Anti-inflammatory drugs and NSAIDS Flashcards
___ is the main precursor molecule on which COX enzymes act to produce prostaglandins and leukotrienes
Arachidonic acid (from cell membranes) is the main precursor molecule on which COX enzymes act to produce prostaglandins and leukotrienes
The products of the cyclooxygenase pathway include ___, ___ and ___
What are the functions of the products of the COX pathway?
The products of the cyclooxygenase pathway: prostacyclin (PGI2), thromboxane (TXA2) and prostaglandins (D2 and E2)
Prostacyclin inhibits platelet aggregation/promotes vasodilation (recall that this is produced by the endothelial cells)
Thromboxane promotes platelet aggregation (produced by platelets)
Prostaglandins (PGD2 and PGE2): promote increased vascular permability and fever
___ are the body’s natural downregulators of inflammation
The action of glucocorticoids include ___, downregulation of cytokines and ___ activity
Glucocorticoids
Inhibition of Phospholipase A2, downregulate cytokines directly by acting on immune cells, and transcriptionally downregulate synthesis of COX
Generally, how do glucocorticoids downregulate inflammation?
In general, glucocorticoids will upregulate inhibitory processes (like apoptosis or Treg cells which produce anti-inflammatory cytokines), and downregulate either the production of pro-inflammatory cytokines or the number of effector cells – as in the case with mast cells and basophils)
The anti-inflammatory cytokines that are upregulated are ___, while IL-2, ___, 12, ___ and TNFa are all downregulated
The anti-inflammatory cytokines that are upregulated are IL-10, while IL-2, 6, 12, IFNy and TNFa are all downregulated
The direct mechanisms of action of glucocorticoids include binding to transcription factors, ___ or ___
Indirectly, glucocorticoids can also ___ or sequester other transcription factors
Steroids can bind to transcription factors to repress transcription, or sit directly on DNA on glucocorticoid response elements, or bind to membrane receptors
Indirectly, glucocorticoids can also modify of histone acetylating and deacetylating enzymes or sequester other transcription factors
___ is the most potent of all steroids and is generally immunosuppressive and anti-inflammatory
Dexamethasone
(Dexter, boy genius! figured out how to suppress inflammation+ the immune system!) the best there is i.e. most potent
___ is given as a pro-drug, prednisolone (cleaved and activated by ___) and is generally anti-inflammatory and used in autoimmune diseases such as Crohn’s disease
Prednisone is given as a pro-drug, prednisolone (cleaved and activated by 3b-hydroxysteroid-dehydrogenase (3b-HSD) in the liver) and is generally anti-inflammatory and used in autoimmune diseases such as Crohn’s disease
In general, Crohn’s disease is a type of inflammatory bowel disease that affects which parts of the GI tract?
Almost everywhere. **Note also that this is an autoimmune disorder**
Prednisone is also used for ___, an autoimmune disorder characterized by DOPAMIN RASH characteristics
Prednisone is also used for systemic lupus erythematosus (SLE), an autoimmune disorder characterized by DOPAMIN RASH characteristics
___ is primarily used for skin irritation but can be chemically modified and given IV for MS flares, or in premature babies to promote lung maturation
Betamethasone is primarily used for skin irritation but can be chemically modified and given IV for MS flares, or in premature babies to promote lung maturation
(beta-get that skin fixed; beta lungs in premie babies and beta for MS flares)
___ is primarily used for allergic rhinitis (you’ve used this before) and is a pretty potent anti-histamine
Fluticasone/flonase is primarily used for allergic rhinitis (you’ve used this before) and is a pretty potent anti-histamine
(something about somebody tryna play the FLUT -as in fluticasone- with their NOSE - as is rhinitis, also as in sone spelled different)
What are DMARDS and what conditions are they used to treat generally?
Disease-modifying anti-rheumatic drugs
Generally used for rheumatoid arthritis, and other inflammatory conditions that affect the joints
Describe the priming and effector phases that result in RA
Which 2 cytokines are produced that are the main targets of biologics?
