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59 Cards in this Set
- Front
- Back
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what problems can arise after a heart transplant?
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graft REJECTION, INFECTION (esp in hospital environment), HYPERTENSION (>95% after 5 yrs), hyperlipidemia, diabetes, coronary allograft vasculopathy (CAV), renal insufficiency, obesity, osteoporosis, gout, cancer, depression, drug side effects and drug-drug interactions
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what are the 5 main principles of organ transplant therapy?
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1. maximize ABO and HLA matches 2. multidrug approach to immunosuppression 3. intensity of immunosuppression is greater early on and if there is est'd rejection (induction tx/early maintenance tx, weaning, maintenance tx) 4. careful post-op monitoring for rejection, drug toxicity, and infection (special tx for est'd rejection) 5. withdraw or reduce doses of drugs exhibiting serious toxicities
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what are the 3 main types of heart transplant drugs?
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1. immunosuppressant drugs for graft rejection 2. drugs used for other common problems associated w/transplant 3. drugs used to help deal w/drug-drug interactions
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what mediates the process of graft rejection?
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t-cell lymphocytes (form TCR-MHC complex, activate calcineurin)
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what is the primary function of calcineurin?
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dephosphorylates NF-AT --> this leads to activation of IL-2 and other cytokines --> expansion of immune response
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what is induction therapy?
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intense perioperative immunosuppression, usually done in ~70% of 1st time transplant patients
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what are the agents of choice for induction tx? how do they work?
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daclizumab and basiliximab --> monoclonal antibodies that bind to IL-2 receptor and prevent IL-2 binding (prevent T-cell proliferation, suppress immune response)
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what is maintenance therapy?
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combination tx --> use several drugs at lower doses against many targets of T-cell activation; therapy is gradually decreased over time
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what types of drugs are used in maintenance tx?
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steroids (methylprednisolone, prednisone), calcineurin inhibitors (tacrolimus, cyclosporine), and an antimetabolite (mycophenolate, azathioprine)
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which one is the preferred antimetabolite: mycophenolate of azathioprine?
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mycophenolate (better tolerated, fewer side effects)
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what is the mechanism of action of steroids?
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glucocorticoids bind to cytoplasmic receptors and inhibits transcription factors in nucleus (AP-1 and NF-kappaB) to decrease lymphocyte proliferation
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when are steroids used?
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maintenance tx, rejection tx, induction tx
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what are the side effects of glucocorticoids?
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a lot --> HTN, emotional changes, buffalo hump, the list goes on and on
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what is the mechanism of action of calcineurin inhibitors?
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hydrophobic molecules bind to immunophilins, immunophilin-drug complex binds and blocks calcineurin activation --> inhibits NF-AT phosphorylation --> results in blocking of T-cell proliferation
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what is the main adverse effect of calcineurin inhibitors?
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nephrotoxicity
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name 2 calcineurin inhibitors
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tacrolimus (prograf), cyclosporine (neoral)
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mechanism of action of antimetabolites
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mycophenolate blocks de novo purine biosynthesis, azathioprine is incorporated into DNA --> both inhibit DNA synthesis, thereby reducing lymphocyte proliferation
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what are the TOR inhibitors (sirolimus, everolimus)?
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new maintenance tx in development. molecules similar to tacrolimus but not associated w/the same nephrotoxicity.
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TOR inhibitors inhibit lymphocyte proliferation (G1 to S), but also inhibit smooth muscle and endothelial cell proliferation. why might this be a good thing?
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decreases graft atherosclerosis.
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what are the types of transplant rejection?
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hyperacute, acute cellular, acute humoral, chronic
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what causes hyperacute transplant rejections?
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preformed antibodies to ABO, HLA, or endothelial antigens (rare but catastrophic)
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what is acute cellular transplant rejection?
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most common in 3-6 months, t-cell mediated, occurs in ~50% of patients
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what is acute humoral rejection?
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occurs days-wks after transplant, caused by antibodies to donor HLA or endothelial cell antigens, ~7% of patients
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what is chronic rejection?
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occurs months-yrs after transplant, occurs in ~50% of patients after 5 yrs
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how do you treat acute cellular rejection?
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1st episode w/IV solumedrol for 3 days; subsequent episode w/IV solumedrol or increased poral prednisone; severe rejection w/rescue therapy
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rejection rescue therapy
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anti-lymphocyte antibody dosing --> thymoglobulin is 1st choice, OKT3, ATGAM
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how do you treat acute humoral rejection?
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1st episode w/IV solumedrol then oral prednisone; maybe plasmapheresis. refractory humoral rejection w/plasmapheresis again, consider rituximab (monoclonal antibody to b-cells)
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how do you treat chronic rejection (coronary allograft vasculopathy, CAV)?
