Cardiovascular Drugs

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Cardiovascular Drugs

  1. 1. CV DRUGS
  2. 2. HYPERLIPIDEMIA
  3. 3. HLD DRUGS Mechanism of Action Clinical Use Side Effects Statins Inhibit HMG-CoA reductase, modify platelets and endothelium, suppress inflammation Lower LDL (1st line for hyperlipidemia) Myopathy, hepatotoxicity, drug interactions Ezetimibe Inhibit NPC1L1 at brush border in small intestine Lower LDL (2nd line for hyperlipidemia, use is decreasing) Muscle weakness, transaminitis (worse w/ statins) Bile acid resins (“C” drugs) Bind cholesterol in intestinal lumen and prevent recycling to liver Lower LDL (3rd line for hyperlipidemia) GI (gas, diarrhea), drug interactions, no systemic side effects b/c not absorbed Niacin Decreases lipolysis in adipose tissue, increases HDL by decreasing hepatic removal of HDL Increases HDL, decreases TGs Cutaneous flushing due to PGs (take aspirin), insulin resistance Fibrates Activate PPAR-alpha to enhance oxidation of FAs Increases HDL, decreases TGs GI, myopathy, augment effects of oral hypoglycemic drugs for diabetes Fish oil Not well defined, PPAR-alpha agonist? Decreases TGs May prolong bleeding time
  4. 4. ANTIANGINAL
  5. 5. ANTIANGINAL Mechanism of Action Clinical Use Side Effects Nitrates (1) Metabolized to NO  relax great veins  decrease venous return  decrease preload  reduces work of heart and O2 consumption (2) Relax arterioles somewhat  decreased TPR  decreased aortic pressure  decreased ejection time (3) Dilate coronary arteries somewhat Short-acting nitroglycerin: acute treatment before angina, prophylactic before activity Long-acting isosorbide: chronic anginal treatment Both short- and long-acting: headache, nausea, dizziness, hypotension, don’t use with sildenafil! Long-acting: tolerance (need nitrate-free interval) Ranolazine Reduces late Na channel current Last-resort in refractory angina that cannot be treated with PCI or CABG (pt is usually poor surgical candidate) Hydralazine Unknown cellular mechanism Vasodilates arterioles  reducing afterload Antihypertensive that works particularly well in African American pts and pregnant women Causes reflex tachycardia  use beta-blocker! Headache, SLE-like syndrome
  6. 6. ANTIANGINAL/ CHF DRUGS Mechanism of Action Clinical Use Side Effects Beta-blockers (Non-selective and β1 selective) Decrease O2 consumption by decreasing HR and contractility. Also decrease renin production to some extent, decreasing BP. Don’t use in Printzmetal angina or cocaine intoxication  β blockade causes coronary vasoconstriction. Chronic angina (mortality benefit!), heart failure (mortality benefit!), hypertension Common: fatigue, impotence, depression. Bradyarrhythmias, bronchospasm (β2 blockade), peripheral arterial vasospasm (β2 blockade) Careful with diabetics NOT WITH PRINZMETAL Calcium channel blockers (CCBs) Non-dihydropyridines: verapamil and diltiazem  reduce Ca channel activity in arteries AND myocardium (decreases TPR  decreased myocardial consumption; decreased myocardial contractility) Dihydropyridines: “-ipines”  reduces Ca channel activity in arteries, no effect on cardiac myocytes Non-dihyropyridines: chronic stable angina, variant angina, beta-blocker intolerance, mortality benefit in normal LV fxn ONLY. Dihydropyridines: hypertension, variant angina, sometimes in CHF Non-dihydropyridines: hypotension, bradycardia, AV block, peripheral edema (diltiazem) Dihydropyridines: peripheral edema, hypotension, headache, flushing
  7. 7. CCBs are contraindicated in HF
  8. 8. ANTITHROMBOTICS
  9. 9. Describe basic platelet physiology • Lifespan of platelet: T ½ = 10 days • Adhesion: Platelets adhere to exposed subendothelial collagen when there’s endothelial damage. This occurs through glycoprotein receptors via von Willebrand factor. • Activation: Platelets stick to exposed basement membrane proteins through glycoproteins (VCAM-1). This activate platelets, causing ADP and serotonin to be released and TXA2 to be synthesized and released . These will activate more platelets. • Platelet aggregation: GP IIb/IIIa is a glycoprotein receptor on platelets responsible for binding to fibrinogen. When the platelet is activated, GP IIb/IIIa will bind to the RGD motif of fibrinogen. Fibrinogen is a dimer, so a second platelet can bind to the other end, which leads to platelet aggregation and the formation of the platelet plug
  10. 10. Central role of factors X, prothrombin, and thrombin in the coagulation cascade.