Naïve T cells get primed and become helper T cells. Th2 cells interact with B cells which will release autoantibodies, and Th17 will release IL-17 which is very pro-inflammatory
*IL6 and TNFa are also produced priming/effector phase, and are the main targets of biologics*
Which DMARD was originally used for chemotherapy but works to reduce inflammation and joint damage in RA when used in low doses?
Methotrexate
**if you’re doing to do drugs, it has to be METH and apparently you can combine it with other drugs! It used to be used for cancer, turns out just a little bit (at low doses) can treat rheumatoid arthritis (reduce inflammation + joint damage)**
What is the mechanism of action of methotrexate?
Likely the accumulation of adenosine (folic acid metabolism) which prevents the activation and proliferation of B and T cells
(recall that it messes up purine biosynthesis in bugs and is given for that reason)
**METHotrexate don’t like that FOLATE so ade-no where you gon get more B and T cells from now**
___ can be used alone or with methotrexate, and works by inhibiting pyrimidine synthesis (and thus dna), thereby blocking lymphocyte proliferation
Leflunomide (ARAVA) can be used alone or with methotrexate, and works by inhibiting pyrimidine synthesis (and thus dna), thereby blocking lymphocyte proliferation
**LEF(t)enant = 2nd to the captain (can be used a 2nd line of defense, also used with methotrexate) block pyriMIDine synthesis**
Which sulfa drug is used in the treatment of rheumatoid arthritis and of arthritis associated with ankylosing spondylitis and inflammatory bowel disease (ulcerative colitis and Crohn disease)?
Sulfasalazine (Azulfidine)
**the blue drug that likes to sul(f)a but it can’t because its got ankylosing spondylitis and IBD so it always has to go to the bathroom**
____ was originally developed as an antimalarial and can treat RA (early in the course)? *note that chronic use of this is toxic to the retina*
Hydroxychloroquine (Plaquenil) was originally developed as an antimalarial and can treat RA (early in the course)? *note that chronic use of this is toxic to the retina*
**if you chronically go to the pool (hydro + chlorine) your eyes start to burn b/c the hydroxychloroquine is toxic to the retina**
What are the 3 cytokines primarily targeted by most biologics?
Primarily inhibiting IL1, IL6 and TNFa
Etanercept, Golimumab, Adalimumab, Certolizumab, Infliximab all inhibit which pro-inflammatory cytokine?
All inhibit TNFa
IL1 is inhibited by ___ and ___ and IL6/IL6 receptor are inhibited by ___
IL1 is inhibited by Anakinra and Canakinumab, and IL6/IL6 receptor are inhibited by Tocilizumab
**Anakinra - sounds like ankara but is often mispronounced; number 1 cloth there is
Canakinumab - a tribe where the ankara came from? Idk. Probably also the number 1 tribe**
**Tocilizumab - “To Kill Ze Mob”, errbody in there is a devil worshiper (remember the #triple6sign)**
What is the mechanism of action of etenarcept (enbrel)?
Blocks TNF signaling by binding it (basically it’s a fake TNF receptor – fusion protein made from rDNA coding for the TNF receptor + human IgG1)
**etenercept is fake TNF**
___ is also a chimera that binds to both soluble and membrane-bound TNFa and induces programmed cell death of T-activated lymphocytes
Infliximab (Remicade) is also a chimera that binds to both soluble and membrane-bound TNFa and induces programmed cell death of T-activated lymphocytes
**binds both soluble and membrane bound bc its inflixed aka conflicted**
___ is the monoclonal antibody (mAb) binds to soluble TNFa, thereby downregulating macrophage and T cell function
Adalimumab (Humira) is the monoclonal antibody (mAb) binds to soluble TNFa, thereby downregulating macrophage and T cell function
