441-postMT only

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jgiantess
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441-postMT only
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2011-12-18 03:47:59
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pharmacology
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  1. HRT
    • anti-resorptive (anti-catabolic).
    • considered for tx of mod-severe vasomotor symptoms of postmenopause only
    • osteoporosis prevention is a secondary benefit
  2. Etidronate
    • first-gen bisphosphonate, least potent anti-resorptive(anti-catabolic). R1 -CH3, R2 -OH
    • Incorporates into bone, released when hydroxyapatite dissolved by osteoclasts
    • Preferentially taken up by osteoclasts -> impair recruitment, differentiation, activity of osteoclasts. Increase osteoclast apoptosis.
    • Dose that inhibits bone resorption also impairs bone mineralization --> osteomalacia.
    • Therefore give: 400mg etid x14d, then 500mg CaCO3 x76d.
    • 1o px post-men: no effect
    • 2o px post-men: 50% RR vertebral fracture. NSS for non-vert, hip, wrist.
  3. Alendronate
    • 2nd gen bisphosphonate. anti-resorptive (anti-catabolic). R1 -OH, R2 -CH2CH2CH2NH2
    • Incorporates into bone, released when hydroxyapatite dissolved by osteoclasts
    • Preferentially taken up by osteoclasts -> impair recruitment, differentiation, activity of osteoclasts. Increase osteoclast apoptosis.
    • 1o px: 45% RR vertebral fracture (vs. NOT risedronate, and zolen was not tested)
    • 2o px: 50% RR in vert, non-vert, hip fx (all 3 drugs)
    • Orally, poorly absorbed (1-5%). Empty stomach, water only. t1/2 is 1 hour in plasma, 10 years in bone.
    • 10mg/d or 70mg/week
  4. Risedronate:
    • 2nd gen bisphosphonate. anti-resorptive (anti-catabolic). R1 -OH, R2 -CH2N-ring.
    • Incorporates into bone, released when hydroxyapatite dissolved by osteoclasts
    • Preferentially taken up by osteoclasts -> impair recruitment, differentiation, activity of osteoclasts. Increase osteoclast apoptosis.
    • 1o px: no effect
    • 2o px: 50% RR in vert, non-vert, hip fx (all 3 drugs)
    • Orally, poorly absorbed (1-5%). Empty stomach, water only. t1/2 is 1 hour in plasma, 10 years in bone.
    • 5mg/d, or 35mg/week, or 75mg/day x2 days/month.
  5. Zoledronate:
    • 3rd gen bisphosphonate. anti-resorptive (anti-catabolic). R1 -OH, R2 CH2N-ring.
    • Incorporates into bone, released when hydroxyapatite dissolved by osteoclasts
    • Preferentially taken up by osteoclasts -> impair recruitment, differentiation, activity of osteoclasts. Increase osteoclast apoptosis.
    • 1o px: not tested
    • 2o px: 50% RR in vert, non-vert, hip fx (all 3 drugs)
    • Injected 5mg once/year by IV infusion.
  6. Calcitonin
    • peptide hormone in calcium homeostasis; decreases Plasma Calcium. Anti-resorptive (anti-catabolic).
    • Suppresses activity of osteoclasts, decreases bone resorption.
    • 30% RR in vertebral fx, but not non-vertebral.
    • May have analgesic effect.
    • 2nd line tx for post-men osteo, 1st line tx for pain ass'd with acute vert fx.
  7. Denosumab (prolia)
    • osteoporosis anti-resorptive (anti-catabolic)
    • monoclonal Ab to RANKL that mimcs action of OPG, prevents RANKL from binding to RANK.
    • Decrease in osteoclast formation and bone resorption.
    • Px severe osteoporosis in post-men: 60% RR vertebral, 20% RR non-vertebral, 40% RR hip
    • May also be useful in conditions characterized by temporary rapid bone resorp (i.e. aromatase inhib tx)
    • Injection: 60mg SC q6mo.
  8. Teriparatide
    • recombinante human PTH.
    • Increases recruitment and differentioatn of osteoblasts and decreases apoptosis.
    • Given intermittently, get net bone forming effect: increases bone remodeling, with anabolic window: initial stimulation of bone formation before resorption takes place. Window lasts 12-18 months.
    • 2o post-men: 65% RR vert, 53% RR non-vert. No sig decrease in hip fx.
    • Also for glucocorticoid-induced osteo in high-risk pts.
    • Tx duration limited 2 years.Once daily injections.
  9. Acetylsalicylic Acid (Aspirin)
    • antiplatelet: thromboxane A2 inhibitor.
    • Irreversibly inhibits platelet COX1, blocking TXA2 formation (and therefore no platelet shape change, granule release, or aggregation). Overall decreased platelet aggregation (but weakest since blocks only one pathway).
    • Low doses (75-325mg) preferentially inhibits platelet COX over endothelial COX2 (which is important in prostacyclin).
