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268 Cards in this Set
- Front
- Back
What are the 2 types of edema?
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1)generalized-a clinical manifestation of many primary disorders caused by excessive accumulation of fluid in the interstitial space (affected by many parameters)
-there is a pressure flow balance btwn arterioles, caps, and venules and when this is disturbed by a disease or drugs the transudation pressure increases resulting in accum. of fluid in the interstitium -also, salt and water is retained w/in the body leading to generalized edema 2)localized |
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What are some diseases often associated with edema?
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CHF, hepatic cirrhosis, nephritis, nephrosis, renal damage due to HTN, diseases involving increased steroid hormone secretion, pre-eclampsia, toxemia, HS rxns like anaphylactic shock
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What conditions will promote the development of edema?
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1)altered blood circ. (increased arterial and venous pressure
2)altered blood comp. (decreased osmotic gradient, salt and water retention) 3)inadequate lymph drainage |
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Where is the nephron does most reabsorption of K+ occur?
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in the proximal tubule and this IS NOT influenced by drugs
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Where does secretion of K+ occur?
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in the distal tubules
-involves exchange of Na with K with or without aldosterone -this can be modified by aldosterone-antagonists and K sparing diuretics |
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Where are Ca and Mg reabsorbed?
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in the thick ascending limb of Henle
-thiazide diuretics increase Ca reabsorption -loop diuretics enhance Ca and Mg excretion at the thick ascending limb |
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What are the 2 mechanisms by which organic compounds such as glucose, amino acids, and vitamins are reabsorbed in the proximal tubule?
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1)diffusion-rate depends on lipid solubility, pKa, pH, etc
-weak acids at low pH will remain mostly as unionized (lipid soluble) and are easily diffusible across the epithelium 2)carrier mediated transport-uric acid is an example and can be influenced by drugs (probenecid, etc) |
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List the carbonic anhydrase inhibitors.
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acetazolamide
dorzolamide brinzolamide |
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What is the mechanism of action of carbonic anhydrase inhibitors?
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-they inhibit the CA enzyme in the luminal membranes of the proximal tubule cells which blocks bicarbonate reabsorption
-this reduces the availability of H+ for exchange with Na+ resulting in increased Na loss -increased Na presence in the distal tubules with increase Na/K exchage resulting in increased K loss |
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What are the effects of carbonic anhydrase inhibitors?
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-bicarbonate diuresis
-alkalinization of the urine -reduction in total body bicarb. stores -hyperchloremic metabolic acidosis -diuretic effectiveness decreases in several days -inhibition of bicarb. transport in the eye and choroid plexus, reducing the production of aq. humor and CSF |
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Describe the pharmacokinetics of carbonic anhydrase inhibitors.
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-well absorbed orally
-effect seen after 30 mins -renal excretion -dose must be reduced in renal insufficiency |
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What are the toxicity issues associated with carbonic anhydrase inhibitors?
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-hyperchloremic metabolic acidosis
-renal stones -renal potassium wasting |
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What are the contraindications for giving carbonic anhydrase inhibitors?
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hepatic cirrhosis (decreases the excretion of ammonia)
sulfonamide hypersensitivity |
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What are the clinical indications for using carbonic anhydrase inhibitors?
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1)glaucoma-systemically use acetazolamide, topically use dorzolamide or brinzolamide
2)urinary alkalinization-increases excretion of weak acids 3)metabolic alkalosis 4)acute mountain sickness 5)epilepsy - used as an adjuvant |
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What is the mechanism of action of loop diuretics?
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they all block the 1 Na/1K/ 2Cl co-transporter in the thick ascending limb of Loop of Henle and therefore interfere with the reabsorption of Na and Cl
-by this mechanism, loop diuretics reduce the concentration gradient of the renal medulla and thereby impair both the concentrating and diluting capacity of the kidney |
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What effect do loop diuretics have on Magnesium and Calcium excretion?
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they increase it which reduces their plasma levels
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What are the effects of loop diuretics in the body?
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-they cause hypokalemia and alkalosis, they induce K+ loss b/c they increase the Na load at the distal exchange sites where K is lost in exchange for Na
-they cause hypochloremic, hypokalemic alkalosis (increased loss of K, Cl, and H ions) -diminish the normal lumen positive potential -induce PG synthesis in the kidney-therefore COX inhibitors may interfere with their actions -relieve pulmonary congestion by increasing systemic venous capacitance |
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Describe the pharmacokinetics of loop diuretics.
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-oral and parenteral administration
-well absorbed orally -onset of action in 30-60 minutes following oral admin. -renal excretion |
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What are the toxicities associated with loop diuretics?
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-abormalities of fluid and electrolyte balance due to high potency
-hypokalemic met. alkalosis -hypocalcemia and hypomagmesia -hypouricemia -GI upsets, burning abdominal pain (furosemide) -all of them can cause irreversible ototoxicity when concurrently given with aminoglycosides -allergy, neutropenia, thrombocytopenia, allergic interstitial nephritis, leading to reversible renal failure -thromboembolic complications, NM weakness, derm rxns (urticaria, erythema multiforme) |
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WHat are the drug interactions of loop diuretics?
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-aminoglycosides (ototoxicity)
-lithium (loss of Na increases Li retention) -digoxin (loss of K ) |
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What are the therapeutic uses of loop diuretics?
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-used for moving large volume of fluids (tx. of CHF, pulm. edema)
-tx of CHF in pts. who are not responding to thiazides -edema associated with impaired renal function, including reduced GFR -severe peripheral edema -pulmonary congestion following acute MI -to tx hypercalcemia -furosemide is infused with normal saline to remove excess K+ in cases of hyperkalemia |
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Describe the pharmacokinetics of loop diuretics.
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-well absorbed orally
-peak concentration in 30 mins -90% or more is bound to plasma protein -half life is 1.5 hrs, duration is about 6 hrs -peak diuretic effect in 60-90 mins -partial metabolism in the liver -more than 50% excreted unchanged in the urine -1mg of Bumetanide is equiv. to 40 mg of furosemide |
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Describe the main differences btwn. ethacrynic acid and the other loop diuretics.
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-similar mechanism of action to furosemide
-not a sulfonamide derivative so can be used in ppl allergic to sulfonamides -higher risk of ototoxicity |
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What are the most widely used diuretics today?
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thiazides
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What are the main clinical indications for the use of thiazides?
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-HTN, CHF
-nephrolithiasis -nephrogenic diabetes insipidus |
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What is the mechanism of action of thiazide diuretics?
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-inhibition of Na resporption at the cortical diluting site
-effect is dependent on PG synthesis so action may be inhibited by NSAIDs |
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What are some of the effects of thiazides?
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-also have a minor carbonic anhydrase inhibitor like effect
-increase ATP dependent K+channel opening causing hyperpolarization -they lower systemic BP and enhance the anti-hypertensive action of other drugs -hypokalemia -cause plasma volume contraction which serves as a stimulus for aldosterone secretion which encourages K loss=also leads to hypokalemia -hyperuricemia-decrease the excretion of uric acid, primarily a result of inhibition of tubular uric acid secretion b/c thiazides and urin acid compete for the same secretory mechanism of the renal tubule -decrease in Ca excretion- -Mg loss -iodide and bromide loss -hyperglycemia |
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How do thiazides lead to a decrease in Ca excretion?
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-PTH dependent Gs phosphorylates Ca channels, increases Ca reabsorption
-not effective in osteoporosis -lower Ca levels in tubular fluid may be beneficial in renal calculosis |
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How do thiazides lead to hyperglycemia?
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-may decrease the release in insulin and increase glucose tolerance, this has clinical importance in type 2 diabetics
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Describe the pharmacokinetics of thiazides.
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-all are given orally, well absorbed, and well tolerated
-all are secreted by the organic acid secreting system (they compete with uric acid) -indapamide is excreted by the biliary system which makes it useful in pts. with renal insufficiency |
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What are the toxicities and adverse rxns associated with thiazides?
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-hypokalemia during prolonged therapy in certain cardiac pts.; digitalized pts. and those with cirrhosis are at greatest risk, thiazides can ppt. digitalis tox.
-hyperglycemia and carb. intolerance -hypeuricemia -elevated serum lipid levels (except indapamide) -hyponatremic may occur if water intake is excessive -blood dyscrasia-leukopenia, aplastic anemia, thrombocytopenia, etc -necrotizing vasculitis of skin and kidney in older folks -lithium tox. is aggravated by thiazides -augmentation of the effects of NM blocking agents like tubocurarine -displacement of bilirubin by thiazides could aggravate jaundice in infants |
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Describe metolazone.
