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76 Cards in this Set
- Front
- Back
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What is involved in thrombogenesis as a mechanism of blood coagulation?
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-platelet adhesion, platelet aggregation--> platelet plug
-fibrin (from coagulation pathway): solidifies/stabilizes plug -adenosine diphosphate (ADP) -Eicosanoids: thromboxane A2 (TXA2) and prostacyclin (PGI2) |
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What is invovled in coagulation as a mechanism of blood coagulation?
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-Thrombin (factor IIa):
a. converts fibrinogen to fibrin b.activates factors V, VIII, XI (positive feedback loop) c. platelet activation 'd. activates factor XIII (cross-links fibrin molecules) -tissues factor pathway inhibitor (TFPI) -antithrombin (site of action for heparin) -protein C and Protein S (site of action for warfarin; Ca2+ dependent, anticoagulant proteins) |
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How do you measure clotting time if activateed partial throboplastin (aPTT)? Prothrombin time?
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-aPTT is recalcified plasma +negatively charged phospholipids and particulate substance (kaolin, alumnium silicate)
-surface for coagulation to occur -normal aPTT is 26-33 seconds -prothrombin is recalcified plasma and thromboplastin -normal PT is 12-14 seconds |
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What is involved in fibrin inhibition?
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-a1-antiprotease
-a2-macroglobulin' -a2 antiplasmin -antithrombin |
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What is involved in fibrinolysis?
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-plasminogen-->plasmin (digests fibrin)
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What are indirect thrombin inhibitors (heparin)? chemistry? mechanism of action?
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-unfractionated heparin (UFH), low molecular weight hepatic, fondparinus, monopolsaccharide
-5 unit stricture gives binding ability 1.in the presence of heparin, antithrombin complexes rapidly -inhibits thrombin 2.forms heparin-antithrombin complex |
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What is the pharmacokinetics of indirect thrombin inhibitors (heparin)?
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-USP unit: quantity of heparin that oreveents 1 mL of citrated sheep plasma from clotting for 1 hour after addtion of .2 mL of 1% CaCl2
-intravenous infusion or subcutaneous injection -cleared and degraded by reticuloendothelial system |
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What toxicity can occur with indirect thrombin inhibitors?
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-bleeding (1-33%)
-thrombocytopenia -thrombosis -is not teratogenic -protamine sulfate antagonist |
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What are direct thrombin inhibitors?
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-bind specifically to active site of thrombin
-do not require accessoryy protein (antithrombin) -do not bind to alterenate plasma proteins (platelet factor 4) -includes: Hirudin (lespirudin and desirudin) |
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What are low-molecular weight heparins as indirect thrombin inhibitors?
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-1-10 KD (smaller than thrombin)
-inhibition of factor Xa by antithrombin -diffeerent pharmacokinetic profile (half-life is longer than heparin) |
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What is hirudin (lepirudin and desirudin) as direct thrombin inhibitors? Administration and monitoring?
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-irreversible thrombin inhibitor
-can inactivate fibrin-bound thrombin -administered parenterally, monitored by aPTT |
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What are oral anticoagulants? Chemisty? mechanism of action?
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-vitamin K analog (warfarin sodium)
-slower onset of action than heparin -vitamin K antagonist -occurs in the liver -inhibits carboxylation of vitamin K-dependent clotting factors -inhbits carboxylation of C and S proteins -inhibits carboxylation reactions in othere tissues such as mineralization |
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What is the pharmacokinetics of oral anticoagulants?
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-extensivly protein bount (99%)
-metabolized to active products in liveer -S-enantiomer is potent -half-life is 25-60 hours |
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What is the toxicity of oral anticoagulants?
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-bleeding (antidotes include vitamin K and fresh frozen plasma)
-birth defects -skin necrosis -therapeutic monitoring by prolongation of PT to 1.2-2.5 times normal and internation normalized ratio (INR) |
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What are thrombolytic drugs? chemistry? mechanism of action?
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-plasmin (enzyme that dissolved clots)
-alpha-2-antiplasmin (inactivates plasmin) -tPA released from endothelial cells -binds to fibrin, activatees bound plasminogen -hepatic clearance -half-life is 5-10 min. |
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What is toxicity of thrombolytic drugs?
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-hemorrhge (lysis of fibrin in "physiologic thrombi" and systemic lytic state)
-antidote is aminocaproic acid (lysine analog and inhibits fibrinolysis) |
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What are the antiplatelet drugs?