  11. 11. ANTIPLATELET DRUG Mechanism of Action Clinical Scenario Aspirin Irreversible, nonselective COX-1 and -2 inhibitor Angina, acute MI, TIA, stroke Dipyridamole Blocks uptake of adenosine, PDE inhibitor Prophylaxis (prosthetic heart valves, stroke) ADP Receptor Antagonists Clopidogrel Irreversibly inhibits ADP receptors (use in people allergic to aspirin) Recent MI, unstable angina, recent stroke, PAD, post-stenting Prasugrel Irreversibly inhibits ADP receptors, *metabolized more efficiently Prevention of CV thrombosis, PCI Ticagrelor Reversibly inhibits ADP receptors, not a pro-drug Prevention of CV thrombosis after MI GpIIb/IIIa Inhibitors Abciximab Monoclonal Ab that blocks GpIIb/IIIa During PCI Eptifibatide Small molecule that blocks Gp IIb/IIIa During PCI Tirofiban Small molecule that blocks Gp IIb/IIIa During PCI
  12. 12. Aspirin • MOA: Non-selective, irreversible inhibitor of both cyclooxygenase-1 and -2 (COX-1 and -2). NSAIDs block formation of TXA2 and PGI2. Blocking TXA2 is beneficial because TXA2 normally triggers platelet aggregation. • Clinical Use: Low dose (30mg/day) used for prevention of MI, High dose (70-375mg) used in acute cases of stable angina, unstable angina, STEMI and NSTEMI. • Extremely important to use in patients with known CV disease. • Adverse effects: GI discomfort, modest increase in peptic ulcer disease and GI/systemic bleeding (remember that prostaglandin, which aspirin inhibits, protects the stomach)
  13. 13. ADP Receptor Inhibitors
  14. 14. ADP Receptor Inhibitor MOA • Inhibit ADP-mediated activation of platelets. • Extracellular ADP normally activates platelets by binding to two types of purinoceptors, P2Y1 (acts via phospholipase C to increase intraplatelet Ca) and P2Y12 (acts via inhibitory G protein to reduce cAMP production, which increases intraplatelet Ca). • ADP-induced platelet activation requires simultaneous activation of both the P2Y1 and P2Y12 purinoceptors. • The ADP receptor antagonists irreversibly block P2Y12 receptors, inhibiting platelet aggregation. • Contraindications for all agents in this class: • Active pathological bleeding such as peptic ulcer or intracranial hemorrhage
  15. 15. Clopidogrel • Clinical Use: The most commonly used agent. Pro-drug that must be metabolized to active metabolite by the CYP2C19 enzyme in the liver. • Slightly better than aspirin in preventing MI and stroke. • Used as aspirin substitute for patients who are allergic/intolerant to aspirin. • Used after placement of coronary stents. • Adverse effects: Bleeding, dyspepsia, diarrhea, very rare severe neutropenia and thrombotic thrombocytopenic purpura (TTP)
  16. 16. Prasugrel • Clinical Use: Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently. • This drug is mainly used during percutaneous coronary interventions (PCI) in the cath lab.
  17. 17. Ticagrelor • Clinical Use: percutaneous coronary interventions • 1. Direct acting - not a prodrug; does not require metabolic activation  Rapid onset of inhibitory effect on the P2Y12 receptor  Greater inhibition of platelet aggregation than clopidogrel • 2. Reversibly bound - Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel • Functional recovery of all circulating platelets • Adverse effects • Dyspnea • Bradyarryhthmias
  18. 18. GP IIb/IIIa Inhibitors
  19. 19. High Risk of Bleeding
  20. 20. Abciximab • Genetically engineered monoclonal antibody • Its Fc portion has been cleaved off so it can only bind to and inhibit platelets without splenic uptake and which reduces thrombocytopenia. • Clinical Use: • Adjunct (to heparin and aspirin) during percutaneous coronary interventions (PCI: balloon angioplasty, stenting, atheroablation) • Prevention of acute cardiac ischemic complications in patients at high risk for abrupt closure of the treated coronary vessel • Use in patients with unstable angina not responding to conventional medical therapy, when PCI is planned within 24 hours.
  21. 21. Eptifibatide • A synthetic cyclic heptapeptide with a KGD sequence, which more specifically blocks GP IIb/IIIa receptors. • Modeled after disintegrins found in snake venom, which contain the arginine-glycine-aspartic acid (RGD) motif. • Approved for use in patients with acute coronary syndrome (ACS): unstable angina or acute myocardial infarction. • Also used in patients during percutaneous coronary intervention (PCI).
  22. 22. Tirofiban • First in class synthetic, non-peptide, GP IIb/IIIa inhibitor (peptidomimetic). Based on RGD sequence. • In patients with unstable angina, tirofiban reduced myocardial infarctions and deaths by 22% when used with heparin and aspirin. • Approved for use with heparin for the treatment of ACS and during PCI.
  23. 23. Use Warfarin instead of Antiplatelet Agents for Atrial Fibrillation
  24. 24. Anticoagulants • Unfractionated Heparin • Low Molecular Weight Heparin • Fondaparinaux • Bivalirudin • Warfarin • Clinical Use: DVT prophylaxis and treatment, pulmonary embolism (PE), ACS, PCI
  25. 25. ANTICOAGULANT Mechanism of Action Clinical Scenario Heparins UFH Anti-thrombin and anti-Xa activity DVT, PE, post-MI, UA/NSTEMI, coats stents LMWH (enoxaparin, dalteparin) Mostly anti-Xa activity Similar to UFH, but easier dosing, no monitoring and less. Fondaparinux Synthetic inhibitor of factor Xa, even more selective than LWMH Prophylaxis after knee, hip replacement Direct Thrombin & Xa Inhibitors Lepirudin Direct thrombin inhibitor Used in pts w/ HIT Bivalirudin Direct thrombin inhibitor Unstable angina & PTCA, for pts w/ HIT Argatroban Direct thrombin inhibitor Thrombosis in pts w/ HIT Dabigatran Direct thrombin inhibitor After hip/knee replacement, pts w/ Afib Ximelagatran Binds to thrombin active site Discontinued RivaroXaban Direct Xa inhibitor—binds to free and unbound Xa Afib, after hip/knee replacement Warfarin Competitively inhibits vitamin K (II, VII, IX, X, protein C, protein S) VTE prevention, DVT, Afib, prosthetic heart valves, MI
  26. 26. Thrombin • Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). Thrombin is a "trypsin-like" serine protease protein. • Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions. • Additionally, thrombin is the most potent of the activators of platelets and platelet aggregation so inhibition of thrombin also diminishes platelet aggregation. • Thrombin is also known to be a mitogen for smooth muscle cell proliferation.
