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Throughout the years, medicine has been on an endeavor to discover new and better drugs capable of fighting various diseases and symptoms more effectively. Two symptoms in need of better medications are pain and inflammation. Traditionally, opiate based medications have been used to combat pain. The Chinese have been using opium based analgesics for thousands of years. Opiate based drugs like morphine also gained popularity in World War II. Another type of drug, steroid based drugs, have also proved to be very effective anti-inflammatory drugs. However, both of these classes of drugs have their issues. Opiate drugs have bad side effects such as addiction and steroids also have bad side effects like kidney failure. Both are also expensive, hard to make, and require prescriptions. Non-steroidal anti-inflammatory drugs (NSAIDs) are great drugs that reduce pain and inflammation. Many are available over the counter, and do not have many negative side effects.
Cyclooxygenase and Prostaglandins
Cyclooxygenase (COX) is a well known and studied enzyme that is found in many mammalian tissues. COX is responsible for the conversion of arachidonic acid into various prostanoids. Arachidonic acid is an omega 6 fatty acid 20:4 (-6). The production of this fatty acid is like the general synthesis of most fatty acids in that a phospholipid is converted to arachidonic acid via a phospholipase. Arachidonic acid can then be transformed into many biochemical substrates that are important for physiological processes. Arachidonic acid is converted via cyclooxygenase to the substrate prostaglandin H2 (PGH2). Prostaglandin H2 is the precursor to the prostanoids prostaglandins (PG) and thromboxane. PG and thromboxane are chemicals used for many processes such as blood clotting and vasoconstriction (1).
Figure 1 Conversion arachidonic acid to various prostaglandins. (1)
Cyclooxygenase activities were known before the enzyme itself was actually discovered. For many years aspirin was used as a non opiate pain killer and anti-inflammatory with adequate effects. The actual process of cyclooxygenase was not known until 1971 when it was determined that aspirin could inhibit the production of prostaglandin synthesis via blockage of cyclooxygenase enzyme (2).
There are currently three known isoformes of cyclooxygenase. They are known as COX-1, COX-2 and COX-3. However, COX-3 has only been recently discovered and for many reasons, some researchers still question its actual existence (3). COX-1 and COX-2 are from two different genes, but contain approximately 60% homology (4). They are the product of different expression and regulations. COX-1 is considered a constitutive enzyme because of its finding in a wide amount of tissues including kidneys. It is also used for many "housekeeping" duties. COX-1 is expressed in the Bowman's capsule, as well as the cortical and medullary collecting ducts. COX-2 is not found in as many tissues as COX-1, but it is found in the kidney and more specifically it is found in the macula densa, thick ascending limb, and the inner medullary collecting duct (5, 6, 7).
COX enzymes convert arachidonic acid into PGH2. The PGH2 is then converted by a number of prostaglandin synthases to a wide variety of prostanoids including prostaglandins and thromboxanes. Each of these prostaglandin synthases are found in many parts of the kidney. The prostaglandins can be even further classified into subtypes including PGE, PG I, PGD and PGF. The prostaglandins work mainly through a family of related G-protein linked receptors labeled EP, FP, IP, and DP for the prostaglandin subtypes. FP, DP and an EP subtype 1 work to increase cytosolic Ca2+. On the other hand, DP, IP and EP subtypes 2 and 4 work to increase cyclic adenosine monophosphate (cAMP) (8). The most commonly found prostaglandin in the kidney is that of prostaglandin E subtype 2 (PGE2) (1, 9, 10).
It is widely known that COX and prostaglandins play a very important role in renal homeostasis. These roles include modulating renal blood flow (RBF), glomerulal filtration rate (GFR), and interaction with the rennin-angiotensin system. RBF is the amount of blood delivered to the kidney in one hour. GFR is the rate in which the kidneys filter the blood. Both RBF and GFR are very important indicators of renal sufficiency. Both these rates are controlled through various mechanisms like tubuloglomerular feedback and a variety of biochemicals. In either case, the main control of these rates is through pressure regulations and blood flow in the Bowman's capsule as well as in the efferent and afferent arterioles. Arteriole tone is modulated by vasoconstrictors. These vasoconstrictors constrict the arterioles to lessen the amount of blood flow through them. The pressure decrease causes a decrease in blood flow and filtration (11,12).
Prostaglandins are notorious for their vasodilation capabilities. Their vasodilator effect is the main reason for swelling because it causes an increase in blood flow. In the kidney, it is believed that COX-2 derived prostanoids cause vasodilation in the arterioles of the nephrons. This vasodilation counteracts the vasoconstriction that is the result of various vasoconstrictors such as Angiotensin II (13). This will cause a reverse of vasoconstriction and lead to increase in RBF and GFR. In fact, studies have indicated that COX-2 derived prostaglandins contribute directly to the renal vascular resistance of the afferent arteriole (14, 15).
