Anti-inflammatory and Analgesic Drugs PDF

Anti-inflammatory and analgesic Drugs Chapter 40 Lippincott's illustrated reviews in pharmacology, 7th edition. South Asian edition Anti-inflammatory, Antipyretic, and Analgesic Agents....

Anti-inflammatory and analgesic Drugs Chapter 40 Lippincott's illustrated reviews in pharmacology, 7th edition. South Asian edition Anti-inflammatory, Antipyretic, and Analgesic Agents. Disease-Modifying Antirheumatic Drugs (DMARDS) Treatment of Gout Majdi M. Bkhaitan 2023/2024 1 Objectives Upon Describe the mechanism of action of the various anti-inflammatory agents. completion of this chapter, Describe the therapeutic actions, indications, pharmacokinetics, contraindications, most common adverse reactions, and important drug– you will be drug interactions associated with each class of anti-inflammatory agents. able to: Discuss the use of anti-inflammatory drugs across the lifespan. Describe the classes of drugs used for the treatment of each clinical type of gout and RA and the main drugs in each class. For each of the main drugs used in the treatment of gout and RA , describe the pharmacodynamics, pharmacokinetics and common side effects 2  Algesia: Sensitivity to pain Analgesia: Lack of algesia or the inability to feel pain without loss of consciousness Analgesic: A drug that produces analgesia or a drug that is used to relieve pain Pyro-: Fever, heat or high temperature Antipyretic: A Drug that treats or prevents fever Anti-inflammatory: A Drug that treats or decreases inflammation and its symptoms This Photo by Unknown author is licensed under CC BY. 3 Pain sensation can be influenced or modified as follows: Elimination of the cause of pain. Lowering of the sensitivity of nociceptors (antipyretic analgesics, local anesthetics). Interrupting nociceptive conduction in sensory nerves (local anesthetics) Suppression of transmission of nociceptive impulses in the spinal medulla (opioids) Inhibition of pain perception (opioids, general anesthetics) Altering emotional responses to pain, i.e., pain behavior (antidepressants as co-analgesics) 4  The Inflammatory Response Inflammation is a response to tissue injury and infection. The two phases of inflammation are the vascular phase, which occurs 10 to 15 minutes after an injury, and the delayed phase. The vascular phase is associated with vasodilation and increased capillary permeability, during which blood substances and fluid leave the plasma and go to the injured site. The delayed phase occurs when leukocytes infiltrate the inflamed tissue. The process of inflammation is a protective mechanism in which the body attempts to neutralize and destroy harmful agents at the site of injury and to establish conditions for tissue repair. However, inappropriate activation of the immune system can result in inflammation and immune-mediated diseases such as rheumatoid arthritis (RA). Normally, the immune system can differentiate between self and non-self. In RA, white blood cells (WBCs) view the synovium as non-self and initiate an inflammatory attack. 6  WBC activation leads to stimulation of T lymphocytes which recruit and activate monocytes and macrophages. These cells secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1, into the synovial cavity, ultimately leading to joint destruction and other systemic abnormalities characteristic of RA In addition to T lymphocyte activation, B lymphocytes are also involved and produce rheumatoid factor and other autoantibodies to maintain inflammation. These defensive reactions cause progressive tissue injury, resulting in joint damage and erosions, functional disability, pain, and reduced quality of life. Pharmacotherapy for RA includes anti-inflammatory and/or immunosuppressive agents that modulate/reduce the inflammatory process, with the goals of reducing inflammation and pain, and halting or slowing disease progression. Although there is a relationship between inflammation and infection, these terms should not be used interchangeably. Infection is caused by microorganisms and results in inflammation.​ 7  The five characteristics of inflammation, called the cardinal signs of inflammation, are redness, swelling (edema), heat, pain, and loss of function. 8  When a cell is stimulated (by physiological or pathological stimuli), the enzyme phospholipase A2 will be activated and cause the release of arachidonic acid from the cell membrane to make eicosanoids. Eicosanoids are signaling molecules derived from arachidonic acid (main precursor) and include prostaglandins, thromboxane, Prostacyclin and leukotrienes. Prostaglandins that have been isolated from the exudate at inflammatory sites are among them. Prostaglandins (chemical mediators) have many effects: vasodilation, relaxation of smooth muscle, increased capillary permeability, and sensitization of nerve cells to pain. Cyclooxygenase (COX) is the enzyme responsible for converting arachidonic acid into prostaglandins and their products. This synthesis of prostaglandins causes inflammation and pain at a tissue injury site. There are two enzyme forms of cyclooxygenase: COX-1 and COX-2. COX-1 produces prostaglandins that protects the stomach lining and regulates blood platelets. COX-2 triggers inflammation and pain. 9  COX-2 is found in the brain, kidney, bone and at sites of chronic disease and inflammation. Expression is increased by stress and injury. COX-1 is a constitutive enzyme that regulates normal cellular processes. It is responsible for synthesizing most of the following: PGI2 (prostacyclin) produced by blood vessels: causes vasodilation, ↓ platelet aggregation and protects the kidneys by renal afferent vasodilation to maintain blood flow. PGE2: gastric protection (↓ acid, ↑ bicarbonate, ↑ blood flow, ↑mucus production to protect stomach), in lungs causes bronchodilation. TXA2 (thromboxane A2) released by platelets: causes vasoconstriction and ↑ platelet aggregation. COX-1 Inhibition by anti-inflammatory drugs causes side effects due to blocked normal function: gastric ulcer, water retention, kidney injury 10 Prostaglandins (PGs) and COX enzymes Cell is activated by physical, chemical or hormonal Phospholipase A2 enzyme stimuli Arachidonic acid Lipoxygenase Pathway Leukotrienes (release from cell membrane by PLA2) Cyclooxygenase Pathway Bronchoconstriction & mucus production (COX-1) (COX-2) Physiological Prostaglandins Pathological prostaglandins 1-Gastic Protection (↓ gastric acid, 1-Inflammation (vasodilation & ↑ capillary ↑ mucus production, maintain blood flow) permeability) 2-Renal protection (maintain blood flow) 2-Edema and pain 3-Regulate smooth muscle tone in 3-Leukocytosis (↑ immune cells in blood) vessels and lungs (vasodilation and 4-Activate WBCs to release cytokines bronchodilation) (↑inflammation and immune response) 4-Regulate blood clotting 11 Prostaglandins (PGs) 13 Alprostadil Alprostadil is a PGE1 analog that is naturally produced in tissues such as seminal vesicles and cavernous tissues, in the placenta, and in the ductus arteriosus of the fetus. PGE1 maintains the opening of the ductus arteriosus during pregnancy. The ductus closes soon after delivery to allow normal blood circulation between the lungs and the heart. In neonates with congenital heart conditions, infusion of alprostadil keeps the ductus open, allowing time until surgical correction is possible. Alprostadil is also used for erectile dysfunction Lubiprostone Lubiprostone is a PGE1 derivative indicated for the