  27. 27. UFH • MOA: binds with antithrombin III and stimulates its anti protease activity. Once bound to UFH, the natural anticoagulant effect of antithrombin is potentiated, resulting in accelerated binding and inactivation of serine proteases such as coagulation factors X a and thrombin. • Antithrombin III inactivates several enzymes of the coagulation system. It inactivates factors IIa (thrombin), IXa, XIa and Xa. • Side Effects: Bleeding, Heparin Induced Thrombocytopenia • Contraindications: hypersensitivity, actively bleeding, hemophiliacs, severe hypertension, infective endocarditis, active tuberculosis, GI ulcers, visceral carcinomas, advanced hepatic or renal disease, or blood brain barrier is compromised (brain or eye surgery, lumbar puncture).
  28. 28. LMWH • Enoxaparin and Dalteparin • LMWHs are derived by enzymatic or chemical cleavage from UFH into a mixture of glycosaminoglycans. They inhibit factor Xa to a greater extent because they retain the specific sequence that binds antithrombin during the breakdown process. LMWHs are cleared renally, so must use caution in renal failure. • Superior bioavailability, limited nonspecific binding, and non-dose-dependent half-lives facilitate once or twice-daily subcutaneous dosing based solely on weight and without laboratory monitoring. • Cleared by renal mechanisms. • Less heparin-induced thrombocytopenia (HIT).
  29. 29. Mechanism of HIT and HITT • Allergy-like adverse reaction to heparin. Occurs in about 3% of patients treated for more than 4 days. • Type I: occurs due to mild direct platelet activation by heparin. Associated with early (within 4 days) decrease in platelet count, typically recovers in 3 days, not associated with major clinical sequelae. • Type 2: occurs due to antibodies to complexes between heparin and platelet factor 4 (PF4). Associated with substantial fall in platelet count between days 4 and 14 of treatment. Generally causes life-threatening thrombotic and thromboembolic complications (e.g., DVT, PE, MI, stroke, occlusion of limb arteries that can lead to amputation). Mortality is 20-30% without treatment.
  30. 30. HIT • HIT Type I is a benign form of HIT that is not associated with an increased risk of thrombosis. Its mechanism is unclear, but it appears that heparin causes a non-immune-mediated platelet aggregation, thus reducing the circulating platelet count, called thrombocytopenia. It generally does not lower platelets less than 100,000 (normal is 150,000-300,000). It appears in the first 2 days of heparin exposure and it can be managed expectantly without discontinuation of heparin. • HIT Type 2 is a clinically significant syndrome that typically develops between days 4 and 14 of heparin treatment. It is life- and limb-threatening with mortality 20-30%. Platelets typically fall to about 60,000. All forms of heparin must be discontinued immediately. Type 2 HIT is due to antibodies to platelet factor 4 (PF4) complexed to heparin.
  31. 31. PF4 • PF4 is a small, positively charged molecule of uncertain biological function normally found in the alpha-granules of platelets. When platelets are activated, PF4 is released into circulation and some of it binds to the platelet surface. Because of opposite charges, heparin (negatively charged) binds to the PF4 molecules, exposing epitopes that act as immunogens leading to antibody production. • People who develop HIT produce an IgG antibody against the heparin-PF4 complex, which binds to the heparin-PF4 complex on the platelet surface through the Fab region. The Fc portion of the HIT antibody can then bind to the platelet Fc receptor, triggering the aggregation of platelets. Activated platelets release PF4, perpetuating the cycle of heparin-induced platelet activation. Platelet activation also leads to the activation of the coagulation cascade. • HIT antibodies can form complexes with endogenous heparan sulfate on the endothelial surface and induce tissue factor expression, further activating the coagulation cascade. Thrombocytopenia is largely due to clearance of activated platelets and antibody-coated platelets by reticuloendothelial system. • Therefore, although there is thrombocytopenia present (normally leads to bleeding), the huge amount of platelet activation and coagulation cascade activation leads to thrombosis.
  32. 32. Direct Thrombin Inhibitors • Bivalirudin: anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty • Argatroban: used for prophylaxis or treatment of thrombosis with HIT and recently approved for use in patients with or at risk for HIT undergoing percutaneous coronary interventions • Lepirudin: patients with HIT. no longer produced as of May 31, 2012 • Direct thrombin inhibitors can inhibit thrombin in clots and can be used in patients with HIT. The action of InDirect inhibitors are dependent on Antithrombin and can bind only “soluble” thrombin that is unbound to Fibrin. • Direct Thrombin Inhibitors bind to the active site of Thrombin and can inactivate Thrombin regardless of the presence of Fibrin.
