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What are the 3 major pathways involved in Arachidonic Acid metabolism and what do they generate?
- 5-LOX (lipoxygenases) --> leuokotrienes
- COX --> prostanoids
- CYP450 --> epoxyeicosatrienoic acid
What is released from membrane phospholipids by the hydrolyzing action of phospholipases?
What are the two ultimate products of archidonic acid metabolism into prostanoids after being metabolized by COX?
Where do you find COX-1 and what happens when it is inhibited?
- Found in most tissues
- Inhibition leads to GI, renal, and other toxicities
Where do you find COX-2?
Neurons, kidney, bones, reproductive tissues, and some cancers
Which COX (1 or 2) is inhibited by inflammatory cytokines?
- COX-2 is highly induced (10-10,000 fold by IL-1 and TNF)
- COX-1 shows no induction
Why don't we care about COX-3?
No "functional" COX-3 in humans; in dogs, yes
Which of the pathways in AA metabolism is inhibited by inflammation?
Only COX (cyclooxygenase)
What are the first two products of COX metabolism of AA?
- Prostaglandin G2
- Prostaglandin H2
What stimulates COX-1 to syntehsize prostaglandins?
Circulating hormones; normal renal function, homeostasis, gastric mucosa integrity
Salicylates, APAP, and NSAIDs are responsible for what percentage of adverse drug events?
Salicylates, APAP, and NSAIDs are minor analgesics that are good in relieving pain from _____ and _____?
Injury or inflammation
Antiinflammatory drugs inhibit _____ at the site of _____
Analgesia - inhibits _____ production that sensitizes pain receptors
Antipyretics inhibit _____ production in the _____ as a response to bacterial pyrogens and IL-1
Prostanoid; CNS (hypothalamus)
_____ induces neurotransmitters, such as cAMP, to reset the body's temperature set point in response to bacterial pyrogens. This causes _____, _____, and _____.
- Fever; somnolence, lethargy
Where are NSAIDs normally absorbed?
Upper small intestine
What percentage of NSAIDs are bound to albumin plasma proteins?
What are the main enzymes that metabolize NSAIDs in the liver?
UGT and SULT
How are NSAIDs excreted?
- Renally - filtration and active transport
- SOME hepatic elimination
What is the most common effect of NSAID toxicity?
- Gastric or intestinal ulceration
- (PGE2 actively promotes protective gastric juices, which are inhibited by taking NSAIDs)
H2 blockers (ranitidine) are not effective at preventing gastric ulceration, but PPIs can be effective prophylactically or as treatment.
Another treatment is _____, which is a PGE2 analog
Renally, what can happen because of NSAID toxicity?
- Decreased blood flow
- Increased hypertension
- Increased retention of water, Na+, K+
NSAIDs can inhibit TxA2, which can be a problem. Why?
Causes problems with platelet aggregation, bleeding
What is the COX-2 hypothesis?
Selective COX-2 inhibitors should cause less GI ulcerations than non-selective COX inhibitors
Historically, where do salicylates originate?
- Willow Bark
- Oil of Wintergreen
Salicylic acid inhibits _____ in vivo, but doesn't inhibit _____ in vitro.
Aspirin inhibits TxA2 production, which results in what?
Irreversible decreased platelet aggregation, bleeding
What is unique about aspirin's half-life?
What is a unique, non-dose-dependent AE occasionally seen in aspirin?
What is Reye's Syndrome and when might it occur?
Sudden loss of consciousness, cerebral edema, fatty liver and renal tubules, brain damage upon recovery
Salicylates in conjunction with chickenpox or flu
What might happen in pregnant women taking aspirin?
Premature closure of ductus arteriosus
APAP has very little _____
What enzyme metabolizes APAP after it has saturated the UGT and SULT pathways?
What are 2 ways to induce CYP 2E1?
What are 2 treatments for APAP hepatotoxicity?
- Activated charcoal
APAP is not an effective antiinflammatory, but has antipyretic and analgesic properties. It primarily acts where?
In the CNS
NSAIDs function as competitive inhibitors of what?
Arachidonate (AA) binding sites
NSAIDs reversibly/irreversibly inhibit platelet aggregation.
NSAID drug of choice due to low toxicity - metabolized by CYP 2C9 (which it also inhibits)
NSAID of choice due to low toxicity profile - LONG t1/2
Drug of choice for gout - frequent adverse effects (35-50%)
Available with misoprostol (Arthrotec) to decrease GI toxicity
The only NSAIDs that appear that appear to be effective for the regression of colorectal polyps
Sulindac and celecoxib
Only for analgesic purposes, but too toxic for extended use
Can be as effective as opiates for pain, high GI toxicity
Name the 2 Class I salicylates.
Name the Class II para-aminophenol.
Name 5 Class III traditional NSAIDs.
Name the Class IV (COX-2 selective inhibitor)