PAIN KILLERS AND YOUR KIDNEY..

1. PAIN KILLERS AND YOUR KIDNEY..

2. An analgesic is any medicine intended to relieve pain. • Over-the-counter analgesics—that is, painkillers available without a prescription—include aspirin, acetaminophen, ibuprofen, naproxen sodium, and others. • These drugs present no danger for most people when taken in the recommended dosage. • But some conditions make taking even these common painkillers dangerous for the kidneys.

3. Also, taking one of these drugs regularly over a long period of time may increase the risk for kidney problems. • Most drugs that can cause kidney damage are excreted only through the kidneys. • That is, they are not broken down by the liver, as alcohol is, or passed out of the body through the digestive tract.

4. CLASSIFICATION • I) TYPE-I (BASED ON DEGREE OF ANALGESIA) • MILD  MODERATE  STRONG acetylsalicylic acid                  codeine **                                  morphine **  (aspirin or “ASA”)                pentazocine ** (Talwin)               hydromorphone ** (Dilaudid) acetaminophen                       oxycodone **                             methadone**  (Tylenol, Datril, etc)              NSAIDs                                      meperidine ** propoxyphene **                   hydrocodone **  (Darvon) •     * = prescription    ** = prescription and a controlled substance (potential for abuse exists)

5. TYPE-II (BASED ON STRONG ANALGESIC PROPERTY) 1) Natural opioids         1. morphine sulfate 2) Semi-synthetic analgesics          1. hydromorphone (Dilaudid)          2. oxymorphone (Numorphan) 3) Synthetic analgesics          1. meperidine (Demerol)          2. methadone (Dolophine)          3. anileridine (Leritine) --withdrawn in 1981          4. fentanyl citrate (Sublimaze, or topically as Duragesic)          5. nalbuphine (Nubain)          6. butorphanol (Stadol)

6. TYPE-III (BASED ON OPIOID LIKE PROPERTY) • Opioid/Narcotic/Morphine-like Analgesic: i) Phenathrene derivative: Morphine, Codeine ii) Benzoisoquinoline derivative: Papaverine • Non-opioid/Non-narcotic/Aspirin-like/Antipyretic-Antiinflammatory: Aspirin • ONLY ANTIPYRETIC NO ANTIINFLAMMATORY: Acetaminophen

7. TYPE-IV (NSAID’S): NON-SELECTIVE COX INHIBITORS: 1) Salicylates-Aspirin 2) Propionic acid derivatives-Ibuprofen 3) Anthranilic acid derivatives-Mephenamic acid 4) Oxicam derivatives-Piroxicam 5) Aryl-acetic acid derivatives-Diclofenac 6) Pyrolo-pyrrole derivative-Ketorolac 7) Indole derivative-Indomethacin 8) Pyrazolone derivative-Phenylbutazone PREFERENTIAL COX-2 INHIBITORS:Nimesulide SELECTIVE COX-2 INHIBITORS:Celecoxib ANALGESIC-ANTIPYRETIC WITH POOR ANTIINFLAMMATORY ACTION: 1) Paraaminophenolderivative:Paracetamol 2) Pyrazolonederivative:Metamizol 3) Benzoxazocinederivative:Nefopam

8. Mode of action • Most NSAIDs act as non-selective inhibitors ofthe enzyme cyclooxygenase, inhibiting boththe cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2) isoenzymes.Cyclooxygenase catalyzes the formation ofprostaglandins and thromboxane fromarachidonic acid (itself derived from the cellularphospholipidbilayer by phospholipase A2). • Prostaglandins act as messenger molecules in the process of inflammation.

9. Biosynthesis of PGs phospholipid(in cell wall lipid) ↓←-------(phospholipase A2) arachidonic acid PGsynthase↓cox1 &2 ↓ Prostaglandins leukotrine ↓ ↓ Prostacyclinthromboxane

10. Pharmacokinetics • Most NSAIDs are weak acids, They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound inplasma (typically >95%), usually to albumin. • Most NSAIDs are metabolized in the liver toinactive metabolites which are typicallyexcreted in the urine . • Ibuprofen and diclofenac have short half-lives (2-3 hours). • Some NSAIDs (typically oxicams have very long half-lives (e.g. 20-60 hours)

11. Adverse effects of NSAIDS • The two main adverse drug reactionsassociated with NSAIDs relate togastrointestinal (GI) effects and renal effects ofthe agents. • These effects are dose-dependent, and inmany cases severe enough to pose the risk ofulcer perforation, upper gastrointestinalbleeding, and death, limiting the use of NSAIDtherapy.

