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277 Cards in this Set
- Front
- Back
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Carbonic Anhydrase Inhibitors - the names of the members of the group
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Acetazolamide (Diamox)
Brinzolamide (Azopt) Dorzolamide (Trusopt) |
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Carbonic Anhydrase Inhibitors - locus and mechanism of their action
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inhibit the carbonic anhydrase (CA) enzyme in the proximal tubule cells
inhibit bicarbonate reabsorption |
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How do topical CA Inhibitors treat glaucoma?
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inhibit bicarb transport to reduce aqueous humor
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what do CA Inhibitors do to urine?
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alkalize it
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Carbonic Anhydrase Inhibitors - pharmacokinetics
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Oral absorption & topical administration; Effects diminish in a few days; Renal extretion
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Carbonic Anhydrase Inhibitors - toxicities and contraindications
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Toxicities:
• hyperchloremic metabolic acidosis • renal stones • renal potassium wasting Contraindications: • hepatic cirrhosis • sulfonamide hypersensitivity |
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Carbonic Anhydrase Inhibitors - clinical applications
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• Glaucoma
o systemically: acetazolamide o topically: dorzolamide, brinzolamide • Urinary alkalinization • Metabolic alkalosis • Acute mountain sickness |
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Loop Diuretics - the names of the members of the group
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Furosemide (Lasix) Bumetanide (Bumex)
Torsemide (Demadex) Ethacrynic Acid (Edecrin) |
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Which Loop Diuretics are sulfonamide derivatives?
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Furosemide, Bumetanide, and Torsemide
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Loop Diuretics - locus and mechanism of their action
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Location: thick ascending limb of Loop of Henle; Mechanism: inhibition of sodium transport
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How do Loop Diuretics relieve pulmonary congestion?
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by increasing systemic venous capacitance
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How and where do Loop Diuretics induce K+ loss?
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they increase the sodium load at the distal exchange sites where K+ is lost in exchange for Na+
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Loop Diuretics - pharmacokinetics
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• oral or parenteral administration
• renal excretion |
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Loop Diuretics - major side effects and toxicities
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• hypokalemic metabolic alkalosis
• hypocalcemia and hypomagnesemia • hyperuricemia • ototoxicity • allergic interstitial nephritis • excessive sodium and water loss |
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Loop Diuretics - possible interactions with other drugs
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• aminoglycosides (enhanced ototoxicity)
• lithium (loss of Na+ increases Li+ retention, ↑ toxicity) • digoxin (loss of potassium ↑ toxicity) • loop agents & thiazides may produce diuresis when none of them is effective alone • potassium sparing diuretics & loop agents may balance out potassium losses • induce PG synthesis in the kidney – therefore COX inhibitors may interfere with their actions |
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Loop Diuretics - clinical applications
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High ceiling diuretics for CHF, and pulmonary edema; Acute renal failure; hypercalcemia; hyperkalemia; pulmonary congestion following MI
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Furosemide (Lasix)
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Prototype Loop Diuretic
More effective than thiazides at reducing edema associated with impaired renal function. Furosemide causes reduction of venous tone even before diuresis ensues |
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Ethacrynic Acid (Edecrin)
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• Mechanism of action is the same, adverse effects are similar to that of furosemide
• not a sulfonamide derivative, so it can be use in people allergic to sulfonamides • higher risk of ototoxicity |
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Thiazides
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most widely used diuretics.
• Hydrochlorothiazide (Esidrix) is the prototype of thiazides. • The major difference between the members of this series is potency & duration of action. |
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Thiazide Diuretics - the names of the members of the group
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Hydrochlorothiazide (Esidrix) Metolazone (Mykrox) Indapamide (Lozol)
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Thiazide Diuretics - locus and mechanism of their action
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• Inhibition of sodium resorption at the cortical diluting site (distal convoluted tubule)
• effect dependent on PG synthesis, action may be inhibited by NSAIDs |
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Thiazide Diuretics - Effects
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• thiazides have a minor carbonic anhydrase inhibitor-like effect as well
• increase ATP-dependent K+ channel opening (hyper-polarization; similarly to minoxidil, diazoxide) • thiazides lower systemic blood pressure and enhance the antihypertensive action of other drugs |
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Thiazide Diuretics - pharmacokinetics
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• orally absorbed
• All are secreted by the organic acid secreting system. They compete with uric acid in renal tubules • There are some differences o Chlorthalidone is slowly absorbed, therefore appears to have longer duration o Indapamide is excreted by biliary system, therefore is useful in patients with renal insufficiency. o The different derivatives have different potencies and PHK |
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Thiazide Diuretics - clinical applications
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o Hypertension, CHF
o Nephrolithiasis o Nephrogenic diabetes insipidus |
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Thiazide Diuretics - major side effects and toxicities
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• Hypokalemic metabolic acidosis
• Hyperglycemia and carbohydrate intolerance may occur • Hyperuricemia • Hyperlipidemia (except indapamide) • Blood Dyscrasia • Necrotizing vasculitis • Lithium toxicity • jaundice in infants. |
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Thiazide Diuretics - possible interactions with other drugs
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• loop agents & thiazides may produce diuresis when none of them is effective alone
• K+ sparing diuretics & thiazides may balance out K+ losses • thiazides lower systemic BP and enhance the antihypertensive action of other drugs |
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Metolazone (Mykrox)
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• similar to the thiazide diuretics, acts to increase excretion of sodium, chloride, and water by inhibiting sodium ion transport across the renal tubular epithelium
• exerts its effect primarily at the level of the cortical diluting segment of the nephron • it may have proximal tubular activity as well • metolazone is able to produce diuresis in patients with a reduced GFR (i.e., less than 20 mL/min). |
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Indapamide (Lozol)
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• Indapamide is a sulfonamide-like structure and consequently resembles thiazides in its mechanism of action. Pronounced vasodilation. Does not increase plasma lipids.
Effects • diuresis - (salt and water loss by inhibiting Na+ reabsorption at cortical diluting sites). • relaxation of blood vessels calcium-channel blockade in smooth muscle cells - a direct antihypertensive effect. • appears to reduce LVH (left ventricular hypertrophy) • no detrimental effects on either glucose tolerance or serum lipids Pharmacokinetics: • Rapid oral absorption • Effect on blood pressure, appears in one week, peaks at 8-12 weeks • Extensive hepatic metabolism • 50% is excreted in the urine, unchanged • t½ = 14-18 hours • No accumulation even in the presence of renal insufficiency (an advantage over thiazides) Adverse Reactions • More or less similar to those of thiazides |
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Potassium Sparing Diuretics - the names of the members of the group
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Amiloride (Midamor)
Triamterene (Dyrenium) |
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Potassium Sparing Diuretics - locus and mechanism of their action
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inhibit sodium flux in the collecting tubules
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Potassium Sparing Diuretics - pharmacokinetics
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oral administration; some liver metabolism; excreted in urine
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Potassium Sparing Diuretics - major side effects and toxicities
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• hyperkalemia is the only serious toxicity (on chronic use or in combination with other potassium sparing agents)
• nausea, vomiting, leg cramps, dizziness, etc. • mild azotemia, increased blood urea nitrogen, etc. • megaloblastic anemia in cirrhotic patients is presumably due to an adverse action on folic acid metabolism |
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Potassium Sparing Diuretics - possible interactions with other drugs
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triamterene and spironolactone should not be administered simultaneously (may cause severe hyperkalemia)
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Potassium Sparing Diuretics - clinical applications
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mineralocorticoid excess; CHF; nephrotic syndrome; hepatic cirrhosis; in combination with other drugs (HCTZ); low diuretic ceiling;
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Amiloride (Midamor)
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amiloride is the DOC for lithium induced DI if lithium cannot be discontinued. Lithium uncouples the V2 receptor from cAMP production. Amiloride decreases lithium entrance into cells in the collecting tubule
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Aldosterone antagonist and potassium sparing diuretics
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1. Aldosterone antagonists (spironolactone, eplerenone)
2. Direct inhibitors of sodium flux (triamterene, amiloride) • These drugs interfere with Na+ reabsorption at the distal exchange site. In doing so, they permit loss of Na+ and water and cause conservation of K+ (hence, they are called potassium sparing diuretics) • they are weak as diuretics in comparison with thiazides and loop diuretics they can effectively reduce K+ loss and minimize alkalosis |
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Aldosterone Antagonists - the names of the members of the group
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Spironolactone (Aldactone) Eplerenone (Inspra)
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Spironolactone - locus and mechanism of their action
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• spironolactone is a competitive inhibitor of aldosterone
• also binds to glucocorticoid and sex hormone receptors at high doses • aldosterone inhibition promotes the excretion of sodium and retention of potassium at the collecting tubules |
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Spironolactone - pharmacokinetics
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• usually given orally
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Spironolactone - major side effects and toxicities
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• relatively few; occasional G.I. upsets, nausea, vomiting, cramps, dizziness, etc.
