ANTIHYPERTENSIVES,
     DIURETICS,
ANTICOAGULANTS AND
   DYSLIPIDEMICS

    PHARMACOLOGY
       NUR 3703
     BY LINDA SELF
Hypertension
• Hypertension common in US, up to
  60 million afflicted
• Leads to MI, heart failure, stroke and
  renal di...
Blood Pressure
Classification according to
         the JNC 7
• Normal SBP<120 and DBP <80
• Prehypertension SBP 120-139 a...
Types of Hypertension
• Essential or primary—etiology ?.
  Contributors include: salt sensitivity,
  insulin resistance, g...
BP review
• Any condition that affects heart rate,
  stroke volume or peripheral vascular
  resistance affects arterial bl...
BP review
• BP regulation operates in a negative
  feedback system
• Baroreceptors and chemoreceptors in the
  carotid art...
BP review
Normally, when the arterial blood pressure
   is elevated
1. Kidneys will excrete more fluid
2. Fluid loss will ...
BP review cont.
5. Vascular endothelium produces
  vasodilating substances (nitric oxide,
  prostacyclin) which reduce blo...
Essential Hypertension
• Activation of sympathetic nervous system
  causing prolonged vasoconstriction
• Activation of RAA...
Essential Hypertension
• Also felt that hyperinsulinemia and
  insulin resistance cause endothelial
  dysfunction by enhan...
Nonpharmacologic
         Management of
          Hypertension
•   Weight reduction
•   Exercise
•   Salt restriction in d...
Antihypertensive Drugs
• Classes:
1. Angiotensin converting enzyme
   inhibitors (ACEI)
2. Angiotensin II Receptor Blocker...
ACEIs
• Block the enzymes that convert
  angiotensin I to angiotensin II
  (potent vasoconstrictor)
• Have action of vasod...
ACEIs
• Reverse remodeling of heart muscle
  and blood vessels
• Reno-protective
• Excellent for heart failure and
  hyper...
ACEIs
• Useful in heart failure as decrease
  peripheral vascular resistance,
  cardiac workload and ventricular
  remodel...
ACEIs
• Can cause hyperkalemia
• Should never be used during
  pregnancy
• May not be as effective in African
  Americans—...
ACEIs
•   Lotensin (benazepril)
•   Capoten (captopril)
•   Vasotec (enalapril)
•   Zestril (lisinopril)
•   Altace (ramip...
Angiotensin II Receptor
      Blockers (ARBs)
• Block effects of angiotensin II,
  compete with angiotensin II for
  tissu...
ARBs
• Similar end results as seen with
  ACEIs
• Less likely to cause hyperkalemia
• Persistence of cough is rare
• Proto...
Examples of ARBs
•   Atacand (candesartan)
•   Cozaar (losartan)
•   Diovan (valsartan)
•   Micardia (telmisartan)
•   Ben...
Antiadrenergics
• Inhibit activity of the sympathetic
  nervous system
• Effective in decreasing heart rate,
  force of my...
Antiadrenergics
• Alpha 1 adrenergics receptor
  blocking agents dilate vessels and
  decrease peripheral vascular
  resis...
Antiadrenergics-Alpha 1
• Cardura (doxazosin)
• Minipress (prazosin)
• Hytrin (terazosin)
Antiadrenergics
• Centrally acting sympatholytics
  stimulate presynaptic alpha 2
  receptors in the brain
• Less norepine...
Antiadrenergics—Alpha 2
         agonists
• Centrally acting agents also can
  result in fluid and sodium retention
• Cata...
Beta Adrenergic Blockers

• Decrease heart rate, force of myocardial
  contraction, cardiac output, and renin
  release fr...
Beta Blockers
•   Inderal (propranolol)
•   Corgard (nadolol)
•   Lopressor (metoprolol)
•   Tenormin (atenolol)
•   Kerlo...
Calcium Channel Blocking
          Agents
• Useful in hypertension as dilate
  peripheral arteries and decrease
  peripher...
Calcium Channel Blocking
             Agents
• Norvasc (amlodipine)
• Cardizem (diltiazem)
• Plendil (felodipine)
• Procar...
Diuretics
• Useful in hypertension due to their
  sodium and water depletion
• May be used as monotherapy
• Preferred in t...
Diuretics
• Hydrodiuril (HCTZ)
Vasodilators
• Relax smooth muscle in blood
  vessels resulting in dilation and
  decreased peripheral vascular
  resistan...
Vasodilators
• Limited effect when used alone.
  Vasodilating action that lowers BP
  also stimulates SNS. This, in turn,
...
Vasodilators
• Corlopam (felodapam)—IV infusion,
  in hypertensive emergencies, avoid
  in patients with allergies to sulf...
Ethnic Considerations
• Use calcium channel blockers,
  diuretics and alpha blockers most
  effective in African Americans...