  10. Clopidogrel (Plavix)
    • antiplatelet: ADP-inhibitor. pro-drug.
    • selectively irreversibly blocks ADP binding to P2Y12 platelet receptor, therefore no ADP-induced platelet aggregation because no activation of GPIIb/IIIa receptors. (Also partially prevents aggregation by other agonists since ADP is released from all activated platelets irrespective of agonist.)
    • As save as aspirin.
  11. Ticlopidine (Ticlid)
    • antiplatelet: ADP-inhibitor. pro-drug.
    • interferes with platelet-fibrinogen binding and platelet-platelet int'n, maybe due to inhibition of ADP to P2Y12.
    • Reserved for pts who cannot tolerate ASA.
  12. Prasugrel (effient)
    • antiplatelet: ADP-inhibitor. pro-drug - converted by intestinal and hepatic CYP450.
    • irreversibly binds P2Y12 for lifespan, inhibits platelet activation and aggregation.
    • Can be taken together with ASA.
  13. Abiciximab (ReoPro)
    • antiplatelet: GPIIb/IIIa receptor antagonist.
    • Most potent antiplatelet agents because blocks final common pathway of all stimuli (thrombin, ADP, collagen). Prevents fibrinogen-mediated cross-linkage.
    • monoclonal antiplatelet Ab, prevents binding of fibrinogen and VWF to prevent aggregation.
    • Max inhibition observed when >80% of receptors blocked.
  14. Eptifibatide (Integrilin)
    • antiplatelet: GPIIb/IIIa receptor antagonist.
    • Most potent antiplatelet agents because blocks final common pathway of all stimuli (thrombin, ADP, collagen). Prevents fibrinogen-mediated cross-linkage.
    • small-molecule peptide, resembles fibrinogen RGD recognition sequence.
    • Reversibly inhibits platelet aggreg by preventing binding of fibrinogen and VWF to receptors.
  15. Tirofiban (Aggrastat)
    • antiplatelet: GPIIb/IIIa receptor antagonist.
    • Most potent antiplatelet agents because blocks final common pathway of all stimuli (thrombin, ADP, collagen). Prevents fibrinogen-mediated cross-linkage.
    • non-peptide antagonist of fibrnogen binding to receptor.
    • Reversible. Occupies receptor, therefore inhibits binding of fibrinogen and VWF to receptor.
  16. Dipyridamole
    • antiplatelet: phosphodiesterase inhibitor.
    • reduces platelet adhesiveness by increasing cAMP --> release prostacyclin. Also vasodilator.
  17. Heparin (unfractionated)
    • Anticoagulant: indirect thrombin inhibitor.
    • 5,000-30,000 daltons, injectable. Extracted from porcine mucosa. Strongly anionic due to sulfate and carboxyl groups.
    • Very polar, does not cross membranes easily. Binds to plasma ANTITHROMBIN III via pentasaccharide sequence. Increases affinity of antithrombin to Xa and thrombin (among others), promotes inhibition of Xa
    • Pentasaccharide only (<18 monosac's long, MW<6,000) - only inhibits factor Xa.
    • Longer heps (>18ms, MW>6,000) - have stronger inhibitory capacity against thrombin (heparin must bind to both antithrombin AND thrombin [at exosite 2] to form a ternary complex).
    • Rapid acting - peak after 2-4 hours.
  18. Low Molecular Weight Heparin
    • Anticoagulant: indirect thrombin inhibitor.
    • 4,000-6,000 daltons, injectable. Extracted from porcine mucosa. Strongly anionic due to sulfate and carboxyl groups.
    • Better bioavailability (less binding to endothelium and plasma proteins).
    • Longer t1/2...predictable anticoagulant response.
    • e.g. dalteparin, enoxaparin, nadroparin, tinzaparin.
  19. Lepirudin
    • Anticoagulant: direct thrombin inhibitor.
    • recombinant Hirudin
    • Bivalent irreversible binding to thrombin catalytic site and exosite 1.
    • inhibits free and bound thrombin.
    • No HIT.
  20. Bivalirudin
    • Anticoagulant: direct thrombin inhibitor.
    • short synthetic peptide, resembles Hirudin.
    • Bivalent reversible binding to thrombin catalytic site and exosite 1.
    • inhibits free and bound thrombin.
    • No HIT.
  21. Argatroban.
    • Anticoagulant: direct thrombin inhibitor.
    • small molecule, binds only to catalytic site -> monovalent.
    • Reversible, inhibits free and bound thrombin.
    • No HIT.
  22. Dabigatran
    • Anticoagulant: direct thrombin inhibitor.
    • first oral direct monovalent thrombin (factor IIa) inhibitor.
    • Is a prodrug that is converted by esterases in blood.
    • Reversible, inhibits free and bound thrombin.
    • No HIT.
  23. Fondaparinux
    • Anticoagulant: factor Xa inhibitor, indirect (binds to antithrombin to enhance affinity 300x).
    • synthetic pentasaccharide with the sequence of heparin. Parenteral.
