BMS150 Wk4 Anti-inflammatory Drugs PDF

Anti-inflammatory Medications NSAIDs & Glucocorticoids BMS 150 Week 5 Video Links Video 3 Video 4 Video 5 Phospholipase A2 Recall: from the pathophysiology of inflammation Most likely to be induced during inflammation Overview Membrane Phospholipids Non-steroidal antiinflammatory drugs Stimulus (ex...

Anti-inflammatory Medications NSAIDs & Glucocorticoids BMS 150 Week 5 Video Links Video 3 Video 4 Video 5 Phospholipase A2 Recall: from the pathophysiology of inflammation Most likely to be induced during inflammation Overview Membrane Phospholipids Non-steroidal antiinflammatory drugs Stimulus (ex membrane damage) Phospholipase A2 Glucocorticoids NSAIDS Lipoxygenase Inhibitors Arachidonic Acid Cyclooxygenase Lipoxygenase Blocks production of proinflammatory prostaglandins Prostaglandins (i.e. series 2) Thromboxanes (ie TXA2) Leukotrienes NSAIDs NSAID - Non-Steroidal Anti-Inflammatory Drug General NSAID mechanism: ▪ Block cyclooxygenase at both central and peripheral sites* Blocks formation of the various prostaglandins (PGs) and thromboxane Blockade of prostaglandin formation results in moderate anti-inflammatory, analgesic and anti-pyretic effects Blockade of thromboxane causes inhibition of platelet activation ▪ Decreases likelihood of formation of clots – more when we cover hematology, only aspirin is therapeutically effective Blocks it irreversibly - best at anti-platelet agent Not effective at reducing inflammation * FYI for now: Tylenol does not block peripheral sites, so not considered an NSAID PG/TX overview * Endothelium PGI2: Vasodilation and inhibition of platelet aggregation Kidney PGE2: Promotes renal blood flow via vasodilation Can have toxicity if we block these prostaglandins bc some needed for normal organ functions Stomach Platelets PGE1: Gastric protection ( acid, bicarb. & mucous) TXA2: Vasoconstriction and platelet aggregation Block causes adverse effects Macrophages, WBC’s, Endothelum PGI2: Vasodilation and inhibition of platelet aggregation PGE2: Vasodilation, increased vascular permeability, lowering of pain threshold, pyretic Block causes therapeutic effects Cyclooxygenases (COX) COX-1 – a “housekeeping” enzyme that is always present and regulated in a variety of tissues: ▪ Gastric mucosa – production of protective, bicarbonaterich mucous ▪ Kidney – regulation of blood flow and filtration ▪ Platelets – platelet aggregation for hemostasis Prostaglandins perform a number of useful functions outside of inflammation COX-2 – an “induced” enzyme that is mostly produced by immune cells in response to inflammation COX-1 vs COX-2 – details are FYI Inflammatory mediators (ex Il-1, TNF-α) COX-1 COX-2 (constitutive) (inducible) Endothelium Platelets Stomach PGI2: Vasodilation and inhibition of platelet aggregation TXA2: Vasoconstriction and platelet aggregation PGE1: Gastric protection ( acid, bicarb. & mucous) Kidney PGE2: Promotes renal blood flow via vasodilation “Housekeeping” functions Macrophages, WBC’s, Endothelium PGI2: Vasodilation and inhibition of platelet aggregation PGE2: Vasodilation, increased vascular permeability, lowering of pain threshold, pyretic Inflammation What are COX-inhibitors used for? Gout, RA, OA Indications: Treatment of inflammatory joint disorders Treatment of osteoarthritis Short-term treatment of pain associated with inflammation (i.e. post-op pain, pain after dental procedures) Treatment of fever Treatment of dysmenorrhea (analgesic) Only aspirin can irreversibly block thromboxane production by platelets – thus it is the only NSAID that is used to prevent platelet aggregation - - - - - - COX-inhibitors - FAQs Most COX-inhibitors block both COX-1 and COX-2 Is there an advantage to blocking COX-2 selectively instead of both COX-1 and COX-2? ▪ Selective COX-2 inhibitors are somewhat less likely to cause GI bleeding (less inhibition of gastric mucous production) This does not seem to be the case long-term, though ▪ Unfortunately, selective COX-2 inhibitors are associated with development of heart attacks and strokes more often than most non-selective medications Only one is approved in Canada – celecoxib (Celebrex) Consideration of patient risk factors is important prior to prescribing celecoxib COX-inhibitors - FAQs Why do NSAIDS (COX-2 inhibitors and many other common NSAIDS) increase the risk of heart attack? ▪ One theory = inhibition of PGI2 formation Endothelial cells reduce platelet aggregation w/ PGI2 COX-inhibitors - FAQs The GI toxicity of oral systemic NSAIDs can be severe in those with a history of bleeding peptic ulcers – can this be avoided? ▪ Patients can take the NSAID with an antacid that reduces the risk of GI damage (FYI – a proton-pump inhibitor) ▪ Patients can take the NSAID with a medication that activates prostaglandin receptors in the GI tract (FYI – misoprostol) Renal toxicity of NSAIDs can be significant, due to impairing the vascular reflexes that control renal blood flow ▪ Need to evaluate renal function if using long-term, especially in the elderly