E2: NSAIDs and Acetaminophen Flashcards by Blake Beecroft (AZ PA Mast 21)

What are the 4 signs of inflammation?

Erythema (rubor)
Edema (calor)
Tenderness (tumor)
Pain (dolor)

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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!

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Leukotrienes are responsible for what effect in the lungs?

Bronchospasm

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MOA for Aspirin (ASA, Acetylsalicylic acid)

Nonselective, irreversible inhibitor of COX-1 and COX-2

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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

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Why is plasma concentration of ASA low?

Rapidly hydrolyzed in the plasma, liver, and erythrocytes

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What kinetics does ASA follow at low doses? High doeses?

Low doses: First order kinetics

High doses (above 600mg): Zero order kinetics

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How is ASA excreted? What can increase excretion?

Renal excretion

-Alkalization of the urine promotes excretion

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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

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What is an adverse effect of ASA use? (Describe the process)

Respiratory alkalosis -> metabolic and respiratory acidosis

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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

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Aspirin should be avoided in patients with any of the following conditions (4):

Hypoprothembinemia
Vit K deficiency
Hemophilia
Severe hepatic damage

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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

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Uricosuric effects of aspirin are _____ and ____ dependent.

Biphasic and dose dependent

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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.

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What adverse affect can aspirin have on the lungs?

Aspirin asthma (increased leukotriene synthesis)

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What are 4 adverse effects of aspirin on the GI system?

GI upset
Gastritis
Ulcer (increased gastric acid production)
Bleeding

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What are 4 severe effects of aspirin on the kidneys?

Renal damage
Acute renal failure
Interstitial nephritis
Nephrotic syndrome

Know this one!

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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.

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How much salicylic acid is required for a fatal dose (acute poisoning)?

10-30 g of aspirin

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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

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How is ASA different from all the other NSAIDs?

ASA is IRREVERSIBLE, all other NSAIDs are reversible!

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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

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MOA of Celecoxib (Celebrex)

Selective COX-2 inhibitor (REVERSIBLE)

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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.

1. GI - pain, bleeding, ulcer, diarrhea, pancreatitis 2. CNS - depression, HA, dizziness 3. Lung - bronoconstrction 4. Bone marrow - Agranulocytosis, aplastic anemia 5. Nephrotoxic 6. Hepatotoxic 7. 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 >>> 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