Pharmacologic Therapy for Acute Pain

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Questions and Answers

What is the main mechanism of action of acetaminophen in the central nervous system?

Inhibits COX2 activity through competitive inhibition

Crosses the blood-brain barrier and selectively inhibits COX3 (correct)

Enhances glucuronidation processes in the liver

Promotes the synthesis of anti-inflammatory eicosanoids

What is a significant misconception regarding NSAIDs and their therapeutic effectiveness?

COX-1 and COX-2 have identical roles in inflammation.

The effectiveness of NSAIDs is equal across different patient populations.

NSAIDs vary widely in therapeutic effectiveness depending on the indication.

All NSAIDs function by the same mechanism. (correct)

How does the pharmacokinetics of acetaminophen differ from other NSAIDs?

Increased metabolism through CYP pathways

Excellent bioavailability and uniform distribution (correct)

Decreased elimination half-life in children

Higher protein binding compared to other NSAIDs

Which statement accurately reflects the role of COX-2 in the body?

COX-2 can produce anti-inflammatory PG such as PGJ2. Signup and view all the answers

Which of the following is a potential adverse effect of acetaminophen at therapeutic doses?

Rash or other allergic reactions Signup and view all the answers

What mechanism is NOT involved in the anti-inflammatory actions of some NSAIDs?

Activation of bradykinin pathways. Signup and view all the answers

What is the primary risk of acetaminophen overdose?

Severe renal necrosis and hepatotoxicity Signup and view all the answers

What condition may increase susceptibility to liver injury from acetaminophen?

Heavy alcohol consumption or GSH depletion Signup and view all the answers

Which of the following statements about the pharmacokinetics of NSAIDs is incorrect?

Antacids enhance the absorption of NSAIDs. Signup and view all the answers

Which metabolic process primarily detoxifies acetaminophen?

Glucuronidation and sulfation pathways Signup and view all the answers

What potential cardiovascular adverse effect is associated with NSAIDs?

Hypertension. Signup and view all the answers

Which of the following pathways is NOT involved in the anti-inflammatory mechanisms attributed to NSAIDs?

Promotion of cytokine release. Signup and view all the answers

What are early symptoms of hepatic damage due to acetaminophen toxicity?

Nausea, vomiting, diarrhea, and abdominal pain Signup and view all the answers

What component becomes toxic in acetaminophen overdose leading to cell necrosis?

NAPQI, due to conjugation saturation Signup and view all the answers

Which NSAID is associated with the inhibition of both COX and 5LOX?

Ketoprofen. Signup and view all the answers

What is the main consequence of COX-1 involvement in inflammation?

Regulates homeostasis and protective mucosal functions. Signup and view all the answers

Which of the following NSAIDs is known for longer half-life and slower onset?

Naproxen. Signup and view all the answers

What role does PGJ2 play in inflammation?

Generates anti-inflammatory responses. Signup and view all the answers

Which eicosanoids contribute to central sensitization in the nervous system?

PGE2, PGD2, PGI2, PGF2α Signup and view all the answers

What is the primary mechanism through which NSAIDs exert their pain-relieving effects?

Competitive and reversible inhibition of COX enzymes Signup and view all the answers

Which statement accurately describes COX-2 inhibitors compared to non-selective NSAIDs?

Non-selective NSAIDs preferentially inhibit COX-1 over COX-2. Signup and view all the answers

How do endogenous pyrogens such as IL-1β affect body temperature regulation?

They induce COX-2 in the hypothalamic area, increasing PGE2 synthesis. Signup and view all the answers

What differentiates the action of aspirin from that of traditional NSAIDs?

Aspirin irreversibly acetylates COX-1. Signup and view all the answers

Which of the following is a reason why selective COX-2 inhibitors are used over traditional NSAIDs?

They cause less gastrointestinal side effects compared to non-selective NSAIDs. Signup and view all the answers

What role do cytokines play in the development of fever?

They form endogenous pyrogens that stimulate PGE2 production. Signup and view all the answers

What is the relationship between COX-1 and COX-2 expression in terms of eicosanoid production?

Both COX-1 and COX-2 can contribute to eicosanoid production in the spinal cord. Signup and view all the answers

Study Notes

NSAIDs and Central Actions

NSAIDs exert central effects by modulating prostaglandins (PGE2, PGD2, PGI2, PGF2α), contributing to central sensitization.
COX-1 and COX-2 are present in the spinal cord, involved in releasing prostaglandins in response to peripheral pain stimuli.

Eicosanoids and Fever

Body temperature regulation relies on energy production and loss balance.
Endogenous pyrogens like IL-1β, IL-6, TNF-α, and interferons form in response to infections, inflammation, or malignancy.
COX-2 induction in the preoptic hypothalamic area increases PGE2, which elevates body temperature via thermosensitive neurons.

Classification and Selectivity of NSAIDs

NSAIDs are classified based on their selectivity for COX enzymes.
Ration of IC50 for COX-1 to COX-2 indicates selectivity, with higher ratios suggesting non-selective NSAIDs.
Selective COX-2 inhibitors (Coxibs) are designed to minimize gastrointestinal side effects while maintaining efficacy.

Mechanism of Action

NSAIDs act as competitive, reversible inhibitors of COX, blocking arachidonic acid from entering the enzyme channel.
Aspirin irreversibly inhibits COX-1 by acetylating a serine residue, leading to prolonged effects.
Selective COX-2 inhibitors, being bulkier, can effectively block COX-2 without affecting COX-1.

Misconceptions and Additional Mechanisms

Not all NSAIDs have equal therapeutic effectiveness; they can have various anti-inflammatory mechanisms:
- Inhibition of leukocyte movement and chemotaxis.
- Down-regulation of IL-1 production and other mediators of inflammation.
- Prevention of cartilage matrix breakdown.
Some NSAIDs also possess unique additional actions contributing to their efficacy.

Pharmacokinetics of NSAIDs

Generally well-absorbed orally; food delays absorption; antacids do not reduce absorption.
High protein binding and wide distribution, including across the CNS.
Hepatic metabolism and renal excretion influence their half-lives, with variable effects seen across different NSAIDs.

Adverse Effects of NSAIDs

Cardiovascular risks include hypertension and potential for myocardial infarction (MI) and congestive heart failure (CHF).
CNS effects can include headaches, tinnitus, and dizziness; rare cases of aseptic meningitis reported.
Acetaminophen (paracetamol) shows lower side effects on GI, CV, and respiratory systems compared to traditional NSAIDs.

Acetaminophen Pharmacokinetics

Exhibits excellent bioavailability and uniform distribution in body fluids.
Primarily metabolized via glucuronidation and to a lesser extent via CYP pathways, forming a reactive intermediate (NAPQI).
Children exhibit reduced glucuronidation capacity compared to adults.

Acetaminophen Adverse Effects and Overdose

At therapeutic doses, acetaminophen generally presents minimal adverse effects, but can cause liver damage at high doses (>4g/day).
Overdose can lead to severe toxicity, hepatic injury, and potential multi-organ damage; doses exceeding 15g can be fatal.
Onset of toxicity can involve nausea and abdominal pain, necessitating emergency treatment when overdose is suspected.

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Description

This quiz focuses on the pharmacologic therapy for acute pain, emphasizing the roles of NSAIDs and eicosanoids such as PGE2, PGD2, and others in central sensitization and pain levels. Understanding how COX-1 and COX-2 contribute to pain responses in the spinal cord is also covered.