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268 Cards in this Set

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What are the 2 types of edema?
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
What are some diseases often associated with edema?
CHF, hepatic cirrhosis, nephritis, nephrosis, renal damage due to HTN, diseases involving increased steroid hormone secretion, pre-eclampsia, toxemia, HS rxns like anaphylactic shock
What conditions will promote the development of edema?
1)altered blood circ. (increased arterial and venous pressure
2)altered blood comp. (decreased osmotic gradient, salt and water retention)
3)inadequate lymph drainage
Where is the nephron does most reabsorption of K+ occur?
in the proximal tubule and this IS NOT influenced by drugs
Where does secretion of K+ occur?
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
Where are Ca and Mg reabsorbed?
in the thick ascending limb of Henle
-thiazide diuretics increase Ca reabsorption
-loop diuretics enhance Ca and Mg excretion at the thick ascending limb
What are the 2 mechanisms by which organic compounds such as glucose, amino acids, and vitamins are reabsorbed in the proximal tubule?
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)
List the carbonic anhydrase inhibitors.
acetazolamide
dorzolamide
brinzolamide
What is the mechanism of action of carbonic anhydrase inhibitors?
-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
What are the effects of carbonic anhydrase inhibitors?
-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
Describe the pharmacokinetics of carbonic anhydrase inhibitors.
-well absorbed orally
-effect seen after 30 mins
-renal excretion
-dose must be reduced in renal insufficiency
What are the toxicity issues associated with carbonic anhydrase inhibitors?
-hyperchloremic metabolic acidosis
-renal stones
-renal potassium wasting
What are the contraindications for giving carbonic anhydrase inhibitors?
hepatic cirrhosis (decreases the excretion of ammonia)
sulfonamide hypersensitivity
What are the clinical indications for using carbonic anhydrase inhibitors?
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
What is the mechanism of action of loop diuretics?
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
What effect do loop diuretics have on Magnesium and Calcium excretion?
they increase it which reduces their plasma levels
What are the effects of loop diuretics in the body?
-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
Describe the pharmacokinetics of loop diuretics.
-oral and parenteral administration
-well absorbed orally
-onset of action in 30-60 minutes following oral admin.
-renal excretion
What are the toxicities associated with loop diuretics?
-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)
WHat are the drug interactions of loop diuretics?
-aminoglycosides (ototoxicity)
-lithium (loss of Na increases Li retention)
-digoxin (loss of K )
What are the therapeutic uses of loop diuretics?
-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
Describe the pharmacokinetics of loop diuretics.
-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
Describe the main differences btwn. ethacrynic acid and the other loop diuretics.
-similar mechanism of action to furosemide
-not a sulfonamide derivative so can be used in ppl allergic to sulfonamides
-higher risk of ototoxicity
What are the most widely used diuretics today?
thiazides
What are the main clinical indications for the use of thiazides?
-HTN, CHF
-nephrolithiasis
-nephrogenic diabetes insipidus
What is the mechanism of action of thiazide diuretics?
-inhibition of Na resporption at the cortical diluting site
-effect is dependent on PG synthesis so action may be inhibited by NSAIDs
What are some of the effects of thiazides?
-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
How do thiazides lead to a decrease in Ca excretion?
-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
How do thiazides lead to hyperglycemia?
-may decrease the release in insulin and increase glucose tolerance, this has clinical importance in type 2 diabetics
Describe the pharmacokinetics of thiazides.
-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
What are the toxicities and adverse rxns associated with thiazides?
-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
Describe metolazone.
-similar to thiazide diuretics
-may have proximal tubular activity as well
-able to produce diuresis in pts. with a reduced GFR
Describe indapamide.
-a sulfonamide like structure and consequently resembles thiazides in it mechanism of action
-pronounced vasodilation
-does NOT increased plasma lipids
Describe eplerenone.
-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
Describe triamterene and amiloride.
-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
Describe the potential toxicities of potassium sparing diuretics.
-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)
What are the therapeutic uses for potassium sparing diuretics?
-main use is in combo with potassium losing diuretics
-amiloride is the DOC for lithium induced DI
Describe the characteristics of osmotic diuretics.