• gynecomastia • occasional hyperkalemia |
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Spironolactone - possible interactions with other drugs
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triamterene and spironolactone should not be administered simultaneously (may cause severe hyperkalemia)
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Spironolactone - clinical applications
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• Edema associated with CHF, cirrhosis and nephrotic syndrome
• spironolactone is the most effective in hyperaldosteronism • K+ supplementation is unnecessary when patients on thiazides or other K+ depleting diuretics are treated with spironolactone |
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Eplerenone (Inspra)
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• the first of a unique class of oral antihypertensive agents called selective aldosterone receptor antagonists (SARA).
• similar in action to spironolactone at the aldosterone receptor • 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 principal risk associated with eplerenone use • in the EPHESUS trial, the addition of eplerenone to standard medical therapy has been shown to reduce all-cause mortality (by 15%) for patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure |
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Osmotic Diuretics
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Mannitol (Osmitrol)
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Osmotic Diuretics - locus and mechanism of their action
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water retention in the proximal tubules and in the descending limb of loop of Henle
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Osmotic Diuretics - pharmacokinetics
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No oral absorption; IV administration; glomerular filtration
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Osmotic Diuretics - major side effects and toxicities
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extracellualr volume expansion; dehydration and hypernatremia; Contraindications: CHF
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Osmotic Diuretics - Clinical Applications
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• increase urine volume
• reduce intraocular and intracranial pressure |
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Mannitol (Osmitrol)
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• DOC to produce osmotic diuresis - most effective, less irritating, less likely to cause thrombophlebitis, does not cause tissue necrosis following extravasation and safer in patients with renal failure
• works even when the filtration rate is low • administered 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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ADH Agonists - the names of the members of the group
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Vasopressin
Desmopressin |
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ADH Antagonists - the names of the members of the group
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Demeclocycline (Declomycin)
Lithium Conivaptan (Vaprisol) Tolvaptan (Samsca) |
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When do you need an ADH Antagonist?
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• a variety of medical conditions, including congestive heart failure and syndrome of inappropriate ADH secretion (SIADH), cause water retention as the result of ADH excess
• dangerous hyponatremia can result. |
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Drugs that Induce SIADH
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TCA-s
Carbamazepine Sulfonylureas chlorpropamide Antipsychotics SSRI-s SNRI-s venlafaxine Opioids Vinblastine Vincristine |
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Vasopressin
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• exogenous, parenteral form of antidiuretic hormone (ADH
• used to prevent or control polyuria, polydipsia, and dehydration in patients with central diabetes insipidus • intravenous vasopressin is included in the Advanced Cardiac Life Support (ACLS) algorithm as an alternative to epinephrine for the treatment of cardiac arrest associated with asystole or pulseless electrical activity |
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Desmopressin
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• a synthetic analog of arginine vasopressin (antidiuretic hormone, or ADH)
• it is more potent and much longer acting than vasopressin • strong V2 agonist and has no effect on V1 receptors increases plasma factor VIII (FVIII) and von Willebrand factor (vWF) to a greater extent than equivalent weights of vasopressin the hemostatic effects of desmopressin are mediated through V2 receptor agonist activity, as patients 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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Demeclocycline (Declomycin)
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• a tetracycline antibiotic
• produces a nephrogenic diabetes insipidus by uncoupling the V2 receptor from adenylyl cyclase enzyme • demeclocycline is preferred over lithium due to demeclocycline's lower risk of toxicity |
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Lithium
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• produces nephrogenic diabetes insipidus by uncoupling the V2 receptor from adenylyl cyclase enzyme
• more toxic than demeclocycline • see lithium in CNS pharmacology too |
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Conivaptan (Vaprisol)
Tolvaptan (Samsca) |
• non-peptide dual V1A and V2 vasopressin receptor antagonists
• increase urine output and decreases reabsorption of free water by antagonizing • very new drugs, little experience |
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Proximal tubule
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• About 70-75% of the contents of the glomerular filtrate are absorbed by
• active reabsorption of Na+ • co-transport of Na+ along with glucose, amino acids and organic acids • exchange of H+ with Na+ via the enzyme of carbonic anhydrase • water is transported passively throughout the whole process DRUGS: CA Inhibitors; Osmotics |
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Thin Descending and Thin Ascending Limb of Loop of Henle:
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• The transport of water and electrolytes in this section is passive.
• The filtrate that is not absorbed in the proximal tubule passes into this section of the Loop which is highly permeable to osmotic flow of water. Consequently, the tubular fluid becomes hypertonic as it approaches the tip of the Loop. DRUGS: Osmotics |
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Thick Ascending Loop of Henle
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• Na+ , K+ and 2Cl- Co-transport (Active Process)
• This segment of the loop is extremely impermeable to water. However, it pumps chloride, sodium, and potassium into the interstitium. • Ca++ and Mg++ are also reabsorbed at this segment. • DRUGS: Loop diuretics |
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Distal Diluting Site
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• Much of the remaining Na+ and Cl- are reabsorbed in a segment consisting of cortical diluting portion of ascending limb and the early section of distal tubule (also called "Distal Diluting Site").
• The tubular urine becomes markedly dilute. This segment is also impermeable to water. • DRUGS: Thiazides |
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Distal Tubules and Collecting Ducts
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• More Na+ is reabsorbed here by two distinct mechanisms:
• Exchange of Na+ with K+ (with or without aldosterone) • Exchange of Na+ with H+ catalyzed by carbonic anhydrase DRUGS: CA Inhibitors, K+ sparing Diuretics and Aldosterone Antagonists |
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Collecting Ducts
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• The fluid that enters the collecting ducts is generally hypotonic and will be voided as either diluted or as concentrated urine depending upon the absence or presence of circulating ADH (Antidiuretic Hormone).
• ADH increases the permeability of the collecting ducts to water, whereby water diffuses into the interstitium and produces concentrated urine. In the absence of ADH, water permeability is reduced and the hypotonic tubular fluid is simply voided as diluted urine. DRUGS: Spironolactone, Eplerenone |
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Potassium Reabsorption and Secretion
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• Potassium undergoes both tubular reabsorption, (proximal tubules), and secretion at distal tubules.
• Reabsorption of K+ occurs largely in the proximal tubule, and this process cannot be influenced by drugs. • Secretion of K+ occurs in the distal tubules. This process 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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What drugs influence Reabsorption of Calcium and Magnesium and where do they act?
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• Thiazide diuretics increase Ca++ reabsorption in the renal tubules.
• Loop diuretics enhance Ca++ excretion and Mg++ excretion at the thick ascending limb |
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Describe Tubular Transport of Organic Compounds
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• Glucose, amino acids, vitamins and other essentials are first filtered and then reabsorbed. They do not appear in the voided urine unless they are in excessively high concentrations (i.e. beyond the transport capacity). They can be affected by drugs. Indeed, drug induced glucosuria and aminoaciduria are manifestations of nephrotoxicity.
• Reabsorption occurs by two mechanisms, diffusion, and carrier mediated reabsorption o Diffusion: The rate of diffusion depends upon lipid solubility, pKa, pH, etc. Weak acids at low pH will remain mostly as unionized (lipid soluble) and are easily diffusible across the epithelium and vice-versa. o Carrier Mediated Reabsorption: Uric acid is an example of organic compound that is secreted and reabsorbed by carrier dependent mechanism and can be influenced by certain drugs (Probenecid, Sulfinpyrazone, etc.) |
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What Edematous states call for clinical application of antidiuretics?
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• CHF
• kidney disease • hepatic cirrhosis |
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What nonedematous states call for clinical application of antidiuretics?
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• hypertension
• nephrolithiasis • hypercalcemia • diabetes insipidus |
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Order of the expected maximum diuretic effect:
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loop >> thiazides >> CA inhibitors > K+ sparing
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How long are Carbonate Anhydrase Inhibitors useful?
