MSK Pharm from FA Flashcards
Lipoxygenase pathway yields what (generally)?
Leukotrienes
(remember Lipoxygenase and Cycloxygenases both come from Arachidonic acid)
Name the 4 leukotrienes in FA. What do they do?
LTB4: attracts neutrophils (“neutrophils arrive B4 others”
LTC4, LTD4, LTE4: incr bronchial tone, vasoconstriction, incr vascular permeability
what products come from the Cycloxygenase pathway?
Prostacyclin, Prostaglandins, Thromboxane
-these moderate vascular, bronchial, & uterine tone in different ways.
PGI2: what is it/what does it do?
what cell/tissue releases it?
Prostacyclin from COX pathway
anticoagulation & vascular dilatation
(decreases these: platelet aggregation, vascular tone, bronchial tone, uterine tone)
Released by endothelial cells. Kind of opposes TXA2 from platelets.
PGE2, PGF2a: what do they do?
Increase uterine tone
decrease bronchial tone
TXA2: what does it do?
what cell/tissue releases it?
(Thromboxane)
incr platelet aggregation, incr vasoconstriction, incr bronchial tone
Released by platelets. Kind of opposes PGI2 from endothelial cells.
Aspirin: mech?
Irreversibly inhibits COX1 and COX2 via covalent acetylation.
–> decr synthesis of TXA2 and Prostaglandins.
Effect: incr bleeding time until new platelets are synthesized (~7d).
Aspirin: effect on PT? PTT?
None.
only affects bleeding time.
Aspirin: use (3 dose levels)?
Low dose: decr platelet aggregation (<300mg)
Medium dose: anti-fever, analgesic
High dose: anti-inflammatory (>2400mg)
Aspirin: tox (adults)?
Gastric ulcers
Tinnitus (CN VIII)
Chronic use: renal failure, interstitial nephritis, upper GI bleeds.
Stimulates resp centers -> hyperventilation and resp alkalosis.
Aspirin: tox (children)?
Risk of Reye syndrome for kids treated with aspirin for viral infection.
(rash/vomiting/liver damage)
COX 1 preferentially expressed where?
GI tract, platelets
COX 1 blockers: general side effects?
GI ulceration, bleeding
COX 2 receptors preferentially expressed where?
sites of inflammation
advantage to COX 2-specific blockers?
avoid side effects of COX1 (ulceration, bleeding)
Class?
ibuprofen, naproxen, aspirin, indomethacin, ketorolac, diclofenac
NSAIDs
NSAIDs: mech?
reversibly inhibit COS1 and COX 2.
Block prostaglandin synthesis
exception: aspirin = IRREVERsible block.
NSAIDs: use?
anti-fever, analgesic, anti-inflammatory
Indomethacin: unique use beyond usual NSAIDs use?
Close PDA
NSAIDs: tox?
interstitial nephritis, gastric ulcer, renal ischemia
how do NSAIDs cause gastric ulcers?
renal ischemia?
NSAIDs block prostaglandin synth
–>PGs protect gastric mucosa against ulceration
–>PGs vasodilate afferent arteriole
Name a COX-2 specific blocker?
celecoxib
celecoxib: Mech?
reversibly inhibit COX-2 (found in inflammatory cells and vasc endothelial cells).
Mediates inflammation and pain
does NOT block COX1 -> spares gastric mucosa.
celecoxib: effect on platelet function?
None because TXA2 production is dependent on COX1, not COX 2.
celecoxib: Use?
Rheumatoid arthritis, osteoarthritis
(esp patients with gastritis or ulcers)
celecoxib: tox?
incr risk of thrombosis
sulfa drug: watch out for allergies
Acetaminophen: mech?
reversibly inhibits COX, mainly in CNS
inactivated in periphery
Acetaminophen: use?
anti-fever
analgesic
NOT anti-inflammatory
Acetaminophen: use specific to children?
children with viral illness: don’t give aspirin due to possible Reye’s (brain swelling -> encephalopathy & liver damage)
use acetaminophen instead
Acetaminophen: tox?
OD -> hepatic necrosis (metabolite from acetaminophen = NAPQ1; depletes glutathione -> causes liver toxicity)
Acetaminophen: antidote to an OD?
N-acetylcysteine
mech: regenerates glutathione in the liver
Bisphosphonates (alendronate, -dronates): mech?
inhibit osteoclast activity
pyrophosphate analogs; bind hydroxyapatite in bone, thus inhibiting osteoclasts
Bisphosphonates (alendronate, -dronates): use?
Osteoporosis
hypercalcemia
Paget disease of bone
Bisphosphonates (alendronate, -dronates): tox?
- Corrosive esophagitis (ie pill esophagitis; take water w pill and don’t lie down for 30 min)
- Osteonecrosis of the jaw
Name 3 preventive gout drugs.
generally what is their mech?
Allopurinol, Febuxostat, Probenecid
A, F: interrupt the process of Purine metabolism -> less uric acid in blood
Allopurinol, Febuxostat: mech?
(gout drugs)
Inhibit xanthine oxidase
-> less uric acid in blood
Allopurinol: why do we give this to people with leukemia/lymphoma?
- decreases the destruction of azathioprine and 6-MP (which are normally degraded by xanthine oxidase)
- prevents urate nephropathy from tumor lysis
what do we NOT give to pts with chronic gout?
Salicylates (aspirin)
they decrease clearance of uric acid
Probenecid: mech?
(gout drug)
inhibits reabsorption of uric acid in PCT
(also inhibits secretion of PCN)
3 drugs we give for acute gout?
NSAIDs (naproxen, indomethacin)
Glucocorticoids (oral or right into the joint!)
Colchicine
Colchicine: mech?
binds/stabilizes tubulin
- > inhibits microtubule polymerization
- > decr leukocyte chemotaxis and degranulation
Colchicine: tox?
GI side effects
given in escalating doses until the patient can’t handle the GI issues
3 TNF-a inhibitors?
what are they for, generally?
Etanercept
Infliximab
Adalimumab
-Used for autoimmune diseases (RA, ank spond, IBD etc)
Etanercept, Infliximab, Adalimumab: tox?
- > increased infection since TNF blockers prevents activation of macrophages and destruction of phagocytosed microbes
- > reactivation of latent TB
Infliximab, Adalimumab: mech? use?
anti-TNFa monoclonal antibody
PAIR: Psoriasis, Ank spond, IBD, RA
Etanercept: mech? use?
decoy TNF receptor
fusion protein produced by recombinant DNA: receptor for TNF-a + IgG Fc region)
Use (PAR): Psoriasis, Ank Spond, RA
Antidote for acetaminophen tox?
How does it work (2 mechs)?
N-acetylcysteine
- regenerates glutathione -> allows NAPQI (toxic metabolite) to be cleared
- donates sulfhydryl groups -> increases amt of acetaminophen that can be metabolized
* Normally Acetaminophen is 90% metabolized by sulfation and glucuronide conjugation. 10% turns into NAPQI (via CP450 system, toxic, requires glutathione to be cleared). In overdose, NAPQI increases -> centrilobular necrosis.*