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-similar to thiazide diuretics
-may have proximal tubular activity as well -able to produce diuresis in pts. with a reduced GFR |
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Describe indapamide.
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-a sulfonamide like structure and consequently resembles thiazides in it mechanism of action
-pronounced vasodilation -does NOT increased plasma lipids |
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Describe eplerenone.
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-the first of a unique class of oral antiHTN agents called selective aldosterone receptor antagonists (SARA)
-similar in action to spironolactone -lower incidence of endocrine related side effects due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors -metabolized by cytochrome P450 3A4 and is subject to many drug interactions that increase the likelihood of developing hyperkalemia -the addition of eplerenone to standard medical therapy has been shown to reduce all-cause mortality for pts. with acute MI complicated by LV dysfunction and heart failure |
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Describe triamterene and amiloride.
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-they are considered K+ sparing diuretics b/c they inhibit the Na/K pump in the distal renal tubule independently of aldosterone
-they have a weak diuretic effect -oral admin -absorption from GI tract is rapid -they are excreted into the urine -action not significantly affect by alkalosis or acidosis -they do not cause retention of urates |
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Describe the potential toxicities of potassium sparing diuretics.
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-hyperkalemia is the only serious tox.
-N/V, leg cramps, dizziness, etc -mild azotemia (increased blood urea nitrogen) -megaloblastic anemia is cirrhotic pts. is presumably due to an adverse action on folic acid metabolism -triamterene presumably inhibits DHFR -should not give triamterene with spironolactone (may cause severe hyperkalemia) |
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What are the therapeutic uses for potassium sparing diuretics?
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-main use is in combo with potassium losing diuretics
-amiloride is the DOC for lithium induced DI |
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Describe the characteristics of osmotic diuretics.
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-freely filterable at the glomerulus
-undergo very limited absorption from the renal tubules -pharmacologically inactive or inert |
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What is the mechanism of action of osmotic diuretics?
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-increase the osmolality of the tubular fluid when administered in sufficiently large quantity
-produce diuresis by inhibiting water reabsorption in the proximal tubules and in the loop of Henle |
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Describe Mannitol.
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-DOC to produce osmotic diuresis b/c it is most effective, less irritating, less likely to cause thrombophlebitis, does not cause tissue necrosis following extravasation and safer in pts. with renal failure
-works even when the filtration rate is low -admin. intravenously, usually with furosemide to produce diuresis in the early phase of acute oliguria, renal failure -not absorbed orally, not metabolized, filtered in the glomeruli but not reabsorbed |
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What are the potential toxicities of mannitol?
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-excessive admin. may cause over expansion of intravascular space (pulmonary edema, CHF), or excessive cellular dehydration
-may cause increased cerebral blood flow and risks of cerebral bleeding in neurosurgical pts. |
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What are the therapeutic uses of mannitol?
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-for the prophylaxis of acute renal failure
-to reduce intraocular pressure and volume prior to eye surgery -to reduce intracranial pressure in pts. with brain edema -to reduce the pressure and volume of the CSF -to protect the kidney against nephrotoxic substances that may reach high concentration |
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What is the order of expected maximum diuretic effect?
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loop>>thiazides>>CA inhibitors (only work for a few days)>K sparing
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Describe vasopressin.
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-exogenous, parenteral form of ADH
-used to prevent or control polyuria, polydipsia, and dehydration in pts. with central diabetes insipidus -IV vasopressin is included in the ACLS algorithm as an alternative to epi for the tx of cardiac arrest associated with asystole or pulseless electrical activity |
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Describe desmopressin.
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-a synthetic analog of vasopressin (ADH)
-more potent and much longer acting than vasopressin -strong V2 agonist and has no effect on V1 receptors -increases plasma factor VIII and von willebrand factor to a greater extent than equivalent weights of vasopressin -the hemostatic effects of desmopressin are mediated through V2 receptor agonist activity as pts. with nephrogenic diabetes insipidus who lack this receptor do not have a hemostatic response to desmopressin -effective in Hemophilia A and von willebrand disease |
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Describe ADH antagonists.
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-a variety of medical conditions, including CHF and SIADH cause water retention as the result of ADH excess
-dangerous hyponatremia can result and therefore ADH antagonists will help resolve this |
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Describe conivaptan and tolvaptan.
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-non peptide dual V1a and V2 vasopressin receptor antagonists
-increase urine output and decreases reabsorption of free water by antagonizing ADH -these are very new drugs, little experience with them |
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Describe demeclocycline.
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-a tetracycline abx
-produces a nephrogenic DI by uncoupling the V2 receptor from Adenylyl cyclase enzyme -it is preferred over lithium due to its lower risk of toxicity |
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Describe the effect that lithium has on the kidney.
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it produces nephrogenic DI by uncoupling the V2 receptor from AC enzyme
-more toxic than demeclocycline |
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What drugs can cause drug-induced SIADH?
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TCAs
carbamazepine sulfonylureas chlorpropamide antipsychotics SSRIs SNRIs venlafaxine opioids vinblastine vincristine |
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Describe the effects and mechanism of niacin.
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-a water soluble vitamin that is excreted in the urine
-lowers plasma VLDL and LDL by inhibiting VLDL secretion -also inhibits hepatic cholesterologenesis -increased clearance in the LPL pathway -increases levels of HDL (most effective agent) |
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What are the therapeutic uses of niacin?
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-most effective in heterozygous familial hypercholesterolemia esp. when combined with bile acid binding resin
-also effective in familial combined hyperlipoproteinemia, familial dysbetalipoproteinemia, and hypercholesterolemia |
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What are the adverse effects associated with niacin?
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-generally mild toxic effects
-cutaneous vasodilation, warm sensation, pruritis, dry skin, PG dependent and a small dose of aspirin prevents this -nausea and abdom. discomfort -may impair glucose tolerance -hyperuricemia -rarely may cause hepatotoxicity |
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What are the effects and mechanism of fibric acid derivatives?
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-function primarily as a ligand for the nuclear transcription regulator, PPAR-alpha
-they produce increased LPL activity to promote catabolism of VLDL, decrease TGs by lowering VLDL concentration, decrease cholesterol by inhibiting hepatic cholesterologensis |
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Describe the PKC of fibric acid derivatives.
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oral absorption, high plasma protein binding, renal excretion about 70%
-enterohepatic circulation -half life about 1.5 hr |
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What are the therapeutic uses of fibric acid derivatives?
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effective in familial dysbetalipoproteinemia and hypertriglyceridemia
-innefective in primary chylomicronemia, familial hypercholesterolemia |
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What are the adverse effects associated with fibric acid derivatives?
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-skin rashes, GI sx, arrhythmias, hypokalemia, myopathy
-increased blood aminotransferases and alk. phosphokinase -increased incidence of cholelithiasis and gallstones -potentiate anticoagulant action of coumadin -inhibits metabolism of statins -clofibrate is seldom used b/c it increases risk for GI and hepatobiliary neoplasms |
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What are the names of the fibric acid derivative drugs?
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gemfibrozil
clofibrate (seldom used) fenofibrate |
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What are the names of the bile acid binding resins?
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cholestyramine
colesevelam colestipol |
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Describe the effects and mechanism of the bile acid binding resins.
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-they are large cationic exchange resins that are insoluble in water
-they act by binding bile acids and prevent their intestinal reabsorption -reduction in bile acids increases the expression of hepatic LDL receptors to increase uptake of plasma LDL, the reduced LDL levels will reduce plasma cholesterol levels |
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Describe the PCK of bile acid binding resins.
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they are not absorbed
-should be taken with meals (b/c bile production is needed for effect) |
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What are the therapeutic uses of bile acid binding resins?
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-effective whenever LDL is elevated as in heterzygous familial hypercholesterolemia and combined hyperlipoproteinemia
-no effect in homozygous familial hypercholesterolemia, no functional receptors -not effective in hypertriglyceridemia |
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What are the adverse effects of bile acid binding resins?
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-they are the safest hypolipidemics b/c they are not absorbed
-most common toxic effects are constipation and bloating -steatorrhea may occur in pts. with cholestasis -gallstone formation may be enhanced in obese pts. -may cause hypoprothrombinemia due to vit. K malabsorption -may impair absorption of certain drugs like digitalis, thiazides, tetracycline, thyroxine, or aspirin |
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Describe the effects and mechanism of HMG-CoA reductase inhibitors.
