Glucocorticoids

and other anti-inflammatory agents

What is the main glucocorticoid?

cortisol

What is the main mineralocorticoid?

aldosterone

How do glucocorticoids activate their receptors (GR)?

carbohydrate metabolizing activity

How do mineralocorticoids activate their receptors (MR)?

electrolyte balance regulating activity

What is the mechanism of glucocorticoids?

transverse cell membranes to act on cytoplasmic steroid receptors

What are the clinical uses of glucocorticoids?

immunosuppression and suppression of inflammation

What are the adverse effects of glucocorticoids due to?

due to their lack of specificity

What is the characteristic of glucocorticoid receptor activation?

physiologic response is slow or delayed but response duration is long and will persists through the life cycle of that protein

Why do responses elicited by GR activation require hours to days before they are apparent?

response requires a change in transcription of genes and translation of proteins

What is the fast drug action of glucocorticoids?

inhibit PLA2 activation by inducing dephosphorylation of active form

What is the slow drug action of glucocorticoids?

inhibit the expression

What are the metabolic effects of GR activation?

gluconeogenesis (hyperglycemia), protein catabolism (increase protein in plasma and muscle atrophy) and lipolysis (fatty liver)

What is the metabolic effect of GR activation in adipose tissue?

increase free fatty acids

What is the metabolic effect of GR activation in the liver?

increase ketone bodies and glucose

What is the metabolic effect of GR activation in muscles?

increase amino acids

What impact do glucocorticoids have of the HPA axis (hypothalamus-pituitary axis)?

negative feedback allows for reduced production of corticotropin-releasing hormone (CRH) and adenocorticotropic hormone (ACTH)

What is immunosuppression?

reduced activation of the immune system

What is inflammation?

biologic response of vascular tissues to stimuli such as pathogens and damaged cells

What are the anti-inflammatory effects of GR activation?

reduced capillary blood to reduce edema, reduced vasoproliferation, suppresses granulocytes/mast cells differentiation, prevent release of inflammatory mediators such as histamine and arachidonic acid, inhibits the production of pro-inflammatory cytokines

Due to increased release of endogenous steroids or treatment with exogenous corticosteroids, what types of leukogram can be seen? Shows immunosuppression.

stress leukogram (neutrophilia, monocytosis, eosinopenia, and lymphopenia)

What is hydrocortisone?

1:1 affinity binds to either one (GR or MR) with a 12h duration (short acting)

What is prednisone?

5:0.8 is a bit more selective for GR with a 12h-36h duration (intermediate acting)

What is prednisolone?

5:0.8 is a bit more selective for GR with a 12h-36h duration (intermediate acting)

What is dexamethasone?

25:0 is really selective for GR with a >48h duration (long acting)

What does a glucocorticoid prodrug require?

GR activation requires hydroxylation at a particular residue

What are the oral glucocorticoids?

prednisone, prednisolone, dexamethasone, hydrocortisone

What are the topical glucocorticoids?

hydrocortisone, prednisolone, dexamethasone

What are the inhalation glucocorticoids?

fluticasone

Why must you use prednisolone (prodrug) in cats?

they don’t convert it from prednisone very well

What is fluticasone used for?

inhalers in cats for allergic bronchial disease

What is a common drug combination?

trimeprazine (phenothiazine derivative with antihistamine properties) and prednisolone (temaril-P); synergize together

What are the clinical applications for the use of glucocorticoids?

autoimmune disorders, neoplastic diseases, emergency management of anaphylaxis/asthma, canine atopic dermatitis, inflammatory ocular disease

What are the steps of the dosing schedule for glucocorticoids?

induction period, maintenance dose, and withdrawal period; all should be the shortest periods possible

What animal is considered glucocorticoid resistant? What does this require?

cats have reduced expression of GR receptors so they require higher doses

What are the adverse effects of glucocorticoids?

cushing’s disease, adrenal atrophy, hepatomegaly, hyperglycemia, polyuria/polydipsia, proteinuria, may potentiate viremia or secondary infections

Why should you never use glucocorticoids in combination with an NSAID?

gastric ulceration adverse effect

What is the anagram that is helpful for glucocorticoid toxicity?

cushingoid (cushing’s like): having the constellation of symptoms and signs cause by an excess of cortisol hormone

What does the C stand for in cushingoid?

cataracts

What does the U stand for in cushingoid?

ulcers

What does the S stand for in cushingoid?

striae, skin thinning

What does the H stand for in cushingoid?

hypertension, hepatomegaly

What does the I stand for in cushingoid?

immunosuppression, infections

What does the N stand for in cushingoid?

necrosis of femoral heads

What does the G stand for in cushingoid?

glucose elevation

What does the O stand for in cushingoid?

osteoporosis, obesity

What does the I stand for in cushingoid?

impaired would healing

What does the D stand for in cushingoid?

depression/mood changes

What is another inflammatory mediator that glucocorticoids target?

histamine

What are the sources of histamine?

plants and animals (in all tissues)

Where is histamine stored?

high in skin/epidermis, GI mucosa (non-mast cells) and lungs (mast cells); bound to heparin in mast cells, basophils in blood

What is a histamine release?

antigen antibody reaction leading to degranulation of mast cells

What is the H1 receptor of histamine?

contractile; coupled with phospholipase C

What is the H2 receptor of histamine?

gastic secretion, vessel relaxation; coupled with cAMP

Histamine _______ large vessels.

constricts

Histamine _______ smaller vessels such as capillaries and venules.

dilates

What is the use of H1 antihistamines?

triple response for red spots, edema, red flare

What symptoms prompt you to start glucocorticoids? Specifically H1 antihistamines.

anaphylaxis, swelling, itching, bronchospasm, hypotension, shock

What agents induce histamine release?

liberators such large protein molecules (egg white, serum, venom, toxins), surface active agents, proteolytic enzymes, drugs, etc

How do antihistamines block histamine?

competitive antagonism; do not prevent release

What histamine receptor blocks gastric acid production?

H2

True or False: H1 blockers are more effective in prevention of flare up.

true

What are the first generation H1 antihistamines?

diphenhydramine (given BID or TID)

What are the second generation H1 antihistamines?

cetirizine, fexofenadine, loratidine (given SID and provide less sedation)

Why do second generation H1 antihistamines provide less sedation than first generation?

first generation cross the BB more easily while second generation are better substrates for P glycoprotein in the brain (effluxed more readily so less CNS penetration/retention)

True or False: P-Glycoprotein transport imparts drug resistance. Think multi-drug resistance protein.

true

Why do 2nd generation H1 blockers have a SID to BID dose with 1st generations have BID to TID?

2nd generation typically have a longer half life

What are the commonly used antihistamines in veterinary medicine?

Temaril P, diphenhydramine, chlorpheniramine, hydroxyzine, clementine, loratidine, cetirizine

Given the following list: Temaril P, diphenhydramine, chlorpheniramine, hydroxyzine, clementine, loratidine, cetirizine. Which of the following are 2nd generation antihistamines?

last two; loratidine, cetirizine

What is pentoxifyllene?

phosphodiesterase (PDE) inhibitor induces vasodilation, reduces inflammatory cytokine production, and reduces erythrocyte and platelet aggregation

What is pentoxifyllene used for?

dermatitis and contact allergy; navicular syndrome in horses

Why do you usually co-administer glucocorticoids and antihistamines such as prednisone and diphenhydramine in preparation of a mast cell tumor removal?

they can degranulate randomly or when manipulated during surgery