Non Steroidal Anti-Inflammatory Drugs PDF

NON STEROID ANTI-INFLAMMATORY DRUGS • They are drugs with anti-inflammatory effects such as glucocorticoids, which are steroids. • They are also called non-steroidal anti-inflammatories or non-narcotic analgesics or analgesic anti-inflammatories or antipyretic-analgesics. • The anti-inflammatory eff...

NON STEROID ANTI-INFLAMMATORY DRUGS • They are drugs with anti-inflammatory effects such as glucocorticoids, which are steroids. • They are also called non-steroidal anti-inflammatories or non-narcotic analgesics or analgesic anti-inflammatories or antipyretic-analgesics. • The anti-inflammatory effect is weaker than glucocorticoids, and the analgesic effect is weaker than narcotics. 1 2 INFLAMMATION • Inflammation is characterised by • Increased temperature in the inflamed area • Redness • Swelling • Pain • Loss of function 3 ANALGESICS • Nonopioid (Non-opioids) Opioid Adjuvant (Secondary) 4 MAIN EFFECTS OF NSAIDS • They provide the four basic properties with a drug 1-Analgesic 2- Antipyretic 3- Anti-inflammatory 4- They have uricosuric (increasing uric acid excretion) effects. 5 ANALGESIC EFFECTS OF NSAIDS • They induce analgesia without causing numbness and loss of consciousness. • They do not create dependency and tolerance. • Due to their anti-inflammatory effects, they are used especially in rheumatic diseases such as arthritis, osteoarthritis and all mild and moderate pain. • Narcotics are preferred for severe pain such as colic, fracture, infarction, burn pain and for also severe pain that does not require anti-inflammatory effects. 6 SITUATIONS WHERE NSAIDS ARE PREFERRED • Minor musculoskeletal trauma Soft tissue inflammation Superficial surgical intervention Minor gynecological procedures Acute pain of mild to moderate severity (headache, toothache) Ureteral colic, dysmenorrhea 7 PAIN MEDIATORS • Two types of mediators play a role in the formation of pain. 1-Algesic mediators: • Direct stimuli of the nerve ending: • Histamine, serotonin, bradykinin, substance P, angiotensin 2-Hyperalgesic pain mediators: • They do not cause pain on their own, they increase the sensitivity of nerve endings to algesic agents, strengthen their pain-causing effects. • Hyperalgesic agents have been shown to increase the level of cAMP by activating adenylate cyclase in sensory nerve endings and to increase Ca+2 entry to the nerve ending. • Prostacyclin and prostaglandins (PGE2), hydroperoxy and hydroxy fatty acids, and leukotrienes. 8 THE MECHANISM OF ANALGESIC EFFECT • The analgesic effect is largely due to the peripheral effects, and in some cases to the purely peripheral effects. • They reduce the synthesis of prostaglandins (hyperalgesic mediators) from arachidonic acid, which increases the sensitivity of peripheral somatic nerves to painful stimuli. • They prevent the synthesis of prostaglandin and other eicosanoids by inhibiting the enzyme cyclooxygenase (COX-1 and COX-2). • They also prevent pain as a result of anti-inflammatory action. • It is also suggested that they induce analgesia by reducing the activity of prostaglandin in pain-related synapses in the CNS. • The cyclooxygenase inhibitory effect of paracetamol, metamizole is very weak. They are thought to have a central effect through the serotonergic and opiatergic system in the brain. 9 COX ENZYME TYPES COX 1: • Constitutive (structural) cyclooxygenase. • It creates products that perform a protective function. • It plays a role in the synthesis of prostanoid in platelets, vascular endothelium, gastric mucosa, kidney, pancreatic Langerhans islands, vesica seminalis and brain with physiological stimuli. It is selectively inhibited by low-dose aspirin. • COX 2: • Inducible cyclooxygenase. It is induced by various growth factors and cytokines. It is responsible for the formation of pro-inflammatory prostaglandins. • COX 3: • It is present in the central nervous system, anti-inflammatories inhibit all three (except for COX2 selectives). 