-freely filterable at the glomerulus
-undergo very limited absorption from the renal tubules
-pharmacologically inactive or inert
What is the mechanism of action of osmotic diuretics?
-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
Describe Mannitol.
-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
What are the potential toxicities of mannitol?
-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.
What are the therapeutic uses of mannitol?
-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
What is the order of expected maximum diuretic effect?
loop>>thiazides>>CA inhibitors (only work for a few days)>K sparing
Describe vasopressin.
-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
Describe desmopressin.
-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
Describe ADH antagonists.
-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
Describe conivaptan and tolvaptan.
-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
Describe demeclocycline.
-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
Describe the effect that lithium has on the kidney.
it produces nephrogenic DI by uncoupling the V2 receptor from AC enzyme
-more toxic than demeclocycline
What drugs can cause drug-induced SIADH?
TCAs
carbamazepine
sulfonylureas
chlorpropamide
antipsychotics
SSRIs
SNRIs
venlafaxine
opioids
vinblastine
vincristine
Describe the effects and mechanism of niacin.
-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)
What are the therapeutic uses of niacin?
-most effective in heterozygous familial hypercholesterolemia esp. when combined with bile acid binding resin
-also effective in familial combined hyperlipoproteinemia, familial dysbetalipoproteinemia, and hypercholesterolemia
What are the adverse effects associated with niacin?
-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
What are the effects and mechanism of fibric acid derivatives?
-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
Describe the PKC of fibric acid derivatives.
oral absorption, high plasma protein binding, renal excretion about 70%
-enterohepatic circulation
-half life about 1.5 hr
What are the therapeutic uses of fibric acid derivatives?
effective in familial dysbetalipoproteinemia and hypertriglyceridemia
-innefective in primary chylomicronemia, familial hypercholesterolemia
What are the adverse effects associated with fibric acid derivatives?
-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
What are the names of the fibric acid derivative drugs?
gemfibrozil
clofibrate (seldom used)
fenofibrate
What are the names of the bile acid binding resins?
cholestyramine
colesevelam
colestipol
Describe the effects and mechanism of the bile acid binding resins.
-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
Describe the PCK of bile acid binding resins.
they are not absorbed
-should be taken with meals (b/c bile production is needed for effect)
What are the therapeutic uses of bile acid binding resins?
-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
What are the adverse effects of bile acid binding resins?
-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
Describe the effects and mechanism of HMG-CoA reductase inhibitors.
-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
Describe the PCK of statins.
-high first pass, liver metabolism, GI excretion
-given in the evening (diurnal pattern of cholesterol synthesis)
What are the therapeutic uses of statins?
-most effective when plasma LDL is elevated as in heterozygous familial hypercholesterolemia or combined hyperlipoproteinemia
What are the adverse effects of statins?
-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
What are the drug interactions of statins?
-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
What is ezetemibe?
-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
Describe orlistat.
-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.
What structures in the heart have slow response fibers?
SA node
AV node

-the rest of the structures have fast reponse fibers (atria, ventricles, bundle of HIS, purkinje cells)
Describe phase 0 of generation of an AP in the heart.
-opening of Na channels, rapid depolarization, inactivation of the Na channels
Describe phase 1 of AP generation in the heart.
rapid partial repolarization due to the inactivation of fast sodium channels
Describe phase 2 of AP generation in the heart.
plateau phase, Ca channels are open
Describe phase 3 of AP generation in the heart.
repolarization, Ca channels inactivated, K channels open, Na channels turning to rested state
Describe phase 4 of AP generation in the heart.
resting membrane potential, spontaneous depolarization can now occur
What parameters influence the conduction velocity of a cardiac cell?
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
What are the determining factors of the rate of pacemaker cells?
-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)
What are the 2 main disturbances of impulse conduction in the heart?
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
What are the main features of antiarrhythmic drugs?
-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
Describe the general effects of antiarrhythmic agents at regular vs. higher doses.
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
What are class I antiarrhythmic agents?
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
What are class II antiarrhythmics agents?
beta blockers
-reduces adrenergic activity on the heart
What are class III antiarrhythmic agents?
K channels blockers: extend ERP
What are class IV antiarrhythmic agents?
