Lecture 13 + 14

Question 1

Why is it so important to know about corticosteroids?

Answer 1

1. Used very commonly for a very long list of diseases
2. An enormous list of actions - work on every cell in the body
3. An enormous list of side effects - can’t give too much or stop too abruptly
4. Very real potential for harm and commonly used inappropriately

Question 2

Describe the difference between corticosteroids in “physiology” and “pharmacology terms”:

Answer 2

physiology - steroids produced by the adrenal cortex (e.g. cortisol and aldosterone)
pharmacology - synthetic steroids with a corticosteroid like effects (e.g. prednisolone, dexmethasone, methylprednisolone)

Question 3

Where are the glucocorticoids produced and what is an example of one?

Answer 3

Zona Fasciculata “zone” of the adrenal cortex e.g. cortisol

Question 4

Where are the mineralocorticoids produced and what is an example of one?

Answer 4

Zona glomerulosa “zone” of the adrenal cortex. e.g. aldosterone

Question 5

What is the common progenitor of anabolic and corticosteroids?

Answer 5

Progesterone

Question 6

Describe the mechanism of action of the glucocorticoid drugs:

Answer 6

1. The steroid hormone travels around in the blood attached to a carrier protein
2. The cortisol then leaves the carrier protein and enters the cytoplasm of the cell where is binds to a GR (cytoplasmic glucocorticoid receptor)
3. The steroid GR complex then enters the nucleus of the cell
4. Then binds to the glucocorticoid response element (GRE)
5. Transcription to RNA then processing to mRNA
6. Then translation results in altered protein synthesis and then biological effects

Question 7

Name some of the corticosteroid physiological effects?

Answer 7

1. Make energy available centrally
2. Getting ready for a metabolically stressful event
3. Improving physical ability
4. Not wasting energy on maintenance
5. Making sure we don’t make more cortisol
6. Urinating more and hence drinking more (mineralocorticoid)
7. Urinating less. Not a stress component (glucocorticoids)

Question 8

How do glucocorticoids exert their inflammatory and immune effects?

Answer 8

1. Inhibit phospholipase A2 hence decreasing arachidonic acid - hence they suppress COX (1 and 2) and LOX synthesis (hence decreasing prostaglandins and leukotrienes)
2. They also have immunomodulatory effects

Question 9

Name some of the immunomodulatory effects of glucocorticoids:

Answer 9

1. Decreased CMI
2. “breaks a fever”
3. Affecting inflammation
4. Hindering acute inflammation
5. Anti-inflammatory
6. Anti-inflammatory and side effects
7. Anti-inflammatory
8. Anti-allergy

Question 10

Name four clinical applications of where corticosteroids may be used:

Answer 10

1. Replacement in adrenal insufficiency (Addison’s = under active adrenal cortex - often long term physiological maintenance therapy)
2. Induction (=initiating birth) - often used with a prostaglandin (PGF2a)
3. Supraphysiologic to help with ketosis - disease of metabolic stress
4. Supraphysiologic to supress:
   Allergy- atopy (=environmental skin allergies) - very common clinical disease and used in insect bite hypersensitivity
   Inflammation- often used inappropriately for every single itis (e.g. arthritis) - inappropriate use as its a band aid solution when we should be treating the underlying cause
   Immune disease (e.g. autoimmune disorders) - IMHA and ITP

Question 11

When should corticosteroids not be used?

Answer 11

They should never be used in cases of shock

Question 12

Provide an example of a corticosteroid that has greater affinity for the mineralocorticoid receptor and briefly explain an application of this:

Answer 12

Fludrocortisone- preferential affinity at the mineralocorticoid receptor. Can be used in addison’s disease which is more of a deficiency in mineralocorticoid production than a deficiency in glucocorticoid production

Question 13

Rank the following conditions in order of the corticosteroid dose required and explain how they would change for cat:

Anti-pruritic, anti-inflammatory, immunosupressive

Answer 13

Anti-pruritic (anti-allergy) - 0.5 mg/kg/day

Anti-inflammatory - 1 mg/kg/day

Immunosuppressive - 2mg/kg/day

Double these for cats

Always try to use the lowest possible dose for patients

Question 14

Why is it important not to stop giving the drug cortisone too quickly?

Answer 14

The drug is so similar to cortisol that is actually has a negative regulatory effect CRH and ACTH. So if we stop the drug too quickly we can get a hypoadrenocortical crisis.

Question 15

How should you prescribe doses of prednisolone for a short duration of treatment ?

Answer 15

Give decreasing doses that taper of until the end of treatment.

Question 16

How should prenisolone be prescribed for a patients atopy over a longer period of time?

Answer 16

Keep making the doses lower and lower until the effect is no longer seen.

Question 17

What are the corticosteroid side effects that are observed?