treatment of chronic idiopathic constipation, opioid-induced constipation, and irritable bowel syndrome with constipation. It stimulates chloride channels in the luminal cells of the intestinal epithelium, thereby increasing intestinal fluid secretion. Nausea and diarrhea are the most common adverse effects of lubiprostone. Nausea can be decreased if taken with food. 14 Prostaglandin F2α analogs E.g. Bimatoprost, Latanoprost, Tafluprost, and Travoprost Are indicated for the treatment of open-angle glaucoma. By binding to prostaglandin receptors, they increase uveoscleral outflow, reducing intraocular pressure. They are administered as ophthalmic solutions once a day and are as effective as timolol or better in reducing intraocular pressure. Bimatoprost increases eyelash prominence, length, and darkness and is approved for the treatment of eyelash hypotrichosis. Ocular reactions include blurred vision, iris color change (increased brown pigmentation), increased number and pigment of eyelashes, ocular irritation, and foreign body sensation. Misoprostol It is a PGE1 analog, is used to protect the mucosal lining of the stomach during chronic NSAID treatment. Misoprostol interacts with prostaglandin receptors on parietal cells within the stomach, reducing gastric acid secretion. And have a Gl cytoprotective effect by stimulating mucus and bicarbonate production. 15  It is used off-label in obstetric settings for labor induction, since it increases uterine contractions. Misoprostol has the potential to induce abortion. Therefore, the drug is contraindicated during pregnancy. Its use is limited by common adverse effects including diarrhea and abdominal pain. Prostacyclin (PGI2) analogs Epoprostenol is a naturally occurring prostacyclin Treprostinil and iloprost are synthetic analogs of prostacyclin Potent pulmonary vasodilators that are used for the treatment of pulmonary arterial hypertension (PAH). These drugs mimic the effects of prostacyclin in endothelial cells, producing a significant reduction in pulmonary arterial resistance with a subsequent increase in cardiac index and oxygen delivery. 16  Drugs such as aspirin inhibit the biosynthesis of prostaglandin and are therefore called prostaglandin inhibitors. Because prostaglandin inhibitors affect the inflammatory process, they are more commonly called anti- inflammatory agents. Anti-inflammatory agents also relieve pain (analgesic), reduce elevated body temperature (antipyretic), and inhibit platelet aggregation (anticoagulant). Anti- Aspirin is the oldest anti-inflammatory drug, but it was first used for its analgesic and antipyretic properties. inflammatory As a result of searching for a more effective drug with agents fewer side effects, many other anti-inflammatory agents, or prostaglandin inhibitors, have been discovered. Although these drugs have potent anti-inflammatory effects that mimic the effects of corticosteroids (cortisone), they are not chemically related to corticosteroids and therefore are called nonsteroidal anti- inflammatory drugs (NSAIDs). Most NSAIDs are used to decrease inflammation and pain for patients who have some type of arthritic condition. 17  NSAID Classification Non-selective COX inhibitors (1st generation) Salicylates Aspirin Acetic Acids Diclofenac, Indomethacin, Etodolac Propionic Acids Ibuprofen , Naproxen Fenamates Mefenamic acid Oxicam Derivatives Piroxicam COX-2 Selective Inhibitor (2nd generation) Coxib class (celecoxib) Differences in safety and efficacy of NSAIDs may be explained by their relative selectivity to COX-1 & COX-2 enzymes. Related Agent – Acetaminophen, Acetaminophen is a related drug and a widely used agent. It has antipyretic and analgesic properties but does not have the anti-inflammatory effects of the salicylates or the NSAIDs. 18 19 Mechanism of action of NSAID’s Inactivate cyclooxygenases involved in prostaglandins biosynthesis. There are two forms of cyclooxygenase, COX-1 and COX-2. Aspirin and traditional NSAIDs inhibit both COX-1 and COX-2 enzymes. COX-1 is normally synthesized continuously and present in all tissues COX-2 is induced by inflammatory chemical mediators such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF- α), but it does not seem to be involved in the other tissue functions. Overall, prostaglandins produced by COX-2 are associated with pain and other signs of inflammation. COX-2 inhibitors are thought to act only at sites of trauma and injury to produce more specific block of the inflammatory reaction. By interfering with this part of the inflammatory reaction, NSAIDs block inflammation before all the signs and symptoms can develop. The COX-2 selective inhibitors are designed to affect only the activity of COX-2, the enzyme that becomes active in response to trauma and injury 20  Most NSAIDs also block various other functions of the prostaglandins, including protection of the stomach lining, regulation of blood clotting, and water and salt balance in the kidney. The adverse effects associated with most NSAIDs are related to blocking of both these enzymes and changes in the functions that they influence—GI integrity, blood clotting, and sodium and water balance. 22 Therapeutic effects 1. Analgesic Inhibit COX-2 synthesis of prostaglandins that sensitize nerve endings to pain caused by local mediators (e.g., bradykinin & histamine). Thus, by decreasing PGE2 synthesis, the sensation of pain can be decreased. As COX-2 is expressed during times of inflammation and injury, it is thought that inhibition of this enzyme is responsible for the analgesic activity of NSAIDs. No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy The NSAIDs are used mainly for the management of mild-to-moderate pain arising from musculoskeletal disorders. One exception is ketorolac, which can be used for more severe pain, but for only a short duration. 2. Antipyretic Relieve fever, the drugs act on the hypothalamus to decrease its response to pyrogens and reset the “thermostat” at a lower level. This can be caused by PGE2 synthesis, which is stimulated when endogenous fever-producing agents (pyrogens), such as cytokines. NSAIDs have no effect on normal body temperature. 23 3. Anti-inflammatory Inhibition of cyclooxygenase diminishes the formation of prostaglandins and, thus, modulates aspects of inflammation mediated by prostaglandins. NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of the disease nor induce remission 4. Antiplatelet aggregating effect Effects that differ in mechanism and extent between aspirin and other NSAID’s Aspirin binds irreversibly to platelets COX-1 leading to its inactivation Most other NSAIDs bind reversibly with platelets COX-1 so that antiplatelet effects occur only while the drug is present in blood. No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy The choice of NSAID depends on personal experience and the patient’s response to the drug. A patient may have little response to one NSAID and a huge response to another. 