NON-NARCOTIC ANALGESICS II.docx

NON-NARCOTIC ANALGESICS II NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Non-selective NSAIDS Salicylates: acetylsalicylic acid (aspirin) and its derivatives Propionic acid derivatives: ibuprofen, naproxen, ketoprofen and flurbiprofen Acetic acid derivatives: indomethacin, diclofenac, nabum...

NON-NARCOTIC ANALGESICS II NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Non-selective NSAIDS Salicylates: acetylsalicylic acid (aspirin) and its derivatives Propionic acid derivatives: ibuprofen, naproxen, ketoprofen and flurbiprofen Acetic acid derivatives: indomethacin, diclofenac, nabumetone, sulindac and etodolac Oxicam derivatives: piroxicam, meloxicam Fenamate derivatives: mefenamic acid COX-2 selective inhibitors Celecoxib SALICYLATES SIDE EFFECTS Respiration: Direct effect: Direct stimulation of the respiratory center in the medulla in medium to large doses. Hyperventilation is characterized by an increase in the depth and a pronounced increase in respiratory rate. The plasma CO2 tension (PCO2) falls, and primary respiratory alkalosis ensues. Indirect effect Increase in O2 consumption and CO2 production (especially in skeletal muscle) in anti-inflammatory doses. Mechanism is due to salicylate-induced uncoupling of oxidative phosphorylation. Increased production of CO2 stimulates respiration. Hyperventilation is characterized by an increase in depth of respiration and only a slight increase in rate. Increased alveolar ventilation balances the increased CO2 production and thus plasma PCO2 does not change or decreases slightly. Acid-Base Electrolyte Balance: Therapeutic doses of salicylates produce changes in the acid-base and electrolyte pattern. Compensation for the initial event, respiratory alkalosis is achieved by: Increased renal excretion of bicarbonate which is accompanied by Na+ and K+ excretion Plasma bicarbonate is lowered, and blood pH returns to normal. This is the stage of compensatory respiratory acidosis often seen in adults given intensive salicylate therapy. At high toxic salicylate levels, there is uncompensated respiratory acidosis plus metabolic acidosis, with the latter seen in children. This stage is characterized by: The enhanced production of CO2 outstrips its alveolar excretion because of direct salicylate-induced depression of respiration. Plasma PCO2 increases Blood pH decreases Metabolic acidosis is caused by the accumulation of strong acids such as sulfuric and phosphoric acids. Changes in acid-base balance during salicylate intoxication also causes alterations of water and electrolyte balance: The low plasma PCO2 leads to decreased renal tubular reabsorption of bicarbonate and increased renal excretion of Na+, K+ and water. Water is also lost by salicylate-induced sweating and hyperventilation leading to dehydration. Hepatic and Renal Effects: In large doses, salicylates can cause hepatic injury after several months of treatment. The injury is reversible after discontinuation of treatment. Salicylates may play a role in the severe hepatic injury and encephalopathy associated with Reye’s syndrome (consequence of viral infection in children). Large doses of salicylates may cause hyperglycemia and glycosuria and can deplete liver and muscle glycogen. Retention of salt and water, as well as acute reduction in renal function (↓ RBF and GFR) in patients with congestive heart failure, renal disease and hypovolemia. GI Effects: Epigastric distress, nausea and vomiting. Gastric ulceration, GI hemorrhage and erosive gastritis Gastric damage caused by salicylates may be due to: Direct irritant effect on mucosa (e.g., by an undissolved tablet) Inhibition of biosynthesis of protective prostaglandins (PGE2 and PGI2) Hematologic Effects: A single dose of aspirin can prolong bleeding time of normal persons for a period of 4 to 7 days. Due to acetylation of the active site of COX in platelets leading to a reduction in the biosynthesis of TXA2 Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency and hemophilia should avoid the use of aspirin. Aspirin is used widely for the prophylaxis of thromboembolic disease. Uricosuric Effects: Low doses (1-2 g/day): ↓ urate excretion; ↑plasma urate concentration Intermediate doses (2-3 g/day): No effect Large doses (> 5 g/day): Uricosuria; ↓ plasma urate concentration Neurological Effects: In high doses, salicylates may cause stimulation (including convulsions) followed by depression. May induce nausea and vomiting probably by stimulating the chemoreceptor trigger zone in the medulla. Ototoxic Effects: High doses may cause hearing impairment, alterations of perceived sounds and tinnitus. May be due to a direct effect of salicylic acid (side effect not associated with other NSAIDs) SALICYLATES Intoxication Children are particularly prone to intoxication. Salicylism (mild form of intoxication) is characterized by: headache, dizziness, tinnitus, difficulty