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-lovastatin and simvastatin are inactive and have to be hydrolyzed to form the active Beta-hydroxyl derivatives
-atorvastatin, fluvastatin, and pravastatin are already active -active forms are structural analogs of HMG-CoA reductase intermediate in mevalonate synthesis -they reduce LDL by inhibiting the reductase to increase high-affinity LDL receptors -decrease plasma TG and increase HDL cholesterol -they also decrease CRP, enhance production of NO, increase plaque stability, reduce lipoprotein oxidation, decrease platelet aggregation |
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Describe the PCK of statins.
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-high first pass, liver metabolism, GI excretion
-given in the evening (diurnal pattern of cholesterol synthesis) |
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What are the therapeutic uses of statins?
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-most effective when plasma LDL is elevated as in heterozygous familial hypercholesterolemia or combined hyperlipoproteinemia
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What are the adverse effects of statins?
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-elevation of serum aminotransferase
-may produce liver damage in alcoholics -increased serum creatine kinase activity-associated with physical activity -rhabdomyolysis-myoglobinuria-->renal shutdown -all statins are contraindicated in pregnancy |
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What are the drug interactions of statins?
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-macrolides, cyclosporine, ketoconazole, verapamil, and ritonavir increase the plasma concentration of statins
-phenytoin, griseofulvin, barbiturates, rifampin decrease the plasma concentrations of statins -grapefruit juice enhances bioavailability -gemfibrozil inhibits their metabolism |
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What is ezetemibe?
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-selectively blocks the intestinal absoprtion of cholesterol
-when used as monotherapy it reduces LDL cholesterol by about 18% (not as much as statins-25-40%) -combining ezetimibe with a statin results in a synergistic cholesterol-lowering effect -metabolized by glucuronidation, no interactions known -enterohepatically recirculated |
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Describe orlistat.
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-used therapeutically for wt. loss
-inhibits pancreatic lipase which decreases TG breakdown in the intestine -causes oily stools, diarrhea, decreased absorption of lipid-soluble vits. |
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What structures in the heart have slow response fibers?
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SA node
AV node -the rest of the structures have fast reponse fibers (atria, ventricles, bundle of HIS, purkinje cells) |
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Describe phase 0 of generation of an AP in the heart.
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-opening of Na channels, rapid depolarization, inactivation of the Na channels
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Describe phase 1 of AP generation in the heart.
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rapid partial repolarization due to the inactivation of fast sodium channels
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Describe phase 2 of AP generation in the heart.
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plateau phase, Ca channels are open
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Describe phase 3 of AP generation in the heart.
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repolarization, Ca channels inactivated, K channels open, Na channels turning to rested state
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Describe phase 4 of AP generation in the heart.
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resting membrane potential, spontaneous depolarization can now occur
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What parameters influence the conduction velocity of a cardiac cell?
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1)max. rate of depolarization (Vmax of phase 0)
2)threshold potential 3)resting membrane potential (mV)-determines Vmax -there is an important relationship btwn. the rate of phase 0 depolarization and RMP (mV) at the time of stimulation -the Vmax of Phase 0 is highest when the membrane potential is maximum, so factors that partially reduce the membrane potential from -93 to -50 will REDUCE the conduction velocity of the membrane |
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What are the determining factors of the rate of pacemaker cells?
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-duration of the action potential (not commonly changed)
-duration of the diastolic interval -max. diastolic potential (when made more neg. it slows the pacemaker) -slope of phase 4 depolarization (when slope is lower it slows the pacemaker rate) -threshold potential (when made more positive it slows the pacemaker rate) |
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What are the 2 main disturbances of impulse conduction in the heart?
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1)simple block
-AV nodal block -BBB 2)reentry mechanism -obstacle to homogenous conduction -unidirectional block at some pt -conduction time along the circuit is long enough to find excitable tissues |
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What are the main features of antiarrhythmic drugs?
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-they decrease the automaticity of ectopic pacemakers more than that of the SA node
-reduce conduction and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissues -accomplished by selectively blocking Na or Ca channels of depol. cells -have high affinity for activated or inactivated but low affinity for rested channels (use-dependent or state dependent action) -in cells with abnormal automaticity these drugs reduce phase 4 depolarization -beta blockers remove the chronotropic action of NE |
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Describe the general effects of antiarrhythmic agents at regular vs. higher doses.
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regular:
-suppress ectopic automaticity, abnormal conduction, and have minimal effects on normal cells higher doses: -depress conduction in normal tissues -produce drug induced arrhythmia -REMEMBER: ANTIARRHYTHMICS CAN ACTUALLY PPT. LETHAL ARRHYTHMIAS IF TOO MUCH GIVEN |
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What are class I antiarrhythmic agents?
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they all block Na channels
Class A: preferentially blocks open or activated Na channels, lengthens the duration of action potential (ERP increased) Class B: blocks inactivated Na channels, shortens the duration of the AP (ERP decreased) Class C:blocks ALL Na channels, no effect on the duration of AP |
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What are class II antiarrhythmics agents?
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beta blockers
-reduces adrenergic activity on the heart |
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What are class III antiarrhythmic agents?
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K channels blockers: extend ERP
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What are class IV antiarrhythmic agents?
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Ca channel blockers: decrease HR, contractility
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Describe the mechanism of action of quinidine.
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-class IA antiarrhthmic
-it is a myocardial depressant and produces antiarrhythmic effects by binding to open and activated Na channels -decreasing the myocardial automaticity and membrane responsiveness -increases diastolic threshold -slows max. rate of rise of the cellular AP (Vmax of 0 phase) -prolongs the AP duration prolonging the effective refractory period (ERP) -increases the ration of ERP/APD and prevents the closely coupled "re-entry" circuit in the Purkinje fibers -blocks K channels (prolongs depolarization) |
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What are some of the other cardiac effects of quinidine?
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-causes muscarinic receptor blockade which can increase HR and AV conduction
-causes certain EKG changes such as widening of QRS and QT intervals -causes SA block, AV block, ventricular arrhythmia and severe hypotension at toxic doses |
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What are some of the other systemic effects of quinidine?
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-blocks alpha receptors and may cause reflex tachy
-GI irritation, N/V, diarrhea -CNS stim., convulsions at high doses --has a curare like effect (membrane stabilizing) on the sk. mm -potentiates the action of NM blocking agents |
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Describe the PHK of quinidine.
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-oral admin most common
-absorption essentially complete -bioavail. variable due to first pass effect -max. blood levels reached in 90 mins -half life about 6 hrs -80% metab. in liver, other by kidney -70-80% is plasma protein bound, a major metabolite of quinidine is also active |
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Describe the toxicity of quinidine.
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-has a low therapeutic index, potentially dangerous drug
-cardiac tox. is the most significant -causes severe hypotension and shock like effect by virtue of its alpha blockade action -paradoxical tachycardia -quinidine syncope and death (mostly in pts. receiving digitalis too) -torsade de pointes -diarrhea -cinchonism: loss of hearing, angioedema, vertigo, tinnitus, visual disturbances, vascular collapse, thrombocytopenic purpura |
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What are the CI to quinidine therapy?
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-pre-existing complete AV block (vent. arrest may happen)
-thrombocytopenia associated with previous quinidine therapy (allergic response) |
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What are the therapeutic uses of quinidine?
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-it is a broad spectrum antiarrhythmic drug effective for acute or chronic tx of varieties of supraventricular and ventricular arrhythmias
|
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What are the drug interactions of quinidine?
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-drugs like phenytoin and phenobarbitol are likely to shorten the duration of action of quinidine
-quinidine may increase prothrombin time in pts. receiving oral anticoag. warfarin -quin. and nitroglycerin will produce a significant vasodilation and fall in BP -increased plasma K may enhance toxic effects of quinidine -may exaggerate sk. mm. weakness or increase the paralyzing effects of curare and curare-like drugs, aminoglycosides |
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Describe procainamide.
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-similar to quinidine
-short duration of action -high incidence of adverse rxns upon chronic use -can be admin. IV, may be useful in pts. with severe vent. arrhythmias who are unresponsive to lidocaine -it is well absorbed orally, bioavail 75% -peak plasma levels in 15-60 mins -acetylated to NAPA in the liver -the rate of acetylation is under genetic control and shows bimodal dist. into slow and fast acetylators (fast have higher plasma ratio of NAPA/procainamide) |
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What are the toxicities associated with procainamide?
