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Nephropathy

Nephropathy

Nephropathy refers to damage to or disease of the kidney. One cause of nephropathy is the long term usage of analgesics. The pain medicines which can cause kidney problems include aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs, or NSAIDs.

See also


- Diabetic nephropathy
- Hypertensive nephropathy
- Nephritis Category:Nephrology Category:Organ disorders

Kidney

The kidneys are bean-shaped excretory organs in vertebrates. Part of the urinary system, the kidneys filter wastes (especially urea) from the blood and excrete them, along with water, as urine. The medical field that studies the kidneys and diseases affecting the kidney is called nephrology, from the Greek name for the kidney; the adjective meaning "kidney-related" is renal, from the Latin.

Location

In humans the kidneys are two organs located in the posterior part of the abdomen. There is one on each side of the spine just below the liver and spleen. Superior to each kidney is an adrenal gland (also called the suprarenal gland). The kidneys are retroperitoneal, which means they lie behind the peritoneum, the lining of the abdominal cavity. They are approximately at the vertebral level T12 to L3, and the right kidney usually lies slightly lower than the left in order to accommodate the liver. The upper parts of the kidneys are partially protected by the eleventh and twelfth ribs, and each whole kidney is surrounded by two layers of fat (the perirenal fat and the pararenal fat) which help to cushion it. rib

Structure

Organization

In a normal human adult, each kidney is about 11 cm long and about 5 cm thick, weighing 150 grams. The kidneys are "bean-shaped" organs, and have a concave side facing inwards (medially). On this medial aspect of each kidney is an opening, called the hilum, which admits the renal artery, the renal vein, nerves, and the ureter. The outermost portion of the kidney is called the renal cortex, which sits directly beneath the kidney's loose connective tissue capsule. Deep to the cortex lies the renal medulla, which is divided into 10-20 renal pyramids in humans. Each pyramid together with the associated overlying cortex forms a renal lobe. The tip of each pyramid (called a papilla) empties into a calyx, each of which empty into the renal pelvis. The pelvis transmits urine to the urinary bladder via the ureter.

Nephron

The basic functional unit of the kidney is the nephron, of which there are more than a million in each normal adult human kidney. Nephrons regulate water and soluble matter (especially electrolytes) in the body by first filtering the blood, then reabsorbing some necessary fluid and molecules while secreting other, unneeded molecules. Reabsorption and secretion are accomplished with both cotransport and countertransport mechanisms established in the nephrons and associated collecting ducts.

Collecting duct system

Fluid flows from the nephron into the collecting duct system. Because their embryonic origin is different than the renal tubules, the collecting ducts are not usually considered part of the nephron proper. The medullary collecting ducts play an important role in water retention and urine concentration. In the presence of antidiuretic hormone (ADH; also called vasopressin), these ducts become permeable to water and facilitate its reabsorption. The inability of the collecting ducts to respond to ADH may cause excessive urination, called diabetes insipidus. Fluids become more concentrated along the collecting tubules and ducts to form urine, which is then drained into the bladder via the ureter.

Juxtaglomerular apparatus

The site where the ascending loop of Henle touches the afferent arteriole, is called the juxtaglomerular apparatus. It contains a tightly-packed area of cells in the distal tubule, the macula densa, as well as specialized smooth muscle cells called the juxtaglomerular cells. Juxtaglomerular cells are the site of renin synthesis and secretion, and thus play a critical role in the renin-angiotensin system.

Function

Filtration

Renal functions include the excretion of waste material from the bloodstream, secretion of hormones - particularly erythropoietin and renin and maintaining serum electrolyte, acid-base levels and osmolality.

Homeostasis

The kidney regulates the pH, mineral ion concentration, and water composition of the blood. By exchanging hydronium ions and hydroxyl ions, the blood plasma is maintained by the kidney at pH 7.4. Urine, on the other hand, becomes either acidic at pH 5 or alkaline at pH 8. Sodium ions are controlled in a homeostatic process involving aldosterone which increases sodium ion absorption in the distal convoluted tubules. Any rise or drop in blood osmotic pressure due to a lack or excess of water is detected by the hypothalamus, which notifies the pituitary gland via negative feedback. A lack of water causes the posterior pituitary gland to secrete antidiuretic hormone, which results in water reabsorption and urine concentration. Tissue fluid concentration thus returns to a mean of 98%.

Hormone secretion

The kidneys secrete a variety of hormones, including erythropoietin, renin, and vitamin D.