  33. 33. Warfarin • MOA: Related to vitamin K and acts as competitive inhibitor. Blocks vitamin K cycle by inhibiting vitamin K epoxide reductase and vitamin K reductase, preventing gamma-carboxylation of factors II, VII, IX, X, and proteins C and S. • Side Effects: • Bleeding (1% per year for major bleeds) • Skin necrosis can occur between days 3-8. • “Purple toe syndrome” in patients with underlying atherosclerotic disease. Warfarin can break off cholesterol emboli and send them to the limbs. • Many drug interactions (cyt P450)
  34. 34. Treatment Regimens
  35. 35. Fibrinolytic Drugs • Mechanism of Action: all work directly or indirectly to cut inactive plasminogen to its active form, plasmin. Plasmin then degrades fibrinogen and fibrin network in thrombi and blood clots, actually dissolving the clot (the drugs we have previously discussed mostly prevent or stabilize existing clots). There are endogenous PAs in the body known as tissue-type PA (tPA) or urokinase (uPA). Fibrinolytics are modeled after these drugs. • Clinical Use: short-term treatment of multiple pulmonary emboli, DVT, acute MI (“time is muscle” in the heart, meaning use within several hours) • Side Effect: bleeding!, do not use with severely elevated blood pressures (higher risk of bleeding)
  36. 36. FIBRINOLYTICS Mechanism of Action Clinical Use Side Effects Streptokinase When complexed with plasminogen, can convert other plasminogen molecules into plasmin, massive lytic state Rarely used Produced by beta-hemolytic Streptococci, 6% allergic reactions; see below Urokinase plasminogen activator (uPA) Not specific for fibrin, so produces massive lytic state Rarely used See below Tissue-type plasminogen activator (tPA; alteplase) More specific for clots because fibrin acts as cofactor for tPA’s activation of plasminogen (half-life = 3 min) Thrombolytic in ACS when no access to PCI, ischemic stroke, PE; administered as IV infusion See below Reteplase (rPA) Derivative of tPA with longer half-life Same; can be administered as IV bolus See below Tenecteplase (TNK-tPA) Derivative of tPA with longer half-life Same; can be administered as IV bolus See below All Fibrinolytics Break down plasminogen to plasmin, which degrades fibrinogen and fibrin. Thrombolytic in ACS, ischemic stroke, PE BLEEDING!, do not use with elevated BP
  37. 37. Contraindications for Fibrinolytics • Active internal bleeding • History of CVA • Recent surgery or trauma • Intracranial neoplasm or aneurysm • Known bleeding disorder • Severe uncontrolled HTN
  38. 38. Primary Hemostasis • Platelets are responsible for primary hemostasis (formation of a platelet plug) by a three-part process: • (1) adhesion to the site of injury, • (2) release reaction (secretion of platelet products and activation of key surface receptors), and • (3) platelet aggregation. • • When there is damage to the endothelial cells, basement membrane proteins are exposed. Platelets bind to these proteins through integrin receptors and agonists such as collagen and thrombin then bind to the platelets themselves. • These interactions activate platelets, causing (1), the release of granules containing ADP and serotonin (5-HT), and (2), stimulation of thromboxane A2 (TXA2) synthesis. Both (1) and (2) activate more platelets. • ADP interacts with ADP receptors found on platelets, leading to platelet aggregation. ADP causes the expression of GP IIb/IIIa receptors. • GP IIb/IIIa receptor: This receptor is located on the platelets and binds fibrinogen molecules as additional platelets are recruited. This allows the platelets to tightly link to one another.
  39. 39. Secondary Hemostasis • The coagulation cascade is secondary hemostasis. The coagulation cascade results in the formation of a fibrin clot that can reinforce the primary platelet plug. • Factor X is converted to Factor Xa via the extrinsic and intrinsic coagulation pathways. Factor Xa converts prothrombin (aka Factor II) to thrombin (aka Factor IIa). Thrombin can then convert soluble fibrinogen to insoluble fibrin, which crosslinks to form the clot. Thrombin also activates Factor XIII, which stabilizes the fibrin clot.
  40. 40. Fibrinolytic System • The fibrinolytic system is how the body breaks down a clot. It leads to (1), cleavage of the fibrin mesh, and (2), destruction of coagulation factors. Plasmin is the major protease enzyme of this system – it binds to fibrin and degrades it. Conversion from its inactive form, plasminogen, is controlled by tissue plasminogen activator (t-PA).
  41. 41. CHF PHARMACOLOGY
  42. 42. Adrenergic System • The fall in CO is sensed by baroreceptors in the carotid sinus and aortic arch  they decrease their firing, and the signal is sent through CN IX and X to the cardiovascular control center in medulla • This results in increased sympathetic outflow to the heart and peripheral circulation, and parasympathetic tone is diminished. • The immediate consequences of this are an increased heart rate, increased ventricular contractility and vasoconstriction, sweating, skin vasoconstriction, increased renin release, cardiac deterioration (fibrosis etc.)
  43. 43. Renin-Angiotensin-Aldosterone • 1) Decreased renal perfusion, 2) Decreased salt delivery to macula densa, 3) Direct stimulation of juxtaglomerular β2 receptors by sympathetic nervous system  Renin Secretion • Renin cleaves angiotensinogen to angiotensin, which is cleaved by ACE to form angiotensin II (a potent vasoconstrictor). • constricted arterioles and raises total peripheral resistance • Angiotensin II also increases intravascular blood pressure by stimulating thirst and increasing aldosterone secretion. • Aldosterone promotes sodium reabsorption from the distal convoluted tubule of the kidney, and increases intravascular volume
  44. 44. Explain why heart failure can cause pulmonary congestion and/or peripheral edema. • Compensations only work for a while, and eventually become harmful. Increased circulating volume and venous return can further engorge the lung vasculature and/or lead to peripheral edema. • If the Left Ventricle or Right Ventricle is unable to work properly, there will be a backup of fluid. • LV heart failure will lead to an increased LA pressure, and increased pressure in the pulmonary veins and capillaries, which leads to fluid leakage and congestion. • RV heart failure will lead to an increased RA pressure, and an increased venous pressure in the SVC and IVC, leading to peripheral edema.
  45. 45. Describe how nitrates reduce dyspnea in patients with acute CHF, and recognize that hypotension is a possible side effect. • Nitropaste • 1. Dilates veins and reduces preload, so it leads to reduced congestion. • 2. Dilates arteries and reduces TPR and afterload, leading to improved CO. • BP must be monitored to avoid hypotension
  46. 46. Identify the mechanisms by which morphine reduces dyspnea in patients with acute congestive heart failure. • In acute CHF, dyspnea is caused by pulmonary edema and acute LV failure. • Morphine • 1. CNS-mediated reduction in breathing rate, and reduces discomfort from breathing so quickly. • 2. CNS- mediated SNA reduction leads to a reduction in TPR and tachycardia, and increased capacity of peripheral circulation. • 3. Vasodilation caused by peripheral histamine release, and a convenient anxiolytic effect.