10 PREREQUISITE FOR THE USE OF ANALGESICS • The physician should take the drug he uses., • Mechanism of action, Side effects, Drug interaction, He should know the doses in detail. 11 PURPOSE OF PAIN TREATMENT • To produce the strongest analgesic effect. Causing the fewest side effects. The optimal dose. To choose the easiest way of application. • Recommendations should be made for exacerbation pains and side effects. Oral route should be preferred. Treatment should be reviewed and evaluated over time. 12 PROPERTIES OF AN IDEAL ANALGESIC • It should be effective when used orally. It must have a sufficient analgesic effect. It should not be tolerant and addictive. It should have a specific effect in central nervous system. There must be an antidote. 13 ANTIPYRETIC EFFECT • Regulation of body temperature is carried out by the thermoregulatory center, which is located in the preoptic region of the hypothalamus. • Whether the agent is infectious or not, the development and characteristics of the fever event are the same. • Endogenous pyrogens such as interleukin (IL) 1, tumor necrosis factor (TNF), IL-6, interferon beta and interferon gamma secreted in the presence of microorganisms. 14 ANTIPYRETIC EFFECT • They stimulate neurons, as well as astrocytes and microglia cells, increasing their release of PG (especially PGE2) in the preoptic region. • Secreted PGs affect • The thermoregulatory center with paracrine communication, • The hypothalamic autonomic centers involved in the fire reaction, and • The ADH-secreting neurons 15 ANTIPYRETIC EFFECT • They reduce fever due to infection and inflammation. They do not affect the normal temperature. They are not able to reduce the fever of allergic, malignant hyperthermia, heat stroke. They reduce the synthesis of prostaglandins, which causes the thermoregulatory center to be highly tuned. They increase heat loss by vasodilation (they reduce sympathetic tone in the skin vessels). 16 SITUATIONS IN WHICH THE FEVER NEEDS TO BE REDUCED • In elderly people with coronary insufficiency and cerebrovascular disorders In pregnant women In young children with convulsions and to prevent convulsions Hyperthermia The treatment should be stopped when the fever drops to 38 ° C. 17 MEDICINES THAT CAN CAUSE FEVER • Phenothiazine, anticholinergic drugs, cocaine use disrupts temperature regulation. Malignant hyperthermia (MH): • Is a pharmacogenetic muscle disease characterized by hypermetabolism, muscle rigidity and muscle injury due to succinylcholine and all inhalation anesthetics. • Body temperature reaches to 46 ° C. 18 MECHANISMS OF ANTI-INFLAMMATORY ACTION • Cyclooxygenase inhibition • Synthesis of PG, TxA2, prostacyclin, cyclic endoperoxide, hydroperoxyde fatty acids decreases. • They reduce the synthesis of cytokines that cause inflammation, especially interleukins. Inhibition of polymorphonuclear leukocyte activation. They reduce the formation of active oxygen radicals. They stabilize the lysosome membrane (lysozyme myeloperoxidase, collagenase, elastase, proteoglycanase, cathepsin release decreases). 19 MembranePhospholipids Phospholipase A2 en C yc l oo se na ge xy po xi g Li as e Arachidonic Acide Prostaglandines Tromboxanes Prostacyclines Other Sit. P450 products Leukotrienes 20 Cellular Membrane Phospholipase PhospholipaseA2 Arachidonic Acide Cyclooksigenase I&II Prostaglandine H2 TXA2 synthase PGI2 synthase Tromboxan A2 Prostacyclin (PGI2) isomerase reductase Prostaglandin D2 Prostaglandin F2α Prostaglandin E2 21 PHYSICOCHEMICAL PROPERTIES THAT INCREASE ANTI-INFLAMMATORY ACTIVITY • Both anti-inflammatory analgesics and their metabolites are weak acids. • They easily pass into the cell from the acidic environment where they are less ionized. • They concentrate inside the cell, which is more basic (ion trap). • They are concentrated in inflammatory tissue cells, gastric parietal cells and renal medula cells 22 CLASSIFICATION 1-Salicylates 2-Para-amino phenol derivatives 3-Pyrazolone derivatives 4-Profenes (phenyl propionic acid derivatives) 5-Phenyl acetic acid derivatives 6-Indole acetic acid derivatives 7-Phenamic acid derivatives 