Terms


- renal capsule: The membranous covering of the kidney.
- cortex: The outer layer over the internal medulla. It contains blood vessels, glomeruli (which are the kidneys' "filters") and urine tubes and is supported by a fibrous matrix.
- hilus: The opening in the middle of the concave medial border for nerves and blood vessels to pass into the renal sinus.
- renal column: The structures which support the cortex. They consist of lines of blood vessels and urinary tubes and a fibrous material.
- renal sinus: The cavity which houses the renal pyramids.
- calyces: The recesses in the internal medulla which hold the pyramids. They are used to subdivide the sections of the kidney. (singular - calyx)
- papillae: The small conical projections along the wall of the renal sinus. They have openings through which urine passes into the calyces. (singular - papilla)
- renal pyramids: The conical segments within the internal medulla. They contain the secreting apparatus and tubules and are also called malpighian pyramids.
- renal artery: Two renal arteries come from the aorta, each connecting to a kidney. The artery divides into five branches, each of which leads to a ball of capillaries. The arteries supply (unfiltered) blood to the kidneys. The left kidney receives about 60% of the renal bloodflow.
- renal vein: The filtered blood returns to circulation through the renal veins which join into the inferior vena cava.
- renal pelvis: Basically just a funnel, the renal pelvis accepts the urine and channels it out of the hilus into the ureter.
- ureter: A narrow tube 40 cm long and 4 mm in diameter. Passing from the renal pelvis out of the hilus and down to the bladder. The ureter carries urine from the kidneys to the bladder by means of peristalsis.

Diseases and disorders

Congenital


- Polycystic kidney disease
- Congenital hydronephrosis
- Renal dysplasia
- Congenital obstruction of urinary tract
- Horseshoe kidney
- Duplicated ureter

Acquired


- Renal failure
  - Acute renal failure
  - Chronic renal failure
- Kidney stones are a relatively common and particularly painful disorder.
- Pyelonephritis is infection of the kidneys and is frequently caused by complication of a urinary tract infection.
- Azotemia is a toxic condition characterized by abnormal and dangerously high levels of urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood.
- Hydronephrosis is the enlargement of one or both of the kidneys caused by obstruction of the flow of urine.
- In nephrotic syndrome, the glomerulus has been damaged so that a large amount of protein in the blood enters the urine. Other frequent features of the nephrotic syndrome include swelling, low serum albumin, and high cholesterol.
- kidney tumors
  - Wilms tumor
  - Renal cell carcinoma
- Glomerulonephritis
- Diabetic nephropathy
- Lupus nephritis
- Minimal change disease
- Trauma

Dialysis and kidney transplants

Generally, humans can live normally with just one kidney. Only when the amount of functioning kidney tissue is greatly diminished will renal failure develop. If renal function is impaired, various forms of medications are used, while others are contraindicated. Provided that treatment is begun early, before a serum creatinine of 2 mg/dl, it may be possible to reverse chronic kidney failure due to diabetes or high blood pressure. If creatinine clearance (a measure of renal function) has fallen very low ("end-stage renal failure"), or if the renal dysfunction leads to severe symptoms, dialysis is commenced. Dialysis is a medical procedure, performed in various different forms, where the blood is filtered outside of the body. Kidney transplantation is the only cure for advanced chronic renal failure; dialysis, while correcting the abnormalities to a degree, is seen as a form of "buying time" to bridge the inevitable wait for a suitable organ. The first successful kidney transplant was announced on March 4, 1954 at Peter Bent Brigham Hospital in Boston. The surgery was performed by Dr. Joseph E. Murray, who was awarded the Nobel Prize in Medicine in 1990 for this feat. There are two types of kidney transplants: living donor transplant and a cadaveric (dead donor) transplant. When a kidney from a living donor, usually a blood relative, is transplanted into the patient's body, the donor's blood group and tissue type must be judged compatible with the patient's, and extensive medical tests are done to determine the health of the donor. Before a cadaveric donor's organs can be transplanted, a series of medical tests have to be done to determine if the organs are healthy. Also, in some countries, the family of the donor must give its consent for the organ donation. In both cases, the recipient of the new organ needs to take drugs to suppress their immune system to help prevent their body from rejecting the new kidney [http://www.mayoclinic.org/kidney-transplant/livingdonor.html].

Medical terminology


- Medical terms related to the kidneys involve the prefixes renal- and nephro-.
- Surgical removal of the kidney is a nephrectomy, while a radical nephrectomy is removal of the kidney, its surrounding tissue, lymph nodes, and potentially the adrenal gland. A radical nephrectomy is performed for removal of cancers.

See also


- Urology
- Nephrology
- Nephropathy
- Human anatomy Category:Abdomen Category:Endocrine system Category:Urinary system ja:腎臓 simple:Kidney

Aspirin

Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an anticoagulant (blood thinning) effect and is used in long-term low-doses to prevent heart attacks. The brand name Aspirin was coined by the Bayer company of Germany. In some countries the name is used as a generic term for the drug rather than the manufacturer's trademark. In countries in which Aspirin remains a trademark, the initialism ASA is used as a generic term (ASS in German language countries, for Acetylsalicylsäure; AAS in Spanish language countries, for ácido acetilsalicílico). Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms in children. Low-dose long-term aspirin irreversibly blocks formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets. High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect. tablet Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in stronger doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Aspirin was the first discovered member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.