24  Salicylates Aspirin comes from the family of salicylates derived from salicylic acid. Aspirin is also called acetylsalicylic acid (ASA).The abbreviation frequently used for aspirin is ASA. Aspirin is available as OTC, and was one of the most widely used NSAID’s before the introduction of ibuprofen Because high doses of aspirin are usually needed to relieve inflammation, gastric distress is a common problem. In such cases, enteric-coated (EC) tablets may be used. Aspirin should not be taken with other NSAIDs because it decreases the blood level and effectiveness of other NSAIDs. Low-dose Aspirin ( 400 mcg/mL. 30 31 Treatment of salicylate poisoning Mild salicylism, stopping the drug or reducing the dose is usually sufficient. Severe salicylate overdose: Treatment is symptomatic and aimed at preventing further absorption from the GIT; increasing urinary excretion; and correcting fluid, electrolyte, and acid– base imbalances. Gastric lavage and activated charcoal help reduce absorption. IV sodium bicarbonate for more rapidly excreted, and hemodialysis effectively removes salicylates from the blood. IV fluids are indicated when high fever or dehydration is present. Contraindications and Cautions Salicylates are contraindicated in the presence of known allergy to salicylates. Bleeding abnormalities because of the changes in platelet aggregation associated with these drugs. Impaired renal function because the drug is excreted in the urine. Surgery or other invasive procedures scheduled within 1 week because of the risk of increased bleeding. Pregnancy or lactation because of the potential adverse effects on the neonate or mother. 32 Contraindications and Cautions (cont.) Aspirin should not be used in children younger than 12 years of age, and it is contraindicated for any elevated temperature, regardless of the cause, because of the danger of Reye’s syndrome (neurologic problems associated with viral infection treated with salicylates). In these circumstances, acetaminophen is recommended instead of aspirin. Clinically Drug - Drug Interactions NSAID’s in general decrease diuretic effect when taken with loop diuretics. Decreased antihypertensive effect of β-blockers if these drugs are combined. Increased risk of bleeding with oral anticoagulants Alternatively, aspirin can displace other highly protein- bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents 33  Propionic Acid Derivatives The propionic acid group is a relatively new group of NSAIDs. These drugs are aspirin-like but have stronger effects and create less GI irritation. They are nonselective cyclooxygenase inhibitors. Drugs in this group are highly protein-bound, so drug interactions might occur, Propionic acid derivatives are better tolerated than other NSAIDs. Gastric upset occurs, but it is not as severe as with aspirin and indomethacin. Six propionic acid agents are ibuprofen, fenoprofen calcium (Nalfon), naproxen (Naprosyn), ketoprofen (Orudis), flurbiprofen (Ansaid), and oxaprozin (Daypro). Other Amongst all, naproxen is found to have higher analgesic efficacy. NSAID’s Ibuprofen It is commonly prescribed analgesic having weak anti- inflammatory activity. It is used at a dose of 400 to 600 mg three times a day. It has a very weak antiplatelet activity and shares common side effects of other NSAIDS. Fenoprofen and oxaprozin are like ibuprofen in their 34 pharmacology.  Naproxen Apart from analgesic property, naproxen also shows good anti-inflammatory property. Therefore, it is used for rheumatoid arthritis, dysmenorrhea, and migraine. The plasma half-life of naproxen is 14 hours in young and it doubles in elderly patients due to age-related decrease in renal function. It is used at a dose of 250 mg two to three times a day. Acetic acid derivatives Other Indomethacin NSAID’s Indomethacin is approximately 20 times more potent nonselective inhibitor of COX pathway compared to aspirin. It is an acetic acid derivative. It inhibits infiltration of polymorphonuclear leukocytes and suppresses the biosynthesis of mucopolysaccharides. It is a potent anti-inflammatory with the analgesic and antipyretic properties equivalent to aspirin. 35  Due to a higher incidence of adverse effects, indomethacin is not used as a first-line drug for many inflammatory conditions such as arthritis of various origins. Ketorolac Among NSAIDs, ketorolac is an aryl acetic acid derivative with a potent analgesic having comparatively a lesser anti-inflammatory property. In the control of postoperative pain, it is equivalent to that of morphine. Its use is limited to acute pain control for shorter periods (2-6 days) Nabumetone Nabumetone is an acetic acid derivative. It is a prodrug and upon conversion, it shows potent nonselective COX inhibition. Diclofenac It is an acetic acid derivative. It has preferential activity on COX-2 (similar to celecoxib). It is a potent compound, having good analgesic, antipyretic, and anti-inflammatory activities, as compared to naproxen, indomethacin, etc. 36  It is used at a dose of 50 mg three times a day or 75 mg twice daily. It is also administered as 75 mg intramuscular injection. Its ethyl ammonium salt is used for making ointments for topical applications (used as 1% topical gel or ointment). It is also used as 0.1% eye drop for ocular inflammatory conditions) Upon oral administration, it is absorbed well but undergoes extensive first-pass metabolism. It accumulates in synovial fluid; therefore, its pharmacological activity is more than its plasma half-life and correlation. It is metabolized in liver and excreted through urine and bile. It is not recommended for children, nursing mothers, and pregnant women. Oxicams : Piroxicam and Meloxicam Piroxicam is an oxicam. It is a potent anti-inflammatory with good analgesic and antipyretic compounds. It is a nonselective and reversible COX inhibitor known to have longer activity. However, due to serious skin reactions besides GI-related side effects, it is not considered a first-line therapy for arthritis. 37  Meloxicam is a preferential COX-2 inhibitor. Although it belongs to the category of oxicams, it shows preferentiality to COX-2 as compared to piroxicam. Its pharmacological activities are similar to piroxicam but its gastric site effects are much lesser. It is used at a dose of 7.5 to 15 mg once daily. Nimesulide It is a preferential COX-2 inhibitor. It is an arylsulfonanilide derivative lacking an acidic group like most of the NSAIDS. Its anti-inflammatory, analgesic, and antipyretic activities are comparable with other NSAIDs. People who have aspirin-induced allergy are reported to tolerate nimesulide. Its use in children has been banned in many countries. Metamizole (Dipyrone) Metamizole is a pyrazoline derivative. It has analgesic and antipyretic properties but weak anti-inflammatory property. It has been reported to cause agranulocytosis; therefore, it is banned in USA. However, it is used in other European countries without any serious toxicities. Mild GI irritation and GI-related side effects have been reported. It is used at a dose of 0.5 to 1.5 g orally or by intramuscular or intravenous routes. 