8-Oxicams 9-COX-2 inhibitors (coxibs) 10- Others 23 1-SALICYLATES • Acetylsalicylic acid Sodium salicylate Diflunisal Methyl salicylate Local use as an analgesic Salicylic acid Keratolytic, Local use Phenyl salicylate: Local use in sunburn Used in inflammatory bowel diseases: Mesalazine Olsalazine 24 1-SALICYLATES ACETYLSALICIYLIC ACID • The most widely used and inexpensive analgesic. • It hasanalgesic, antipyretic and anti-inflammatory properties. • It selectively inhibits COX 1 with low doses. • At an analgesic dose, it irreversiblely inhibits both COXs by acetylating (other NSAIDs are reversible). • It inhibits the aggregation of platelets as a result of COX 1 inhibition. • If used in combination with other NSAIDs, they prevent the antiplatelet effect of aspirin (they should be given 2 hours after aspirin). 25 1-SALICYLATES ACETYLSALICYLIC ACID PHARMACOKINETICS • Aspirin is used only orally. It is absorbed from the stomach. 20 min after intake it rises on the minimum effective concentration (MEC) in the blood. Absorption is accelerated and irritation is reduced with buffered tablets. It is metabolized in the liver and blood by hydrolyzing to salicylate. It shows dose-dependent (non-linear) kinetics, metabolism slows down at high doses. (When 300 mg is given, the half-life is 3 hours, while when taken at a dose of 10 g, this period increases to 19 hours) 26 1-SALICYLATES SODIUM SALICYLATE FARMACOKINETICS • Sodium salicylate is used in the form of intestine-coated tablets. • There are also preparations specific to parenteral administration (iv). • Since its absorption is late, it is not preferred in acute painful cases. • The effect starts late and lasts longer. • Gastric side effects of sodium salicylate, which is given in the form of intestine coated tablets, are less than aspirin and buffered aspirin. • It is used in the same dose as aspirin in cases of rheumatic fever. 27 1-SALICYLATES DIFLUSINAL • It is a difluorophenyl derivative of salicylic acid. • It shows equal activity with the same amount of aspirin and paracetamol. • As a pain reliever (especially toothache) it is given orally at a dose of 1 g initially and then 0.5 g every 8-12 hours. • The most common side effects are GI-related side effects. • It has weak potential for nephrotoxic and hepatotoxic effects. • It can be used in diarrhea due to radiation and food allergy. 28 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS Gastrointestinal tract irritation, bleeding and ulcers 1. Frequent stomach ulcers Peptic ulcer often appears in the stomach NSAIDs, especially indomethacin that enter the enterohepatic cycle, can cause ulcers and bleeding in the upper part of the small intestine It is more common especially in women and the elderly Other factors that increase the status of having Peptic Ulcer Previous history of ulcers or GI bleeding Increasing the dose or prolonging the duration of treatment Use of more than one NSAIDs Concomitant use with other ulcerogenic drugs (glucocorticoids, colchicine, neoplastic drugs that cause mucositis) Concomitant use with oral anticoagulants Excessive alcohol intake Smoking General condition indulgence 29 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS • In terms of the potential to cause gastrointestinal side effects; 1-Ketorolac, indomethacin, azapropazone, piroxicam and tolmetin are the riskiest. 2-Aspirin, naproxen, fenoprofen and sulindak moderately. 3-Ibuprofen, diclofenac, etodolac, diflunisal less and more light. 4-Specific COX2 inhibitors. 30 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS • To avoid gastrointestinal side effects: • Proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole) H2 receptor antagonists (Famotidine, ranitidine, nizatidine) Misoprostol for colic and diarrhea, • Sucralfat: Not very effective on stomach lesions 31 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 2. Prolongation of bleeding time • It causes bleeding by reducing the synthesis of thromboxane A2 (TxA2, stimulates platelet aggregation). The dose of anticoagulants should be adjusted because heparin and the oral anticoagulant potentiate the effect of warfarin. In high doses, it reduces the synthesis of factors II, VII, IX, X and fibrinogen in liver. • Prolongs prothrombin time and bleeding time. In chronic aspirin users, aspirin should be discontinued one week before surgery to avoid postoperative bleeding. Rarely they can cause thrombocytopenia, hemolytic anemia, agranulocytosis, leukopenia, aplastic anemia. 