History of discovery

NSAID Hippocrates, a Greek physician for whom the Hippocratic Oath is named, wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. This remedy is also mentioned in texts from ancient Sumeria, Egypt and Assyria. Native Americans claim to have used it for headaches, fever, sore muscles, rheumatism, and chills. The Reverend Edward Stone, a vicar from Chipping Norton in Oxfordshire England, noted in 1763 that the bark of the willow was effective in reducing a fever. The active extract of the bark, called salicin, after the Latin name for the White willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin is highly acidic when in a saturated solution with water (pH = 2.4), and is called salicylic acid for that reason. This chemical was also isolated from meadowsweet flowers (genus Filipendula, formerly classified in Spiraea) by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as irritated stomach and diarrhea, and even death when consumed in high doses. In 1853, a French chemist named Charles Frederic Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetosalicylic anhydride. Gerhardt's product worked but he had no desire to market it and abandoned his discovery. In 1897, Felix Hoffmann, a researcher at Friedrich Bayer & Co. in Germany, derivatized one of the hydroxyl functional groups in salicylic acid with an acetyl group (forming the acetyl ester) which greatly reduced the negative effects. This was the first synthetic drug, not a copy of something that existed in nature, and the start of the pharmaceuticals industry. Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side effects of salicylic acid. With good results, he then convinced Bayer to market the new wonder drug. Aspirin was patented on March 6, 1899. It was marketed alongside another of Hoffmann's products, an acetylated synthetic of morphine called Heroin. Heroin was initially the more successful of the two painkillers, but as Heroin's shortcoming of addictiveness became more obvious, Aspirin stepped to the forefront. Aspirin was originally sold as a powder and was an instant success; in 1915, Bayer introduced Aspirin tablets. Several claims to invention of aspirin have arisen. Acetylsalicylic acid was already being manufactured by the Chemische Fabrik von Heyden Company in 1897, although without a brand name. Arthur Eichengrün claimed in 1949 that he planned and directed the synthesis of aspirin while Hoffmann's role was restricted to the initial lab synthesis using Eichengrün's process. In 1999, Walter Sneader of the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow re-examined the case and agreed with Eichengrün's account. Bayer continues to recognize Felix Hoffmann as aspirin's official inventor. Despite its argued origin, Bayer's marketing was responsible for bringing it to the world. It was not until the 1970s that the mechanism of action of aspirin and similar drugs called NSAIDs was elucidated (see below).

Synthesis of aspirin

Aspirin (acetylsalicylic acid) can be synthesized from salicylic acid and acetic anhydride. It is a common experiment performed in organic chemistry labs, and generally tends to produce low yields due to the relative difficulty of its extraction from an aqueous state. Image:Aspirin-synthesis.gif

History of the name "Aspirin"

Image:Aspirin-synthesis.gif The name "aspirin" is composed of a- (from the acetyl group) -spir- (from the spiraea flower) and -in (a common ending for drugs at the time). Bayer registered it as a trademark on March 6, 1899. However, the German company lost the right to use the trademark in many countries as the Allies seized and resold its foreign assets after World War I. The right to use "Aspirin" in the United States (along with all other Bayer trademarks) was purchased from the U.S. government by Sterling Drug, Inc in 1918. Even before the patent for the drug expired in 1917, Bayer had been unable to stop competitors from copying the formula and using the name elsewhere, and so with a flooded market, the public was unable to recognize "Aspirin" as coming from only one manufacturer. Sterling was subsequently unable to prevent "Aspirin" from being ruled a genericized trademark in a U.S. federal court in 1921. Other countries (such as Canada) still consider "Aspirin" a protected trademark.

How it works

In a piece of research for which he was awarded both a Nobel prizein Physiology or Medicine in 1982 and a knighthood, John Robert Vane, who was then employed by the Royal College of Surgeons in London, showed in 1971 that aspirin suppresses the production of prostaglandins and thromboxanes. This happens because cyclooxygenase, an enzyme which participates in the production of prostaglandins and thromboxanes, is irreversibly inhibited when aspirin acetylates it. This makes aspirin different from other NSAIDS (such as diclofenac and ibuprofen) which are reversible inhibitors. Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the hypothalamic thermostat and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin. More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that only inhibit COX-2, with the hope that this would reduce the gastrointestinal side effects. However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors. Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties :
- It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria.
- It induces the formation of NO-radicals in the body that enable the white blood cells (leucocyts) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005. Also recently aspirin has been proven to prevent carcinoma of the colon, if given in low doses over years.

