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Lec.13-14-15 Prostaglandins Are unsaturated fatty acid derivatives, these compounds are sometimes referred to as eicosanoids. Prostaglandins and related compounds produced in minute quantities by virtually all tissues. They generally act locally on the tissues in which they synthesized. Actions 1. Uterine Contractions. Prostaglandin E2 (PGE2) increase uterine activity. 2. Body Temperature. PGE2, PGF2, and PGI2 induce fever. 3. Airway Effects. PGE and PGI cause bronchodilation, whereas PGF, PGD, and TXA lead to bronchoconstriction. 4. GI Effects. PGE and PGI2 decrease gastric acid secretions. Misoprostol (Cytotec) is a PGE1 derivative that is used to reduce gastric ulcerations from the NSAIDs. 5. Pain Sensitization. PGE and PGI2 sensitize afferent nerve endings to pain 1 الصفحة 6. Cardiovascular: a. TXA2 from platelets and PGI2 from vessel walls are important local hormones in the control of microcirculation b. Prostaglandin E1 (PGE1) relax vascular smooth muscle, inhibit platelet aggregation, and maintain a patent ductus arteriosus. (Indomethacin [Indocin] induces closure of ductus arteriosus by blocking prostaglandin synthesis.) 7. Immunologic. PGE2 and PGI2 limit T-cell proliferation, whereas leukotrienes and TXA2 stimulate T-cell proliferation. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. Mechanism of action NSAIDs act primarily by inhibiting the cyclooxygenase enzymes (COX) that catalyze the first step in prostanoid biosynthesis. There are two COX isoforms: 1-The constitutive COX1 isoform tends to be homeostatic in function, While, 2-COX2 induced during inflammation and tends to facilitate the inflammatory response Differences in safety and efficacy of the NSAIDs may explained by relative selectivity for the COX1 or COX2 enzyme. Inhibition of COX-2 is thought lead to the antiinflammatory and analgesic actions of NSAIDs, while inhibition of COX-1 is responsible for prevention of cardiovascular events and most adverse events. Pharmacological actions of NSAIDs 1 • An anti-inflammatory action: prostacyclin the signs the decrease in prostaglandin E2 and reduces vasodilatation and, indirectly, and symptoms action on underlying of inflammation; oedema. NSAIDs suppress they have little or no chronic disease itself. 2 الصفحة 2 • An analgesic effect: decreased prostaglandin generation means less sensitization of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. a result of decreased The Relief of headache is probably prostaglandin-mediated vasodilatation. NSAIDs are effective against mild or moderate pain. 3• An antipyretic effect: interleukin-1 releases prostaglandins in the nervous system, temperature central where they elevate the hypothalamic set point for control, thus causing fever. NSAIDs prevent this. 4• GI effects: Normally: PGI2 (prostacyclin) inhibit gastric acid secretion PGE2 and PGF2α stimulate the synthesis of protective mucus in both stomach and small intestine. NSAIDs inhibit the formation of these PGs resulting in increased gastric acid secretion and decreased mucus production which may cause epigastric pain, ulceration, and/or hemorrhage. Important NSAIDs classification. 1-Non selective COX inhibitors: Aspirin, Ibuprofen, Naproxen, Indomethacin, Piroxicam. 2- Newer agents with more selective inhibition of COX-2 (and thus fewer adverse effects on the gastrointestinal tract) include: Celecoxib and Etoricoxib. Clinical indications 1-Antithrombotic: e.g. aspirin for patients at high risk of arterial thrombosis (e.g.following myocardial infarction). Low doses of aspirin can irreversibly inhibit thromboxane production in platelets via acetylation of cyclooxygenase .and because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of thromboxane persists for the lifetime of the platelet (3–7 days). As a result of the decrease 3 الصفحة in TXA2 production, platelet aggregation (the first step in thrombus formation) is reduced, producing an antiplatelet effect with a prolonged bleeding time. 2-An anti-inflammatory: The majority of NSAIDs are anti-inflammatory. An important exception is (paracetamol). 3-Analgesia (e.g. for headache, dysmenorrhoea, postoperative pain): backache, bony metastases, • –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) 4-Antipyretic: paracetamol. Unwanted effects. Many stemming from inhibition of the constitutive housekeeping enzyme COX-1 isoform, are common, particularly in the elderly, and include the following: 1. Dyspepsia, nausea, vomiting intestinal and other gastrointestinal effects. Gastric and damage may occur in chronic users, with risk of hemorrhage, ulceration and perforation, which can be life threatening. The cause is suppression of gastro protective prostaglandins in the gastric mucosa. (see GIT effect). 2. Skin reactions. 