Non-steroidal Anti-inflammatory Drugs (NSAIDs) PDF

Non-steroidal Anti-inflammatory Drugs, Acetaminophen, Gout and Disease Modifying Agents Michael Parker Ph.D. Dept. of Pharmacology; Rm. 1357 [email protected] I. Nonsteroidal Anti-inflammatory Drugs NSAIDs are drugs that decrease production of inflammatory mediators (pr...

Non-steroidal Anti-inflammatory Drugs, Acetaminophen, Gout and Disease Modifying Agents Michael Parker Ph.D. Dept. of Pharmacology; Rm. 1357 [email protected] I. Nonsteroidal Anti-inflammatory Drugs NSAIDs are drugs that decrease production of inflammatory mediators (predominately prostaglandins) possess anti-inflammatory, analgesic, and anti-pyretic effects. Most NSAID’s work best for mild to moderate pain, although efficacy varies between drugs in this class. NSAID’s are generally safer than corticosteroids for long-term use, although some drugs in this class have strong adverse effects & are contraindicated in specific patient populations. Some common adverse effects include mild to moderate gastrointestinal irritation, some agents are hepatotoxic or nephrotoxic. Inflammation Survival is dependent on the ability of an organism to mount an inflammatory response to injuries, pathogens or disease. There are several cellular and plasma derived cellular mediators of inflammation including cytokines, complement activation and eicosanoids. This normal response can be exaggerated and prolonged and seems to serve no benefit and can lead to chronic pain and tissue destruction. NSAIDs act by blocking the production of proinflammatory prostanoids through the inhibition of the cyclooxygenase enzymes. There are 2 cyclooxygenase enzymes: COX-1 is a constitutively expressed, housekeeping enzyme found in most cells. COX-2 is an inducible enzyme thought to play an important role in inflammation and facilitates the inflammatory response – Also important for renal development and vascular prostacyclin production (vasodilation) Prostanoids, the product of cyclooxygenase activity, are expressed in many tissues. They have a variety of actions in these tissues which correlate to some of the benefits and adverse effects of NSAIDs. Tissue Effects of Prostanoids Smooth muscle Vascular smooth muscle thromboxane A2 causes vasoconstriction In vascular smooth muscle PGE2 and PGI2 are vasodilators Airways – PGs relax – TXA2 and PGF2α contract Leukotrienes contract – In asthma aspirin (and others) can cause: 1  Bronchospasm, dyspnea, wheezing: caused by excessive production of cysteinyl leukotrienes Gastric epithelial cells COX1 is expressed constitutively and generates prostaglandins which stimulate the secretions of mucin and bicarbonate into the lumen of the stomach. COX1 generated prostaglandins can also decrease acid production and secretion by the parietal cells in the gastric mucosa. NSAIDs most common side effects – Gastrointestinal distress + bleeding, gastritis – Acid production, mucus/bicarb secretion COX-1 – COX2 selective agents are beneficial in patients with ulcers. Platelets and blood cells PGE2 and PGI2 inhibit the aggregation of platelets (derived from COX2 in endothelium) COX-1 increases Thromboxane A2 (TXA2) which stimulates platelet aggregation and is increased in M.I. – Low dose aspirin can inhibit thromboxane A2 formation specifically in platelets. This is the cardio-protective action. – However COx-2 inhibition can increase clotting and consequently drugs that either selectively or non-selectively block COX-2 have a higher risk of thrombotic events. Kidney Regulate hemodynamics and glomerular and tubular function so use these agents with caution in renal disease. – COX inhibitors can reduce renal function – Worsen hypertension and CHF Reproductive organs Female – Uterus: increases uterine contractions effects lining Prostaglandins stimulate and initiate labor and can induce abortion Dysmenorrhea—uterine contractions during menstruation causing pain (NSAIDS help) Ductus Arteriosus PGs maintain a patent ductus arteriosus in utero So if NSAIDS are given late in pregnancy they cause premature closure which can cause pulmonary hypertension in the newborn – If the baby is premature NSAIDS can help close High dose indomethacin and ibuprofen are used for this Central and Peripheral nervous system actions PGE1 and PGE2 increase body temperature at hypothalamus PGD2 can induce natural sleep 2  PGEs inhibit NE from postganglionic sympathetic nerve endings – NSAIDs block and can cause vasoconstriction. PGE2 can cause hyperalgesia at sites of inflammation by reducing threshold of nociceptor neurons and recruiting leukocytes which release inflammatory mediators. – These two actions play a part in the analgesic actions of NSAIDs but most of the analgesia is due to the central action of preventing PGE2 induced reduction of glycinergic inhibition. NSAIDs main physiologic effects are mediated by blocking cyclooxygenases responsible for prostaglandin synthesis and the effects listed above. Pharmacology of NSAIDs Most NSAIDs are organic acids (except nabumetone) and are reversible (except aspirin): – Some are short acting: t½ 10 hrs Since