38 General Side Effects and Adverse Reactions for First- Generation NSAIDs Most NSAIDs tend to have fewer side effects than aspirin when taken at anti- inflammatory doses, but gastric irritation is still a common problem when NSAIDs are taken without food. In addition, sodium and water retention may occur. Alcoholic beverages consumed with NSAIDs may increase gastric irritation and should be avoided 39  NSAIDs cross the placenta and cross into breast milk. Therefore, they are not recommended during pregnancy and lactation because of the potential adverse effects on the fetus or neonate In the third trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus. Paracetamol is preferred if analgesic or antipyretic effects are needed during pregnancy 40  Cyclooxygenase - 2 selective inhibitors Celecoxib It is a selective COX-2 inhibitor, and it is significantly more selective for inhibition of COX- 2 than COX-1. Unlike the inhibition of COX-1 by aspirin (which is irreversible), the inhibition of COX-2 is reversible. Therapeutic uses: Celecoxib is approved for the treatment of RA, osteoarthritis, and acute pain. Celecoxib has similar efficacy to NSAIDs in the treatment of pain 41 Pharmacokinetics: Celecoxib is readily absorbed after oral administration. It is extensively metabolized in the liver by cytochrome P450 (CYP2C9). t1/2=11Hrs. excreted through bile and urine. celecoxib should be avoided in patients with severe hepatic or renal disease Adverse Effects Celecoxib is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is lost when aspirin is added to celecoxib therapy. Patients who are at a high risk of ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib. Like other NSAIDs, celecoxib has a similar risk for cardiovascular events. Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib. Inhibitors of CYP2C9, such as fluconazole, may increase serum levels of celecoxib. 42  Relative selectivity of some commonly used NSAIDs. Data shown as the logarithm of their ratio of IC80 (drug concentration to achieve 80% inhibition of cyclooxygenase). *Aspirin graphed for IC50 value due to it showing significantly more COX-1 selectivity at lower doses and graph using higher concentrations does not accurately reflect the usage or selectivity of aspirin. 43 44  Summary of nonsteroidal anti-inflammatory agents (NSAIDs). CNS = central nervous system; COX-2 = cyclooxygenase-2; GI = gastrointestinal. *As a group, with the exception of aspirin, these drugs may have the potential to increase risk of myocardial infarction and stroke. 45  N -Acetyl-P–Aminophenol (APAP) Acetaminophen, Paracetamol It is effective in eliminating mild to moderate pain and headaches and is useful for its antipyretic effect. Acetaminophen does not possess anti-inflammatory action. Its onset of action is rapid, and the duration of action is 5 hours or less. Severe adverse reactions may occur with an overdose, so acetaminophen in liquid or chewable form should be kept out of children’s reach. Related Drugs Indication (Acetaminophen Indicated for the treatment of pain and fever associated with influenza. or Paracetamol) prophylaxis of children receiving diphtheria, pertussis - tetanus (DPT) immunizations (aspirin may mask Reye's syndrome in children). Relief of musculoskeletal pain associated with arthritis. Equal to aspirin in analgesic and antipyretic effects, but it lacks anti -inflammatory and antiplatelet effects. Does not cause nausea, vomiting, or GI bleeding, does not interfere with blood clotting. It constitutes 25% of all OTC drugs sold. Examples of OTC products that contain acetaminophen include Panadol; Tylenol; Revanin 46  Well and rapidly absorbed from GIT, peak plasma conc. reached within 0.5 - 2 hrs. Duration of action is 3 -4 hrs. Because of acetaminophen’s short half-life, it can be administered every 4 hours as needed with a maximum dose of 4g/day. However, it is suggested that a patient who frequently takes acetaminophen limit the dose to 2000mg/day (2g/day) to avoid the possibility of hepatic or renal dysfunction. Pharmacokinetics Metabolized in liver; 94% excreted in urine as inactive metabolite 4% is metabolized to a toxic metabolite, which is inactivated by conjugation with glutathione and excreted in urine. In the absence of glutathione, or excessive doses the toxic metabolite N -Acetyl-p-benzoquinone imine (NAPQI) combines with liver cells and causes damage or fatal liver necrosis. In alcoholic people, usual therapeutic doses may cause or increase liver damage. 47 Adverse effects At normal therapeutic doses, paracetamol has few significant adverse effects. With large doses of paracetamol, the available glutathione in the liver becomes depleted by the toxic metabolite, and (NAPQI) reacts with the sulfhydryl groups of hepatic proteins. Hepatic necrosis, a serious and potentially life-threatening condition, can result. Patients with hepatic disease, viral hepatitis, or a history of alcoholism are at a higher risk of paracetamol- induced hepatotoxicity. Paracetamol should be avoided in patients with severe hepatic impairment. It is used at a dose of 325 to 650 mg three to five times a day and the total adult dose of paracetamol per day is restricted to 2600 mg. 48 49  Every year children die from inadvertent acetaminophen overdose when parents give their child more than one OTC drug containing acetaminophen or administer a high dose of acetaminophen. Gastric lavage is recommended if overdose is detected within 4 hours after ingestion Activated charcoal used to inhibit absorption. N-Acetylcysteine (NAC): is the antidote, there is significant clinical evidence to support that oral and intravenous NAC are equally efficacious in the prevention of hepatotoxicity. Toxicity The Drug provides cysteine, a precursor substance required for the Treatment synthesis of glutathione. Acetylcysteine is most beneficial if given within 8 -10 hrs. of acetaminophen ingestion, but may be helpful up to 36 hrs. Oral initially 140 mg/kg, then 70mg every 4 hours up to 72 hours. IV 150 mg/kg by infusion over 15 minutes followed by 50 mg/kg 4 hourly for 72 hours Does not reverse damage that already occurred Contraindications and Cautions Allergy to acetaminophen. Hepatic dysfunction or chronic alcoholism. 50 Antiarthritic Drugs DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARD’S) 51  Rheumatoid Arthritis (RA)  Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis.  It affects the wrist and small joints of the hand causing joint pain, swelling and joint damage.  For most people with RA, early treatment can control joint pain and swelling, and lessen joint damage. Normally, the immune system can differentiate between self and non-self. In RA, WBCs view the synovium as non-self and initiate an inflammatory attack. This leads to activation of T-lymphocytes which activate monocytes and macrophages. B-lymphocytes are also involved WBC’s secrete inflammatory cytokines (TNF-α and IL- 1) into the synovial cavity (increase cellular infiltration, degradation of cartilage, joint space narrowing, bone erosion and systemic manifestations). These reactions cause progressive tissue injury, joint damage and erosions, functional disability, significant pain, and reduction in quality of life 52  Traditional Disease-Modifying Antirheumatic Drugs (DMARDS) Traditional DMARDs (methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine) are used in the treatment of RA to slow the course of the disease, induce remission, and prevent further destruction of the joints and involved tissues. Following diagnosis of RA, these agents should be started as soon as possible to delay progression of the disease (usually within 3 months of diagnosis). Monotherapy may be initiated with any of the traditional DMARDs; methotrexate is generally preferred. For patients with inadequate response to monotherapy, a combination of traditional DMARDs, or use of a TNF inhibitor or non-TNF biologic agent may be needed. NSAIDs or glucocorticoids can also be used for their anti-inflammatory actions 54 Pharmacotherapy of RA 55 Methotrexate It is a folic acid antagonist that inhibits cytokine production and purine nucleotide biosynthesis, leading to immunosuppressive and anti-inflammatory effects. Response to methotrexate usually occurs within 3 to 6 weeks of starting treatment. Other traditional DMARDs, or