HEALTH AND MEDICAL PRODUCTS:ANALGESICS

ANALGESICS

An analgesic is a drug that relieves the sensation of pain. Pain is often described as a primitive physiological experience that, through an atmosphere of suffering, acts as a protective mechanism to warn of actual or potential damage to biological tissues in humans and nearly all other types of animals. The principle nociceptors (pain receptors) include several million free sensory nerve endings with large receptive fields that are present in all of the tissues and organs of the body (excluding the brain). While a small number of nociceptors are located in deep tissues and vis- ceral organs, they are especially common in areas such as the superficial portions of the skin, joint capsules, bone tissue, and surrounding blood vessel walls. Nociceptors are often categorized as belonging to one of three different population types: those sensitive to temperature extremes, to mechanical damage (e.g., swelling/inflammation), or to the presence of chemicals/toxins released by damaged and/or injured cells.

Stimulation of the dendrites of the nociceptor neurons by a specific stimulus (e.g., temperature change, mechanical damage, toxin exposure) often causes a neurophysiological change (called a depolarization), which may then lead to the transmission of a nerve impulse (in the form of an action potential) to the CNS. Two types of nerve cell fibers (called axons), type A and type C, carry painful sensations. Type A, myelinated fibers carry sensations of “fast pain” (e.g., prickling pain), and type C, unmyelinated fibers carry sensations of “slow pain” (e.g., burning, itching, and aching pain). Type A and type C fibers transmit nerve impulses through neurons of the lateral spinothalamic pathway of the spinal cord and brain, eventually transmitting pain impulses through the thalamus and to the primary sensory cerebral cortex (within the cerebrum) of the brain, where conscious attention of the pain is processed.

After tissue injury, damaged cell membranes release an omega six fatty acid derivative compound called arachidonic acid into the interstitial fluid space surrounding tissue cells. Within the interstitial fluid, an enzyme called fatty acid cyclo-oxygenase (also called prostaglandin endoperoxide syn- thetase) converts arachidonic acid molecules to prostaglandins (PGs). There are currently two known forms of cyclo-oxygenase, cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). The COX-1 isoform is con- stitutively expressed in most normal cells and tissues, including the stom- ach. COX-2 is generally induced only in settings of inflammation by cytokines and other chemical mediators of the inflammatory response. However, COX-2 is constitutively expressed in certain areas of the kid- ney and brain. In general, COX-1 converts arachidonic acid to PGI2, which protects the stomach lining from acidic digestive juices, whereas COX-2 converts arachidonic acid to PGE2, which acts on nerve endings to cause the sensation of pain. Thus, the enzymatic processes involved with PG synthesis are of pharmacological concern, because PGs, named for the seminal fluid and prostate tissue in which they were discovered, are chemical messengers of the immune system responsible for inflammation and pain.

The capacity of PGs to sensitize pain receptors to mechanical and chemical stimulation appears to result from a lowering of the depolari- zation threshold of the nociceptors of type C fibers, thereby increasing the nerve transmission of pain sensation to the brain. Other potent pain- producing nociceptor-activating chemicals include bradykinin and cytokines. Bradykinin, a member of the kinin system group of proteins, is de- rived by cleavage of precursor plasma protein (plasma kininogen) molecules and is a potent vasodilator, a contractor of a variety of different kinds of extravascular smooth muscle tissue (e.g., bronchial), and an inducer of in- creased vascular permeability. Cytokines are low-molecular-weight peptides or glycoproteins produced by multiple cell types, such as lymphocytes, monocytes/macrophages, mast cells, eosinophils, and endothelial cells lining blood vessels. The four major categories of cytokines are interferons, colony-stimulating factors, tumor necrosis factors, and interleukins. Interferons interfere with virus replication; colony-stimulating factors support the growth and differentiation of cellular elements within bone marrow; tumor necrosis factors (TNFs) cause a bleeding (hemorrhagic) tissue death (necrosis) of tumors when injected into various types of animals; and interleukins (ILs) allow for communication between (inter-) various populations of white blood cells (leukocyte-leukin). Bradykinin and cyto- kines (e.g., TNFa, IL-1, and IL-8) liberate PGs to promote enhanced pain sensitivity (called hyperalgesia).

