Corticosteroids and Inflammation Flashcards

Question

Innate vs adaptive (acquired)=Soluble factors

Answer 1

Innate = complement, type 1 interferon, select cytokines and chemokines Adaptive = select cytokine and chemokines

Answer 2

non steroidal anti inflammatory drugs Medicines widely used to relieve pain, reduce inflammation and bring down high temp But these are used for short period time - only potent for 4-6 hours, not a realistic medication for chronic diseases Cannot take them chronically

Answer 3

involve selective eradication of immunocompetent cells (cytokines or immune cells) or down regulation of the immune response without deleting the target cell (cannot just get rid of all immune cells, need immune system at some balance- drugs are to bring balance to your life) in either case, the goal is to balance the activity and selectivity of the drug to optimize clinical efficacy while preventing adverse effects.

Answer 4

antiproliferative/antimetabolite agents, glucocorticoids, immunophilin-binding agents (block cytokines and chemokines), and biopharmaceuticals (antibody based drugs). The usefulness of these compounds is limited by their severe toxicities.

Answer 5

Cyclophosphamide or nitrogen mustards Inhibit proliferation of t cells and b cells = stop from turning on adaptive arm of immune system Global drugs that bind dna complex and inhibit replication= Have pleiotropic effects Have to hit this drug right before inflammation gets bad = Has to be someone who has inflammatory disease - chronic and confirmed disease The antiproliferative/ antimetabolic drugs are cytotoxic and inhibit cell division and the proliferation of both T and B cells. The alkylating agents include cyclophosphamide,nitrogen mustards, and nitrosoureas that covalently complex to DNA

Answer 6

Stopping ability of immune cells to take in all they need for functional metabolism = essentially inhibit replication Attack metabolic function = cannot eat folic acid or pyrimidine that they require to proliferate= stops and b and t cells from proliferation The antimetabolites are compounds that resemble normal metabolic compounds, including folic acid, pyrimidines, or purines, and block the proliferation of B and T cells by inhibiting the synthesis of building blocks necessary for cell replication.

Answer 7

Inhibitor of dihydrofolate and stops immune cells from proliferating through inhibiting metabolism For someone diagnosed with chronic illness and confirmed = So timing very important, Can have effects in body as well Methotrexate Is a competitive inhibitor of dihydrofolate reductase, which converts dihydrofolic acid to tetrahydrofolic acid, thereby preventing the regeneration of folic acid required for purine and pyrimidine synthesis

Answer 8

calcineurin and mtor inhibitors For someone who has been diagnosed and is suffering for a long time - from inflammatory disease Drugs block production of - ex = IL 12= Ex = cyclophilin and FKBP-12 = drugs, Blocks production of cytokines IL 12 and TNF-a

Answer 9

the immunophilins are proteins with both chaperone and enzymatic activity and have diverse functions ranging from neurotrophic actions to the regulation of cell proliferation. Of importance for immunosuppression are the immunophilins cyclophilin and FKBP-12, both of which are targets for drug action. In lymphocytes,cyclosporine binds to cyclophilin A the complex formed binds to calcineurin and inhibits the phosphatase activity necessary for the expression of inflammatory cytokines such as IL-2 and TNF-α.

Answer 10

Most widely used immunosuppressive agent High effective for autoimmune inflammatory diseases And for preventing graft rejection - during transplant = Usually need to be on anti inflammatory so body will not have inflammatory response

Answer 11

Prednisone is the prototypical glucocorticoid and exerts its effects both directly and indirectly by binding to glucocorticoid receptors

Answer 12

the glucocorticoids inhibit the vasodilation and increased vascular permeability that ensue upon inflammatory insult, as well as prevent leukocyte migration. Turn everything off

Answer 13

They also decrease T-cell activation and the expression of IL-2, IL-1, IL-6, and nuclear factor κ–light-chain-enhancer of activated B cells (NF-κB).

Answer 14

The glucocorticoids also bind to glucocorticoid-responsive elements on DNA to decrease the expression of proinflammatory and activate the expression of anti-inflammatory genes Downregluate pre existing inflammation

Answer 15

Pleiotropic Do not need to know what disease is

Answer 16

Glucocorticoids = steroids Steroids = biologically active organic compound with 4 rings arranged in a specific molecular configuration

Answer 17

2 principal functions = Important components of cell membranes which can alter membrane fluidity Are signalling molecules= Travel throughout body and become systemic quickly, Effective at spreading throughout body

Answer 18

In technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids(as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for "glucocorticoid"

Answer 19

Mineralocorticoids Are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance).