nontraditional ones can be added in combination if there is inadequate response to monotherapy with this agent. Doses of methotrexate required for RA treatment are much lower than those needed in cancer chemotherapy and generally administered once weekly, thereby minimizing adverse effects adverse effects Mucosal ulceration and nausea. Cytopenia’s (particularly leukopenia) and Cirrhosis of the liver with chronic administration Supplementation with folic acid may improve tolerability of methotrexate and reduce gastrointestinal and hepatic adverse effects. Periodic liver function tests, complete blood counts, and monitoring for signs of infection are recommended Methotrexate is contraindicated in pregnancy 56 Hydroxychloroquine It was used originally in lupus & malaria treatment , However it’s mechanism in RA therapy is unknown For early/mild RA, It is often used in combination with methotrexate. Response is expected within 6 weeks to 6 months. Lower adverse effects on the liver and the immune system than other DMARDs. It may cause ocular toxicity, irreversible retinal damage and corneal deposits. It may also cause CNS disturbances, GI upset, and skin discoloration and eruptions. Leflunomide An Immunomodulatory agent, used alone or in combination with methotrexate It is considered a prodrug and it inhibits dihydroorotate dehydrogenase (DHODH) enzyme which is important for pyrimidine synthesis thus causing cell arrest of the autoimmune lymphocytes. Pregnancy category X adverse effects: headache, diarrhea, nausea. Can cause weight loss, allergic reactions, including a flu-like 57 syndrome, skin rash, alopecia, and hypokalemia.  It is not recommended in patients with liver disease as it can be hepatotoxic is also contraindicated in pregnancy. Monitor: signs of infection, complete blood counts, and liver enzymes. Sulfasalazine It has recommendations for use similar to leflunomide in the treatment of RA. Its mechanism of action in treating RA is unclear. The onset of activity is 1 to 3 months, and it is associated with GI adverse effects (nausea, vomiting, anorexia) and leukopenia. 58  Biologic Disease-Modifying Antirheumatic Drugs IL-1 and TNF-α are proinflammatory cytokines involved in the pathogenesis of RA. When secreted by synovial macrophages, IL-1 and TNF-α stimulate synovial cells to proliferate and synthesize collagenase, thereby degrading cartilage, stimulating bone resorption, and inhibiting proteoglycan synthesis. The TNF-α inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab) are biologic DMARDs which have been shown to: decrease signs and symptoms of RA, reduce progression of structural damage, and improve physical function. Clinical response can be seen within 2 weeks of therapy. TNF-α inhibitors are usually employed in RA after a patient has an inadequate response to traditional DMARDs. These agents may be used alone or in combination with traditional DMARDs. If a patient has failed monotherapy with one TNF-α inhibitor, a traditional DMARD may be added, or therapy with a non-TNF biologic agent or a different TNF-α inhibitor may be tried. 59  TNF-α inhibitors find use in a number of disorders in addition of RA, such as ulcerative colitis and Crohn’s disease, psoriasis, and ankylosing spondylitis. Biologic DMARDs include also the non-TNF biologic agents (abatacept, rituximab, tocilizumab). Like TNF-α inhibitors, non-TNF biologics are generally used in RA after a patient has an inadequate response to traditional DMARDs, and they may be used alone or in combination with traditional DMARDs. If a patient has failed monotherapy with one non-TNF biologic, a trial of another non-TNF biologic with or without methotrexate is warranted (required) 60  Adverse effects  An increased risk of lymphoma and other cancers has been observed with the use of TNF-α inhibitors.  Patients receiving biologic DMARDs are at increased risk for infections, such as tuberculosis, fungal opportunistic infections, and sepsis.  TNF-α inhibitors and non-TNF biologic agents should not be used together due to the risk of severe infections.  Reactivation of hepatitis B may occur with use of these agents. Contraindications Live vaccinations should not be administered to patients taking any of the biologic DMARDs. TNF-α inhibitors should be used cautiously in those with heart failure, as they can cause and/or worsen pre-existing heart failure 61  Non-TNF biologic agents Abatacept Competes with CD28 (on T-cells) for binding with antigen presenting cells, thereby it prevents full T-cell activation. Rituximab Antibody directed against the CD20 antigen found on the surface of B lymphocytes, resulting in B-cell depletion. Tocilizumab IL-6 receptor blocker. Administered as an IV infusion every 4 weeks Anakinra IL-1 receptor antagonist. Associated with neutropenia. Tofacitinib (oral) Oral inhibitor of Janus kinase (enzymes that modulate immune cell activity). It is indicated for the treatment of moderate-to-severe established RA in patients who have had an inadequate response or intolerance to methotrexate. Hemoglobin must be greater than 9 g/dL to start and must be monitored during therapy due to the risk for anemia. lymphocyte and neutrophil counts should be checked and monitored 62 63 GOUT TREATMENT 64  Treatment of Gout Gout is a disease characterized by hyperuricemia. Hyperuricemia  deposition of sodium uric acid (urate) crystals in tissues, especially the joints and kidney  inflammatory process as uric acid has needle-shaped crystals. Uric acid is a poorly soluble substance that is the major end product of purine metabolism. The cause of hyperuricemia is an imbalance between overproduction of uric acid and/or the inability of the patient to excrete it via renal elimination Pathogenesis: Urate crystals are initially phagocytosed by granulocytes which leads to the release of prostaglandins and lysosomal enzymes, neutrophils migrate into the joint space and amplify the ongoing inflammatory process. In the later phases of the attack, increased numbers of macrophages appear, ingest the urate crystals, and release more inflammatory mediators 65 In certain mammals 67 Clinical types of gout Acute gouty arthritis characterized by warmth, intense pain, swelling, and extreme tenderness in a joint, usually in a big toe, knees, ankles, wrists, or elbows Chronic Recurrent gouty attacks (Chronic Tophaceous Gout) Urate crystals deposit over the tip of the elbow and in the finger joints. If this form of gout remains untreated, the affected joint may begin to erode and ultimately be destroyed. Sometimes, the affected joints may look similar to rheumatoid arthritis. Aims of gout treatment Reduction of pain and inflammation. Reduction of hyperuricemia. This can be accomplished by interfering with uric acid synthesis or increasing uric acid excretion. 