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-aspirin
-dipyridamole -cilostazol -ticlopidine -clopidogrel |
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What is the mechanism of action of asprin as an antiplatelet drug?
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-prevents thromboxane formation A2-vasoconstriction, platelet aggregation
-irreveersible cyclooxygenase inhibition -causes dialation and anticoagulation |
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What is the mechanism of action of dipyridamole as an antiplatelet drug?
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-vasodilator
-effect in combination with warfarin '-increases platelet cAMP concentration (inhibition of cyclic nucleotide phoisphodieterase and blockade of adeneosine uptake) |
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What is the mechanism of action of ticlopidine/clopidogrel as an antiplatelet drug? toxicity?
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-inhibits the inhibitor
-increased cAMP -irreversbile inhibitor of P2Y12 receptor -prodrug is activated by CYP450 -leukopenia and thrombotic thrombocytopenix purpura can occur with use |
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What is the mechanism of action of cilostazol as an antiplatelet drug?
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-phosphodiesterase inhibitor
-increase cAMP -inhibits platelet aggregation, promotes vasodilation |
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What are glyycoprotein IIb/IIIa receptors?
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-integrin family adhesion recptor
-receptor for fibrinogen,, vitronectin, fibrionectin,, von willebrand factor -links platelets via fibrinogen to form aggregated plug -required for clot retraction |
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What is abciximab as a glycoprotein IIb/IIIa antagonist?
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-fab fragment'
-prevents bidning of fibrinogeen, von willebrand factor -can have hypersensitivity reactions |
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What is tirofiban (aggrastat) and epitifibatide (integrillin) as glycoprotein IIb/IIIa antagonists?
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-based on hemorrhagic snake venom
-RGD sequence (arg-gly-asp), recognized by integrin -intravenous therapy |
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What hormones are involved in renal function?
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-anti-diuretic hormone (collecting tubule and collecting duct
-aldosterone (collecting tubule) (promotes Na+ and K+ excretion) |
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What is involved in calcium transport in renal function?
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1. Proximal tubules – 70%
2. Thick ascending limb of the loop of Henle a. Na+/K+/2Cl- cotransporter b. Lumen-positive electrical potential – Ca2+, Mg2+ reabsorption |
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What is the distal tubule of renal function?
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a. Na+Cl- cotransporter
b. Apical Ca2+ channel c. Basolateral Na+/Ca2+ exchanger |
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What is the chemistry of osmotic diuretics? prototype?
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a. Osmotically active substances in plasma and tubular fluid
b. Prototype – mannitol (urea, glycerine, isosorbide) |
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What is the site of action of osmotic diuretics? Mechanism of action?
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-proximal tubule, descending limb
a. Increase in osmotic pressure in tubular fluid b. Increase in renal blood flow (medulla) |
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What is the pharmacokinetics of osmotic diuretics?
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a. Parenteral
b. Oral --> osmotic diarrhea c. Renal elimination |
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What is the pharmacodynamics of osmotic diuretics?
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a. Water excretion > Na+ excretion --> hypernatremia
b. Extracts water from cells --> ECF volume expansion c. Decrease blood viscosity d. Suppress renin release |
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What are the adverse effects of osmotic diuretics?
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a. Acute ECF volume expansion -->hyponatremia (prior to diuresis)
1) Congestive heart failure 2) Pulmonary edema b. Dehydration |
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What are clinical indications for use of osmotic diuretics?
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a. Increase urine volume (acute renal failure)
b. Reduction of intracranial and intraocular pressures |
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What is the chemistry of carbonic anhydrase inhibitors? prototypes?
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a. Sulfonamide derivatives
b. Prototype – acetazolamide (Diamox) dichlorphenamide (Daranide), methazolamide (Neptazane) |
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What is the site of action of carbonic anhydrase inhibitors? mechanism of action?
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-proximal tubule
-Carbonic anhydrase (1) Type IV – basolateral and luminal membranes (2) Type II – cytoplasm -decreased bicarbonate formation and increased retainment of water |
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What are the pharmacodynamics of carbonic anhydrase inhibitors?
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- increased bicarbonate excretion--> decreased bicarbonate in ECF (metabolic acidosis)
-increase sodium chloride reabsorption-->hyperchloremia -efficacy decreases with use over several days (osmotic pressure by bicarbonate) -increased potassium secretion and excretion--> hypokalemia -decreased renal blood flor and GFR (decreased renin release)-->due to constriction of afferent arterioles |
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What are the adverse effects from use of carbonic anhydrase inhibitors?