Indications

Aspirin, as many older drugs, has proven to be useful in many conditions, and despite its well known toxicity, it is widely used, since physicians are familiar with its properties. Indications include:
- Fever
- Pain (Specially useful in osteoid osteoma, arthritis and chronic pain conditions)
- Migraine
- Myocardial infarction prophylaxis (low dose)
- Drug of choice for rheumatic fever

Contraindications and Warnings


- Do NOT take this medicine if you are allergic to aspirin, ibuprofen or naproxen.
- Talk to your doctor if your symptoms do NOT improve after a few days of therapy.
- If you have kidney disease, ulcers, mild diabetes, gout, gastritis, talk to your doctor before using this medicine.
- Taking aspirin with alcohol increases the chance of stomach bleeding. Avoid alcohol with this medicine.
- Giving aspirin to children, including teenagers having a cold or flu can cause a serious condition known as Reye's syndrome.
- Patients with hemophilia, other bleeding tendencies, or a bleeding ulcer should not take salicylates.

Common side effects


- Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.
- Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high dosed antacids, ranitidine or omeprazol.
- Frequently central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side effects will occur.
- Sweating, seen with high doses, independent from antipyretic action
- Long-term treatment with high doses (arthritis and rheumatic fever) : often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye's syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30% of those afflicted will eventually die. Prompt hospital treatment may be life-saving.
- Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.
- Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.
- Skin reactions, angioedema, and bronchospasm have all been seen infrequently.

Overdose

Aspirin overdose has serious consequences and is potentially lethal. 52 deaths involving single-ingredient aspirin were reported in the United States in the year 2000. Effects of overdose include:
- Tinnitus
- Abdominal pain
- Hypokalemia
- Hypoglycemia
- Pyrexia
- Hyperventilation
- dysrhythmia
- Hypotension
- Hallucination
- Renal failure
- confusion
- Seizure
- Coma
- Death Overdose can be acute or chronic; that is, a person can overdose by taking one very large dose or smaller doses over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality rate of 25%. The most common cause of death during an aspirin overdose is noncardiogenic pulmonary edema. An acute overdose patient must be taken to a hospital immediately. Contrary to the urban legend, you can die from eating a bottle of pills, even if you subsequently throw up. Treatment of an acute overdose requires ingestion of activated charcoal to neutralize the acetylsalicylic acid in the gastrointestinal tract, followed by a stomach pump with subsequent re-ingestion of activated charcoal. Patients are then monitored for at least 24 hours and typically given intravenous potassium chloride to counteract hypokalemia, sodium bicarbonate to neutralize salicylate in the blood and restore the blood's sensitive pH balance, and dextrose to restore blood sugar levels. Frequent blood work is performed to check metabolic, salicylate, and blood sugar levels; arterial blood gas assessments are performed to test for respiratory alkalosis and metabolic acidosis. If the overdose was intentional, the patient will undergo psychiatric evaluation as with any suicide attempt.

External links


- http://www.bayeraspirin.com
- http://almaz.com/nobel/medicine/aspirin.html
- http://chemed.chem.purdue.edu/genchem/topicreview/bp/1biochem/research7.html
- http://www.med.mcgill.ca/mjm/issues/v02n02/aspirin.html
- http://www.jhu.edu/~jhumag/0297web/health.html
- http://www.howstuffworks.com/aspirin

References

# Litovitz TL. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001;19(5):337-395 Category:Non-steroidal anti-inflammatory drugs Category:Over-the-counter substances Category:Anticoagulants Category:Aromatic compounds Category:Esters Category:Carboxylic acids ko:아스피린 ms:Aspirin ja:アスピリン th:แอสไพริน

Acetaminophen

Paracetamol (INN) or acetaminophen (USAN) is a popular analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is remarkably safe in standard doses, but because of its wide availability, deliberate or accidental overdoses are not uncommon. Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties, and so it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. In normal doses paracetamol does not irritate the lining of the stomach nor affect blood coagulation, the kidneys or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics, paracetamol does not cause euphoria or alter mood in any way. Paracetamol and NSAIDs have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal. The words acetaminophen and paracetamol both come from the chemical names for the compound: N-acetyl-para-aminophenol and para-acetyl-amino-phenol.

History

In ancient and medieval times, the only antipyretic agents known were compounds contained in willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds contained in cinchona bark. Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle and late 19th century. When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s; Acetanilide in 1886 and Phenacetin in 1887. By this time, paracetamol had already been synthesized by Harmon Northrop Morse via the reduction of p-nitrophenol with tin in glacial acetic acid. While this was first performed in 1873, paracetamol was not used medically for another two decades. In 1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time. In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a non-lethal blood condition. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol (acetaminophen), since it did not have the toxic effects of acetanilide. (Brodie and Axelrod, 1948) The product went on sale in the United States in 1955 under the brand name Tylenol. In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach", since other analgesic agents of the time contained aspirin, a known stomach irritant. In June 1958 a children's formulation, Panadol Elixir, was released. In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side effects and little interaction with other pharmaceutical agents. The U.S. patent on paracetamol has expired and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations are protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".

