Anti-Inflammatory Agents PDF

Inflammation: a complex protective response to injury caused by damaging agents It is aimed at the inactivation or removal of these agents and promoting healing COX-1: exists in the tissue as a constitutive isoform COX-2: produced by cytokines stimulation as part of an inflammatory response...

Inflammation: a complex protective response to injury caused by damaging agents It is aimed at the inactivation or removal of these agents and promoting healing COX-1: exists in the tissue as a constitutive isoform COX-2: produced by cytokines stimulation as part of an inflammatory response PGE2 (pro-inflammatory): vasodilation, bronchodilation, inhibition of gastric acid secretion, stimulation of gastric mucus secretion, sensitization of pain receptors to chemical and mechanical stimuli, promotion of anterior pituitary hormones release PGF2α: uterus contraction, bronchoconstriction, decrease in intraocular tension TXA2(thromboxane): produced by platelets induction of platelet aggregation, vasoconstriction PGI2: inhibition of platelet aggregation, potent vasodilation Balancing act of thromboxane Prostaglandins: Are not initiators for pain, they are mediators for pain; not in the pathway of pain they just sensitize the nociceptors that DO cause the pain sensation Naciceptors convey the pain signal to brain When you reduce the sensitization = no signal for pain MOA of NSAIDS: Act by inhibiting Cyclooxygenases (COX) => decreased PG production COX-1: Constitutively expressed => “house-keeping” function COX-2: Induced by pro-inflammatory factors (TNHα, IL-1) PGs do not cause pain, but sensitize nociceptors to stimulation (e.g. by 5-HT, bradykinin, capsaicin, …) NSAIDs have antipyretic effects (reduce fever)  ○ IL1 is released by macrophages; IL1 is expressed from macrophages which are apart of innate immune system and defends our body from bacteria, foreign material IL-1 release from activated macrophages (bacteria, etc.) induces COX-2 in the brain => PG E produced => affects thermoregulation => fever Aspirin (ASA): Therapeutic use: ○ Antipyretic, analgesic, anti-inflammatory activity at high doses (325 mg) ○ Cardiovascular threshold dose 81 mg (inhibits platelet aggregation), but maybe dose dependant ○ Low doses (81 mg/ day) diminish risk of recurrence of MI, of stroke and of colon cancer Platelet effect ○ Physiologically TXA2 enhances platelet adhesion while PGI2 depress it ○ At low doses (81 mg/day) aspirin irreversibly inhibits TXA2 ○ Lack of TXA2 persists for the entire lifetime of the platelet (3-7 days) ○ As a result thrombus formation decreases (anticoagulant effect) Kidney effects ○ Prevents synthesis of PGE 2 and PGI 2 responsible for maintaining renal blood flow The net effect is vasoconstriction of these two Pressure goes up and kills our kidneys so patients with longterm kidney disease are highly contraindicated If a patient has a glomerular filtration rate < 30, give tylenol instead ○ May cause Na+ retention, edema, and hyperkalemia ○ Doesn’t cause interstitial nephritis as the rest of the NSAIDs Adverse effects ○ GI: epigastric distress (the lining of stomach that is always on by COX-1 and because COX-1 is inhibited in ASA, will experience gastric distress), nausea, vomits, and microscopic bleeding (inhibition of TXA2) ○ Hematologic: prolongs bleeding time and as anticoagulant doses must be adjusted ○ Due to prolonged effect should be discontinued 1 week prior to surgery ○ Respiratory: toxic doses of respiratory depression combination of respiratory and metabolic acidosis Hypersensitivity ○ 15% of patients will have any kind of reaction but anaphylactic shock is uncommon Reye Syndrome ○ Fatal fulminating hepatitis with cerebral edema and liver dysfunction; specially encountered in children ○ CI after viral infection Toxicity  ○ Mild (salicylism): nausea, vomits, hyperventilation, headache, dizziness, and tinnitus ○ Severe (salicylate intoxication): vasomotor collapse, combined respiratory and metabolic acidosis, and coma Propionic acid derivatives Anti-inflammatory, analgesic and antipyretic action ○ Ibuprofen (Motrin ®)- has more effect on kidney The same mechanism & pharmacological actions of aspirin except that it is reversible inhibitor for COX enzymes More potent as anti-inflammatory than aspirin!!! Rapidly absorbed after oral ingestion Half-life 1-2 hours Highly bound to plasma proteins Protein binding = no effect; need to give 400 mg Ibuprofen for an effect Excreted through the kidney as metabolites CI in kidney dysfunctions Clinical uses: Analgesic Antipyretic Anti-inflammatory Acute gouty arthritis Patent ductus arteriosus Formulations: Oral preparations Topical cream for osteoarthritis A liquid gel for rapid relief of postsurgical dental pain Intravenous route for patent ductus arteriosus Adverse effects Gastric upset (less frequent than aspirin) Fluid retention Hypersensetivity reactions Ocular disturbances Rare hematologic