Analgesic Antipyretic and Antiinflammatory agents

AnalgesicAntipyretic & Antiinflammatory agents   The antiinflammatory, analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and side effects. The prototype is aspirin; hence these compounds are often referred to as aspirin-like drugs; they also are frequently called nonsteroidal antiinflammatory drugs, or NSAIDs. Mechanism of Action of NSAIDs   The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production, the enzymatic activities involved in prostaglandin synthesis. The first enzyme in the prostaglandin synthetic pathway is prostaglandin endoperoxide synthase, or fatty acid cyclooxygenase. This enzyme converts arachidonic acid to the unstable intermediates PGG2 and PGH2. It is now appreciated that there are two forms of cyclooxygenase, termed cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is expressed in all tissues and serves a variety of homeostatic physiologic functions. COX-1 is responsible for the production of protective prostaglandins in the kidney and stomach, as well as the functional thromboxane of platelets.  COX-2, Not normally found in most tissues, expressed under conditions of tissue damage and plays an active role in the inflammatory response.  Inflammation     Inflammatory responses occur in three distinct phases, each apparently mediated by different mechanisms: an acute transient phase, characterized by local vasodilatation and increased capillary permeability; a delayed, subacute phase, most prominently characterized by infiltration of leukocytes and phagocytic cells; and a chronic proliferative phase, in which tissue degeneration and fibrosis occur. Pain     NSAIDs usually are classified as mild analgesics A consideration of the type of pain as well as its intensity is important in the assessment of analgesic efficacy. they are particularly effective in settings in which inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli. Pain that accompanies inflammation and tissue injury probably results from local stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia), in part a consequence of increased excitability of central neurons in the spinal cord In general, NSAIDs do not affect the hyperalgesia or the pain caused by direct action of prostaglandins, consistent with the notion that the analgesic effects of these agents are due to inhibition of prostaglandin synthesis. Fever    Regulation of body temperature requires a delicate balance between the production and loss of heat; the hypothalamus regulates the set point at which body temperature is maintained The cytokines increase the synthesis of PGE2 in the hypothalamic area, and PGE2, via increases in cyclic AMP, triggers the hypothalamus to elevate body temperature by promoting increases in heat generation and decreases in heat loss. NSAIDs suppress this response by inhibiting the synthesis of PGE2 Shared Therapeutic Activities and Side Effects of NSAIDs All NSAIDs are antipyretic, analgesic, and antiinflammatory  these drugs usually are effective only against pain of low-to-moderate intensity  NSAIDs do not change the perception of sensory modalities other than pain.  As antipyretics, NSAIDs reduce the body temperature    NSAIDs find their chief clinical application as antiinflammatory agents in the treatment of musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In general, NSAIDs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury to tissue during severe episodes Aspirin – Mech of Action    Aspirin covalently modifies both COX-1 and COX-2, thus resulting in an irreversible inhibition of cyclooxygenase activity. In the structure of COX-1, aspirin acetylates serine 530, preventing the binding of arachidonic acid to the active site of the enzyme and thus the ability of the enzyme to make prostaglandins. In COX-2, aspirin acetylates a homologous serine at position 516.  Platelets are especially susceptible to aspirinmediated irreversible inactivation of cyclooxygenase because they have little or no capacity for protein biosynthesis and thus cannot regenerate the cyclooxygenase enzyme. In practical terms, this means that a single dose of aspirin will inhibit the platelet cyclooxygenase for the life of the platelet (8 to 11 days); in human beings, a daily dose of aspirin as small as 40 mg is sufficient to produce this effect. Analgesia     The types of pain usually relieved by aspirin are those of low intensity that arise from integumental structures rather than from viscera, especially headache, myalgia, and arthralgia. aspirins are more widely used for pain relief than are any other classes of drugs. Long-term use does not lead to tolerance or addiction, and toxicity is lower than that of opioid analgesics. aspirin alleviate pain by virtue of a peripheral action; direct effects on the CNS also may be involved. Other neurological effects   In high doses, aspirin have toxic effects on the CNS, consisting of stimulation (including convulsions) followed by depression. Confusion, dizziness, tinnitus, high-tone deafness, delirium, psychosis, stupor, and coma may occur. The tinnitus and hearing loss caused by aspirin poisoning are due to increased labyrinthine pressure or an effect on the hair cells of the cochlea, perhaps secondary to vasoconstriction in the auditory microvasculature. aspirin induce nausea and vomiting, which result from stimulation of sites that are accessible from the cerebrospinal fluid (CSF), probably in the medullary chemoreceptor trigger zone. Respiration    aspirin