NSAIDs

A 16-year-old female comes to the physician’s office because of menstrual cramps. She had menarche at age 13. Her menses lasts for 4-5 days, and she has 28-day cycles. For the first 2-3 days of her menses she states that she has very bad cramping. The cramps have occurred since menarche and seem to have worsened in the past year.

They have been so bad at times that she has missed school and has not been able to participate in her after-school sports. She has been taking acetaminophen and over-the-counter “menstrual cramp” pills without adequate relief. She has no significant medical history, takes no medications regularly, and is not sexually active. Her examination is normal. You assess the problem as primary dysmenorrhea and prescribe diclofenac to be used on an as-needed basis.

What are the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs)?

What is the mechanism of the anti-inflammatory action of NSAIDs?

Answers to case: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Summary: A 16-year-old female with dysmenorrhea is prescribed diclofenac [Voltaren-XR].

Effects of NSAIDs:

Anti-inflammatory, analgesic, and antipyretic.

Mechanism of action:

Anti-inflammatory effect primarily resulting from inhibition of cyclooxygenase 1 and/or cyclooxygenase 2; may also involve interference with other mediators of inflammation, modulation of T-cell function, stabilization of lysosomal membranes, and inhibition of chemotaxis.

Clinical correlation

NSAIDs are widely used for acute and chronic conditions that cause pain, injury, inflammation, or fever. They are available over-the-counter and by prescription. The anti-inflammatory effect is a result of the inhibition of cyclooxygenase (COX), which converts arachidonic acid to prostaglandins. There are two major subtypes of the COX enzyme, with the COX-2 subtype primarily mediating the pain and inflammation responses in tissues throughout the body. COX-1 has significant activity in producing prostaglandins that appear to protect the GI mucosal lining.

Aspirin irreversibly inactivates both COX-1 and COX-2, whereas all other NSAIDs are reversible inhibitors of one or both of these enzymes. The analgesic effect of these medications is thought to be related to the peripheral inhibition of prostaglandin production, but there may be a central inhibition of pain stimuli as well. The antipyretic effect is thought to involve inhibition of IL-1- and IL-6-induced production of prostaglandins in the hypothalamus affecting the thermoregulatory system, resulting in vasodilation and increased heat loss. Nonsteroidal antiinflammatory drugs are metabolized in the liver and excreted by the kidney.

They exhibit cross-sensitivity with each other and with aspirin. All NSAIDs can cause non-dose-related episodes of acute renal failure and nephrotic syndrome. They should be used with caution in those with renal insufficiency or in patients taking other potentially nephro-toxic agents. Aspirin and NSAIDs that nonselectively inhibit both COX-1 and COX-2 commonly produce GI disturbances and ulceration. They are con-traindicated in persons with known peptic ulcer disease. Newer agents with higher selectivity for COX-2 inhibition have fewer GI side effects and may reduce the rate of NSAID-related gastric ulcers, but have been linked to increased risk of cardiovascular disease.

Approach to pharmacology of NSAIDs

Objectives

1. Know the mechanism of action of aspirin and other NSAIDs.
2. Know the therapeutic uses of Nonsteroidal anti-inflammatory drugs.
3. Know the adverse effects, toxicities, and contraindications to NSAID use.

Definitions

Inflammation:

A local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, and swelling.

Familial adenomatous polyposis (FAP):

A genetic disorder leading to abnormal growths in the colon.

Class

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs and are available in various formulations both over-the-counter and by prescription. They are widely used for the relief of pain and fever and to reduce inflammation. There are more than 23 NSAIDs available, and they represent a number of structural classes. Table Classes of NSAIDs summarizes this class of drugs. They are all small acidic compounds. All are orally active with some pharmacologic differences but they all share the following:

Table: Classes of NSAIDs

CARBOXYLIC ACIDS			PYRAZOLONES	OXICAMS
Salicylates	Acetic acids	Propionic acids	Phenylbutazone	Piroxicam
Acetylsalicyclic acid	Indomethacin	Ibuprofen	Apazone	Meloxicam
Salicyclic acid	Diclofenac	Naproxen
	Sulindac	Ketoprofen
	Tolmetin	Pranoprofen Miroprofen

Analgesic activity

Effective against pain of low-to-moderate intensity. Lower maximal effects compared to opioids, but no CNS liability.

Anti-inflammatory activity

It is their chief clinical application. They provide symptomatic relief only.

Antipyretic activity

Gastric and intestinal ulceration. Two mechanisms include local irritation caused by acidic drug, and inhibition of prostaglandins, which exert a cyto-protective effect.

Carboxylic Acids

The salicylates, acetylsalicylic acid (ASA, aspirin), and sodium salicy-late have been used for hundreds of years for their analgesic properties. ASA acts to covalently and irreversibly inhibit both COX-1 and COX-2. COX-1 becomes acetylated at a serine in the cyclooxygenase-active site, rendering the enzyme inactive.

COX-2 is also covalently modified but at a different serine residue. This also eliminates cyclooxygenase activity and alters COX-2 to produce 15-HETE. 15-HETE can be further metabolized to a potent anti-inflammatory compound, 15-epilipoxin A₄. Some of the anti-inflammatory activity of aspirin might be mediated by this metabolite. Inhibition of cyclooxygenase activity of both COX isoforms decreases prostaglandin and thromboxane production, but does not effect the production of eicosanoids through the lipoxygenase pathway. Sodium and magnesium salicylate lack the acetyl group that modifies the COXs and are much weaker anti-inflammatory agents. Their mechanism of action may be to reduce free radical production that is necessary to activate the cyclooxygenases.

