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74 Cards in this Set
- Front
- Back
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General characteristics of NSAIDs?
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One of most commonly used drug classes
common in aging population due to more inflammatory conditions, which also accounts for higher toxic events Generally safe if not at risk for Renal, Gi, or CV issues |
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General features/observations about inflammation?
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Acute:
Mediated by autocoid disease - chemical messenger Immune Response Chronic: common problem: rheumatoid arthritis Role of inflammation: cell dmg assoc with inflammation release of lysosomal enzymes liberation of arachidonic acid - eicosonoid synthesis. |
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General properties of most NSAIDs?
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Analgesic, Antipyretic, Anti-inflammatory, Antiplatelet
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What are some good, general treatments for rheumatoid arthritis?
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Analgesics
NSAIDs Anti-inflammatory steroids DMARDs |
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What are some good, general treatments for Osteoarthritis?
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Acetaminophin
aspirin or other NSAIDs Intra-articular anti-inflam steroids Opioid analgesics |
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What are some general uses of NSAIDs?
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AAA
risk reduction for stroke or MI (antiplatelet) closure of patent ductus arteriosis treatment of chemical derangement in Bartter's Syndrome Chemoprevention of certain cancers such as colon cancer. |
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Mechanism of action for NSAIDs?
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All inhibit COX
Inhibition of prostaglandin synthesis is largely responsible for therapeutic side effect Generally provide symptomatic relief rather than affect the course of a disease |
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General side effects of nonselective NSAIDs
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GI issues
Dyspepsia peptic ulcer dz bleeding Renal acute renal failure (vasoconstriction) electrolyte/fluid abnormalities (hyperkalemia, hyponatremia, edema) CV attenuates antiplatelet actuvity of aspirin Worsens HTN, increases BP CNS: aseptic meningitis, psychosis, cognitive dysfunction |
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Describe COX 1
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Expressed in most cells/tissues
Housekeeping protein enzyme products important for normal homeostasis important for protective and maintenance functions gastric protection platelet aggreagation vascular homeostasis kidney function |
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Describe COX 2
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Mostly inducible
at site of imflammation, cytokines stimulate induction of COX 2 undetectable in most tissues proinflammatory and mitogenic function PG's in inflammatory sites synoviocytes, macrophages |
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How do NSAIDs affect COX 1 and 2?
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Inhibit them
extent of inhibition varies between drugs Patient response is HIGHLY VARIABLE |
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Side effects of nonselective COX inhibitors?
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Bad GI effects
affects kidney function |
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Why are COX 2 inhibitors preferred over non-selective or COX1?
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Because there are lower GI side effects. However, renal side effects still occur.
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What effects do NSAIDs have on renal function?
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In normal patients, the side effects are negligible.
Inhibition of PG synthesis can be significant in pts with stimulated PG synthesis, such as in renal disease acute renal failure due to PG being absent. PG normally opposes vasoconstriction, and so NSAIDs would cause high amounts of VC. |
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How is hyperkalemia started by NSAID use?
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Mediated by the effect of NSAID (via PG's) on the renin/angiotensis/aldosterone system.
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How do NSAIDs effect the development of edema and hyponatremia?
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Mediated by the effect of NSAIDs (via PG) on ADH activity resulting in reduced free water excretion
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How do NSAIDs increase BP?
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Due to inhibition of renal COX that affects volume load and sodium levels.
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Describe the general characteristics of salicylates.
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Prototype NSAID
NONSELECTIVE COX inhibitor Most NSAIDs are nonselective Selective refers to COX 2 IRREVERSIBLE INHIBITOR Salicylate and other NSAIDs inhibit by different mechanisms and are reversible. Non-acetylated salicylates everything else but aspirin non-selective reversible |
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How do dosages affect the therapeutic effects of aspirin?
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Varies with dose.
Low Dose: Antithrombotic (antiplatelet) 75-81 mg /day Inhibits COX 1, lowers TXA2 Medium dose: Analgesic/Antipyretic Inhibits COX 1&2 relieves mild to moderate pain by peripheral and central effects (lowering PGE2) ~650-4g/day High Dose: Anti-inflammatory Usefullness limited by toxicity 4-8g/day |
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Describe the mechanism of action for aspirin.