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-similar to quinidine including torsade de pointes
-SLE like syndrome in about 30% of pts. after prolonged use -causes increased titer in ANA abs in about 30% of pts. -occasional HS rxns |
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What are the CI to procainamide?
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-complete AV block
-use with great caution in partial AV block |
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What are the therapeutic uses of procainamide?
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-tx a wide variety of cardiac arrhyth. such as:
-vent. arrhythmias-except those resulting from digitalis intox. -supravent. arrhythmias-atrial flutter and fib. |
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Describe disopyramide.
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-it is structurally unrelated to other commonly used anti-arrhyth. agents like quinidine and procainamide
-effective in the management of unifocal, multifocal, and paired PVCs as well as episodes of V. tach |
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What are the toxicities associated with disopyramide?
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-prolongation of the QT interval and prominent U waves
-widening of QRS and increased P wave duration -can cause torsades de pointes -increases His-Purkinje conduction time but does not affect AV conduction time -significant neg. inotropic effect, aggravates heart failure -anticholinergic effects: dry mouth, urinary hesitancy, constipation, etc -CI in glaucoma |
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What is the therapeutic use of disopyramide?
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V. tach
|
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Describe the mechanism of action of lidocaine.
|
-a class IB antiarrhythmic agent
-binds to the inactivated Na channels, fast binding and dissociation -decreases APD, shortens ERP due to block of the slow Na "window" currents |
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What are the effects of lidocaine?
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-no significant effects on QRS, QT intervals
-causes less hypotension than procainamide -little or no depressant action on myocardial contractility -no vagal blocking action like that of quinidine, procainamide, or disopyramide -antiarrhythmic action develops immed. after IV loading dose and declines rapidly upon discontinuation of infusion -can't be used orally (first pass metabo) so not suitable for maintenance or in an outpatient setting -not effective for supraventricular arrhythmias |
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Describe the PHK of lidocaine.
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-IV ONLY
-IV loading dose is 50 mg-100 mg at a rate of 25-30 mg/minute -very rapid onset of action 1-2 mins -primarily metabolized in liver -therapeutic level is 1-5 mg/ml, toxic is 6-10 mg/mL |
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What are the toxicities associated with lidocaine?
|
-infrequently see bradycardia and aggravation of arrhythmia
-unwanted effects mostly seen in pts. with hepatic disease and CHF -very large doses may depress myocardial contractility and AV conduction |
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What is the therapeutic use of lidocaine?
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tx of vent. arrhythmias
|
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Describe phenytoin.
|
-a class IB antiarrhythmic
-it is a classical antiepileptic drug and may also be useful in the tx of vent. arrhythmias induced by digitalis tox. -short term admin. as an antiarrhythmic agent -binds to active and inactivated Na channels -shortens ERP |
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What are the effects of phenytoin?
|
-depression of myocardial automaticity
-does not depress conduction at AV system or in the ventricles -little or no effect on myo. contractility at therapeutic doses -hypotension occurs only on rapid IV injection -oral and parenteral admin. -has complex PHK, first order at low doses, zero order at higher doses -onset within 1 hr following IV loading dose -protein binding 95% |
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What are the toxicities associated with phenytoin?
|
-dose related toxic effects are nystagmus, ataxia, slurred speech, mental confusion
-elevates blood glucose at higher levels -pts. with renal insuff. or DM are more susceptible -dermatological manifestations -may induce folic acid defic. |
|
Describe tocainide.
|
-blockade of fast Na channels
-orally active antiarrhythmic agent similar in action to lidocaine and useful in V. arrhythmias -well absorbed: 90% bioavail., no significant first pass, hepatic metabolism |
|
What toxicities are associated with tocainide?
|
-mostly on CNS and GI-not serious
-may increase Vent. rates in pts. with atrial flutter or fib. -may aggravate CHF and conduction disturbances -allergy to lidocaine like drugs, and second or third degree heart blocks are CI |
|
What are the uses of tocainide?
|
-for all kinds of symptomatic ventricular ectopia and V. arrhythmias, but does not prevent sudden death
|
|
Describe mexiletine.
|
-oral local anesthetic type antiarrhythmic agent similar to lidocaine and tocainide
-used to treat life-threatening ventricular arrhythmias -also been used in the tx of pain associated with diabetic neuropathy -tox. is minor CNS effects -used for acute or chronic vent. arrhythmias, useful in pts. resistant to lidocaine |
|
Describe flecainide.
|
-local anesthetic antiarrhythmic agent
-class IC -binds to all Na channels, no effect on APD, no ANS effects -slow dissociation from binding -significantly slow His-Purkinje conduction and cause QRS widening -shorten the action potential of purkinje fibers w/o affecting the surrounding myocardial tissue |
|
What toxicities are associated with flecainide?
|
-most common is blurred vision
-worsening of heart failure, prolongation of PR interval and QRS complex -risks of proarrhythmic effects in some pts. particularly those with ventricular dysfunction |
|
What are the uses of flecainide?
|
-life threatening V. arrhythmias
-for conversion to and/or maintenance of sinus rhythm in pts. with paroxysmal atrial fibrillation and/or atrial flutter associated with disabling sx and w/o structural heart disease -prevention of various forms of paroxysmal supraventricular tachy. |
|
What are the CI of flecainide?
|
-pre-existing AV block
-pts with cardiogenic shock -CHF |
|
Describe propafenone.
|
-oral antiarrhythmic similar to flecainide
-used for suppression of life-threatening vent. arrhythmias -structurally similar to beta blockers and possesses beta blocking activity -therapy should be started in hospital to allow for appropriate EKG monitoring -high first pass metabo -slow and fast metab. phenotypes |
|
Who should propafenone be used on?
|
should be reserved for refractory pts. with severe, life threatening arrhythmias b/c the Ic agents have been shown to possess proarrhythmic characteristics
|
|
Describe Moricizine.
|
-oral class IC antiarrhythmic agent
-chemically unrelated to any other antiarrhythmic -has electrophysiologic features of all 3 subclasses (class A, B, and C) -indicated for tx of life threatening vent. arrhythmias |
|
Describe amiodarone.
|
Class III antiarrhythmic
-approved for tx of refractory life threatening vent. --effective against both supraventricular and ventricular arrhythmias -roles are expanding to include the tx of atrial and/or ventricular arrhythmias -blocks K channels -binds to inactivated Na channels (class I) -some Ca channel blocking effect (class IV) -powerful inhibitor of abnormal automaticity -slows sinus rate, conduction, and prolongs QT and QRS -causes peripheral vasodilation (alpha blocking effect) |
|
What drugs slow phase 3 repolarization?
|
thioridazine
TCA-s class IA class III |
|
Describe the PHK of amiodarone.
|
-oral of IV admin
-extensive distribution -half life is 13-103 days! -loading takes 15-30 days -liver metabolism |
|
What toxicities are associated with amiodarone?
|
-bradycardia, heart block, heart failure
-pulmonary fibrosis at higher doses -deposited in tissues, cornea, skin, photodermatitis -thyroid dysfunction -liver tox -DOES NOT CAUSE TORSADES DE POINTES |
|
Describe sotalol (betapace).
|
-racemic mixture of isomers
-l-isomer:nonselective beta blocker -d-isomer:prolongs APD (class III) -has no ISA or membrane stabilizing activity like class I -used in vent. and supravent. arrhythmias -adverse effects of beta receptor blockade, torsade de pointes |
|
Describe Bretylium.
|
-parenteral class III antiarrhythmic agent
-increases the action potential duration without affecting the 0 phase depolarization or resting membrane potential of ventricular tissue -indicated for tx of ventricular fib. and unstable vent. tachy., but not considered 1st line agent -clinically, it causes an initial increase in BP and HR, these effects are short lived and then followed by adrenergic blockade resulting in vasodilation and hypotension -tolerance to hypotension develops after several days of therapy although increased sensitivity to circulating catecholamines ensues |
|
Describe the PHK of bretylium.
|
-admin. via IV or IM injection
-duration of action 6-24 hrs -afib. effects beginning w/in mins following IV injection and suppression of V. tachy beginning within 20 mins-6 hrs following IM or IV injection -half life in pts. with normal renal function is 4-17 hrs, it is 31-105 hrs in pts. with impaired renal function -its clearance is directly correlated with creatinine clearance |
|
What are the adverse effects of bretylium?