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CA inhibitors work only for a few days!
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Neurogenic diabetes insipidus
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treated with desmopressin, a drug that is similar to vasopressin (ADH), yet is a selective activator of V2 receptors in the kidney. Remember that V1 receptors are present in smooth muscle, and their activation leads to vasoconstriction and bronchoconstriction.
In congenital nephrogenic diabetes insipidus, treatment is aimed at reducing urine volume using a low-sodium diet and a thiazide diuretic. This causes natriuresis that produces some contraction of the extracellular fluid volume, decreased glomerular filtration rate, decreased delivery of fluid to the collecting duct, and a decreased urine volume. Amiloride is advantageous in lithium-induced nephrogenic diabetes insipidus if lithium cannot be discontinued. Lithium uncouples the V2 receptor from cAMP production. Amiloride decreases lithium entrance into cells in the collecting tubule. |
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Main causes of High Output CHF
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Hyperthyroidism
Anemia Arteriovenous shunts Thiamine deficiency (beriberi) |
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Main causes of Low Output CHF
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Coronary artery disease, hypertension
Myocardial infarction Persistent arrhythmias Rheumatic heart disease General cardiomyopathy |
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Compare and Contrast Heart work conditions in High and Low output CHF
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High: Heart is healthy but exhausted by working too hard
Low: Heart fails to pump enough blood to meet tissue needs |
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Which type of CHF will benefit from protropic drugs?
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Low Output.
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What type of drug should be used to reduce preload in CHF patients?
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Diuretic or Venodilator
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What type of drug should be used to reduce afterload in CHF patients?
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Arteriodilator
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What type of drug should be used to increase contractility in CHF patients?
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Inotropic drugs
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What is the goal of B-blockers in CHF treatment?
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Reduce Cardiac workload by slowing HR
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Digitalis is 4th most commonly prescribed drug in US. Why is it such a popular glycoside in CHF treatment?
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1. Convenient PHK
2. Alternative routes of administration 3. available measurements of serum levels 4. only glycoside available in US |
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What treatment affects does Digitalis have on CHF heart?
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increased contractility (stroke volume)
- inhibits Na,K-ATPase decreases heart rate increases cardiac output |
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what are the vascular effects of Digitalis?
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Normal heart: vasoconstriction
Failing heart: +contractility => +cardiac output and -baroreceptor activity = vasodilation |
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does Digitalis cause diuresis?
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Only in edematous patients with CHF
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Digitalis - Mechanism of Action
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inhibition of membrane sodium pump Na+,K+-ATPase (also known as the Digitalis receptor)
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Digitalis - major PHK properties
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Oral availability (75% absorbed)
Half-life - 40 hours Renal elimination >80% Narrow margin of safety |
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Digitalis - toxicities
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•Therapeutic dose is 50-60% of the toxic dose
• First signs of intoxication are GI: anorexia, nausea, vomiting, diarrhea, abdominal discomfort, copious salivation • Most dangerous are cardiac toxicity: various arrhythmias including sinus bradycardia, ectopic ventricular beats, AV block, and bigeminy. Ventricular fibrillation is the most common cause of death • CNS side effects: headache, fatigue, malaise, drowsiness, trigeminal neuralgia, disorientation and hallucinations, color and visual disturbances occur occasionally in the elderly • skin rashes, eosinophilia, and gynecomastia are rare |
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How do you treat Digitalis toxicity?
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o discontinuing Digitalis administration;
o oral or intravenous potassium (never calcium!!!); o lidocaine, phenytoin, or propranolol; and o immunotherapy with Digitalis Immune Fab |
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Digitalis Drug Interactions?
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pharmacokinetic interactions may either enhance toxicity or reduce effectiveness:
• enhance toxicity by: • ↓ digoxin renal clearance or volume of distribution (quinidine, amiodarone, captopril, verapamil, diltiazem, cyclosporine) •↑ digoxin GI absorption (erythromycin, omeprazole, etc.) •reduce toxicity by •↓ digoxin GI absorption (cholestyramine, bran, etc.) •pharmacokinetic interaction with quinidine often occurs: o because quinidine displaces digoxin from tissue binding sites and depresses its renal clearance therefore toxicity results from increased plasma digoxin levels •pharmacodynamic interactions that may enhance toxicity include: o diuretics which ↓ serum and tissue K+ , hypokalemia often occurs with thiazide or loop diuretics o β-adrenergic antagonists which ↓ SA or AV node activity o calcium-channel antagonists which ↓ myocardial contractility o catecholamines which may sensitize the myocardium to digoxin |
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Digitalis - special considerations?
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Elderly more susceptible to toxicity
Infants require %50 dose than weight ratio suggests due to high metabolism Hyperthyroidism predisposes to toxicity |
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Phosphodiesterase inhibitors (bipyridines) - Group members?
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Inamrinone (Inocor)
milrinone (Primacor) |
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Bipyridines- Mechanism of Action
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inhibit cAMP phosphodiesterase isozyme in cardiac and vascular muscle, which normally degrades cAMP
• increased diastolic function and myocardial contractility |
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Bipyridines- major PHK properties
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administered IV or orally
liver metabolism and urinary excretion |
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Bipyridines- toxicities
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chronic oral inotrope therapy did not consistently alleviate symptoms, but did increase the risk of mortality and hospitalization
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Bipyridine - Uses/Therapuetic Effects?
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Use in CHF patients who can be closely monitired and have not responded to conventional therapy (digitalis, diuretics, and/or vasodilators).
- increased cardiac output - decreased pulmonary capillary wedge pressure - decreased vascular resistance - mild-to-moderate increases in heart rate, w/o increase in myocardial O2 consumption |
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Bipyridines- special considerations?
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also referred to as inodilators
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Sympathomimetics - members of the group?
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Dopamine (Intropin)
Dobutamine (Dobutrex) Calcium sensitizers (Levosimendan, pimobendan) |
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Sympathomimetics - mechanism of action
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D1 receptors. Sympathetic response
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Sympathomimetics - uses/effects
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• It is useful in acute heart failure following cardiovascular surgery and in severe refractory congestive heart failure
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Sympathomimetics - actions on cardiac and other tissues
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• Exerts positive inotropic effect due to a direct action on the heart
• In low doses, it increases cardiac output. and renal blood flow • Lowers peripheral resistance • Enhances sodium excretion |
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Sympathomimetics - major PHK properties
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• IV administration
• renal excretion |
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How is Dopabutamine different than Dopamine
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• selective beta-1 agonist
• positive inotropic effect, somewhat less tachycardia • reduced filling pressure and increased oxygen consumption |
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Calcium sensitizers are experimental drugs. What are their promising benefits?
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• increase cardiac tissue sensitivity to calcium without increasing tissue concentrations of calcium;
• inhibit phosphodiesterase III and sensitizes troponin-C myofilaments to intracellular calcium ions; • Uses: under review for the management of acute and chronic congestive heart failure (ongoing clinical studies: SURVIVE, REVIVE) |
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In treatment of CHF, what drugs groups do not have positive inotropic effects?
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1. Diuretics
2. ACE Inhibitors 3. Beta blockers 4. Vasodilators |
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What benefits do diuretics have in treating CHF?
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• reduce salt and water retention
• reduce venous pressure • reduce edema • lead to reduction of cardiac size |
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What role do Thiazides play in treating CHF?
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maintenance therapy
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What is hBNP?
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human B-type natriuretic peptide
produced by the ventricular muscle elevated in patients with heart failure |
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Explain Nesiritide (Natrecor) in treating CHF?
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• intravenous recombinant purified preparation of human B-type natriuretic peptide (hBNP),
• indicated for the acute treatment of decompensated congestive heart failure (CHF), • has primarily been studied in patients with elevated pulmonary capillary wedge pressure (i.e., PCWP > 18—20 mmHg). • reduces PCWP and improves the symptoms of heart failure, including global clinical status, dyspnea, and fatigue • clinical trials show pts do not tolerance to nesiritide as they do to IV nitroglycerin • may cause symptomatic hypotension, a serious dose-limiting effect |
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ACE Inhibitors - members of the group?