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Antiinflammatory effects:
higher doses needed for analgesic or antipyretic effects prolongs bleeding time most pts cannot tolerate high doses (GI Tox) Can interfere with uric acid elimination and aggravate control of gout. |
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What are the adverse side effects of aspirin?
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GI Toxicity:
IMPORTANT target of adverse effects Dyspepsia, gastritis, peptic ulcers, bleeding loss of cytoprotective actions of GI PG's Decreased mucin and bicarb production The above hold in general for the NSAIDs. Bronchoconstriction COX inhib. leads to excessive LT's. Renal toxicity interference with PG modulation of renal blood flow important in chronic use Liver Toxicity (Rare) |
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Describe the clinical signs of salicylism.
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Tinnitus (common, look for sign)
headache hearing loss dizziness drowsiness mental confusion Sweating Nausea, vomiting |
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Describe the acid-base abnormalities seen in pts taking salicylates.
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Net effect - veriety of effects can be seen. Mostly Respiratory alkalosis or mixed resp. alk/met. acid.
Direct stimulation of respiratory center early fall in pCO2 -> resp. alkalosis. Kidneys compensate by raising excreted bicarb, leading to compensated resp. alkalosis, with a normal pH and low bicarb and pCO2. Anion gap met. acidosis can follow due to organic acid accumulation acute resp. acid. rare in early toxicity, but may show up in severe poisoning later on. |
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How should a pt be managed if they have aspirin toxicity?
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Primarily supportive
decontamination activated charcoal, gastric lavage (if early) volume resuscitation, unless cerebral or pulmonary edema supplemental glucose for pts with altered mental status alkalinization hemodialysis altered mental status pulm. or cerebral edema renal insuff. fluid overload prevents alkalinization. |
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What are some drug-drug interactions with aspirin?
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Increased bleeding with warfarin and heparin
increased hypoglycemia w/ insulin and sulfonylureas interfere with uricosuric effects of probenacid High incidence of Reyes syndrome in chindren w/ aspiring use to treat viral illness. Use acetaminophin instead. |
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Characteristics of other non-acetylated salicylate drugs?
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Many different drugs
Typically have less GI and renal toxicity |
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What are some uses of non-salicylate NSAIDs?
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Dysmenorrhea, RA and OA, Ankylosing spondylitis, acute gout, other inflammatory conditions.
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What is the mechanism of action for non-salicylate NSAIDs?
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Nonselective COX inhibitors
reversible inhibition decrease synthesis of PG's Relative affinity for the COX isozyme varies Have teh same antipyretic, analgesic, anti-infalmmatory effects as aspirin, as well as reversible inhibition of platelet aggregation. |
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Describe the anti-inflammatory effects of non-salicylate NSAIDs.
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Not immediate
maximal when steady state levels are reached. Effects include: lower capillary permeability lower lysosomal enzyme release lower release of mediators from PMN, basophile, and mast cells. affects lymphokine realse from T cells. |
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List the adverse effects of non-salicylate NSAIDs.
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ALL have the same averse effect profile.
Many individuals cannot tolerate aspirin or salicylates as starting drugs in treatment of RA or OA, so NSAIDs are used. Most NSAIDs have anti-inflammatory efficacy similar to aspirin but lower adverse effects. |
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What effects to NSAIDs and misoprostol have on a pt, and what happend when the two are combined?
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NSAIDs inhibit PG synthesis to increase gastric acid levels, and lower protective bicarb
Misoprostol is a PGE analog, which lowers gastric acid synthesis and stimulates bicar and mucin production. These two drugs together can help patients who might be at a high risk for developing GI toxicity. |
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What other drugs can be used to lower GI Toxicity from NSAIDs?
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Proton-pump inhibitors.
Omeprazone, landoprazole, dexlansoprazole, esomeproazole, pantoprazole |
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What effects do NSAIDs cause on the kidney?
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All can produce some degree of nephrotoxicity.
acute renal failure - large doses, PG inhibition, renal VC chronically - analgesic nephropathy may be irreversible occurs after few years of continuous use papillary necrosis mechanism not clear |
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What effects do NSAIDs have on the CNS?
