Flashcards in NSAIDs: Aspirin and other Salicylates and Acetaminophen Deck (28)
Moving on to Aspirin and Other Salicylates. What does Salicylates include?
Aspirin (acetyl Salicylate)
Magnesium Choline Salicylate
What is unique about Aspirin?
Irreversible acetylating cyclooxygenase
--all the other salicylates and NSAIDs are reversible inhibitors of COX
Some of the pharmacologic effects of aspirin are due to what?
First lets discuss the actions of aspirin, the first are respiratory actions. At therapeutic doses aspirin increases alveolar ventilation, how?
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
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?
Lack of TXA2 lasts for the lifetime of the platelet
Therefore decrease in TXA2 levels results inhibition of platelet aggregation and a prolonged bleeding time.
Aspirin also inhibits COX in endothelial cells, but its action is not permanent, why?
These cells are able to synthesize new COX molecules
--additionally at low doses of aspirin the endothelial cell production of PGI2 is relatively unaffected
What are the anti-inflammtory, antipyretic and analgesic uses of aspirin?
Mild to moderate pain in headaches, joint/muscle pain, and dysmenorrhea
High doses: RA and other inflammatory joint conditions
Used a antipyretic
Aspirin is used to inhibit platelet aggregation. Low doses are prophylactically used to?
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
Aspirin is used in colon cancer for what?
50% decrease in risk of colon cancer
What is the dose for salicylates?
Analgesic and antipyretic: low doses
--anti-inflammatory at higher doses
Low dose aspirin are used for cardioprotective effects
Next on to the metabolism of aspirin, it is hydrolyzed to what?
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
When doses of aspirin of 1g or more are administered, the conjugated enzymes become saturated and what is observed?
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)
Moving on to the adverse effects of Aspirin. In regards to blood, what are some adverse effects?
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
In what kinds of patients should aspirin be avoided?
Vitamin K deficiency
What is Reyes Syndrome?
Fatal, fulminating hepatitis with cerebral edema
--aspirin should be avoided in kids with fevers
Aspirin and uric acid use the same transport system. Therefore low doses of aspirin do what?
Compete with uric acid for secretion into the tubular fluid and thus reduce uric acid secretion
Large doses of aspirin do what to the uric acid transport system?
Compete with uric acid for reabsorption and thus increase uric acid excretion in the urine
What are the hepatic effects of aspirin?
Usually in patients treated with high doses
-onset occurs several months after treatment
--injury is usually reversible
--dont use in chronic liver disease
The last topic for discuss is Salicylate intoxication, what is mild chronic salicylate intoxication called?
--syndrome includes HA, dizziness, tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst
what is severe intoxication of salicylates?
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
Prolonged exposure to high doses of salicylates leads to depression of the medulla, and what occurs?
Central respiratory depression and circulatory collapse
Enhanced CO2 production continues, respiratory acidosis ensues.
Resp failure can occur
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?
NOT an NSAID
--weak COX1 and COX2 inhibitor in peripheral tissues and has no significant anti-inflammatory effects.
Acetaminophen is the drug of choice for what conditions?
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.
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?
Hepatic Injury as a result of acetaminophen use continues to be a serious health problem
Acetaminophen is hepatically metabolized. what is the MOA of hepatic injury?
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.
What is the antidote for Acetaminophen overdose?
Acetaminophen has a narrow therapeutic range, esp in certain populations, What populations?
People who consume alcohol or have pre-existing liver disease