stimulate respiration directly and indirectly. Full therapeutic doses of aspirin increase oxygen consumption and CO2 production (especially in skeletal muscle); these effects are a result of aspirin- induced uncoupling of oxidative phosphorylation. The increased production of CO2 stimulates respiration. Aspirin can directly stimulate the respiratory center in the medulla. This results in marked hyperventilation, characterized by an increase in depth and a pronounced increase in rate. Patients with aspirin poisoning may have prominent increases in respiratory minute volume, and respiratory alkalosis develops. A depressant effect of aspirin on the medulla appears after high doses or after prolonged exposure. Cardiovascular Effects Ordinary therapeutic doses of aspirins have no important direct cardiovascular actions. The peripheral vessels tend to dilate after large doses because of a direct effect on their smooth muscle.  Toxic amounts depress the circulation both directly and by central vasomotor paralysis.  Gastrointestinal Effects   The ingestion of aspirin may result in epigastric distress, nausea, and vomiting. aspirin also may cause gastric ulceration; exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis all have been reported in patients on high-dose therapy but also may occur even when low doses are administered. Hepatic and Renal Effects     at least two forms of hepatic injury. In one form, hepatotoxicity is dose- dependent and usually is associated with plasma concentrations that are maintained above 150 mg/ml. severe hepatic injury and encephalopathy observed in Reye's syndrome This syndrome is a rare but often fatal consequence of infection with varicella and various other viruses, especially the influenza virus. It has been proposed that aspirin and the viral illness may act to damage mitochondria The use of aspirins in children or adolescents with chickenpox or influenza is contraindicated. Pharmacokinetics and Metabolism.    Absorption. Orally ingested aspirins are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable concentrations are found in plasma in less than 30 minutes; after a single dose, a peak value is reached in about 2 hours and then gradually declines. Distribution. After absorption, aspirin is distributed throughout most body tissues and most transcellular fluids, primarily by pHdependent passive processes. aspirin is actively transported by a low-capacity, saturable system out of the CSF across the choroid plexus. The drug readily crosses the placental barrier. Biotransformation and Excretion. The biotransformation of aspirin takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. Toxicity   Symptoms and Signs. Mild chronic aspirin intoxication is termed salicylism. When fully developed, the syndrome includes headache, dizziness, ringing in the ears, difficulty in hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea. A more severe degree of aspirin intoxication is characterized by more pronounced CNS disturbances (including generalized convulsions and coma), skin eruptions, and marked alterations in acid-base balance. Fever is usually prominent Treatment. aspirin poisoning represents an acute medical emergency, and death may result despite all recommended procedures. The treatment is directed at cardiovascular and respiratory support and correction of acid-base abnormalities plus use of measures to speed excretion of aspirin. ACETAMINOPHEN   Acetaminophen is an effective alternative to aspirin as an analgesic-antipyretic agent; however, unlike aspirin, its antiinflammatory activity is weak and thus it is not a useful agent to treat inflammatory conditions. The failure of acetaminophen to exert antiinflammatory activity may be attributed to the fact that acetaminophen is only a weak inhibitor of cyclooxygenase ( reversible) in the presence of the high concentrations of peroxides that are found in inflammatory lesions Pharmacokinetics and Metabolism   Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract. The concentration in plasma reaches a peak in 30 to 60 minutes, and the half-life in plasma is about 2 hours after therapeutic doses. Acetaminophen is relatively uniformly distributed throughout most body fluids. After therapeutic doses, 90% to 100% of the drug may be recovered in the urine within the first day, primarily after hepatic conjugation with glucuronic acid (about 60%), sulfuric acid (about 35%), or cysteine (about 3%); small amounts of hydroxylated and deacetylated metabolites also have been detected.  ingestion of large doses of acetaminophen, Nacetyl-benzoquinoneimine (highly reactive intermediate) is formed in amounts sufficient to deplete hepatic glutathione; under these circumstances, reaction with sulfhydryl groups in hepatic proteins is increased and hepatic necrosis can result, perhaps in part as a result of intracellular accumulation of Ca2+, activation of Ca2+-dependent endonuclease, and resultant DNA fragmentation (apoptosis). Toxicity  The most serious adverse effect of acute overdosage of acetaminophen is a dose-dependent, potentially fatal hepatic necrosis   Nausea, vomiting, anorexia, and abdominal pain occur during the initial 24 hours and may persist for a week or more The principal antidotal treatment is the administration of sulfhydryl compounds, which probably act, in part, by replenishing hepatic stores of glutathione. Nacetylcysteine  Skin rash and other allergic reactions occur occasionally PROPIONIC ACID DERIVATIVES    buprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, and oxaprozin The pharmacodynamic properties of the propionic acid derivatives do not differ significantly. All are effective reversible cyclooxygenase inhibitors, although there is considerable variation in their potency. For example, naproxen is approximately 20 times more potent than aspirin, while ibuprofen, fenoprofen, and aspirin are roughly equipotent as cyclooxygenase inhibitors. All of these agents alter platelet function and prolong bleeding time, and it should be assumed that any patient who is intolerant of aspirin also may suffer a severe reaction after administration of one of these drugs. Pharmacokinetics and Metabolism - Ibuprofen    Ibuprofen is rapidly absorbed after oral administration, and peak concentrations in plasma are observed after 1 to 2 hours. The half-life in plasma is about 2 hours. Absorption also is efficient, although slower, from suppositories. Ibuprofen is extensively (99%) bound to plasma proteins The excretion of ibuprofen is rapid and complete. More than 90% of an ingested dose is excreted in the urine as metabolites or their conjugates. The major metabolites are a hydroxylated and a carboxylated compound. Toxic Effects     Ibuprofen has been used in patients with a history of gastrointestinal intolerance to other NSAIDs. Gastrointestinal side effects are experienced by 5% to 15% of patients taking ibuprofen; epigastric pain, nausea, heartburn, and sensations of "fullness" in the gastrointestinal tract are the usual difficulties. Other side effects of ibuprofen have been reported less frequently. They include thrombocytopenia, skin rashes, headache, dizziness and blurred vision, and, in a few cases, toxic amblyopia, fluid retention, and edema. Patients who develop ocular disturbances should discontinue the use of ibuprofen. Ibuprofen is not recommended for use by pregnant women, or by those who are breast-feeding their infants Naproxen    Pharmacokinetics and Metabolism. Naproxen is fully absorbed when administered orally. The rapidity, but not the extent, of absorption is influenced by the presence of food in the stomach. Peak concentrations in plasma occur within 2 to 4 hours and are somewhat more rapid after the administration of naproxen sodium. Absorption may be accelerated by the concurrent administration of sodium bicarbonate or reduced by magnesium oxide or aluminum hydroxide. Naproxen also is absorbed rectally, but peak concentrations in plasma are achieved more slowly. The half-life of naproxen in plasma is about 14 hours; this value is increased about twofold in elderly subjects and may necessitate adjustment of dosage. Metabolites of naproxen are almost entirely excreted in the urine. About 30% of the drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as the glucuronide or other conjugates. Naproxen is almost completely (99%) bound to plasma proteins following normal therapeutic doses. Naproxen crosses the placenta and appears in the milk of lactating women at approximately 1% of the maternal plasma concentration.  Toxic Effects. Although the incidence of gastrointestinal and CNS side effects is about equal to that caused by aspirin, naproxen is better tolerated in both regards. Gastrointestinal complications have ranged from relatively mild dyspepsia, gastric discomfort, and heartburn to nausea, vomiting, and gastric bleeding. CNS side effects range from drowsiness, headache, dizziness, and sweating to fatigue, depression, and ototoxicity. Less common reactions include pruritus and a variety of dermatological problems. Nonacetylated SalicylatesCelecoxib (Celebrex)    Celebrex relieves the pain and inflammation of osteoarthritis and rheumatoid arthritis. It is the first of a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) called "COX-2 inhibitors." however, it does not interfere with COX-1; Celecoxib is highly selective for COX-2 (375X more than COX-1) Celebrex is therefore less likely to cause the bleeding and ulcers that sometimes accompany sustained use of the older NSAIDs. It does not affect platelet aggregation. Celebrex has also been found to reduce the number of colorectal polyps (growths in the wall of the lower intestine and rectum) in people who suffer from the condition called familial adenomatous polyposis (FAP), an inherited tendency to develop large numbers of colorectal polyps that eventually become cancerous. Side effects    Celebrex and other NSAID medicines can cause serious problems such as liver damage. Some of the warning signs of liver damage are nausea, vomiting, tiredness, loss of appetite, itching, yellow coloring of skin or eyes, “flu-like” symptoms and dark urine. If these happen, stop taking Celebrex and call your health care provider right away. Celebrex and other NSAID medicines can cause serious kidney problems that include sudden kidney failure or worsening of kidney problems that you already have. Celebrex and other NSAID medicines can cause fluid retention and swelling. Fluid retention can be a serious problem if high blood pressure or heart failure is also present  Celebrex contains a sulfonamide derivative as one of its components, which are well known to cause Stevens-Johnson syndrome.  The reaction usually develops within 1-4 weeks from the onset of starting drug therapy. However, the beginning symptoms can develop within hours or days and include mild rash, or mucosal lesions or fever of an unexplained origin. Mucosal lesions include lesions of the mouth, eyes, GI and respiratory tract, anus and vagina.