Hypertensive Emergencies

• Is defined as having end organ
  damage or diastolic BP of 120 torr or
  higher
• With oral me...
Hypertensive Emergencies

• Nitroglycerine—tolerance develops
  over 24-48 hours
• Nitroprusside—intraarterial bood
  pres...
Hypertensive Emergencies

• Corlopam (felodopam)—IV infusion,
  use short term.
Herbals that affect BP
•   Ephedra (ma huang)
•   Gingseng
•   Yohimbe (for erectile dysfunction)
•   caffeine
• In regards to anti-hypertensives,
  should not abruptly stop any of
  them. May develop rebound
  hypertension.
Diuretics
• Indicated for the treatment of
  edematous and nonedematous
  conditions
• May be useful in preventing renal
 ...
Diuretics
• Act on kidneys to decrease
  absorption of sodium, chloride, water
  and other substances such as
  calcium
• ...
Diuretics
Used to manage:
• Edema and ascites
• Management of heart failure
• Hypertension
Thiazide Diuretics
• Chemically related to sulfonamides so
  caution with sulfa allergies
• Used in long term management o...
Thiazide Diuretics
• Diuril (chlorothiazide)
• Hygroton (chlorthalidone)
• HydroDIURIL (hydrochlorothiazide)
Loop Diuretics
• Inhibit sodium and chloride
  reabsorption in the ascending limb of
  the Loop of Henle
• Potent diuresis...
Loop Diuretics
• Bumex (bumetamide) more potent
  than Lasix
• Can give either as oral agents, IV or
  IM
• Rapid administ...
Potassium Sparing
          Diuretics
• Act at distal tubule to decrease
  reabsorption of sodium and
  potassium excretio...
Osmotic Diuretics
• Produce rapid diuresis by increasing
  the solute load of the glomerular
  filtrate
• Water is pulled ...
Osmotic Diuretics
• Help reduce increased ICP,
  reduction of intraocular pressure
  before certain ophthalmic surgery
  a...
Drugs that affect
          Coagulation
• Thrombosis may occur in both arteries
  and veins
• Arterial thrombi cause disea...
Hemostasis
• Hemostasis is the prevention or stoppage
  of blood loss from an injured blood
  vessel. Process involves
  v...
Clot Lysis
• When clot is being formed,
  plasminogen is bound to fibrin and
  becomes a component of the clot
• After tea...
Blood Coagulation Factors
•   I fibrinogen
•   II prothrombin
•   Ill thromboplastin
•   IV calcium
•   V Labile factor
• ...
Anticoagulants
• Given to prevent formation of new
  clots and extension of clots already
  present; do not dissolve clots...
Heparin
• Usually will give a loading dose then
  calculated dosage per 24h; e.g. 15-
  25units/kg/h for IV dosing
• Monit...
Heparin
• Combines w/antithrombin III which
  will inactivate clotting factors IX, X,
  XI and XII, inhibits conversion of...
Low Molecular Weight
        Heparins
• Given subcutaneously in abdomen
  and do not require close monitoring
  of blood c...
Coumadin (warfarin)
• Most commonly used oral
  anticoagulant
• Drug acts in liver to prevent
  synthesis of vitamin K-dep...
Coumadin (warfarin)
• Anticoagulant effects do not occur
  for 3-5 days after warfarin is started
• Has no effect on plate...
Coumadin
• INR is based on prothrombin time.
  Normal baseline or control PT is 12
  seconds, therapeutic value is 1.5
  t...
Coumadin
• Dosage reduction in patients with biliary
  tract disorders, liver disease,
  malabsorption syndromes, and
  hy...
Other anticoagulants
• Orgaran (danaparoid)—low
  molecular weight, heparin-like drug.
  Given subq. Used in management of...
Other Anticoagulants cont.
 Trade and generic names
•   Refludan (lepirudin)
•   Argatroban (same generic name)
•   Arixtr...
Antiplatelet Drugs
• Arterial thrombi are composed primarily of
  platelets
• Antiplatelet drugs act by inhibiting platele...
Thromboxane A2 Inhibitors

• Work by inhibiting synthesis of
  prostaglandins. TA inhibitors work by
  acetylating cycloox...
Adenosine Diphosphate
    Receptor Antagonists
• Ticlid (ticlopidine)
• Inhibit platelet aggregation by preventing
  ADP-i...
Adenosine Diphosphate
    Receptor Antagonists
• Plavix (clopidogrel)
• Fewer side effects than ASA or
  Ticlid
• indicate...
Glycoprotein IIb/IIIa
     Receptor Antagonists
• Reopro (abciximab) is a monoclonal
  antibody that prevents the binding ...
Reopro cont.
• Used with aspirin and heparin and is
  contraindicated in clients who have
  recently received oral anticoa...
Other glycoprotein IIb/IIIa
   Receptor antagonists
• Integrilin (Eptifibatide)
• Aggrastat (tirofiban)
• Similar mechanis...