  47. 47. Frank Starling Relationship
  48. 48. Understand why reducing peripheral resistance increases cardiac output in a heart failure patient but not in a normal individual or one with hypertension but without heart failure • In the normal heart reducing TPR/afterload produces little change in CO but in HF, the reduced ventricular contraction cannot overcome outflow resistance. Reducing peripheral resistance in CHF patients reduces the afterload on the LV which permits increased SV and CO in patients.
  49. 49. Indicate the benefit of reducing cardiac return in a volume-overloaded heart failure patient. • Reducing cardiac return in a volume-overloaded heart failure patient reduces the preload on the left ventricle, which in turn, causes diastolic pressure to fall out of the range that promotes pulmonary congestion.
  50. 50. Digoxin • MOA: Digoxin binds to the outward K+ binding site of the Na+/K+ ATPase and inhibits the enzyme. This reduces the transmembrane Na+ gradient. Reduction of the Na+ gradient reduces the action of the Na+/Ca2+ exchanger, causing intracellular [Ca2+] to build up. This increases the sarcoplasmic reticulum [Ca2+], which will release more Ca2+ upon release. The ultimate effect is an increase in contractile force. • Digoxin has a narrow therapeutic window of 0.7-1.2 ng/dL. It is renally excreted, so many drugs affect its renal clearance. • Hypercalcemia, Hypokalemia and Hypomagnesia all increase toxicity. • Side Effects: • GI: anorexia, vomiting, nausea, diarrhea • CNS: visual disturbances • Cardiac dysrhythmias (bradyarrhythmias evolving into heart block or ventricular arrhythmias) • Digoxin may be beneficial to patients with atrial fibrillation because it promotes AV block, which allows the ventricular rate to slow; after which, antiarrhythmics can be used return normal sinus rhythm.
  51. 51. ACE Inhibitors • Lisinopril • 3 beneficial effects: vasodilation, natriuresis (excretion of Na+), attenuation of cardiac remodeling • MOA: ↓ AngII and ↑bradykinin • ↓ afterload and TPR due to ↓vasoconstrictor action of AngII, ↓ NE release by AngII, ↑ vasodilation by bradykinin • ↓ preload by ↓ venoconstriction and ↓ intravascular volume (natriuretic) • ↓ aldosterone secretion • ↓ remodeling of myocardium • SE: • Due to bradykinin accumulation : cough, skin rashes, angiodema • K retention (bad news in presence of K-sparing diuretic, good news in presence of furosemide • First dose orthostatic hypotension • Risk of severe fetal injury if the drug is used after the first trimester. • Acute Renal failure in patient with bilateral high grade renal artery stenosis.
  52. 52. Beta Blockers • Carvedilol, Metoprolol • Action: • Improve cardiac performance by ↓ HR, ↑diastolic ventricular relaxation & by ↓O2 consumption. • ↓ renin release and contribute to ↓Angiotensin II and Aldosterone. • ↓ the cardiotoxic effects of NE (fibrosis, remodeling) • Protect against arrhythmias including ventricular fib. • Can reduce afterload • DECREASE SYMPATHETIC NA • 3rd line agent (after ACE inhibitors and loop diuretics). • Indicated for treatment of stable symptomatic HF stages II & III. • Therapy must be started only when a patient is not fluid overloaded otherwise the reduced contractility would result in a worsening of HF due to increased preload, venous pressure and congestion. • Only 2nd and 3rd generations are used.
  53. 53. Why is SNA so increased in Heart Failure • Inhibitory cardiopulmonary reflexes (baroreceptor /cardiac ventricular reflex) are down-regulated. • Excitatory sympathetic reflexes from the heart and ischemic tissues are enhanced. • Release of NE from sympathetic terminals is increased by Ang II & aldosterone. • Hypoxic impulse – peripheral chemoreflex • Muscle metaboreflex
  54. 54. Aldosterone Antagonists • Spironolactone & eplerenone • Action: • K+ sparing diuretics. • ↓effects of aldosterone • Potentiate diuretic effect of furosemide • Promote K retention which is anti-dysrhythmic if K is low • ↓ direct and indirect (via NE) toxicity of aldosterone on heart • Improve the ratio of vagal / sympathetic drive to the heart (↓sinus node dysfunction, ↑vagal tone). • ↓ overall mortality in HF patients already treated with ACEI + loop diuretic. • Eplerenone has fewer GI and sexual side effects
  55. 55. MOA Thiazides • Inhibit Na+Cl– cotransporter in the distal convoluted tubule • ↓NaCl reabsorption • Commonly used to ↓ ventricular preload. • Not potent enough beyond stage II to be given as sole diuretic, because their already small natriuretic • Action is further decreased by the reduction in GFR. • Potentiate effect of loop diuretics • Hydrochlorothiazide, Metolazone • SE: hypokalemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia, metabolic acidosis, hypersensitivity
  56. 56. MOA Loop Diuretics • Compete for the Cl- binding site on the Na-K-2Cl in loop of Henle • ↓ NaCl reabsorption • Commonly used to ↓ Na and H2O retention • More effective than other diuretics in HF • Maintain their effectiveness despite low GFR • Effectively treats congestion and edema • Used in stage II and beyond • Furosemide: optimal dose 40mg IV bolus • SE: Hypokalemia, ototoxicity, metabolic acidosis, hypovolemia, hyperuricemia, hypomagnesia, sulfa allergy
  57. 57. Isosorbide Dinitrate with Hydralazine • Isosorbide ↓preload. Hydralazine ↓afterload. • Effective but not uniformly well tolerated (because of hydralazine). • 3rd-line alternative and usually less effective than ACEIs or ARBs. • Used in patients who cannot tolerate ACEIs • This combo produces added benefits in subsets of African-Americans when added to the standard regimen (Diuretic + BB + ACEI or ARB) • Hydralazine: - high incidence (about 20%) of side-effects in <10% of patients with most serious SE: reversible lupus-like syndrome.