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Captopril (Capoten)
Enalapril (Vasotec) Losartan (Cozaar) - Agiotensin II receptor inhibitor |
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ACE Inhibitors - mechanism of action
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counteract increased renin-angiotensin system activity during CHF
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ACE Inhibitors - uses/effects
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• chronic ACE inhibitor and angiotensin receptor inhibitor therapy can reduce CHF mortality by 28-40 %
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ACE Inhibitors - actions on cardiac and other tissues
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diminish cardiac workload by:
• decreasing afterload - ↓ angiotensin-vasoconstriction • decreasing preload - ↓ aldosterone release (↓sodium retention) |
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What are the three major effects of angiotensin II?
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1. Altered Peripheral Resistance = Vasoconstriction => Rapid Pressor Response
2. Altered Renal Function = Sodium Retention => Slow Pressor Response 3. Altered cardiovascular Structure => Vascular and Cardiac Hypertrophy and Remodeling |
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ACE Inhibitors - toxicities
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• dry cough may occur with ACE inhibitors but not with losartan
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Beta Blockers - members of the group?
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Bisoprolol (Zebeta)
Carvedilol (Coreg) Metoprolol (Lopressor) |
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Beta Blockers - mechanism of action
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Blocks beta receptors… DUH!
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Beta Blockers - uses/effects
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• patients with diastolic dysfunction or cardiomyopathies (without severe CHF) respond favorably to beta blockers (decreased heart rate, improved ejection)
• studies have shown reduction of mortality in stable class II and III CHF, probably because of o attenuation of the effects of high concentration of catecholamines o up-regulation of beta receptors o decreased heart rate o reduced remodeling o antiarrhythmic effect (many of the other antiarrhythmic agents don’t have similar beneficial effects!!!) |
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Beta Blockers - actions on cardiac and other tissues
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o up-regulation of beta receptors
o decreased heart rate o reduced remodeling o antiarrhythmic effec |
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Beta Blockers - toxicities
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dangerous in severe CHF because of their negative inotropic effect
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Vasodilators - members of the group?
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Sodium nitroprusside (Nitropress)
Hydralazine (Apresoline) Isosorbide dinitrate (Isordil) |
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Vasodilators - mechanism of action
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Sodium nitroprusside - dilates veins and arteries
nitroglycerin or isosorbide dinitrate - dilates veins more than arteries hydralazine - peripheral vasodilator; relaxation of arteriolar smooth muscle |
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Vasodilators - uses/effects
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reduction in preload (through venodilation), afterload (through arteriolar dilation) or both.
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Vasodilators - actions on cardiac and other tissues
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reduced preload
reduced afterload reduced remodeling hydralazine-induced reflex autonomic response increases heart rate, cardiac output, and left ventricular ejection fraction |
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Vasodilators - major PHK properties
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sodium nitroprusside is infused intravenously
nitroglycerin or isosorbide dinitrate given orally |
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Vasodilators - toxicities
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excessive hypotension
tolerance |
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Vasodilators - special considerations
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tolerance precludes their long-term use; however, some evidence suggests that long term use can also reduce damaging remodeling of the heart
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what consititues an arrhythmia?
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electrical irregularities of the heart (origin, rate, rhythm and conduction of the impulse)
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which parts of heart have Fast Response Fibers?
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• Atria
• Ventricles • Bundle of His • Purkinje cells |
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which parts of heart have Slow Response Fibers?
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• S-A Node
• A-V Node |
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What are the four Electrical properties of cardiac cell?
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1. Excitability
2. Automaticity 3. Effective Refractory Period (ERP) 4. Action Potential Duration (APD) |
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Define and describe Excitability of cardiac cell
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Excitability is the ability of a myocardial cell to respond to a stimulus by producing an action potential. Excitability is intimately related to threshold potential. The threshold potential is the membrane potential to which the cell must be depolarized to initiate phase 0 depolarization.
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Define and describe Automaticity of cardiac cell
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the cell's inherent ability to initiate a cardiac impulse.
Several regions of myocardium, such as S-A node, A-V node, Bundle of His, and Purkinje cells possess automaticity. Normally, the automaticity of the S-A node is the highest. Hence, the S-A node is the primary pacemaker. The discharge rates of other cells (A-V node, Bundle of His, Purkinje fibers) are lower. |
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Define and describe ERP of cardiac cell
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ERP is the shortest interval at which a premature stimulus results in a propagated response. The ERP usually includes phase 0, 1, 2 and most of 3. ERP can be either increased or decreased by several types of drugs (catecholamines, cholinergic drugs, digitalis and antiarrhythmic drugs).
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Define and describe APD of cardiac cell
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Action potential duration is the time interval between the point of depolarization and repolarization. Normally, the ERP and APD are closely linked.
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Define and describe the phases of Action Potential generation in the cardiac cell
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Phase 0 -- opening of the sodium channels, rapid depolarization, inactivation of the sodium channels; (in SA and AV node, the 0 Phase is Ca++ current dependent (slow response)
Phase 1 -- rapid partial repolarization due to the inactivation of fast sodium channels Phase 2 -- plateau phase, calcium channels are open Phase 3 -- repolarization, calcium channels inactivated, potassium channels open, sodium channels turning to rested state Phase 4 -- resting membrane potential, spontaneous depolarization |
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What is the aim of antiarrhythmiac therapy?
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• reduce ectopic pacemaker activity
• modify conduction or refractoriness to disable reentry |
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What are the mechanisms of antiarrhythmiac therapy?
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• sodium channel blockade
• blockade of sympathetic effects • prolongation of the effective refractory period • calcium channel blockade |
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What are the Main features of antiarrhythmic drugs
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• decrease 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 the sodium and calcium channels of depolarized 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 norepinephrine (NE) |
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What mechanism do all Class I antiarrhymics have in common?
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all block sodium channels
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Who are the Class IA antiarrhymics and what is their mechanism of action and primary effect?
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Drugs: quinidine, procainamide, disopyramide
Mechanism: preferentially blocks open or activated sodium channels Effect: lengthens the duration of action potential (ERP ↑ ) |
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Who are the Class IB antiarrhymics, what is their mechanism of action and primary effect?
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Drugs: lidocaine, mexiletine, tocainide, phenytoin
Mechanism: blocks inactivated sodium channels Effect: shortens the duration of action potential (ERP ↓) |
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Who are the Class IC antiarrhymics, what is their mechanism of action and primary effect?
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Drug: flecainide
Mechanism: blocks all sodium channels Effect: no effect on the duration of action potential (ERP ∅) |
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Who are the Class II antiarrhymics, what is their mechanism of action and primary effect?
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Drugs: Beta blockers
Mechanism: block beta receptors (DUH) Effect: reduces adrenergic activity on the heart |
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Who are the Class III antiarrhymics, what is their mechanism of action and primary effect?
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Drugs: bretylium, sotalol, amiodarone
Mechanism: K+ channel inhibitors Effect: extend ERP |
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Who are the Class IV antiarrhymics, what is their mechanism of action and primary effect?
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Drugs: verapamil, diltiazem, bepridil
Mechanism: calcium channel blockers Effect: decrease heart rate, contractility |
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What is the prototype Class IA Agent
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Quinidine (Cardioquin)
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Quinidine - mechanism of action
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o binding to open and activated sodium channels (“state dependent” blockade)
o decreasing the myocardial automaticity and membrane responsiveness o increasing the diastolic threshold o slowing maximal rate of rise of the cellular action potential (Vmax of 0 phase) o prolonging the Action Potential Duration (APD) Prolonging the Effective Refractory Period (ERP) o increasing the ratio of ERP/ADP and preventing the closely coupled "re-entry circuit" in the Purkinje fibers o blocking K+ channels (prolongs depolarization) |
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Quinidine - other cardiac effects
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o Quinidine causes muscarinic receptor blockade, which can increase HR and AV conduction
o Quinidine causes certain EKG changes - such as widening of QRS and QT intervals, etc. These are the manifestations of toxicity o Quinidine causes S-A block, A-V block, ventricular, arrhythmia, and severe hypotension at toxic doses. |
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Quinidine - PHK
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• oral administration is most common, relatively safe and rapid in onset
• absorption is essentially complete • bioavailability is variable due to "first pass" effect • I.V. administration is hazardous (causes severe hypotension), I.M. injection is painful • maximal blood levels are reached in 90 minutes • about 80% of the drug is metabolized by the liver, 20% is excreted through the kidney • t1/2 is about 6 hours. The t1/2 is prolonged in congestive heart failure or in renal insufficiency • 70%-80% quinidine is plasma protein bound • a major metabolite of quinidine is also active |
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Quinidine - Toxicity
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• quinidine is a potentially dangerous drug with a low therapeutic index.