**Adalimumab - Ada don’t got no Abs (A for alpha as in TNFalpha) so her belly stay swishing and swashing and looking soluble, not solid**
The characteristics that define NSAIDs include being analgesic, ___, ___ and anti___
The characteristics that define NSAIDs include being analgesic, anti-inflammatory, anti-thrombotic and anti-pyretic
**note that COX2 inhibitors don’t exert anticoagulant effects but COX1 inhibitors do**
The prostanoids include ___ (involved in platelet aggregation), ___ (made by endothelial cells to inhibit) platelet aggregation, and ___
The prostanoids include thromboxane (TXA2) (involved in platelet aggregation), PGI2/prostacyclin (made by endothelial cells to inhibit) platelet aggregation, and prostaglandins
(think of taking two taxis with your two pigs, one for each, otherwise you’d have to cycle and you won’t be glandin’ about that)
Prostaglandins include PGE1, ___, ___, ___ and ___ (the last 2 are short lived)
All the prostanoids are synthesized from the short-lived precursor ___
Prostaglandins include PGE1, PGE2 (fEver), PGFa, PGH2 and PGJ2 (the last 2 are short lived)
All the prostanoids are synthesized from the short-lived precursor PGH2
Name the enzymes through which the following prostaglandins are synthesized:
PGI2
TXA2
PGE2
PGFa
PGD2
PGI synthase
TX synthase
mPGES1
PGF synthase
L/H/PGD synthase
(she said not to focus on PGD2 but you need to know it for step)
___ is a constitutively active cyclooxygenase enzyme (although it can be induced in the brain) and is the only COX enzyme in platelets
COX 1 is a constitutively active cyclooxygenase enzyme (although it can be induced in the brain) and is the only COX enzyme in platelets
(note that if you’re using a COX2 inh, you can still have effects from COX1 because it’ll still be active)
___ is the inducible cyclooxygenase enzyme but is constitutive in the brain. It’s activity is stimulated by cytokines and the production of PGE2 is tightly linked to the upregulation of this enzyme.
COX2 is the inducible cyclooxygenase enzyme but is constitutive in the brain. It’s activity is stimulated by cytokines and the production of PGE2 is tightly linked to the upregulation of this enzyme.
What type of NSAID are aspirin and diflusinal?
Salicylate
(if Saly’s late and she takes aspirin, she gets diflusinal)
The proprionic acid derivative types of NSAIDs include ___ and ___
The proprionic acid derivative types of NSAIDs include ibuprofen and naproxen (the ones that end in “en”)
What type of NSAID is indomethacin?
Indole derivative (indo for indole derivative)
**note that this is Rx only and mainly used in the hospital**
Examples of oxicam NSAIDs are ___ and ___
Peroxicam and meloxicam (literally anything that has an oxycam in its name, although I oxy-can’t with these lectures :/ )
What is an example of a Cox 2 inhibitor?
Celecoxib/celebrex
(celebrate inhibiting Cox 2)
T/F: Tylenol is a strong anti-inflammatory NSAID
Falsehood. Acetaminophen is NOT an NSAID, although its used like an NSAID. It’s weakly anti-inflammatory
**note that its used frequently in children to prevent Reyes syndrome**
The primary side effect of acetaminophen is___, caused by the formation of the harmful intermediate ___
Hepatotoxicity (exacerbated with combined alcohol use)
NAPQI (recall that this is also the same intermediate that forms in glutathione conjugation if there’s not enough glutathione. NAPQI is dangerous to hepatocytes)
How is NAPQI harmful to the liver?
NAPQI causes reduced expression of CD44 on T cells >> apoptosis of hepatocytes
(see image below)
The main mechanism of action of aspirin is___
The main mechanism of action of aspirin is inhibition of cyclooxygenase enzymes.
**note that at low doses, aspirin only inhibits COX1, whereas at higher doses it inhibits both COX 1 and 2**
Why do the effects of aspirin on platelets last a long time?