  58. 58. MOA Dobutamine • β1/β2 agonist with α1-AR agonist activity. • ↑CO and ↑ SV without much ↑ in HR and, typically, a slight ↓ in TPR. • IV administration • Only for short term support of circulation in patients with decompensated CHF or cardiac decompensation caused by cardiac surgery or acute MI. • Blocked by Beta Blockers
  59. 59. MOA Dopamine • Mixed DA receptor agonist (α1/β1/β2/D1). • At low dose infusion rate (<2-10 μg/ min), D1-receptor activation predominates and causes rather selective renal, splanchnic and coronary vasodilation relieving some of the work of the heart. • At intermediate doses (2-10 μg/ min) dopamine is a β1-agonist that also releases NE from sympathetic terminals by a mechanism akin to amphetamine. This effect produces β1-mediated ionotropic effect on heart (good) and tachycardia (bad) and some degree of vasoconstriction and afterload increase (bad). • This dose range may be also appropriate for acute treatment of CHF. • At still higher doses (>10 μg/ min), DA is a powerful α1 agonist. This dose range is inappropriate in CHF but is useful in hypotensive states such as shock. • Side-effects (concern with hi-dose therapy): tachycardia, tachyarrhythmias.
  60. 60. MOA Milrinone • Inhibits type III phosphodiesterase (PDE). PDE inhibitors prevent the hydrolysis of cAMP and cGMP. • In the heart PDE inhibitors have a positive inotropic effect since cAMP increases intracellular Ca release and contractility. • In VSM PDE inhibitors generally produce relaxation because VSM contraction is typically reduced by cAMP (e.g. caused by beta-2AR agonists)or by cGMP (e.g. caused by NO). • Overall effects in HF: • Combination of inotropic effect and decreased preload/afterload has short term benefits. • PDE inhibitors cannot be used chronically because they increase mortality (probable reason: they increase contractile demand in a sick heart and they cause ventriculararrhythmias). • SE: nausea and vomiting, cardiac arrhythmias, thrombocytopenia
  61. 61. Recombinant ANP/BNP • Nesiritide is synthetic human natriuretic peptide (BNP). This drug is natriuretic, diuretic, has vasodilator effects and inhibits the effects of renin and aldosterone. • BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. • BNP infusion may be useful for the treatment of decompensated congestive heart failure requiring hospitalization. • The clinical potential of BNP is limited as it is a peptide and requires infusion. • SE: dizziness, nausea, cardiac arrhythmias, hypotension, headache • NOT in patients with BP<90mmHg
  62. 62. Diuretics reduce preload and increase CO
  63. 63. Acute HF Profile
  64. 64. Names to Know • Inotropics • Glycosides/digitalis • Digoxin • Digitoxin • Phosphodiesterase inhibitors • inamrinone (Inocor), milrinone (Primacor) • Beta-agonists • dobutamine (Dobutrex), dopamine • Diuretics • Thiazides • hydrochlorothiazide (Hydrodiuril). Metolazone. • Loop diuretics • furosemide (Lasix), bumetanide (Bumex) • Potassium-sparing • spironolactone (Aldactone), eplerenone. • Vasodilators • ACE inhibitors • Captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril) • Other vasodilators • Isosorbide dinitrate (Isordil, others) • Hydralazine (Apresoline) • Sodium nitroprusside
  65. 65. ANTI-ARRHYTMICS
  66. 66. Overview • I. INa (fast sodium channels; inhibition) • 1A: Procainamide, quinidine, disopyramide • 1B: Lidocaine, Mexiletine, Phenytoin, Tocainide • 1C: Encainide, Flecainide, Propafenone • II. Beta-adrenergic receptor antagonists (Ca channels all cells) • Esmolol, Metoprolol, Propanolol, Acebutolol • III. Delayed rectifiers (K channels, inhibition) • Amiodarone, Sotalol, Dronedarone, Dofetilide, Ibutilide • IV. Calcium channels • Diltiazem • Verapamil • Others • Adenosine: adenosine A1 receptors (agonist) • Digoxin: Na/K ATPase blocker • MgSO4
  67. 67. Rate vs. Rhythm Control • Rate control consists of restoring the ventricular rate to normal which, usually, restores hemodynamic stability. This may be achieved by rendering the AV node more refractory (less excitable) using pharmacological agents such as beta-blockers or calcium channel blockers. • Rhythm control means returning the heart rate to sinus rhythm, i.e. under the sole control of the SA node. This is more difficult to achieve pharmacologically. • Class I and III target rhythm in the SA node, while all classes can target rate
  68. 68. Hypoxia • 1. During hypoxia, ATP production is insufficient  Dysfunction of of the Na/K ATPase  potassium equilibrium potential ++++ and the diastolic potential +++  enhanced propensity to get activated inappropriately. • 2. Hypoxia-induced depolarization  fast sodium channels remain inactive during diastole  fewer channels can open during phase 0 of the action potential  membrane potential changes more slowly (reduced dV/dt)  AP propagates more slowly along the ventricle. • Increased spontaneous activation potential + the slowing of the action potential in and around an ischemic area can lead to reentry.