68 Treatment of gout Drugs used in the treatment of gout Example A- Treatment of an acute attack NSAIDs Immunosuppressive Colchicine Glucocorticoids B- Prophylaxis against recurrent attacks (reduction of plasma uric acid concentration) Agents that reduce uric acid synthesis (xanthine Allopurinol, Febuxostat oxidase inhibitors) Sulfinpyrazone, Agents that increase uric acid excretion (Uricosurics) probenecid 70 71 Acute Gout Treatment (Management of attacks) Precipitating Factors Acute gout attacks can result from excessive alcohol consumption, a diet rich in purines, and kidney disease. Therapeutic Options NSAIDs, corticosteroids, or colchicine are effective alternatives for the management of acute gouty arthritis. The NSAID drug of choice Indomethacin is considered the NSAID of choice (all NSAIDs are likely to be effective in decreasing pain and inflammation). Aspirin and other salicylates are not used in gout as they inhibit uric acid excretion in the urine, exacerbating serum concentrations In acute/severe attacks: Intraarticular corticosteroids (when only one or two joints affected) is appropriate in the acute setting, with systemic corticosteroid therapy for more widespread joint involvement. The most commonly used oral corticosteroid is prednisone Prophylactic urate-lowering therapy Indicated in patients if they have: More than two attacks/year or chronic kidney disease or kidney stones or tophi (deposit of urate crystals in joints, bones, cartilage, or other). 72 Colchicine Colchicine was once the drug of choice for treatment of acute gout. Mechanism of action it produces its anti-inflammatory effects by binding to the intracellular protein tubulin, preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis to the affected area. It is absorbed readily after oral administration, reaches peak plasma levels within 2 hours, half-life is 9 hours. undergoes enterohepatic recirculation and exhibits high interpatient variability in the elimination half-life. Metabolites are excreted in the intestinal tract and urine. 73 Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects. Indications Acute gouty attack. Prophylaxis of gout during initial treatment by allopurinol and uricosurics. Colchicine must be administered within 36 hours of onset of attack to be effective Side effects Diarrhea (often), nausea, vomiting, and abdominal pain (occasionally). Because colchicine can severely damage the liver and kidney, dosage must be carefully limited and monitored. Overdose is often fatal. Chronic use: may lead to myopathy, neutropenia, aplastic anemia, and alopecia. The drug should not be used in pregnancy, and it should be used with caution in patients with hepatic, renal, or cardiovascular disease. 74  Chronic Gout Treatment Treatment Aim Urate-lowering therapy to reduce the frequency of attacks and complications of chronic gout. Therapeutic Strategy The use of xanthine oxidase inhibitors (allopurinol or febuxostat) to reduce the synthesis of uric acid (first-line treatment for prevention). Uricosuric agents (probenecid) are used for patients who don’t tolerate or achieve adequate response to xanthine inhibitors. Caution: Initiation of urate-lowering therapy can precipitate an acute gout attack due to rapid changes in serum urate concentrations. Medications for the prevention of an acute gout attack (low-dose colchicine, NSAIDs, or corticosteroids) should be initiated with urate-lowering therapy and continued for at least 6 months 75 Allopurinol A purine analogue, xanthine oxidase inhibitor Reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase. Used for treatment of gout and hyperuricemia secondary to other conditions, such as that associated with certain malignancies and renal disease. Complete PO absorption. The metabolite is alloxanthin (oxypurinol), which is also a xanthine oxidase inhibitor with a half-life of 15-18 hours. Thus, effective inhibition of xanthine oxidase can be maintained with once-daily dosage. Tolerated by most. Hypersensitivity (skin rashes) are the most common adverse reactions. Risk with reduced renal function (avoid if CrCl500 mg/dL). 32  Omega-3 PUFA supplementation has not been proven to reduce cardiovascular morbidity and mortality. Common side effects of omega-3 PUFAs include gastrointestinal effects (abdominal pain, nausea, diarrhea) and a fishy aftertaste. There may be an increased bleeding risk when omega-3 PUFAs are taken with anticoagulants or antiplatelet agents. 33  Combination drug therapy It is sometimes necessary to use two antihyperlipidemic drugs to achieve treatment goals. Patients with established ASCVD an elevated 10-year risk of ASCVD, or those that do not achieve intended LDL-C reductions on maximally tolerated statin therapy may be considered for combination therapy. Ezetimibe and PCSK9 inhibitors can be considered for add-on therapy, since there is evidence that these combinations further reduce ASCVD events in patients already taking statin therapy. Combination drug therapy is not without risks. Liver and muscle toxicity occur more frequently with lipid-lowering drug combinations. 34 35 36 37 Combination therapy for dyslipidemia SATATINS Fibrates Niacin Bile Acid Resins Chol. Absorption Inhibitors http://www.jaoa.org/content/103/1_suppl/9S.full.pdf 38  Drugs Affecting Hemostasis Chapter 21Lippincott's illustrated reviews in pharmacology, 7th edition. South Asian edition Majdi M. Bkhaitan 2022/2023 39  Objectives At the end of this chapter the student is expected to: Explain the mechanism of action of anticoagulants, antiplatelets, and thrombolytics. Compare the actions for anticoagulants, antiplatelets, and thrombolytics. Compare the use and toxicities of heparin and warfarin. Differentiate between the side effects and adverse reactions of anticoagulants, antiplatelets, and thrombolytics. 40 Hemostasis Hemostasis is defined as stopping blood loss or bleeding Hemostasis is an orchestrated, balanced and tightly regulated process that can be subdivided into three sequential processes: Primary hemostasis: Platelet aggregation Interaction of the injured endothelium von Willebrand factor (VWF) with platelets is crucial for the formation of a platelet plug at the injury site Secondary hemostasis: fibrin formation the coagulation factors are activated on the surface of injured endothelium and activated platelets, which ultimately form a fibrin mesh that stabilizes the platelet plug to allow wound healing Tertiary hemostasis: fibrinolysis fibrinolysis is activated to dissolve the platelet plug and return the normal architecture of the endothelium, smooth endothelial lining, and normal lumen size. 41 Formation of hemostatic plug 43 Disorders of hemostasis Thrombosis The formation of an unwanted clot within a blood vessel, is the most common abnormality of hemostasis. Thrombotic disorders include acute myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), and acute ischemic stroke. These conditions are treated with drugs such as anticoagulants and fibrinolytics. Bleeding disorders Related to the failure of hemostasis are less common than thromboembolic disorders. Bleeding disorders include hemophilia, which is treated with transfusion of recombinant factor VIII, and vitamin K deficiency, which is treated with vitamin K supplementation. 51  Thrombus vs embolus A clot that adheres to a vessel wall is called a “thrombus” whereas an intravascular clot that floats in the blood is termed an “embolus.” A detached thrombus becomes an embolus Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients. Arterial thrombosis most often occurs in medium-sized vessels rendered thrombogenic by atherosclerosis. Arterial thrombosis usually consists of a platelet-rich clot In contrast, venous thrombosis is triggered by blood stasis or inappropriate activation of the coagulation cascade Venous thrombosis typically involves a clot that is rich in fibrin, with fewer platelets than are observed with arterial clots. 