12. COMMONLY USED ANALGESICS • ASPIRIN • IBUPROFEN • MEPHENAMIC ACID • DICLOFENAC • ACETAMINOPHEN • CELECOXIB • NIMESULIDE • MORPHINE SULPHATE • OTHER OPIOIDS

13. ASPIRIN • For mild to moderate pain, not for visceral pain • THE THREE MAJOR EFFECTS OF THE SALICYLATES          a. analgesic          b. antipyretic               "pyrexis" Greek for "heat", therefore, antipyretic =          c. anti-inflammatory

14. IBUPROFEN • ADVERSE EFFECT: 1)Gastric discomfort, Nausea,Vomiting 2)CNS side effects 3)Rashes, Itching, Hypersensitivity USES: 1)Most common drug in dental treatment 2)Musculoskeletal pain

15. MEPHENAMIC ACID • ADVERSE EFFECTS: 1)Diarrohea 2)Epigastric distress 3)CNS manifestations 4)Skin rashes • USES: 1)Analgesic 2)Dysmenorrhoea

16. DICLOFENAC • ADVERSE EFFECTS: 1)Mild-epigastric pain, nausea, headache 2)Gastric ulceration • USES: 1)Toothache 2)Rheumatoid and osteoarthritis 3)Post-traumatic and post-operative inflammatory condition

17. ACETAMINOPHEN(PARACETAMOL) • OTHER NAMES FOR ACETAMINOPHEN INCLUDE: TYLENOL, DATRIL, PANADOL, MAPAP, APAP • Actions of acetaminophen            a. analgesic and anti-pyretic ONLY NO ANTI-INFLAMMATORY ACTION           b. no effect on platelets            c. no effect on ulceration or GI bleeding at therapeutic doses           • COMPLETELY SAFE, RIGHT? WRONG!            a. overdosage causes IRREVERSIBLE kidney and liver damage            b. death from overdosage not immediate            c. some damage possible even at chronic therapeutic doses            d. OVERDOSES TREATED WITH ACETYLCYSTEINE (Mucomyst)

18. MORPHINE SULPHATE 1) Opioid receptors-this receptor is the site of action for morphine, its congeners, and the narcotic antagonists 2) Elevates pain threshold and alters pain perception 3) Other General Effects:              a. respiratory depression, even in small doses              b. drowsiness, mental clouding, inability to concentrate              c. constipation                --opioids used to treat diarrhea                --camphorated tincture of opium PAREGORIC                --diphenoxylate (mixed with atropine, it is called LOMOTIL) •              d. physical dependence              e. constriction of pupils •              f. effect on urinary tract                 a. increase in urethral tone                    --constriction, causing urinary retention                    --consider KIDNEY STONE patients!                 b. increase in bladder tone                    --increased urge to urinate                  (but! the urethra is constricted, making urination difficult...what a dilemma) •              g. tolerance possible 4) Uses:              a. analgesic/pre-op              b. has antitussive properties, but not used for this

19. OTHER OPIOIDS • 1. Semisynthetics         --minor alterations in the structure of the morphine molecule, usually altering comparative potency           a. hydromorphone (Dilaudid) --5x potency of morphine (1-3mg SQ)           b. oxymorphone--10x potency (1mg SQ) • 2. Synthetics           a. meperidine (Demerol) i. 1/10 potency of morphine, 50-100mg IM, PO               ii. fewer side effects, less constipation •           b. methadone i. 5-10mg po, IM               ii. less euphoria               iii. some withdrawal symptoms               iv. use for heroin addiction •           c. fentanyl citrate (Sublimaze) --short acting; surgical use only in injection form • TECHNOLOGY TAKES OVER, HOWEVER! NOW AVAILABLE IN THE   NEW IMPROVED TOPICAL PATCH FORM! DURAGESIC! •                    –it delivers analgesic in micrograms per hour, hence the dosages of 25mcg, 50mcg, 75mcg, 100mcg                    –one patch is good for 3 days (72 hours)          • d. alfentanyl (Alfenta) --also short acting, and also reserved for surgical use

20. TRAMADOL • Tramadol 50, 100and 150 mg provided significantly more analgesia than placeboas determined by single-patient data meta-analysis, and alsohas been shown by single-patient data meta-analysis to haveanalgesic efficacy equal to that of aspirin 650 mg plus codeine60 mg • Unlike aspirin, acetaminophen and codeine, which havean analgesic duration of approximately four hours, tramadolprovides analgesia for five to six hours after dental surgery. • Also, tramadol successfully managed pain for patients with chronicperiodontitis, chronic pulpitis and alveolitis.

24. Analgesic use has been associated with two different forms of kidney damage: • acute renal failure • a type of chronic kidney disease called analgesic nephropathy.