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-hyperchloremia--> metabolic acidosis
-renal stones from calcium salts -hypokalemia -allergic reactions (sulfoamide moiety) |
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What are clinical indications for use of carbonic anhydrase inhibitors?
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-for glaucoma with use of topical agents (dorzolamide and brinzolamide)
- for use with urinary alkalinization a. by enhancement of excretion of poorly soluble weak acids (uric acid, cysteine) b. bicarbonate administration preferable - use for metabolic alkalosis -use for acute moutain sickness -adjuvants in epilepsy |
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What is the chemistry of loop diuretics? prototype?
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-high-ceiling diuretics
-furosemide (lasix) -bumetanide (bumex) -torsemide (demedex) |
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What is the site of action of loop diuretics? mechanism of action?
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-Thick ascending Loop of Henle
-inhibition of sodium/potassium/chloride symport -inhibits calcium and magnesium reabsorption -increase in GFR a. synthesis of vasodilatory porstaglandins b. blocks tubuloglomerular feedback -stimulate renin release |
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What are the pharmacokinetics of loop diuretics?
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-tubular secretion of organic anions
-has drug interactions with NSAIDS and probenecid |
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What ar ethe pharmacodynamics of loop diuretics?
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-decrease sodium chloride reabsorption leads to decrease in ECF volume
-decreased calcium and magnesium rebasoprtion leasds to hypomagnesemia and rarely hypocalcemia -stimulates renal prostaglandin synthesis -increase in potassium and hydrogen secretion and excretion |
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What are the adverse effects of loop duretic use?
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-hypokalemia
-hyperuricemia -hypomagnesemia -hypochloremia--> metabolic acidosis -ototoxicity |
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What ar ethe clinical indications for loop diuretic use?
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-chronic congestive heart failure
-acute renal failure or nephrotic syndrome -acute pulmonary edema -anion overdose of bromide fluoride and iodide |
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What is the chemistry of thiazide diuretics? prototype?
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-sulfonamide dereivatives
-hydrochlorothiazide |
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What is the site of thiazide diuretics? mechanism of action?
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-distal convoluted tubule (early distal tubule)
-inhibition of sodium/calcium cotransport |
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What are the pharmacokinetics of thiazide diuretics?
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-secretion of organic anions
-competes with uric acid |
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What are the pharmacodynamics of thiazide diuretics?
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-weak carbonic anhydrase inhibition
-increased calcium reabsortpion and decreased magnesium reabsorption -increased potassium and hydrogen secretion (excretion) -stimulate renal prostaglandin synthesis |
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What are the adverse effects of use of thiazide diuretics?
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-hypokalemia
-hypochloremia (metablic acidosis) -hypomagnesmia -hyperuricemia -carbohydrate intolerance -increase in serum lipid and lipoprotein concentrations |
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What are clinical indications for use of thiazide diuretics?
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-hypertension
-edema (congestive heart failure, cirrhosis, and nepehrotic syndrome) -nephrolithiasis (hypercaciuria and osteoporosis -nephrogenic diabetes isipidus |
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What is the chemistry of potassium sparing diuretics? prototypes?
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-organic bases (amiloride and triameterene)
-mineralocorticoid (spironolactone) |
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What is the site of action of potassium diuretics? Mechanism of action (drug specific)?
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-inhibition of sodium channels in luminal membrane (amiloride)
-competitive antagonist of minercorticoid receptor (spironolactone) |
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What are the pharmacokinetics (metabolism) of potassium diuretics?
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-canrenone is activee metabolite of spironolactone
-4-hydroxytrimterene is active metabolite of trimerterene -amiloride and trimeterene are organic bases |
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What are the pharmacokinetics of potassium diuretics?
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-decrease sodium reabsorption
-decrease potassium secretion leads to hyperkalemia -decrease hydrogen secretion leads to metabolic acidosis |
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What are adverse effects of use of potassium diuretics?
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-hyperkalemia
-metabolic acidosis -spironolactone causes steroid effects via progesterone and androgen receptors (causes gynecomastia, hirsutism, and peptic ulcers) -triameterene is a weak folate antagonist |
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What are clinica;l indications for use of potassium diuretics?
