NSAIDs and Acetaminophen Lecture Notes PDF

College of Medicine – ‫كلية الطب‬ Dr. Asmaa F. Sharif Ph D., JMHPE, MSc, MBBCh – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 1...

College of Medicine – ‫كلية الطب‬ Dr. Asmaa F. Sharif Ph D., JMHPE, MSc, MBBCh – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 1 No.   Define NSAIDs College of Medicine – ‫كلية الطب‬  Describe the classification of this group of drugs  Describe the general mechanism of actions.  Know the difference between the selective & non-selective NSAIDs.  Define the following terms ( Analgesic, Antipyretics, Anti- inflammatory& Anti-platelet).  Describe the general therapeutic uses, adverse effects, contraindications of NSAID  Know some examples of each group of NSAIDs. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 2 No.   Are group of drugs that have analgesic, and antipyretic effect. Besides, specific preparations produce anti-platelet & anti- College of Medicine – ‫كلية الطب‬ inflammatory effects in specific doses.  Analgesic: ◦ Drug that relieve pain.  Antipyretic ◦ Drug that lower the elevated body temperature to normal.  Anti-inflammatory ◦ Refers to the property of a substance or treatment that reduces inflammation or swelling.  Anti-platelet ◦ Is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. 3  1. Non-selective COX inhibitors (inhibit COX-1 and COX-2): Aspirin and most analgesics College of Medicine – ‫كلية الطب‬ 2. Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam 4  Non-selective COX inhibitors (inhibit COX-1 and COX-2): 1) Salicylic acid derivatives: Aspirin, aloxiprine, amino salicylic acid, diflunisal, methyl salicylate, etc. College of Medicine – ‫كلية الطب‬ 2) Acetic acid derivatives: – Carboxylic acetic acid: indomethacin, sulindac, etodolac. – Phenyl acetic acid: diclofenac 3) Propionic acid derivatives: Ibuprofen, ketoprofen, fenoprufen, naproxen. 4) Fenamic acid derivatives: mefenamic acid, fulfenamic acid. 5) Pyrazalone derivatives: phenylbutazone, azapropazone 6)Oxicams: piroxicam, tenoxicam. Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam 11/30/2024 5  A) COX-1: Constitutive (Physiological) 1- Stomach : Decreases HCI (Prevent peptic ulcer, through forming PGE2). College of Medicine – ‫كلية الطب‬ 2- CVS: Vasoconstriction & coagulation (through TXA2 that enhance platelet aggregation) 3- Kidney : Renal VD (through PGE2) B) COX-2: Inducible (stimulated by inflammation) 1- Pathological Infection: Toxins IL-1 & TNF stimulates COX-II increases PG Inflammation. 2- CVS: vasodilatation & coagulation (PGI2 decreases platelet aggregation) 3- Kidneys: Renal VD (through PGI2) C) COX-3: in brain, mainly: a- Hypothalamus: Fever. b- Thalamus: Pain 6  College of Medicine – ‫كلية الطب‬ 11/30/2024 7  Oral administration College of Medicine – ‫كلية الطب‬ Most NSAIDs are weak Most metabolized in acid (absorbed well in liver (oxidation & stomach and intestinal conjugation) mucosa) 95% bound to plasma-protein (high bioavailability)  Phospholipid From Cell Membrane Phospholipase A2 College of Medicine – ‫كلية الطب‬ Arachidonic acid CycloOxygenase 1 CycloOxygenase 2 Prostaglandin Prostaglandin Leukotrienes Thromboxane Prostacyclin Phospholipase can be inhibited by Corticosteroid. CycloOxygenase 1 can be inhibited by NSAIDs. CycloOxygenase 2 can be inhibited by NSAIDs and COX-2 inhibitor. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 10 No.  1- Plant source: Salicylic acid is obtained from park of willow tree. (Bitter taste, gastric irritant substance). Acetylation of salicylic acid produces acetyl salicylic acid and it was nominated Aspirin. College of Medicine – ‫كلية الطب‬ 2- Absorption: a- Orally from upper G.I.T. (stomach) Acidic pH increase absorption of salicylates. b- Better absorbed from stomach But More from intestine (More surface area & time of contact). 11/30/2024 11  3- Distribution: a- All over the body & passes B.B.B. & placental barrier. College of Medicine – ‫كلية الطب‬ b- Use in late pregnancy: premature closure of ductus arteriosus, delayed labour, increased postpartum hemorrhage. c- Used safely in first trimester pregnancy. 4- Hepatic Metabolism and excretion : ❑ Metabolism occurs by the hepatic microsomal enzymes. ❑ Excretion is mainly renal. (Dual route of elimination) ❖ First order elimination (therapeutic dose) ❖ Zero order elimination (toxic dose) ❑ Alkalinization of urine increases renal excretion of Salicylates. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 12 No.   Aspirin is non-selective and the only irreversible COX inhibitor leading to inhibition of both PGs and TXs. This College of Medicine – ‫كلية الطب‬ distinguishes it from other NSAIDs, which reversibly inhibit COX enzyme. Small dose of aspirin : 1-2 gm. (analgesic antipyretic dose). Large dose of aspirin: 5 gm. (anti-inflammatory dose) – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 13 No.   1. Analgesic action: for mild to moderate intensity pain (not severe pain). Mechanism: – Peripheral effect (pronounced effect): decrease PGs synthesis in College of Medicine – ‫كلية الطب‬ the peripheral inflamed tissues. – Central effect: decrease PGs synthesis in the subcortical sites (thalamus and hypothalamus).  2. Antipyretic effect: Aspirin is antipyretic but NOT hypothermic agent. Mechanism: – Decrease PGE2 synthesis in the hypothalamus. 14   3. Anti-inflammatory, anti-immunological and anti-rheumatic effects: Mechanism: By inhibition of COX enzyme, it ↓ synthesis of PGs and TXs, and College of Medicine – ‫كلية الطب‬ possibly other inflammatory mediators leads to: – Decrease inflammatory cell activation and chemotaxis. – Decrease capillary permeability.  4. CVS effects: -Low dose aspirin (used as cardio-protective agent): irreversible inhibition of COX enzyme and decreases TXA2 production in the antiplatelet (antiplatelet effect) -High dose aspirin inhibits prothrombin (prolong bleeding time) 15   5. GIT effects: salicylates can produce 2 types of gastric College of Medicine – ‫كلية الطب‬ ulcer: -Acute gastric ulcer: occurs as a result of acute ingestion of large doses of salicylates. -Chronic gastric ulcer: occurs as a result of chronic ingestion of salicylates.  6. Uterus: Prolongation of pregnancy and delay of labor due to inhibition of PG necessary for uterine contraction 11/30/2024 16   7. Renal effects (Analgesic nephropathy): Prevent the synthesis of PGE2 and PGI2 (through COX- College of Medicine – ‫كلية الطب‬ o 1&2) that are responsible for maintaining renal blood flow o Edema due to Na & water retention (Patients with a history of heart failure or kidney disease are at particularly high risk) o May increase blood pressure o May lead to acute kidney injury due to hypo perfusion (vasoconstriction). 11/30/2024 17  1. Anti-inflammatory actions  Osteoarthritis, gout, and rheumatic arthritis. 2. Analgesic action College of Medicine – ‫كلية الطب‬  Common conditions (for example, headache, arthralgia, myalgia, and dysmenorrhea) 3. Antipyretic action  Treatment of fever. 4. CVS protective agent  Low dose aspirin (used as cardio-protective agent): as antiplatelet to reduce the risk of death & cerbero /cardiovascular events in patients with previous stroke, unstable angina, or in high risk patients. 5. keratolytic and counter-irritant: Salicylic acid has keratolytic action and is used for treatment of warts. Methyl salicylic acid is used as a counter-irritant for local rheumatic pain. 11/30/2024 18  1. Gastrointestinal:  Through COX-1 inhibition: Increase risk of gastric ulcer & College of Medicine – ‫كلية الطب‬ bleeding 2. Increase the risk of bleeding (antiplatelet effect):  Aspirin irreversibly COX-1–mediated TXA2 formation, while other NSAIDs reversibly inhibit the production of TXA2. So, bleeding due to antiplatelet effect is seen more with aspirin 3. Action on the kidney: Analgesic nephropathy, and salt and water retention – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 19 No.  4. Hypersensitivity reactions: Bronchospasm (aspirin asthma) in patients with history of asthma or allergic rhinitis due to accumulation of LTs College of Medicine – ‫كلية الطب‬ (Leukotriene shift phenomenon) 5. Reye’s syndrome: Aspirin in some children with viral infection (e.g. Influenza or Chicken pox) Encephalopathy & Hepatotoxicity: contraindicated below 12 years. 6. Teratogenicity if taken last trimester 7. Idiosyncrasy (Hemolysis in patients with Favism). 11/30/2024 20   GIT disorders: peptic ulcer, gastritis, hemorrhagic pancreatitis, etc. College of Medicine – ‫كلية الطب‬  Hemorrhagic disorders: hemophilia, thrombocytopenia, etc.  Chronic renal diseases: aspirin may aggravate renal failure.  