Lesson 31 - Pharmacology of Inflammation PDF

Lesson 31 Pharmacology of Inflammation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  INFLAMMATION HEAT REDNESS SWELLING PAIN LOSS OF FUNCTION INFLAMMATION: The body's defensive response...

Lesson 31 Pharmacology of Inflammation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  INFLAMMATION HEAT REDNESS SWELLING PAIN LOSS OF FUNCTION INFLAMMATION: The body's defensive response to invasion by a pathogen, cellular or tissue damage caused by trauma, or after antigenic stimulation. The initial damage can be of various types (biological, chemical, physical, pathological) and causes the release of mediators that can be: PROSTAGLANDINS AND LEUKOTRIENES (EICOSANOIDS) histamine, serotonin, interleukins (pro-inflammatory factors that promote the release of 5-HT and histamine) 1. Introduction Anti-inflammatory drugs may be divided conveniently into five major groups: Inhibitors of the cyclo-oxygenase (COX) enzyme(s): Non-steroidal anti-inflammatory drugs (NSAIDs) Coxibs Antirheumatoid drugs Disease-modifying Antirheumatic Drugs (DMARDs) Glucocorticoids Drugs specifically used to control gout Antihistamines used for the treatment of allergic inflammation. Biosynthesis Of Eicosanoids 2. EICOSANOIDS VASCULAR EFFECTS & PLATELETS TXA2 Vasoconstriction Platelet activation and aggregation PGE, PGI2 Vasodilation Platelet Inhibition 2. EICOSANOIDS INFLAMMATION PGE, PGI2 Vasodilation Oedema LTC4/LTD4 Increased permeability LTB4 Chemotaxis Tissue damage 2. Eicosanoids PAIN & FEVER PGE2 Promotes the transmission of pain and its levels are increased with fever KIDNEYS PGE, PGI2 Protective effect Diuretic effect: increase renal blood flow and glomerular filtration GASTROINTESTINAL TRACT PGE, PGI2 Protective role: vasodilators and at higher doses, decreased acid secretion 2. Eicosanoids RESPIRATORY LTC4/LTD4/LTE4 Contraction of human bronchiolar muscle Increased mucus secretion Do you remember which drug acts on CysLT-receptors and in which diseases are used? UTERUS PGE Oxytocic effect 2. Eicosanoids CLINICAL USES Gynaecological and obstetric Termination of pregnancy: misoprostol (analogue of PGE1) Induction of labour: dinoprostone or misoprostol Postpartum haemorrhage: carboprost increase uterine contractions-> reduces bleedin Gastrointestinal: To prevent ulcers associated with NSAID use: misoprostol Cardiovascular: Ductus arteriosus until surgical correction of the defect in babies with certain congenital heart malformations: alprostadil (PGE1 ) To inhibit platelet aggregation: poprostenol (PGI2 ), especially if heparin is contraindicated (hemodyalisis) Primary pulmonary hypertension: epoprostenol or treprostinil (PGI2) Ophthalmic: Open-angle glaucoma: latanoprost eye drops  3. Cyclo-Oxygenase Inhibitors Mechanism of action COX-1 is a constitutive COX-2 is induced in enzyme expressed in Homology of 60% inflammatory cells most tissues, including when they are blood platelets. activated COX-2 constitutively expressed in the kidney, generating PGI2 COX-1 is involved in the Synthesis of COX-1 is involved in PGs the Synthesis of TXs PGE2 PGI2  3. Cyclo-Oxygenase Inhibitors COX-1: is expressed in most tissues but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function), and is stimulated by hormones or growth factors. COX-2 is a highly regulated enzyme that is constitutively expressed in the brain, kidney, bone but which is undetectable in most other tissues. Its expression is increased during states of inflammation. Another distinguishing characteristic of COX-2 is that its expression is inhibited by glucocorticoids. This observation may contribute to the significant antiinflammatory effects of the glucocorticoids. 11 3. Cyclo-Oxygenase Inhibitors NSAIDs PGD2, PGE2, PGF2, PGI2 12 3. Cyclo-Oxygenase Inhibitors 3. Cyclo-Oxygenase Inhibitors 3. Cyclo-Oxygenase Inhibitors Pharmacological Actions The anti-inflammatory effect of the NSAIDs are related to inhibition of COX-2, while their physiological effects are largely a result of their inhibition of COX-1 ANTI-INFLAMMATORY Decrease in PGE2 and prostacyclin (PGI2) reduces vasodilatation and, indirectly, oedema. ANTIPYRETIC NSAIDs prevent fever caused by PGs in the CNS. ANALGESIC Less sensitization of nociceptive nerve endings to inflammatory mediators. Relief of headache: result of decreased PGE2- mediated vasodilation. 3. Cyclo-Oxygenase Inhibitors Common ADRs: Gastric and intestinal damage: chronic use of NSAIDS, with risk of haemorrhage, ulceration and perforation (misoprostol o PPI) Adverse cardiovascular effects: They occur mostly with the use of COXIBs. Hypertension and increased thrombotic risk drive increased rates of stroke and myocardial infarction. Heart failure is worsened. Hypersensitivity reactions: common manifestations include skin reactions and exacerbation of asthma.