Answer 20

The primary mineralocorticoid is aldosterone

Answer 21

Glucocorticoids = can turn off immune system and are important for inflammation Mineralocorticoids= more important for calcium and sodium intake developed drugs that specifically target glucocorticoids and not mineralocorticoids.

Answer 22

Hormones are chemically and structurally diverse compounds. chemical messenger that circulates in body and effects on distant cells Quickly transported Body produces glucocorticoids to resolve inflammation glucocorticoids play a role in your body's natural anti-inflammatory resolution of inflammation - signalled through your hypothalamus

Answer 23

Divided into three main classes based on chemical composition: 1. the amino acid analogues, 2. the peptides, and 3. the steroids.

Answer 24

Amino acid hormones: are all derived from tyrosine and include epinephrine (Epi)and the iodothyronines or thyroid hormones.

Answer 25

peptide hormones: are subclassified on the basis of size and glycosylation state and may be single-or double-chain peptides.

Answer 26

steroid hormones:are all derived from cholesterol and may be subclassified as adrenal steroids or sex steroids, the former synthesized primarily in the adrenal cortex and the latter synthesized in the ovaries or testes

Answer 27

The endocrine system is a messenger system comprising feedback loops of hormones that are released by internal glands directly into the circulatory system hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, resolution of inflammation and mood.

Answer 28

Glucocorticoids can have many effects in body Pharmacovigeinelnece comes in Overuse = many systemic effects

Answer 29

All secreted steroids are synthesized from cholesterol, which itself can be synthesized de novo or derived from circulating lipoproteins. - also take in cholesterol from food so amount of cholesterol we take in will also affect ability to produce drugs, or glucocorticoids - can lead to overproduction Similar metabolic pathways mediate steroid synthesis in all organs. The organ-specific formation of secreted steroids depends on the presence of specific catalytic enzymes. The action of steroids is mediated largely by altering gene transcription through interaction with the deoxyribonucleic acid (DNA) of the promoter region of genes

Answer 30

CYP17 Cholesterol → aldosterone (mineralocorticoids) or cortisol (glucocorticoids)= cortisol → sex hormones Pregnenolone and progesterone into cortisol = by enzyme CYP17 (17 alpha-hydroxylase)

Answer 31

How does body signal cholesterol to turn into cortical steroids Need adrenal, pituitary and hypothalamus glands to signal this In vertebrates, the hypothalamus is the neural control center for all endocrine systems

Answer 32

During time of stress = stress, illness, hypoglycemia, hemmorage, injury, whatever Something signals into hypothalamus to produce CRH (corticotropin releasing hormone), Also produces AVP = arginine vasopressin CRH acts on pituitary gland = produces ACTH (adrenocorticotropic hormone) ACTH acts on adrenal gland = where cholesterol transformed and produces cortisol or glucocorticoids

Answer 33

CRH acts as peptide, 41 aa, prohormone produced in hypothalamus Pituitary gland promotes production of POMC Pomc = proopiomelanocortin processed to release acth CRH acts on g protein coupled receptors - CRHR1 and 2 in anterior pituitary to stimulate POMC synthesis

Answer 34

Pro homormone convertase ⅓ (PC1/3) sequentially cleaves POMC to pro ACTH → ACTH a

Answer 35

Body takes ACTH from pituitary to adrenal gland - on top of kidneys ACTH regulates glucocorticoid synthesis in adrenal cortex Specifically acts on one cortex ACTH regulations glucocorticoids synthesis in zonae fasciculata/reticularis

Answer 36

Encourages CYP11B1 and CYP17 to take cholesterol and produce it into cortisol CYP17 acts first = pregnenolone to 17 alpha-hydroxypregneneolone and then downstream = CYP11B1 acts at last step = 11-deoxycortisol to cortisol

Answer 37

ACTH = increases delivery of cholesterol to inner mitochondrial membrane Increases transcription of steroidogenic enzymes Important for production of pregnenolone - gets cleaved into cortisol

Answer 38

Functions like a feedback loop Stress= hypothalamus produces CRH → cortisol from adrenals Cortisol signals back to hypothalamus to stop producing CRH Feedback loop When reach threshold of cortisol = stops producing more Pathway affected when exogenous glucocorticoids

Answer 39

Hormones exert their effects by binding to and activating receptors on target cells.