32 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 3. Effects on liver and kidney • They cause analgesic nephropathy. Decreased renal blood flow and GFR may cause Na+ and water retention, hyperkalemia, acute renal failure. Can cause acute interstitial nephritis, nephrotic syndrome, papillary necrosis very rarely. While paracetamol does not inhibit kidney PG production, diclofenac and indomethacin reduce it by 50%. Aspirin, nimesulide, sulindak and acetaminophen are hepatotoxic. (Acetaminophen is one of the few drugs known to cause fatal acute liver necrosis in overdose). Liver enzymes may be elevated and may lead to jaundice and liver failure. 33 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 4. Cardiovascular Effects • NSAIDs can exacerbate hypertension and congestive heart failure. Hypertension is partly due to water and salt retention. They reduce the antihypertensive efficacy of diuretics, ACE inhibitors, beta-blockers (except sulindak). Salicylates provide mild respiratory stimulation at therapeutic doses, while central respiratory and circulatory inhibition at toxic doses. 5. Allergic reactions • Allergic reaction is observed in 0.3% of patients using NSAIDs Most often itching, redness and urticaria of the skin Asthma (especially in patients with nasal polyps) and angioedema The cause of mucous membrane and gingival ulcerations in dentistry may be a hypersensitivity reaction due to NSAIDs in some cases. 34 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 6. Salicylism • It is a poisoning picture that occurs at very high doses (in the treatment of rheumatoid fever or rheumatoid arthritis cases). The first symptom is hearing loss and tinnitus (Tinnitus). Headache, dizziness, drowsiness, blurred vision, hearing loss, tinnitus, hyperventilation, nausea, vomiting, sometimes diarrhea. If the dose is increased further, severe intoxication is characterized by dyspnea, slurred speech, excitation, mania, hallucinations, delirium. Delirium is an acute, reversible mental disorder characterized by impaired consciousness, emotional lability, hallucinations or illusions, and inappropriate, impulsive, unrealistic, and harsh behavior. Salicyllism occurs more quickly in hypo-albuminemia Hyperthermia acidosis, dehydration, skin rashes, hypoglycaemia in the children. Mortality due to circulatory and respiratory depression in coma Toxic effects are seen with 10-30 g aspirin in adults and 150-200 mg/kg in children. 35 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 7. Reye Syndrome • It is an acute encephalitis accompanied by fatty liver degeneration. It has been associated with the use of aspirin during viral infections. It is recommended that aspirin should not be used in children under the age of 16 except in cases where it must be used, such as Kawasaki syndrome. • Kawasaki syndrome: A severe childhood disease accompanied by fever, rash lymphadenopathy, polyarteritis 36 SIDE EFFECTS OF ASPIRIN AND ALL OTHER NSAIDS 8. Others • Aspirin secretes catecholamines from the adrenal medulla in high doses, causing glycogenolysis, hyperglycemia and glycosuria. In diabetes mellitus, the same dose increases glucose ironization, lowers glycemia, and reduces insulin requirement. Hypoglycemia occurs in pediatric poisoning in a child. NSAIDs delay wound scarring. Salicylates and indomethacin are chondrotoxic, impair cartilage production, and anti-inflammatory drugs should not be used in patients with impaired cartilage production, such as osteoarthritis, without significant pain. Salicylates remove thyroid hormones bound to plasma proteins from the binding site and reduce TSH secretion. Long-term use of NSAIDs can cause temporary infertility. 