(ASPIRIN) 3. Cyclo-Oxygenase Inhibitors Common ADRs: Renal effects: result from inhibition of prostaglandins involved in regulation of renal blood flow and electrolyte resorption: papillary necrosis and fluid retention, raised blood pressure Analgesic-associated nephropathy: following long-term high- dose regimes of NSAIDs and is often irreversible Liver disorders, bone marrow depression (rare)  3. Cyclo-Oxygenase Inhibitors ASPIRIN AND SALICYLATES Mechanism of action It acts by irreversibly inactivating COX-1 and COX-2. At low doses (75 mg/day) inhibits platelet aggregation Pharmacokinetics Oral administration, rapidly absorbed in the gut 75% is metabolised in the liver. ADRs: Therapeutic doses: gastric irritation and contribute to GI bleeding and peptic ulcers Larger doses: dizziness, deafness and tinnitus (‘salicylism’) At higher doses fever, dehydration, and severe metabolic acidosis Aspirin hypersensitivity, Asthma 3. Cyclo-Oxygenase Inhibitors ASPIRIN AND SALICYLATES Treat salicylate overdose 1. Induction of vomiting and gastric lavage to remove unabsorbed drug 2. Intravenous administration of sodium bicarbonate to counteract metabolic acidosis, increase the ionization of salicylate in the kidneys, and thereby enhance the rate of excretion of salicylate 3. Administration of fluids, electrolytes, and other supportive care, as needed.  2. Cyclo-Oxygenase Inhibitors ASPIRIN AND SALICYLATES Contraindications The use of aspirin in children with viral infectiom → Reye Syndrome Use Concomitantly with warfarin: hazardous increase in the risk of bleeding (INTERACTION!) It should not be used in gout: low doses of aspirin may, on their own, reduce urate excretion Aspirin also antagonises the effect of some antihypertensive and uricosuric agents such as probenecid and sulfinpyrazone. 2. Cyclo-Oxygenase Inhibitors ASPIRIN AND SALICYLATES Other information Cancer – especially colonic and rectal cancer: aspirin (and some COX-2 inhibitors) may reduce the incidence of several types of cancer. Their effect may be related their inhibitory action on platelets, which are thought to be involved in the metastasis formation in some cancers (angiogenesis) 3. Cyclo-Oxygenase Inhibitors IBUPROFEN, KETOPROFEN, NAPROXEN Mechanism of action Non-selectively inhibiting COX isozymes: analgesic, antipyretic, and anti- inflammatory effects. Pharmacokinetics Naproxen has a longer half-life (14 hours) than ibuprofen or ketoprofen (2 hours). ADRs: Dose-dependent gastric irritation, nausea, dyspepsia, and bleeding. Long-term administration of high doses: peptic ulcer disease Hepatic toxicity and renal toxicity.  3. Cyclo-Oxygenase Inhibitors INDOMETHACIN One of the most potent inhibitors of COX isozymes. Usually reserved for the management of moderate to severe acute inflammatory conditions. It is used to stimulate the closure of a patent ductus arteriosus in newborns. KETOROLAC First NSAID available for parenteral use for either IV or IM administration. Produced a level of analgesia comparable to that produced by morphine but caused less nausea, vomiting, and drowsiness. Short-term management of moderate pain, such as postoperative pain associated with dental surgery. 3. Cyclo-Oxygenase Inhibitors PARACETAMOL Mechanism of action Paracetamol is classified among NSAIDs, but in reality, it is NOT an anti-inflammatory drug, ONLY has Analgesic and antipyretic effects The mechanism of action is not yet fully understood. Pharmacokinetics Peak plasma concentrations reached in 30–60 min. The plasma half-life of therapeutic doses is 2–4 h Extensively metabolized by several pathways in the liver. Most of the drug is conjugated with sulfate and glucuronide, and these metabolites are excreted in the urine. Small amount of acetaminophen is converted by cytochrome P450 to a potentially hepatotoxic quinone intermediate (HEPATOTOXICITY) 3. Cyclo-Oxygenase Inhibitors Paracetamol 3. Cyclo-Oxygenase Inhibitors PARACETAMOL ADRs: Therapeutic doses, side effects are rare: allergic skin reactions sometimes occur Large doses over a long period may cause kidney damage. Toxic doses cause potentially fatal hepatotoxicity, and nephrotoxicity. Paracetamol use has not been associated with Reye syndrome, so paracetamol can be safely given to children with fever caused by viral illnesses.  3. Cyclo-Oxygenase Inhibitors CLINICAL USES OF NSAIDs Antithrombotic : aspirin for patients at high risk of arterial thrombosis (e.g. following myocardial infarction Analgesia (e.g. for headache, dysmenorrhea, backache, bony metastases, postoperative pain): Short-term use: e.g. aspirin , paracetamol , ibuprofen Chronic pain: more potent, longer-lasting drugs (e.g. naproxen , piroxicam ) often combined with a low-potency opioid (e.g. Codeine) To reduce the requirement for narcotic analgesics NSAIDs considered first-line agents for mild to moderate migraine attacks (1 phase) or for severe attacks that have responded in the past to NSAIDs or nonopiate analgesics Anti-inflammatory : e.g. ibuprofen , naproxen for symptomatic relief in rheumatoid arthritis, gout, soft tissue disorders Antipyretic : paracetamol 27 4. Selective Cyclooxygenase-2 Inhibitors (COXIBs) CELECOXIB, ETORICOXIB Potent analgesic, antipyretic, and anti-inflammatory agents. Offered to patients for whom treatment with conventional NSAIDs would pose a high probability of serious GI side effects. Cardiovascular risk should be assessed prior to long-term treatment! Indications Used for symptomatic relief in the treatment of osteoarthritis and rheumatoid arthritis and some other conditions 4. Selective Cyclooxygenase-2 Inhibitors (COXIBs) CELECOXIB, ETORICOXIB ADRs: Headache, dizziness, rashes and peripheral oedema caused by fluid retention Enhanced cardiovascular risk Interactions Celecoxib is metabolized by CYP2C9, drugs such as fluconazole, fluvastatin, and zafirlukast may inhibit its metabolism and increase its serum concentration.