25. Acute Kidney Failure • Here is acute kidney failure which can happen suddenly by the use of over-the-counter pain killers. • This includes aspirin, Advil and Aleve. • These patients in pain were often dehydrated or hadn't taken a sufficient amount of fluids throughout the days they were taking the pain-relieving medicines. • This also happened in heavy alcohol users, lupus patients, older folks and those who already have kidney disease whether they knew it or not.

26. Acute kidney failure usually occurs when the blood supply to the kidneys is suddenly interrupted or when the kidneys become overloaded with toxins "Extremely large doses of aspirin and paracetamol can cause acute renal failure, usually when taken as a suicide attempt.

27. MICROSCOPIC VIEW

28. DIAGNOSIS: Diagnosis of kidney failure is confirmed by : • blood tests measuring the buildup of waste products in the blood - BUN, creatinine, and GFR. • This is the rate with which blood is filtered through the kidneys and can be calculated based upon the creatinine level, age, race, and gender. • Abnormal fliud levels in the body. • Abnormal levels on phosphate,calcium,potassium in urine and blood.

29. Analgesic nephropathy • This can occur after taking any kind of painkiller regularly for many years. • This kind of chronic kidney disease can cause kidney failure. • The kidney patient will then have to go on dialysis and wait for a kidney transplant.

30. Prolonged or frequent use of two common over-the-counter pain medicines increases a person's chances of developing irreversible kidney failure. • Adults who take the equivalent of more than two tablets of ibuprofen a day for seven years have roughly nine times the risk of kidney failure seen in people who take about two tablets a week.

31. Similar consumption of acetaminophen, the most popular painkiller in the United States, increases the risk of kidney failure about twofold.

32. MICROSCOPIC VIEW

33. TREATMENT If you have been taking analgesics regularly to control chronic pain, you may be advised to find new ways to treat your pain: • behavior modification or relaxation techniques. • change your diet,depending on how much your kidney function has declined • limit the fluids you drink, • take medications to avoid anemia and bone problems caused by kidney disease. • Your doctor will monitor your kidney function with regular urine and blood tests.

34. If serious pain requires the use of a pain • killer, make sure not to • over medicate yourself • consult your physician if you begin • experiencing any symptoms • associated with kidney failure such as • extreme fatigue, itching, • headaches, weight loss, appetite loss or • nausea.

35. RENAL PAPILLARY NECROSIS DEF: RENAL PAPILLARY NECROSIS is a disorder of kidneys in which all or part renal papillae die. The renal papillae is the area where the openings of collecting ducts enter the kidney.

36. One of the most common and most preventable etiologic factors is the use of analgesics. • Etiology Generally, any condition associated with ischemia predisposes an individual to papillary necrosis. Important general considerations include shock, massive fluid sequestration (eg, as in pancreatitis), dehydration, hypovolemia, and hypoxia.

37. A useful mnemonic device for the conditions associated with renal papillary necrosis is POSTCARDS, which stands for the following: • Pyelonephritis • Obstruction of the urinary tract • Sickle cell hemoglobinopathies, including sickle cell trait • Tuberculosis • Cirrhosis of the liver, chronic alcoholism • Analgesic abuse • Renal transplant rejection, radiation • Diabetes mellitus • Systemic vasculitis

38. In this figure, the multifactorial nature of renal papillary necrosis is represented by 5 of the disease's most frequently associated conditions: infection, obstruction, diabetes mellitus, analgesic abuse, and sickle cell disease. Each circle represents a condition. Note how the conditions overlap; the red areas show the coexistence of 2 conditions, and the black areas represent 3 coexistent conditions. Multiple conditions exhibit synergism and, therefore, worsen both the severity of the disease and the prognosis.

39. Renal papillary necrosis (RPN) is characterized by coagulative necrosis of the renal medullary pyramids and papillae brought on by several associated conditions and toxins that exhibit synergism toward the development of ischemia. • The clinical course of renal papillary necrosis varies depending on the degree of vascular impairment, the presence of associated causal factors, the overall health of the patient, the presence of bilateral involvement, and, specifically, the number of affected papillae.

40. Renal papillary necrosis can lead to secondary infection of desquamated necrotic foci, deposition of calculi, and/or separation and eventual sloughing of papillae, with impending acute urinary tract obstruction. • Multiple sloughed papillae can obstruct their respective calyces or can congregate and embolize to more distal sites (eg, ureteropelvic junction, ureter, ureterovesical junction). • Previously undiagnosed congenital anomalies (eg, partial ureteropelvic junction obstruction) can provide a narrowed area where the sloughed papilla can nest and obstruct.

41. Renal papillary necrosis is potentially disastrous and, in the presence of bilateral involvement or an obstructed solitary kidney, may lead to renal failure. • The infectious sequelae of renal papillary necrosis are more serious if the patient has multiple medical problems, particularly diabetes mellitus.