Glycoprotein IIb/IIIba
receptor antagonists cont.
• Contraindications include: recent
  bleeding, history of thrombocytope...
Phosphodiesterase
          Inhibitors
• Pletal (cilostazol) increases cAMP which
  then inhibits platelet aggregation and...
Miscellaneous
• Persantine (dipyridamole) inhibits
  platelet aggregation but mechanism
  is unclear
• Used for prevention...
Thrombolytics
• Given to dissolve thrombi
• Stimulate conversion of plasminogen
  to plasmin, an enzyme that breaks
  down...
Thrombolytics
• Goal is to re-establish blood flow
  and prevent tissue damage
• Also used to dissolve clots in arterial
 ...
Thrombolytics
• Activase (alteplase), Retavase (reteplase)
  and TNKase (tenecteplase) are tissue
  plasminogen activators...
Thrombolytics cont.
• Xigris (drotrecogin alfa) is a
  recombinant version of human
  activated protein C. Is approved for...
Drugs Used to Control
          Bleeding
• Amicar (aminocaproic acid) and
  Cyklokapron (tranexamic acid) are
  used to st...
Important reminders
•    Risk factors for thromboembolism
1.   Obesity
2.   MI
3.   Atrial fibrillation
4.   Prosthetic he...
Overview of cholesterol
          panel
Total cholesterol
Desirable-less than 200
Borderline high—200-239
High—240 or grea...
Overview cont.
HDL
• High >60
• Low <40
Triglycerides
Normal—less than 150
Borderline high—150-199
High--200 to 499
Very h...
Dyslipidemia
• Associated with athersclerosis and
  numerous pathophysiologic effects
• Elevated total cholesterol, high L...
Contributors to
dyslipidemia
•   Hypothyroidism
•   Diabetes mellitus
•   Alcoholism
•   Obesity, beta blockers, oral
    ...
Dyslipidemia cont.
• High dietary intake also increases
  the conversion of VLDL to LDL
  cholesterol, and high dietary in...
Types of Lipoproteins
• LDL—unfavorable type. Transports 75%
  of serum cholesterol to peripheral tissues
  and the liver....
Initial Management
• Treat conditions that contribute to elevated lipids
  (DM, hypothyroidism)
• Start low fat diet
• Inc...
Drug Therapy
• Based on the type of dyslipidemia
  and its severity
• Classes of agents include: HMB-
  CoA reductase inhi...
HMG-CoA reductase
    inhibitors or “statins”
• Inhibit an enzyme
  (hydroxymethylglutaryl-coenzyme A
  reductase) require...
Statins cont.
• Drugs also reduce C reactive
  protein, associated with
  inflammation and development of
  CAD
• Undergo ...
Statins cont.
• Adverse effects include:HA, diarrhea,
  rashes, headaches, constipation,
  hepatotoxicity and myopathy.
• ...
Statins cont.
• Do not take with grapefruit juice
• Pregnancy category X
• Examples: Lipitor (atorvastatin),
  Pravachol (...
Bile Acid Sequestrants
• Bind bile acids in the intestinal
  lumen. This causes the bile acids to
  be excreted in feces a...
Bile Acid Sequestrants
• Especially lower LDL
• Examples are: Questran
  (cholestyramine) and Welchol
  (colesevelam)
• Of...
Fibrates
• Tricor (fenofibrate)
• Lopid (gemfibrozil)
• These drugs increase oxidation of
  fatty acids in liver and muscl...
Fibrates cont.
• Can cause hepatotoxicity
• Main side effects include: diarrhea,
  GI discomfort, cause gallstones,
  inte...
Niacin (nicotinic acid)
• Decreases both cholesterol and
  triglycerides
• Bottom line—decreases hepatic
  synthesis of TG...
Niacin
• Side effects include: flushing,
  pruritus, gastric irritation. May cause
  hyperglycemia, hyperuricemia,
  eleva...
Niacin
• More effective in preventing heart
  disease when used in combination
  with another dyslipidemic such as a
  bil...
• Zetia (ezetimibe) Inhibits absorption
  of cholesterol from small intestine
• Don’t give with Questran
  (cholestyramine...