    • Long t1/2. Lower risk of HIT.
  24. Rivaroxaban
    • Anticoagulant: factor Xa inhibitor, DIRECT and oral.
    • Competitively, selectively, directly inhibits factor Xa...10,000x greater.
    • Prolongs clotting times in human plasma.
  25. Warfarin, Nicoumalone
    • Anticoagulant: vitamin K antagonist
    • Structure similar to Vitamin K, therefore competitively inhibits and interferes with hepatic synthesis of Vit K-dependent clotting factors - II, VII, IX, X, anticoagulant protein C. (decreases availability of hydroquinone).
    • Substrate of CYP450. No effect on previously synthesized factors...first anticoag effect at 8-12 hours.
    • Effective anticoag at least 1 week - due to half-lives of clotting factors.
  26. Heparan sulfate-Danaparoid
    • Anticoagulant: alternative
    • mixture of non-heparin low MW sulfated glycosaminoglycuronans...some affinity to antithrombin...ahtithrombotic.
    • Choice for pts with HIT.
  27. Xigris - recombinant human protein C - drotrecogin alfa.
    • Anticoagulant: alternative
    • Protein C, with co-factor protein S, degrades factors Va and VIIIa --> natural anticoag by inhibiting activation of prothrombin and factor X.
  28. Aminocaproic acid
    plasmin inhibitor, used as necessary to counteract effects of thrombolytic drugs.
  29. Streptokinase
    • Thrombolytic: 1st gen
    • purified from beta-hemolytic streptococci
    • forms active complex with plasminogen to convert uncomplexed plasminogen to active plasmin.
    • Non-selective between circulating and fibrin-bound plasminogen.
    • Non-fibrin selective: also catalyzes degradation of fibrinogen and factors V and VII.
    • Given by infusion...need loading dose to over come antibodies.
  30. t-PA (tissue plasminogen activator)
    • Thrombolytic: 2nd gen
    • mostly from recombinant DNA, is also a naturally occurring intrinsic compound.
    • Low affinity for plasminogen, but rapidly activates plasminogen bound to fibrin in a thrombus or hemostatic plug (specific to stuff at fibrin surface x00 times more than in circulation).
    • Fibrin-selective - esp at low doses (no fibrinogen)
    • short half-life - administered as initial bolus then infusion.
  31. r-PA
    • Thrombolytic: 3rd gen
    • recombinant PA.
    • less expensive to make but less fibrin-specific
  32. tenecteplase
    • Thrombolytic: 3rd gen
    • more fibrin specific than t-PA, made by introducing aa modifications to t-PA. longer half-life.
  33. digoxin
    • positive inotropic drug: used for refractory CHF. Also potent anti-arrhythmic (through vagus nerve mediation, release of ACh prolongs AV refractory period)
    • reversibly inhibits Na-K ATPase of cardiac muscle membrane, leads to increase in intracellular Na concentration, thereby indirectly inhibiting Na-Ca exchanger (already lots of Na in cell, NCX can't bring more Na in to take out Ca).
    • Ca2+ intracellular increases, --> more available for troponin C binding sites, --> increased systolic force of contraction --> increased cardiac output.
    • Improves circulation leads to reduced sympathetic activity.
    • Also has vagal effects: reduce SA node firing (decreased automaticity), slows AV node conduction (anti-arrhythmic).
    • Delayed afterdepolarization problem: from calcium overload in SR, leads to spontaneous Ca release.
  34. milrinone
    • positive inotropic: phosphodiesterase inhibitor: used for refractory CHF. short term therapy.
    • Increases cardiac cAMP -> activation of protein kinase allows phosphorylation of cellular proteins (i.e. slow Ca2+ channel) --> increase Ca2+ influx, more Ca in SR --> increased CO.
    • In vascular SM, cAMP promotes direct relaxation.
  35. dobutamine
    positive inotropic: B-adrenoceptor agonist -> increase cAMP --------> increase cardiac output.
  36. Nesiritide
    • synthetic brain natriuretic peptide (===ANP)
    • increases cGMP in smooth muscle cells -> decrease Ca, decrease force of contraction, leads to SM relaxation.
    • Reduces venous and arteriolar tone --> powerful vasodilator.
    • Also causes diuresis.
  37. Quinidine
    • Class IA antiarrhythmic: Na+ Channel Blocker
    • blocks Na+ channel @ open and activated state.
    • also blocks K+ channel to prolong AP.
    • overall, increases refractory period, decreases re-entry.
    • SE: cinchonism, diarrhea, ab cramps, N/V, hypotension, Torsades de Pointes, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias, fever, hepatitis, thrombocytopenia, hemolytic anemia.