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Headache, psychosis, photosensitivity
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What are some drug interactions assoc. w/ NSAIDs?
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increased activity of...
sulfonylurea hypoglycemics Methotrexat Lithium Treatment of HTN May decrease activity of ACE inhibitors, loop diuretics, and beta blockers. |
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What are some general characteristics of Indomethacin?
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One of the msot toxic NSAIDs
Has all of the general properties of NSAIDs Not usually used to treat fever generally don't start with in treating RA. Special use in treating neonates w/ patent ductus arteriosis Safest if used briefly. ~20% of pts have to stop due to side effects. |
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What are some adverse effects of Indomethacin?
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Similar to other NSAIDs.
More likely ot have CNS effects Frontal headaches occur in ~25%. |
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What are some contraindication when using Indomethacin?
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Similar to other NSAIDs
Avoid in pts with epilepsy, hx of psychosis. |
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What are some general characteristics of Ibuprofen?
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Very extensively used
Low cost and low toxicity profile Use in RA limited - short duration for 4x/day. Indications for use similar to aspirin |
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What are some adverse effects of ibuprofen?
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Similar to aspirin, NV effects are still the most common side effects.
May negate aspirins cardioprotective effects by antagonizing aspirin's irreversible platelet inhibition. |
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What are some general characteristics of Naproxen?
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One of the omst frequently prescribed NSAIDs.
Half-life allows 2x/day dosing all of the typical NSAID uses. Middle of the road for toxicity risks. ~14% incidence with GI effects Toxicity profile similar to other NSAIDs. |
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What are some general characteristics of Ketorolac?
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Used as an analgesic, not antiinflam.
available for parenteral use Good for moderate to severe pain. |
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What are some characteristics of COX 2 inhibitors?
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Developed to retain anti-inflam. properties, but to reduce GI issues.
Inhibits COX 2, which normally causes inflammation and pain. relatively more selective for COX 2 Have better GI safety profile, but still most common AE is GI issues. No safer to kidneys than non-selective |
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Describe Celecoxib
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Primarily used for pain assoc. with
RA OA Aklylosing Spondylitis mangement of acute pain in adults Increased incidence of MI's assoc w/ use of COX 2 inhibitors Some cancers express COX 2 Over expression has been associated with a decreased survival rate. COX 2 inhibitors may be useful in prevention and treatment of these tumors. |
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Describe acetaminophin.
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NOT AN NSAID
also knows as paracetamol. |
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What is the mechanism of action of acetaminophin?
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Inhibits COX 2
mostly in CNS weak inhibitor in periphery. No anti-inflam. effects Used mostly for analgesic and antipyretic effects, esp. when aspirin can't be used children patients on anticoagulants gouty patients. |
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What factors does acetaminophin typically have a lower effect on?
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platelet aggregation
CV system Respiration Acid-base balance uric acid secretion |
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What are some effects that are typically missing from acetaminophin use?
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gastric irritation
GI erosion leeding No bronchospasm |
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What are some adverse reactions to acetaminophin use?
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Dose dependent hepatic necrosis (THINK PICTURE FROM INTRO TO PHARM, CYP450).
Usually in acute overdose. |
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What are some characteristics of acute acteominophin toxicity?
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NV, abdominal pain
severe hepatic necrosis When you see effects of dmg, it's too late! NAC given within 24 hours can protect liver. Get bloodlevels and estimate time of poisoning. If levels are high, give NAC. Can be given orally or IV. Kidneys may also suffer from necrosis Severe hypoglycemia may occur KNOW RUMACK-MATTHEW NOMOGRAM |
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What are some characteristics of DMARDs?
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More toxic than NSAIDs
Traditionally reserved for later Rx. May SLOW PROGRESS of RA. Most have no analgesic or antipyretic properties For many, MoA is not well defined. Biologic agents selectively inhibit proinflam. cytokine and/or block its receptor Nonbiologic agents: interfere with multiple inflam. pathways. Immunosuppressive drugs (Cytotox, antiproliferatives) |
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What is the current treatment approach with RA?
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Realization that Ra progresses aggressively and rapidly in most pts.