effects (agranulocytosis & aplastic anemia) Contraindications Peptic ulcer Allergic patients to aspirin Kidney impairment Liver diseases Pregnancy Hemophilic patients The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition of ASPIRIN (limit cardioprotective effect of aspirin)  ○ Naproxen (Naprosyn ® ) ○ Fenporofen (Nalton ® ) ○ Ketoprofen (Ketoprofen®) ○ Flurbiprofen (Ansaid®) ○ Oxaprozin (Daypro®) (strongest derivative used once a day) ○ Widely used agents for rheumatoid arthritis and ankylosing spondylitis because GI effects are less toxic than aspirin All are reversible inhibitors of cyclooxygenase Most common SE include dyspepsia due to gastric bleeding, headache, tinnitus, and dizziness Heteroaryl Acetic Acids: Diclofenac More potent than Indomethacin and Naproxen More potent as an anti-inflammatory than analgesics and antipyretics Clinical applications ○ 1. Any inflammatory conditions ○ 2. Musculoskeletal pain ○ 3. Dysmenorrhea ○ 4. Acute gouty arthritis ○ 5. Fever ○ 6. Ophthalmic to prevent or treat ophthalmic inflammation (Acular) Diclofenac is supplied as either the sodium or potassium salt, most often supplied as the sodium salt Diclofenac sodium has a tendency to retain salt & water in the body, predisposing to cardiovascular events ○ Less likely to use in patients w/ HBP, cardiovascular disease ○ Water will follow sodium and more blood volume = higher pressures Diclofenac potassium is preferred in patients with cardiovascular diseases Topical gel (OTC) and ophthalmic formulation available Combo Preparations ○ Diclofenac with Misoprostol (PGE1) decreases upper gastrointestinal ulceration, but results in diarrhea ○ Diclofenac with Omeprazole to prevent recurrent bleeding Side Effects ○ Gastric upset ○ Renal impairment ○ Elevation of serum aminotransferase (hepatic enzymes- liver) ○ Salt & water retention which can lead to elevated BP Heteroaryl Acetic Acids: Ketorolac (Toradol/Acular) Antipyretic, analgesic, and anti-inflammatory properties Indicated for short-term management of acute pain that requires the caliber of pain management offered by opioids  May be used to initiate tx of post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, and headaches Better analgesic than anti-inflammatory Oral and ophthalmic formulations available (used post-op cataract surgery) Should use the lowest possible dose, and avoid using ketorolac for an extended period of time (ideally < 5 days) Common SE ○ Headache ○ Upset stomach ○ Nausea ○ Vomiting ○ Diarrhea ○ Stomach pain ○ Bloating Acetic acid derivatives Indometacin ○ An indole-acetic acid derivative ○ Used for symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants ○ More potent than aspirin as anti-inflammatory agent but as toxic dose ○ Effective as analgesic for uveitis and post-operative ophthalmic procedures ○ Antipyretic for Hodgkin’s lymphoma ○ Abortive treatment gout High levels of uric acid in the system ○ Treatment of scleritis ○ Delay labor by suppressing uterine contractions ○ Absorbed PO and largely bound to plasma proteins Sulindac (Clinoril): indene acetic acid class of NSAIDs (oral NSAIDs can be used for uveitis) and is chemically related to indomethacin ○ Not DJ’s choice; derivative of indomethacin which is better but he did not talk about it due to MOA being confusing ○ Used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute subacromial bursitis or supraspinatus tendinitis, and acute gouty arthritis ○ A prodrug, derived from sulfinyl indene, that is converted to an active sulfide compound by liver enzymes ○ May be associated with fewer gastrointestinal side effects than other NSAIDs, except for the COX-2 inhibitor drug class ○ The sulfide metabolite undergoes enterohepatic circulation thus maintaining constant blood levels of the compound without inducing gastrointestinal effects, where the drug is excreted in the bile and then reabsorbed from the intestines  ○ The full mechanism of action is not fully understood, sulindac is thought to primarily mediate its action by inhibiting prostaglandin synthesis by inhibiting COX-1 and COX-2 COX-2 Selective NSAID: Celecoxib (Celebrex) Selective irreversible COX-2 inhibitor at therapeutic doses; it is approved for osteoarthritis and not as an analgesic agent It does not interfere with platelet function Well absorbed orally and metabolized in liver in CYP450 and excreted in feces and urine Characteristics ○ Highly selective inhibitors to COX-2 enzyme ○ Potent anti-inflammatory ○ Have analgesic & antipyretic properties ○ Highly bound to plasma proteins ○ Lower incidence of gastric upset ○ No effect on platelet aggregation (COX1) ○ Renal toxicities (not recommended for patients w/ severe renal insufficiency) ○ High incidence of cardiovascular thrombotic events with some of them as ROFECOXIB Side effects ○ GI disturbances Duodenal ulcer ○ Displaces other drugs metabolized by CYTP450 ○ *Contraindicated in patients allergic to sulfonamides ○ SAIDs- Steroidal Anti-Inflammatory Drugs Short-acting glucocorticoids (natural) ○ Hydrocortisone ○ Cortisone Intermediate-acting glucocorticoids ○ Prednisone  ○ Prednisolone ○ Methylprednisolone ○ Triamcinolone Long-acting ○ Betamethasone ○ Dexamethasone ○ Paramethasone Topically acting glucocorticoids ○ Beclomethasone dipropionate ○ Budesonide flucinolone ○ Acetonide flucortolone Clinical uses ○ Adrenal insufficiency ○ Arthritis ○ Collagen disease (systemic lupus erythematosus, scleroderma) ○ Bronchial asthma ○ Severe allergic reactions ○ Autoimmune diseases ○ Skin diseases Main SE of SAIDs ○ Susceptibility to infections wounds ○ Delayed healing of wounds ○ Osteoporosis ○ Growth retardation in children ○ Muscular weakness ○ Hyperglycemia ○ Cushing habitus ○ Peptic ulceration Autacoids-Histamine/Anti-histamines 1 & 2 Autacoids Overview  ○ Histamine, serotonin, prostaglandins, & some vasoactive peptides belong to a group of compounds called autacoids ○ They all have the common feature of being formed by the tissues on which they act; thus, they function as local hormones ○ The autacoids also differ from circulating hormones in that they are produced by many tissues rather than in specific endocrine glands Histamines ○ 1st autacoid to be discovered ○ Is a chemical messenger that mediates a wide range of cellular responses, including: Allergic and inflammatory reactions Gastric acid secretion Neurotransmission in parts of the brain ○ Involved in inflammatory and anaphylactic reactions ○ Histamine storage In mast cells, histamine (+ charged) is held by acidic proteins and heparin (- charged) within intracellular granules When the granules are extruded by exocytosis, Na+ ions in e.c.f. exchange with histamine to release it free ○ Histamine conditions causing release Tissue injury Any physical (mechanical) or chemical agent that injuries tissue, skin or mucosa will cause the immediate release of histamine from mast cells Chemical and mechanical mast cell injury causes degranulation and histamine release Allergic reactions Exposure of an antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions Sensitized by IgE, antibodies attached to their surface membranes, causing mast cell degranulation and release of histamine, and other mast cell component ○ Histamine receptor and their function(s) H1 Modulate circadian cycle Itching Systemic vasodilation Bronchoconstriction Ileum contraction H2 Speed up sinus rhythm Stimulation of gastric secretion Smooth muscle relaxation Inhibit antibody synthesis, T-cell proliferation & cytokine production  H3 Decrease acetylcholine, serotonin and norepinephrine neurotransmitter release in the CNS Presynaptic autoreceptors H4 Mediate mast cell chemotaxis ○ Histamine antagonists- Epinephrine The effects of histamine released in the body can reduced in several ways Physiologically, endogenous epinephrine (adrenaline) have smooth muscle actions opposite to those of histamine, by acting at different receptors Clinically, by injection of exogenous injection of epinephrine, agonist activity causes smooth muscle relaxation, like observed in the treatment for bronchoconstriction that occurs in systemic anaphylaxis and other conditions in which massive release of histamine Use of epinephrine in anaphylaxis Adrenoreceptor agonists (sympathomimetic) ○ Epinephrine is the DOC for the immediate treatment of anaphylactic shock ○ It is an effective physiologic antagonist of many of the mediators of anaphylaxis ○ Sometimes supplemented with antihistamines and corticosteroids, but these agents are neither as efficacious as epinephrine nor as rapid-acting ○ Histamine antagonists- mast cell stabilizers (release inhibitors) Reduce the degranulation of mast cells that results from immunologic triggering by antigen IgE interaction Cromolyn and Nedocromil have this effect and have been used in the treatment of asthma, although the molecular mechanism underlying their action is not fully understood Therapeutic uses: Mild to moderate bronchial asthma ○ To prevent acute attacks ○ Effective in children ○ Reduces need of steroids or bronchodilators ○ Ineffective for an acute attack ○ Becomes effective overtime (e.g., 2-3 weeks) Allergic rhinitis Atopic diseases of the eye Giant papillary conjunctivitis ○ Histamine receptor blockers  These compounds do not influence the formation or release of histamine; rather, they block the receptor-mediated response of a target tissue H1 blockers: First generation (diphenhydramine) ○ Still widely used because they are effective and inexpensive ○ They block H1 receptors and muscarinic receptors ○ Most penetrate the CNS, some used off-label for sedation, dizziness, vertigo, motion sickness ○ ○ Other effects Sedation A common effect, effect varies among chemical subgroups Second generation have little or no sedative or stimulant actions; also have far fewer autonomic effects than the first-generation antihistamines Antinausea and