E2: NSAIDs and Acetaminophen Flashcards
What are the 4 signs of inflammation?
Erythema (rubor)
Edema (calor)
Tenderness (tumor)
Pain (dolor)
Which 2 inflammatory mediators have opposite effects? Describe them.
Thromboxane: Vasoconstrictor, promotes platelet aggregation
Prostacyclin: most effective vasodilating agent and inhibitor of platelet aggregation
Must obtain a balance between the two!
Leukotrienes are responsible for what effect in the lungs?
Bronchospasm
MOA for Aspirin (ASA, Acetylsalicylic acid)
Nonselective, irreversible inhibitor of COX-1 and COX-2
After being orally ingested, where does the distribution of aspirin occur? How does ASA cross the placental barrier? BBB?
Throughout the entire body (includes tissues and extracellular compartments)
READILY crosses placental barrier
Slowly crosses blood brain barrier
Why is plasma concentration of ASA low?
Rapidly hydrolyzed in the plasma, liver, and erythrocytes
What kinetics does ASA follow at low doses? High doeses?
Low doses: First order kinetics
High doses (above 600mg): Zero order kinetics
How is ASA excreted? What can increase excretion?
Renal excretion
-Alkalization of the urine promotes excretion
What are 6 primary effects/uses of ASA?
- Anti-inflammatory effect
- Analgesic effect
- Antipyretic effect
- Decreases incidence of MI (thrombosis prophylaxis)
- Long term use decreases incidence of Colon CA
What is an adverse effect of ASA use? (Describe the process)
Respiratory alkalosis -> metabolic and respiratory acidosis
What effect does aspirin (NOT salicylic acid) have on platelets and how does this affect bleeding time? How long does this effect last?
ASA inhibits the platelet aggregation, therefore increasing the bleeding time.
Effect can last as long as 8-10 days
Aspirin should be avoided in patients with any of the following conditions (4):
Hypoprothembinemia
Vit K deficiency
Hemophilia
Severe hepatic damage
Aspirin should be discontinued how long in advance prior to elective surgery?
At least one week prior
Should also be avoided in last 3 months of pregnancy to avoid post-partum bleeding
Uricosuric effects of aspirin are _____ and ____ dependent.
Biphasic and dose dependent
How does aspirin affect uric acid excretion and plasma urate concentration at low doses? How about high doeses?
Low (1-2 g/day): DECREASES UA excretion, ELEVATES plasma urate conc.
High (5+ g/day): ENHANCES UA excretion, LOWERS plasma urate conc.
What adverse affect can aspirin have on the lungs?
Aspirin asthma (increased leukotriene synthesis)
What are 4 adverse effects of aspirin on the GI system?
GI upset
Gastritis
Ulcer (increased gastric acid production)
Bleeding
What are 4 severe effects of aspirin on the kidneys?
Renal damage
Acute renal failure
Interstitial nephritis
Nephrotic syndrome
Know this one!
What effect does salicylic acid (NOT aspirin) have on the skin? How can this be used therapeutically?
- Irritant to skin and mucosa (destroys epithelial cells)
- Keratolytic effect is used to remove warts, corns, fungal infection, etc.
How much salicylic acid is required for a fatal dose (acute poisoning)?
10-30 g of aspirin
What is Reye’s syndrome? What is the DOC for children w/ fever?
Reye’s: Cerebral edema in children with viral infections
Give them acetaminophen for fevers instead
How is ASA different from all the other NSAIDs?
ASA is IRREVERSIBLE, all other NSAIDs are reversible!
How do nonacetylated salicylates differ from ASA?
- Salicylic acid is active drug
- Effective anti-inflammatory, but less effective analgesic than aspirin
- No irreversible COX inhibition
MOA of Celecoxib (Celebrex)
Selective COX-2 inhibitor (REVERSIBLE)
Celebrex has less potential to cause this condition, but increased risk of developing another:
Less gastropathy and risk of GI bleeding (although still on FDA label)
Increased risk of cardiovascular dz!
What are 4 adverse reaction of Celebrex?
Ulceration
Bleeding
Hypersensitivity
Increased risk of CVD
Celebrex is C/I in the following populations: (5)
GI disease Asthma Breast feeding Pregnancy Renal failure
List the 3 effects of the COX-1 enzyme.
-Protects against gastric irritation
- Promotes platelet aggregation (TXA2)
- Vasoconstriction (TXA2)
List the 3 effects of the COX-2 enzyme.
- Vasodilation (PGI2)
- Inhibits platelet aggregation (PGI2)
-Promotes inflammation
MOA of Nonspecific COX inhibitors.