aspirin is irreversible its effects are longer than that predicted by its ½ life. The COX enzyme must be re-synthesized to return normal function. Organic acids accumulate at sites of inflammation so these drugs are normally targeted to the desired site of action. Most are well absorbed orally metabolized by in the liver followed by renal excretion and highly bound to albumin (>98%) Therapeutic Effects antipyretic, analgesic, antiinflammatory – Except acetaminophen (Tylenol) which is devoid of antiinflammatory action. Acts in the brain as antipyretic and analgesic Analgesia Effective for low to moderate intensity pain Does not change the perception of sensory modalities other than pain. Chronic postoperative pain or pain from inflammation is well controlled – Pain from the hollow viscera, however, is not relieved The exception to this is pain with menstruation Antipyretic All have antipyretic effects even COX-2 selective agents Asprin contraindicated in children with viral induced fever to prevent Reyes syndrome Anti-inflammatory Rheumatoid arthritis and other chronic disorders – Symptomatic relief, do not arrest the progression of the underlying disease Other effects Many of these agents can be used in Gout: with the exception of Aspirin (can worsen at certain doses) and Tolmetin (innefective). Closure of Patent ductus arteriosus Non-selective Cyclooxygenase inhibitors Aspirin, Acetylsalisylic acid, ASA (Bufferin) 3  Readily absorbed from stomach and upper small intestine rapidly converted (T ½ of aspirin is 15 min.) to acetic acid and salicylate (T1/2 2-19 hrs). Hydrolysis is not required for activity. Aspirin is an irreversible COX inhibitor which is about 170xs more selective for COX-1 over COX-2. The metabolism of aspirin is saturable so toxic levels can be reached rapidly. Alkalinization of urine can increase excretion. ♦ Anti-inflammatory effects are due to: o COX inhibition o Possibly interfering with leukocyte adhesion. ♦ Analgesia is due to o Reduced inflammation and a decrease in PGE2 and F2 which cause hyperalgesia o Reduced leukocyte recruitment and activation o Central effects including preventing a decrease in glycinergic inhibition of pain transmission in the dorsal horn. ♦ Antipyretic effects o Reduces elevated temperature  Normal temperatures are minimally affected o Through the inhibition of COX in the hypothalamus ♦ Antiplatelet effects o Through the irreversible acetylation of COX-1 blocks TXA2 formation o Also blocks prostacyclin but clinically the TXA2 effect predominates o Irreversible inhibition in platelets is long (8-11 days, life of the platelet)  The platelets need to be replaced this is why prior to surgical procedures patients are told not to take any NSAIDs within 7 days of surgery This can be a problem with coronary disease, increasing risk of MI Prolonged bleeding time usually returns to normal within 36 hrs. nevertheless 7 days is recommended. Clinical Uses of aspirin o Analgesia, antipyresis, antiinflammatory o Mild to moderate pain (not visceral)  Headache, arthritis, dysmenorrhea  Combined with opioids like oxycodone (Percodan) for moderately severe pain (dentistry) o Rheumatoid arthritis, osteoarthritis etc. (lowest effective dose ~ 3g/day o Prophylactic use for coronary artery disease etc. Selective blocking of TXA2 in platelets  Low dose of 40-80mg/day Aspirin intoxication (Salicylism) This can occur and is fatal if high amounts are ingested (10-30 gms; 300-350µg/ml). Aspirin intoxication is referred to as salicylism, mild chronic symptoms include: headache; dizziness; tinnitus; hearing loss; dimness of vision; mental confusion; lassitude; sweating; thirst; hyperventilation and nausea. More severe symptoms are seen at higher doses and include: convulsions, coma, skin eruptions, acid-base disruptions, fever and dehydration. CNS depression, cardiovascular collapse and respiratory failure lead to death. The treatment for intoxication includes: cardiovascular and respiratory support; removal of agent from the stomach with activated charcoal; correcting acid-base abnormalities; alkalinization of urine to facilitate excretion. 4  Adverse Effects asthma can cause acute bronchoconstriction; can worsen gout; o very low 81mg dose o.k., therapeutic doses ~325mg decreases urate excretion (not good for gout), very high doses increase excretion of urate. Reye’s syndrome is linked to aspirin given to children with viral infections and fever; avoid in GI disease; avoid in head trauma due to risk of bleeding; caution in renal failure; in pregnancy only if necessary it is excreted in breast milk too. Indomethacin (Indocin) Available either orally, I.V., suppository, or as an ophthalmic preparation. It has Anti-inflammatory, Analgesic and Antipyretic actions similar to salicylates but more potent than aspirin, it is not more efficacious It is a non-selective COX-1 and COX-2 inhibitor. Indications: – Primarily for rheumatoid arthritis, osteoarthritis, acute gouty arthritis, eye pain – Used to facilitate closure of patent ductus arteriosus in premature babies Adverse effects: – At higher doses 33% of patients taking