Lecture 13 + 14 Flashcards
Why is it so important to know about corticosteroids?
- Used very commonly for a very long list of diseases
- An enormous list of actions - work on every cell in the body
- An enormous list of side effects - can’t give too much or stop too abruptly
- Very real potential for harm and commonly used inappropriately
Describe the difference between corticosteroids in “physiology” and “pharmacology terms”:
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)
Where are the glucocorticoids produced and what is an example of one?
Zona Fasciculata “zone” of the adrenal cortex e.g. cortisol
Where are the mineralocorticoids produced and what is an example of one?
Zona glomerulosa “zone” of the adrenal cortex. e.g. aldosterone
What is the common progenitor of anabolic and corticosteroids?
Progesterone
Describe the mechanism of action of the glucocorticoid drugs:
- The steroid hormone travels around in the blood attached to a carrier protein
- The cortisol then leaves the carrier protein and enters the cytoplasm of the cell where is binds to a GR (cytoplasmic glucocorticoid receptor)
- The steroid GR complex then enters the nucleus of the cell
- Then binds to the glucocorticoid response element (GRE)
- Transcription to RNA then processing to mRNA
- Then translation results in altered protein synthesis and then biological effects
Name some of the corticosteroid physiological effects?
- Make energy available centrally
- Getting ready for a metabolically stressful event
- Improving physical ability
- Not wasting energy on maintenance
- Making sure we don’t make more cortisol
- Urinating more and hence drinking more (mineralocorticoid)
- Urinating less. Not a stress component (glucocorticoids)
How do glucocorticoids exert their inflammatory and immune effects?
- Inhibit phospholipase A2 hence decreasing arachidonic acid - hence they suppress COX (1 and 2) and LOX synthesis (hence decreasing prostaglandins and leukotrienes)
- They also have immunomodulatory effects
Name some of the immunomodulatory effects of glucocorticoids:
- Decreased CMI
- “breaks a fever”
- Affecting inflammation
- Hindering acute inflammation
- Anti-inflammatory
- Anti-inflammatory and side effects
- Anti-inflammatory
- Anti-allergy
Name four clinical applications of where corticosteroids may be used:
- Replacement in adrenal insufficiency (Addison’s = under active adrenal cortex - often long term physiological maintenance therapy)
- Induction (=initiating birth) - often used with a prostaglandin (PGF2a)
- Supraphysiologic to help with ketosis - disease of metabolic stress
- 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
When should corticosteroids not be used?
They should never be used in cases of shock
Provide an example of a corticosteroid that has greater affinity for the mineralocorticoid receptor and briefly explain an application of this:
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
Rank the following conditions in order of the corticosteroid dose required and explain how they would change for cat:
Anti-pruritic, anti-inflammatory, immunosupressive
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
Why is it important not to stop giving the drug cortisone too quickly?
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.
How should you prescribe doses of prednisolone for a short duration of treatment ?
Give decreasing doses that taper of until the end of treatment.
How should prenisolone be prescribed for a patients atopy over a longer period of time?
Keep making the doses lower and lower until the effect is no longer seen.
What are the corticosteroid side effects that are observed?
- All of the NSAID side effects (COX inhibition)
- Metabolic (all of the iatrogenic hyperadrenocorticism during therapy, sudden cessation of corticosteroids leading to hypoadrenocortical crisis
- Immune system - immunosupression- they are more prone to infections with those infections typically being more severe
What are the common early glucocorticoid side effects that are seen?
PU/PD (ADH inhibition), mood change (euphoria/dysphoria), weight change (PP = polyphagia) a catabolic state, transient adrenal suppression
What are some of the early sporadic glucocorticoid effects that are seen?
peptic ulcer (decreased mucosal blood flow)
What are the late (months to years) common and sporadic effects seen from glucocorticoids?
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.
What is a side effect of corticosteroids within horses?
laminitis - extremely painful condition of the hoof
What is the most commonly used corticosteroid?
prednisolone
What is species can dexamethasone be used for and what is its duration of action?
Used for most species and has a duration of action of about 72 hours
What are the two most powerful corticosteroids that are used?
Triamcinolone
Methylprednisolone
Name a topical corticosteroid that is used:
Hydrocortisone acetate
Hydrocortisone
Is it a good idea to give corticosteroids concurrently with NSAID’s?
No because we will get synergistic side effects as 1 +1 > 2
Is it ok to use corticosteroids and NSAID’s at the same time with horses?
yes, horses seen to be highly resilient to the combined use of NSAID’s and Corticosteroids
What is the outcome of the H1 histamine effect?
- veno- and aterio-dilation leads to increased vascular permeability causing erythema (redness of the skin or mucous membranes) and odema during inflammation
- contraction of the GIT and respiratory smooth muscle causes anaphylaxis
- Therefore, the H1 antagonists are used for histamine mediated inflammatory processes e.g. pollen allergies
When are H1 anti-histamines main effects and mainly used?
mainly used for histamine mediated inflammatory processes e.g pollen allergies
What is the effect of the H2 histamine receptor?
mediates gastric acid secretion using the non-mast cell pool. Therefore H2 antagonists are used for histamine-mediated gastric ulceration.
What are the CNS effects of histamines?
maintain wakefulness and also function in emesis (supression of vomiting)
What are the side effects of the H1 antagonists?
lipophilicity can effect the ability to cross the BBB and cause drowsiness
Briefly describe the process of anaphylaxis:
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)
Why do we not use H1 antihistamines in cases of anaphylaxis?
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)
How would you treat a puppy with a puffy face (hypersensitivity either from a vaccine or bee sting)?
Use an H1 antihistamine in conjunction with a glucocorticoid.
What effects would you see if you gave anithistamines intravenously?
At high doses or after rapid IV administration, seizures or CNS excitement result
What are the antimuscarinic effects that are seen with the use of H1 antihistamines?
“dry as a bone, red as a beet, mad as a hatter” - dry mouth, mydriasis, tachycardia but overall quite safe
What is an example of an H1 antihistamine?
Chlorpheniramine
What are the benefits of a H1 2nd generation antihistamine?
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
How do the immunomodulators work?
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)
Name two immunomodulators:
Oclacitinib and Lokivetmab. Anecdotally, efficacy for canine atopy: lokivetmab > oclacitinib