|
-hypotension and orthostatic hypotension are the most common
-increased arrhythmias (PVC, V. tachy) -sinus bradycardia, sensation of substernal pressure, and ppt of angina |
|
Describe ibutilide.
|
-IV class III antiarrhythmic
-indicated for rapid conversion of atrial fib or a. flutter to normal sinus rhythm -exerts its actions by promoting the influx of Na through slow inward Na channels and prolongs the AP duration -causes a mild slowing of the sinus rate and AV conduction -converts A. fib or flutter to NSR w/out altering BP, HR, QRS duration, or PR interval |
|
Describe dofetilide.
|
-class III antiarrhythmic used for conversion and maintenance of NSR in atrial fib./flutter
-primarily effective for supraventricular arrhythmias -selective and potent blocker of K channels and prolongs ventricular refractoriness -lacks neg. inotropic properties -admin. orally, bioavailability is greater than 90% |
|
What are the adverse effects associated with dofetilide?
|
-serious arrhythmias and cardiac conduction disturbances
-torsade de pointes and QT prolongation -ventricular fib. |
|
Describe verapamil.
|
-a Class IV Ca channel blocker
-blocks slow cardiac Ca channels -slows AV nodal conduction, decreases HR -the atrial arrhythmias that depend upon AV nodal re-entry are interrupted -most pronounced effects on heart, less of periphery -effective in supraventricular tachyarrhythmias -causes peripheral vasodilation, and relaxes sm. mm -also an effective antiHTN and antianginal agent -admin. IV or oral -undergoes first pass metabolism after oral use |
|
What are the toxicities associated with verapamil?
|
-minimal after oral use
-GI intolerance, constipation -bradycardia, neg. inotropic effect, AV block may happen upon IV use -CI in presence of CHF and AV conduction defects -avoid combined use with beta blockers since both will markedly reduce ventricular contractility and enhance AV transmission failure |
|
What are the uses of verapamil?
|
-reentrant supraventricular tachy is the major indication
-reduces vent. rate in a. flutter and fib -rarely effective in V. arrhythmias |
|
Describe diltiazem.
|
-class III antiarrhythmic
-Ca channel blocking agent most similar to verapamil -reduces HR -increases exercise capacity and improves multiple markers of myocardial ischemia -may increase CO by reducing peripheral resistance, reduces LV workload -improves myocardial perfusion |
|
Describe the PHK of diltiazem.
|
-oral absorption, IV available
-dose dependent kinetics, predisposing pts. to accumulation with repeated dosing |
|
What are the uses of diltiazem?
|
-tx of paroxysmal supraventricular tachy. and to control ventricular rate in atrial fibrillation and flutter
-for management of Prinzmetal's variant angina, stable angina pectoris, HTN -prevention of injury following angioplasty |
|
Describe bepridil.
|
rarely used, primarily to control refractive angina
-prolongs action potential and QT (danger of torsades de pointes) -class III antiarrhythmic |
|
Describe adenosine.
|
-very effective in suppressing paroxysmal supravent. tachy and WPW syndrome
-effective only against arrhythmias that depend on reentry mechanism -does not convert ordinary a. flutter or a. fib to NSR -IV injection admin -duration is very short, 10-12 seconds -metabolized from adenosine-->inosine-->AMP (inactive) |
|
What is the mechanism of action of adenosine?
|
-slows conduction in the AV node and thereby interrupts reentry pathways through AV node
-the ventricular slowing is not blocked by atropine but may be blocked by caffeine -involves enhanced K conductance and inhibition of cAMP induced Ca influx |
|
What are the CI of adenosine?
|
AV block
sick sinus syndrome |
|
What are the uses of adenosine?
|
-PSVT
-WPW syndrome -currently the DOC for management of PSVT b/c of very high efficiency and short duration of action |
|
Describe Mg.
|
-originally used for pts. with digitalis induced arrhythmias who were hypomagnesic
-has antiarrhythmic effect in pts with normal Mg levels -may affect K, Na, CA, Na/K ATPase, mechanism is unknown for this -used in digitalis induced arrhythmias, torsade de pointes, seizures and eclampsia associated with pregnancy |
|
Describe potassium.
|
-both insufficient and excess K are arrhythmogenic
-K therapy is directed toward normalizing K gradients and pools in the body -increasing K decreases (depolarizes) membrane potential -increasing serum K has membrane potential stabilizing actions by increased permeability |
|
What are the 2 types of CHF?
|
low output and high output
|
|
What are the main causes of high output CHF and describe its characteristics.
|
hyperthyroidism
anemia AV shunts thiamine deficiency -heart is healthy but exhausted by working too hard -the CO is high at the heart works hard to keep up with the greatly increased body demands -has poor response to inotropic agents |
|
What are the main causes of low output CHF and describe its characteristics.
|
coronary artery disease
MI persistent arrhythmias rheumatic heart disease general cardiomyopathy -the heart fails to pump enough blood to meet tissue needs -CO is low b/c the heart is unable to keep up with the tissue metabolic demands -inotropic agents will improve this type of CHF |
|
What are the major hemodynamic characteristics of CHF?
|
-subnormal CO, caused decreased exercise tolerance with rapid mm. fatigue, tachy, pulmonary edema, and cardiomegaly
-myocardial hypertrophy develops -increased myocardial mm. mass and wall thickness -neurohumoral reflex compensation arises from the increased activity of SNS nerves and the RAA system -bottom line: cardiac workload is increased in ALL FORMS OF CHF |
|
What are the main determinants of cardiac workload?
|
preload
afterload contractility heart rate |
|
What happens to preload on the heart in CHF?
|
it is increased b/c of increased blood volume and increased venous tone
|
|
What happens to afterload on the heart in CHF?
|
it increases b/c of SNS and Renin-angiotensin system which elevate peripheral resistance via arterial constriction
|
|
What happens to the heart rate in CHF?
|
it increases b/c of reflex tachycardia caused from SNS overactivity from baroreflex activation brought about by the reduction in CO
-beta-adrenergic blocking drugs will reduce cardiac work by slowing the HR |
|
What are the controls of normal cardiac contractility?
|
-sensitivity of the contractile proteins to Ca
-the amount of Ca released from the SR -the amount of Ca stored in the SR -the amount of trigger Ca -activity of the Na/Ca exchanger -intracellular Na concentration and activity of the Na/K ATPase |
|
Describe the chemical structure of digoxin.
|
-aglycone or genin consisting of:
-steroid nucleus which has unsaturated 5 member lactone ring at 17 position -series of sugars at C3 of the nucleus -the genin is responsible for all biological activity -3 molecules of sugar influence PHK including absorption, half life, and metabolism |
|
What are the cardiac effects of digoxin?
|
-most important are mechanical and electrophysiological effects
-mechanical effects are on contractility, HR, and CO -contractility is increased (increases SV) -increased rate of tension development and relaxation=positive inotropic -heart rate is reduced -CO is increased |
|
What is the mechanism by which digoxin increases the contractility of the heart?
|
-first, there is inhibition of membrane Na/K ATPase (AKA digitalis receptor)
-increased IC NA concentration -decreased expulsion of IC Ca -increased IC Ca leads to decreased IC K -increased actin-myosin interaction by IC Ca -increased contractility -K and digitalis interact in 2 ways: -both inhibit each other's binding to Na/K ATPase receptor thus K counteracts digitalis tox. -K reduces abnormal cardiac automaticity -Ca enhances or increases digitalis toxicity -therefore, digitalis tox. is treated with K but never with Ca |
|
How is HR slowed by digoxin?
|
-digitalis always causes bradycardia but the mechanisms differ depending on the state of the myocardium
-in normal hearts rate decreases by vagal stim. due to sensitization of arterial baroreceptors, stim. of central vagal nuclei, and increased SA node sensitivity to Ach -in failing hearts, SNS tone is already high then as digitalis increased contractility SNS tone will be reduced |
|
How is CO increased by digitalis?
|
-it is increased in the failing but not the normal heart due to increased peripheral vasoconstriction in ppl with normal hearts
-electrical effects of digitalis result from 2 actions: -direct action of myocard. cells -indirect action by PNS stim. -in A. fib digitalis is used for tx before class IA antiarrhythmic drugs which when given alone may cause PSVT, digoxin will slow vent. rate and prevent this |
|
What are the vascular effects of digitalis?
|
-they depend on the status of the myocardial function
-normal hearts: contraction of sm. mm. leads to vasoconstriction -failing hearts: increased myocardial contractility leads to increased CO and decreased baroreceptor activation which will decrease SNS activity resulting in vasodilation |
|
What effect does digitalis have on the kidneys?