• cardiac toxicity is the most significant, often life threatening. • quinidine causes severe hypotension and shock-like effect by virtue of its alpha-adrenergic receptor blocking action. • paradoxical tachycardia ("anticholinergic" effect) • quinidine syncope and death: This occurs mostly in those patients receiving digitalis and quinidine together. Patients with long QT interval are at great risk. • torsade de pointes • diarrhea, nausea and vomiting is the most often seen extracardiac toxicity • Cinchonism: Loss of hearing, angioedema, vertigo, tinnitus, visual disturbances, thrombocytopenic purpura, vascular collapse. |
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Contraindications to quinidine therapy
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• Pre-existing complete A-V block (ventricular arrest may take place).
• Thrombocytopenia associated with previous quinidine therapy (allergic response). |
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Quinidine - Therapeutic Use
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broad spectrum antiarrhythmic drug effective for acute or chronic treatment of varieties of supraventricular and ventricular arrhythmias.
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Quinidine - Drug interactions
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• Drugs like phenytoin and phenobarbital which induce hepatic microsomal enzymes are likely to shorten the duration of action of quinidine by increasing its metabolism
• quinidine may increase prothrombin time in patients receiving oral anticoagulant warfarin therapy • quinidine and nitroglycerin will produce a significant vasodilation and fall in blood pressure • increased plasma K+ may enhance the toxic effect of quinidine • quinidine may exaggerate skeletal muscle weakness, or increase the paralyzing effect of curare and curare-like drugs, aminoglycosides |
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Procainamide - general differences from Quinidine
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• short duration of action
• high incidence of adverse reactions upon chronic use • can be administered safely I.V. • procainamide may be useful in patients with severe ventricular arrhythmias who are unresponsive to lidocaine |
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Procainamide - mechanism and other cardiac effects
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like Quinidine
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Procainamide - PHK
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• well absorbed after oral administration
• can be administered safely I.V. • peak plasma levels: 15-60 minutes • protein binding: 20% • half-life: 3-5 hours • t1/2 is prolonged in renal insufficiency, hepatic disease and congestive heart failure • metabolism: acetylated to active n-acetyl procainamide (NAPA) in the liver • the rate of acetylation is under genetic control and shows bimodal distribution into "slow" and "fast" acetylators; fast acetylators have higher plasma ratio of NAPA/ procainamide • about 40-60% is excreted in the urine |
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Procainamide - Toxicity
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• in general, like quinidine, including precipitation of new arrhythmias, torsade de pointes
• anorexia, nausea, and vomiting (but procainamide is better tolerated than quinidine in some patients) • Systemic Lupus Erythematosus-like Syndrome (SLE) in about 30% of patients during prolonged use • procainamide causes an increased titer in antinuclear antibodies (ANA) in about 30% of patients • occasional hypersensitivity (rash, urticaria, fever, agranulocytosis, pancytopenia) may be seen • rarely, mental disturbances (depression, hallucination, psychosis) |
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Contraindications to Procainamide therapy
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• Do not use procainamide in complete A-V block
• Use it with great caution in partial A-V block |
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Procainamide - Therapeutic Use
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To treat a wide variety of cardiac arrhythmias such as:
o Ventricular arrhythmias -except those resulting from digitalis intoxication o Supraventricular arrhythmias - atrial flutter and atrial fibrillation, etc. |
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Disopyramide - general differences from Quinidine
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• Disopyramide is structurally unrelated to other commonly used anti-arrhythmic agents like quinidine and procainamide.
• Disopyramide is likely to reduce cardiac index. • Disopyramide is effective in the management of unifocal, multifocal and paired premature ventricular contractions as well as the episodes of ventricular tachycardia |
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Disopyramide - mechanism and other cardiac effects
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• mechanism of action of disopyramide is comparable to quinidine i.e., Na+ channel blockade
• prolongs the Effective Refractory Period (ERP), increases the electric threshold, depresses the conduction velocity • high doses of disopyramide may depress myocardial contractility |
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Disopyramide - PHK
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• administered orally, no significant adverse hemodynamic effects following oral administration
• about 16% is metabolized on the "first pass" through the liver • peak effect 2-4 hours • plasma half-life 6-8 hours, markedly increased in patients with renal insufficiency • 80% is excreted in the kidney in 72 hours (45% as unchanged drug) • 40% protein binding |
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Disopyramide - Toxicity
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• prolongation of QT-interval and prominent U waves
• widening of QRS complex, increased P-wave duration • ventricular arrhythmias, including torsade de pointes and syncope • increases His-Purkinje conduction time but does not affect A-V conduction time • significant negative inotropic effect, aggravates heart failure • anticholinergic effects: dry mouth, urinary hesitancy, constipation, blurred vision, contraindicated in glaucoma • nausea, vomiting, abdominal pain, headache, edema, weight gain, dizziness and fatigue |
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Contraindications to Disopyramide therapy
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• do not use disopyramide in sick sinus syndrome
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Disopyramide - Therapeutic Use
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ventricular tachycardia
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What is the prototype Class I B Agent
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Lidocaine (Xylocaine)
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Lidocaine - mechanism of action
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• binds to the inactivated sodium channels, fast binding and dissociation
• decreases APD, shortens ERP due to block of the slow Na+ “window” currents |
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Lidocaine - other cardiac effects
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• lidocaine has no significant effects on QRS, QT intervals
• it causes less hypotension than procainamide • It has little or no depressant action on myocardial contractility • it has no vagal blocking action like that of quinidine, procainamide or disopyramide • antiarrhythmic action develops immediately after I.V. loading dose and declines rapidly upon discontinuation of infusion. • lidocaine is relatively free of hemodynamic and cardiac complications • cannot be used orally (first pass metabolism), therefore, is not suitable for maintenance or in an outpatient setting • lidocaine is not effective for supraventricular arrhythmias |
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Lidocaine - PHK
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• I.V. only
• I.V. - loading dose (bolus) is 50 mg - 100 mg (1 mg/kg) at a rate of 25-30 mg/minute. Boluses of above strength may be given every 3-5 minutes until the desired effect is achieved or side effects appear. To maintain anti-arrhythmic effect, I.V. infusion must be maintained at a rate of 1-4 mg/minute • onset of action – 1-2 minute • duration of anti-arrhythmic effect – 0-20 minutes • serum t½ - 8-9 minutes (initial active phase of distribution). To maintain serum levels achieved by the bolus, start I.V. infusion within 10 minutes • t½ of second phase - 1.5 - 2 hours • metabolism - primarily in the liver. (90-95%) • excretion - Less than 5% unchanged drug in the urine • therapeutic level – 1-5 mg/ml, toxic level – 6-10 mg/mg |
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Lidocaine - Toxicity
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• minor side effects are lightheadedness, tinnitus, muscle twitches, blurred double vision
• CNS depression, stupor, restlessness, euphoria, hypotension, and convulsion • infrequently bradycardia and aggravation of arrhythmia may occur • very large doses may depress myocardial contractility and A-V conduction (least negative inotropic among the antiarrhythmics) |
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Contraindications to Lidocaine therapy
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• Untoward effects are seen mostly in patients with hepatic disease and congestive heart failure, etc.
• Supreaventricular arrythmias |
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Lidocaine - Therapeutic Use
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use of Lidocaine is limited to the treatment of arrhythmias of ventricular origin
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Phenytoin - mechanism of action
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• binding to active and inactivated sodium channels
• shortens ERP |
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Phenytoin - other cardiac effects
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• depression of myocardial automaticity
• does not depress conduction at A-V system or in the ventricles • little or no depressant effect on myocardial contractility at therapeutic doses • hypotension occurs only on rapid I.V. injection |
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Phenytoin - PHK
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• oral and parenteral administration
• complex pharmacokinetics: lower doses first order, higher doses saturation (zero order) kinetics • onset: within one hour following I.V. loading dose (20 mg/kg); 2-24 hours following oral loading dose of 1 gram • protein binding: 95% (source of interactions) • serum t1/2: 18-24 hours • metabolism: in the liver to inactive metabolites, induces P-450 system • excretion: 75% in urine as metabolites; 1% unchanged in urine • therapeutic level: 20 μg/mL |
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Phenytoin - Toxicity
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• dose related toxic effects are nystagmus, ataxia, slurred speech, mental confusion.
