L17 Flashcards
What is the membrane derived molecule of important in anti-inflammatory drugs? What enzyme makes this?
Arachidonic acid
FROM membrane phospholipids w/ AA
Via phospholipase 2
What are the 2 generic names for Tylenol?
Acetaminophen
Paracetamol
What do you use acetaminophen to treat?
Pain
Fever
- Only weakly anti-inflam
Does acetaminophen have GI side effects?
NOPE
What 4 patient populations are specifically mentioned for acetaminophen use?
Kids
Pregnant women
Aspirin sensitivity
Patients on blood thinners (might be new genetic implications against this)
Which diseases are treated via acetaminophen for first line anti-inflam?
1. Osteoarthritis Others: Allergies: asthma Eye: conjunctivitis GI: IBD Neuro: cerebral edema Transplant: prevent rejection Skin: dermatitis & dermatoses
What can you combine acetaminophen with to enhance its pain killing effects (and in turn use less opiates)?
Codeine
Would you use acetaminophen for RA or a sprained ankle?
NO
Weak anti-inflam
What is the mechanism of action for acetaminophen?
Unknown
Reversible inhibition of COX
What is the most concerning side effect with acetaminophen? Explain the mechanism of action.
Liver toxicity
Acetaminophen + p450 –> NAPQI = toxic metabolite
How does acetaminophen affect Stevens-Johnson syndrome?
Causes SCAR
How can the liver deal with NAPQI? Explain both hepatocyte survival and death.
- Glutathione
- Might be gone/low if alcoholic
W/o you’ll get hetpaocyte damage. You can either:
- Fix the damage by inhibiting T cells: IL10 present
- TNF & IL1 beta present so you can’t change T cells and they induce hepatocyte apoptosis
- Glutathione
What is the body’s natural steroid? Where is it made? Under the influence of what hormone? When is it produced?
Cortisol = glucocorticoid
@ Adrenal cortex (zona fasiculata)
ACTH (adrenocorticotropic hormone) from pituitary gland
For ACUTE protection in emergency
What is the most potent analog of cortisol? Name its uses. Name the diseases it treats.
Dexamethasone
Anti-inflam & IMMUNOSUPRESS
1. RA/arthritis
2. Bacterial meningitis for immune suppression before general antibiotics
What is the effect of cortisol on cytokines produced?
↓TNF alpha & IL6 = pro-inflam
↑IL 10 = anti-inflam
What are the 4 possible mechanisms of cortisol at the DNA?
- DIRECT: binds gluco-corticoid receptor –> TF & binds DNA @ GRE (glucocorticoid response element) to promote synthesis of IL10/anti-inflam molecules
- DIRECT: binds GCR –> TF @ DNA non-GRE elements (other areas)
- INDIRECT: sequesters other TFs
- INDIRECT: with SRC1 (steriod receptor co-activator) changes histones via acetylating & deact enzymes
What are the 2 possible mechanisms of cortisol outside the DNA (non-genomic)?
- Interfere with membranes of the cell or mitochondria
2. Binds membrane GCPR
What glucocorticoid drug in the liver is converted by 3B-HSD? Name its uses.
Prednisone
Many things - Crohn’s when aspirin doesn’t work
What is lupus?
Autoimmune @ joints, organs, skin
Women
Butterfly rash
What do you use to treat lupus?
Flare ups - steroids
- Prednisone = immediate relief
Remission - NSAIDs
What are some side-effects of prednisone?
Weight gain - central obesity Osteoporosis Buffalo hump Can't sleep Etc, etc
Which glucocorticoid is used topically?
Betamethasone
Topical for skin rashes
When is betamethasone used as an injection?
MS flares
Babies - lung maturation
Asthma attack
What is the aerosol spray glucocorticoid? What is it used for?
Fluticasone (flonase)
Allergies!
What are DMARDs? What is unique about these vs NSAIDs? What are the 2 categories?
Disease modifying anti-rheumatic drugs
ALTERS the course of disease - slows/blocks progression (not a cure)
1. Small molecules
2. Biologics
Which diseases are DMARDs first line treatment for?
RA
Lupus
Crohn’s
Esp. methotrexate
What are 2 cytokines elevated in RA?
↑TNF & IL1 –> pro-inflammatory
What are the 2 small molecule DMARDs?
Methotrexate - first choice
Leflunimide
Explain the 2 effects of methotrexate.
1. High doses = chemotherapy No folic acid - X purine synthesis 2. Low doses - immune suppression No folic acid - adenosine accumulation Suppress T & B cells
What is leflunomide’s mechanism? Side effects?
X pyrimidine synthesis –> no DNA synthesis –> no T/B cell proliferation
Side effects - liver & blood toxicity
What are biologics/TNFs?
Biologic response modifiers
Stop inflammation by blocking TNF, one of the cytokines it upregulates, or other molecules of the inflammatory cascade (JAK, CD80/86)
What are the 4 important TNF blocking biologics?
Adali-mu-mab & inflix-imab
Etaner-cept
Goli-mu-mab
Infliximab: Mechanism Effect Drug composition Diseases used Fun facts
IN-FLIXI-MAB TNF alpha binder T cell death Chimeric Ab - 1/2 mouse RA, AS, Crohn's Use w/ methotrexate to decrease infusion reactions
Adalimumab: Mechanism Effect Drug composition Diseases used Fun facts
ADA-LIM-UMAB TNF alpha binder (sponge) Less T/macrophage fxn Monoclonal Ab RA, Crohn's, psoriasis
Etanercept: Mechanism Effect Drug composition Diseases used Fun facts
ETAN-ER-CEPT
Decoy TNF alpha recptor - binds what’s soluble
Less T/macrophage fxn
RA, Crohn’s, AS, etc
What are 2 biologics that bind IL6 and IL1 respective?
IL 6 = tocil-izumab
IL 1 = anak-inra
Monoclonal Ab
What are 2 biologics that inhibit T cells and B cells respectively?
Abatacept - inhibit T cells
- CD20 receptor = target
- Also used as cancer therapy
Rituximab - inhibit B cells
What is the biologic that blocks that JAK/STAT pathway?
TOFA-CITI-NIB
RA when methotrexate fails
Oral pill!!!