in hearing, mental confusion, sweating, thirst, hyperventilation, nausea and vomiting. Severe degree of intoxication is characterized by: pronounced CNS disturbances (e.g., generalized convulsions and coma), skin eruptions and marked alterations in acid-base balance (respiratory and metabolic acidosis). Fever is prominent in children. Dehydration occurs as a result of hyperpyrexia, sweating, vomiting and hyperventilation. Hypoglycemia may be a serious consequence of poisoning in children. Death occurs from respiratory failure after a period of unconsciousness. SALICYLATES TREATMENT SALICYLATES THERAPEUTIC USES Symptomatic treatment of mild cases of poisoning. Absorption of salicylates can be reduced by emesis, gastric aspiration and administration of activated charcoal. Administration of intravenous fluids to correct acid-base imbalance. Hemodialysis Analgesia Antipyresis Rheumatoid arthritis Aspirin is used to reduce the risk of death and myocardial infarction in patients with coronary artery disease. Methyl salicylate is a common ingredient of ointments and deep-heating liniments used in the management of musculoskeletal pain. Salicylic acid is applied topically as a keratolytic agent for warts, corns and fungal infections. PROPIONIC ACID DERIVATIVES Include ibuprofen, naproxen, ketoprofen and flurbiprofen. Ibuprofen is the most commonly used traditional (non-selective) NSAID in the U.S. Naproxen has a long t1/2 and is 20 times more potent than aspirin in inhibiting COX; directly inhibits leukocyte function and causes less severe GI effects than aspirin. Uses: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis, migraine and primary dysmenorrhea. ACETIC ACID DERIVATIVES Include indomethacin, sulindac, etodolac, diclofenac and ketorolac. In addition to inhibiting COX, these compounds also promote the incorporation of un-esterified arachidonic acid into triglyceride, thus reducing the availability of the substrate for COX and LOX. These compounds are more potent inhibitors of COX than aspirin. Indomethacin directly inhibits the motility of polymorphonuclear leukocytes to inflammation sites. Uses: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gouty arthritis and other musculoskeletal disorders. Indomethacin has specific utility in promoting the closure of a patent ductus arteriosus in newborns (due to inhibition of vasodilatory PGs). OXICAM DERIVATIVES Includes piroxicam and meloxicam. Have similar efficacy as aspirin, naproxen, indomethacin and ibuprofen. Meloxicam shows some COX-2 selectivity. Piroxicam can inhibit the activation of neutrophils, apparently independent of its action on COX. Has a long t1/2; permits once a day dosing. Uses: rheumatoid arthritis and osteoarthritis. FENAMATE DERIVATIVES Prototype: mefenamic acid In addition to inhibition of COX, fenamates (especially meclofenamate) can also block PG receptors. Uses: mefenamate is used for primary dysmenorrhea KETONE DERIVATIVES Nabumetone is a ketone prodrug. Compared to other NSAIDs, it has a preferential activity against COX-2 Converted in liver to active metabolite, 6-methoxy-2-napthylacetic acid. Low incidence of GI disturbances. Uses: rheumatoid arthritis and osteoarthritis. COX-2 SELECTIVE INHIBITORS Celecoxib Has a greater selectivity (about 100 times) for COX-2 than COX-1 isoenzyme. Has anti-inflammatory, antipyretic and analgesic properties similar to traditional NSAIDs but does not share the anti-platelet actions of COX-1 inhibitors. Relative to traditional (non-selective) NSAIDs, the safety profile of selective COX-2 inhibitors is uncertain due to the uncovering of increased thrombogenicity with clinical use. Due to prolonged inhibition of vascular COX-2 within endothelial cells leading to decreased PGI2 formation. Celecoxib is the only FDA approved drug in this class. Uses: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and primary dysmenorrhea. PARA-AMINO PHENOL DERIVATIVES Acetaminophen is the prototypical drug in this group. An active metabolite of phenacetin. Has analgesic and antipyretic actions similar to those of the salicylates but has a weak anti-inflammatory actions. A weak effect on COX may be due to the fact that acetaminophen can only inhibit the enzyme in an environment that is low in peroxides (during inflammation, high concentrations of peroxides are generated by leukocytes). Inhibits the generation of nitric oxide because its anti-nociceptive actions can be reversed by L-arginine. Acetaminophen may be more effective against COX in the brain than in the periphery (could explain its antipyretic efficacy). Compared to NSAIDs, acetaminophen: Has no effect on the respiratory system. Has no effect on platelet aggregation. Has no effect on uric acid excretion or on acid-base balance. Does not cause gastric irritation or bleeding. Pharmacokinetics: Active orally. A small proportion of acetaminophen undergoes cytochrome