Aspirin covalently inhibits the COX enzymes (which is irreversible) so its effect lasts up until the life of the platelets)
Why would you have to discontinue using aleve or ibuprofen before surgery? The main difference between the two is ___
They both inhibit clotting
Half life and duration of action
___ is used to delay premature labor and is contra-indicated in people with GI diseases (causes GI and CNS side effects)
Indomethacin
**you indn’t want to have your baby early coz you’ve been doing meth**
Generally, oxicams are used to treat ___. In particular, ___ is given for oestoarthritis because it has less effects on the GI tract and at lower doses, is a highly selective COX2 inhibitor
Generally, oxicams are used to treat arthritis. In particular, meloxicam is given for oestoarthritis because it has less effects on the GI tract and at lower doses, is a highly selective COX2 inhibitor
___ is a phenyl acetic acid derivative that’s used in eye drops (also anti-inflammatory and sometimes used post op)
Ketorlac is a phenyl acetic acid derivative that’s used in eye drops (also anti-inflammatory and sometimes used post op)
Ketor lacs an eye (he’s a one-eyed monster but he’s got 20/20 vision tho)
___ is used for arthritis but has GI effects so it isn’t prescribed much
Tolmetin
(tol much etin is bad for gut but helps your joints)
Diclofenac is used post-op/post-trauma, for ___ and ___
Diclofenac is used post-op/post-trauma, for acute migraines and dysmenorrhea
**the D is for dysmenorrhea** (and then i guess you just have to remember migraines)
Some of the side effects of NSAIDs in the following systems are___:
GI
Blood
Uterine
Liver
Renal
Increased bleeding time and blood loss happens due to decreased thromboxane
Gastritis/ulceration, renal involvement, delayed parturition + dystocia occur due to decreased PGE2 and PGI2 (which are gut protective I think), as well as decreased PGF2a
*Liver toxicity is not by the same mechanism as Tylenol*
What are SCARs?
Severe cutaneous adverse reactions are those that can cause permanent damage such as disfigurement, blindness and death, and are directly tied to the specific drug
The most severe type of SCAR is ___ which is characterized by a life threatening skin condition (similar to TEN, toxic epidermal necrolysis) in which cell death causes the epidermis to separate from the dermis. Common sites of lesions are in mucosal membranes.
The most severe type of SCAR is Stevens-Johnson syndrome which is characterized by a life threatening skin condition (similar to TEN, toxic epidermal necrolysis) in which cell death causes the epidermis to separate from the dermis. Common sites of lesions are in mucosal membranes.
Another SCAR associated with NSAIDs is ___
Spontaneous abortion
What are the effects of aspirin intoxication? (from pro-longed use)
(see image below)
What are the mechanisms of signaling for the receptors for the the following prostanoids?
PGI2
PGE2
PGFa
TXA2
PGE2 acts thru 4 different receptors; mainly thru EP4 and EP2 which are synergistic and increase cyclic AMP;
PGI2 also works through increasing cAMP signaling
PGE2 can also work thru EP3 which has varied effects (increasing Ca2+ signaling and modulating cAMP signaling)
TXA2 works through TPa/b (which works the same way as EP3)
(see image below)
**note that the receptors are all GPCRs**
What are the analogs for the following:
PGE1
PGE2
PGF2a
Misoprostol = PGE1 (you’re the 1st to get to the restaurant so you order miso soup for the table)
Dinoprostone = PGE2 (dinoprostonE for E2)
Dinoprost = PGF2a (stimulates uterine contraction) (dinoFrost)
The following prostanoid analogs are for which specific prostanoids?
Carboprost
Epoprostenol
Latanoprost, Travoprost
Carboprost = PGF2a **carboFrost**
Epoprostenol = PGI2 (prostacylin) (epopro-stacyclin-ol)
Latanoprost, Travoprost = PGF2a *something about the kid with the weed and being given glaucoma, refer back to text*
Misoprostol is used for what?
Misoprostol – prevents NSAID induced gastric ulcers. Also used for labor induction (miscarriage to contract te uterus stop bleeding, abortifacient- but not to be confused with Mifepristone, a PR antagonist). Can sometimes be used together for voluntary abortion.
**mis for miscarriage, -ol b/c you lose all the church’s respect coz you had an abortion, the l is for labor**
___ is used for cervical ripening (Cervidil) and ___ is for labor induction
Dinoprostone – cervical ripening (Cervidil) (you’re stoned so you’re ripe for that thing to just slide outa there)
Dinoprost – labor induction (so you can start to get that thing out - dinoprostart)
What are the following used for?
Carboprost
Epoprostenol
Latanoprost, Travoprost
Carboprost – post-partum hemorrage
Epoprostenol – vasodialator, used in pulmonary hypertension if other treatments fail
Latanoprost, Travoprost – glaucoma