Aspirin can be used to reduce pain, temperature, and inflammation. The anti-inflammatory properties make it useful in rheumatoid arthritis (RA), rheumatic fever, and other diseases that produce joint pain.

The adverse effects of aspirin are dose related. At low doses, most adverse effects are confined to the GI tract, commonly gastritis. At higher doses patients suffer “salicylism,” tinnitus, vomiting, and vertigo. Serious aspirin overdose affects the medulla directly and depresses respiration.

Acetic and Propionic Acids

Indomethacin, ibuprofen, diclofenac, and naproxen are other important NSAIDs. Although they reduce prostaglandin production by inhibiting COX-1 and COX-2, the mechanism of this inhibition is different from aspirin. These drugs are reversible inhibitors of the enzyme and appear to act by interfering with the binding of arachidonate. All have been approved for rheumatic disorders, osteoarthritis, localized musculoskeletal pain, dysmenorrhea, and headache.

All are readily absorbed from the GI tract. Indomethacin and diclofenac are the most potent of these drugs in inhibiting cyclooxygenase. Indomethacin also has the highest incidence (35-50%) of adverse effects, most commonly GI. Indomethacin has been found to produce ulceration of the upper GI tract. Naproxen and ibuprofen are also associated with frequent GI adverse effects but are less severe and better tolerated. All of the NSAIDs can produce renal toxici-ties including acute renal failure.

Specific COX-2 Inhibitors

Considerable effort has gone into the development of agents that specifically inhibit COX-2 compared to COX-1. In theory, such agents would be efficacious for treating inflammatory states but have fewer adverse effects, especially in the GI tract because COX-1 would still be able to provide cytoprotection. Two clinical trials support this notion but these drugs still produce adverse effects in the GI tract. Additional studies on total mortality and morbidity will be necessary.

Celecoxib [Celebrex] is the only specific COX-2 inhibitor in the US market. Rofecoxib [Vioxx] and valdecoxib [Bextra] were removed from the market due to an increase in risk of cardiovascular disease and stroke. It is unclear whether all members of this class are associated with this increase in cardiovascular risk which appears mostly due to myocardial infarction. Celecoxib is useful in treating osteoarthritis, RA, anky-losing spondylitis, dysmenorrhea, acute pain, and pain caused by migraine.

Celecoxib is approved for the treatment of FAR Adverse effects are diminished with COX-2-specific inhibitors, but there are still significant side effects. Rare instances of serious stomach and intestinal bleeding have been reported. Hepatotoxicity and acute renal failure have also occurred. Less serious side effects include dyspepsia, diarrhea, peripheral edema, and dizziness.

Other Agents

Acetaminophen is a non-anti-inflammatory analgesic agent. It is about as effective at reducing fever and as an analgesic as aspirin, but it lacks anti-inflammatory activity and does not inhibit platelet aggregation. The most important toxicity of acetaminophen is hepatotoxicity. This is caused by the metabolism of the drug to N-acetyl-p-benzoquinoneimine (NAPB), which is usually eliminated by hepatic conjugation with glutathione. Toxic levels of acetaminophen deplete glutathione and NAPB accumulates to toxic levels. Other adverse effects include skin rash and mild dyspepsia.

Questions

[1] Which of the following is the most effective in reducing risk of myocardial infarction?

A. Acetaminophen

B. Aspirin

C. Celecoxib

D. Ibuprofen

[2] Which of the following is the advantage of specific cyclooxygenase-2 (COX-2) inhibitors?

A. Decreased GI side effects

B. Decreased vasoconstrictor activity

C. Increased anti-inflammatory activity

D. Increased inhibition of platelet aggregation

[3] A 26-year-old woman takes a “handful” of acetaminophen in a suicide attempt. At the emergency department, it is determined that she has taken enough to be potentially harmful. Which of the following is the best treatment for this patient?

A. Calcium gluconate

B. IgG against acetaminophen

C. JV-acetylcysteine

D. Penicillamine

Answers

[1] B. Aspirin. Because aspirin irreversibly inhibits cyclooxygenase, it effectively eliminates thromboxane production by platelets. It can do this at low doses that do not impair the production of beneficial PGI₂ by endothelial cells.

[2] A. In theory, inhibition of COX-2 would reduce inflammation and pain while leaving the cytoprotective actions of COX-1 intact. However, the two enzymes appear to overlap in their functions to a considerable degree.

[3] C. Excess acetaminophen is metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, NAPB, which has an extremely short half-life and is rapidly conjugated with glu-tathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPB formation or reduced glutathione stores, NAPB is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis. The antidote for acetaminophen poisoning is N-acetyl-L-cysteine (NAC), which prevents the formation and accumulation of NAPB, increases glutathione stores, combines directly with NAPB as a glutathione substitute, and enhances sulfate conjugation.

Pharmacology pearls

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

Acetaminophen does not have anti-inflammatory activity.

The COX-2-specific anti-inflammatory agents may have fewer GI side effects but increase the risk of cardiovascular events.