|
-they are only affected slightly if at all
-diuresis occurs only in edematous pts. with CHF as a result of hemodynamic improvement -no diuresis in normal subjects or in other types of edema |
|
What are the GI effects of digitalis?
|
-anorexia and diarrhea due to direct GI irritation
-vomiting due to stim. of the chemoreceptor trigger zone -abdominal pain due to mesenteric arteriolar constriction |
|
Describe the loading vs. maintenance doses of digoxin.
|
-at a constant dosing rate, steady state will take 1 week to reach
-for rapid digitalization, 3 separate doses are given over 24-36 hrs followed by reg. maint. doses -digoxin is fairly well absorbed orally but inactivated by enteric bacteria in 10% of pts |
|
What are the adverse effects of digoxin?
|
-all digitalis glycosides produce the same effects, there are NO "non-toxic" digitalis glycosides
-they have a narrow margin of safety, tox. is common -the therapeutic dose is 50-60 of the toxic dose so side effects will ALWAYS OCCUR with therapeutic doses -earliest signs are GI, N/V, etc -cardiac tox.-can stim. various arrhythmias including sinus brady, ectopic vent. beats, AV block, and bigeminy, V fib is most common cause of death -skin rashes, eosinophilia, and gynecomastia are rare -CNS side effects HA, fatigue, malaise, hallucinations, etc.. -incidence and severity of tox. has declined b/c of serum level monitoring, recognition of interactions, alternative drugs |
|
How is digitalis toxicity treated?
|
-discontinue tx
-oral or IV K (NEVER Ca) -lidocaine, phenytoin, or propanolol and immunotherapy with digitalis immune Fab - |
|
What are the drug interactions of digoxin?
|
-pharmacokinetic interactions may either enhance tox. or reduce effectiveness
-enhance tox. by decreasing digoxin renal clearance or vol. of dist. (quinidine, amiodarone, captopril, verapamil, cyclosporine, diltiazem), increasing digoxin GI absorption (erythro, omeprazole, etc) -reduce tox. by decreasing GI absorption (cholestyramine, bran, etc) -pharmacokinetic interaction with quinidine often occurs b/c it displaces digoxin from tissue binding sites and depresses its renal clearance -->increased plasma digoxin levels -pharmacodynamic interactions that enhance tox: -diuretics which decrease serum and tissue K (thiazides or loops) -beta antagonists which decrease SA or AV node activity -Ca-channel antagonists which decrease contractility -catecholamines sensitize the myocardium to digoxin -hypothyroidism predisposes to intox. by reducing renal clearance-->elevates serum digoxin levels |
|
Why are the elderly more susceptible to digitalis intoxication?
|
b/c their serum digoxin levels are elevated by hypochlorhydria or reduced renal clearance
|
|
What are the PDE inhibitors?
|
inamrinone
milrinone -belong to a new class of bipyridine inotropic/vasodilator agents called inodilators |
|
What is the mechanism of action of PDE inhibitors (inodilators)?
|
-they inhibit cAMP PDE isoenzyme in cardiac and vasc. mm. which normally degrades cAMP
-b/c cAMP levels are increased, both diastolic function and myocardial contractility are improved |
|
What are the uses of inodilators like milrinone and inamrinone?
|
-should be used only in pts. who can be closely monitored and who have not responded adequately to conventional therapy
-cAMP dependent inotropes have not been shown to be safe or effective in the long term tx of heart failure -chronic oral inotrope has actually been shown to increase the risk of mortality and hospitalization -in pts. with ischemic heart disease improvement in LV function has been reported -admin. to pts. with CHF has resulted in dose-related effects including increased CO, decreased pulm. cap. wedge pressure and decreased vasc. resistance, these are accompanied by mild to moderate increases in HR but w/o an increase in myocardial O2 consumption |
|
Describe the functions of dopamine.
|
-indicated in severe refractory CHF
-exerts positive inotropic effect due to a direct action on the heart -in low doses, it increases CO and renal blood flow -lowers peripheral resistance -enhances Na excretion -it is useful in acute heart failure following CV surgery in severe refractory CHF -new studies reveal that it is NOT useful in treating shock -IV admin |
|
Describe the functions of dobutamine.
|
-selective beta-1 agonist
-positive inotropic effect, somewhat less tachy. -reduced filling pressure and increased O2 consumption -IV admin. |
|
Describe the use of the calcium sensitizers.
|
can be used in tx of CHF
-they are experimental drugs -increase cardiac tissue sensitivity to Ca increasing tissue concentrations of Ca -inhibit PDE III and sensitizes troponin C myofilaments to IC Ca ions -the uses are under review for the management of acute and chronic CHF |
|
What is BNP?
|
produced by the ventricular mm. and endogenous concentrations of BNP are elevated in pts. with heart failure
|
|
What is nesiritide?
|
-IV recombinant purified preparation of human BNP
-indicated for the acute tx of decompensated CHF -has primarily been studied in pts. with elevated pulm. cap. wedge pressure -in decompensated heart failure, its use reduces PCWP and improves the sx of heart failure including dyspnea and fatigue -requires close BP monitoring to prevent symptomatic hypotension which is a serious dose limiting effect |
|
What are the factors that increase the renin-angiotensin system activity in CHF?
|
-reduced renal perfusion, activating renal renin secretion
-increased SNS activity causing Beta adrenergic stim. of JG apparatus -antiHTN drugs that stim. renin secretion -diuretics which reduce Na at macula densa -vasodilators which reduce renal perfusion pressure |
|
What do ACE inhibitors do?
|
they counteract the increased renin-angiotensin system activity during CHF
|
|
How does ACE inhibitor therapy diminish cardiac workload?
|
-decreases afterload by decreasing angiotensin which normally would cause vasoconstriction
-descreases preload by decreasing aldosterone release |
|
How are vasodilators effective in tx CHF?
|
by providing reduction in preload through venodilation, afterload, or both
|
|
Describe sodium nitroprusside.
|
it is infused IV in acutely decompensated CHF as long as cerebral and renal perfusion can be maintained
-dilates both veins and arteries to reduce both preload and afterload -the most common adverse effect is excessive hypotension |
|
Describe organic nitrates like nitroglycerin and isosorbide dinitrate.
|
they are given orally and dilate veins more than arteries
-this lowers preload more than afterload -tolerance precludes their long term use |
|
Describe hydralazine.
|
-it is a peripheral vasodilator
-it causes relaxation of arteriolar sm. mm. via a direct effect -induces reflex autonomic response which increases HR, CO, and LV EF -due to Na and water retention plasma volume increases and tolerance can develop |
|
What is the most common cause of tx failure in HTN pts?
|
non-compliance b/c they don't feel ill so they don't take meds which can have undesirable side effects
|
|
What is the "poly pill"?
|
company still trying to gain approval for this six component product used for the prevention of coronary heart disease
-would include a statin, an ACE inhibitor, a thiazide diuretic, a beta blocker, aspirin, and folic acid -idea proposed by Nicholas Wald and Malcolm Law |
|
What are the 4 main classes of antiHTN agents?
|
oral diuretics
sympatholytics direct vasodilators angiotensin inhibitor |
|
Which thiazide diuretic is also a direct vasodilator?
|
indapamide
|
|
What is the long term effect of thiazides on lowering BP?
|
they decrease Na content in mm. cells and decrease sensitivity to vasopressor agents
-after 6-8 wks they activate K channels to cause a decline in peripheral resistance |
|
In what populations are thiazide diuretics more effective in lowering BP?
|
young african americans
|
|
What is the first choice of diuretics in lowering BP?
|
thiazides, low doses in combo therapy to counteract Na and fluid retention
-they are much cheaper than the others too |
|
What drugs are often admin. with sympatholytic drugs in the tx of HTN and why?
|
usually combined with a diuretic b/c they activate baroreflexes and generally cause Na retention
|
|
What are the centrally acting sympatholytics?
|
methyldopa
clonidine |
|
What is the mechanism of action of the centrally acting sympatholytics?
|
-they are unique b/c they act in the brain as agonists
-they stimulate medullary alpha2 receptors to reduce peripheral SNS nerve activity -stimulate presynaptic alpha2 receptors and reduce transmitter release to relevant sites -stimulate postsynaptic alpha2 receptors and inhibit appropriate neurons -lowers BP by decreasing vasomotor tone AND decreasing renal renin secretion -clonidine lower HR and CO more than methyldopa b/c it acts directly whereas methyldopa is a prodrug that is converted to its active form |
|
What are the common adverse effects of the centrally acting sympatholytics?
