Nonsteroidal Anti-Inflammatory Drugs and other Nonopioid Analgesic-Antipyretic Drugs

Chapter 18 Nonsteroidal Anti-Inflammatory Drugs and other Nonopioid Analgesic-Antipyretic Drugs



I. General Considerations

A. Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Inhibit the synthesis of eicosanoids from arachidonic acid (Fig. 18-1; Table 18-1).

B. Basic mechanisms

1. These drugs primarily inhibit cyclooxygenase (COX), the enzyme responsible for the first step of prostaglandin synthesis.


a. COX-1 is constituently expressed in many tissues.

image

18-1 Schematic representation of the arachidonic acid pathway, which depicts the mediators formed from arachidonic acid, their biologic function, and drugs that stimulate or inhibit their formation. NSAID, nonsteroidal anti-inflammatory drug.



Table 18-1 Important Actions of Eicosanoid Products

image


COX-1 is constituently expressed.


b. COX-2 is induced by cytokines in inflammatory cells and is found in endothelial cells.


COX-2 is up-regulated by cytokines in inflammatory cells; also, in endothelial cells.


c. COX-3 is a putative isoform found in the brain.

2. Aspirin is the only irreversible inhibitor of COX.


Aspirin is an irreversible inhibitor of both COX-1 and -2 enzymes.


II. NSAIDs (Box 18-1)

A. Aspirin and other salicylates

1. Aspirin (acetylsalicylic acid), the prototype NSAID, is the standard against which all other NSAIDs are measured.


BOX 18-1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) And Other Nonopioid Analgesics



NSAIDs


Aspirin


Diclofenac


Ibuprofen


Indomethacin


Ketoprofen


Ketorolac (parenteral)


Naproxen


Oxaprozin


Piroxicam


Sulindac



COX-2 Inhibitors (Selective NSAIDs)


Celecoxib


Rofecoxib (removed from market)


Valdecoxib (removed from market)



Nonopioid and Non-NSAID Analgesic


Acetaminophen



Aspirin is the only NSAID without a boxed warning of increased cardiovascular events with prolonged use.


2. Mechanism of action


a. Many effects of aspirin are due to irreversible inhibition of prostaglandin synthesis through acetylation of both COX-1 and COX-2.

b. Antiplatelet effect (see Chapter 16)

• Prolonged bleeding time but no change in the other coagulation indicators (e.g., prothrombin time [PT], partial thromboplastin time [PTT])

c. Antithrombotic effect

• Inhibition of thromboxane A2 (TXA2) synthesis (potent platelet aggregator and vasoconstrictor) via irreversible inhibition of platelet COX-1 that lasts for the life span of platelets (see Chapter 16)


The life span of platelets is about 8 days


Aspirin most widely used anti-platelet drug.


3. Dose-dependent pharmacokinetics


Salicylic acid metabolism switches from first to zero-order kinetics at high doses; metabolism becomes dose-dependent.



a. Acetylsalicylic acid (t1/2 = 15 min) is enzymatically and rapidly metabolized to salicylic acid (a reversible inhibitor of cyclooxygenase).

b. When conjugation pathways become saturated, small increases in the dose of aspirin can produce relatively large increases in plasma salicylate levels.

c. A low dose of aspirin (600 mg) gives first-order kinetics, t1/2 is 3 to 5 hours (salicylate)

• Analgesic, antipyretic, platelet inhibitor

d. High dose of aspirin (>4000 mg) gives zero-order kinetics, t1/2 greater than 12 hours (salicylate)

• Anti-inflammatory

e. Excreted in urine as salicylic acid, salicyluric acid, glucuronic acid conjugates

4. Uses


Aspirin and other NSAIDs are antipyretic, analgesic, and anti-inflammatory.



a. Fever, acute rheumatic fever

b. Headache

c. Mild pain

d. Dysmenorrhea

e. Inflammatory conditions such as osteoarthritis and rheumatoid arthritis (RA)

f. Prevention of platelet aggregation in:

(1) Coronary artery disease

(2) Myocardial infarction

(3) Atrial fibrillation


COX-1 inhibitors decrease platelet aggregation; COX-2 inhibitors do not.


5. Adverse effects

a. Gastric irritation, gastrointestinal (GI) bleeding, peptic ulcer disease

• Occurs to some degree with the use of all NSAIDs

b. Salicylism (tinnitus, vertigo leading to deafness) with overdose (see Chapter 30); reversible with dosage reduction


High dose of aspirin produces salicylism (tinnitus, vertigo leading to deafness).


c. Primary respiratory alkalosis often followed by a primary increased anion gap metabolic acidosis


Aspirin overdose causes respiratory alkalosis followed by metabolic acidosis.



(1) This is called a mixed blood gas disorder.

(a) Arterial pH is normal.

(b) More often occurs in children than in adults

(2) Respiratory acidosis due to eventual suppression of the medullary respiratory center may also occur as a late finding.

d. Renal failure

(1) Possibly due to decrease in prostaglandin E2 or I2 production (vasodilators of afferent arterioles)

(2) Leads to acute ischemic tubular necrosis


Extensive use of NSAIDs can contribute to hypertension.

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Nonsteroidal Anti-Inflammatory Drugs and other Nonopioid Analgesic-Antipyretic Drugs

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