3. Reversible renal insufficiency. Seen mainly in individuals with compromised renal function when the compensatory prostaglandin I2/E2-mediated vasodilatation is inhibited. 4. Adverse cardiovascular effects. These can occur with many NSAIDs and coxibs and may related to inhibition of COX-2 in the macula densa or elsewhere leading to hypertension. 5. Nephropathy. This can occur following long-term high-dose regimes of NSAIDs and is often irreversible. 6. Closure of patent ductus arteriosus (PDA ):Indomethacin is used to achieve closure of a patent ductus arteriosus in neonates. However, 4 الصفحة Prescription of NSAIDs should generally avoided in pregnant women, particularly in 3rd trimester, owing to the risk of premature closure of the ductus arteriosus. Pharmacokinetics of NSAIDs In general, NSAIDs are absorbed almost completely from GIT, tend not to undergo 1st-pass elimination, are highly bound to plasma albumin and have small volume of distribution. Their t1/2 values in plasma tend to group into: a- short (1-5) hours or b- long (10-60) hours The vast majority of NSAIDs are weakly acidic drugs that localise preferentially in the synovial tissue of inflamed joints. Aspirin (acetylsalicylic acid (ASA). Is the oldest NSAIDs drug. It acts by irreversibly inactivating COX-1 and COX-2. In addition to its anti-inflammatory actions, aspirin inhibits platelet aggregation, and its main clinical use now is in the therapy of cardiovascular disease. •It is given orally and is rapidly absorbed; 75% is metabolized in the liver. •Elimination of its metabolite salicylate follows first-order kinetics with low doses (half-life 4h), and saturation kinetics with high doses (half-life over 15 h). Unwanted effects: 1- With therapeutic doses: some gastric bleeding is common. When aspirin enters the gastric epithelial cells (pH=7.4) it will ionise, become less diffusible and so will localise there. This ION TRAPPING is one mechanism whereby ASA is concentrated in, and so harms the gastric mucosa. 2- With larger doses: dizziness, deafness and tinnitus (‘salicylism’); compensated respiratory alkalosis may occur. 5 الصفحة 3- With toxic doses acidosis (e.g. from self-poisoning): uncompensated metabolic may occur, particularly In children. 4-Aspirin has linked with a rare but serious post viral encephalitis (Reye’s syndrome: which is an often fatal, fulminating hepatitis with cerebral edema): Aspirin and other salicylates given during viral infections have been associated with an increased incidence of Reye syndrome, (especially encountered in children), who, therefore, should given paracetamol instead of aspirin in case fever. 5- If given concomitantly with warfarin, aspirin can cause a potentially hazardous increase in the risk of bleeding. Aspirin is not given, at least 1 week prior to surgery.? Doses Doses of 75-150 mg/day used to prevent thrombotic vascular occlusion; 300 mg as immediate treatment for myocardial infarction; 300-900 mg every 4-6 h for analgesia. Paracetamol Is a commonly used drug that is available over the counter. It has potent analgesic and antipyretic actions but rather weaker anti-inflammatory effects than other NSAIDs. Its COX inhibitory action seems to be specific to the CNS enzyme. Pharmacokinetics • It given orally and metabolized in the liver by conjugation reaction (half-life2–4 h). •Toxic doses cause nausea and vomiting, then, after 24–48 h, potentially fatal liver damage. • Agents that increase glutathione methionine) can prevent (intravenous acetylcysteine or oral liver damage if given early. Dose. The oral dose is 500 mg to 1 g every 4 to 6 h, maximum daily dose 4 g. 6 الصفحة COX2- selective NSAIDs COX2-inhibitors, as a group, have an advantage by showing a lower risk for the development of GI bleeding. These agents also have no significant effects on platelets. However, the COX2-selective agents (like the traditional NSAIDs) may cause renal insufficiency and increase the risk of hypertension. The incidence of gastroduodenal ulcers in patients taking Celecoxib was less than that found in patients taking Naproxen, Diclofenac or ibuprofen. NB: Celecoxib inhibits COX2-derived synthesis of endothelial prostacyclin (PGI2) “which inhibit platelets aggregation and cause vasodilation but allow the continued production of COX1-derived thromboxane (TXA2) (which promote platelet aggregation and vasoconstriction).These effects may increase the risk of cardiovascular events. For that reason, “Coxibs” used cautiously in patients with history of heart failure, hypertension and other risk factors for heart disease; and they are contraindicated in ischaemic heart disease (angina, myocardial infarction “MI”), cerebrovascular disease, and peripheral arterial disease. Celecoxib approved for osteoarthritis and rheumatoid arthritis; pain including bone pain ,dental pain, and headache; and ankylosing spondylitis. 7 الصفحة الصفحة 8 الصفحة 9