COX derived prostaglandins may also be involved with renal homeostasis of salt levels. One of the kidneys main functions is to control excretion and re-absorption of various electrolytes by blood flow. It can also regulate serum electrolyte levels through hormones such as vasopressin, which increases water retention to lower serum salt levels. A study has shown that, in animals, reduction in sodium intake can induce an expression of COX up to three times its normal expression (16). A recent study has even shown that COX may be very important in long-term regulation of renal homeostasis when salt intake is low (17). It was also found that COX inhibitors decrease GFR in salt depleted elderly subjects (18) It has also been shown that a high salt diet increases COX2 expression (19, 20). The exact mechanisms are not known, but may perhaps have to do again with blood flow. However, the evidence is still there to support that COX prostaglandins are involved in salt regulation.
The salt regulation has to do with the kidneys ability to sense alterations in salt levels via changes in the changes in the rate of the Na/K/2CL co-transporter. These changes are sensed by the macula densa and cause change in afferent tone and, more importantly, change in rennin release (21,22). The changes cause various interactions of the renin-angiotensin system. The macula densa release rennin in response to salt changes (23). Renin converts the prehormone angiotensinogen into angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I into angiotensin II. Angiotensin II causes vasoconstriction in the arterioles leading to less RBF, thus leading to an increase in systemic blood pressure (12, 24). Another effect of COX is actually involved in the release in renin itself. Studies have shown that COX can in fact increase renin release; likewise other studies have shown that COX inhibitors can lower renin release (25). The effects of renin release by COX can have many implications.
Aspirin was one of the first drugs to be used as a NSAID. NSAIDs are very popular for their effect and are found very commonly as over the counter medications. The main goal of NSAIDs is to reduce the pain and inflammation associated with injuries or disease. Since the discovery of aspirin's effect and inhibition of cyclooxygenase, NSAIDs have been proven to be a great non opiate painkiller and a non-steroid like fever and swelling reducer. NSAIDs are not only good for their action, but they also alleviate physician use of steroids and opiates, which in themselves have many complications. These drugs are commonly referred to non steroidal since steroids are given for similar symptoms and have similar effects both physically and biologically.
NSAIDs work by inhibiting COX. This then inhibits the formation of prostaglandins, which are major contributors to pain and inflammation. There are two major types of NSAIDs: nonspecific and specific COX inhibitors. Specific COX inhibitors, as their name implies, work to inhibit COX1 or COX2. Non specific NSAIDs are the most commonly used. They can be subcategorized by their chemical structure including propionic acid derivatives, acetic acid derivatives, enolic acid derivatives and fenamic acid derivates. These NSAIDs, although structurally different, maintain the same wanted effects and side effects.
There are several major brands of NSAIDs. Most are common over-the-counter (OTC) drugs and include naproxen, ibuprofen, aspirin, etodolac, and ketoprofen. These OTC NSAIDs are non specific. Some common COX2 specific NSAIDs are celecoxib, rofecoxib, and parecoxib. These are usually prescription required.
Renal insufficiency and adverse renal effects (ARE) are broad names given to diseases and symptoms associated with lower than desired kidney performance. There are some different types of adverse renal effects including electrolyte imbalances, hypertension and renal failure. The kidney is a very important organ responsible for electrolyte balance and blood pressure. The kidney can sense and respond to changes in serum electrolyte and blood pressure and adjust appropriately. The kidney controls metabolite and electrolyte secretion and reabsorbption. It excretes the unwanted and harmful metabolites. It can excrete electrolytes when levels are high and it can reabsorb electrolytes when systemic levels are low. The kidney does this in various ways including sensing salt levels and controlling blood flow to the nephrons, as mentioned before. The blood flow to the nephrons will control how much pressure is in the glomerulus, there by controlling excretion rates as well as blood pressure. Metabolites are excreted readily through pours and transport proteins.
Since the kidney controls blood pressure and electrolyte balance, it is easy to see why renal insufficiency could be a serious complication. Many physiological functions, including electrical heart impulses and muscle contraction, rely on a fine balance of electrolyte levels. If there is not a delicate balance, then many serious complications could result, such as cardiac arrhythmias. The important electrolytes include sodium, potassium, and calcium. The kidney excretes and reabsorbs salts through proteins located in the tubules of the nephrons. There are even special cells in the tubules of the nephrons that sense serum electrolyte changes and cause an increase or decrease of renal blood flow by various hormones or paracrine factors. Hypertension is a serious chronic complication that could lead to heart failure. The kidney can be a cause of hypertension, such as when there is kidney damage which could lead to fluid retention. The kidney could also be affected by hypertension, in which the elevated pressures in the arterioles could lead to damage to the glomerulus and arterioles. There are many possible causes for hypertension, but hypertension may exist without any found cause. Since renal functions are dependent on renal blood flow, hypertension could cause increases in pressures that damage the capillaries in the kidney (26).
Renal nephropathy is the general term for kidney damage. Many conditions are considered causes for nephropathy including glomerulitis and tubulitis, which are inflammation of the glomerulus and tubules respectively. Nephritis is a term associated with inflammation of the kidney, mostly in the glomerulus and tubules as just discussed. There are several causes for nephropathy and nephritis including trauma. Other causes include diabetic complications, hypertension, and NSAID (26).