37 1-SALICYLATES ASPIRIN AND PREGNANCY • It is used to prevent recurrent pregnancy losses, premature birth and preeclampsia in pregnant women. Apart from this, it is not recommended for use in pregnant women. All NSAIDs should not be used for a long time in pregnant women and even for a short time in the period close to birth. They cause premature closure of the ductus arteriosus in the baby and pulmonary hypertension. They increase the incidence of postpartum hemorrhages and intracranial hemorrhages in the infant when used close to childbirth. C in the first 2 trimesters of pregnancy and D in the last trimester. Acetaminophen should be used if necessary. 38 FDA PREGNANCY DRUG RISK CATEGORIES 39 LACTATION • The use of analgesic anti-inflammatories is not recommended. If absolute use is required, short-acting, inactive metabolites and small amounts of pass into the milk ibuprofen, diclofenac, or flurbiprofen are recommended. Another approach is to use none of them while breastfeeding. 40 2. PARA-AMINO PHENOL DERIVATIVES • Acetaminophen (paracetamol) Acetanilid: Phenacetin: It causes analgesic nephropathy. It is banned. 41 2. PARA-AMINO PHENOL DERIVATIVES • ACETOMINOPHEN • Tablet, paediatric elixir, syrup, suppository, suspension, solution for infusion Combined preparations: • Propiphenazon (Minoset plus tab, Panalgine tab®®) Cafeine (Vermidon tab, Termalgine plus tab®®) Phenobarbital (Para-Nox® ve Pirofen® suppository) 42 2. PARA-AMINO PHENOL DERIVATIVES PARASETAMOL • Analgesic, antipyretic effects are close to aspirin. No anti-inflammatory effect. The antithrombotic effect is weak. It is one of the few drugs that, when taken in overdose (1 time 10 g or more), causes acute fatal liver necrosis. N-acetylcysteine, L-methionine, cysteamine are used in the treatment. The potential for hepatotoxic effects in the child is weaker. When used for a long time, the risk of analgesic nephropathy increases. 43 3-PYRAZOLONE DERIVATIVES • Aminopyrine (Carcinogenic) Propifenazone Metamizole sodium (Dipyrone) Phenylbutazone • Oksifenbutazon Strong analgesic and antipyretic Weak anti-inflammatory Powerful anti-inflammatory Water and salt retention and gastroenteropathy Metimazol, antitiroid 44 3-PYRAZOLONE DERIVATIVES PROPYPHENAZONE • Aljil®, Minoset plus®, Panalgine® tab Metamizole sodium (Dipyrone) Novalgin® tab, syrup, drop, ampoule Adepiron® tab, syrup, ampoule Can be administered oral, im, iv routes There are preparations combined with paracetamol, caffeine Metabolized in liver CNS excitation, It can cause herpes, labialis and angioedema in susceptible people. 45 3-PYRAZOLONE DERIVATIVES METAMIZOL SODIUM (DIPIRON) • The cyclooxygenase inhibitor effect and anti-inflammatory effect are weak, the analgesic effect is strong. It also has antipyretic properties. There is also a central aspect of its analgesic effect. It activates pain inhibitory pathways that descend into the spinal cord. It is a predrug that converts to its active form 4-methylaminoantipyrine in the body (non-enzymatic - with stomach acid). It has an anticholinergic effect. Therefore, it also has an antispasmodic effect. IV administration may cause anaphylaxis. Side effect of bone marrow depression. Its metabolites stain urine red 46 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) • Ibuprofen Naproksen Fenbufen Tiaprofenik asid Ketoprofen Deksketoprofen Phenopprofen kalsiyum Flurbiprofen İndoprofen Zomepirak •After aspirin and paracetamol The most commonly used analgesic drug group 47 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) • Ibuprofen Naproksen Tiaprofenik asid Ketoprofen Deksketoprofen Flurbiprofen 48 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) IBUPROFEN • It is the most used one in this group. Its antipyretic, analgesic and anti-inflammatory properties are less than other phenylpropionicaside derivatives and indomethacin. Side effects are also less. Its analgesic effect is evident at a dose of 1.2 g per day and its anti-inflammatory effect is evident at a dose of 1.6 and 2.4 g. The analgesic effect occurs within 1 hour, while the anti-inflammatory effect becomes evident after 4 weeks. • Indications: • Headache Pain caused by teeth and surrounding tissues Dysmenorrhea It is frequently used in mild and moderate postoperative pain. It is used to relieve pain and inflammation in rheumatic diseases. Like indomethacin, but more effective and safe, it is used in newborns to close the patent ductus arteriosus. 