Lesson 2: Glucocorticoids and Immunosuppressants

glucocorticoids, mineralocorticoids, adrenal sex hormones

major classes of adrenal steroids

1. general effects on metabolism, water and electrolyte balance, and organ systems

2. negative feedback effects

3. anti-inflammatory and immunosuppressive effects

pharmacological actions of glucocorticoids

glucocorticoids

cortisol and corticosterone; predominantly affect carbohydrate metabolism

mineralocorticoids

aldosterone; predominantly affect electrolyte and water metabolism

adrenal sex hormones

mainly androgens; have limited importance

adrenal cortex

glucocorticoids are steroid agents produced and released by the?

cholesterol

cells of the adrenal cortex synthesize glucocorticoids from?

corticosteroids

refers to any steroidal hormone secreted by the adrenal cortex but is often used synonymously from glucocorticoids

cortisol (hydrocortisone), corticosterone

two most impt naturally occurring glucocorticoids

zona fasiculata

what part of the adrenal cortex are glucocorticoids produced from?

CRH, ACTH

in negative feedback effect, high concentration of glucocorticoid inhibit the release of ______ from hypothalamus and _______ from the anterior pituitary gland

glucocorticoid base

refers to the unesterified steroid component and determines its glucocorticoid, mineralocorticoid, anti-inflammatory potency, and extent of duration of action

hydrocortisone, cortisone

short-acting glucocorticoids (<12h, AIP: 1, 0.8, MP: ++)

prednisone, prednisolone, methylprednisolone, triamcinolone

intermediate-acting glucocorticoids (12-36h, AIP: 3.5-5, MP: +,+,0,0)

paramethasone, betamethasone, dexamethasone

long-acting glucocorticoids (>48h, AIP: 10-25-30, MP: 0)

esterification of glucocorticoid at carbon 21

influence the duration of action and mode of transmission

phosphates, hemisuccinate

glucocorticoid ester w rapid onset of action

• for IV and IM routes

acetate, diacetate, tebutate

glucocorticoid ester w slow absorption (2-14 days duration)

• poorly water soluble

• avail as depot

acetonide, pivalate

glucocorticoid ester w very long duration of action (wks to mos)

hpaa suppression leading to secondary hypoadrenocorticism

one of the major adverse effects of glucocorticoid therapy

alternate-day therpy

therapeutic success of glucocorticoids w fewer side effects is possible w what type of therapy?

mitotane

a relative of DDT; found to suppress adrenal cortical activity in dogs but is less successful in other spp

- indicated in the tx of canine pituitary-dependent hyperadrenocorticism (cushing's syndrome)

amphenone b

inhibits 17-ketosteroid production in human and dog

metyrapone

effectively blocks cortisol production but not corticosterone production in young pigs

cyclosporin a

specifically inhibits t cells early in their immune response to antigenic and regulatory stimuli w/o affecting suppressor t cells

cyclophitin

cyclosporin binds w its cytoplasmic receptor protein called?

tacrolimus

- a macrolide antibiotic w a very similar mechanism of action to cyclosporin

- active at lower concentration than cyclosporin

fk binding protein (FKBP)

cytoplasmic receptor of tacrolimus

rapamycin

a macrolide wc interferes w signal transduction pathway blocking the cell cycle of activated t cells in g1 phase by inhibiting a novel kinase

mTOR

what is the novel kinase that rapamycin inhibits called?

rapamycin-fkbp

rapamycin binds to this receptor

glucocorticoids

- inhibitors of cytokine gene expression

- like cyclosporin, this restrain the clonal proliferation of t cells through decreasing transcription of gene for IL-2 and many other cytokine genes and interleukin in both induction and effector phase of immune response

cyclophosphamide

an alkylating agent with particular action on lymphocytes

chlorambucil

an alkylating cytotoxic agent similar to cyclophosphamide

azathioprine

a thiopurine antimetabolite used primarily in the tx of autoimmune dss and to prevent organ transplant rejection

- both cell-mediated and antibody-mediated immune reactions are depressed

mycophenolate mofetil

a semi-synthetic derivative of a fungal antibiotic, converted to mycophenolic acid wc restrains proliferation of both b and t lymphocytes and reduces the production of cytotoxic t cells by inhibiting inosine monophosphate dehydrogenase

circadian rhythm

in the normal animal, the blood glucocorticoid concentration varies with the ______ _________

true

high levels of glucocorticoids exert a negative feedback to the hypothalamus and pituitary gland to inhibit the synthesis and release of crh and acth.