DMARDs can slow the progress if introduced early current recommendations are to start with DMARDs as soon as RA is diagnosed Methotrexate introduced early in treatment ahs shows significant impact on Dz. |
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What are some general characteristics of Methotrexate?
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GOLD STANDARD for treating RA
DMARD drug of choice for RA. particularly for moderate to severe RA usu. used with selective COX 2 inhib. or etanercept. anti-rheumatic mechanism unknown anticancer MOA - inhibits dihydrofolate reductase anti-RA effects begin earlier than Gold, penicillamine, antimalarial drugs |
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What are some adverse effects of methotrexate?
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Hepatotoxicity, pulmonary damage, myelosuppression, stomatitis.
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What is Hydroxychloroquine?
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antimalarial drug
mechanism unclear for RA Use for early, mild RA w/o poo prognostic features can take 2-3 months to see improvement |
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What are some side effects of Hydroxychloroquine?
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GI Upset
Most common SE requiring discontinuation Skin changes almost any type allergic in nature may develop hyperpigmentation irreversible retinopathy (rare) requires monitoring |
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What is Sulfasalazine?
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anti-inflam agent
also used to treat IBD MoA unclear lowers B cell functions, suppress T-cell functions, inhibit inflam cytokine release Use: preferred over hydroxychloroquine in pts w/ more symptoms and signs of active synovitis clinical improvements seen in 1-2 months. |
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What are some side effects of sulfasalazine?
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30% discont. due to toxicity
GI CNS Rash Leukopenia Male infertility (reversible) Idiosyncratic hypersensitivity or immune-related. drug should be stopped immediately rashes, hepatitis, pneumonitis, agranulocytosis, aplastic anemia |
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What is Leflunomide?
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Option for pts nonresponsive or who cant handle MTX
Inhibits de novo pyrimadine synthesis anti-prolif effects in lymphocytes |
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What are some adverse effects of Leflynomide?
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HTX
Hepatotoxicity Monitor liver enzymes |
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What are some other DMARDs that have immunosuppressant activity?
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Cyclosporine
Cyclophosphamide Azathioprine |
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How are gold salts used?
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MoA unclear
seems to decrease vone and articular destruction 75% of pts show some improvement no antipyretic or analgesic properties takes several months for effects to begin. |
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How and when are gold salts usually administered?
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Oral and IM preps
Most effective in the rapid progressive stages of RA short term efficacy established long term remains controversial |
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What are some AE of using gold salts?
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High discon rate due to toxicities
less likely in oral prep, but also not as effective. dermatitis, hematological abnormalities, nephrotoxicity. |
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What is penicillamine?
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A chelating agent used usu when gold does not work.
Usually used for copper poisoning and wilson's dz MoA unclear decreases bone destruction in RA takes several months for effects to be seen 70% sho improvement |
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What are some adverse effects of penicillamine?
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More frequent effects than with gold salts
severe effects limit use GI effects risk of aplastic anemia & agranulocytosis some nephrotoxicity allergy |
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What do biological response modifiers typically do?
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Alter TNF alpha activity.
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Describe Etanercept.
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Form of recombinant NF alpha receptor.
Responses may occur within a couple of weeks. competes with endogenous receptor for free NF alpha. Conbined with MTX, gets increased efficacy w/ no increase in AE. |
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What are some AE of Etanercept?
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Injection site reactions 14-37%
URI activation of latent TB opportunistic infections EXPENSIVE!! 15k/year |
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What is Infliximab?
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Monoclonal Ab to TNF alpha.
bind and neutralizes TNF alpha given by inection |
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What are some adverse effects of Infliximab?
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Risk of infection
hypersensitivity reactions formation of Ab and SLE-like syndrome EXPENSIVE!! |
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What health condition is currently being investigated with regards to Infliximab use?
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Heart failure.
Contraindicated in pts with moderate to severe HF. Advised to watch for signs of HF in pts on this drug. |
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What is Anakinra?
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Recombinant form of the IL-1 receptor antagonist.
mimics body's endogenous mehcanism for regulating IL-1 Blocks inflammatory and immunologic reactions of IL-1 produced in RA |
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What are some AE's of Anakinra?
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Pain, inflammation, and erythema at injection sites
increased risk of infections pneumonia |