49 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) NAPROXEN • It is the drug with the longest duration of action in this group, and 2 times intake a day is sufficient. It inhibits the enzyme cyclooxygenase 20 times stronger than aspirin. It also inhibits leukocyte activation and migration. Rheumatoid arthritis and osteoarthritis. In ankylosing spondylitis (more effective than indomethacin). It inhibits platelet aggregation and prolongs bleeding time. In lesions of the joints and periarticular tissue due to trauma. Acute gout. Pain in musculoskeletal diseases Mild and moderate pain other than inflammation, In dysmenorrhea pain, It is used for postoperative toothaches. It can also be used as an antipyretic. 50 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) NAPROXEN • It provides stronger analgesia than aspirin. It is not recommended under 15 years of age, except for children with juvenile rheumatoid arthritis. GI related side effects and headache, dizziness, drowsiness, sweating, depression, interruption. When given to pregnant women before birth, it increases neonatal jaundice. 51 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) KETOPROFEN • Inhibits cyclooxygenase (especially COX1) and lipooxygenase enzyme (reduces the formation of LTB4) Stabilizes lysosomal membranes, suppresses leukocyte migration, eliminates the effects of bradykinin It has analgesic, antipyretic and anti-inflammatory effects Its anti-inflammatory effect is close to indomethacin, and it is used in indications where it is used 52 4. PROFENS (PHENYLPROPIONICACID DERIVATIVES) FLURBIPROFEN • In addition to the side effects of NSAIDs, rigidity, ataxia, tremor and myoclonus are rarely seen. TIAPROFENIC ACIDE • Its anti-inflammatory effect is weaker than that of naproxen. It does not inhibit the synthesis of proteoglycans of cartilage tissue. Osteoarthritis, rheumatoid arthritis and inflammation of soft tissue. Both in their illnesses and traumas. It can cause cystitis, in which case the drug should be discontinued. 53 5-PHENYL ACETIC ACID DERIVATIVES DICLOFENAC SODIUM • Applicable by IM route It also inhibits leukocyte function. It has been found to be as effective as aspirin and indomethacin against rheumatoid arthritis and effective as indomethacin against osteoarthritis. 54 6-INDOLE ACETIC ACID DERIVATIVES • Indomethacin Tolmetin Ketorolac trometamol Sulindac Asemetanin Etodolac 55 6-INDOL ACETIC ACID DERIVATIVES INDOMETHACIN • It is used for its anti-inflammatory effect; It is not used as an analgesic and antipyretic because of its high side effects. In rheumatic diseases such as ankylosing spondylitis, osteoarthritis and rheumatoid arthritis. In acute gout arthritis (low dose in the prophylaxis of seizures). It is used in cases of bursitis, tendonitis and traumatic synovitis • Side effects: • Frequent headaches, dizziness and GI disorders Regarding the CNS, they can cause frontal headache, dizziness, confusion, numbness, hallucinations and syncope. May cause convulsions and seizures in people with epilepsy May increase blood pressure May impair kidney function, water-salt retention Although rare, it can cause toxic hepatitis Corneal opacity and retinal disorder 56 6-INDOLE ACETIC ACID DERIVATIVES • KETOROLAC TROMETHAMINE • Since GI causes bleeding, acute kidney failure and anaphylactic shock, its use is now prohibited. There are only 0.5% eye drops. • SULINDAC • The prodrug converts to a sulfur derivative in liver with little interaction with antihypertensive drugs. • ETODOLAK • At low doses, COX-2 is selective; at high doses (anti-inflammatory) inhibits COX-1. In clinical trials, it has been observed that it causes fewer adverse events related to the upper GI than non-selective NSAIDs. 