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Chapter 70: Cox Inhibitors, NSAIDS, and AcetaminophenCyclooxygenase (COX)General InfoEnzyme that converts arachidonic acid into prostoglandins and related compoundsProstaglandinsSensitize pain receptors Promote uterine contractionPromote normal renal functionStimulate secretion of gastric mucous (to protect the stomach from all the acid in there)Lower set-point for temp in the hypothalamusCOX’s are bad for people with renal failure.Cox 2 causes renal vasodilation and renal perfusionCox 1’s are usually good, Cox 2’s are usually badClassifications of Cox InhibitorsAnti-inflammatory properties NSAIDs – (Non-Steroidal Anti Inflammatory) Cox’s fall in this group First generation – NonselectiveAspirin (Cardio-protective)Second generation “coxibs” – selectiveSelective to COX 2. Celebrex is an exampleNon- anti-inflammatory propertiesAcetaminophen (Tylenol) COX inhibitor, but no anti-inflammatory, so it’s not as good as the others Aspirin is the only one that is Cardio-protective, the others are not. Most first generations are cardio-toxic. They wanted to get away from using COX 1’s inhibitors because they (Cox 1’s) are protective of the stomach. If I take a first generation what I’ve done is taken away from the protection in my stomach. This leads to ulcers and bleeding, one of the main problems for this drug. 1st Generation Non-Selective COX InhibitorsProtoype: acetylsalicylic acid (Aspirin) ASAMOA / TE / UsesNon-selective COX Inh- inhibits both cox 1 and 2 Analgesic, antipyretic, anti-inflammatorySuppression of platelet aggregationIrreversible for 8 d – life of the plateletTreat / prevent Ischemic stroke, TIA, MIs (acute & old), anginas, adjunct to angioplasty & revascularizationADMERapidly absorbed orally, slower rectallyHalf-life (2 h to 20 h)Distributes to all body tissues – pregnant? Don’t give to preggers, can make the baby bleed. Excretion pH dependent (increases pH, Increases excretion 4x) Side EffectsGastric distress, heartburn (related to the acidity of aspirin, because it’s actually an acid), and nauseaAdverse EffectsGastrointestinal – (occult (hidden) and overt)Occult blood in the stool. You have to look for it by collecting a sample. BleedingRenal impairment – Signs? acute/reversible – Na+/H2OPre-existing condition dependentSalicylism (overdose of aspirin) – acid/base – tinnitus (ringing in the ears, first sign). Reye’s syndrome A children’s disease. Basically children liver failure. Aspirin can give rise to this, so it’s contraindicated in children. They watch them very closely. Hypersensitivity – asthma – rhinorrhea (runny nose) to shock1st generation is broad spectrum. They aren’t good for kidneys. The damage can be irreversible. When you’re kidneys quit working your serum sodium goes up. Where sodium goes, water follows. This causes hypertension. ContraindicationsPUD & Bleeding disorders (cause it can give you ulcers and thins your blood, if they already have these, don’t give them aspirin that will only make it worse!) HypersensitivityExtreme caution in pregnancyD-D InteractionsAnticoagulants & other NSAIDs Glucocorticoids (gastric ulcertion)Ibuprofen – impairs cardioprotective propertiesAcute Poisoning (LD=Lethal Dose)LD adult = 20-25 g - LD children = 4 gLD 50 is the dose that will be lethal to 50 percent of the population. Aspirin is an acid, so if you overdose on it your body becomes acidic. That acidity results in exitation. They come in hyperventilating and ultimately (cause they’ve been breathing like that for so long), it will depress respiration, they become stuporous and coma, and die. You also get a fever from the acid. Sxms Resp excitation depression Hyperthermia, stupor, coma, deathTreatmentSupportive, charcoal, alkalinization of urineSupportive treatment= trying to bring the fever down. Use tepid water or icepacks to the armpits and groin. Try to get their core temperature down. You can also have acute renal failure, which would mean they need dialysis. You give them an alkaline shot in the blood it will alkaline the urine. DialysisAdditional Info on 1st Generation Non-Selective COX InhibitorsPeople take baby aspirin to suppress platelet aggregation, to keep them from having a heart attack. It actually binds to the platelets (once it’s stuck to it it’s stuck to it until the platelet dies). Makes the blood flow more smoothly thru the vessels. Not used to treat hemmorhagic stroke (because a bleed caused the stroke, not a clot). If you have a stent, if you have a valve, if you have a graft in a vessel, they’re going to put you on something that will minimize the stickiness of the platelets. The platelets see these things as foreign objects and want to stick to them. That’s a bad thing!If someone is having an MI (heart attack) the best thing you can do is give them an aspirin. Have them chew it and hold it under their tongue for fast absorption. It could save their friggin life!Non-ASA 1st Generation COX InhibitorsNot caridoprotective –CONVERSE – hold in CABG (a kind of heart surgery, Coronary Artery Bypass Graft) procedures and at least 14 days afterwardIndicated