|
-sedation and other CNS effects such as N/V, nightmares, etc
-dry mouth -sudden withdrawal of clonidine may cause a HTN crisis -clonidine in toxic doses may actually produce pressor effects -methyldopa may also produce hemolytic anemia with a positive Coombs test, increased prolactin secretion, gynecomastia, hepatotox. |
|
What are the drug interactions of the centrally acting sympatholytics?
|
-TCA and yohimbine inhibit therapeutic action
|
|
Describe the use of ganglion blockers in the tx of HTN.
|
no longer used b/c of TOO MANY side effects b/c they block both PNS and SNS systems
-mecamylamine shows promise in tx Tourette's |
|
How do guanethidine and reserpine act?
|
by binding to secretory vesicles that normally store and release NE in peripheral adrenergic nerve endings
-reserpine inhibits the active transport of NE into the vesicle (serious interaction with MAOIs) -guaenthidine is taken up by the nerve ending and replaces NE in the vesicles, inhibits exocytosis (interaction with TCAs, cocaine, indirect sympathomimetics) -may elevate BP by sudden release of endogenous NE, produce HTN crisis in pheochromocytoma -their final effect is that they reduce SNS activity by preventing NE release |
|
What are the common adverse effects of reserpine and guanethidine?
|
-they are rarely used for monotherapy b/c of unpleasant side effects
-guan:postural hypotension, fluid retention, diarrhea, retrograde ejaculation -reserpine:sedation, psychic depression, stuffy nose, dry mouth, GI disturbances |
|
What are the common adverse effects of alpha 1 blockers?
|
postural hypotension (first dose phenomenon)
-do not adversely effect plasma lipids and may actually be beneficial -increased renin leads to Na and water retention |
|
Who are beta blockers most effective in tx HTN?
|
white young ppl
-recommended in monotherapy only in young white males -but often combined with other antiHTN drugs to counteract reflex tachy and increased renin secretion |
|
Which beta blocker also modulates the endogenous production of NO resulting in peripheral vasodilation?
|
nebivolol
|
|
What are some of the common adverse effects of beta-adrenergic antagonists?
|
-propanolol can cause heart and lung side effects (negative inotropic, chrono, dromo, bronchoconstriction), GI problems, CNS such as insomnia
-usually increase exercise tolerance when used for tx of angina but by reducing CO they can also decrease exercise tolerance by causing early fatigue -may predispose to atherogenesis by increasing plasma TGs and decreasing HDL cholesterol -may mask the sx of hypoglycemia and delays recovery with hypoglycemia b/c responses are mediated by epinephrine -CI in pts. with diabetes, severe CHF, heart block, asthma |
|
What groups of pts. are beta blockers preferred in?
|
angina
following MI migraine |
|
In what populations are beta blockers least preferred drugs in?
|
high physcial activity
african heritage DM hypercholesterolemia peripheral vascular disease |
|
What are the 2 main combined alpha and beta blockers?
|
labetalol
carvedilol |
|
What method of admin. is used for giving vasodilators for tx of chronic antiHTN tx?
|
oral
-IV given for HTN emergencies |
|
What are the oral vasodilators given for HTN?
|
hydralazine
minoxidil |
|
What are the IV vasodilators given for HTN tx?
|
sodium nitroprusside
diazoxide fenoldopam |
|
What is the mechanism of action of the vasodilators?
|
they act directly on arteriolar sm.mm to cause relaxation and thus reduce vascular resistance to lower BP
-hydralazine, minoxidil, and diazoxide dilate arteries selectively w/o relaxing venous sm. mm. -nitroprusside dilates both art. and veins -antiHTN effects diminish with time b/c of reflex tachy and increased renin secretion -should not be used alone or for monotherapy |
|
What drugs are often given with hydralazine and minoxidil?
|
diuretics to avoid fluid retention
beta adrenergic blockers to diminish reflex responses |
|
What are the possible side effects seen with hydralazine and minoxidil?
|
may induce angina attacks and myocardial ischemia in pts. with coronary artery disease
-minoxidil can cause hypertrichosis (excess hair growth on the body) |
|
What are the vasodilators that work through NO?
|
hydralazine
sodium nitroprusside |
|
What is the mechanism of hydralazine?
|
dilates arterioles but not veins
-used in severe HTN -combined with other agents -oral admin -combo with isosorbide dinitrate is esp effective in the af. amer pop |
|
Describe sodium nitroprusside.
|
-metabolized rapidly to thiocyanate and excreted by kidney
-rapidly lowers BP and effects disappears in minutes after discontinuation -IV infusion only -can cause cyanide accumulation, metabolic acidosis, arrhythmias, excessive hypotension, death |
|
What are the K channel regulators that function in vasodilation?
|
minoxidil-opens the K channels and stabilizes the membrane, dilates arterioles but not veins, this is topical rogaine
diazoxide-hyperpolarizes arterial sm. mm. cells by activating ATP sensitive K channels, inhibits insulin secretion and causes hyperglycemia |
|
What is fenoldopam?
|
specific agonist on D1 receptors
-postsynaptic D1 receptor stimulation relaxes arteriolar sm. mm. -IV admin., liver metabolism, half life 5 mins |
|
What does "-dipine" imply?
|
Ca channel blocker
|
|
What drugs cause gingival hyperplasia?
|
"dipine's"
phenytoin cyclosporine |
|
What are the strongest vasodilators that are Ca channel blockers?
|
dihydropyridines like nifedipine
|
|
What Ca channel blocker has the strongest cardiac effects?
|
verapamil
|
|
What Ca channel blocker is the most lipid soluble?
|
nimodipine
|
|
In what pt. populations are ACE inhibitors the first choice of tx?
|
diabetes
chronic renal disease L ventricular hypertrophy |
|
What are the drug interactions of ACE inhibitors?
|
K sparing diuretics
NSAIDs |
|
What are the angiotensin receptor blocking agents?
|
the "sartan's"
losartan valsartan |
|
How is variant or angiospastic or Prinzmetal's angina tx?
|
it is reversed by nitrates or Ca channel blockers
|
|
How do nitrates work?
|
-they cause vasodilation by releasing nitrite ion-->metabolized to NO-->activates GC-->increases cGMP-->relaxes vascular sm. mm.
-all vascular sm. mm. cells are relaxes but vasodilation is uneven -large veins are markedly dilated due to increase venous capacitance and decrease preload -arterioles and precapillary sphincters are dilated less and arteriolar dilation will decrease afterload -nitrates can also increase cardiac workload by lowering BP which reflexively increasing SNS activity which increases HR and myocardial contractility |
|
What are the 2 mechanisms for anginal relief during nitrate therapy?
|
1)predominant relief mechanism: decreased myocardial O2 rqrment. due to marked dilation of large veins, decreasing preload and cardiac work
2)secondary relief mechanism: redistribution of regional coronary blood flow from normal to ischemic areas even though total flow remains unchanged |
|
What are some of the other effects of nitrates on the body besides the heart?
|
-decreased platelet aggregation and production of methemoglobin from rxn of nitrite ion with hgb
-sodium nitrite is used to induce methgb formation for tx of cyanide poinsoning b/c methgb has a very high affinity for cyanide ion -also have been used as sex enhancing drugs to enhance erection (viagra) |
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How does sildenafil work?
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AKA viagra
-increases cGMP in the corpus cavernosum by inhibiting cGMP degradation by PDE type 5 -combo of viagra and nitrites is contraindicated....could cause severe hypotension |
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What are the 2 important effects of intracellular Ca?
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-triggers mm. contraction in both the myocardium and vascular sm. mm
-required for pacemaker activity of the SA node and for conduction through the AV node |
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What are some of the non-cardiac effects of Ca channel blockers?
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-decreased insulin secretion
-decreased platelet aggregation |
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What are the PHK of Ca channel blockers?
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-oral admin with considerable first pass efect
-liver metabolism is minimal, renal excretion accounts for the majority of elim. -half life is 3-5 hrs -slow release formulation is available to allow for once a day dosing (except amlodipine and bepridil w/half lives of 40 and 25 so there is no need for slow release formulation) |
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What beta blockers are used for the tx of angina?
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atenolol
metoprolol propanolol nadolol |
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Does beta blockade produce coronary vasodilation?