• dizziness and transient nervousness which will disappear at reduced dose or on slow administration • phenytoin elevates blood glucose level at higher doses • dermatological manifestations, fever, rash, blood dyscrasia, toxic hepatitis, liver damage |
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Contraindications to Phenytoin therapy
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• patients with renal insufficiency and diabetes are more susceptible
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Phenytoin - Therapeutic Use
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• phenytoin is a classical antiepileptic drug (anti-grand mal drug) and may also be useful in the treatment of ventricular arrhythmias induced by digitalis toxicity
• since the introduction of digitalis immune fab, its use has declined • short term administration as an antiarrhythmic agent |
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Phenytoin - Drug interactions
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• warfarin, disulfiram, phenylbutazone, INH, etc. inhibit the metabolism of phenytoin and enhance its toxicity
• Induces the P450 system, enhances the metabolism of many drugs (amiodarone, carbamazepine, clozapine, dihydropyridine Ca++ channel blockers, fluvoxamine, imipramine, etc.) • phenytoin may induce folic acid deficiency |
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Tocainide - mechanism of action
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• blockade of the fast sodium channels
• orally active antiarrhythmic agent similar in action to lidocaine and primarily useful in ventricular arrhythmias. • well absorbed: 90% bioavailability; no significant "first pass", hepatic metabolism |
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Tocainide - PHK
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• well absorbed orally: 90% bioavailability; no significant "first pass", hepatic metabolism
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Tocainide - Toxicity
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• mostly on CNS and G.I. - not serious
• leukopenia, thrombocytopenia and agranulocytosis, etc. are drug related • may increase ventricular rate in patients with atrial flutter or atrial fibrillation • may aggravate congestive heart failure and conduction disturbances |
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Tocainide - Contraindications
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• allergy to lidocaine like drugs; and second or third degree heart block
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Tocainide - Therapeutic Use
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• for all kinds of symptomatic ventricular ectopia and ventricular arrhythmias, however, it does not prevent sudden death
• may be useful in patients refractory to quinidine, procainamide, disopyramide, propranolol, etc. |
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Mexiletine - mechanism of action
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• oral, local anesthetic-type antiarrhythmic agent similar to lidocaine and tocainide
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Mexiletine - PHK
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• no extensive first pass metabolism upon oral use
• t½ about 12 hours |
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Mexiletine - Toxicity
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Minor CNS effects; tremor, dizziness, blurred vision, hypotension, bradycardia, etc.
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Mexiletine - Therapeutic Use
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• For acute or chronic ventricular arrhythmias. Useful in patients resistant to lidocaine
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What is the prototype Class I C Agent
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Flecainide
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Flecainide - mechanism of action
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• binds to all sodium 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 without affecting the surrounding myocardial tissue |
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Flecainide - PHK
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• oral absorption is good
• no extensive plasma protein binding • t½ is about 13 hrs. for single dose; 16 hrs. for multiple doses • no "first pass" metabolism • excreted by the kidney - partly metabolized |
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Flecainide - Toxicity
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• most common - blurred vision
• dizziness, nausea, palpitation, tremors, paresthesia, metallic taste occurs • worsening of heart failure, prolongation of PR interval and QRS complex • risks of proarrhythmic effects in some patients (4-12%) particularly those with ventricular dysfunction (increased ventricular ectopia, ventricular tachycardia, and V. fibrillation, etc.) see Cardiac Arrhythmia Suppression Trial (CAST) |
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Flecainide - Contraindications
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• pre-existing A-V block (II or III degree)
• patients with cardiogenic shock • congestive heart failure |
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Flecainide - Therapeutic Use
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• life-threatening ventricular arrhythmias
• for conversion to and/or maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter associated with disabling symptoms and without structural heart disease • prevention of various forms of paroxysmal supraventricular tachycardia (PSVT) caused by both reentrant and non-reentrant mechanisms. |
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Propafenone - Special considerations
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• Class I C Agent
• similar to flecainide • oral antiarrhythmic agent • high “first pass” metabolism • slow and fast metabolizing phenotypes • Use of propafenone should be reserved for refractory patients with severe, life-threatening arrhythmias because the Ic agents have been shown to possess proarrhythmic characteristics! |
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Moricizine - Special considerations
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• oral class IC antiarrhythmic agent.
• chemically unrelated to any other antiarrhythmic • although sometimes referred to as a class IC agent, classification of moricizine within the class I antiarrhythmics is difficult since the drug has electrophysiologic features of all three subclasses, class IA, IB, and IC • indicated for the treatment of life-threatening ventricular arrhythmias |
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What is the prototype Class III Agent
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Amiodarone (Cordarone)
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Amiodarone - mechanism of action
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• blocks potassium channels (Class III)
• binds to inactivated sodium channels (Class I) • some calcium channel blocking effect (Class IV) • powerful inhibitor of abnormal automaticity • slows sinus rate, conduction and prolongs QT and QRS • causes peripheral vasodilatation (alpha blocking effect) |
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Amiodarone - PHK
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• oral or I.V. administration
• extensive distribution (Vd = 70 L/kg) • half-life: 13-103 days!!! • loading takes 15-30 days • liver metabolism |
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Amiodarone - Toxicity
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• bradycardia, heart block, heart failure
• pulmonary fibrosis (5-15%) at higher doses • deposited in tissues, cornea (yellowish-brown), skin (grayish-blue), photodermatitis • thyroid disfunction • liver toxicity • constipation |
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Amiodarone - Therapeutic Use
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• effective against both supraventricular and ventricular arrhythmias
• considered for patients receiving ACLS for ventricular fibrillation/pulseless ventricular tachycardia; • ACLS algorithms also include amiodarone as a recommended antiarrhythmic for the treatment of stable ventricular tachycardia during cardiopulmonary resuscitation • although amiodarone possesses many adverse effects, some of which are severe and potentially fatal, it has not been associated with proarrhythmic effects as frequently as other antiarrhythmics have |
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Which Drugs slow phase 3 repolarization:
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thioridazine
TCA-s Class I A Class III |
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Which antiarrythmic drug will not cause torsades the points
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Amiodarone
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Sotalol - Special considerations
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• racemic mixture of isomers
o l-isomer: nonselective beta blocker (Class II) o d-isomer: prolongs action potential duration (Class III) • has no intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity (Class I) • used in ventricular and supraventricular arrhythmias • orally effective, excreted by the kidney Toxicity: • adverse effects of beta receptor blockade • torsade de pointes |
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Ibutilide - Special considerations
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• intravenous Class III antiarrhythmic agent
• indicated for rapid conversion of atrial fibrillation or atrial flutter to normal sinus rhythm • ibutilide exerts its actions by promoting the influx of sodium through slow inward sodium channels and prolongs the action potential duration • causes a mild slowing of the sinus rate and AV conduction. • converts atrial fibrillation or flutter to normal sinus rhythm without altering blood pressure, heart rate, QRS duration, or PR interval. |
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Bretylium - mechanism of action
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• parenteral Class III antiarrhythmic agent
• increases the action potential duration without affecting 0 phase depolarization or resting membrane potential of ventricular tissue • causes an initial increase in blood pressure and heart rate; these effects are short-lived and are followed by adrenergic blockade resulting in vasodilation and, commonly, hypotension. |
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Bretylium - PHK
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• administered via IV or IM injection
• duration of action 6-24 hours, • antifibrillatory effects beginning within minutes following IV injection, and suppression of ventricular tachycardia beginning within 20 minutes-6 hours following IM or IV injection. • 70-80% is excreted unchanged in the urine • half-life in patients with normal renal function is 4-17 hours, while the half-life in patients with impaired renal function is 31-105 hours. Bretylium clearance is directly correlated with creatinine clearance. |
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Bretylium - Toxicity
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• hypotension and orthostatic hypotension are the most common adverse cardiovascular
• increased arrhythmias (e.g., premature ventricular contractions (PVCs), ventricular tachycardia) • sinus bradycardia, sensation of substernal pressure, and precipitation of angina |
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Bretylium - Therapeutic Use
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ventricular fibrillation and unstable ventricular tachycardia, although it is not considered a first-line agent
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Dofetilide - mechanism of action
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• selective and potent blocker of potassium channels and prolongs ventricular refractoriness
• lacks negative inotropic properties |
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Dofetilide - PHK
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• administered orally, bioavailability is greater than 90%
• maximal plasma concentrations occurring in about 2—3 hours in fasted patients • half life of dofetilide is approximately 10 hours; • 80% of a single dose of dofetilide is excreted in urine |
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Dofetilide - Toxicity
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• serious arrhythmias and cardiac conduction disturbances may occur with dofetilide
• torsade de pointes and QT prolongation • ventricular fibrillation • headache, chest pain, dizziness, respiratory tract infection, dyspnea, influenza syndrome, insomnia |
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Dofetilide - Therapeutic Use
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• class III antiarrhythmic used for the conversion and maintenance of normal sinus rhythm in atrial fibrillation/flutter
• primarily effective for supraventricular arrhythmias |
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What is the prototype Class IV Agent
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Verapamil
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Verapamil - mechanism and effects
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• blocks slow cardiac Ca++ channels
• slows AV nodal conduction, decreases heart rate • the atrial arrhythmias that depend upon A-V-Nodal Re-entry are interrupted • most pronounced effects are on the heart, less on the periphery • effective in supraventricular tachyarrhythmias • causes peripheral vasodilation, and relaxes smooth muscle • also an effective antihypertensive and antianginal agent |
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Verapamil - PHK
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• administered I.V. or orally
• up to 70% of administered dose is excreted by the kidneys • undergoes "first pass" hepatic metabolism after oral use |
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Verapamil - Toxicity
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• minimal after oral use
• G.I. intolerance, constipation are more common • bradycardia, negative inotropic effect, A-V block, etc. may be encountered upon I.V. use • contraindicated in the presence of CHF and A-V conduction defects • avoid combined use of Verapamil and beta-blockers, since both drugs will markedly reduce ventricular contractility, and enhance A-V transmission failure |
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Verapamil - Contraindications
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Only use for supraventricular tachycardia. Administration to patients with ventricular tachycardia can cause ventricular fibrillation, severe hemodynamic deterioration, or death.