Available forms

Panadol, which is marketed in Europe, Asia and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form or under a number of trade names: for instance Tylenol (McNeil-PPC, Inc), Anacin-3 and Datril. In some formulations paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol 1/2/3/4 and in the US only available by prescription, while over-the-counter in Canada. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Pediapirin, and Perfalgan. Paracetamol is also combined with oxycodone and marketed in the U.S. as Percocet. Percocet It is commonly administered in tablet, liquid suspension, or suppository form. The common adult dose is 500 mg to 1000 mg four times a day. The recommended maximum daily dose, for adults, is 4 grams. Doses above 150 mg/kg or 7.5 g for an adult are likely to cause hepatotoxicity (liver damage). In recommended doses paracetamol is safe for children and infants as well as for adults. Because of the widespread availability of paracetamol, its effectiveness is often underestimated.

Mechanism of action

hepatotoxicity Paracetamol has long been suspected of having a similar mechanism of action to aspirin because of the similarity in structure. That is, it has been assumed that paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX) enzyme. However, there are important differences between the effects of aspirin and paracetamol. Prostaglandins participate in the inflammatory response, but paracetamol has no appreciable anti-inflammatory action. Furthermore, COX also produces thromboxanes which aid in blood clotting — aspirin reduces blood clotting, but paracetamol does not. Finally, aspirin and the other NSAIDs commonly have detrimental effects on the stomach lining, where prostaglandins serve a protective role, but paracetamol is safe. Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, Boutaud et al. (2002) found that paracetamol indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Swierkosz et al. (2002) reported data suggesting that paracetamol selectively blocks a variant of the COX enzyme that is different from the then known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. It has also been suggested that administration of paracetamol increases the bioavailability of serotonin (5-HT) but the mechanism is unknown.

Metabolism

Paracetamol is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system. The toxic effects of paracetamol are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not paracetamol itself or any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.

Toxicity

Overview

Paracetamol has a narrow therapeutic index. This means that the common dose is close to the overdose, making it a relatively dangerous substance. Paracetamol single doses above 10 grams or chronic doses over 5 grams per day in a well-nourished non-consumer of alcohol, or above 4 grams per day in a poorly nourished consumer of alcohol, can cause significant injury to the liver. Without timely treatment, paracetamol overdoses can lead to liver failure and death within days. Because of the wide over-the-counter availability of the drug, it is sometimes used in suicide attempts. Paracetamol should not be taken after alcohol consumption, because the liver, when engaged in alcohol breakdown, cannot properly dispose of paracetamol, thus increasing the risk of hepatotoxicity. When used responsibly, Paracetamol is one of the safest medications available for analgesia. The drug lacks effects on the cyclooxygenase system so does not cause injury to the esophagus, stomach, small intestine or large intestine, in contrast to NSAIDs. Additionally, patients with kidney disease are able to take paracetamol whereas NSAIDs can cause acute renal failure in certain patients. Paracetamol also lacks problems with drug interactions. The analgesic potency is equivalent in non-inflammatory conditions to NSAIDs as long as the dose of paracetamol is adequate. 1 gram of paracetamol three times a day is equivalent to analgesia provided by NSAIDs in osteoarthritis, for example. When coadministered with amitriptyline 50 mg twice a day, the combination is as effective as paracetamol with codeine, but does not lose effectiveness as an analgesic over time as does chronic administration of narcotics. Unlike aspirin, paracetamol does not contribute to the risk of Reye's syndrome in children with viral illnesses. These factors have made paracetamol the analgesic of choice for mild and moderate pain for patients in hospitals and makes it the leading analgesic for outpatient use. Paracetamol is extremely toxic to cats and should not be given to them under any circumstances. Any cases of suspected ingestion should be taken to a veterinarian immediately for decontamination. Treatment in cats is very similar to treatment in people.

Mechanism of toxicity

As mentioned above, paracetamol is mostly converted to inactive compounds by conjugation with sulfate and glucuronide, with a small portion being metabolized via the cytochrome P450 enzyme system. The cytochrome P450 system oxidizes paracetamol to produce a highly reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI). Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. Subsequently, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, clinically leading to acute hepatic necrosis. In animal studies, 70% of hepatic glutathione must be depleted before hepatotoxicity occurs.