52 Drugs that decrease, prevent or dissolve thrombi (Antithrombotics): Anticoagulants Thrombolytic drugs Antiplatelet aggregating (e.g., Alteplase, agents (e.g., Heparin, Warfarin) Tenecteplaes) (e.g., Aspirin, Break down the Interfere with the Clopidogrel) clotting cascade and thrombus that has Alter the formation of thrombin formation been formed by the platelet plug preventing coagulation stimulating the but not affecting the plasmin system already formed clot. 53 Anti platelet aggregation drugs (Antithrombotics) Thromboxane inhibitor Aspirin ADP receptor antagonist Clopidogril Glycoprotein IIb/IIIa receptor inhibitors Abciximab 54  ↓PDE fibrinogen Ca2+ Ca2+ Ca2+ cAMP Ca2+ Ca2+ Ca Inactive GPIIb/ IIIa Ca2+ Ca Ca2+ Ca2+ Ca2+ Ca2+ 2+ Ca 2+ receptors Ca2+ 2+ Ca2+ Ca Ca2+ Ca 2+ Ca cAMP 2+ Ca 2+ active GPIIb/ IIIa 2+ receptors Resting Platelet collagenProstacycline Exposure of vWF Nitric oxide TxA2, subendothelial cells Endothelial cells ADP, Collagen fibers 5-HT vWF: von Willebrand factor 55 Activation and aggregation of platelets. GP = glycoprotein 56  Antiplatelets are used to prevent thrombosis in the arteries by suppressing platelet aggregation. Heparin and warfarin prevent thrombosis in the veins. Antiplatelet drug therapy is mainly for prophylactic use in: Prevention of repeat myocardial infarction or stroke Prevention of stroke for patients having transient ischemic attacks (TIAs). “Prevention of myocardial infarction or stroke for patients with familial history” 57 TXA2 biosynthesis inhibitors: Aspirin Mechanism of action Irreversible inhibition of cyclooxygenase 1 (COX 1) which leads to decrease production of thromboxane A2 TXA2 which functions as platelet aggregation inducer and a potent vasoconstrictor. Since platelets do not synthesize new proteins, the action of aspirin on platelet cyclooxygenase is permanent, lasting for the life of the platelet (7 to 10 days). Repeated doses of aspirin produce a cumulative effect on platelet function. the recommended aspirin dose is 81, 162,or 325mg/d. Because aspirin has prolonged antiplatelet activity, it should be discontinued at least 7 days before surgery. 58 Therapeutic use Aspirin is the only antiplatelet agent that irreversibly inhibits platelet function. Aspirin is used in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent Ml, and to decrease mortality in the setting of primary and secondary prevention of MI. Complete inactivation of platelets occurs with 75 mg of aspirin given daily. The recommended antiplatelet dose of aspirin ranges from 50 to 325 mg daily. The half-life of aspirin ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 hours Adverse effects contraindication and interactions Higher doses of aspirin increase drug-related toxicities as well as the probability that aspirin may also inhibit prostacyclin production. 59  Bleeding time is prolonged by aspirin treatment, causing complications that include an increased incidence of hemorrhagic stroke and gastrointestinal (GI) bleeding, especially at higher doses of the drug. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site. Ibuprofen, if taken within the 2 hours prior to aspirin, can obstruct the access of aspirin to the serine residue and, thereby, antagonize platelet inhibition by aspirin. Therefore, immediate-release aspirin should be taken at least 60 minutes before or at least 8 hours after ibuprofen. Platelet's count must be monitored, Aspirin is contraindicated in case of platelets less than 50.000 60 ADP receptors Antagonists (P2Y12 receptor antagonists) Mechanism of action : Ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor are P2Y12 ADP receptor inhibitors that also block platelet aggregation but by a mechanism different from that of aspirin. They inhibits the binding of ADP to its receptors on platelets → inhibit the activation of the GP IIb/IIIa receptors → inhibit platelets binding to fibrinogen and to each other. Ticagrelor and cangrelor bind to the P2Y12 ADP receptor in a reversible manner. The other agents bind irreversibly. Clopidogrel (Plavix) is an antiplatelet drug frequently used after myocardial infarction or stroke to prevent a second event. It may be prescribed singly or with aspirin. It has been stated that Plavix and aspirin are more effective in inhibiting platelet aggregation if used together than if used as separate antiplatelet therapies. The maximum inhibition of platelet aggregation is achieved in 3 to 5 days 61 Therapeutic use Clopidogrel is approved for prevention of atherosclerotic events in patients with a recent Ml or stroke and in those with established peripheral arterial disease. It is also approved for prophylaxis of thrombotic events in acute coronary syndromes (unstable angina or non-ST-elevation Ml). Additionally, clopidogrel is used to prevent thrombotic events associated with percutaneous coronary intervention (PCI) with or without coronary stenting. Prasugrel is approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes (unstable angina, non-ST-elevation Ml, and ST-elevation Ml managed with PCI. Ticagrelor is approved for the prevention of arterial thromboembolism in patients with unstable angina and acute Ml, including those undergoing PCI. Cangrelor is approved as an adjunct during PCI to reduce thrombotic events in select patients. These agents can cause prolonged bleeding for which there is no antidote. These drugs should not be taken if the patient has a bleeding peptic ulcer, any active 62 bleeding, or intracranial hemorrhage. Ticlopidine is associated with severe hematologic reactions that limit its use, such as agranulocytosis, Thrombotic thrombocytopenic purpura (TTP), Aplastic anemia. Clopidogrel on the other hand causes fewer adverse reactions Clopidogrel is a prodrug, and its therapeutic efficacy relies on its active metabolite, which is produced via metabolism by CYP 2C19. Genetic polymorphism of CYP 2C19 leads to a reduced clinical response in patients who are "poor metabolizers" of clopidogrel. Tests are currently available to identify poor metabolizers, and it is recommended that other antiplatelet agents (prasugrel or ticagrelor) be prescribed for these patients. Ticagrelor carries a black box warning for diminished In addition, other drugs that inhibit CYP 2C19, effectiveness with concomitant such as omeprazole and esomeprazole, should use of aspirin doses above 100 mg be avoided while on clopidogrel. 63 Glycoprotein IIb/IIIa receptor (integrin) inhibitors: Abciximab Mechanism of action Block the binding of fibrinogen to the glycoprotein IIb/IIIa receptor on the platelet surface. By binding to GP lIb/lIla, they block the binding of fibrinogen and von Willebrand factor and, consequently, aggregation does not occur They are called platelet glycoprotein (GP) IIb/IIIa receptor. Antagonists. Eptifibatide and tirofiban act similarly to abciximab, by blocking the GP lIb/lIla receptor. Uses They are used primarily for acute coronary syndromes (unstable angina or non–Q-wave myocardial infarction) 64  for preventing re-occlusion of coronary arteries following percutaneous transluminal coronary angioplasty (PTCA) together with aspirin and heparin These drugs are usually given before and after PTCA. The drug of choice for angioplasty is abciximab. Following IV infusion, the antiplatelet effects for abciximab persist for 24 to 48 hours The major adverse effect of these agents is bleeding, especially if used with anticoagulants 65 Dipyridamole  Dipyridamole, a coronary vasodilator, increases intracellular levels of cAMP by inhibiting phosphodiesterase, thereby resulting in decreased thromboxane A2 synthesis.  The drug may potentiate the effect of prostacyclin and, therefore, decrease platelet adhesion to thrombogenic surfaces.  