57 7-PHENOMIC ACETIC ACID DERIVATIVES • Mefenamic acid Flufenamic acid Etofenamate Tolfenamic acid: It has been indicated for migraine pain, but it is not used much 58 8-OXICAMS AND OTHERS • Piroxicam • It is one of the longest-acting analgesics due to its slow elimination (50 hours). For quick effect, 20 mg is taken sublingually. • Tenoxicam • İm. • It is one of the longest-acting analgesics due to its slow elimination (60-75 hours). • Meloxicam • İm. • It is relatively selective to COX2 (the other is etodolak), its main uses are osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. 59 8-OXICAMS AND OTHERS • Proquazone • Non-acidic quinazolone derivative. • Azapropazone • They are long-acting. Once a day is enough. High risk of GI side effects. • Nimesulide • Itis 5-16 times more selective to COX2 than COX1. It is a methane sulfonanilide compound. It has analgesic, antipyretic and anti-inflammatory effect. It is not used under the age of twelve. It is not recommended to use it for more than 15 days due to hepatotoxicity. 60 COX INHIBITORS • COX inhibitors are divided into 4 groups: 1. COX-1 specific: Low-dose aspirin used in cardiovascular prophylaxis only. 2. Non-COX-1 specifics: Most of the NSAIDs used in the clinic 3. COX-2 specific (selective): Coxibs 4. Inhibitors relatively specific to COX-2: Meloxicam and Etodolac 61 9-SPECIFIC COX-2 INHIBITORS (COXIBS) • Celecoxib Refokoxib Valdekoxib Etoricoxib Lumiracoxib *None of the coxibs are currently marketed in Turkey 62 SITUATIONS WHERE NSAIDS ARE USED • Rheumatoid arthritis Ankylosing spondylitis Osteoarthritis (Degenerative joint disease and soft tissue impairment.) Psoriatic arthritis Reiter's syndrome Rheumatic fever (Single analgesic aspirin or Na salicylate) Musculoskeletal lesions (bursitis, tendinitis, tendocynovitis, fibromyositis, low back pain, etc.) Bone and joint pain due to tumor metastasis Cancer pains Colic and postoperative pains Cardiovascular diseases Genital diseases (Premature birth, dysmenorrhea) Eye surgeries Prevention of colorectal cancer (COX-2 inh is being tried) 63 PERIOPERATIVE USE • They can be used for pain prophylaxis before some short-term surgical interventions. • Benefit/harm ratios • Benefit: Harm : Do not depress breathing Increased tendency to bleed Do not delay gastric emptying Gastropathy Do not impair psychomotor performance Renal dysfunction Do not cause nausea and vomiting Not suppressing stress • By using them in combination with narcotics, they reduce the dose of narcotics. 64 NSAID- ADVANTAGES • They stop the transmission of pain at the peripheral level They reduce the inflammatory response They are not addictive They do not cause respiratory depression They have a synergistic effect on other groups of analgesics They do not sedate They do not disturb sleep patterns They do not suppress psychological activity They do not reduce gastric motility They do not cause urinary retention 65 DRUG INTERACTIONS • Concominant use of alcohol, corticosteroids, corticotropin, potassium tablets increase gastric side effects. • With diuretics, beta blockers, ACE inhibitors, their antihypertensive efficacy is reduced. • Concomitant use of heparin with warfarin increases the risk of bleeding. • Concomitant use with digoxin, cyclosporine, lithium, methotrexate, phenytoin, sulfonylurea, valproic acid increases blood levels and thus side effects. 66 SECONDARY ADJUVANT ANALGESICS • ANTIDEPRESSANTS • They are not primarily analgesics. They are drugs used together with analgesics to increase the effects of analgesics, or alone as analgesics in some pain syndromes. They are preferred in neuropathic pain and cancer pain. Triklosetik asit • Selektive serotonine re-uptake inhibitör. • Serotonine noradrenaline re-uptake inhibitör. 2. ANTICONVULSANT • Carbamazepine • Gabapentin • Clonazepam 3. HORMONES • Steroids • Calcitone 4. MUSCLE RELAXANTS • Baclofen • Tizanidine 67