. reduction in bronchial/nasal secretions
               --diphenhydramine (Benadryl/Benylin)

      C. Uses of the classic antihistamines
          a. "hay fever" and general allergies
          b. allergic rashes--slight decrease in swelling, itching

             --Caladryl, a topical combination of Calamine lotion with diphenhydramine (Benadryl) seems like an ideal blend; however, topical use of antihistamines does not appear to be all that effective; 0.5% hydrocortisone cream is now available OTC and is a far better choice to relieve such inflammation

          c. in specific allergies (bee sting, food allergies)

          d. as adjunct in anaphylaxis
           --epinephrine still drug of choice

 
     D. Side effects--the classic antihistamines
          1. drowsiness
          2. xerostomia, overdrying of mucous membranes
              --bloody noses, sore throats

          3. in extreme cases,
              blurred vision (eyes dry out)
              cardiac stimulation, CNS stimulation

      E. Dental considerations
          1. diphenhydramine 1% IV
           --potential substitute as a local anesthetic when patient is allergic to both ester and amide
          2. side effects/xerostomia
           --most hay fever meds represent a combination of an antihistamine, a decongestant (vasoconstrictor such as pseudoephedrine [Sudafed]), and an anticholinergic (scopolamine, methscopolamine bromide, etc.), all of which can cause some power xerostomia
           --texts refer to this as an "unhealthy oral environment"

      F. Contraindications
          1. asthmatics--possible formation of viscous mucous plugs in presence of dried tissues
          2. bladder obstruction
          3. narrow-angle glaucoma

  "May cause drowsiness.  Avoid alcohol use and do not operate heavy machinery while on this medication."

    A. Primary use
       1. ulcer therapy
       2. hypersecretion syndromes

    B. Cimetidine (Tagamet) inhibits a hepatic microsomal enzyme system that metabolizes many drugs; as a result, patients taking cimetidine should be carefully monitored whenever other agents are added to their regimen
        1. side effects
            a. gynecomastia, impotence in men
            b. galactorrhea in women
            c. confusion, dementia-like syndromes

V. The Non-Sedating Antihistamines
 A. Astemazole (Hismanal)
  Of recent note (February 1998), astemazole has been the subject of alert with regard to its potential for serious drug-drug interactions, especially with erythromycins, antifungal agents, grape juice, cisapride (Propulcid), and many others.  The combination, especially in the presence of preexisting liver disease, has resulted in potentially fatal cardiac irregularities.
  --usual dose, 10mg daily

 B. loratadine (Claritin)
  --10mg daily dose, alone or in a sustained release form with pseudoephedrine (Sudafed)

 C. terfenadine (Seldane)
  --pulled from the market as of 1 February 1998; it was a 60mg daily dose and had the distinction of being the first nonsedating antihistamine with the drug-drug interactions outlined above for astemazole

 D. cetirizine (Zyrtec), with decongestant–Zyrtec-D
  --5 or 10mg daily

 E. fexofenadine (Allegra)
  --chemically similar to the withdrawn Seldane above, and distributed by the same manufacturer
  --interestingly enough, the FDA announced its withdrawal of drug approval for Seldane the very week that the generic (at a 40% savings) became available on the market, and only after the manufacturer of Seldane had Allegra available to market as an alternative..... hmmmmmm

1. Define urticaria.
2. Define angioedema.
3. Which antihistamine causes the greatest amount of sedation?
4. List three “non-sedating” prescription antihistamines.
5. Discuss the differences between H-1 and H-2 receptor-type antihistamines.
6. Discuss the effects of chronic steroid use on fat redeposition in the body.
7. What is a hazard of use of ophthalmic steroids?
8. What is a recommendation to patients who have to take oral steroids?
9. What is a recommendation to patients who must apply topical steroids?
10. What are the hazards of ingesting metabolic steroids for the purpose of body building?

End of Module Ten
Steroids and Antihistamines
Contact: Jim Middleton
KCC Dental Hygiene Pharmacology
January 2002