  38. Procainamide
    • Class IA antiarrhythmic: Na+ Channel Blocker
    • blocks Na+ channel @ open and activated state.
    • also blocks K+ channel to prolong AP.
    • overall, increases refractory period, decreases re-entry.
    • SE: systemic lupus erythematosus, diarrhea, nausea, vomiting, Torsades de Pointes, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias, agranulocytosis.

  39. Disopyramide
    • Class IA antiarrhythmic: Na+ Channel Blocker
    • blocks Na+ channel @ open and activated state.
    • also blocks K+ channel to prolong AP.overall, increases refractory period, decreases re-entry.

  40. Lidocaine
    • Class IB antiarrhythmic: Na+ Channel Blocker
    • major block Na+ channel @ open and INactivated
    • minor block Na+ channel @ open and activated
    • shortens depol, quickens repol, and shortens AP
    • overall: decreases refractory period, and decreases re-entry.
    • SE: dizziness, sedation, slurred speech, blurred vision, paresthesia, muscle twitching, confusion, N/V, seizures, psychosis, sinus arrest, aggravation of underlying conduction disturbances.

  41. Mexiletine
    • Class IB antiarrhythmic: Na+ Channel Blocker
    • major block Na+ channel @ open and INactivated
    • minor block Na+ channel @ open and activated
    • shortens depol, quickens repol, and shortens AP
    • overall: decreases refractory period, and decreases re-entry.
    • SE: dizziness, sedation, anxiety, confusion, paresthesia, tremor, ataxia, blurred vision, N/V, anorexia, aggravation of underlying conduction disturbances or vent arrhythmias.

  42. Tocainide
    • Class IB antiarrhythmic: Na+ Channel Blocker
    • major block Na+ channel @ open and INactivated
    • minor block Na+ channel @ open and activated
    • shortens depol, quickens repol, and shortens AP
    • overall: decreases refractory period, and decreases re-entry.

  43. Propafenone
    • Class IC antiarrhythmic: Na+ Channel Blocker
    • most significant effect on Na+ channels @ open & activated
    • mild effect on Na+ channels @ open & inactivated
    • 0 effect on K+ and repol, no change in ERP
    • but refractory period of AV node increased.
    • for Atrial flutter and fibrillation and VT/VF.
    • SE: dizziness, fatigue, bronchospasm, headache, taste disturbances, N/V, bradycardia or AV block, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias.

  44. Flecainide
    • Class IC antiarrhythmic: Na+ Channel Blocker
    • most significant effect on Na+ channels @ open & activated
    • mild effect on Na+ channels @ open & inactivated
    • 0 effect on K+ and repol, no change in ERP
    • but refractory period of AV node increased.
    • for Atrial flutter and fibrillation and VT/VF.
    • SE: blurred vision, dizziness, dyspnea, headache, tremor, nausea, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias.

