Pharmacology of COX Inhibitors and Prostaglandins

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Questions and Answers

What is the primary mechanism by which NSAIDs provide analgesia?

They enhance glycinergic inhibition at nociceptor neurons. (correct)

They increase synthesis of prostaglandins.

They induce vasodilation at inflammatory sites.

They inhibit the release of leukocytes.

Which of the following NSAIDs is known for its irreversible effects?

Indomethacin

Aspirin (correct)

Nabumetone

Ibuprofen

What possible risk is associated with administering NSAIDs late in pregnancy?

Inhibition of labor induction

Premature closure of the ductus arteriosus (correct)

Increased uterine contractions

Prevention of premature birth

How do prostaglandins impact the ductus arteriosus during fetal life?

They maintain its patency. Signup and view all the answers

What is a reported side effect of NSAIDs related to renal function?

Decreased urine output Signup and view all the answers

Which of the following statements about the pharmacology of NSAIDs is true?

They accumulate at sites of inflammation due to their properties. Signup and view all the answers

Which of the following is a common therapeutic effect attributed to NSAIDs?

Antipyretic Signup and view all the answers

What is the effect of PGE2 on nociceptor neurons?

It reduces the threshold for pain sensations. Signup and view all the answers

What is the primary mechanism by which indomethacin exerts its effects as an NSAID?

Non-selective COX-1 and COX-2 inhibition Signup and view all the answers

Which therapeutic use is NOT indicated for naproxen?

Closure of patent ductus arteriosus Signup and view all the answers

What is a common adverse effect associated with the use of indomethacin?

Headache Signup and view all the answers

Which statement regarding the use of aspirin in pregnancy is true?

Aspirin may be used if necessary. Signup and view all the answers

Which NSAID is noted for its possible superiority in analgesia and tolerability?

Naproxen Signup and view all the answers

Which of the following NSAIDs has the highest likelihood of gastrointestinal adverse effects?

Indomethacin Signup and view all the answers

Which of the following conditions should aspirin be avoided?

Head trauma Signup and view all the answers

What is the main property that differentiates propionic acid derivatives from aspirin?

They have lower toxicity levels. Signup and view all the answers

What mechanism is primarily responsible for aspirin's antipyretic effects?

Inhibition of COX in the hypothalamus Signup and view all the answers

Which of the following statements about aspirin's antiplatelet effects is correct?

It irreversibly acetylates COX-1, blocking TXA2 formation. Signup and view all the answers

In the case of aspirin intoxication, which symptom is associated with more severe cases?

Convulsions Signup and view all the answers

What is the typical low dose of aspirin recommended for prophylactic use in coronary artery disease?

40-80 mg/day Signup and view all the answers

Which type of pain is aspirin most effective for treating?

Mild to moderate pain (not visceral) Signup and view all the answers

What is recommended regarding NSAID consumption prior to surgical procedures?

NSAIDs should be avoided within 7 days of surgery. Signup and view all the answers

What is the lowest effective daily dose of aspirin for chronic inflammatory conditions like rheumatoid arthritis?

3 g/day Signup and view all the answers

Which of the following treatments is part of the management for aspirin intoxication?

Alkalinization of urine to facilitate excretion Signup and view all the answers

Study Notes

COX Inhibitors

Can reduce renal function
Can worsen hypertension and congestive heart failure (CHF)

Reproductive Organs

Female
- Uterus
  - Prostaglandins stimulate and initiate labor and can induce abortion
  - Cause uterine contractions during menstruation causing pain (dysmenorrhea)
    - Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) help reduce pain
Ductus Arteriosus
- Prostaglandins maintain a patent ductus arteriosus in utero
  - NSAIDs given late in pregnancy can cause premature closure, leading to pulmonary hypertension in the newborn
  - NSAIDs can help close the ductus arteriosus in premature babies
    - High doses of indomethacin and ibuprofen are used for this

Central and Peripheral Nervous System Actions

Prostaglandin E1 (PGE1) and Prostaglandin E2 (PGE2) increase body temperature at the hypothalamus
Prostaglandin D2 (PGD2) can induce natural sleep
PGE1 and PGE2 inhibit norepinephrine (NE) release from postganglionic sympathetic nerve endings
- NSAIDs block this effect, causing vasoconstriction
- PGE2 can cause hyperalgesia by reducing the threshold of nociceptor neurons and increasing leukocyte recruitment, causing inflammation
The analgesic effects of NSAIDs are mostly due to their central action of preventing PGE2-induced reduction of glycinergic inhibition