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ANTIHYPERTENSIVES, DIURETICS, ANTICOAGULANTS AND DYSLIPIDEMICS

  1. 1. ANTIHYPERTENSIVES, DIURETICS, ANTICOAGULANTS AND DYSLIPIDEMICS PHARMACOLOGY NUR 3703 BY LINDA SELF
  2. 2. Hypertension • Hypertension common in US, up to 60 million afflicted • Leads to MI, heart failure, stroke and renal disease • Strong correlation with metabolic syndrome
  3. 3. Blood Pressure Classification according to the JNC 7 • Normal SBP<120 and DBP <80 • Prehypertension SBP 120-139 and DBP 80-89 • Stage 1 Hypertension SBP 140-159 or DBP 90-99 • Stage 2 Hypertension SBP > or equal to 160 or DBP > or equal to 100
  4. 4. Types of Hypertension • Essential or primary—etiology ?. Contributors include: salt sensitivity, insulin resistance, genetics, sleep apnea, environmental factors,others • Secondary—renal, adrenal, coarctation of the aorta, steroids, pregnancy
  5. 5. BP review • Any condition that affects heart rate, stroke volume or peripheral vascular resistance affects arterial blood pressure • Compensatory mechanisms to maintain balance between hypotension and hypertension
  6. 6. BP review • BP regulation operates in a negative feedback system • Baroreceptors and chemoreceptors in the carotid arteries and aortic arch detect changes in arterial blood pressure and in pO2, pCO2 and H+. • Increased BP results in increased stretch of vessels; activation of vagus and stimulation of medulla via sympathetic or parasympathetic pathways.
  7. 7. BP review Normally, when the arterial blood pressure is elevated 1. Kidneys will excrete more fluid 2. Fluid loss will result in decreased ECF volume and blood volume 3. Decreased blood flow to the heart will reduce cardiac output 4. Decreased CO reduces arterial blood pressure
  8. 8. BP review cont. 5. Vascular endothelium produces vasodilating substances (nitric oxide, prostacyclin) which reduce blood pressure
  9. 9. Essential Hypertension • Activation of sympathetic nervous system causing prolonged vasoconstriction • Activation of RAAS plays integral part as well • In combination, mechanisms cause prolonged increased vascular resistance; this in turn results in a thickening of vessel walls, less production of nitric oxide (vasodilator) and increased endothelin (increased vascular tone)
  10. 10. Essential Hypertension • Also felt that hyperinsulinemia and insulin resistance cause endothelial dysfunction by enhanced oxygen free radical-mediated damage and decreased nitric oxide bioavailability. Also is an increased sympathetic response; results in increased vascular tone and constriction
  11. 11. Nonpharmacologic Management of Hypertension • Weight reduction • Exercise • Salt restriction in diet • Stress reduction • DASH eating plan • Moderation in alcohol intake • If systolic BP cannot be maintained <140 systolic, tx.
  12. 12. Antihypertensive Drugs • Classes: 1. Angiotensin converting enzyme inhibitors (ACEI) 2. Angiotensin II Receptor Blockers 3. Antiadrenergics 4. Calcium channel blockers 5. Diuretics 6. Direct vasodilators 7. Renin inhibitors
  13. 13. ACEIs • Block the enzymes that convert angiotensin I to angiotensin II (potent vasoconstrictor) • Have action of vasodilation and decrease aldosterone production • Inhibit breakdown of bradykinins (vasodilator) prolonging effect
  14. 14. ACEIs • Reverse remodeling of heart muscle and blood vessels • Reno-protective • Excellent for heart failure and hypertension • Improve post-myocardial infarction survival • Used alone or in combination
  15. 15. ACEIs • Useful in heart failure as decrease peripheral vascular resistance, cardiac workload and ventricular remodeling • Captopril is the prototype • Low incidence of side effects • Can cause cough or hypotension when first started
  16. 16. ACEIs • Can cause hyperkalemia • Should never be used during pregnancy • May not be as effective in African Americans—may add diuretic in this population to increase efficacy
  17. 17. ACEIs • Lotensin (benazepril) • Capoten (captopril) • Vasotec (enalapril) • Zestril (lisinopril) • Altace (ramipril) • Aceon (perindopril)
  18. 18. Angiotensin II Receptor Blockers (ARBs) • Block effects of angiotensin II, compete with angiotensin II for tissue binding sites • Block the receptors in brain, kidneys, heart, vessels and adrenal tissue
  19. 19. ARBs • Similar end results as seen with ACEIs • Less likely to cause hyperkalemia • Persistence of cough is rare • Prototype is Cozaar (losartan)
  20. 20. Examples of ARBs • Atacand (candesartan) • Cozaar (losartan) • Diovan (valsartan) • Micardia (telmisartan) • Benicar (olmesartan)
  21. 21. Antiadrenergics • Inhibit activity of the sympathetic nervous system • Effective in decreasing heart rate, force of myocardial contraction, cardiac output, and blood pressure