this drug need to stop due to the adverse effects. GI pain + hemorrhage, diarrhea, pancreatitis, headache, rarely psychosis, hallucinations and some renal problems can occur. Propionic acid Derivatives: These agents are better tolerated than aspirin and indomethacin. Their efficacy is similar to aspirin but aspirin is cheaper. These agents are indicated for the alleviation of pain and inflammation in many disorders including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, tendonitis, bursitis and dysmenorrhea. They are all relatively equal but naproxen might have an advantage in analgesia and tolerability. Ibuprofen (Motrin, Advil) Dose range 1200mg- 3200mg/day – Can be given w/ food to reduce GI effects – ½ life 2hrs 5-15% of patients stop due to GI problems – Not recommended during pregnancy or breast feeding – Toxicity is similar to salicylism Less anti-inflammatory action than other NSAIDs Alternative to indomethacin for patent ductus arteriosus Injectable formulation for pain and fever in patients unable to take oral Naproxen (Aleve, Naprosyn) Fully absorbed peak in 2-4 hrs. 5  ½ life 14 hrs – 2 xs higher in elderly requires reduction Very similar to Ibuprofen The FDA issued a public health advisory in December 2004 in response to recent data from a long-term clinical trial (up to three years) suggesting that long-term use of a non- selective NSAID, naproxen, may be associated with an increased cardiovascular (CV) risk compared to placebo. Other NSAIDs Ketorolac (Toradol) Ketorolac is a potent analgesic and a moderately effective anti-inflammatory agent. Which is used for the short term treatment of moderately severe acute pain (up to 5 days) such as postoperative pain, it can be used in place of opioids like morphine and is as efficacious. High potency can cause more frequent renal toxicity, and adverse GI and platelet effects. It is also used topically for inflammation of eye. COX-2 Selective agents This class of agents was produced to inhibit the inducible COX-2 at sites of inflammation without affecting constitutively active COX-1. The benefit of this is to preserve anti- inflammatory and analgesic actions without producing the adverse gastrointestinal and platelet actions due to inhibition of the COX-1 enzyme. There are constitutively active COX-2 enzymes present in the kidneys and in bone so inhibition of these enzymes can cause renal toxicity and adversely effect bone repair. These agents are indicated primarily for osteoarthritis, rheumatoid arthritis, and familial adenomatous polyposis. Celecoxib (Celebrex) similar efficacy as other NSAIDs with fewer adverse GI effects Pfizer has said that the prothrombotic effects seen with Vioxx don’t happen at therapeutic doses of Celebrex (less COX2 selectivity than vioxx). FDA requires a black box warning 4/2005 Diclofenac (Cataflam, Voltaren) This is a relatively high potency agent that is more selective for COX-2 over COX-1. Used for long term treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis – Formulations oral with different release times; topical (gel and patch) – Arthrotec: combined formulation with misoprostol (prostaglandin analog- this is designed to reduce GI problems) Adverse effects: – severe hepatic reactions may occur at any time during oral diclofenac therapy. II. Acetaminophen (Tylenol) 6  This is an alternative to aspirin for analgesia and antipyresis. Acetaminophen has no anti-inflammatory actions. Acetaminophen’s therapeutic actions are due to inhibition of COX- 1, COX-2 and COX-3 in the CNS where it produces analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating center. It does not inhibit peripheral COX enzymes and therefore does not inhibit platelet aggregation nor does it cause severe GI problems like other NSAIDs. Because of the lack of peripheral action it is recommended for the elderly and for young children for analgesia and antipyresis. Pharmacology: It is rapidly absorbed with a T ½ 2hrs and 20-50 % protein binding. Hepatic metabolism through conjugation and hydroxylation – N-acetyl-para-benzoquinoneimine (builds up with high dose) Therapeutic uses: – Analgesia, antipyresis Children with viral infections, adjunct in gout, salicylate toxicities etc Recently shown to be an alternative to indomethacin and ibuprofen for patent ductus arteriosus If aspirin is contraindicated with peptic ulcer or bleeding problems Toxicity: A few minor problems like rashes but at high doses or with chronic use Fatal Hepatic Necrosis and possible Acute Renal Failure can occur. – Hepatotoxicity and nephrotoxicity are due to the oxidative metabolite, N-acetyl- para-benzoquinoneimine (NAPQI). It accumulates in the liver and to a lesser degree in the kidney and causes tissue necrosis. This leads to a depletion of glutathione in the liver which causes hepatotoxicity – 10-15 grms hepatotoxic—25grms fatal, much less is toxic to alcoholics (even in the therapeutic range) who have liver damage. Treatment: (immediate to avoid more damage) – Gastric lavage and Addition of sulfhydryl compounds replenish glutathione N-acetylcysteine (Mucosil) and infusion reactions. 7