42. Renal papillary necrosis is considered a sequela of ischemia occurring in the renal papillae and the medulla. • Various insults generate this ischemia, one of which may be infection. • The boggy inflammatory interstitium of the pyelonephritic kidney compresses the medullary vasculature and, thus, predisposes the patient to ischemia and renal papillary necrosis. • This vasculature can become compressed, attenuated, or impaired from several other associated diseases, most notably diabetes mellitus, urinary tract obstruction, and analgesic nephropathy. • Therefore, renal papillary necrosis is a distinct clinical and pathophysiological entity primarily caused by ischemia that can develop without pyelonephritis or urinary tract infection and is likely a focus for infectious complications. • Renal papillary necrosis has a well-documented association with several diseases that predispose a patient to ischemia.

43. One of the most common and most preventable etiologic factors is the use of analgesics. • A classic factor is phenacetin, with its highly toxic metabolite, p-phenetidin. • Recently, however, the rising popularity of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly those that inhibit cyclooxygenases (ie, COX-1, COX-2) has led to a relatively high frequency of adverse events in patients at risk for renal papillary necrosis.

44. In healthy individuals in whom renal arterial blood flow is not compromised, NSAIDs have little effect unless they are used in excess. • This is mostly true because the kidney is not relying on the vasodilatory effects of prostaglandin to supply adequate perfusion. • However, in patients who are predisposed to renal hypoperfusion, local prostaglandin synthesis protects the glomeruli and tubules from ischemia. • The inhibition of prostaglandin synthesis by NSAIDs that inhibit COX-1 and, as recently reported, COX-2, removes this protective mechanism and predisposes the kidney to further renal hypoperfusion and, ultimately, ischemia. • An extremely important precaution is to strictly monitor patients with prior renal disease or any of the above-mentioned etiologic conditions when prescribing NSAIDs.

45. Additionally, note that a short course of NSAIDs has caused papillary necrosis and nonoliguric renal failure in otherwise healthy individuals as young as age 17 years. • A case such as this may be an anomaly, but caution is warranted when prescribing NSAIDs, and adequate hydration is recommended. • These precautions should also be extended to patients receiving specific COX-2 inhibitors. Touted as being safer than COX-1 inhibitors because they spare the gastrointestinal tract, COX-2 inhibitors have been shown to significantly decrease renal medullary prostaglandin levels. Therefore, care should be exercised when administering even the COX-2 inhibitors to patients with a predisposition to renal disease or renal papillary necrosis, and otherwise healthy patients should maintain adequate hydration and avoid physiologic stress while on these medications.

46. Recently, multiple publications have described indinavir-induced renal papillary necrosis. In one study, diagnosis was delayed as the initial symptoms were attributed to suspected urinary tuberculosis. These studies demonstrate the necessity of renal function monitoring during HIV treatment above that of calculus monitoring.7,8

47. Pathophysiology • Renal papillary necrosis is classified as focal (ie, involving only the tip of the papilla) or diffuse (ie, involving the whole papilla and areas of the medulla), depending primarily on the patient's degree of impaired vasculature. • Renal papillary necrosis may simply affect a single papilla, or the entire kidney may be grossly involved. • Once again, renal papillary necrosis is more often a bilateral process; many of the predisposing factors are systemic. • Renal papillary necrosis never involves the entire medulla; the disease is always strictly limited to the inner, more distal zone of the medulla and the papilla.

48. Researchers recognize 2 pathologic forms of renal papillary necrosis—the medullary form and the papillary form. • The pathogenic form is dictated by the degree of vascular impairment. • The medullary form is characterized by intact fornices, discrete grain-sized necrotic areas, and later defects in the papillae. • Clinicians often observe sinus tracts extruding from irregular medullary cavities. In the papillary form, the calycealfornices and the entire papillary surface are destroyed, demarcated, and sequestered. • If these fornices and papillary surfaces are not sloughed, they reepithelialize and acquire a smoother appearance.

49. Patients with medullary ischemia develop decreased glomerular filtration rates, salt wasting, an impaired ability to concentrate, and polyuria because the vasarectae supply the medulla and serve the countercurrent exchange mechanism.

50. The pathologic findings on a cut section include gray-white to yellow necrosis that resembles infection on the tips or distal two thirds of the pyramids. • Microscopically, the tissue shows characteristic coagulative infarct necrosis, with preserved tubule outlines. • The leukocytic response is limited to the junctions between preserved and destroyed tissue. • After the acute phase, scars that can be observed on the cortical surface as fibrous depressions replace the inflammatory foci. • This pyelonephritic scar is usually associated with inflammation, fibrosis, and a deformation of the underlying calyces and pelvis.