in RA and OA – shortest time, lowest effective doseReversible inhibitionDON’T impair platelets, they cause water retentionExamplesIbuprofen, Fenoprofen, other “profens”Ketorolac (Toradol) – 5 d – renal (lowers renal excretion, don’t give for more than 5 days) Naproxen (Naprosyn) – better tolerated2nd Generation Selective Cox InhibitorsPrototype: Celecoxib (Celebrex)Benefits: Lower GI bleeding risk than the others!Uses:OA, RA, Acute pain, dysmenorrhealFamilial adenomatous polyposis- if you have these and you take this, you can develop cancer in those. They can become cancerous, as it wereNOT Cardio ProtectiveDoesn’t cause the mental cloudiness that the narcotic pain pills do! Adverse EffectsDyspepsia (basically indigestion), abdominal painRenal toxicityGI ulceration/bleedingSulfonamide allergyContraindicated(Or used with extreme caution) with blood thinners because celebrex can cause bleeding.Another 2nd Generation Selective Cox InhibitorTylenol (Acetaminophen)MOA: Inhibits prostaglandin synthesis in CNSRemember, prostaglandins help amplify the pain in your body!Uses: Pain, fever, NOT anti-inflammatoryBenefits: 0% GI Bleeding, renal impairmentAdverse EffectsHepatotoxicity- short term, if they are on long term therapy with Tylenol it can be hepatotoxic in only 2g/dETOH connection- alcohol impairs the conversion of toxic metabolites to non toxic metabolites. Acute Toxicity- Sxms 24-72 hours post Overdose (you can overdose and it may take a while for you to notice)N/V/D, sweating, abd pain, liver failure, and comaMucomyst- the antidote for Tylenol (if given w/i 24 hours)! Because you don’t see symptoms for 24-72 hours, you have a high risk for liver damage. The quicker you get help the less your chances of liver damage, duh! Chapter 71: Glucocorticoids in Non-Endocrine DiseasesPhysiology of Glucocorticoids in Non-Endocrine DiseasesArtificial ones are nearly identical to natural onesMetabolic EffectsBreakdown of fats, proteins, carbs - glucose (part of the stress response. They want sugar and they want it now! Fight/Flight. From the adrenals. So we can go fast and fight hard. Rob proteins for glucose production (actually steals proteins to make glucose) Fats redistributed long-term to “moon” face (they get chipmunk cheeks, their face gets very round) Cardiovascular EffectsLow levels Like 5 mg – permeable vessels, dilated vessels (can get hypotension) Increase RBCs and PMN (polymorphonuclear) Leukocytes (going to have an elevated hemoglobin and their white cell count can go up) Decrease Lymphs, Eosins, basophils, and monosites Effects During StressLarge quantity glucocorts / epi secretedIf inadequate = circulatory failureYou have to have steroids in your body or you will dieEffects on water and electrolytesAldosterone effect: increases Na, increases H20, lowers KWhen you are on steroid therapy you retain water and you get puffyHigh doses- impair intestinal Ca absorption (hypocalcemia, cause you aren’t absorbing it, but excreting it out)Respiratory System in neonates- RSD (? I don’t know what this means)Fun FactsThey make you feel absolutely wonderful while they are doing all these bad things to your body. Hilton called it Sweet Poison. They used to think the effects were short term and only while you were on it. But now they know the effects are longer than that. Even More Actions of Glucocorticoids!Inhibit synthesis of prostaglandins, leukotriens, and histaminesImpedes the function of phagocytes and lymphocytes in inflammatory responseUsed for anaphylaxisTells the body that everything is absolutely great! But they are liars! Everything is not absolutely great! Glucocorticoids kick ass but suck for you and your bodyGlucocorticoidsTE / UsesAnti-inflammatory and immunosuppressant effects (high doses)Rheumatoid arthritisSystemic lupus erythematosus Inflammatory bowel diseaseMiscellaneous inflammatory disordersAllergic conditionsAsthmaDermatologic disordersNeoplasms – toxic to malignant lymphocytes (in some of your blood cancers)Can also stimulate your appetite Suppression of allograft rejectionPrevention of respiratory distress syndromeAdverse EffectsAdrenal insufficiencyOsteoporosis (resorption, rebuilding & calcium) (limits absorption of calcium. They tell the body that the bone isn’t broken, so new bone isn’t made) Infection – esp. Pneumocystis Carinii Pneumonia (PCP) Glucose intolerance (raises you’re blood sugar, long term use can cause you to become diabetic) Myopathy Fluid and electrolyte disturbanceGrowth retardation (in children esp, because of the bone remodeling stuff). Psychologic disturbancesCataracts (from deposits in the lids) and glaucomaPeptic ulcer diseaseIatrogenic Cushing’s syndrome (related to the adrenals) Use in pregnancy and lactationD-D InteractionsInteractions related to potassium lossNonsteroidal anti-inflammatory drugsInsulin and oral hypoglycemics Vaccines (because you won’t get the immune or inflammatory response you are looking for from the vaccine because, remember, they stop your body from having an inflammatory response!)Adrenal SuppressionAtrophyStress & “flat” response (Alt. day Tx – so they