Chronic liver diseases: (those patients have bleeding tendency).  Uncontrolled hypertension: risk of fatal bleeding.  Gout: small-to moderate doses may inhibit uric acid excretion.  Before surgery: aspirin must be stopped at least 7 days before surgery.  Children with viral infections – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 21 No.  Be cautios in asthmatic patient. They cause worsening of bronchial asthma College of Medicine – ‫كلية الطب‬ 22  Diclofenac  It is less gastric irritant than other NSAIDs but more College of Medicine – ‫كلية الطب‬ nephrotoxic.  Topical gel is available for local rheumatic pain and osteoarthritis of the knee and hands. Ibuprofen Ibuprofen is a good alternative to aspirin in children with flu fevers. Long-term use of ibuprofen is associated with an increased incidence of hypertension in women. 11/30/2024 23  Indomethacin  It is approved to speed up the closure of ductus arteriosus in College of Medicine – ‫كلية الطب‬ premature infants Piroxicam It has long t half (45 hr.) Bleeding and ulceration are more common with piroxicam like aspirin compared to the other NSAIDS 11/30/2024 24  If a patient is taking aspirin has to undergo a surgical operation, when he must stop aspirin before the College of Medicine – ‫كلية الطب‬ operation?  He must stop aspirin at least 7-10 days before the surgery because aspirin irreversibly inhibits platelet COX-1 enzyme prevents. And the patient has to synthesize new platelets (life span of platelets 7-10 days) – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 25 No. College of Medicine – ‫كلية الطب‬ 1- Celecoxib 2- Rofecoxib – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 26 No.   Selective COX-2 inhibitors directly targets COX-2 enzyme responsible for inflammation and pain. College of Medicine – ‫كلية الطب‬  They reduce the risk of peptic ulceration but doesn’t seem to affect other adverse effects (especially renal problems)  Analgesic, antipyretic & anti-inflammatory in cases of 1. Osteoarthritis and rheumatic arthritis 2. Acute mild to moderate pain. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 27 No.  Advantages 1. Gastrointestinal: Very Low incidence of serious gastrointestinal effects just May cause dyspepsia, diarrhea, & abdominal pain College of Medicine – ‫كلية الطب‬ 2. platelet effect (less risk of bleeding) Adverse effects 1. Cardiac effects  High risk for cardiac adverse effects.  Some of COX-2 inhibitors such as rofecoxib withdrawn from the market because of cardiovascular effects.  Contraindicated in patients with unstable angina or transient ischemic strokes. 2. Action on the kidney  Similar action to (nonselective COX inhibitors) but to lesser extent. – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 28 No. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 29 No.  College of Medicine – ‫كلية الطب‬ Paracetamol Acetaminophen 30  *Absorbed Orally and IV. *Pass BBB and placental Barrier. * Hepatic metabolism: 85% (Conjugation with Glucuronic acid & Sulfate ): Inactive metabolite. 5-10% by CYP 450 ( N-Acetyl-P-Benzo-Quinone (NABQ) which is a toxic metabolite. College of Medicine – ‫كلية الطب‬ 5% Renal excretion. 11/30/2024 31  Mechanism of action:  Inhibits PGs synthesis in CNS (proposed through COX-3) College of Medicine – ‫كلية الطب‬  Less effect on COX enzymes in peripheral tissues: o Weak anti-inflammatory effect o No antiplatelet effect. o No effect on C.V.S or Gastric acidity 11/30/2024 32  Therapeutic action & uses: Antipyretic effect: use for fever College of Medicine – ‫كلية الطب‬   Analgesic: use for mild to moderate pain Adverse effects:  Generally safe  Good choice for children, pregnant women and patients with renal impairment Dosage forms:  Oral, suppositories, IV 33  Toxicity:  Toxic dose of Paracetamol (> 10 g in Adults & 4 g in Children) Hepatotoxic & acute liver failure Fatal. College of Medicine – ‫كلية الطب‬ Mechanism of toxicity Acetaminophen is converted to toxic metabolite (n-acetyl- Benzoquinone) in the liver that needs to be detoxified by glutathione. When glutathione is depleted, the toxic metabolite bind s covalently to hepatocytes and produce damage Management:  Intravenous N-Acetylcysteine is the antidote. It restores the hepatic glutathione stores 34 College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 11/30/2024 35 No.