  45. Esmolol
    • Class II antiarrhythmic: B-adrenoceptor antagonist
    • blocks B1 receptor and SNS stimulation, decreases cAMP
    • @ pacemaker cells:
    • 1) decrease slope of Phase 4: opposes adrenaline effect at transient Ca2+ channels
    • 2) decrease slope of Phase 0: inhibits slow L-type Ca2+ channels, decrease HR
    • @ nonpacemaker cells:
    • at Phase 0, blocks inward Na+ current - increase ERP, decrease conduction.
    • Antihypertensive: B1 selective blocker at low doses
    • therefore, less effect on bronchioles
  46. Propranolol
    • Class II antiarrhythmic: B-adrenoceptor antagonist
    • blocks B1 receptor and SNS stimulation, decreases cAMP
    • @ pacemaker cells:
    • 1) decrease slope of Phase 4: opposes adrenaline effect at transient Ca2+ channels
    • 2) decrease slope of Phase 0: inhibits slow L-type Ca2+ channels, decrease HR
    • @ nonpacemaker cells:
    • at Phase 0, blocks inward Na+ current - increase ERP, decrease conduction.
    • Antihypertensive: non-cardioselective beta-adrenoceptor antagonist
    • blocks B1R - less CO, less renin release so fall in angiotensin II levels and decrease in tubular Na reabs.
    • block B2R - presynaptically, reduce NE overflow. Also - (bad) - increases risk of bronchoconstriction, peripheral VC, masking of compensatory response ass'd with hypoglyc...etc.
  47. Metoprolol
    • Class II antiarrhythmic: B-adrenoceptor antagonist
    • blocks B1 receptor and SNS stimulation, decreases cAMP
    • @ pacemaker cells:
    • 1) decrease slope of Phase 4: opposes adrenaline effect at transient Ca2+ channels
    • 2) decrease slope of Phase 0: inhibits slow L-type Ca2+ channels, decrease HR
    • @ nonpacemaker cells:
    • at Phase 0, blocks inward Na+ current - increase ERP, decrease conduction.
    • Antihypertensive: B1 selective blocker at low doses
    • therefore, less effect on bronchioles
  48. Atenolol
    • Class II antiarrhythmic: B-adrenoceptor antagonist
    • blocks B1 receptor and SNS stimulation, decreases cAMP
    • @ pacemaker cells:
    • 1) decrease slope of Phase 4: opposes adrenaline effect at transient Ca2+ channels
    • 2) decrease slope of Phase 0: inhibits slow L-type Ca2+ channels, decrease HR
    • @ nonpacemaker cells:
    • at Phase 0, blocks inward Na+ current - increase ERP, decrease conduction.
    • Antihypertensive: B1 selective blocker at low doses
    • therefore, less effect on bronchioles
  49. Amiodarone
    • Class III antiarrhythmic: K+ channel blocker
    • blocks K+ in plateau phase & blocks repolarization
    • prolongs AP, increases ERP, more risk of TdP
    • Amiodarone has characteristics of all Vaughan Williams classes:
    • 1) Na+ channel blocker
    • 2) non-comp, non-sel B-blocker
    • 3) K+ channel blocker
    • 4) small degree of Ca2+ blocker activity
    • initial action: B-blockade (by blocking Ca2+ currents, block AP initiation by SA)
    • chronic: K+ effect, prolonged repolarization.
    • SE: tremor, ataxia, paresthesia, insomnia, corneal microdeposits, optic neuropathy/neuritis, nausea, vomiting, anorexia, constipation, TdP, brady or AV block, pulmonary fibrosis, liver fxn test abnorms, hepatitis, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray skin discoloration, hypotension (IV), phlebitis (IV)

  50. Dronedarone
    • Class III antiarrhythmic: K+ channel blocker
    • blocks K+ in plateau phase & blocks repolarization
    • prolongs AP, increases ERP, more risk of TdP

  51. Sotalol
    • Class III antiarrhythmic: K+ channel blocker
    • blocks K+ in plateau phase & blocks repolarization
    • prolongs AP, increases ERP, more risk of TdP
    • Antihypertensive: non-cardioselective beta-adrenoceptor antagonist
    • blocks B1R - less CO, less renin release so fall in angiotensin II levels and decrease in tubular Na reabs.
    • blocks B2R - presynaptically, reduce NE overflow. Also - (bad) - increases risk of bronchoconstriction, peripheral VC, masking of compensatory response ass'd with hypoglyc...etc.
    • SE: dizziness, weakness, fatigue, N/V, diarrhea, brady, TdP, bronchospasm, aggravation of underlying HF