MOA: REVERSIBLY inhibit both COX enzymes (some may show slight specificity towards COX-2)
What is the drug of first choice for nonspecific COX inhibitors? What is the worst (but potent) drug?
Best: ibuprofen
Worst: Indomethacin
List the 7 areas of typical toxicities for the nonspecific COX inhibitors.
- GI - pain, bleeding, ulcer, diarrhea, pancreatitis
- CNS - depression, HA, dizziness
- Lung - bronoconstrction
- Bone marrow - Agranulocytosis, aplastic anemia
- Nephrotoxic
- Hepatotoxic
- Hypersensitivity rxns
Aside from inhibition of COX enzymes, what are the 2 other MOAs for Indomethacin?
- Reduce polymorphic nucleotide migration (immune system activation)
- Inhibit phospholipase A (which reduces release of Pge)
*Very potent = lots of SE
What is the primary use of indomethacin?
Tx of patent ductus arteriosus
Aside from being a potent COX inhibitor, what is another MOA of Diclofenac (Voltaren)?
Decreases arachidonic acid bioavailability
What are the primary side effects associated with Diclofenac and how can this be avoided?
GI side effects
Combine with misoprostol
What is the primary use of Ketorolac (Toradol)? When should this med be discontinued?
Used as analgesic in post-surgical pain (can be combined with opioids)
Frequent GI effects after 5 days of use
Which NSAID is the DOC and has the lowest incidence of side effects?
Ibuprofen
Ibuprofen in combination with ASA will have what affect?
Decreases the effect on platelet aggregation
How is ibuprofen excreted?
Renal excretion
What are some adverse effects of ibuprofen?
Overall, toxicity is low!
- N/V, diarrhea, constipation, heartburn
- GI bleeding
- Dizziness, light headedness, HA, etc.
What is the mean plasma half-life of naproxen?
13 hours (take once a day)
Where is naproxen primarily excreted?
Largely in the urine
Naproxen is C/I in what pt population and why?
Pregnancy - crosses BBB
Why does naproxen have drug interactions? Name 2 examples.
Naproxen extensively bound to plasma proteins so displacement causes adverse drug rxns
Ex: oral anticoagulants, hypoglycemic agnets
List 5 adverse effects of naproxen.
GI upset Heartburn/dyspepsia Abd pain Constipation/diarrhea Gastric bleeding (but less than ASA!)
What 2 medications have a long half-life and high incidence of GI effcts?
Piroxicam and Meloxicam
MOA for Piroxicam and Meloxicam (3)
Inhibits PMN migration and lymphocyte function
Decreases oxygen radical production
Which NSAID is very potent but with serious side effects? (No longer prescribed in US)
Phenylbutazone
Why is acetaminophen preferred over ASA?
- Better tolerated
- Lacks several SE of ASA (ex: PUD, inhibition of blood clotting, etc.)
What is one potentially fatal side effect of acetaminophen?
Fatal hepatic necrosis (overdose)
What is the half life of acetaminophen? Where is it metabolized and where is it excreted?
T1/2= 2-3 hours
Metabolzied by liver, excreted by kidney
What are the 2 pharmacodynamic properties of acetaminophen? What 2 pharmacodynamic properties is it lacking?
Antipyretic action
Analgesic action
*NO anti-inflammatory action or platelet effects
What are 4 uses of acetaminophen?
Mild-moderate pain
Fever (CHILDREN)
Adjunct to anti-inflammatory therapy
Combined w/ codeine, sedatives, cough suppressants, etc.
List 4 adverse effects of acetaminophen.
Skin rash
Cross-sensitivity with salicylates
Neutropenia
Dose-dependent fatal hepatic necrosis
In adults, hepatotoxicity from acetaminophen occurs after ingestion of _____ grams. Why does this hepatotoxicity occur?
10-15
Due to hydroxylated intermediate metabolite causing liver damage (metabolites»_space;> available glutathione)
What are 2 signs of hepatotoxicity? What 3 conditions can hepatotoxicity progress to?
Signs: serum transaminase, lactic acid dehydrogenase
Can progress to encephalopathy, coma, and death
What can increase toxicity of liver associated with acetaminophen overdose?
Chronic alcohol consumption
What is the tx for acetaminophen intoxication?
Specific antidote: N-acetylcysteine
If a pt has no hx of PUD, you can prescribe:
Any NSAID
If a pt has a hx of PUD but not its not active, you can prescribe:
- Celecoxib w/ or w/out antacids
- Some NSAIDs w/ misopristol or “-prazols”
If a pt has active PUD, you can prescribe:
Acetaminophen and/or opioids only