  69. 69. Cholinergic Stimulation • Cholinergic receptor stimulation (muscarinic) produces much the same effects in the SA and AV node but their consequences on heart function are different. • A. Shared effects of cholinergic receptor stimulation in the SA and AV node: • Combined inhibition of If and activation of I K,Ach decreases the rate of diastolic depolarization • Decreased calcium current  phase 0 dV/dt is smaller and threshold of the AP is higher • B. Consequences of these actions in the SA node: • If inhibition, activation of I K,ACh plus increase in AP threshold slows down the action potential frequency causing bradycardia (negative chronotropic effect). • The reduction of phase 0 dV/dt is unimportant functionally. • BRADYCARDIA • C. Consequences of the actions of ACh in the AV node: • Decrease in phase 0 dV/dt slows action potential velocity and increases atrio-ventricular delay. • Slower diastolic depolarization + increase of the AP threshold  AV node less excitable. • LOWER EXCITABILITY
  70. 70. Sympathetic Stimulation • Beta1-adrenergic receptor stimulation of the heart occurs naturally during exercise and emotional stress because of a rise in sympathetic tone. • A. Shared effects of Beta1-adrenergic receptor stimulation in the SA and AV node: • Activation of If and increased rate of diastolic depolarization (phase 4) • Increased ICa (calcium current)  phase 0 dV/dt is larger and AP threshold is lower • B. Consequence of these actions in the SA node: • If activation plus lowering of AP threshold speeds up the AP frequency (tachycardia, positive chronotropic effect). • Increase in phase 0 dV/dt within the SA node is inconsequential for cardiac physiology. • C. Consequences of these actions in the AV node: • Increase in phase 0 dV/dt speeds up action potential velocity and reduces AV delay (positive dromotropic effect). • Rapid diastolic depolarization plus the lowering of the AP threshold renders the AV node more excitable.
  71. 71. Hypokalemia and Hyperkalemia • >5.5 mM = high • >6.5 or <3 symptoms = emergency • >7 = arrhythmia • Hypokalemia • Increased AP duration → Arrhythmia • Delayed rectifier K+ current weaker  delays repolarization • Lengthens QT interval • Causes: Diuretics (especially thiazides or loop diuretics), Vomiting and diarrhea, Diabetes, metabolic alkalosis, β2 agonists, xanthenes, steroids, Cushing’s syndrome, Liver cirrhosis • Hyperkalemia • EK more positive → Cells closer to AP threshold → abnormal automaticity foci • Decreases AP duration, refractory period • Can inactivate Na+ channels → widens QRS • Causes: Spironolactone, ACE Inh., Ang. II receptor antagonists, Heparins, Renal failure, Hyperaldosteronism, Tissue destruction, Metabolic acidosis • Hypocalcemia increases AP duration and is arrhythmogenic
  72. 72. Abnormal Automaticity • Modulated by the autonomic nervous system • Sympathetic and Parasympathetic Stimulation • Cardiac injury may cause acquisition of spontaneous automaticity in non pacemaker cells due to leaky membranes • Sinus node: Sinus Tachycardia • AV node: AV junctional tachycardia • Ectopic focus: Ectopic atrial tachycardia and some VT • Rx: • 1) Reduce slope of phase 4 • 2) Make diastolic potential more negative • 3) Raise threshold.
  73. 73. Triggered Activity • Early afterdepolarizations • Occur during phase 2 or 3 in condutions that prolong QT intervals • Can de caused by Na+ or Ca+ influx • Torsades de pointes • Delayed afterdoplarizations • Develop in states of high intracellular calcium • APBs, VPBs, digitalis arrythmias, idiopathic VT • Stimulated by preceding action potential, NOT spontaneous • Rx: • 1) Shorten AP duration • 2) Correct Calcium overload
  74. 74. Reentry • 2 Critical Conditions • Unidirectional Block • Slowed conduction through reentry path • Anatomic: atrial flutter, AVNRT, VT due to scar tissue • Functional: Afib, polymorphic VT, Vfib • Rx • 1) Decrease conduction in circuit • 2) Increase refractory period in reentrant circuit • 3) Suppress premature beats that can initiate reentry
  75. 75. AP velocity in ventricular myocytes is defined by fast sodium currents, not by speed of repolarization.
  76. 76. AP velocity through the AV node is largely regulated via the calcium channel current.
  77. 77. Pacemaker cells do NOT have a resting membrane potential.
  78. 78. Class IA • MOA: Moderate blockade of fast sodium channels • 1. Conduction through the ischemic area is already slow because few Na channels are in the closed state. Class I drugs bind to these channels prolongs phase 0 slowing rate of conduction  decreased reentry • 2. Increases ERP of the healthy tissue adjacent to the ischemic region. K+ blockade prolongs AP and refractory period  decreased reentry • 3. Increase threshold and decrease slope of phase 4 depolarization  Inhibition of pacemaker channels  decreased automaticity • Prolonged QRS and QT • Use: Reentrant and ectopic supraventricular/ventricular tachycardias • Drugs: • Quinidine: GI, cinchonism, QT elongation  torsades de pointes • Procainamide: Less QT elongation, lupus like syndrome • Disopyramide: Anticholinergic  constipation, urinary retention, glaucoma
  79. 79. Class IB • MOA: Mild blockade of fast sodium channels • Inhibits reentrant arrhythmias by reducing slope of phase 0 depolarization and slowing conduction velocity • Suppresses ectopic automaticity by decreasing slope of phase 4 spontaneous depolarization and raising threshold • Shortens AP and RP by blocking small sodium current in phase 2 • NO QT prolongation • Preferentially targets diseased and ischemic cells • Lidocaine suppresses delayed afterdepolarizations • Use: Ventricular arrhythmias due to ischemia and digitalis toxicity • Little effect on atrial activity • Drugs • Lidocaine: IV only, confusion, paresthesia, dizziness, seizures • Mexiletine: Oral, Dizziness, tremor, slurred speech, nausea, vomiting
  80. 80. Class IC • MOA: Potent block of fast sodium channels • Decrease upstroke of AP • Decrease conduction velocity in atrial, ventricular, and Purkinje fibers • Prolong refractory period in AV node • No change in AP duration • Increased mortality shown in patients with underlying structural heart disease • Use: Supraventricular arrhythmias without structural disease • Avoid in patients with LV dysfunction or CAD  can lead to heart failure • Drugs: • Flecainide: Oral, aggravation of ventricular arrhythmias and CHF, confusion, dizziness, and blurred vision • Propafenone: Also exhibits Beta blocker activity, few side effects apart from dizziness and taste disturbance.