Answer 40

These receptors can be located on the cell surface, as for peptide hormones, or within the cell, as in the case of steroids and thyroid hormones. Glucocorticoids block transcription - bind directly to dna

Answer 41

After receptor activation, intracellular signalling pathways (e.g., second messenger systems or ligand-activated transcription factors) are modulated, which acutely or chronically alter cellular physiology and potentially whole organism physiology

Answer 42

Are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. STeroid hormone receptors inside cells = must get inside Steroids = lipophilic - helps get through membrane

Answer 43

Up to 20% of all genes in immune cells are regulated by glucocorticoids Binds to dna via glucocorticoid receptor Can induce transactivation = Turn on genes OR transrepression No clear mechanism

Answer 44

IN CELL = chaperons that complex with steroid and allow it to go into nucleus Can eventually turn off inflammation = Not just through one mechanism - many different mechanisms Glucocorticoids can stop cytokine production, replication of t cells, many different immune responses

Answer 45

Changes in cell proliferation, survival, differentiation, migration Decreased pro-inflammatory cytokines, interleukins, prostaglandins DECREASE INFLAMMATION Inhibits innate and adaptive

Answer 46

Inhibits innate immune cells inhibiting these innate immune cells such as eosinophils or mast cells from producing, degranulating and producing lipid mediators such as arachidonic acid or leukotrienes or prostaglandins. But it also stops antigen presentation and proliferation of T cells, as well as the production of specific cytokines

Answer 47

Generally transcriptional activation Metabolic –increase glucose to protect the brain and heart (“fight or flight”) Increase blood glucose decreasing fat deposits (increased lipolysis) increased protein catabolism and decreased synthesis

Answer 48

increasing glycogen breakdown (glycogenolysis) increasing glucose synthesis (gluconeogenesis) Activate system = activate system so have more glucose available - more energy Can also cause weight gain

Answer 49

when someone is on oral contraceptives and they need to take glucocorticoids, the dosage would be different than someone who's not on oral contraceptives. Since affects biosynthesis pathway

Answer 50

Glucocorticoids are administered through most routes, but local administration is preferred to minimize adverse effects associated with systemic actions Since drugs can act on whole body

Answer 51

Circulating cortisol is 80%–90% bound to plasma proteins with high affinity to corticosteroid-binding globulin (CBG, transcortin), 5%–10% loosely bound to albumin, and 3%–10% as the free, active fraction Once glucocorticoids in system =can move through system by binding to CBG

Answer 52

CBG can also bind synthetic glucocorticoids such as prednisone and prednisolone, but not dexamethasone, resulting in almost 100% of plasma dexamethasone bioactive

Answer 53

Corticosteroid-binding globulin (CBG) transports glucocorticoids in the blood and thereby modulates the tissue availability of these hormones If need glucocorticoid to get to tissue - can be difficult if give it the drug iv or orally = First gets into systemic circulation and is bound to CBG and might not get to tissue Basically, binding to CBG helps transport the hormone but inflammation, stress, induced release of molecules like elastase releases the steroid from the complex

Answer 54

When giving someone a glucocorticoid the CBG binding and loss of bioavailability needs to be considered EX = mutation in enzyme that allows you to break CBG from corticosteroid, If cannot separate = cannot go into cell

Answer 55

Most glucocorticoids are absorbed rapidly and readily from the GI tract and from synovial and conjunctival spaces because of their lipophilic character, but they are absorbed very slowly through the skin. SOME ORgans absorb glucocorticoids easier

Answer 56

Elevated concentrations of estrogen, such as occurs in pregnancy, contraceptive use, or hormone replacement therapy, increase the biosynthesis of CBG in the liver, requiring increased plasma cortisol concentrations to maintain an appropriate bioactive fraction Need to give all info to doctors

Answer 57

Weight also matters Since lipophilic If obese = more fat = more lost from site you want it to go Circadian rhythm affects the drug Circadian rhythm is the name given to your body's 24-hour “internal clock.” Sleep = glucocorticoids shift up and then go down in morning

Answer 58

enhances glucocorticoid and mineralocorticoid activity Change at 9th position = Introduction of fluorine enhances mineralocorticoid, glucocorticoid activities