Analgesic drugs are a heterogeneous group of compounds, often chemically unrelated, that share certain therapeutic actions and side ef- fects. Over-the-counter (OTC) oral analgesics contain active ingredients including acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, ketoprofen, and naproxen sodium. OTC oral analgesics are generally recommended safe for treatment of pain for approximately seven to ten days, with labels warning individuals to seek professional medical advice for chronic pain symptoms. Whereas the general side effects of all OTC oral analgesics may include kidney damage, the specific side effects of oral NSAIDs may include irritation of the inner stomach lining, general digestive upset, ulcers, and bleeding in the digestive tract. In general, acetaminophen and NSAIDs are nonselective COX enzyme inhibitors (they inhibit both COX-1 and COX-2 en- zymes with little selectivity) and thereby decrease the sensation of pain by inhibiting PG production.

Acetaminophen (paracetamol; N-acetyl-p-aminophenol; C8H9NO2) is the least toxic member of a class of analgesic (and antipyretic [antifever]) medications known as the p-aminophenols. A major metabolite of phen- acetin (the so-called coal tar analgesic) and acetanilide, acetaminophen is an effective and fast-acting analgesic that acts centrally to relieve mild to moderate pain. As early as 1886, acetanilide was used to alleviate fever, but it proved too toxic for general public use. Subsequent investigations of similar chemical compounds in the 1880s led to trials of p-aminophenol, which also proved to be excessively toxic for human use, and phenacetin (also called acetophenetidin; it was banned by the U.S. Food and Drug Administration in 1983 after reports of its tendency to cause human kid- ney damage and blood disorders when used excessively). In 1893, acet- aminophen was introduced, and since 1949, when it was recognized as the major active metabolite of both acetanilide and phenacetin, it has gained a prominent household position as an effective alternative to NSAIDs as an analgesic-antipyretic. While promoted in 1955 for children’s fever and pain, acetaminophen became available as an OTC drug in 1960. How- ever, unlike aspirin, acetaminophen possesses weak anti-inflammatory activity; thus, it is not a useful agent in treating pain associated with in- flammation. Acetaminophen acts to alleviate the pain of fever by effectively inhibiting the cyclo-oxygenase enzyme in the brain and PG production, producing its analgesic effect by increasing the pain threshold. The fail- ure of acetaminophen to exert anti-inflammatory activity at sites of in- flammation in peripheral body tissues may be attributed to the fact that acetaminophen is only a weak inhibitor of the enzyme cyclo-oxygenase. Moreover, acetaminophen is thought to inhibit this enzyme activity only in environments that are low in the chemical called peroxide (e.g., brain tissue). This characteristic may in part explain the poor anti-inflammatory activity of acetaminophen, as sites of peripheral inflammation usually contain increased concentrations of peroxides released by white blood cells (leukocytes). Primarily metabolized within the liver, minor metabo- lites contribute significantly to the toxic effects of acetaminophen. These include potentially lethal and/or irreversible liver damage when con- sumed in excess of recommended therapeutic doses. However, single or repeated therapeutic doses of acetaminophen typically elicit no deleteri- ous effects on the cardiovascular and respiratory systems. In addition, unlike aspirin and other salicylate-based analgesic drugs, acetaminophen at normal therapeutic doses does not affect acid-base balance within the body, does not interfere with bleeding time (hemostasis) or with kidney tubular secretion of uric acid wastes, does not inhibit platelet aggrega- tion, and does not produce stomach irritation, erosion, or bleeding after administration.

The OTC oral NSAIDs, including aspirin, ibuprofen, ketoprofen, and naproxen sodium, are particularly effective in settings in which inflammation has caused the sensitization of pain receptors to normally painless mechanical or chemical stimuli. It is generally accepted that pain associ- ated with inflammation and tissue injury most likely results from local stimulation of nociceptors and excessive pain sensitivity. Pain after in- flammation can be attributable to damage to the actual nerves, pressure from the swelling of excess tissue fluid buildup on the nerve endings, or irritation from cellular chemical toxins released from injured tissues. During the inflammatory process, PGs are secreted into the interstitial space between tissues and can prolong and increase the severity of the inflammation response and associated pain. Thus, NSAIDs act specifically as anti-inflammatory agents, and thereby decrease the sensation of pain, by inhibiting COX activity and PG synthesis. The vast majority of NSAIDs available as OTC oral analgesics are organic acids and, in contrast to aspirin, act as reversible, competitive inhibitors of cyclo-oxygenase activity. Aspirin is unique among the NSAIDs in that it chemically modifies both the COX-1 and COX-2 enzymes, which results in an irreversible inhibi- tion of cyclo-oxygenase enzyme activity. Because aspirin and other NSAIDs are organic acids, they are well absorbed orally, bind to plasma blood proteins, accumulate at sites of inflammation, and thus act effectively as anti-inflammatory drugs. In contrast to aspirin, whose duration of pain- alleviating action is determined by the rate of new cyclo-oxygenase enzyme synthesis, the duration of action of all other NSAIDs (reversible inhibitors of cyclo-oxygenase activity) is predominantly related to the ability of the body to clear the NSAID drug through the kidneys via urine excretion.