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Verapamil - Therapeutic Use
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• reentrant supraventricular tachycardia is the major indication for Verapamil (adenosine is the drug of choice).
• reduces ventricular rate in atrial flutter and atrial fibrillation • it is rarely effective in ventricular arrhythmias |
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Diltiazem - mechanism and effects
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• calcium-channel blocking agent most similar to verapamil
• inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes • reduces heart rate • increases exercise capacity and improves multiple markers of myocardial ischemia • may increase cardiac output (decreased peripheral resistance), reduces left ventricular workload • improves myocardial perfusion |
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Diltiazem - PHK
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• oral absorption, I.V. available
• dose-dependent kinetics, predisposing patients to accumulation with repeated dosing • half-life of diltiazem ranges from 3.5—9 hours and is usually 4—6 hours |
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Diltiazem - Toxicity
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• similar to those of verapamil
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Bepridil (Vascor) - Special considerations
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• rarely used, primarily to control refractive angina
• prolongs action potential and QT (danger of torsade de pointes) |
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Diltiazem - Therapeutic Use
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• in the treatment of paroxysmal supraventricular tachycardia and to control of ventricular rate in atrial fibrillation and flutter
• for the management of Prinzmetal's variant angina, stable angina pectoris, hypertension • prevention of injury following angioplasty. |
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Adenosine - mechanism and effects
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• adenosine slows conduction in the A-V node and thereby interrupts "Reentry Pathways" through A-V node.
• the ventricular slowing is not blocked by atropine but may be blocked by caffeine • its mechanism of action involves enhanced K+ conductance and inhibition of cAMP-induced Ca++ influx. |
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Adenosine - PHK
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• Route - I.V. injection
• duration is very short, 10-12 seconds, t½ is less than 10 seconds • Metabolism - Adenosine → Inosine → AMP (inactive) |
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Adenosine - Toxicity
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• very low at recommended dose
• flushing • shortness of breath • chest burning • bronchospasms • headache • hypotension • nausea • paresthesia |
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Adenosine - Contraindications
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• A-V Block
• Sick Sinus Syndrome |
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Adenosine - Therapeutic Use
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• PSVP (dependent upon reentry pathways)
• Wolff-Parkinson-White Syndrome • Adenosine is currently the drug of choice for prompt management of paroxysmal supraventricular tachycardia (PSVT) because of very high efficiency (90-95%) and very short duration of action. |
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Magnesium - mechanism and effects
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• originally used for patients with digitalis induced arrhythmias who were hypomagnesemic
• has antiarrhythmic effect in patients with normal magnesium levels • may affect potassium, sodium, calcium channels, Na+/K+ATPase, mechanism unknown |
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Magnesium - PHK
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• intravenous administration of magnesium sulfate produces an immediate effect that lasts for about 30 minutes
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Magnesium - Therapeutic Use
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• digitalis induced arrhythmias
• torsade de pointes • the management of seizures and/or hypertension seizures associated with severe toxemia of pregnancy (e.g., eclampsia) |
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Potassium - Special considerations
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• both insufficient and excess potassium are arrhythmogenic
• potassium therapy is directed toward normalizing potassium gradients and pools in the body • increasing serum K+ decreases (depolarizes) resting potential • increasing serum K+ has membrane potential stabilizing action by increased potassium permeability |
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What diuretics are used to control hypertension
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Hydrochlorothiazide (Esidrix)
Metolazone (Mykrox) Indapamide (Lozol) Furosemide (Lasix) Triamterene (Dyrenium) Eplerenone (Inspra) |
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Which antihypertensives act on the vasomotor center of the brain?
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Methyldopa
Clonidine Guanabenz Guanfacine |
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Which antihypertensives act on the sympathetic nerve terminals?
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Guanethidine
Guanadrel Reserpine |
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Which antihypertensives act on the sympathetic ganglia?
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Trimethahpan
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Which antihypertensives act on the B-receptors of the heart?
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Proponol and other B-blockers
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Which antihypertensives act on the Angiotensin receptors of vessels?
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Losartan and other Angiotensin receptor blockers
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Which antihypertensives act on the alpha receptors of vessels?
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Prazosin and other a1-blockers
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Which antihypertensives act on vascular smooth muscle?
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Hydralazine
Minoxidil Nitroprusside Diazoxide Verapamil and other Ca+ channel blockers Fenoldopam |
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Which antihypertensives act on the kidney tubules?
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Thiazides and other diuretics
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Which antihypertensives act on the B-receptors of juxtaglomerular vessels that release renin?
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Proponol and other B-blockers
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Why is it important to adjust lifestyle before starting antiHTN drug therapy?
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life-style modifications will reduce cardiovascular risks and number and doses of antihypertensive medications
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What is the most common cause of failed HTN drug therapy?
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noncompliance.
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What is most important cardiovascular disease risk factor in persons older than 50 years?
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systolic blood pressure of more than 140 mm Hg is a much more important than diastolic blood pressure.
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What is initial initial drug treatment for most patients with uncomplicated hypertension
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Thiazide type diuretics
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What is the antihypertensive polypill?
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one tablet that would include a statin, an ACE inhibitor, a thiazide diuretic, a beta blocker, aspirin, and folic acid
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What are the four groups of Antihypertensive Agents?
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1. Oral diuretics
2. Sympatholytics 3. Direct vasodilators 4. Angiotensin inhibitor |
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Thiazides are diuretics and antihypertensives. What is an important difference in the therapy approaches?
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antihypertensive doses are much lower than those for diuresis
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Hpw do thiazides lower blood pressure? Separate short term effects and long term effects.
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Short term treatment: reducing body sodium stores and decreasing blood volume and cardiac output
Long term treatment: decrease sodium content in muscle cells, and decrease sensitivity to vasopressor agents; activate potassium channels to cause a decline in peripheral resistance |
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therapeutic uses of Thiazide diuretics in HTN pts
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recommended for mild to moderate hypertension
o as monotherapy they will lower blood pressure in 40-60% of patients o in combination they will enhance the efficacy of other antihypertensive drugs |
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Common side efects and toxicities of Thiazide diuretics?
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o impotence (particularly in the elderly)
o gout due to hyperuricemia o increased renin secretion o potassium depletion leading to hypo-kalemia o muscle cramps, o polymorphic ventricular arrhythmia o ischemic ventricular fibrillation o increased plasma lipid concentration o reduced glucose tolerance o others |
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Who are thiazieds most effective for?