  52. Dofetilide
    • Class III antiarrhythmic: K+ channel blocker
    • blocks K+ in plateau phase & blocks repolarization
    • prolongs AP, increases ERP, more risk of TdP
    • SE: headache, dizziness, TdP

  53. Ibutilide
    • Class III antiarrhythmic: K+ channel blocker
    • blocks K+ in plateau phase & blocks repolarization
    • prolongs AP, increases ERP, more risk of TdP
    • SE: headache, TdP, hypotension

  54. Verapamil
    • Class 4 Antiarrhythmic: Ca2+ Channel Blocker
    • blocks voltage sensitive Ca2+ current during Phase 2 plateau of non-pacemaker myocytes
    • also decreases automaticity and conduction velocity in both SA and AV nodes.
    • antihypertensive. Calcium Channel Blocker - primary action at the heart muscles (myocardium), some in conducting tissue.
    • Decrease Calcium entry into heart muscle, decrease cardiac output.

  55. acetazolamide, methazolamide, dorzolamide, brinzolamide
    • weak diuretic: carbonic anhydrase inhibitor
    • Used primarily for glaucoma: blocks CA in ciliary cells to prevent HCO3- secretion into aqueous humor...and reduce Na and H2O transport --> decrease IOP)
    • Also may be used for acute mountain sickness and epilepsy.
    • Very weak diuretic; CA is in luminal membrane of proximal tubule, so by blocking CA, deplete intracellular H+ and Na/H+ exchanger is inhibited so Na+ stays in lumen.
    • but 99% of CA must be inhibited before diuretic activity expressed. Even if it is blocked, not much effect because thick ascending limb can compensate for the less effective proximal reabsorption.
  56. furosemide
    • diuretic: loop-acting
    • @ thick ascending limb, inhibits Na+/K+/2Cl- co-transporter.
    • Inhibits NaCl reabsorption --> increases NaCl, K+, water, Mg2+ and Ca2+ excretion
    • (hypokalemia due to diversion of Na+ to be reabsorbed at distal tubule, where K+ can easily be excreted)
    • can cause hypomagnesemia.
  57. ethacrynic acid
    • diuretic: loop-acting
    • @ thick ascending limb, inhibits Na+/K+/2Cl- co-transporter.
    • Inhibits NaCl reabsorption --> increases NaCl, K+, water, Mg2+ and Ca2+ excretion
    • (hypokalemia due to diversion of Na+ to be reabsorbed at distal tubule, where K+ can easily be excreted)
    • can cause hypomagnesemia.
  58. bumetanide
    • diuretic: loop-acting
    • @ thick ascending limb, inhibits Na+/K+/2Cl- co-transporter.
    • Inhibits NaCl reabsorption --> increases NaCl, K+, water, Mg2+ and Ca2+ excretion
    • (hypokalemia due to diversion of Na+ to be reabsorbed at distal tubule, where K+ can easily be excreted)
    • can cause hypomagnesemia.
  59. hydrochlorothiazide
    • diuretic: thiazide. Diuretic of choice for HTN.
    • @ early distal tubule, inhibits Na+/Cl- co-transporter.
    • Inhibits reabsorption of NaCl, therefore decreasing urinary excretion of Ca2+ by enhancing Na/Ca exchanger at basolateral membrane to bring Na+ into cell and Ca2+ back into blood. Increases diuresis.
    • Also promotes vasodilation (hyperpolarization of smooth muscle, involving EDHF, PGI2, NO).
    • can cause hypokalemia, similar to loop diuretics.
  60. indapamide
    • diuretic: thiazide. Diuretic of choice for HTN.
    • @ early distal tubule, inhibits Na+/Cl- co-transporter.
    • Inhibits reabsorption of NaCl, therefore decreasing urinary excretion of Ca2+ by enhancing Na/Ca exchanger at basolateral membrane to bring Na+ into cell and Ca2+ back into blood.
    • Also promotes vasodilation (hyperpolarization of smooth muscle).
    • can cause hypokalemia, similar to loop diuretics.
  61. metolazone
    • diuretic: thiazide. Diuretic of choice for HTN.
    • @ early distal tubule, inhibits Na+/Cl- co-transporter.
    • Inhibits reabsorption of NaCl, therefore decreasing urinary excretion of Ca2+ by enhancing Na/Ca exchanger at basolateral membrane to bring Na+ into cell and Ca2+ back into blood.
    • Also promotes vasodilation (hyperpolarization of smooth muscle).
    • can cause hypokalemia, similar to loop diuretics.
  62. spironolactone
    • diuretic: potassium-sparing, aldosterone antagonist.
    • @ late distal tubule & collecting duct, competitive antagonist of aldosterone.
    • Competitively inhibits binding of aldosterone to MR (mineralcorticoid receptors), decrease expression of AIP which increase Na+ channels and Na+/K+ ATP-ase and more ATP... therefore increasing Na+, Cl-, water excretion, and decreases K+ and H+ in urine (no more negative lumen voltage from aldosterone-induced increased Na+ conductance).
    • i.e. Na+ not coming into cell, so K+ doesn't have to leave. ===potassium sparing.
  63. eplerenone
    • diuretic: potassium-sparing, aldosterone antagonist.
    • @ late distal tubule & collecting duct, competitive antagonist of aldosterone.
