Glucocorticoids

Physiologic Control of Secretion

Figure 1. Hypothalamic-pituitary-adrenal axis.
Hypothalamic-Pituitary-Adrenal Axis

Pharmacodynamics / Pharmacokinetics (Primary)

  1. 90% of glucocorticoid protein bound
  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.
  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

Concequences of Glucocorticoid pharmacology

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.

Systemic Effects of Glucocorticoids

Central Nervous System Euphoria and behavioral changes
Maintenance of alpha rhythm
Lower Seizure Threshold
Autonomic Nervous System Required for normal sensitivity of adrenergic receptors
Gastrointestinal Tract Decreased calcium and iron absorption
Facilitation of fat absorption
Increased acid, pepsin, and trypsin
Structural alteration of mucin
Skeletal Muscle Weakness (excess and deficiency)
Muscle atrophy (chronic excess)
Skin Atrophy and thinning (chronic excess)
Calcinosis Cutis
Hematopeoietic system Involution of lymphoid tissue (species dependent)
Decrease in peripheral lymphocytes, monocytes, eosinophils
Increase in peripheral neutrophils, platelets, RBCs
Decreased Clotting Time
Decreased phagocyte competence
Cardiovascular system Positive inotropic effect
Increased blood pressure (increased blood volume)
Kidneys Increased reabsorption of water, sodium, chloride
Increased excretion of potassium, calcium
Increased extracellular fluid
Bone Inhibition of collagen synthesis by fibroblasts
Acceleration of Bone resorption
Antagonism of Vitamin D
Cells "Stabilization" of liposomal membranes
Inhibition of macrophage response to migration inhibition factor
Lymphocyte sensitization blocked
Cellular response to inflammatory mediators blocked
Inhibition of fibroblast proliferation
Reproductive Tract Parturition induced during the latter part of pregnancy in ruminants and horses
Less reliable in dogs and cats
Teratogenesis during early pregnancy.

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.

Table 2. Comparison of Glucocorticoid Bases.
Base Relative Potency1 K/Na Effect Equivalent Dose2
mg (Total dose)s/th>
Duration (HPA)3 Structural
Difference
Short Acting
Hydrocortisone 1 ++ 20 12
Cortisone4 0.8 ++ 25 12 11 ketol
Intermediate Acting
Prednisone4 3.5 + 6 12 - 36 1 ketol; 1=2
Prednisolone 4.0 + 5 12 - 36 1=2
Methylprednisolone 5.0 0 4 12 - 36 6-me; 1=2
Triamcinolone 5.0 0 4 12 - 36 9-F;16-OH;1=2
Long Acting
Paramethasone 10 0 2 > 48 6-F;16-me;1=2
Betamethasone 25 0 0.8 >48 9-F;16-bme;1=2
Dexamethasone 30 0 0.7 >48 9-F;16-me;1=2
1. Glucocorticoid potency
2. Dose suggested is replacement therapy for a 20 kg. dog
3. Durations for other effects are likely to be different (see mechanism of action notes)
4. pro-drug, activated by conversion to hydrocortisone or prednisolone.


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

IM, SubQ, Intralesional

IV



Table 3. Available Glucocorticoid Products
Base Oral Intravenous
Rapid IM, SC Absorption
Intralesional
Slow IM, SC Absorption
Topical
Betamethasone Free base Na phosphate Na phosphate + Acetate Free base
Benzoate
Dipropionate
Valerate
Cortisone Acetate   Acetate  
Dexamethasone Free base Na phosphate Acetate Free base
Fluprednisolone Free base      
Hydrocortisone Free base
Cypionate
Na phosphate
Na succinate
Acetate Free base
Acetate
Meprednisone Free base      
Methylprednisolone Free base Na succinate Acetate Acetate
Paramethasone Acetate      
Prednisolone Free base Na phosphate
Na succinate
Acetate
Tebutate
Na phosphate
+ Acetate
Free base
Acetate
Na succinate
Prednisone Free base      
Triamcinolone Free base
Acetonide
Diacetate
  Acetonide
Diacetate
Hexacetonide
Free base
Acetonide


Glucocorticoid Replacement Therapy

Control clinical signs of Primary Hypoadrenocorticism

Categories

Treatment - Emergency

Treatment - Maintenance

Control clinical signs of Secondary Hypoadrenocorticism

Categories

Treatment - Emergency

Treatment - Maintenance

"Axis Recovery"

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

Discontinuing therapy

Inhibit immunologic responses

Dosing

Reducing dose rates

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?

How?

Which drugs?

Why?

Intravenous use

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.