Dipyridamole is used for stroke prevention and is usually given in combination with aspirin.  Patients with unstable angina should not use dipyridamole because of its vasodilating properties, which may worsen ischemia (coronary steal phenomenon).  Dipyridamole commonly causes headache and dizziness and can lead to orthostatic hypotension (especially if administered IV). Cilostazol Cilostazol is an oral antiplatelet agent that also has vasodilating activity. Cilostazol and its active metabolites inhibit phosphodiesterase type Ill. It is approved to reduce the symptoms of intermittent claudication. 66 Anticoagulants 67 Coagulation process components The coagulation process that generates thrombin consists of two interrelated pathways, the extrinsic and the intrinsic systems. The extrinsic system is initiated by the activation of clotting factor VII by tissue factor (also known as thromboplastin). Tissue factor is a membrane protein that is normally separated from the blood by the endothelial cells that line the vasculature. In response to vascular injury, the tissue factor becomes exposed to blood. it can bind and activate factor VII, initiating the extrinsic pathway. The intrinsic system is triggered by the activation of clotting factor XII. This occurs when blood encounters the collagen in the damaged wall of a blood vessel. 68 Dr. Amal Youssef XII XIIa XI XIa Extrinsic pathway Intrinsic pathway IX Ca ++ VIIa IXa X Ca ++ Ca ++ VIIIa,PL X TF Common pathway Xa Prothrombin (II) Ca ++ Va, PL Thrombin (IIa) Fibrinogen Fibrin monomer (Soluble) 2. Platelets aggregate and form a "plug" Fibrin polymer XIIIa (insoluble) 69 1. Exposure of subendothelial cells  IIa Activated II X Xa coagulation factors IX IXa coagulation factors VII VIIa Vitamin K Vitamin K epoxide (Reduced) Active (Oxidized) Inactive Factors II, VII, IX, and X require reduced vitamin K as a cofactor for their synthesis by the liver (Vit K-dependent coagulation factors). The reduced vitamin K cofactor is converted to vitamin K epoxide (inactive) during the reaction. Vitamin K epoxide reductase (VKOR), normally converts vitamin K Dr. Amal Youssef epoxide to reduced vitamin K (active) 70 Blood clotting cascade 71  Blood clots in 4 to 8 minutes in a glass tube. Clotting is prevented by EDTA or citrate: by binding Ca2+ in the blood Coagulation Recalcified (adding Ca2+)plasma clots in 2 to 4 minutes. lab tests in Activated partial thromboplastin time (aPTT): Clotting vitro (APTT time after recalcification is shortened to 25 to 35 seconds by the addition of negatively charged & PT and phospholipids, such as kaolin (aluminum silicate). INR) Prothrombin time (PT): Recalcified plasma will clot in 12 to 14 seconds after addition of "thromboplastin" (a saline extract of brain that contains tissue factor and phospholipids); International normalized ratio (INR):INR=[PT patient]/[PT normal] Desired INR in treated patient is usually around (2-3) 73  ANTICOAGULANT DRUGS Blood coagulates by transformation of soluble fibrinogen into insoluble fibrin. Circulating proteins interact in a “cascade,” where clotting factors undergo limited proteolysis to become active serine proteases. Anticoagulants are drugs which decrease the formation of fibrin clot and can be classified in 4 categories. The endogenous anticoagulants, protein C and protein S, cause proteolysis of factors Va and VIIIa 74 Anticoagulants mechanism of action Anticoagulants inhibit the formation of fibrin clots. 1. Indirect 3. Oral Direct Thrombin Anti-thrombin III Factor Xa Inhibitors Inhibitors Xa Ca++ , Va, PL Prothrombin (II) Thrombin (IIa) 2. Warfarin & Other Coumarin Fibrinogen Fibrin Anticoagulants 75 Indirect Thrombin Inhibitors: Heparin &Low Molecular Weight Heparin They include Unfractionated heparin (UFH) Low-molecular-weight heparin (LMWH) e.g.: enoxaparin, dalteparin Heparin is an injectable, rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombi. Heparin occurs naturally as a macromolecule complexed with histamine in mast cells, where its physiologic role is unknown. It is extracted for commercial use from animal intestinal mucosa. Unfractionated heparin is a mixture of straight-chain, anionic glycosaminoglycans with a wide range of molecular weights. It is strongly acidic because of the presence of sulfate and carboxylic acid groups. 76  The realization that low molecular weight forms of heparin (LMWHs) can also act as anticoagulants led to the isolation of enoxaparin and dalteparin, produced by depolymerization of unfractionated heparin. The LMWHs are heterogeneous compounds about one-third the size of unfractionated heparin. Mechanism of Action Heparin binds to endogenous antithrombin III (ATIII). The heparin–ATIII complex combines with and irreversibly inactivates thrombin and several other factors, particularly factor Xa. In the presence of heparin, ATIII proteolyzes thrombin and factor Xa approximately 1000-fold faster than in its absence. LMW heparins like heparin , bind ATIII. These complexes have a more selective action on Xa but they fail to affect thrombin 77 78 Therapeutic use Treatment of acute venous thromboembolism (DVT or PE) Prophylaxis of postoperative venous thrombosis in patients undergoing surgery (for example, hip replacement) Acute MI These drugs are the anticoagulants of choice for treating pregnant women, because they do not cross the placenta, due to their large size and negative charge With glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents. LMWHs do not require the same intense monitoring as heparin, thereby saving laboratory costs and nursing time. These advantages make LMWHs useful for both inpatient and outpatient therapy. 79 Pharmacokinetics Heparin must be administered subcutaneously or intravenously, because the drug does not readily cross membranes (Figure). The LMWHs are usually administered subcutaneously. [Note: Enoxaparin can be administered intravenously in the treatment of MI.] Heparin is often initiated as an intravenous bolus to achieve immediate anticoagulation. This is followed by lower doses or continuous infusion of heparin, titrated to the desired level of anticoagulation according to the activated partial thromboplastin time (aPTT) or anti-Xa level. 80  Whereas the anticoagulant effect with heparin occurs within minutes of IV administration (or 1 to 2 hours after subcutaneous injection), the maximum anti-factor Xa activity of the LMWHs occurs about 4 hours after subcutaneous injection. Usually not necessary to monitor coagulation values with LMWHs because the plasma levels and pharmacokinetics of these drugs are more predictable. However, in renally impaired, pregnant, and obese patients, monitoring of factor Xa levels is recommended with LMWHs. In the blood, heparin binds to many proteins that neutralize its activity, causing unpredictable pharmacokinetics. The half-life of heparin is approximately 1.5 hours, whereas the half-life of the LMWHs is longer than that of heparin, ranging from 3 to 12 hours 81 Heparin: Toxicity Bleeding, 1% to 33% of patients. Episodes increases with the total daily dose of heparin. Excessive bleeding may be managed by: Discontinuing the drug. Administration of Protamine sulfate (Antidote) (~1 mg of protamine for every 100 U of heparin remaining in the patient). Protamine is used routinely to reverse the anticoagulant effect of heparin following cardiac surgery and other vascular procedures. 2. Thrombocytopenia (platelet,