    • Competitively inhibits binding of aldosterone to MR (mineralcorticoid receptors), decrease expression of AIP which increase Na+ channels and Na+/K+ ATP-ase and more ATP... therefore increasing Na+, Cl-, water excretion, and decreases K+ and H+ in urine (no more negative lumen voltage from aldosterone-induced increased Na+ conductance).
    • i.e. Na+ not coming into cell, so K+ doesn't have to leave. ===potassium sparing.
  64. triamterene
    • diuretic: potassium-sparing, non-aldosterone, direct sodium channel inhibitor.
    • @ late distal tubule & collecting duct.
    • Inhibits entry of Na+ from tubule lumen side...decreases electrical potential across membrane which is the driving force for K+ exchange, therefore increases Na+, Cl-, water excretion; decreases K+ in urine.
  65. amiloride
    • diuretic: potassium-sparing, non-aldosterone, direct sodium channel inhibitor.
    • @ late distal tubule & collecting duct.
    • Inhibits entry of Na+ from tubule lumen side...decreases electrical potential across membrane which is the driving force for K+ exchange, therefore increases Na+, Cl-, water excretion; decreases K+ in urine.
  66. mannitol
    • diuretic: osmotic.
    • Increases osmotic pressure in tubules, holds water in as passes down proximal tubule and loop of henle.
    • Blocks 10-15% filtered Na+.
  67. captopril
    • Angiotensin-converting enzyme inhibitor
    • lowers total peripheral resistance and decreases BP
    • inhibits ACE, which converts Angiotensin I to II
    • therefore, decreases ATII-mediated VC --> decreased PVR
    • and decreases aldosterone secretion --> decreased sodium retention and ECF volume
    • and decreases ADH secretion, decreases thirst.
    • May also block degradation of bradykinin (==VD in lungs, fluid --> dry cough)
  68. losartan
    • Angiotensin-II receptor blocker/antagonist
    • lowers total peripheral resistance and decreases BP
    • competitive antagonist of Angiotensin II at AT1 receptors.
    • Prevents: VC sm, aldosterone secretion, release of adrenal catecholamines, thirst, ADH release.
    • More complete inhibition of angiotensin action than ACEI because chymase also makes AngII.
  69. aliskiren
    • direct renin inhibitor.
    • antihypertensive, blocks renin proteolytic activity of ang-> angI. Suppresses whole RAAS system.
    • Also can block compensatory rise in Plasma Renin Activity (due to loss of stimulation fo AT1 receptors of JGC, compensatory increase in renin release).
  70. timolol
    antihypertensive: non-cardioselective B blocker
  71. nadolol
    antihypertensive: non-cardioselective B blocker
  72. bisoprolol
    • antihypertensive: cardioselective B blocker
    • B1 selective at low doses
  73. labetalol
    antihypertensive: mixed B and A antagonism
  74. carvedilol
    antihypertensive: mixed B and A antagonism
  75. acebutolol
    • antihypertensive: B blocking and partial agonist activity
    • lower blood pressure by decreasing cardiac output (B1) and vascular resistance (B2)
  76. pindolol
    • antihypertensive: B blocking and partial agonist activity
    • lower blood pressure by decreasing cardiac output (B1) and vascular resistance (B2)
  77. prazosin
    • antihypertensive: alpha-1 specific blocker
    • Acts at post-synaptic receptors to prevent phosphorylation/activation of myosin light chain kinase and contraction...
    • leads to arteriole and venous sm dilation --> decrease TPR and arteriol pressure.
    • therefore, prevents catecholamine-induced vasoconstriction.
    • Only acts at vascular smooth muscle.
  78. doxazosin
    • antihypertensive: alpha-1 specific blocker
    • newer...gradual onset of action.
  79. sildenafil, tadalafil, vardenafil
    • vasodilator, not used for treatment of hypertension.
    • phosphodiesterase 5 inhibitor, tx erectile dysfunction.
    • Prevents breakdown of cGMP to 5'GMP to sustain effect of NO--> cGMP --> relaxation of smooth muscle of corpus cavernosum and blood vessel --> maintain erection.
    • Sildenafil may be used to treat primary pulmonary HTN alone OR with endothelin receptor antagonists and prostacyclin.
  80. alprostadil
    • vasodilator. prostaglandin E1 analog.
    • Used in tx of erectile dysfunction.
    • Acts locally, directly increases cAMP in smooth muscle --> decrease calcium --> relaxation. No involvement of NO.
    • Initiates erection whether stimulation present or not.
  81. diltiazem
    • Class 4 Antiarrhythmic: Ca2+ Channel Blocker
    • blocks voltage sensitive Ca2+ current during Phase 2 plateau of non-pacemaker myocytes
    • also decreases automaticity and conduction velocity in both SA and AV nodes.
    • Antihypertensive. Calcium Channel Blocker: primary action on conducting tissues.
    • Decreases flow of Calcium through transmission of nerve impulses. Slows generation of action potentials at SA node, slows conduction of action potentials through AV node.
    • decreases conduction, decrease force of contraction.