Risk factors for toxicity

The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 140 mg/kg have a reasonable likelihood of causing toxicity. In adults, single doses of more than 25 grams have a high risk of lethality. Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of smaller doses. However, unintentional paracetamol overdose in children rarely causes illness or death. This may be due in part to the immature cytochrome P450 (CYP) enzyme system in children. Excessive consumption of alcohol can impair liver function and increase the potential toxicity of paracetamol. For this reason, other analgesics such as aspirin or ibuprofen are recommended for hangovers. Some individuals are more susceptible to hepatotoxicity, with toxic doses as low as 4 g/day, and death with as little as 6 g/day. Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves. It is well documented that concomitant use of the CYP2E1 inducer isoniazid increases the risk of hepatotoxicity, though whether CYP2E1 induction is related to the hepatotoxicity in this case is unclear (Crippin, 1993; Nolan et al., 1994). Chronic alcoholism, which also induces CYP2E1, is also well known to increase the risk of paracetamol-induced hepatotoxicity (Zimmerman & Maddrey, 1995). Concomitant use of other drugs which induce CYP enzymes such as antiepileptics (including carbamazepine, phenytoin, barbiturates, etc) have also been reported as risk factors.

Natural history

Individuals who have overdosed on paracetamol generally have no specific symptoms for the first 24 hours. Although anorexia, nausea, vomiting, and diaphoresis are common initially, these symptoms resolve after several hours. After resolution of these non-specific symptoms, individuals tend to feel better, and may believe that the worst is over. If a toxic dose was absorbed, after this brief feeling of relative wellness, the individual develops overt hepatic failure. In massive overdoses, coma and metabolic acidosis may occur prior to hepatic failure. Damage generally occurs in hepatocytes as they metabolize the paracetamol. However, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or multi-system organ failure. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it is possible that the toxic metabolite is produced more in the kidneys than in the liver. The prognosis of paracetamol varies depending on the dose and the appropriate treatment. In some cases, massive hepatic necrosis leads to fulminant hepatic failure with complications of bleeding, hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks.

Diagnosis

Evidence of liver toxicity may develop in 1 to 4 days, although in severe cases it may be evident in 12 hours. Right upper quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times (particularly, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. Generally the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity. Drug nomograms are available that will estimate a risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion. To determine the risk of potential hepatotoxicity, the paracetamol level should be traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote. (see below)

Treatment

The treatment for uncomplicated paracetamol overdose, similar to any other overdose, is gastrointestinal decontamination. In addition, N-acetylcysteine (NAC) administration (either intravenous or oral) plays an important role. There is considerable room for physician judgment regarding gastrointestinal decontamination with gastric lavage and/or activated charcoal administration. Paracetamol absorption from the gastrointestinal tract is complete within 2 hours under normal circumstances. This is somewhat slowed when it is ingested with food. Ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and (oral) NAC. Gastric lavage is helpful within the first 2 to 4 hours of paracetamol ingestion. Activated charcoal is often more helpful than gastric lavage. Activated charcoal absorbs paracetamol well and therefore reduces its gastrointestinal absorption. Administering activated charcoal also poses less risk of aspiration than gastric lavage. Previously there was reluctance to give activated charcoal in paracetamol overdose, because of concern that it may also absorb NAC. Studies have shown that no more than 39% of oral NAC is absorbed when they are administered together. Other studies have shown that activated charcoal seems to be beneficial to the clinical outcome. There is uniform agreement on administering activated charcoal within the first 4 hours of paracetamol overdose; administering activated charcoal after the first 4 hours is a clinical judgment and is considered a benign therapy. If concern exists that other drugs were ingested with the paracetamol, then activated charcoal should be given. There are conflicting recommendations regarding whether to change the dosing of oral NAC after the administration of activated charcoal, and even whether the dosing of NAC needs to be altered at all. NAC presumably works by supplying sulfhydryl groups to react with the toxic metabolite so that it does not damage cells. If given within 8 hours of ingestion, NAC reliably prevents toxicity. If NAC is started more than 8 hours after paracetamol ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver had already begun, and the risk of acute hepatic necrosis and death increase dramatically. Oral NAC (available in the United States under the name Mucomyst®) is a safe drug, is indicated in paracetamol overdose during pregnancy, and life-threatening adverse reactions do not occur. The manufacturer's recommendation is avoidance of administration if an encephalopathy is present, due to the theoretical concerns that it may worsen encephalopathy. Intravenous NAC is commercially available outside the United States of America (under the name Parvolex®). In early 2004, the United States Food and Drug Administration approved a pyrogen-free NAC preparation (Acetadote) for continuous intravenous infusion over 20 hours (total dose 300 mg/kg) in patients presenting within 10 hours after ingestion. This formulation has been used successfully for years in other countries, including Australia, Canada, and Great Britain. Recommended administration involves infusion of a 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg infusion over 4 hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. The oral formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use. It is a good option in patients who cannot tolerate enteral NAC or for whom enteral intake is contraindicated. Intravenous NAC is associated with allergic reactions such as anaphylaxis and bronchospasm. In clinical practice, if the patient presents more than 8 hours after the paracetamol overdose, then activated charcoal is probably not useful, and NAC should be started immediately. In earlier presentations the doctor can give charcoal as soon as the patient arrives, start giving NAC, and wait for the paracetamol level from the laboratory. If the patient presents less than 8 hours after paracetamol overdose, the risk of serious hepatotoxicity has been rare. If repeat doses of charcoal are indicated because of another ingested drug, then subsequent doses of charcoal and NAC should be staggered every two hours. NAC is most effective if given early, but still has beneficial effects if given as late as 48 hours after paracetamol ingestion. In general, oral NAC is given enterally as a 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 more doses. NAC can be difficult to administer because of its taste and its tendency to cause nausea and vomiting. To maximize tolerance, it can be diluted down to a 5% solution from its commercially available 10% or 20% solutions. Baseline laboratory studies should include bilirubin, AST, ALT, and prothrombin time (with INR). Studies should be repeated at least daily. Once it has been determined that a potentially toxic overdose has occurred, NAC must be continued for the entire 17 dose regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, NAC should be continued beyond the standard 17 doses until hepatic function improves or until the patient has a liver transplant. The mortality rate from paracetamol overdose starts to climb 2 days after the ingestion, reaches a maximum on day 4, and then gradually decreases. Patients with a poor course should be identified early and transferred to a center capable of liver transplantation. Acidemia is the most ominous indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH of < 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in prothrombin time from day 3 to day 4. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality) while a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).

