NSAIDs: Aspirin and other Salicylates and Acetaminophen

Question 1

Moving on to Aspirin and Other Salicylates. What does Salicylates include?

Answer 1

Aspirin (acetyl Salicylate)
Magnesium Choline Salicylate
Sodium Salicylate
Salicyl Salicylate

Question 2

What is unique about Aspirin?

Answer 2

Irreversible acetylating cyclooxygenase

–all the other salicylates and NSAIDs are reversible inhibitors of COX

Question 3

Some of the pharmacologic effects of aspirin are due to what?

Answer 3

Salicylate metabolite

Question 4

First lets discuss the actions of aspirin, the first are respiratory actions. At therapeutic doses aspirin increases alveolar ventilation, how?

Answer 4

Salicylates uncouple oxidative phosphorylation
–leads to elevated CO2 and increased respiration
High doses work on the respiratory center in the medulla, resulting in hyperventilation n respiratory alkalosis – compensated for by the kidney
Toxic levels: central respiratory paralysis occurs and respiratory acidosis ensues

Question 5

Next action of aspirin is on the platelets. Low dose aspirin irreversibly inhibits TXA2 production in platelets. Since platelets lack nuclei, they cannot synthesize new enzyme, what does this mean?

Answer 5

Lack of TXA2 lasts for the lifetime of the platelet
–7-10 days
Therefore decrease in TXA2 levels results inhibition of platelet aggregation and a prolonged bleeding time.

Question 6

Aspirin also inhibits COX in endothelial cells, but its action is not permanent, why?

Answer 6

These cells are able to synthesize new COX molecules

–additionally at low doses of aspirin the endothelial cell production of PGI2 is relatively unaffected

Question 7

What are the anti-inflammtory, antipyretic and analgesic uses of aspirin?

Answer 7

Mild to moderate pain in headaches, joint/muscle pain, and dysmenorrhea
High doses: RA and other inflammatory joint conditions
Used a antipyretic

Question 8

Aspirin is used to inhibit platelet aggregation. Low doses are prophylactically used to?

Answer 8

1. Reduce the risk of recurrent TIAs and strokes
2. Reduce the risk of death in those having an acute MI
3. Reduce the risk of recurrent nonfatal MI and/or death in patients with previous MI or unstable angina
4. Reduce risk of MI and sudden death in patients with chronic stable angina

Question 9

Aspirin is used in colon cancer for what?

Answer 9

50% decrease in risk of colon cancer

Question 10

What is the dose for salicylates?

Answer 10

Analgesic and antipyretic: low doses
–anti-inflammatory at higher doses
Low dose aspirin are used for cardioprotective effects

Question 11

Next on to the metabolism of aspirin, it is hydrolyzed to what?

Answer 11

To salicylate and acetic acid by esterases in the tissues and blood
–at low doses it is converted by the liver to hydrosoluble conjugates (with glycine and glucuronate) that are rapidly excreted in the kidney, resulting in first order kinetics

Question 12

When doses of aspirin of 1g or more are administered, the conjugated enzymes become saturated and what is observed?

Answer 12

Zero order kinetics (ROE is constant) (therefore time to eliminate increases as dose increases)
–first order is not observed until the amount of salicylate remaining in the body drops to the amount equivalent to about 300mg of aspirin (Clearance is constant)

Question 13

Moving on to the adverse effects of Aspirin. In regards to blood, what are some adverse effects?

Answer 13

1. Irreversible acetylation of platelet COX reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time
   - -aspirin should be stopped one week before surgery

Question 14

In what kinds of patients should aspirin be avoided?

Answer 14

Hepatic damage
Hypoprothrombinemia
Vitamin K deficiency
Hemophilia

Question 15

What is Reyes Syndrome?

Answer 15

Fatal, fulminating hepatitis with cerebral edema

–aspirin should be avoided in kids with fevers

Question 16

Aspirin and uric acid use the same transport system. Therefore low doses of aspirin do what?

Answer 16

Compete with uric acid for secretion into the tubular fluid and thus reduce uric acid secretion

Question 17

Large doses of aspirin do what to the uric acid transport system?

Answer 17

Compete with uric acid for reabsorption and thus increase uric acid excretion in the urine

Question 18

What are the hepatic effects of aspirin?

Answer 18

Usually in patients treated with high doses

• onset occurs several months after treatment
• -injury is usually reversible
• -dont use in chronic liver disease

Question 19

The last topic for discuss is Salicylate intoxication, what is mild chronic salicylate intoxication called?

Answer 19

Salicylism
–syndrome includes HA, dizziness, tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst

Question 20

what is severe intoxication of salicylates?

Answer 20

After large doses of salicylates are administered, severe intoxication may result
–after an acute overdose patients typically present to the hospital with a mixed respiratory alkalosis and metabolic acidosis

Question 21

Prolonged exposure to high doses of salicylates leads to depression of the medulla, and what occurs?

Answer 21

Central respiratory depression and circulatory collapse
Enhanced CO2 production continues, respiratory acidosis ensues.
Resp failure can occur

Question 22

Lastly is Acetaminophen. It is one of the most important drugs used for treatment of mild to moderate pain when anti-inflammatory is not needed. What kind of drug is acetaminophen?

Answer 22

NOT an NSAID

–weak COX1 and COX2 inhibitor in peripheral tissues and has no significant anti-inflammatory effects.

Question 23

Acetaminophen is the drug of choice for what conditions?

Answer 23

1. Children with fever and flulike symptoms
2. Short term treatment of fever and minor pain during pregnancy
3. Inadequate therapy for inflammatory conditions such as RA, though it can be used with anti-inflammatory drugs.

Question 24

Acetaminophen is considered a safe drug, esp because it lacks the GI, renal, and bleeding adverse effects seen with NSAIDs. However, what effect can acetaminophen have?

Answer 24

Hepatic Injury as a result of acetaminophen use continues to be a serious health problem

Question 25

Acetaminophen is hepatically metabolized. what is the MOA of hepatic injury?

Answer 25

90% of the acetaminophen dose is metabolized to sulfate and glucuronide conjugates, which are eliminated in the urine.
A small amount is metabolized by CYP2E1 to NAPQI, a metabolite that is hepato toxic.
NAPQI is conjugated with glutathione and the conjugate is excreted in the urine
With overdose, glutathione stores become depleted and NAPQI is not detoxified and can cause hepatotoxicity.

Question 26

What is the antidote for Acetaminophen overdose?

Answer 26

N-acetylcysteine

Question 27

Acetaminophen has a narrow therapeutic range, esp in certain populations, What populations?

Answer 27

People who consume alcohol or have pre-existing liver disease

Question 28

Acetaminophen overdoses are the most common cause of???

Answer 28

Acute liver failure in the US