  22. 22. Antiadrenergics • Alpha 1 adrenergics receptor blocking agents dilate vessels and decrease peripheral vascular resistance • Can experience first dose phenomenon with orthostatic hypotension, dizziness, syncope, possible sodium and fluid retention
  23. 23. Antiadrenergics-Alpha 1 • Cardura (doxazosin) • Minipress (prazosin) • Hytrin (terazosin)
  24. 24. Antiadrenergics • Centrally acting sympatholytics stimulate presynaptic alpha 2 receptors in the brain • Less norepinephrine is released and sympathetic outflow is reduced • Results in decreased cardiac output, heart rate, peripheral vascular resistance and blood pressure
  25. 25. Antiadrenergics—Alpha 2 agonists • Centrally acting agents also can result in fluid and sodium retention • Catapres (clonidine)—orally or by patch • Tenex (guanfacine) • Aldomet (methyldopa)
  26. 26. Beta Adrenergic Blockers • Decrease heart rate, force of myocardial contraction, cardiac output, and renin release from the kidneys • Drugs of choice with patients with tachycardia, angina, MI, left ventricular hypertrophy and high renin hypertension • Most are pregnancy category C and D
  27. 27. Beta Blockers • Inderal (propranolol) • Corgard (nadolol) • Lopressor (metoprolol) • Tenormin (atenolol) • Kerlone (betaxolol) for glaucoma (ophthalmic), hypertension (orally)
  28. 28. Calcium Channel Blocking Agents • Useful in hypertension as dilate peripheral arteries and decrease peripheral vascular resistance by relaxing vascular smooth muscle • Monotherapy or in combination • Tolerated well in renal failure
  29. 29. Calcium Channel Blocking Agents • Norvasc (amlodipine) • Cardizem (diltiazem) • Plendil (felodipine) • Procardia (nifedipine) • Calan (verapamil)—may cause gingival hyperplasia • Note these are also Pregnancy category C
  30. 30. Diuretics • Useful in hypertension due to their sodium and water depletion • May be used as monotherapy • Preferred in the elderly and in African- Americans • Should be included in any multi-drug regimen • Thiazide diuretics are most commonly used diuretics for hypertension
  31. 31. Diuretics • Hydrodiuril (HCTZ)
  32. 32. Vasodilators • Relax smooth muscle in blood vessels resulting in dilation and decreased peripheral vascular resistance • Reduce afterload so helpful in heart failure • May cause sodium and water retention
  33. 33. Vasodilators • Limited effect when used alone. Vasodilating action that lowers BP also stimulates SNS. This, in turn, triggers reflexive compensatory mechanisms that raise BP
  34. 34. Vasodilators • Corlopam (felodapam)—IV infusion, in hypertensive emergencies, avoid in patients with allergies to sulfites • Apresoline (hydralazine)—IV, IM or PO. Can cause orthostatic hypotension. • Rogaine (Minoxidil) po or topical
  35. 35. Ethnic Considerations • Use calcium channel blockers, diuretics and alpha blockers most effective in African Americans; beta blockers, ACEIs and some ARBs are not as effective as in Caucasians • Beta blockers have greater effects on Asians than in Caucasians
  36. 36. Hypertensive Emergencies • Is defined as having end organ damage or diastolic BP of 120 torr or higher • With oral medications, use captopril 25-50mg po every 1 to 2 hours or clonidine , 0.2mg initially then 0.1mg every hour until diastolic blood pressure falls below 110 torr or 0.7mg has been given
  37. 37. Hypertensive Emergencies • Nitroglycerine—tolerance develops over 24-48 hours • Nitroprusside—intraarterial bood pressure should be monitored; metabolized to thiocyanate (precursor to cyanide), a toxic metabolite. Measure serum levels if drug given over 72h. Is photosensitive.
  38. 38. Hypertensive Emergencies • Corlopam (felodopam)—IV infusion, use short term.
  39. 39. Herbals that affect BP • Ephedra (ma huang) • Gingseng • Yohimbe (for erectile dysfunction) • caffeine
  40. 40. • In regards to anti-hypertensives, should not abruptly stop any of them. May develop rebound hypertension.
  41. 41. Diuretics • Indicated for the treatment of edematous and nonedematous conditions • May be useful in preventing renal failure by sustaining urine flow • A minimum daily urine output of approx. 400ml is required to remove normal amounts of metabolic end products
  42. 42. Diuretics • Act on kidneys to decrease absorption of sodium, chloride, water and other substances such as calcium • Major subclasses are: thiazides, loop and potassium-sparing diuretics • Each act at different sites of the nephron
  43. 43. Diuretics Used to manage: • Edema and ascites • Management of heart failure • Hypertension
  44. 44. Thiazide Diuretics • Chemically related to sulfonamides so caution with sulfa allergies • Used in long term management of heart failure and hypertension • Affect distal convoluted tubule • Effectiveness decreases as the GFR decreases. Ineffective when GFR is < 30mL/minute. As rising creatinine noted, should use alternative such as loop diuretic.