Maintain effectiveness of SNS & increase blood sugar when fasting b/n meals Glucocorticoids We make them endogenously ie when blood sugar is low when fasting; hypothalamus detects this, ACTH released from pituitary, adrenal cortex releases cortisol - endogenous glucocorticoid CORTISOL Corticosteroids with strong glucocorticoid effects are anti-inflammatory in nature ▪ Mechanism of action: Block of PLA2 ▪ Other actions – inhibition of leukocyte migration reduction of pro-inflammatory cytokine production - many Therapeutic Uses ▪ Relief of inflammation or flares in autoimmune disease Acute (ex: asthma attack) and chronic (ex: rheumatoid arthritis) Route of administration examples: ▪ Inhaled: asthma attack IBD ▪ Oral: rheumatoid arthritis, IBS, bursitis ▪ Injected: bursitis Inflammatory bowel disease ▪ Topical: dermatitis ▪ Treatment of allergies Most cases should be stopped as soon as the inflammation is done! Glucocorticoids Glucocorticoids are analogues of cortisol, which is released by your adrenal cortex ▪ High levels of cortisol has potent anti-inflammatory effects ▪ Cortisol also increases glucose availability Increased gluconeogenesis Insulin resistance Ie prednisone - commonly used Long-term use of glucocorticoid medication can negatively feed back on the anterior pituitary ▪ Less ACTH → atrophy of the adrenal cortex ▪ Therefore those on long-term glucocorticoids need to be weaned slowly off their medication to allow endogenous ACTH to stimulate “regrowth” of the adrenal glands Glucocorticoids Are potent anti-inflammatory medications ▪ However, they exhibit a wide range of side effects, many serious if they are used long-term ▪ They also do not change disease activity in autoimmune disease They do not preserve articular cartilage or joint architecture in inflammatory arthritis They do not reduce the frequency of surgeries for inflammatory bowel disease or reduce intestinal “scarring” ▪ Therefore the appropriate use of steroids is to limit inflammation for short periods of time Glucocorticoids Select adverse effects ▪ Immunosuppression Increased risk of infection (some serious, i.e. pneumonia) Delayed wound healing ▪ Metabolic Ulcers in GI tract due to catabolic effects Muscle weakness due to proteolytic effect Fat redistribution – especially around the face, trunk and neck Hyperlipidemia Hyperglycemia Glucocorticoids Select adverse effects ▪ Neurologic – irritability, euphoria, even psychosis in some ▪ Bone effects Reduced bone formation and increased bone resorption Interference with metabolic actions of vitamin D leading to a reduction in calcium absorption and an increase in its renal clearance Decreased growth in children Glucocorticoids - FAQs Since glucocorticoids have so many adverse effects, should patients stop them immediately ASAP? ▪ It is VERY, VERY important to wean patients slowly from their glucocorticoid medication if they have been taking: High doses systemically (orally) For weeks or months ▪ If patients suddenly stop their (long-term, systemic) glucocorticoids they can experience an “adrenal crisis” due to inability to produce their own cortisol – dangerous Local glucocorticoids (topical, inhaled, local injections into joints) are much less likely to exhibit systemic side effects or cause adrenal suppression General Vaccine Concepts Name BMS150 Week 5 Vaccination and “therapeutic antibody” concepts Passive Immunization: Transfer of antibodies from a source outside the patient Happens in nature – breastfeeding Also a commonlyused treatment strategy See table Vaccination and therapeutic antibody concepts Passive immunity DOES NOT elicit a host immune response No memory cells develop Once the antibodies have “expired”, immunity is lost Antibodies are removed after 2-3 months by cells of the reticuloendothelial system Passive immunity is/was done for the following reasons: Before antibiotics and vaccines were well developed In situations where humoral immunity is needed immediately Severe infections or weakened patients Nasty toxins Vaccination and therapeutic antibody concepts Active immunization involves administration of a weakened microbe or portion of a microbe → production of memory cells Why are some vaccines given frequently? The organism divides so quickly and results in symptoms so quickly that effective protection depends on adequate titres of antibodies present BEFORE the infection occurs Polio takes forever to divide – therefore the memory cells have “time” to produce antibodies and stimulate CD8 cells to kill it. Live attenuated – disabled microbes are given to elicit a response Inactivated – cells are destroyed (heat, chemicals) Purified macromolecules – toxoids (inactivated bacterial toxins), subunit vaccines, conjugate vaccines Vaccine type Advantages Live attenuated Stronger immune Ex: measles, mumps, polio, response rotavirus, rubella, Thought to need fewer tuberculosis, varicella, doses to attain lifelong yellow fever immunity Disadvantages Needs to be refrigerated May mutate into more virulent forms Inactivated