12 – Steroids

Question 1

Where are corticosteroids produced?

Answer 1

• Adrenal cortex
  o Zona fasciculata=glucocorticoids (ex. cortisol)
  o Zona glomerulosa=mineralocorticoids (ex. aldosterone)
  o Zona reticularis=sex steroids

Question 2

Glucocorticoid effects on metabolism?

Answer 2

• Increase blood glucose
• Lipolysis
• Proteolysis

Question 3

Glucocorticoids increase blood glucose

Answer 3

• increase gluconeogenesis, antagonizing insulin (decrease glucose uptake)
  o why they are good therapy for ketosis(animals in a negative energy balance)=good
  o why diabetes mellitus can occur with chronic GC use=bad

Question 4

Glucocorticoid effects on the immune system: low to moderate dose

Answer 4

• reduce inflammation
  o use for allergic reactions and musculoskeletal inflammation
  o NOT necessarily helpful for pain due to musculoskeletal disease

Question 5

Glucocorticoid effects on the immune system: high dose

Answer 5

• Immunosuppression
  o For immune-mediate conditions

Question 6

Glucocorticoid effects on the immune system

Answer 6

• White blood cell changes (neutrophilia, lymphopenia
  o ‘stress leukogram’

Question 7

Inflammation pathway - peripheral (glucocorticoids)

Answer 7

• Phospholipids broken down into AA=BLOCKED by glucocorticoids
  o Prostaglandins, prostacyclins, thromboxane, leukotrienes
• *block the same pathway of NSAIDs but different enzymes=slightly different results
  o Steroids=produces less leukotrienes (don’t see that with NSAIDs)

Question 8

Glucocorticoid effects on water and electrolyte balance

Answer 8

1. Polyuria/polydipsia
2. Weak mineralocorticoid (aldosterone) effect
3. Increase plasma volume?

Question 9

Polyuria/polydipsia: possible physiological mechanisms (glucocorticoid)

Answer 9

• Cause decrease ADH release from P. pituitary=’central diabetes insipidus’
• MORE LIKELY: Block ADH binding to the V2 receptor on principal cells=’nephrogenic diabetes insipidus’

Question 10

Weak mineralocorticoid (aldosterone-like) effect

Answer 10

• Increase Na+ reabsorption from distal nephron
  o Decrease Na+ loss in urine
• Can lead to potassium wasting
  o Increase K+ loss in urine
  *cannot use it to treat mineralocorticoid deficiency in hypoadrenocorticism (Addison’s disease)

Question 11

Glucocorticoid effect on HPA axis

Answer 11

• SUPPRESSES
• *impacts steroid dosing regimens

Question 12

Glucocorticoid formulations: injectable products

Answer 12

1. Phosphate or succinate esters=’fast-acting’
2. Acetate/acetonide esters=slow
   **SALTS matter

Question 13

Phosphate or succinate esters

Answer 13

• ‘fast-acting’
• IV or IM injections
• Different formulations
  o *Dexamethasone sodium phosphate

Question 14

Acetate/acetonide esters

Answer 14

• SLOW absorption
• IM/SC/Intra-articular
• Ex. methylprednisolone acetate (Depo-Medrol: ‘long-acting’ steroid used mostly in dogs/cats)
• Ex. prednisolone acetate

Question 15

Other routes of administration

Answer 15

• Oral formulations: vet or human products
• Topical
• Inhalant steroids
• Ophthalmic drops

Question 16

Oral formulations examples

Answer 16

• Prednisone/prednisolone
• Dexamethasone tablets/powder

Question 17

Topical

Answer 17

• Some systemic absorption
• Often combined with antifungals and antibiotics

Question 18

High volume of distribution

Answer 18

• Low plasma concentration, but might be high concentration in tissues
• Plasma half-life does NOT correlate with biological effect

Question 19

Glucocorticoid pharmacokinetics

Answer 19

• Generally good oral bioavailability
• High volume of distribution
• Hepatic metabolism

Question 20

Hepatic metabolism

Answer 20

• Prednisone and cortisone=PRO-DRUGS
  o prednisOLone and cortisOL=ACTIVE forms
• horses and cats have POOR metabolism of prednisone to prednisolone

Question 21

Prednisone PK in cats: clinical relevance

Answer 21

• it does work, but dose needs to be higher or effect is NOT as obvious
• rather give them the active drug (prednisolone)

Question 22

Dosing glucocorticoids

Answer 22

• use SMALLEST POSSIBLE dose
• avoid HPA suppression
• *potency is NOT an issue (need to be careful when dosing)

Question 23

Smallest possible dose

Answer 23

• anti-inflammatory: 5-10x physiological dose (lower)
• Immunosuppressive: 20x (moderate)
• ‘shock’ doses: 100-200x (no longer used, dangerous)

Question 24

Avoid HPA suppression

Answer 24

• Don’t stop ‘cold turkey’
• *Taper slowly: use lower doses OR longer dose intervals
• The body thinks there is still lots of steroids in the body=animal not producing their own steroid, NEED time to get back on track

Question 25

Glucocorticoid adverse metabolic effects

Answer 25

- Hyperadrenocorticism (‘cushingoid’: pot belly, lack of fur on ventral abdomen) - Hyperglycemia o Diabetes in cats (Especially Depo-Medrol=long acting)

Question 26

Glucocorticoid adverse hemodynamic effects

Answer 26

- Plasma volume expansion: increase glucose or Na+ - Blood work: decrease in RBC, PCV, Hb o ‘dilution-effect’

Question 27

Prostaglandins are cytoprotective (adverse effects)

Answer 27

- Increase mucosal blood flow - Increase bicarbonate and mucus production - *anti-inflammatory drugs (prostaglandin INHIBITION, ex. steroids) can lead to GI ulceration, pancreatitis, renal damage - **BE CAREFULEWITH CONCURRENT USE OF NSAIDs** - *Do NOT mix steroids with other anti-inflammatories

Question 28

Other glucocorticoid adverse effects

Answer 28

- Muscle atrophy: proteolysis - Delayed wound healing - Laminitis - Polyuria/polydipsia - Abortion - Polyphagia and weight gain (may be beneficial?) - Immune suppression (increase infection risk) - HPA suppression

Question 29

Laminitis (controversial)

Answer 29

- Altered hoof vascular flow? - Weakened coffin bone support to laminae? - Insulin resistance?