References


- Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA (2002). Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc Natl Acad Sci U S A 99 (10), 7130-5. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12011469 Full text]. PMID 12011469.
- Brodie BB & Axelrod J (1948). J. Pharmacol. Exp. Ther. 94, 29-38
- Crippin JS (1993). Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J Gastroenterol 88 (4), 590-2. PMID 8470644.
- Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD (1994). Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 105 (2), 408-11. PMID 7508362.
- Swierkosz TA, Jordan L, McBride M, McGough K, Devlin J, Botting RM (2002). Actions of paracetamol on cyclooxygenases in tissue and cell homogenates of mouse and rabbit. Med Sci Monit 8 (12), BR496-503. PMID 12503027.
- Zimmerman HJ & Maddrey WC (1995). Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 22 (3), 767-73. PMID 7657281.

See also


- Tylenol
- Tylenol scare

External links


- [http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic.html Paracetamol Information Centre]
  - [http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic5.html History of paracetamol]
- [http://www.pharmcast.com/Patents/October2000/100300OG/6126967_Acetaminophen100300.htm US Patent 6,126,967]
- [http://www.assistpainrelief.com/info/paracetamol/ History of paracetamol]
- [http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/paracet_text.htm History & chemistry of paracetamol]
- [http://profiles.nlm.nih.gov/HH/Views/Exhibit/narrative/amines.html The Julius Axelrod Papers]
- [http://www.superbrands-brands.com/volII/brand_panadol.htm Superbrands (Panadol)] Category:Amides Category:Phenols Category:Analgesics Category:Antipyretics Category:Over-the-counter substances th:พาราเซตามอล ms:Asetaminofen ja:アセトアミノフェン

NSAID

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which (amongst a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs). The most prominent members of this group of drugs are aspirin and ibuprofen. Paracetamol (acetaminophen) has negligible anti-inflammatory activity, and is strictly speaking not an NSAID. Beginning in 1829, with the isolation of salicylic acid from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation, respiratory depression, or addiction. NSAIDs, however, are not without their own problems (see below). Certain NSAIDs, including ibuprofen and aspirin, have become accepted as relatively safe and are available over-the-counter without prescription.

Mode of action

Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane, who later received a Nobel Prize for his work.

Examples of NSAIDs

NSAIDs can be broadly classified based on their chemical structure. NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy between the NSAIDs when used at equivalent doses. Rather, differences between compounds tended to be with regards to dosing regimens (related to half-life), route of administration, and tolerability profile. Some more common examples are given below. Paracetamol (acetaminophen), owing to its inhibitory action on cyclooxygenase, is sometimes grouped together with the NSAIDs. Paracetamol, however, does not have any significant anti-inflammatory properties and is not a true NSAID. Though it has not been clearly elucidated, it is suspected that this lack of anti-inflammatory action may be due to the paracetamol inhibiting cyclooxygenase predominantly in the central nervous system. There is also some speculation that paracetamol acts through the inhibition of the recently discovered COX-3 isoform (see below).

salicylates


- aspirin
- methyl salicylate
- diflunisal

arylalkanoic acids


- indomethacin
- sulindac
- diclofenac

2-arylpropionic acids (profens)


- ibuprofen
- ketoprofen
- naproxen
- ketorolac
- carprofen

N-arylanthranilic acids (fenamic acids)


- mefenamic acid

oxicams


- piroxicam
- meloxicam

coxibs


- celecoxib
- rofecoxib (withdrawn from market)
- valdecoxib
- parecoxib
- etoricoxib

sulphonanilides


- nimesulide

Uses of NSAIDs

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease. NSAIDs are generally indicated for the symptomatic relief of the following conditions. (Rossi, 2004)
- rheumatoid arthritis
- osteoarthritis
- inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
- acute gout
- dysmenorrhoea
- metastatic bone pain
- headache and migraine
- postoperative pain
- mild-to-moderate pain due to inflammation and tissue injury
- pyrexia
- renal colic Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States. (Green, 2001). With the aging of the Baby Boomer generation and the associated rise in the incidence of osteoarthritis and other such conditions for which NSAIDs are indicated, the use of NSAIDs may increase further still.