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angiolasty, TOR inhibitors
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what is thymoglobulin?
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antithymocyte globulin --> polyclonal rabbit antibodies to t-cell and b-cell surface antigens (including HLA); induces lymphocyte lysis --> used in rejection rescue tx.
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what is OKT3?
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monoclonal antibody directed against CD3, inhibits T-cell response to antigen and target cell binding; major problem is cytokine release
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what happens in heart failure?
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cardiac output is inadequate, contractility decreases. when congestion is present, we call this congestive heart failure.
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what is the most common cause of heart failure?
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coronary artery disease
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what part of the heart/heart function fails in heart failure
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any part! systole, diastole, right, or left ventricle may fail.
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what are the symptoms of heart failure?
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decreased exercise tolerance (direct), tachycardia (compensatory), peripheral edema (compensatory), cardiomegaly (compensatory)
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what provides extrinsic compensation in heart failure?
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neurohormonal mechanism --> increase in sympathetic tone (increases HR, CTY, vasoconstricts) and increase in RAS (increase fluid retention, vasoconstricts)
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what provides intrinsic compensation in heart failure?
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myocardial hypertrophy (increase in muscle mass) --> can eventually lead to remodeling and apoptosis and diminished performance
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what is the most important non-pharmacological tool in treating heart failure?
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limit sodium intake
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which 3 agents prolong life in patients w/chronic heart failure?
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ACE inhibitors, beta-blackers, spironolactone
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is there a role for positive inotropes in heart failure?
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yes. these traditional therapies can be helpful especially in ACUTE heart failure.
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what is the classic cardiac glycoside?
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digoxin (digitalis). (sidenote: it comes from the foxglove plant)
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what is a big challenge of cardiac glycosides?
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narrow therapeutic index. therapeutic dose is 60% of toxic dose.
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where is the site of action of cardiac glycosides? why is this important?
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potent inhibitors of Na+/K+ ATPase. these channels are on a lot of cells though, so it could cause some real problems. in heart failure, they are helpful because they improve CONTRACTILITY.
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how do cardiac glycosides improve myocyte function?
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increase contractility by blocking Na+K+ ATPase --> increase intracellular calcium.
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what types of drugs are inamrinone and milrinone?
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bipyridines
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how do the bipyridines work?
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raise intracellular calcium --> improve myocyte CONTRACTILITY. works on the beta-receptor-PKA pathway by inhibiting PDE3 isozyme (cAMP); they are also VASODILATORS, promoting smooth muscle relaxation by encouraging the myosin light-chain kinase down the relaxation pathway. nota bene: these are toxic drugs, not high on the list of HF drugs.
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what is dobutamine? what does it do?
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beta-1 agonist. increases cardiac contractility and output via protein kinase A increased intracellular Ca2+
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what do diuretics do?
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increase urine volume, reduce venous pressure, reduce ventricular preload --> reduce edema, cardiac size, improve cardiac efficiency
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how do ACE inhibitors work?
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block angiotensin II production (inhibit angotensin converting enzyme) --> decrease peripheral resistance and afterload; also decrease aldosterone secretion, salt and water retention, preload; decrease sympathetic activity; decrease remodeling morbidity, and mortality
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what's an example of an ACE inhibitor?
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captopril
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what is losasrtan?
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angiotensin receptor blockers. works like an ACE inhibitor, but not quite as well.
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what are examples of vasodilators used in heart failure?
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nitrates, nitrites, calcium channel blockers. also nesitiride (synthetic BNP approved for qiuckly declining CHF patients). these are fairly low on the list of drugs used to treat HF.
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what do vasodilators do?
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dilate veins and arterioles --> reduce preload and afterload. no positive inotropic effects.
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what does nesitiride do?
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increases cGMP in smooth muscle cells --> decreases arterial and venous tone
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what are bisoprolol, carvedilol, and metrpolol? would you prescribe them in heart failure?
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beta-blockers. YES!
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why do beta-blockers help HF patients?
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not really known. appear to help prevent remodeling. decrease mortality and morbidity.
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what is a good initial clinical strategy to treating heart failure?
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reduce workload --> limit physical activity, lose weight, control HTN. (basically, eat less.) limit sodium (dietary salt restriction and/or diuretics)
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what are the first drugs that you give to a patient with heart failure (after lifestyle modification)?
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diuretics for symptoms + ACE inhibitors and ARBs
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CHF patient is on diuretics, ACE inhibitors, ARBs. what do you give him next?
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digitalis, beta-blockers.
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what are drug options for HF patients that are still suffering even though you've already started them on all the basic drugs?
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vasodilators, bipyridines, beta-agonists
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