might give you a dose today, skip a day, another dose, skip a day. Trying to prevent loss of function in your adrenalsGlucocorticoid WithdrawalTaper over 7 daysSwitch from multiple doses to single dosesTaper the dosage to 50% of physiologic valuesMonitor for signs of insufficiencyHypo Tension, hypoglycemia, mylagia, arthralgia and fatigueChapter 73: Drugs Affecting Calcium Levels and Bone MineralizationCalcium PhysiologyCritical to skeletal, nervous, muscular, and cardiovascular systemsBody stores – review (99% of your calcium is in bone, other 1% is in blood) Absorption – occurs in the gut with PTH (parathyroid hormone?) & Vit DGlucocorticoids – effect? They impair absorption in your gut in high dosesExcretionCalcitonin augments calcium eliminationHypercalcemia: Drug TherapyUsually asymptomatic (you usually don’t know it) Causes: PTH, Vit D toxicity, thiazides Drug Therapy (try to make the urine excrete it) Promote urinary excretion – furosemide (lasix) & IV saline Decrease mobilization from bonecalcitonin, bisphosphonates, inorganic phosphates, gallium nitrateDecrease intestinal absorptionGlucocorticoidsIncreases Neuromuscular excitabilityCauses: PTH, Vit D & Absence of Ca++Clinical presentationTetany, convulsions, and spasm of the pharynx TreatmentTreatmentIV Calcium (calcium gluconate)Vitamin DFun Facts: The body lets the bones waste away to keep the serum calcium levels the same. Ca plays a role in muscle contraction and all that shit, so you need it no matter what happens to your bones. You can survive with crappy bones, but you can’t survive with a heart that can’t beat! Drugs for Ca Disorders: Calcium SaltsPrototype: Calcium Citrate (Citracal)MOA / TE / Uses – Keeps levels up, prevents reabsorption to treat mild hypocalcemia in children, adolescents, elderly, post-menopause, & preggersAdverse effects – hypercalcemia DD, DFGlucocorticoids (may have to take higher doses of citrical or whatever) Spinach, beets, bran, cereals – impair absorption of calciumAdverse Effects of IV administrationONLY IV (can cause necrosis elsewhere)IM or extravascular can cause necrosisMay cause severe bradycardia of also on digoxinYou have to keep a close eye on their heart when they are taking this crap!Vitamin D Stuff (Not Calcium Salts)Prototype: cholecalciferol (Vitamin D3)MOA – TE – Uses – increases serum Ca++ and phosphorus levels to prevent osteomalacia / osteoporosisADMEDaily exposure to sun (D2)/vs oral supplementDosage – 800-1000 IntUnits/d or moreThey say you need up to 8000 units a day! We are deficient because people go out and play. Children – 200 or more IN FOODS onlyDon’t supplement children with tablets or pills because they are more susceptible to toxicity. Make them go outside and play for at least an hour a day.Adverse effects: hypercalcemia Drugs For Ca Disorders: Calcitonin-Salmon (not calcium salts of Vit D)Prototype: calcitonin-salmon (Calcimar)MOA – Uses: is similar to natural calcitonin 1) inhibits osteoclasts decreasing bone resoprtion to tx established osteoporosis2) inhibits tubular resorption of Ca++ increasing its excretion to treat hypercalcemia (kidneys will let the calcium go out your pee) Nursing considerations: Intranasal & long-term RxDrugs for Ca Disorders: Biphosphonates (not calcium salts, Vit D, etc.)Prototype: Alendronate (Fosamax)MOA – TE – UsesStructural analogs of pyrophosphate of bone incorporated into bone and inhibit resorption by decreasing osteoclast activity and used to treat osteoporosis, glucocorticoid induced osteopororis, Paget’s, and hypercalcemia of malignancy.Half life may be 180 years? WTF? Weeks? They don’t fucking know. A long freakin timeThey incorporate into the bone. The osteoclasts eat them, and it turns the clasts off. It’s like rat poison for the osteoclasts. They eat it and stop working. Fosamax = rat poison for clastsADME – CRITICAL!! Bioavailability drops if taken with food (0.7%) or drinks other than water (60%)! NEVER TAKE WITH FOOD, COFFEE, TEA, ORANGE JUICE, OR WHATEVER!! ONLY WATER BITCHES!!! Remains for decades once incorporatedAdverse EffectsEsophagitis – implications (sit upright for a while or whatever. From contact of the drug in your espophagus, or people with reflux the drug drops into your stomach and gets absorbed, then the reflux goes back into your esophagus and hurts you. Ocular inflammationOsteonecrosis of the jaw (ONJ) – mostly IV administration. (there isn’t really a treatment for this) Treating Osteoporosis In WomenOther drugs that prevent bone reapbsorptionEstrogen [Premarin]Raloxifene [Evista] Selective estrogen receptor modulator (SERM)Reduces spinal fx (55%)Cardioprotective in high risk women (40%)Reduces estrogen-receptor breast cancerCan cause blood clots / not as bad as estrogenHold dose 72 hr before prolonged immobilization (impending surgery or whatever). Table 73-5Drugs that promote bone formationTeriparatide [Forteo] – recombinant PTH and increases activity of osteoblasts to build bone (instead of suppressing osteoclasts like the other ones) ExpensiveSubQMay promote bone cancer ................
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