Ca channel blockers: decrease HR, contractility
Describe the mechanism of action of quinidine.
-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)
What are some of the other cardiac effects of quinidine?
-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
What are some of the other systemic effects of quinidine?
-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
Describe the PHK of quinidine.
-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
Describe the toxicity of quinidine.
-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
What are the CI to quinidine therapy?
-pre-existing complete AV block (vent. arrest may happen)
-thrombocytopenia associated with previous quinidine therapy (allergic response)
What are the therapeutic uses of quinidine?
-it is a broad spectrum antiarrhythmic drug effective for acute or chronic tx of varieties of supraventricular and ventricular arrhythmias
What are the drug interactions of quinidine?
-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
Describe procainamide.
-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)
What are the toxicities associated with procainamide?
-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
What are the CI to procainamide?
-complete AV block
-use with great caution in partial AV block
What are the therapeutic uses of procainamide?
-tx a wide variety of cardiac arrhyth. such as:
-vent. arrhythmias-except those resulting from digitalis intox.
-supravent. arrhythmias-atrial flutter and fib.
Describe disopyramide.
-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
What are the toxicities associated with disopyramide?
-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
What is the therapeutic use of disopyramide?
V. tach
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
What are the effects of lidocaine?
-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
Describe the PHK of lidocaine.
-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
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
What is the therapeutic use of lidocaine?
tx of vent. arrhythmias
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
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%
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)
How does sildenafil work?
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
What are the 2 important effects of intracellular Ca?
-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
What are some of the non-cardiac effects of Ca channel blockers?
-decreased insulin secretion
-decreased platelet aggregation
What are the PHK of Ca channel blockers?
-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)
What beta blockers are used for the tx of angina?
atenolol
metoprolol
propanolol
nadolol
Does beta blockade produce coronary vasodilation?
no
In what type of angina can beta blockers be harmful in?
variant angina b/c they slow HR, prolong ejection time-->LV EDV increases and this increases myocardial O2 requirement
Describe the mechanism of action of ranolazine.
-it is a partial FA ox. inhibitor
-also inhibits late inward Na current
-decreases LV wall stiffness, improves coronary circulation
What is ranolazine used for?
for the tx of chronic stable angina in pts who have failed to response to other anti-anginal meds
What are the goals of effective angina therapy?
-increase exercise tolerance
-decrease frequency and duration of M. ischemia
How is variant angina usually tx?
nitrates and CCAs are more effective than beta blockers b/c beta blockers will not dilate coronary blood vessels
What are the various combinations of drugs used to tx angina?
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
How is sildenafil metabolized?
mostly by the hepatic cyt. P450 enzyme 3A4
Describe vardenafil.
-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
Describe tadalafil.
-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
What are endothelins?
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
Describe Bosentan.
-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
In what 3 ways is hemostasis achieved?
1)vascular contraction
2)platelet adhesion, activation, aggregation
3)fibrin formation and reinforcement of the platelet plug (coagulation)
What is a white thrombus?
the initial plug formed by platelets in high-pressure arteries
-in general, this dominates in arterial thrombi
What is a red thrombus?
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
What is aPTT?
time to clotting following addition of Ca, neg. charged phospholipids, and kaolin (aluminum silicate)
-it is a measure of the intrinsic coag. pthway
What is PT?
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
How is heparin administered?
IV, not IM b/c will cause hematoma

-mainly cleared by heparinase in the liver
What clotting test is prolonged by heparin?
aPTT
Describe low molecular wt heparins such as enoxaprin.
-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
What are the toxicities of heparin?
-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
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)
-
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
What is lepirudin?
direct inhibitor of thrombin, does not require antithrombin III
-given IV as alternative in heparin induced thrombocytopenia
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
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
What are the drug interactions of warfarin?
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
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
How is the action of warfarin reversed?
-vit. K with discontinuation of warfarin
-fresh frozen plasma
-factor IX concentrates
What is dabigatran?
a direct thrombin inhibitor
What does rivaroxaban do?
inhibitor of factor Xa
-prevention of DVT that may lead to PE after hip replacement or knee surgery
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
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
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
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
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
-
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)