  82. nifedipine, amlodipine, felodipine, nimodipine
    • antihypertensive.
    • Calcium Channel blocker: primarily act on arterioles.
    • Decrease Calcium entry into smooth muscles, cause relaxation and therefore decrease TPR.
  83. minoxidil
    • antihypertensive, used for severe HTN only.
    • decreases TPR, decreases BP.
    • Opens K+ channel of smooth muscle
    • hyperpolarization
    • decreased Ca2+ entry
    • relaxation of smooth muscle.
    • SE: hypertrichosis.
  84. hydralazine
    • antihypertensive, acts directly on smooth muscle of blood vessels, vasodilation as a result of endothelium-derived relaxing factor --> opens K+ channels or NO generation.
    • decreases TPR, decreases BP.
    • SE: may increase CO...may cause myocardial ischemia...
    • Not used alone, when combined with BB and diuretic, drug is better tolerated.
  85. sodium nitroprusside
    • antihypertensive, mainstay for hypertensive crises
    • DIRECT VD of arteries and veins by releasing NO.
    • NO--> guanylate cyclase --> cGMP --> cGMP-dependent protein kinase inhibits Calcium influx...Myosin fails to be phosphorylated...decreased contraction.= relaxation
    • also: venous pooling (decrease preload) and decrease arteriolar resistance (decrease TPR and BP)
    • May cause cyanide poisoning: therefore, must be administered with sodium thiosulfate.
  86. nitroglycerin (glyceryl trinitrite)
    • antihypertensive, organic nitrite. tx of Angina.
    • Enzymatically converted (in presence of intracellular sulfhydryl groups) to S-nitrosothiol --> NO.
    • Increased NO --> improves coronary blood flow.
    • Large first-pass metabolism. Rapid onset.
  87. isosorbide dinitrate
    • antihypertensive, organic nitrite. tx of Angina.
    • Enzymatically converted (in presence of intracellular sulfhydryl groups) to S-nitrosothiol --> NO.
    • Increased NO --> improves coronary blood flow.
    • Large first-pass metabolism. Rapid onset.
  88. isosorbide mononitrate
    • antihypertensive, organic nitrite. tx of Angina.
    • Enzymatically converted (in presence of intracellular sulfhydryl groups) to S-nitrosothiol --> NO.
    • Increased NO --> improves coronary blood flow.
    • No first-pass, longer duration of action.
  89. adenosine (purinergic agonist)
    • acts on A1 receptor of AV node
    • decreases cAMP levels, therefore blocks Ca2+ current due to decreased phosphorylation of Ca2+ channel.
    • Enhances K+ conductance, causes hyperpolarization
    • decreases conducton velosity, increases ERP in AV node
    • slows rate of rise of pacemaker potential
    • SE: flushing and hypotension, paresthesias, SOB, chest pain (bronchospasm)

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