Physiologic Control of Secretion

Pharmacodynamics / Pharmacokinetics (Primary)

1. 90% of glucocorticoid protein bound
• Receptors for CBG-steroid complex on cell surface.
• Corticosteroid Binding Globulin "delivers drug to cells"
• Albumin binding restricts volume of distribution
2. Active transport of bound steroid into cell
3. Binding of glucocorticoid to receptor in cytoplasm (complex)
4. Active transport of complex to nucleus
5. Tight binding of complex to "regulatable" gene sequences.
• Cell type determines which sequences.
6. Binding causes an increase in DNA transcription
7. A variety of proteins may be produced (depending on specific genes activated)

View the Mechanisms of Action Powerpoint here: http://cpharm.vetmed.vt.edu/VM8784/GLUCOCORTICOIDS/Action.ppt

• Strength of binding (steroid to CBG, steroid to receptor, steroid-receptor to DNA) determines potency and duration.
• Pharmacokinetics of circulating glucocorticoid have little effect on potency or duration.
• Ultimate activity of glucocorticoids depends on the nature and quantity of the proteins produced. Pharmacokinetics of the new protein (amount produced and half-life) ultimately determines the potency and duration of the response. Proteins may interact with each other and with DNA to alter binding.
• Gluconeogenesis enzymes
• Lipocortin
• Decreased phospholipase A₂ activity

Pharmacodynamics (Secondary)

Glucocorticoids appear to have activities that are mediated through alternate pathways. These are are probably NOT mediated through the regulation of DNA transcription. Specific receptors have not been clearly identified. The "kinetics" of these effects are different than those mediated through cell nuclei.

• increased sensitivity to adrenergic drugs
• direct vascular effects
• "damage limiting" activity in spinal cord trauma

Systemic Effects of Glucocorticoids

Glucocorticoids as Drugs

Potency is primarily determined by the glucocorticoid base. The ester may control the amount of drug released into the circulatory system which would also influence the magnitude of effect.

Duration is controlled by the base UNLESS the base is attached to an ester that makes it "long-acting" (Table 3). Even then, the base will have some effect. (e.g. dexamethasone acetate injection will have a longer duration of effect than prednisolone acetate).

Glucocorticoid Products (Esters and dose forms)

Selection of a glucocorticoid ester is based on the route of administration and the desired duration and intensity of effect.

Oral

• the ester is irrelevant. All are separated from the base in the GI tract. The base drugs are well absorbed.

IM, SubQ, Intralesional

• Rapidly absorbed products can be used as substitutes for oral preparations. Their absorption and duration are roughly equivalent to the oral base products (and salts).
• Slowly absorbed (Depot) products are designed to provide either low concentrations of glucocorticoids for extended periods of time or high concentrations in a local area (e.g., tumor injections).

IV

• Water soluble salts. These reach sites of action 1/2 - 1 hour faster than oral but are otherwise similar in potency.
• This is the most appropriate route of administration for "EXTREME-DOSE" glucocorticoid therapy (e.g., CNS trauma, shock, etc.)

Glucocorticoid Replacement Therapy

Control clinical signs of Primary Hypoadrenocorticism

Categories

• Idiopathic (Destruction of Adrenal Cortex)
• Iatrogenic (o,p'-DDD)

Treatment - Emergency

• Mineralocorticoid deficiencies
  • Normal Saline
  • Hydrocortisone
• Glucocorticoid deficiencies
  • Hydrocortisone
  • Prednisolone

Treatment - Maintenance

• Mineralocorticoid deficiencies
  • Desoxycorticosterone Pivalate (monthly injections)
    • mineralocorticoid only - VERY reliable
  • 9-fluorohydrocortisone acetate (Florinef®)
    • mixed activity - VARIABLE
• Glucocorticoid deficiencies
  • Prednisone or prednisolone
    Daily oral or daily injection with rapidly absorbed (non-depot) form.