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o more effective in African American than in Caucasian hypertensives
o elderly than in younger hypertensives |
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In treating hypertension, why are sympatholytic drugs more effective when combined with a diuretic?
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activate baroreflexes and generally cause sodium retention and are therefore more effective when combined with a diuretic
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Where do sympatholytic drugs act to interrupt efferent sympathetic pathway?
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o medullary centers
o autonomic ganglia o sympathetic neurons o adrenergic receptors |
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What are the Centrally Acting Sympatholytics?
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clonidine (Catapres)
methyldopa (Aldomet) |
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Centrally Acting Sympatholytics - Mechanism of Action
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• unique because they act in the brain as agonists
• stimulate medullary α2 adrenergic receptors to reduce peripheral sympathetic nerve activity • stimulate presynaptic alpha-2 receptors and reduce transmitter release to relevant sites • stimulate postsynaptic alpha-2 receptors and inhibit appropriate neurons • they may act on different groups of cells • sympathetic inhibition lowers BP not only by decreasing vasoconstrictor tone but also by decreasing renal renin secretion • cardiovascular reflexes remain intact • clonidine lowers heart rate and cardiac output more than methyldopa • clonidine act directly, but methyldopa is a prodrug that is converted to α-methylnorepinephrine • these drugs are usually given orally, but clonidine can be used as a transdermal or skin patch |
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Centrally Acting Sympatholytics - Common Adverse Effects
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• sedation and other CNS effects e.g., nausea, dizziness, nightmares, depression, etc.
• xerostomia (dry mouth) is also common • not recommended for monotherapy because of CNS effects • sudden withdrawal of clonidine may cause a hypertensive crisis • clonidine in toxic doses may produce pressor effects (stimulation of alpha-1 receptors) • methyldopa may also produce: • hemolytic anemia with a positive Coombs test • hepatotoxicity • increased prolactin secretion • gynecomastia and lactation |
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Centrally Acting Sympatholytics - Drug interactions
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tricyclic antidepressants (TCA) and yohimbine inhibit clonidine’s therapeutic action
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What are the Adrenergic Neuron Blockers?
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guanethidine (Ismelin)
reserpine (Serpasil) |
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Adrenergic Neuron Blockers - Mechanism of Action
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• act by binding to secretory vesicles that normally store and release norepinephrine in peripheral adrenergic nerve endings
• reserpine o inhibits the active transport of NE into the vesicle o released NE is metabolized by MAO enzyme o serious interaction with MAOIs • guanethidine o taken up by the nerve ending o replaces NE in the vesicles o inhibits exocytosis o interaction with TCAs, cocaine, indirect sympathomimetics • the final effect is the reduction sympathetic activity by preventing norepinephrine release • reduced sympathetic activity causes vasodilation to lower BP • usually given orally • I.V. guanethidine may elevate blood pressure by sudden release of endogenous norepinephrine, may produce hypertensive crisis in pheochromocytoma |
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Adrenergic Neuron Blockers - Common Adverse Effects
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• guanethidine: postural hypotension, fluid retention, diarrhea, and retrograde ejaculation for;
• reserpine: sedation, psychic depression, stuffy nose, dry mouth, and gastrointestinal disturbances for |
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Adrenergic Neuron Blockers - Drug interactions
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• rarely used for monotherapy because of unpleasant side effects
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What are the α1-adrenergic Antagonists?
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prazosin (Minipress),
terazosin (Hytrin) doxazosin (Cardura) tamsulosin (Flomax) |
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α1-adrenergic Antagonists - Mechanism of Action
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• block α1- without affecting α2-adrenergic receptors
• α1-adrenergic block reduces norepinephrine vasoconstriction to dilate both arteries and veins • blood pressure falls because of decreased peripheral resistance • elicit less reflex tachycardia because α2- receptors are unaffected • the non-selective blockers phentolamine or phenoxybenzamine used for diagnosis and treatment of pheochromocytoma. |
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α1-adrenergic Antagonists - Common Adverse Effects
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• postural hypotension may be pronounced with the first dose (“first dose phenomenon”)
• other side-effects are mild and infrequent; may include: drowsiness, dizziness, palpitations, headache, and fatigue • sodium and water retention (renin ↑) • do not adversely effect plasma lipids, may be beneficial |
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What are the ß-adrenergic Antagonists?
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Nonspecific:
Propranolol (Inderal) Timolol (Blocadren) Nadolol (Corgard) Cardio specific or beta1-blockers: Metoprolol (Lopressor) Atenolol (Tenormin) Nebivolol (Bystolic) Acebutolol (Sectral) Bisoprolol (Zenate) Beta-blockers with Intrinsic Sympathetic Activity (ISA): Pindolol (Visken) Acebutolol (Sectral) Penbutolol (Levatol) Alprenolol (Aptin), Oxprenolol (Trasicor) |
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ß-adrenergic Antagonists - Mechanism of Action
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• lower blood pressure by blocking β-adrenergic receptors in the
o heart to reduce cardiac output, o kidneys to reduce renin secretion, and o CNS to reduce sympathetic vasomotor tone • genetic and age effectiveness opposite to diuretics; more effective in: o Caucasian than in African-American hypertensives, and o young than in elderly hypertensives • recommended for monotherapy only in young Caucasian males • combined with other antihypertensive drugs to counteract: o reflex tachycardia o increased renin secretion • nebivolol also modulates the endogenous production of nitric oxide resulting in peripheral vasodilation |
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ß-adrenergic Antagonists - Common Adverse Effects
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• propranolol can cause side-effects that are mainly
o heart and lung (negative inotropic, chronotropic, dromotropic effect, bronchoconstriction) o GI (diarrhea, constipation, nausea, vomiting) o CNS (insomnia, lassitude, nightmares, depression) • β-adrenergic antagonists usually increase exercise tolerance when used for treatment of angina, but by reducing cardiac output, they can also decrease exercise tolerance which is manifested as an earlier onset of fatigue especially in patients with CHF • also may predispose to atherogenesis by: o increasing plasma triglycerides and o decreasing HDL-cholesterol • β-blockade may mask the symptoms of initial hypoglycemia (tachycardia) and delays recovery from hypoglycemia because hypoglycemic responses are mediated by epinephrine |
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ß-adrenergic Antagonists - Contraindications
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o diabetes
o severe congestive heart failure o heart block o asthma |
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What are the Combined α- and β-Adrenergic Blockers?
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labetalol (Normodyne)
carvedilol (Coreg) |
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Combined α- and β-Adrenergic Blockers - Mechanism of Action
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lower BP in hypertensive emergencies by blocking both α- and β-adrenergic receptors (non-selective ß- and α- antagonists)
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Combined α- and β-Adrenergic Blockers - Common Adverse Effects
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• orthostatic hypotension, bronchospasm
• hepatotoxicity (labetalol, used only in emergencies) |
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What are the Vasodilators used in HTN therapy?
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• oral for chronic antihypertensive treatment
hydralazine (Apresoline) minoxidil (Loniten) • intravenous for hypertensive emergencies sodium nitroprusside (Nipride), diazoxide (Hyperstat IV) fenoldopam (Corlopam) |
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Vasodilators - Mechanism of Action
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• act directly on arteriolar smooth muscles to cause relaxation and thus reduce vascular resistance to lower blood pressure
• hydralazine, minoxidil, and diazoxide dilate arteries selectively without relaxing venous smooth muscles • in contrast, nitroprusside dilates both arteries and veins • antihypertensive effects tend to diminish with time because of reflex tachycardia and increased renin secretion • should not be used alone or for monotherapy • most effective when combined with other drugs to prevent undesirable side-effects • hydralazine and minoxidil are given orally in combination with o diuretics to avoid fluid retention and o β-adrenergic blockers to diminish reflex responses. • oral nitrates are no longer used for chronic antihypertensives because they become ineffective as tolerance develops |
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Vasodilators - Common Adverse Effects
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• hypotension from any vasodilator drug may be accompanied by:
o reflex tachycardia and increased myocardial contraction o increased renin secretion o fluid retention o headaches, flushing o palpitations, dizziness • through reflex increases in cardiac output and oxygen demand as well as decreased diastolic pressure, hydralazine or minoxidil may induce angina attacks and myocardial ischemia in patients with coronary artery disease • minoxidil causes hypertrichosis and may have appreciable cardiovascular effects when used topically for male baldness |
