NON-NARCOTIC ANALGESICS .docx

NON-NARCOTIC ANALGESICS I PATHOPHYSIOLOGY OF INFLAMMATION Inflammation: the immune system’s protective response to injurious stimulus. Inflammatory response can be caused by: Infectious agents Noxious chemicals Thermal or physical trauma These factors release damage- and pathogen-assoc...

NON-NARCOTIC ANALGESICS I PATHOPHYSIOLOGY OF INFLAMMATION Inflammation: the immune system’s protective response to injurious stimulus. Inflammatory response can be caused by: Infectious agents Noxious chemicals Thermal or physical trauma These factors release damage- and pathogen-associated molecules that are recognized by cells charged with immune surveillance. Depending on conditions, inflammation may be exaggerated and sustained with no apparent benefit and with severe adverse consequences (e.g., hypersensitivity, autoimmune diseases, chronic inflammation). Inflammatory Process: Transient local vasodilation and increased capillary permeability. Infiltration of leukocytes and phagocytic cells. Resolution with or without tissue degeneration and fibrosis. Mediators: Chemical: histamine, serotonin, prostaglandins (PGE2, PGI2, PGD2) bradykinins and leukotrienes (LTs) Chemotactic: platelet-activating factor (PAF), complement factor C5a, LTB4 Immunologic: IL-1, tumor necrosis factor (TNF) in concert with other cytokines and growth factors (IL-2, IL-6, IL-8) Others: endothelial intercellular adhesion molecule-1 (ICAM-1), oxygen radicals and nitric oxide PATHOPHYSIOLOGY OF FEVER Body temperature: Heat production vs. heat loss Set point for temperature regulation in the hypothalamus is elevated in fever. Fever may be caused by: Infection (viral or bacterial origin) Inflammation Graft rejection Malignancy Infection, inflammation, etc., can enhance the formation of cytokines such as IL-6, IL-1β, TNFα and interferons (act as endogenous pyrogens) Initial phase of thermoregulatory response: Mediated by ceramide release (triggers IL-1β formation) in neurons of the pre-optic area of the hypothalamus. Late phase response: Is mediated by induction of cyclooxygenase (COX-2) and formation of PGE2 PGE2 acts on EP receptors on thermosensitive neurons which triggers the hypothalamus to elevate body temperature by: Increasing heat generation Decreasing heat loss PATHOPHYSIOLOGY OF PAIN Peripheral terminals of primary afferent fibers that sense pain (nociceptors) can be activated by stimuli such as: Heat Acids Pressure During tissue injury, inflammatory mediators (e.g., bradykinin, H+, serotonin, LTs, ATP, PGs, nerve growth factor) increase the sensitivity of nociceptors and potentiate pain perception. Neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) may also be involved in the generation of pain. PGE2 and PGI2 reduce the threshold of the stimulation of nociceptors leading to peripheral sensitization. PGE2, PGD2, PGI2 and PGF2α contribute to central sensitization (an increase in the excitability of spinal dorsal horn neurons that cause hyperalgesia and allodynia). PATHOPHYSIOLOGY OF RHEUMATOID ARTHRITIS Chronic, systemic, autoimmune and inflammatory disease that primarily affects joints (also affects skin, lungs, muscle and CVS). RA is distinguished by joint swelling and tenderness and destruction of synovial joints, leading to disability and premature death. First joint tissue affected is the synovial membrane which lines the joint cavity Eventually inflammation may spread to articular cartilage, fibrous joint capsule, and surrounding ligaments and tendons causing pain, joint deformity and loss of function Joints commonly affected: fingers, feet, wrists, elbows and ankles Other joints: shoulders, hips and cervical spine Tissues: lungs, heart, kidneys and skin Autoimmune targeting of normal joint proteins leads to: Release of cytokines such as TNF, growth factors and interleukins which induce COX-2 expression. COX-2 increases PGE2 biosynthesis which stimulates pain pathways. 5-LOX-derived leukotrienes activate the surrounding endothelium to recruit inflammatory cells. Macrophages release collagenase and proteases while lymphocyte activity leads to the formation of the immune complex (both processes further damage joint tissue). Chronic inflammation develops. NSAIDs NSAIDs are a heterogeneous group of compounds which share certain therapeutic actions and some side effects. MECHANISM OF ACTION NSAIDs inhibit COX leading to a decrease production of PGs and thromboxanes. There are two isoforms of COX: COX-1: A constitutive enzyme involved in physiologic activities such as vascular homeostasis, maintenance of renal and GI blood flow. COX-2: An inducible enzyme involved in inflammation, fever and pain. It can be induced by cytokines and endotoxins. Non-selective NSAIDs inhibit both COX-1 and COX-2. Most NSAIDS are competitive, reversible, active site inhibitors of COX enzymes. Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity. SHARED PHARMACOLOGICAL ACTIONS Anti-inflammatory action: A decrease in the release of vasodilator PGE2 and PGI2 means less vasodilation and indirectly, less edema. Inhibition of the migration of leukocytes and macrophages into inflammation sites Stabilization of lysosomal membranes Analgesic action: Effective against pain of low to moderate intensity. Decreased PG generation means less sensitization of nociceptive nerve endings to the action of bradykinin, histamine and other chemical mediators. Effective when inflammation has caused peripheral and/or central sensitization of pain perception. Antipyretic action: Due to a decrease in the COX-2 mediated PGE2 generation in response to bacterial or inflammatory pyrogens (which is responsible for elevating the hypothalamic set-point for temperature control). NSAID do not influence normal body temperature or when it is elevated by such factors such as exercise or increases in ambient temperature. Gastric or intestinal ulceration: Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective PGI2 and PGE2 Inhibition of PG-induced inhibition of gastric acid secretion. Local irritation from contact of orally administered drug with gastric mucosa. Increased generation of products of the lipoxygenase pathway. SHARED SIDE EFFECTS Cardiovascular system: COX-2 selective NSAIDs can cause myocardial infarction, stroke and thrombosis. Due to depression of COX-2 dependent PGs (PGI2) formed in the vasculature and kidney without an effect on COX-1 catalyzed formation of platelet thromboxane TXA2. PGI2 inhibits platelet aggregation and constrains the effect of prothrombotic and atherogenic stimuli by TXA2 Reno-vascular action: No effect on renal function or blood pressure in normal human subjects. In patients with congestive heart failure, hepatic cirrhosis, chronic renal disease and hypovolemia, inhibition of vasodilatory PG production leads to a decrease in renal blood flow and glomerular filtration rate. Promote retention of salt and water by: Inhibiting PG-induced inhibition of reabsorption of chloride. Inhibition of action of ADH. Promote hyperkalemia via: Increased reabsorption of K+ Suppression of PG-induced secretion of renin. Chronic uses of high doses of NSAIDs can lead to analgesic nephropathy (a condition of slowly progressive renal failure, decreased concentrating capacity of the renal tubule and sterile pyuria). Pregnancy: NSAIDs can prolong gestation. Myometrial COX-2 expression and levels of PGE2 and PGF2α increase significantly in the myometrium during labor. Use of NSAIDs in late pregnancy can increase the risk of postpartum hemorrhage. Hypersensitivity reactions: Vasomotor rhinitis Generalized urticaria Bronchial asthma SHARED DRUG INTERACTIONS SHARED USES NSAIDs are firmly bound to plasma proteins and can displace the following drugs from plasma protein binding sites: Warfarin Sulfonylurea hypoglycemics Methotrexate NSAIDs can reduce renal excretion of lithium. NSAIDs can reduce the effectiveness of ACE inhibitors. Analgesics Antipyretics Anti-inflammatory agents Cardio-protection Fetal circulatory system: To close inappropriately patent ductus arteriosus in neonates Cancer chemoprevention (especially colon cancer) Bartter syndrome: rare disorder characterized by hypokalemic, hypochloremic metabolic alkalosis with normal BP and hyperplasia of the juxtaglomerular apparatus (leading to increased PGE2 biosynthesis). SALICYLATES Prototype: ASPIRIN 16,000 tons of aspirin (80 million pills) consumed each year in the U.S. Mechanism of action: Acts by acetylating COX-1 and COX-2 leading to inhibition of their activity. Acetylated COX-2 can form 15-epi-lipoxins which have potent anti-inflammatory actions. Pharmacological Actions: Analgesia: Effective in management of pain of low to moderate intensity arising from musculoskeletal disorders. Sites of action of aspirin could be in the brain (depression of pain stimuli at a subcortical site) or in the periphery. Antipyresis: Antipyretic dose < anti-inflammatory dose Altered hypothalamic set-point of body temperature returns to normal in the presence of salicylates. Anti-inflammatory actions: Large doses of salicylates have been used for anti-inflammatory and anti-rheumatic actions. Effect on the immunologic process in mesenchymal and connective tissues: Inhibition of antigen-antibody reactions. Nonspecific stabilization of capillary permeability during immunological insults. Salicylates can influence the metabolism of connective tissue (effect may contribute to its anti-inflammatory actions). Due to an effect on connective tissue mucopolysaccharides that act as barriers to the spread of infection and inflammation. Pharmacokinetics: Absorption: Active orally. Rapid absorption from the stomach and from proximal portions of the small intestine. Presence of food delays absorption of salicylates. Absorption can also occur from topical sites (salicylic acid and methyl salicylates from skin) Distribution: Wide distribution throughout body tissues including the CSF, saliva and milk. Salicylates readily cross the placental barrier. About 80% to 90% of salicylate in plasma is bound to plasma proteins, mainly albumin. Metabolism: Salicylates are metabolized by the liver into salicyluric acid (glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. Excretion: Kidney excretion via carrier facilitated transport mechanism for weak organic acids. Rate of urinary excretion is higher in alkaline than in acid urine. Rate of urinary excretion is also enhanced by a higher rate of urine flow (polyuria). Salicylate clearance is reduced, and salicylate exposure is significantly increased in the elderly. Plasma t1/2 for aspirin is about 20 minutes and for salicylate is 2-3 h. After a large dose, plasma t1/2 of salicylate may rise to 15-30 h.