The most severe form of renal complication is total renal failure. This is when the kidney no longer functions. Reasons could be as previously discussed, but it can also be due to diabetes, trauma, toxins, and drug overdose. Kidney failure is a critical situation. One cannot survive without their kidneys since they are so important for basically maintaining homeostasis. If kidney failure results then one must go on hemodialysis. Dialysis is the definitive therapeutic treatment for kidney failure in which a person is attached to a machine that takes out the blood, filters it, then returns the blood to the body. Once kidney failure results the person is dependent on dialysis unless they receive a kidney transplant (26).
NSAIDs causing Renal Insufficiency
One major question of drug administration is always its effect on the body. Many drugs are great for what they do; however, they have many unwanted side effects. These effects could range from normal effects like vomiting to more severe effects like organ failure. An important issue with drugs is that many times their action is to inhibit a biochemical process. This process may cause problems in one part of the body or it may be important in other parts of the body. So its inhibition could also be detrimental. NSAIDS are a primary example of this issue. They work to block prostaglandin production. Prostaglandins could be bad since they are a cause of pain and inflammation. However, prostaglandins are good in that they work to maintain proper renal function.
The prostaglandin functions in the kidney have already been discussed. Much of the unwanted renal side effects have already been addressed in that NSAID could cause inhibition of prostaglandins that are needed for adequate renal function, such as RBF control. An example is COX release in high salt diets. If COX is blocked, it is obvious that a problem could be made. However, to what extent NSAIDs cause renal insufficiency is still a question.
Under normal physiological conditions and with normal doses of NSAIDs, there seems to no harmful effect on RBF and GFR. Studies have been shown that COX inhibition could lead to reduction of GFR and RBF in physiologically stressed people, such as salt depletion and low salt diets. This is an issue since the kidney needs to absorb more salts and that is done by increasing RBF to bring more electrolytes to the transport proteins. General studies have been performed in elderly patients taking NSAIDs that have concluded that NSAIDs have lowered GFR (27). In addition to lowered RBF, NSAIDs could cause sodium retention. COX2 inhibitors have been shown to cause decreased sodium excretion in some patients (18). Inhibitors have also been demonstrated to have caused sodium retention in elderly subjects with normal salt diets (27, 28). If NSAIDs can cause sodium retention with normal salt diets, then it is important that retention is definitely possible in high salt diets.
It has already been discussed that COX may be needed for the release of renin. If one has a volume issue, like hypovolemia, then lowering renin release as a result of NSAID could be detrimental. The lack of renin will decrease arteriole tone leading to an overall decrease in total vascular resistance. There have been several major double blind randomized controlled studies that looked at the incidence of hypertension in patients taking NSAIDs. These studies looked at a large amount of patients and showed that patients taking COX-2 inhibitors suffered from increase rates if hypertension (29, 30). Since COX-2 plays an important role in vasodilation in the afferent arteriole, blocking COX can cause retention in medullary blood flood. This would cause increase in sodium retention and hypertension. Studies have also been shown that COX inhibitors can interfere with hypertensive agents, such as beta blockers (31).
There have been some reports of complete renal failure in person taking NSAIDs (32). This occurred especially in the elderly. One studied suggested that NSAID use accounted for approximately 18.1% of a population of Medicaid patients. They estimated that after control parameters were removed, the risk for acute renal failure increased by 58% (33). However, many of these studies had small patient populations. Another interesting study was performed to determine the effects of NSAID on human fetuses. In one study, newborn rabbits, which are commonly used as platforms for fetal tests, were administered NSAIDs. Each had low RBF and low GFR (2). This is difficult to class as renal insufficiency since human fetuses are capable of maintaining normal electrolyte and fluid balance. However, these are risk factors for acute renal failure. Other experiments have demonstrated severe renal insufficiency to almost the point of renal failure in the fetus associated with NSAID use (34). It is evident from this that NSAID use during pregnancy is not advised. For this reason, NSAIDs have been giving Class C pregnancy ratings, meaning that evidence has shown fetal harm.
The studies have shown that NSAIDs do in fact cause adverse renal effects and may even lead to renal failure, but this is usually only common in the elderly and those with preexisting conditions. Research studies have shown that prostaglandins are important for renal functions such as RBF and maintaining adequate GFR. It has also been shown that blocking these prostaglandins may inhibit some of these processes. The extent to which NSAIDs cause pathological renal insufficiency was further demonstrated by studies which have shown sodium retention, hypertension, renal damage, and even renal failure. Studies have also been shown to cause fetal renal developmental issues. The degree to which these disorders are prevalent in the population is still to some question since many of these studies have had smaller experimental populations. However, it is ever so evident that caution should be used when administering NSAIDs, especially to patients who already suffer from renal disorders or who are at risk. It is also evident that NSAIDs should not be used during late stage pregnancy to prevent fetal developmental issues.