Ex: cholera, influenza, hepatitis A, plague, polio, rabies Stable (no refrigeration Weaker immune required) response, usually Safer than live vaccines, no more booster shots mutation possible are required Purified macromolecules Ex: diphtheria, tetanus (toxoids); hepatitis B, pertussis, strep. pneumoniae (subunit); haemophilus influenza, strep. pneumoniae (conjugate) Toxoid – immune system Expensive to develop develops antibodies that Effectiveness? immediately bind to toxins Conjugates and subunit vaccines are specific + take advantage of immunogenicity of protein “combos” Vaccination and therapeutic antibody concepts Toxoid? Diphtheria + tetanus secrete toxins that mediate most of the damage to the host Toxoids are inactivated toxins that stimulate antibody production → neutralization of the toxin’s effect Subunit vaccines? A component of the bacterial coat is given to stimulate antibodies against it Can be generated using recombinant DNA techniques The bacterial coat itself often is resistant to phagocytosis – however, if the bacterial coat is opsonized by antibodies, it loses its resistance to phagocytosis Vaccination and therapeutic antibody concepts Conjugates? Not all proteins from microorganisms are strongly immunogenic Strategy – “conjugate” a weakly immunogenic protein with a strongly immunogenic one In general, toxoid and subunit vaccines are bad at activating CD4+ cells Therefore no class switching or improvement in antibody affinity Conjugate vaccines are more effective at eliciting a CD4+ response → better memory cells, higher antibody affinities A bacterial polysaccharide (H. influenzae type B) is conjugated to the highly immunogenic tetanus toxoid Vaccination and therapeutic antibody concepts Adjuvants = substances that enhance the immune response to a vaccine How? Mixed in an emulsion with the immunogen → Slower “release” of the immunogen at the site of injection Modified aluminum Improved recruitment of APCs and salt formation of large, stimulatory (AS04) antigen complexes adjuvants Serves as a Toll-like receptor 4 (TLR-4) agonist Aluminum salts, oilwater emulsion adjuvants Future directions for vaccine development “Killed” vaccines are not very good at stimulating a cytotoxic T-cell response Some (subunit vaccines, toxoids) don’t even elicit a helper Tcell response unless they’re complexed with a more potent immunogen (conjugate) Strategies to improve cellular immunity (in development, not yet in use) Placing the immunogen in a micelle or liposome that allows it to enter the cell → MHC-I binding Genes for virulent microorganisms are expressed by less dangerous microorganisms (recombinant vector vaccines) DNA for a protein expressed by virulent bacteria is “implanted” into the muscle of the host The host muscle cell expresses the protein on its MHC-I → better cytotoxic T-cell activation mRNA vaccines How they work – the basics: 1. 2. 3. 4. 5. mRNA for a protein that you want to mount an immune response to is sequenced mRNA is placed in a “vehicle” that protects it mRNA is endocytosed or phagocytosed by an immune cell – specifically, an APC mRNA is translated to a protein in the cytosol, using the APC’s cellular machinery (aka ribosomes) The protein is degraded by an immunoproteasome, and expressed by the APC Multiple types of expression 6. Helper T-cells and B-cells are activated mRNA vaccines What is the advantage over conventional vaccination? It’s really, really easy to make mRNA specific for the exact protein that you want to use as the antigen You can make a lot of mRNA really quickly There is pretty much zero chance of the mRNA disrupting the genome of any cell Can be a concern with live attenuated viruses Theoretically, a greater degree of control over how the immune system responds to the antigen Why aren’t all vaccines mRNA?? There are tricky challenges to producing them – see below Challenges in mRNA vaccines (FYI) mRNA vaccines that had been tested in the past didn’t work very well for a couple of reasons: No immune response – mRNA didn’t get translated Excessive immune response – a toxic immune “over-reaction” that wasn’t that helpful for the development of immunity What was going wrong? The mRNA would go double-stranded and activate TLRs The TLRs would result in type 1 interferon production… why would this be a problem? The poly-A tails would get too long and destabilize the mRNA Until recently, it wasn’t clearly understood how cells distinguished between viral and eukaryotic mRNA The vaccines now are modified just like eukaryotic mRNA (some uridines are modified to look more eukaryotic, for example) mRNA vaccine production - FYI Fig. 1 | IVT mRNA is formulated into lipid nanoparticle vaccines using a cell-free production pipeline. a | In vitro- transcribed (IVT) mRNA contains five structural elements: a 5′ cap containing 7methylguanosine linked through a triphosphate bridge to a 2′-O-methylated nucleoside, flanking 5′ and 3′ untranslated regions (UTRs), an open reading frame (ORF) and a poly(A) tail. See notes for more details