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no
|
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In what type of angina can beta blockers be harmful in?
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variant angina b/c they slow HR, prolong ejection time-->LV EDV increases and this increases myocardial O2 requirement
|
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Describe the mechanism of action of ranolazine.
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-it is a partial FA ox. inhibitor
-also inhibits late inward Na current -decreases LV wall stiffness, improves coronary circulation |
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What is ranolazine used for?
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for the tx of chronic stable angina in pts who have failed to response to other anti-anginal meds
|
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What are the goals of effective angina therapy?
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-increase exercise tolerance
-decrease frequency and duration of M. ischemia |
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How is variant angina usually tx?
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nitrates and CCAs are more effective than beta blockers b/c beta blockers will not dilate coronary blood vessels
|
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What are the various combinations of drugs used to tx angina?
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most effective combos are:
-beta blockers and CCAs -2 CCAs (nifepidine and verapamil) -potentially harmful effects of CCAs or beta blockers can be prevented by combined tx with nitrates and vice versa -reflex tachy can be minimized by combining nitrates with CCAs or beta blockers |
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How is sildenafil metabolized?
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mostly by the hepatic cyt. P450 enzyme 3A4
|
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Describe vardenafil.
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-similar to sildenafil
-more selective for PDE5 than PDE6 which is present in the retina -leads to fewer visual adverse effects such as those reported with sildenafil -achieves max. plasma concentration sooner than sildenafil or tadalafil which may result in a faster onset of action |
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Describe tadalafil.
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-similar to tadalafil
-duration of tadalafil is longer than that of sildenafil or vardenafil -b/c PDE inhibitors promote erection only in the presence of sex. stimulation the longer duration of action of this drug allows for more spontaneity in sex. activity -no visual disturbances have been reported with this drug |
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What are endothelins?
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they are a family of peptides that are stored in vascular endothelial cells
-their release produces contraction of vasc. sm. mm. -they likely counterbalance the effects of NO |
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Describe Bosentan.
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-it is an endothelin receptor antagonist
-only indicated for use in severe pulmonary HTN -associated with a high frequency of elevated hepatic enzymes potential teratogenic effects, and multiple drug interactions -admin. orally -metabolized by liver CYP enzymes |
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In what 3 ways is hemostasis achieved?
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1)vascular contraction
2)platelet adhesion, activation, aggregation 3)fibrin formation and reinforcement of the platelet plug (coagulation) |
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What is a white thrombus?
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the initial plug formed by platelets in high-pressure arteries
-in general, this dominates in arterial thrombi |
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What is a red thrombus?
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reduced blood flow or stasis allows formation of insoluble fibrin and a mesh-like red thrombus that includes RBCs
-in general, this dominates in venous thrombi |
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What is aPTT?
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time to clotting following addition of Ca, neg. charged phospholipids, and kaolin (aluminum silicate)
-it is a measure of the intrinsic coag. pthway |
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What is PT?
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time to clotting following addition of thromboplastin (contains TF and phospholipids)
-values are usually normalized to an international standard and presented as the INR -a measure of the extrinsic coag. pthway |
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How is heparin administered?
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IV, not IM b/c will cause hematoma
-mainly cleared by heparinase in the liver |
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What clotting test is prolonged by heparin?
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aPTT
|
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Describe low molecular wt heparins such as enoxaprin.
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-they affect less of the clotting cascade (mostly inactivating factor Xa) but they are as effective as regular heparin
-have greater bioavailability than heparin when injected subcu., therefore they can be injected subcu -require less frequent dosing -used for prevention of DVT |
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What are the toxicities of heparin?
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-the main side effect is hemorrhage which is tx by stopping therapy or by giving a heparin antagonist, protamine sulfate (binds to and inactivates heparin)
-HIT or heparin induced thrombocytopenia, a new thrombus while on heparin is assumed to be heparin induced |
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What are the CI and interactions of heparin?
|
-it can alter the protein binding ability of highly bound drugs such as diazepam and propanolol
-may cause modest reductions in BP and pulmonary artery pressure -do not use in pts. actively bleeding, who are HS, have hemophilia, purpura, severe HTN, infective endocarditis, active TB, ulcers, etc.. -do not use during or after surgery of the brain, spinal cord, or eye in pts. undergoing lumbar puncture or regional anesthetic therapy -can use in prego if needed (does not cross placenta) - |
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Describe protamine sulfate.
|
-specific antagonist to heparin
-in the absence of heparin protamine interacts with platelets and fibrinogen producing an anticoagulant effect -adverse CV responses include hypotension due to histamine release, pulmonary HTN, and allergic rxns |
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What is lepirudin?
|
direct inhibitor of thrombin, does not require antithrombin III
-given IV as alternative in heparin induced thrombocytopenia |
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What is the mechanism of warfarin?
|
-prevents reduction of vit. K and intereferes with processing of clotting factors 2, 7, 9, 10
-effect can take from 12-16 hrs to develop b/c the drugs inhibit production of new factors and there is no effect until the old factors have decayed -effects lasts 4-5 days |
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How is warfarin administered?
|
-it is given orally
-it is slowly introduced over a week and the therapeutic range is defined in terms of an INR which is a function of PT -the target INR should be 2-3 for most indications |
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What are the drug interactions of warfarin?
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EVERYTHING ALMOST
-this drug has a million interactions -drugs which decrease availability of vit K or alter the level of clotting factors -agents that impair platelet aggregation and platelet function, such as aspirin can cause severe bleeding -warfarin is 98% bound to plasma albumin (ethacrynic acid will displace it and many others) -agents that inhibit or induce the microsomal liver enzymes -pregnancy and birth control -abx b/c vit. K is synthesized by intestinal flora |
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What are the tox. of warfarin?
|
-hemorrhage
-CI in pregnancy, crosses the placenta and causes birth defects -reduces levels of protein C which has a short half life, warfarin induced thrombosis causing cutaneous necrosis can occur during early therapy |
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How is the action of warfarin reversed?
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-vit. K with discontinuation of warfarin
-fresh frozen plasma -factor IX concentrates |
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What is dabigatran?
|
a direct thrombin inhibitor
|
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What does rivaroxaban do?
|
inhibitor of factor Xa
-prevention of DVT that may lead to PE after hip replacement or knee surgery |
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Describe thrombolytic agents.
|
-they act by converting plasminogen to plasmin which cleaves fibrin to fibrinogen
-causes lysis of formed clots and re-establish tissue perfusion -esp. important in treating heart attacks -the sooner the better to start tx-better within 6 hrs -can use with aspirin, beta blockers, and ACE inhibitors |
|
Describe streptokinase.
|
-forms a complex with plasminogen, increasing fibrinolytic activity
-admin. IV -not fibrin specific causes generalized systemic fibrinolysis -with aspirin, is as effective as other fibrinolytics -may lose efficacy after first course of tx due to ab formation |
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Describe anistreplase.
|
-mixture of plasminogen and streptokinase that has been protected and rendered inert by acylation
-the acyl group hydrolyzes in the blood and the compound then becomes fibrinolytic -has long duration of action -more clot selective than streptokinase and can be admin more rapidly -causes fibrinogenolysis and is antigenic |
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What is aminocaproic acid?
|
-chemically similar to lysine
-completely inhibits plasminogen activation -inhibits streptokinase and urokinase activity and prevents formation of plasmin -used for bleeding disorders like hemophilia, and prophylaxis against re-bleeding in intracranial aneurysms |
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What is the mechanism of aspirin?
|
inhibits TXA2 synthesis in platelets by inhibiting COX enzymes
-decreases platelet aggregation -effects on the platelet are irreversible and last the life of the platelet (7-10 days) -325 mg/day FDA approved for primary prevention of MI |
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What is the mechanism of clopidogrel (and ticlopidine)?
|
-inhibits platelet aggregation
-inhibits the ADP pathway of the platelet -does NOT affect PG metabolism like aspririn does -given orally -this is used in pts allergic to aspirin -used to reduce thrombotic events following MI and stroke - |
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What is abciximab (eptifibatide, tirofiban)?
|
-they inhibit platelet aggregation by inhibiting GP2b/3a receptors
-prevent binding of fibrinogen and vWF to the GP2b3a integrin receptor -combined with heparin in pts undergoing percutaneous coronary intervention -used in unstable angina not responding to conventional therapy -given IV -tox is bleeding and thrombocytopenia -these drugs are VERY expensive (1500/dose) |