Answer 17

1. All of the NSAID side effects (COX inhibition)
2. Metabolic (all of the iatrogenic hyperadrenocorticism during therapy, sudden cessation of corticosteroids leading to hypoadrenocortical crisis
3. Immune system - immunosupression- they are more prone to infections with those infections typically being more severe

Question 18

What are the common early glucocorticoid side effects that are seen?

Answer 18

PU/PD (ADH inhibition), mood change (euphoria/dysphoria), weight change (PP = polyphagia) a catabolic state, transient adrenal suppression

Question 19

What are some of the early sporadic glucocorticoid effects that are seen?

Answer 19

peptic ulcer (decreased mucosal blood flow)

Question 20

What are the late (months to years) common and sporadic effects seen from glucocorticoids?

Answer 20

Common: central obesity (redistribution of fat, pedulous abdomen), hair loss and prolonged adrenal suppression (HPA suppression)
Sporadic: cataracts/diabetes - sugar levels are too high in blood. Sugar deposits in lens and renders it opaque. Hypertension.

Question 21

What is a side effect of corticosteroids within horses?

Answer 21

laminitis - extremely painful condition of the hoof

Question 22

What is the most commonly used corticosteroid?

Answer 22

prednisolone

Question 23

What is species can dexamethasone be used for and what is its duration of action?

Answer 23

Used for most species and has a duration of action of about 72 hours

Question 24

What are the two most powerful corticosteroids that are used?

Answer 24

Triamcinolone

Methylprednisolone

Question 25

Name a topical corticosteroid that is used:

Answer 25

Hydrocortisone acetate

Hydrocortisone

Question 26

Is it a good idea to give corticosteroids concurrently with NSAID’s?

Answer 26

No because we will get synergistic side effects as 1 +1 > 2

Question 27

Is it ok to use corticosteroids and NSAID’s at the same time with horses?

Answer 27

yes, horses seen to be highly resilient to the combined use of NSAID’s and Corticosteroids

Question 28

What is the outcome of the H1 histamine effect?

Answer 28

1. veno- and aterio-dilation leads to increased vascular permeability causing erythema (redness of the skin or mucous membranes) and odema during inflammation
2. contraction of the GIT and respiratory smooth muscle causes anaphylaxis
3. Therefore, the H1 antagonists are used for histamine mediated inflammatory processes e.g. pollen allergies

Question 29

When are H1 anti-histamines main effects and mainly used?

Answer 29

mainly used for histamine mediated inflammatory processes e.g pollen allergies

Question 30

What is the effect of the H2 histamine receptor?

Answer 30

mediates gastric acid secretion using the non-mast cell pool. Therefore H2 antagonists are used for histamine-mediated gastric ulceration.

Question 31

What are the CNS effects of histamines?

Answer 31

maintain wakefulness and also function in emesis (supression of vomiting)

Question 32

What are the side effects of the H1 antagonists?

Answer 32

lipophilicity can effect the ability to cross the BBB and cause drowsiness

Question 33

Briefly describe the process of anaphylaxis:

Answer 33

sees IgE bind to mast cells > massive degranulation > release of large quantities of histamine and release of other mediators > respiratory smooth muscle contraction and bronchiolar constriction and arteriolar vasodilation causing hypotension (species dependant)

Question 34

Why do we not use H1 antihistamines in cases of anaphylaxis?

Answer 34

The drug may work but it is likely that you will be dead before the drug kicks in. Furthermore, it may not work anyway as other mediators are involved in anaphylaxis (e.g. cytokines, eicosanoids)

Question 35

How would you treat a puppy with a puffy face (hypersensitivity either from a vaccine or bee sting)?

Answer 35

Use an H1 antihistamine in conjunction with a glucocorticoid.

Question 36

What effects would you see if you gave anithistamines intravenously?

Answer 36

At high doses or after rapid IV administration, seizures or CNS excitement result

Question 37

What are the antimuscarinic effects that are seen with the use of H1 antihistamines?

Answer 37

“dry as a bone, red as a beet, mad as a hatter” - dry mouth, mydriasis, tachycardia but overall quite safe

Question 38

What is an example of an H1 antihistamine?

Answer 38

Chlorpheniramine

Question 39

What are the benefits of a H1 2nd generation antihistamine?

Answer 39

Less lipophilic so cross the BBB less, result in less drowsiness. They are mainly used for allergies and have not been studied much in veterinary medicine

Question 40

How do the immunomodulators work?

Answer 40

Interleukin-31 is involved in sending message to the brain that is interpreted as itchiness > IL-31 eliciting a pruritic response (dog’s with atopy have higher blood concentrations of IL-31 than those that don’t)

Question 41

Name two immunomodulators:

Answer 41

Oclacitinib and Lokivetmab. Anecdotally, efficacy for canine atopy: lokivetmab > oclacitinib