  45. 45. Thiazide Diuretics • Diuril (chlorothiazide) • Hygroton (chlorthalidone) • HydroDIURIL (hydrochlorothiazide)
  46. 46. Loop Diuretics • Inhibit sodium and chloride reabsorption in the ascending limb of the Loop of Henle • Potent diuresis • Need to restrict dietary sodium when taking these meds • Lasix (furosemide) is the prototype
  47. 47. Loop Diuretics • Bumex (bumetamide) more potent than Lasix • Can give either as oral agents, IV or IM • Rapid administration can cause deafness • Must monitor potassium levels, I&0, also weight would be optimum
  48. 48. Potassium Sparing Diuretics • Act at distal tubule to decrease reabsorption of sodium and potassium excretion • Spironolactone (prototype) blocks the sodium retaining effects of aldosterone • Weak diuretics when used alone, often used in combination • Contraindicated in renal failure
  49. 49. Osmotic Diuretics • Produce rapid diuresis by increasing the solute load of the glomerular filtrate • Water is pulled into the intravascular space and excreted via kidneys • Useful in managing oliguria or anuria • Can prevent acute renal failure during prolonged surgery, trauma or during chemotherapy
  50. 50. Osmotic Diuretics • Help reduce increased ICP, reduction of intraocular pressure before certain ophthalmic surgery and for urinary excretion of toxic substances • Examples include: Osmitrol (mannitol), Ismotic (isosorbide) and Osmoglyn (glycerin)
  51. 51. Drugs that affect Coagulation • Thrombosis may occur in both arteries and veins • Arterial thrombi cause disease by obstructing blood flow which can result in tissue ischemia or death • Venous thrombosis is associated with venous stasis. A venous thrombus is less cohesive than an arterial embolus so venous emboli more prevalent
  52. 52. Hemostasis • Hemostasis is the prevention or stoppage of blood loss from an injured blood vessel. Process involves vasoconstriction, formation of a platelet plug, activation of clotting factors and growth of fibrous tissue into the blood clot making it more stable.
  53. 53. Clot Lysis • When clot is being formed, plasminogen is bound to fibrin and becomes a component of the clot • After tear in blood vessel is repaired, plasminogen is activated by plasminogen activator to produce plasmin. Plasmin (enzyme) breaks down the fibrin mesh and dissolves the clot.
  54. 54. Blood Coagulation Factors • I fibrinogen • II prothrombin • Ill thromboplastin • IV calcium • V Labile factor • VII proconvertin or stable factor • VIII antihemophilic factor • IX Christmas factor • X Stuart factor • XI plasma thromboplastin antecedent • XII Hageman factor • XIII fibrin-stabilizing factor
  55. 55. Anticoagulants • Given to prevent formation of new clots and extension of clots already present; do not dissolve clots already present • Prototype is Heparin • Heparin may be used in pregnancy • Weight based dosing per institutional nomogram
  56. 56. Heparin • Usually will give a loading dose then calculated dosage per 24h; e.g. 15- 25units/kg/h for IV dosing • Monitor aPTT, should be 1.5-2.5 control value—normal value is 35 sec. • Can cause heparin induced thrombocytopenia • Reversal agent is protamine sulfate
  57. 57. Heparin • Combines w/antithrombin III which will inactivate clotting factors IX, X, XI and XII, inhibits conversion of prothrombin to thrombin and prevents thrombus formation. Further affects coagulation by preventing conversion of fibrinogen to fibrin, inhibiting factors V,VIII, XIII and platelet aggregation.
  58. 58. Low Molecular Weight Heparins • Given subcutaneously in abdomen and do not require close monitoring of blood coagulation tests • Still should follow platelet counts • Fragmin (dalteparin) • Lovenox (enoxaparin)
  59. 59. Coumadin (warfarin) • Most commonly used oral anticoagulant • Drug acts in liver to prevent synthesis of vitamin K-dependent clotting factors (II,VII,IX, X). Acts as a competitive antagonist to hepatic use of vitamin K. • Anticoagulant of choice for long-term maintenance therapy.
  60. 60. Coumadin (warfarin) • Anticoagulant effects do not occur for 3-5 days after warfarin is started • Has no effect on platelets or on circulating clotting factors • Regulated according to the INR (international normalized ratio) . Therapeutic values are generally 2 to 3.