P-450-mediated N-hydroxylation to form N-acetyl-benzoquinone-imine (NAPQI), a highly reactive intermediate that is toxic to both the liver and kidneys in high concentrations. NAPQI reacts with –SH groups and is rendered harmless. Acetaminophen Toxicity: Principal toxicity associated with over dosage is potentially fatal hepatic necrosis. Mechanism involves covalent binding of the toxic alkylating metabolite, NAPQI to sulfhydryl groups in glutathione (GSH) to form mercapturic acid. After GSH is depleted, NAPQI combines with sulfhydryl groups on hepatic proteins leading to hepatic necrosis. Depletion of GSH renders hepatocytes highly susceptible to oxidative stress and apoptosis. Early symptoms of hepatic damage include nausea, vomiting, diarrhea and abdominal pain. Treatment: Activated charcoal Use of N-acetylcysteine to detoxify NAPQI. N-acetylcysteine acts by replenishing hepatic stores of GSH. Uses mild to moderate pain such as headache, myalgia, postpartum pain and in other circumstances in which aspirin is an effective analgesic. PHARMACOLOGY OF RHEUMATOID ARTHRITIS SMALL MOLECULES BIOLOGICALS methotrexate leflunomide hydroxychloroquine cyclosporine azathioprine sulfasalazine Inhibitors of TNFα adalimumab, etanercept, infliximab, golimumab, certolizumab Inhibitors of interleukins: sarilumab, tocilizumab, anakinra, canakinumab, secukinumab Inhibitors of Janus kinase: baricitinib, tofacitinib, upadacitinib Others: abatacept (inhibits T lymphocyte activation), rituximab (mediates B Cell lysis) The main inflammatory conditions in which NSAIDs are effective include rheumatoid arthritis osteoarthritis soft tissue rheumatism. NSAIDs have minimal effects on the progression of joint deformity. Disease-modifying anti-rheumatic drugs (DMARDs) reduce the disease activity of rheumatoid arthritis and retard the progression of arthritic tissue destruction. DMARDs include a diverse group of small molecule non-biological and biological (mainly antibodies and binding proteins) agents. SMALL MOLECULES: METHOTREXATE A dihydrofolate reductase inhibitor that inhibits cytokine production and purine nucleotide biosynthesis leading to immunosuppressive and anti-inflammatory actions. Can slow the appearance of new erosions within joints Doses of methotrexate needed for RA is much lower than that need for CA chemotherapy Common side effects associated with RA therapy are mucosal ulceration and nausea LEFLUNOMIDE Is an immunomodulatory drug that inhibits the activity of autoimmune lymphocytes by acting on dihydroorotate dehydrogenase (DHOD) DHOD is important for pyrimidine synthesis, a requirement for activated proliferating lymphocytes Common side effects are headache, GI upset, alopecia and skin rash Used as monotherapy or in combination with methotrexate HYDROXYCHLOROQUINE An anti-malarial drug Mechanism of action in autoimmune disorders is unknown Has less effects on the liver and immune system than other DMARDs Side effects include headache, dizziness, abdominal pain, GI upset and visual disturbances Used for acute and chronic RA Others cyclosporine (calcineurin inhibitor; immunosuppressant) azathioprine (purine synthase inhibitor; immunosuppressant) BIOLOGICALS Biologicals used as DMARDs include inhibitors of TNFα, interleukins and Janus kinase Both IL-1 and TNFα are proinflammatory cytokines involved in the pathogenesis of RA When secreted by synovial macrophages, both cytokines stimulate synovial cells to proliferate and synthesize collagenase leading to: Degradation of cartilage Inhibiting proteoglycan synthesis Stimulation of bone resorption TNFα Inhibitors Drugs in this class includes Adalimumab Infliximab Certolizumab Etanercept golimumab. These drugs can decrease signs and symptoms of RA, reduce the progression of structural damage and improve physical conditions of patients ADALIMUMAB (Prototype) Is a recombinant monoclonal antibody Acts by binding to endogenous TNFα and blocking its activity Active subcutaneously Side effects include nausea, abdominal pain, headache and injection site reactions Drug Interactions: avoid live vaccines, warfarin, cyclosporine and theophylline Used to reduce signs/symptoms of moderate to severe RA Interleukin Inhibitors Drugs in this class include anakinra (IL-1) canakinumab (IL-1β) sarilumab, tocilizumab (IL-6) secukinumab (IL-17α) By inhibiting interleukins, these drugs prevent the inflammatory response in the synovium associated with RA. Janus Kinase Inhibitors Drugs in this class include Baricitinib tofacitinib Janus kinases are cytoplasmic tyrosine kinases that modulate immune cell activity in response to binding of inflammatory mediators to cellular membranes Cytokines, growth factors, interferons can increase Janus kinase activity and activation of the immune system By inhibiting Janus kinase, these drugs block cytokine signaling thus preventing the inflammation and activation of immune system associated with RA.