antiemetic actions Several first-gen H1 antagonists have significant activity in preventing motion sickness They are less effective against an episode of motion sickness already present Anticholinoceptor actions First generation like ethanolamine subgroup, have significant atropin-like effects on peripheral muscarinic receptors Benefits reported for nonallergic rhinorrhea May also cause urinary retention and blurred vision Second generation (Cetirizine) ○ Are specific for H1 receptors because do not cross BBB; they show less CNS side effects  ○ Among these agents, Ioratadine/desloratadine/fexofenadine produce the least sedation ○ H2 blockers (Cimetidine) ○ H1 Antihistamines MOA: Action of all the H1-receptor blockers is qualitatively similar (block H1 receptors) But most of these blockers have additional other related blocking receptor activity Antagonists to cholinergic, adrenergic, or serotonin receptors ○ Antihistamines- PK Absorption These agents are rapidly absorbed after oral administration Peak blood concentrations occur in 1-2 hours Distribution Widely distributed throughout the body First-generation drugs enter CNS readily Metabolism Some of them are extensively metabolized, primarily by microsomal systems in the liver Several of the second-generation agents are metabolized by the CYP3A4 ○ Antihistamines Therapeutic uses Allergic and inflammatory conditions Useful in treating allergies caused by antigens acting on immunoglobulin E antibody–sensitized mast cells DOC for controlling the symptoms of allergic rhinitis and urticaria, because histamine is the principal mediator Are ineffective in treating bronchial asthma, because histamine is only one of several mediators of that condition (LTs are the main mediators) Motion sickness/nausea Along with the antimuscarinic agent scopolamine, certain H1-receptor blockers, such as diphenhydramine, dimenhydrinate, cyclizine, meclizine, and hydroxyzine, are the most effective agents for the prevention of the symptoms of motion sickness  Prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways The antiemetic action of these medications seems to be due to their blockade of central muscarinic receptors Somnifacients Although not the DOC, many first-generation antihistamines, such as diphenhydramine hydroxyzine, have strong sedative properties and are used in the treatment of insomnia Contraindicated in the treatment of individuals working in jobs where wakefulness is critical Nausea and vomiting during pregnancy Several agents have been studied for possible use in treating "morning sickness" The piperazine derivatives were withdrawn from such use when it was demonstrated that they have teratogenic effects in rodents ○ Antihistamines- adverse effects/toxicity Sedation First-generation H1 antihistamines, such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine, bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS The most frequently observed adverse reaction is sedation Dry nose/eyes/mouth Oral antihistamines also exert weak anticholinergic effects, leading not only to a drying of the nasal passage but also to a tendency to dry eye and dry mouth Other CNS actions Other central actions include tinnitus, fatigue, dizziness, lassitude (a sense of weariness), incoordination, blurred vision, and tremors ○ H2 Antihistamines Physiology of acid secretion Parietal cells are located in the body of the stomach and secrete hydrochloric acid(HCl) into the lumen Water and CO₂ are combined to produce hydrogen (H+) ions and HCO₃ ions by the action of the carbonic anhydrase enzyme H+is transported to the lumen of the stomach via the H+/K+ATPasepump HCO₃ is exchanged for chloride(Cl−) ion H+and Cl−combine to form the final product: HCl Types of H2 blockers There are different names and brands of H2 blockers All are available over the counter without a prescription Most work equally as well Side effects may vary from drug to drug  Famotidine (Pepcid AC, Pepcid Oral, Zantac 360) Cimetidine (Tagamet, Tagamet HB) Nizatidine Capsules (Axid AR, Axid Capsules, Nizatidine Capsules) Ranitidine (Zantac) has been removed from the US market due to concerns about safety Competitive H2 receptor antagonists Markedly inhibits basal acid secretion including nocturnal secretion MOA H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine, H2 blockers thus function as competitive antagonists Clinical indications Gastritis GERD Gastric and duodenal ulcer and esophageal reflux disease Stress ulcers prevention Metabolism Metabolized in the liver by the cytochrome P450 system Among the agents, cimetidine is distinctive in its potent inhibition of the P450 system (CYP 1A2, 2C9, and 2D6), which can result in significant drug interactions Side effects SE from H2 blockers is rare Famotidine: the most common side effect is headache Cimetidine: rare but diarrhea, dizziness, rashes, headaches, and gynecomastia may occur; CYP450 inhibitor Nizatidine: rare