Pharmacology of NSAIDs

Most are organic acids (except Nabumetone) and act reversibly (except aspirin)
Some are short-acting, with a half-life of 10 hours
Aspirin is irreversible, resulting in longer-lasting effects than predicted by its half-life
- COX enzyme must be re-synthesized for normal function
Organic acids accumulate at sites of inflammation, targeting the desired site of action
Most are well absorbed orally, metabolized by the liver, renally excreted, and highly bound to albumin (>98%)

Therapeutic Effects

Antipyretic, analgesic, anti-inflammatory
- Acetaminophen (Tylenol) lacks anti-inflammatory action

Adverse Effects

Can cause acute bronchoconstriction in patients with asthma
Can worsen gout
- Low-dose aspirin (81mg) is generally safe, while therapeutic doses (325mg) decrease urate excretion
  - Very high doses increase urate excretion
Reye's syndrome linked to aspirin given to children with viral infections and fever
Avoid in gastrointestinal (GI) disease
Avoid in head trauma due to risk of bleeding
Caution in renal failure
Use with caution during pregnancy, as it is excreted in breast milk

Indomethacin (Indocin)

Available orally, intravenously, as a suppository, and as an ophthalmic preparation
Similar anti-inflammatory, analgesic, and antipyretic actions as salicylates, but more potent than aspirin
Non-selective COX-1 and COX-2 inhibitor
Indications
- Primarily for rheumatoid arthritis, osteoarthritis, acute gouty arthritis, and eye pain
- Used to facilitate closure of patent ductus arteriosus in premature babies
Adverse Effects
- Up to 33% of patients discontinue due to adverse effects
  - GI pain, hemorrhage, diarrhea, pancreatitis, headache, rarely psychosis, hallucinations, and some renal problems can occur

Propionic Acid Derivatives

Better tolerated than aspirin and indomethacin
Similar efficacy to aspirin, but aspirin is cheaper
Indications
- Alleviation of pain and inflammation in many disorders including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, tendonitis, bursitis, and dysmenorrhea
All are relatively equal, but naproxen may have an advantage in analgesia and tolerability

Ibuprofen (Motrin, Advil)

Dose range: 1200mg-3200mg/day
Can be given with food to reduce GI effects
Half-life: 2 hours
5-15% of patients discontinue due to GI problems
Not recommended during pregnancy or breastfeeding
Toxicity is similar to salicylism
Less anti-inflammatory action than other NSAIDs
Alternative to indomethacin for patent ductus arteriosus
Injectable formulation for pain and fever in patients unable to take oral medication

Naproxen (Aleve, Naprosyn)

Fully absorbed, peak plasma concentration reached in 2-4 hours
Antipyretic Effects
- Reduces elevated temperature, minimally affecting normal temperatures
- Through the inhibition of COX in the hypothalamus
Antiplatelet Effects
- Irreversible acetylation of COX-1 blocks thromboxane A2 (TXA2) formation
- Also blocks prostacyclin, but clinically the TXA2 effect predominates
- Irreversible inhibition in platelets is long (8-11 days, lifespan of the platelet)
  - Platelets need to be replaced, so patients are advised not to take NSAIDs within 7 days of surgery
    - Can be problematic with coronary disease, increasing the risk of myocardial infarction (MI)
    - Prolonged bleeding time usually returns to normal within 36 hours, but 7 days is recommended

Clinical Uses of Aspirin

Analgesia, antipyresis, anti-inflammatory
Mild to moderate pain (not visceral)
- Headache, arthritis, dysmenorrhea
- Combined with opioids, like oxycodone (Percodan), for moderately severe pain (dentistry)
Rheumatoid arthritis, osteoarthritis, etc. (lowest effective dose ~ 3g/day)
Prophylactic use for coronary artery disease, etc.
- Selective blocking of TXA2 in platelets
  - Low dose of 40-80mg/day

Aspirin Intoxication (Salicylism)

Can occur and be fatal if high amounts are ingested (10-30gms; 300-350µg/ml)
Mild, Chronic Symptoms
- Headache, dizziness, tinnitus, hearing loss, dimness of vision, mental confusion, lassitude, sweating, thirst, hyperventilation, and nausea
More Severe Symptoms
- Convulsions, coma, skin eruptions, acid-base disruptions, fever, and dehydration
CNS depression, cardiovascular collapse, and respiratory failure can lead to death
Treatment
- Cardiovascular and respiratory support
- Removal of agent from the stomach with activated charcoal
- Correction of acid-base abnormalities
- Alkalinization of urine to facilitate excretion

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Description

Explore the roles of COX inhibitors and prostaglandins in various physiological processes, including reproductive health and nervous system functions. This quiz focuses on their effects, especially in females and neonates, as well as their implications in renal function and hypertension.