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-primary hyperaldosteronism (conn;s syndome, ectopic ACTH production)
-secondary hyperaldosteronism (heart failure, cirrhosis, and nephrotic syndrome) |
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What is hypertension?
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Systolic pressure > 140 mm Hg, diastolic pressure > 90 mm Hg
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What are the compensatory mechanisms for hypertension?
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-arterioles for resistance
-venules for capacitance -heart for pump output -kidneys for volume and renin-aldosterone secretion |
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What is the angiotensin II formation pathway of the renin-angiotensin II aldosterone system?
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-angiotensinogen-->angiotensin I
-then converts with enzyme kininase II to angiotensin II (vasoconstrictor) -bradykinin (vasodilator) converts to inactive products by enzyme kininase II |
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What are the renin release mechanisms of the renin-angiotensin II aldosterone system?
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1. Macula densa pathway
2. Intrarenal baroreceptor pathway 3. β1 Adrenergic receptor (β1AR) pathway |
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What are the various responses to angiotensin II production and effects from each?
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1. Rapid pressor response:
2. Slow pressor response: 3. Myocardial remodeling: 4. Alteration of renal function: |
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What occurs during rapid pressor response from angiotensin II secretion?
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a. ↑ total peripheral resistance
b. Increased cardiac contractility (voltage-gated Ca2+ channels) c. Increase heart rate (facilitation of sympathetic tone) |
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What occurs during slow pressor response from angiotensin II secretion?
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a. Decrease in renal excretory function (right-shift of renal function curve)
b. Endothelin-1, aldosterone |
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What occurs during the alteration of renal function during the renin-angiotensin II aldosterone system?
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a. AII increases Na+Cl- reabsorption in proximal tubule
b. Stimulates synthesis and secretion of aldosterone c. Decreased renal blood flow |
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What is the chemistry of converting enzyme inhibitors as hypertensive agents? prototype?
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-prototype is lisinopril
-lysine derivative of enalaprilat -has no prodrug |
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What is the mehcanism of action of converting enzyme inhibitors as hyprtensive agents?
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-competitive inhibition of converting enzme (peptidyl dipepidase)
a. ↑ bradykinin levels → ↑ prostaglandin synthesis b. Increase renin release -decreased aldostereone secretion |
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What is the pharmacokinetics of converting enzme inhibitors as antihypertensive agents?
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1. t1/2 = 12 h
2. Renal elimination |
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What are thee adverse effects of using converting-enzyme inhibitors as antihypertensive agents?
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1. Angioedema (0.1-0.2%)
2. Cough (5-20%) 3. Hypotension (orthostatic) 4. Fetopathic potential |
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What are clinical indications for use of converting enzyme inhibitors as antihypertensive agents?
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1. Hypertension
2. Diabetic nephropathy 3. Heart failure, myocardial infarction |
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What is the chemistry of angiotensin II recector blockers as antihypertensive agents? Prototype?
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-Losartan
-no produg -potassium salt |
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What is the mechanism of action of angiotensin II receptor blockers as antihypertensive agents?
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a. Competitive binding to AT1R
b. Insurmountable inhibition of biological responses 2. Inhibit all responses to Angiotenesin II |
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What are the adverse effects of use of angiotensin II receptor blockers as antihypertensivee agents?
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-hypotension
-hyperkalemia -fetopathic potential |
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What are the comparisons between angiotensin-convertting enzme inhibitors and angiotensin receptor blockers as antihypertensive agents?
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1. ARBs reduce activation of AT1 receptors more effectively than ACE inhibitors
2. ARBs allow activation of AT2 receptors 3. ACE inhibitors may increase levels of angiotensin degradation peptides more than ARBs 4. ACE inhibitors increase levels of several CE substrates (e.g., bradykinin) |
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What is the prototype for direct renin inhibitors as antihypertensivee agents?
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-aliskiren
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What is the mechanism of action of direct renin inhibitors as antihypertensive agents?
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1. Transition state inhibitor of renin (IC50 0.6 nM)
2. Rate-limiting step in AII formation |
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What is the comparison of direct renin inhibitors with angiotensin converting enzyme inhibitors and angiotensin receptor blockers as antihypertensive agents?
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1. ACEI, ARBs --> compensatory renin secretion, increase AI
a. ARBs: increase AI --> AII, competition for AT1R b. ACEI: increase AI --> non-ACE AII 2. vs. ACEIs: DRIs: no bradykinin potentiation 3. vs. ARBs: may prevent alternate pathways of AII formation |