Adverse effects

The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs), associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents. These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10-20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. (Green, 2001)

Gastrointestinal ADRs

The main ADRs associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins. Common gastrointestinal ADRs include: (Rossi, 2004)
- nausea
- dyspepsia
- ulceration/bleeding
- diarrhoea Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates. (Rossi, 2004) Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration. (Rossi, 2004) Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may be effective, they prove to be expensive for maintenance therapy.

Renal ADRs

NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is probably due to changes in renal haemodynamics (bloodflow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Horses are particularly prone to these adverse affects compared to other domestic animal species. Common ADRs associated with altered renal function include: (Rossi, 2004)
- salt and fluid retention
- hypertension These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect. (Thomas, 2000) In rarer instances NSAIDs may also cause more severe renal conditions. (Rossi, 2004)
- interstitial nephritis
- nephrotic syndrome
- acute renal failure

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. (Moore, 2002) It is somewhat ironic that these antiinflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine. Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. Whilst ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.

Other ADRs

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness (Rossi, 2004). Uncommon ADRs include: heart failure, hyperkalaemia, confusion, bronchospasm, rash (Rossi, 2004).

Newer NSAID'S: Selective COX inhibitors

COX-2 inhibitors

The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents. It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins. COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. When non-selective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen)) lower stomach prostaglandin levels, these protective effects are lost and ulcers of the stomach or duodenum and potentially internal bleeding can result. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAID's. The relatively selective COX-2 inhibiting oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

Controversies with COX-2 inhibitors

While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs), there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac. Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen. (Bombardier et al 2000). This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.

COX-3 inhibitors

Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol, arguably the most widely used analgesic drug in the world. (Chandrasekharan et al 2002). The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. The clinical ramifications and knowledge of COX isozymes are rapidly expanding and may offer significant hope for future treatments of pain, inflammation, and fever.

References


- Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21):1520-8. PMID 11087881.
- Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926-31. PMID 12242329.
- Green GA. Understanding NSAIDS: from aspirin to COX-2. Clin Cornerstone 2002;3:50-59. PMID 11464731.
- Moore DE. Drug-induced cutaneous photosensitivity. Drug Safety 2002;25:345-72. PMID 12020173.
- Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
- Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172:184-185. PMID 10772593.
- ja:非ステロイド性抗炎症薬 th:เอ็นเซด

Hypertensive nephropathy

Hypertensive nephropathy (or "hypertensive nephrosclerosis", or "Hypertensive renal disease") is a medical condition refering to damage to the kidney due to chronic high blood pressure. It should be distinguished from "renovascular hypertension" (I15.0), which is a form of secondary hypertension. In the kidneys, as a result of benign arterial hypertension, hyaline (pink, amorphous, homogeneous material) accumulates in the wall of small arteries and arterioles, producing the thickening of their walls and the narrowing of the lumens - hyaline arteriolosclerosis. Consequent ischemia will produce tubular atrophy, interstitial fibrosis, glomerular alterations (smaller glomeruli with different degrees of hyalinization - from mild to sclerosis of glomeruli) and periglomerular fibrosis. In advanced stages, renal failure will occur. Functional nephrons have dilated tubules, often with hyaline casts in the lumens.

External links


- [http://www.pathologyatlas.ro/Nephroangiosclerosis.html Photo at Atlas of Pathology]
- [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12728683&dopt=Abstract PubMed]
- [http://ndt.oxfordjournals.org/cgi/content/full/15/10/1515 Oxford Journals] Category:Nephrology

Category:Nephrology

Nephrology is the branch of medicine that deals with diseases of the kidney. Category:Medical specialties

Category:Organ disorders

This category contains disorders of the organs Category:Organs Category:Diseases

Categoría:Monumentos de Cantabria

Cantabria Categoría:Cultura de Cantabria

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منبع

مرجع:
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برگ سنجدی نام رنگی است به رنگ برگ سنجد که از خانواده سبز است. برای تهیه این رنگ از این مواد بهره می‌گیرند: نیل، سود، هیدروسولفیت،
پوست پیازی
پوست پیازی نام یکی از رنگ‌ها است. این رنگ نزدیک به صورتی یا چهره ای است. برای تهیه این رنگ از این مواد بهره می‌گیرند: نیل، سود، زاج سفید، روناس و اسپرک. از این رنگ در صنعت