  81. 81. QRS Widening: 1B<<1A<1C
  82. 82. Class II • MOA: Beta Blockers block decrease calcium and If currents • Inhibits reentrant arrhythmias by reducing slope of phase 0 depolarization and slowing conduction velocity. VERY IMPORTANT WHEN SYMPATHETIC TONE IS HIGH • Suppresses ectopic automaticity by decreasing slope of phase 4 spontaneous depolarization and raising threshold • Increases refractory period of AV node. • Afterdepolarizations caused by excessive catecholamines can also be prevented with Beta Blockers. • Increase PR Interval • Use: Atrial flutter, Afib, PSVT, APBs, VPBs, Ventricular arrhythmias. • Drugs: • Propanolol: bronchoconstriction, arrhythmias, fasting hypoglycemia • Acebutolol: bronchoconstriction, bradycardia, impotence, USE FOR DIABETES • Esmolol: bronchoconstriction, bradycardia, impotence, USE FOR DIABETES
  83. 83. Beta blockers affect If and Ca2+ conduction while Calcium Channel Blockers just affect Ca2+ conduction
  84. 84. Class III • MOA: Class III drugs block delayed rectifier K+ channels during phase 3 repolarization • Little effect on Phase 0 depolarization or conduction velocity • Prolong AP of Purkinje and ventricular myocytes • Class III antiarrhythmics increase the ERP by delaying repolarization and delaying the return of the fast sodium channels to the closed state. • Use: Ventricular arrhythmias, atrial flutter, Afib, Bypass tract mediated PSVT, HIGHLY EFFECTIVE, 1st line for cardiac resuscitation, commonly used in ventricular systolic dysfunction • Drugs: • Amiodarone: class I, II, and IV effects, vasodilator, negative inotropy • Pulmonary toxicity, bradycardia, ventricular arrhythmia, early afterdepolarization, torsades de pointes, hypotension, hypothyroidism, GI toxicity, increased LFTs, Muscle weakness, neuropathy, ataxia, tremors, sleep disturbance, corneal microdeposits • Dronedarone: no liver or thyroid toxicity, mainly GI side effects, contraindicated in advanced CHF • Dofetilide: Oral, QT prolongation, torsades de pointes • Ibutilide: IV, QT prolongation, torsades de pointes
  85. 85. Class IV • MOA: Blockade of L-type cardiac calcium channels • Suppress automaticity by slowing phase 4 spontaneous depolarization • Suppress reentry by decreasing slope of phase 0 and conduction velocity • Suppress reentry by lengthening the refractory period of the AV node • Raise threshold potential at SA node • Decrease HR • Decrease rapid atrial transmission • Use: SVT, Atrial Fibrillation, Atrial Flutter, Multifocal Atrial Tachycardia • Drugs: • Verapamil: hypotension, heart block • Diltiazem: hypotension, heart block • Contraindicated with Beta Blockers!
  86. 86. Adenosine • MOA: Binds to adenosine receptors and activates potassium channels  hyperpolarization • Suppresses spontaneous automaticity in SA node • Slows conduction through AV node • Inhibits adenylate cyclase  Decreases cAMP  decrease If and Ca2+ currents • Slows SA node firing and decreases AV node conduction • First line in Afib, rapid termination of reentrant SVT • Not effective in ventricular myocytes • SE: headache, chest pain, flushing, bronchoconstriction, higher doses may be needed in patients using theophylline and caffeine
  87. 87. Digoxin • MOA: The Na/K ATPase pumps 3 K ions into the cell for every 2 Na ions expelled outside the cell. Digoxin binds the enzyme in a region that is close to the K binding site. Dig and K compete for this binding site. This is important because it means that the enzyme is more active during hypokalemia than during hyperkalemia. • ATPase impairment produces some degree of depolarization of the nerve terminals which is interpreted by the brain as being caused by an elevated level of blood pressure. The abnormal activation of the baroreceptors triggers the baroreflex namely a reduction of sympathetic tone and an increase in vagal tone to the heart. These effects combine to reduce AV nodal excitability and therefore protect against ventricular tachycardia in the context of Afib. • Digoxin’s use is reserved to cases of Afib associated with congestive heart failure.
  88. 88. Therapeutic Management of SVTs • Atrial fibrillation: Most common supraventricular arrhythmia • Rate control: with AFib, we attempt to delay AV node transmission by rendering AV node more refractory. • 1. Digoxin (not as effective) • 2. Diltiazem (IV) • 3. Verapamil (IV) • 4. ß-blockers (II) • 5. Amiodarone (III) • 6. Adenosine IV • Doesn't normalize the A-fib, just normalizes HR and makes heart more hemodynamically stable. • Rhythm control: Requires alteration of the sinus node, which is difficult to do pharmacologically. • 1. Can use class IA/C or III drugs • 2. Electrical cardioversion • Prevent thrombus: Anticoagulants to prevent abnormal coagulation in atria • 1. Warfarin, heparin, etc. • CHRONIC treatment: • 1. AV node ablation • 2. Ablation of re-entry areas • 3. Chronic anticoagulation and AV-blocking drugs
  89. 89. Carotid Massage • Carotid massage activates the baroreceptors. It is not recommended on older patients who may have atherosclerotic plaques at the bifurcation of the carotid arteries. • The Valsalva maneuver is an alternate way to cause a vagal discharge that may break an SVT. The maneuver consists of trying to exhale through a closed glottis. An intense vagal discharge occurs at the end of the maneuver.
  90. 90. CHA2DS2VAS2 • Algorithm for Anticoagulation • Congestive Heart Failure • Hypertension • >75 (2) • DM • Stroke/TIA (2) • Vascular disease • >65 • Sex category

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