Aspirin [2-(acetyloxy)benzoic acid; acetylsalicylic acid; C9H8O4] is a member of a family of chemicals called salicylates, which have been used to treat a variety of conditions for more than 2,500 years. The Latin term for willow, salix, provides the historical basis of the name of this family, whose molecules resemble those of both the alcohol and the acid forms of salicylate. The medicinally therapeutic effects of willow tree (genus Salix) bark were known to many diverse cultures of people for centuries. As early as 400 BC, the Greek physician Hippocrates described a bitter powder extracted from willow bark and closely related plants and recommended its use to ease pain and reduce fevers. The use of this product was also promoted by Galen, a second-century Roman physician, and mentioned in medical texts of the Middle Ages and Re- naissance. In 1757, Reverend Edward Stone of England wrote about the success of willow bark in the cure of fevers and aches in a letter to the president of the Royal Society. In 1829, a pharmacist known as H. Ler- oux demonstrated that a bitter glycoside called salicin was the active anti- pyretic ingredient in the willow bark. In 1839, the Italian chemist R. Piria hydrolyzed salicin into glucose and salicyl alcohol and subsequently oxidized salicyl alcohol to salicylic acid. In 1853, C. von Gerhardt ob- tained salicylic acid from the reaction of salicylaldehyde with strong base. This fragrant aldehyde was itself isolated from meadowsweet flowers, which belong to the genus Spiraea. Salicylic acid was also synthesized by a process discovered by H. Kolbe and E. Lautemann in 1860, which led to the introduction of salicylic acid, and related compounds such as so- dium salicylate, in 1875 for the treatment of fever and arthritis. Al- though toxic to the stomach and often causing diarrhea and vomiting, salicylic acid and related compounds were used at high doses to treat pain and inflammation in diseases such as arthritis and to treat fever in ill- nesses such as influenza (flu) for many years. In 1897, the overwhelming success of the salicylate drugs, and also the desire to provide relief for his father’s rheumatoid arthritis, prompted F. Hoffman, a German chemist employed by Friedrich Bayer & Co., to find a less toxic alternative analgesic. He prepared acetylsalicylic acid by chemically modifying salicylic acid (through a reaction with acetic anhydride) based on the work of

C. von Gerhardt more than 40 years earlier and demonstrated that in its acetylated form the salicylate was easily tolerated and possessed a potent analgesic effect. After a clear demonstration of its anti-inflammatory and analgesic effects, H. Dreser, a German chemist also employed by Friedrich Bayer & Co., introduced acetylsalicylic acid into medicine in 1899 in the form of orally administered capsules and powder in envelopes. With commercial production of the acetylated salicylic acid, the term “aspirin” was introduced; it was derived from adding an “a” (for acetylated) to a portion of an older name of the acid, spiraeic acid, which was derived from the genus Spiraea for meadowsweet. Since its acceptance into medical practice at the beginning of the twentieth century, aspirin has be- come one of the most widely available and used drugs for the treatment of illness or injury.

Aspirin covalently modifies both COX-1 and COX-2 enzymes, result- ing in an irreversible inhibition of COX enzyme activity. In the structure of COX-1, aspirin acetylates the serine amino acid residue at position 530 of the long interior protein channel of the enzyme. This chemical alter- ation prevents the binding of arachidonic acid to the active site of the enzyme within the interior enzyme core, prohibiting the enzyme from catalyzing the chemical transformation of arachidonic acid to pain- promoting PGs. In COX-2, aspirin acetylates a homologous serine amino acid residue at position 516 of the long interior protein channel of the enzyme. Thus, covalent modification of the COX-2 enzyme by aspirin blocks the PG synthesis activity of this isoform similar to COX-1. Besides acting as an analgesic, an antipyretic, and an anti-inflammatory drug, as- pirin may also cause changes in kidney function and inhibit blood plate- let function by irreversible inactivation of the cyclo-oxygenase enzyme within the platelets, thereby inhibiting the natural ability of platelets to help form blood clots. As a nonselective COX enzyme inhibitor, aspirin also inhibits the biosynthesis of PGs within the stomach, which normally protect the gastrointestinal tract by inhibiting acid secretion in the stomach and promoting the secretion of protective mucus in the intestine. Thus, aspirin may render the stomach more susceptible to damage and has a strong tendency to cause harmful gastrointestinal side effects, including heartburn (acid reflux) and ulceration of the stomach and/or small intestine.