Answer 59

as present in betamethasone and dexamethasone increases GR activation and virtually eliminates MR activation, yet does increase the duration of action of these compounds a methyl group at position 16 of prednisone= increase glucocorticoid activation and eliminate any mineralocorticoid activation and increase duration of drug Change in 16th position = introduce methyl, minimizes mineralocorticoid activity in 9 alpha-fluoro compounds

Answer 60

Prednisone, prednisolone, and methylprednisolone have intermediate plasma half-lives, whereas betamethasone and dexamethasone are long acting analogues. - depends on disease Have been modified so cna last longer in system Modified also so will not eliminate or turn on production of mineralocorticoids

Answer 61

Inflammatory diseases of skin = eczema= Creams Asthma = Inhalation, Stop inflammation in lung (Only in lung)

Answer 62

Adrenal insufficiency occurs when the adrenal glands do not make enough of the hormone cortisol. The primary kind is known as Addison's disease. It is rare Give glucocorticoids to help, since they cannot produce own cortisol Good and helps since people are hypoglycemia = not enough sugar absorption

Answer 63

involve hormone replacement therapy to correct the levels of steroid hormones thebody isn't producing. Some options for treatment include oral corticosteroids such as: Hydrocortisone (Cortef), prednisone or methylprednisolone to replace cortisol. These hormones are given on a schedule to mimic the normal 24-hour fluctuation of cortisol levels. Fludrocortisone acetate to replace aldosterone

Answer 64

type of blood cancer that begin with an abnormal mutation (change) in stem cells in the bone marrow that leads to an overproduction of any combination of white cells, red cells and platelets - immune cells Reduces the side effects of have excess white blood cells= use glucocorticoids

Answer 65

Side effects = increase of hair, acne, greasy skin, irregular periods biosynthetic pathways of glucocorticoids are really similar to some of your sex hormones reduced fertility, tiredness and fatigue. And then on the other side, you also have increased appetite, weight gain, muscle weakness. And this is really dependent on if you have too low cortisol or if you have too high cortisol Psychiatric, neurologic, skin/soft tissue, musculoskeletal system. Developmental, endocrine, cardiovascular, immunologic, ophthalmic

Answer 66

Adverse Effects of Prolonged Glucocorticoids Therapy= Osteoporosis and fracture Glucose intolerance and diabetes Central obesity Muscle wasting Increased risk of infections Depression Cataracts

Answer 67

≥ 3 months -increase in fracture risk Because = taking glucocorticoids increases calcium absorption by gut and reduces it being exported into bones = fractures

Answer 68

doubled in rheumatoid arthritis patients taking ≥7.5 mg prednisone Since glucocorticoids increase glucose absorption

Answer 69

shut down of HPA axis and adrenal atrophy Hypothalamus turns off production of endogenous cortisols = effect body functions

Answer 70

Oral candidiasis (thrush)–Rinse mouth after inhalation Leads to immunosuppression in mouth = changes in salivary glands that protect mouth from infections HPA axis suppression–Uncommon with low or medium doses Growth inhibition–Pre-pubertal patients Decreased bone density Oral corticosteroids (e.g., prednisone)–Extreme cases–Short duration

Answer 71

if on glucocorticoids for prolonged period and high doses

Answer 72

Physical abnormalities individuals who either had some sort of allergic reaction or have an autoimmune disease that was ineffectively maintained with the specific drugs such as the ones that are blocking the cytokines or the T cell proliferation. So they're on glucocorticoids for months in high doses, milligram doses. = moon face, thickening of neck, gain weight - many side effects But need glucocorticoids to reduce inflammation

Answer 73

Cushing’s disease can be caused by issues with the body’s hormone signalling or from the overuse of steroids.

Answer 74

Have all of it ramped up = Cortisol Increases hypothalamus to produce more = can be caused by tumour in pituitary that does not stop feedback loop Cause different = pitautary ACTH dependent cushing syndrome Same effects as cushing's syndrome

Answer 75

Ectopic ACTH cushing syndrome External ACTH acts on adrenal and produced more cortisol and acts on hypothalamus

Answer 76

Adrenal adenoma = tumour in adrenal gland = production of more corticosteroids = no way to inhibit cycle

Answer 77

Exogenous glucocorticoids = reduce size of adrenal gland and need more and more hormones = iatrogenic cushing's syndrome Causes by exogenous glucocorticoids and loss of function of adrenal gland Phenotype same so hard to tell which kind of cushings it is