Control clinical signs of Secondary Hypoadrenocorticism

Categories

• Idiopathic (Destruction or dysfunction of pituitary)
• Iatrogenic (Chronic glucocorticoid administration)

Treatment - Emergency

• Fluid therapy
• Glucocorticoid (Intravenous glucocorticoid products)

Treatment - Maintenance

"Axis Recovery"

• Slow reduction in dose over extended period of time
• change dose rate every 3-4 weeks, change to EOD for first reduction
• No ACTH (maintains negative feedback on hypothalamus)
• Remember extra pred. for "stress"

• Daily replacement therapy
  • Prednisone or prednisolone preferred
  • 1 mg/kg of hydrocortisone activity each day (dog)
  • 0.2 - 0.25 mg/kg prednisone, prednisolone "normal" secretion rate not known for other species
• "Stressful" Situations
  • additional prednisone or prednisolone

Anti-inflammatory and Anti-immunologic Therapy

Steroids are potent drugs for interrupting events triggered at the cell membrane (prostaglandins, phospholipase, etc.), and cell mediated immunity (antigen recognition, cell migration, etc.)

Steroids are NOT effective inhibitors of antibody synthesis.

Reduce inflammation

Dosing

• approximately 4 x replacement dose
• usually 1 mg/kg prednisone or prednisolone
• various "protocols" lead to success

Discontinuing therapy

• Cold turkey if glucocorticoid therapy of less than 2 weeks duration
• Taper off if Glucocorticoid therpy of greater than 2 weeks duration. Rate of taper should be proportional to duration of prior therapy. The longer the original therapy, the slower the rate of dose reduction.

Inhibit immunologic responses

Dosing

• approximately 16x replacement dose (daily)
• usually initiate with 4 mg/kg prednisone or prednisolone per day in two doses (2 mg/kg q12H)
  • avoids relatively remote potential for acute adverse effects
  • possibly reduces initial efficacy (versus one single daily dose)
• Acute "psychosis" POSSIBLE with these doses (especially in one 4 mg/kg daily dose)

Reducing dose rates

• Goal is to "acheive the lowest dose that will control the disease."
• Disease break may require returning to original remission doses (or higher).

Alternate day therapy (Anti-inflammatory OR Anti-immunologic)

Administration of a single dose of an intermediate-acting glucocorticoid on alternate days in a dose equivalent to that being employed over a 48 hour period.

200 mg given every other day has the same efficacy as 90 mg given every day.

200 mg given every other day produces the same adverse effects as 25 mg given every day.

When?

• any patient who is dosed with glucocorticoids for longer than 14 days

How?

• can be used as one step in "tapering" protocol but with greater risk of disease "breakthrough"
  1 mg/kg SID (change to) 1 mg/kg EOD
• can convert to EOD with SMALL loss of efficacy
  1 mg/kg SID (change to) 2 mg/kg EOD

Which drugs?

• Prednisone, prednisolone, methylprednisolone OK.
• Triamcinolone ????
• Dexamethasone, betamethasone inappropriate
• Substitute rapidly absorbed (non-depot) IM or SC forms for oral

Why?

• Greater reduction in side effects than can be acheived by dose reduction alone.
• Does NOT eliminate side effects, merely minimizes them.

Intravenous use

• Shock: Methylprednisolone sodium succinate (Solu Delta Cortef®) vs. dexamethasone Na phosphate
• Spinal cord trauma: Methylprednisolone sodium succinate

Topic Summary (Glucocorticoids)

1. All glucocorticoid drugs act by the same basic mechanism. (Altering relative production of various mRNA's). Cells control the specific response by controlling specific DNA sequences that can be regulated. Anti-inflammatory (and anti-immunologic) activity cannot be separated from metabolic side effects.
2. Differences between glucocorticoid drugs are potency, duration of action of the base, and pharmacokinetic behavior of the salts.
3. The salt (form) of a glucocorticoid does not effect the duration of action IF the drug is given orally.
4. Injectable replacements for oral glucocorticoids (given daily or on alternate days) include bases for injection, succinate, hemisuccinate, and phosphate salts.
5. Alternate day therapy limits the (metabolic and adrenal axis) toxicity of glucocorticoids while efficacy is maintained.