When aspirin reaches the stomach, the ester is converted back into sa- licylic acid, which then enters the bloodstream to relieve pain by interfering with PG synthesis. The rate at which the acetylsalicylic acid bound with a binder (an inert chemical-binding agent) in a solid orally administered aspirin tablet disintegrates in the stomach is dependent upon pH, such that as pH increases (more alkaline environment), the talet breaks apart more easily, and the faster the “free” salicylic acid is available to be absorbed into the bloodstream. “Buffered” aspirins consist of a combination of aspirin and one or more bases, including magnesium carbonate (MgCO3), magnesium hydroxide [Mg(OH)2], aluminum hydroxide [Al (OH)3], and aluminum glycinate (aluminum salt of the amino acid glycine). While many scientific studies have failed to produce any evidence that buffered aspirin results in quicker or increased overall analgesic effects compared with nonbuffered aspirin, the addition of these bases to the aspirin tablet has been shown to increase the rate of disintegration and subsequent drug absorption into the bloodstream.

Ibuprofen, ketoprofen, and naproxen sodium are all arylpropionic acid derivatives that represent a group of effective and useful analgesic, antipyretic, anti-inflammatory NSAIDs. All of these drugs interfere with the synthesis of prostaglandins via cyclo-oxygenase. For example, ibu- profen and naproxen function as anti-inflammatory drugs by physically plugging (not chemically altering) the long interior protein channels of COX enzymes, thereby preventing molecules of arachidonic acid from entering these enzyme channels and undergoing a chemical transforma- tion in the enzyme’s core into various types of PGs. Although all of these drugs are effective cyclo-oxygenase enzyme inhibitors, there is substan- tial variation in their potency. For example, naproxen is roughly twenty times more potent than aspirin, whereas ibuprofen, ketoprofen, and aspirin generally possess the same cycloxygenase enzyme inhibition potency. Like aspirin, all of these agents may alter platelet function and bleeding time and cause stomach irritation and toxicity. In addition, naproxen in particular may also have prominent inhibitory effects on the functioning of white blood cells.

Reclassified by the Food and Drug Administration from a prescription to an OTC drug in 1984, ibuprofen (p-isobutylhydratropic acid; C13H18O2) was the first member of the propionic acid class of NSAIDs to come into general public use. Ketoprofen (m-benzoylhydratropic acid; C16H14O3) was reclassified similar to ibuprofen in 1995 and shares the pharmacolog- ical properties of other propionic acid-derivative NSAIDs. However, al- though ketoprofen may alleviate pain associated with inflammation by decreasing PG synthesis via inhibition of the cyclo-oxygenase enzyme, this drug may also alleviate inflammatory pain by stabilizing membranes of the cellular organelles called lysozymes, thereby preventing the release of toxic and inflammation-promoting chemicals into body tissues. Ketopro- fen may also decrease pain and inflammation by counteracting the ac- tions of the inflammation-promoting chemical bradykinin. Naproxen [d- 2-(6-methoxy-2-naphthyl)propionic acid; sodium salt: C14H13NaO3] was reclassified in 1994 and also inhibits the cyclo-oxygenase enzyme, thereby interfering with PG synthesis. Interestingly, the half-life drug presence of naproxen in the blood plasma after oral administration is approximately fourteen hours, and this value is increased about two-fold in elderly individuals. In comparison with naproxen, the half-life drug presence of ibuprofen and ketoprofen in the blood plasma after oral administration are each approximately two hours. Thus, for OTC oral naproxen (and naproxen sodium), dosing instructions caution individuals wishing to avoid the toxic physiological effects of the drug not to ingest in excess of three caplets (or tablets) in a twenty-four-hour period unless directed by a physician, and elderly individuals (over sixty-five years of age) are cautioned not to ingest in excess of one caplet every twelve hours unless directed by a physician.