  61. 61. Coumadin • INR is based on prothrombin time. Normal baseline or control PT is 12 seconds, therapeutic value is 1.5 times the control or 18 seconds. • Use of INR has eliminated disparities in different labs
  62. 62. Coumadin • Dosage reduction in patients with biliary tract disorders, liver disease, malabsorption syndromes, and hyperthyroidism. These conditions increase anticoagulant drug effects by reducing absorption of vitamin K or decreasing hepatic synthesis of clotting factors • Has multiple, multiple drug interactions • Counteract with vitamin K
  63. 63. Other anticoagulants • Orgaran (danaparoid)—low molecular weight, heparin-like drug. Given subq. Used in management of hip surgery, ischemic stroke or in those who cannot take heparin. Does not contain heparin. • Refludan (lepirudin)—used as heparin substitutes • Arixtra (fondaparinux) –binds to clot bound factor Xa, inhibits thrombon productions
  64. 64. Other Anticoagulants cont. Trade and generic names • Refludan (lepirudin) • Argatroban (same generic name) • Arixtra (fondaparinux) • Angiomax (bivalirudin)
  65. 65. Antiplatelet Drugs • Arterial thrombi are composed primarily of platelets • Antiplatelet drugs act by inhibiting platelet activation, adhesion, aggregation, or procoagulant activity. • Include drugs that block platelet receptors for thromboxane, ADP, glycoprotein IIb/IIIa and phosphodiesterase inhibitors
  66. 66. Thromboxane A2 Inhibitors • Work by inhibiting synthesis of prostaglandins. TA inhibitors work by acetylating cyclooxygensase, the enzyme in platelets that synthesizes thromboxane A2 (which causes platelet aggregation). • ASA is example. It affects the platelets for the life of the platelet. • NSAIDs not so useful as action wears off as drug wears off
  67. 67. Adenosine Diphosphate Receptor Antagonists • Ticlid (ticlopidine) • Inhibit platelet aggregation by preventing ADP-induced binding between platelets and fibrinogen. This reaction inhibits platelet aggregation irreversibly and persist for the lifespan of the platelet (9- 10 days) • Indicated in TIAs • Adverse effects-neutropenia, diarrhea, skin rashes
  68. 68. Adenosine Diphosphate Receptor Antagonists • Plavix (clopidogrel) • Fewer side effects than ASA or Ticlid • indicated for patients with atherosclerosis for reduction of MI, stroke and vascular death • Does not need reduction in those with renal problems
  69. 69. Glycoprotein IIb/IIIa Receptor Antagonists • Reopro (abciximab) is a monoclonal antibody that prevents the binding of fibrinogen, von Willebrand factor and other molecules to GP IIb/IIIa receptors on activated platelets. This action inhibits platelet aggregation. • Used with percutaneous transluminal coronary angioplasty or removal of atherosclerotic plaque to prevent rethrombosis
  70. 70. Reopro cont. • Used with aspirin and heparin and is contraindicated in clients who have recently received oral anticoagulants or IV dextran. • Other contraindications include active bleeding, thrombocytopenia, history of stroke, surgery or trauma within past 6 weeks, uncontrolled hypertension or hypersensitivity.
  71. 71. Other glycoprotein IIb/IIIa Receptor antagonists • Integrilin (Eptifibatide) • Aggrastat (tirofiban) • Similar mechanism of action as Reopro • Indicated for acute coronary syndrome who are managed medically or by angioplasty or atherectomy
  72. 72. Glycoprotein IIb/IIIba receptor antagonists cont. • Contraindications include: recent bleeding, history of thrombocytopenia, history of stroke within 30 days, major surgery or severe trauma within past month, severe hypertension, hx of intracranial hemorhage, neoplasm, AV malformation, or aneurysm; platelet ct less than 100,000 or creatinine greater than 2 mg/dL
  73. 73. Phosphodiesterase Inhibitors • Pletal (cilostazol) increases cAMP which then inhibits platelet aggregation and produces vasodilation. Drug reversibly inhibits platelet aggregation. • Indicated for intermittent claudication. • Contraindicated in patients with heart failure • Most common SE is diarrhea and headache
  74. 74. Miscellaneous • Persantine (dipyridamole) inhibits platelet aggregation but mechanism is unclear • Used for prevention of thromboembolism after cardiac valve replacement and is given with Coumadin
  75. 75. Thrombolytics • Given to dissolve thrombi • Stimulate conversion of plasminogen to plasmin, an enzyme that breaks down fibrin (the framework of a thrombus) • Used in severe thromboembolic disease such as MI, PE and ileofemoral thrombosis
  76. 76. Thrombolytics • Goal is to re-establish blood flow and prevent tissue damage • Also used to dissolve clots in arterial or venous cannulas or catheters • Must obtain baseline INR, aPTT, platelet count and fibrinogen • Will monitor labs 2-3 hours after thrombolytic tx is instituted to determine efficacy
  77. 77. Thrombolytics • Activase (alteplase), Retavase (reteplase) and TNKase (tenecteplase) are tissue plasminogen activators used mainly in acute MI to dissolve clots. • Eminase (anistreplase), Streptase (streptokinase) and Abbokinase (urokinase) are enzymes that break down fibrin. Used to lyse coronary clots in acute MI.
  78. 78. Thrombolytics cont. • Xigris (drotrecogin alfa) is a recombinant version of human activated protein C. Is approved for use in sepsis. Sepsis causes inappropriate blood clot formation and may lead to DIC. Xigris useful in this situation.
  79. 79. Drugs Used to Control Bleeding • Amicar (aminocaproic acid) and Cyklokapron (tranexamic acid) are used to stop bleeding caused by overdoses of thrombolytic agents • Trasylol (aprotinin) indicated in patients undergoing CABG . Inhibits breakdown of blood clotting factors.