TRUE OR FALSE: this inhibition may become irreversible due to prolonged use of glucocorticoids

hypoadrenocorticism/addison’s disease

due to prolonged use of glucocorticoids, the hypothalamus and pituitary are unable to synthesize and release crh and acth to produce cortisol. what disease results from this?

true

TRUE OR FALSE: glucocorticoids regulate the volume and composition of body fluids mainly through their mineralocorticoid action

true

TRUE OR FALSE: glucocorticoids increase the rate of gluconeogenesis

true

TRUE OR FALSE: glucocorticoids reduce protein synthesis

true

TRUE OR FALSE: glucocorticoids promote redistribution of body fat in the hypercorticoid state, allow lipolysis to occur in response to lipolytic agents

false

TRUE OR FALSE: glucocorticoids make the animal sensitive to the effects of noxious stimuli (such as during inflammation) and of various forms of physical and emotional stress

true

TRUE OR FALSE: glucocorticoids control inflammation by maintaining circulation and normal vascular permeability, and stabilizing lysosomal membrane

true

TRUE OR FALSE: glucocorticoids control inflammation by inhibiting the production of pgs

phospholipase a

glucocorticoids control inflammation by blocking free radical formation through inhibition of what enzyme?

gluconeogenesis

major metabolic effect of glucocorticoids wherein there is reduce uptake and utilization of glucose by tissues, and may reduce the expression of insulin receptors by these target cells → hyperglycemia → increased insulin release from pancreatic beta cells

protein catabolism

major metabolic effect of glucocorticoid wherein there is increased levels of protein in the liver and plasma

• muscle atrophy

lipolysis

major metabolic effect of glucocorticoids wherein there is mobilization of fatty acid and redistribution of fats, particularly to the liver

antidiuretic

another metabolic effect of glucocorticoids is it antagonizes the release of this hormone, causing more urine output

intestinal, gastric acid, gastric mucus

other metabolic effects of glucocorticoids are reduced ______ absorption, enhanced secretion of ____ ____, and reduced production and altered nature of ______ _____

cutaneous, calcium, osteoporosis, mineralization, chondroitin

other metabolic effects of glucocorticoids are _____ atrophy, increased tissue mobilization of _____ that may lead to ______ and soft-tissue __________, and inhibition of ________ growth

retention, excretion

mineralocorticoid effects include the ______ of na, cl, and water, and increased ________ of k and h by renal distal tubules

true

TRUE OR FALSE: glucocorticoids suppress the inflam fxns of leukocytes (granulocytes, mast cells, monocytes-macrophages) by stabilizing their membranes

• this prevents the release of inflam mediators such as histamine and arachidonic metabolites

cyclosporin, tacrolimus, rapamycin

inhibitors of IL-2

glucocorticoids

inhibitors of cytokine gene expression

cyclophosphamide, chlorambucil

cytotoxic agents

azathioprine, mycophenolate mofetil

inhibitors of purine and pyrimidine synthesis

immunoglobulins

blockers of t cell surface molecules involved in signaling

down regulate, reducing

glucocorticoids ____ ______ expression of Fc receptors on macrophages thereby ______ phagocytosis of opsonized particles

stress leukogram

glucocorticoids may induce characteristic blood leukocyte profile (neutrophilia - high neutrophil, lymphopenia - low wbc, monocytosis - high monocyte, eosinopenia - low eosinophil) known as?

true

TRUE OR FALSE: gcs may mediate immunosuppression by influencing several stages of the immune response

suppress, resistant

gcs may directly (suppress/resist) t cells and cell-mediated immune effects. in contrast, b cells are more (suppressed/resistant) to the effects of gcs

false

TRUE OR FALSE: gcs inhibit ab production, other than indirectly removing the “help” that t cells provide for b cell activation

true

TRUE OR FALSE: further effect of gcs on humoral immunity is that of reducing ab affinity for cell membrane epitopes, causing elution of ab from the surface of target cells

true

TRUE OR FALSE: synthetic gcs have less binding w plasma proteins than endogenous gcs

prednisone, cortisone

prodrugs requiring activation in the liver; use of these drugs topically is contraindicated

false

TRUE OR FALSE: adverse effects of gcs are less common in dogs than cats

true

TRUE OR FALSE: adrenal atrophy is slowly reversible ff cessation of therapy, but hypoadrenocorticism may occur if withdrawn suddenly