  80. 80. Important reminders • Risk factors for thromboembolism 1. Obesity 2. MI 3. Atrial fibrillation 4. Prosthetic heart valves 5. ASHD 6. OCP or HRT 7. Hx of DVT or Pe 8. Cigarrette smoking 9. Immobility
  81. 81. Overview of cholesterol panel Total cholesterol Desirable-less than 200 Borderline high—200-239 High—240 or greater LDL Desired <100 Above optimal—100-129 Borderline high—130-159 High-160-189 Very high190
  82. 82. Overview cont. HDL • High >60 • Low <40 Triglycerides Normal—less than 150 Borderline high—150-199 High--200 to 499 Very high—500 or above
  83. 83. Dyslipidemia • Associated with athersclerosis and numerous pathophysiologic effects • Elevated total cholesterol, high LDL and low HDL are all risk factors for CAD • TG indicated excessive caloric intake; excessive proteins and carbohydrates are converted to TG and obesity
  84. 84. Contributors to dyslipidemia • Hypothyroidism • Diabetes mellitus • Alcoholism • Obesity, beta blockers, oral estrogens, gluccorticoids, sertraline, thiazide diuretics, protease inhibitors
  85. 85. Dyslipidemia cont. • High dietary intake also increases the conversion of VLDL to LDL cholesterol, and high dietary intake of TG and saturated fat decreases the activity of LDL receptors and increases synthesis of cholesterol.
  86. 86. Types of Lipoproteins • LDL—unfavorable type. Transports 75% of serum cholesterol to peripheral tissues and the liver. High levels are atherogenic • VLDL—contains 75% TG and 25% cholesterol. Transports endogenous TG to fat and muscle cells. • HDL—favorable type. This LP transports cholesterol back to the liver for catabolism and excretion.
  87. 87. Initial Management • Treat conditions that contribute to elevated lipids (DM, hypothyroidism) • Start low fat diet • Increase intake of fiber-lowers LDL • Cholesterol lowering margarines • Weight reduction • Exercise—increases HDL • Smoking cessation • HRT
  88. 88. Drug Therapy • Based on the type of dyslipidemia and its severity • Classes of agents include: HMB- CoA reductase inhibitors or ―statins‖, fibrates, bile acid sequestrants and niacin in different forms • Lovaza • Zetia
  89. 89. HMG-CoA reductase inhibitors or “statins” • Inhibit an enzyme (hydroxymethylglutaryl-coenzyme A reductase) required for hepatic synthesis of cholesterol • Decrease serum cholesterol, LDL, VLDL and TG • Reach maximal effects within about 6 weeks
  90. 90. Statins cont. • Drugs also reduce C reactive protein, associated with inflammation and development of CAD • Undergo extensive first pass metabolism • Metabolism occurs in liver
  91. 91. Statins cont. • Adverse effects include:HA, diarrhea, rashes, headaches, constipation, hepatotoxicity and myopathy. • Should obtain baseline LFTs and then at 6 and 12 weeks after starting then every 6 months • If serum aminotranferases increase to more than 3x normal, should be reduced or DCed.
  92. 92. Statins cont. • Do not take with grapefruit juice • Pregnancy category X • Examples: Lipitor (atorvastatin), Pravachol (pravastatin), Zocor (simvastatin), Lescol (fluvastatin)
  93. 93. Bile Acid Sequestrants • Bind bile acids in the intestinal lumen. This causes the bile acids to be excreted in feces and prevents their being recirculated to the liver. Thus, the liver will use cholesterol to produce bile acids thus decreasing serum levels.
  94. 94. Bile Acid Sequestrants • Especially lower LDL • Examples are: Questran (cholestyramine) and Welchol (colesevelam) • Often used with patients already on a statin • Long term use can affect absorption of folate, Vitamins A,D,E,K
  95. 95. Fibrates • Tricor (fenofibrate) • Lopid (gemfibrozil) • These drugs increase oxidation of fatty acids in liver and muscle tissue thus decreasing hepatic production of TG, VLDL and increase HDL. • Most effective drugs for reducing TG.
  96. 96. Fibrates cont. • Can cause hepatotoxicity • Main side effects include: diarrhea, GI discomfort, cause gallstones, interact with Coumadin
  97. 97. Niacin (nicotinic acid) • Decreases both cholesterol and triglycerides • Bottom line—decreases hepatic synthesis of TG and secretion of VLDL (which leads to decreased production of LDL) • Need high doses for efficacy
  98. 98. Niacin • Side effects include: flushing, pruritus, gastric irritation. May cause hyperglycemia, hyperuricemia, elevated hepatic aminotransferase enzymes and hepatitis. • Can reduce flushing by starting with low doses, taking dose with meals, and taking ASA 325mg thirty minutes before taking dose
  99. 99. Niacin • More effective in preventing heart disease when used in combination with another dyslipidemic such as a bile acid sequestrant or a fibrate.
  100. 100. • Zetia (ezetimibe) Inhibits absorption of cholesterol from small intestine • Don’t give with Questran (cholestyramine) • Lovaza

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