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CONGESTIVE HEART FAILURE DR. MA. LENY ALDA G. JUSAYAN INTERNAL MEDICINE, FPSECP, RN, RMT Department of Pharmacology
COURSE OBJECTIVES: <ul><li>Explain the pathophysiology of heart failure </li></ul><ul><li>Discuss the different drugs used...
HEART FAILURE <ul><li>Inability of the heart to pump an adequate amount of blood to the body’s needs  </li></ul><ul><li>CO...
Heart Failure (Pump Failure) <ul><li>A disorder in which the heart  loses its ability to pump blood efficiently  throughou...
PATHOPHYSIOLOGY: <ul><ul><li>Heart failure results in DEPRESSION of the ventricular function curve </li></ul></ul><ul><ul>...
Heart Failure   Pathophysiology:   Impaired Cardiac Function <ul><li>Failure to pump:  </li></ul><ul><li>Failure to empty ...
Heart Failure  Compensatory mechanisms of low CO… <ul><li>1.  SNS stimulation…  ↑  HR  and  </li></ul><ul><li>cardiac cont...
Heart Failure  Compensatory mechanisms of low CO… <ul><li>1.  SNS stimulation…  ↑  HR  and  </li></ul><ul><li>cardiac cont...
Compensatory Mechanisms in Heart Failure <ul><li>Mechanisms designed for acute loss in cardiac output </li></ul><ul><li>Ch...
PATHOPHYSIOLOGY: <ul><li>STARLING’S LAW </li></ul><ul><ul><li>“ Within limits, the force of ventricular contraction is a f...
CARDIAC FAILURE    VENOUS PRESSURE    CARDIAC OUTPUT    BLOOD PRESSURE    SYMPATHETIC  ACTIVITY    RENAL BLOOD FLOW ...
NEUROHUMORAL ACTIVATION DURING MYOCARDIAL FAILURE MYOCARDIAL FAILURE    CARDIAC OUTPUT    BLOOD PRESSURE/TISSUE PERFUSIO...
COMPENSATORY RESPONSES DURING HEART FAILURE:    CARDIAC OUTPUT    CAROTID SINUS FIRING    RENAL BLOOD FLOW    SYMPATHE...
Pathophysiology of Cardiac Performance Factor  Mechanism  Therapeutic Strategy  1.  PRELOAD  (work or stress the heart fac...
 
 
 
EFFECTS: <ul><li>DOWN-REGULATORY CHANGES IN THE  β 1-ADRENOCEPTOR-G PROTEIN EFFECTOR SYSTEM </li></ul><ul><li>BETA 2 RECEP...
<ul><li>EXCESSIVE BETA ACTIVATION: </li></ul><ul><ul><li>LEAKAGE OF CALCIUM FROM THE SR VIA RyR2 CHANNELS – VENTRICULAR ST...
INTRINSIC COMPENSATORY RESPONSE: <ul><li>MYOCARDIAL HYPERTROPHY </li></ul><ul><ul><li>Increase in muscle mass to help main...
Causes  of Heart Failure <ul><li>Acute/Chronic  ♥ Problems </li></ul><ul><li>HTN -#1 </li></ul><ul><li>CAD </li></ul><ul><...
CAUSES OF HEART FAILURE: <ul><li>Final common pathway of many kinds of heart diseases </li></ul><ul><ul><li>Ischemic, alco...
CLASSIFICATION: <ul><li>SYSTOLIC DYSFUNCTION: </li></ul><ul><ul><li>Inadequate force is generated to eject blood normally ...
CLASSIFICATION: <ul><li>DIASTOLIC DYSFUNCTION </li></ul><ul><ul><li>Inadequate relaxation to permit normal filling  </li><...
CLASSIFICATION: <ul><li>HIGH OUTPUT FAILURE </li></ul><ul><ul><li>Increase demand of the body with insufficient cardiac ou...
CLASSIFICATION: <ul><li>ACUTE HEART FAILURE </li></ul><ul><ul><li>Sudden development of a large myocardial infarction or r...
CLASSIFICATION: <ul><li>CHRONIC HEART FAILURE </li></ul><ul><ul><li>Typically observed in patients with dilated cardiomyop...
 
PRECIPITATING CAUSES OF HEART FAILURE: <ul><li>Infection </li></ul><ul><li>Anemia </li></ul><ul><li>Thyrotoxicosis & pregn...
CLINICAL MANIFESTATIONS:
LEFT HEART FAILURE
Pulmonary Edema The most severe manifestation of Left Heart Failure  Fluid leak into the pulmonary interstitial spaces (Pu...
PULMONARY CONGESTION & RESPIRATORY SYMPTOMS: <ul><li>Result of dilatation & increasing left ventricular end diastolic pres...
 
 
 
Clinical picture… Left  Heart Failure <ul><li>Dyspnea/Dyspnea on exertion  (most sensitive: absence indicates Tx effective...
Cont. <ul><li>EDEMA OF THE BRONCHIAL MUCOSA </li></ul><ul><ul><li>Increases resistance to airflow producing respiratory di...
Cont: <ul><li>DYSPNEA </li></ul><ul><ul><li>Results from reflexes initiated by vascular distention </li></ul></ul><ul><ul>...
Cont. <ul><li>TACHYCARDIA </li></ul><ul><ul><li>An early compensatory response mediated by increased sympathetic tone </li...
Right  Heart Failure <ul><li>Clinical picture…( Congestion ) </li></ul><ul><ul><li>JVD, hepatomegaly and dependent edema (...
Heart Failure  Clinical manifestations :  Pulmonary Congestion (L)  and Systemic Congestion (R) Right Heart Failure Left H...
PHYSICAL EXAM: <ul><li>Jugular venous distention </li></ul><ul><li>S3 </li></ul><ul><li>Rales </li></ul><ul><li>Pleural ef...
 
Review: Subjective Data <ul><li>Pt. may c/o </li></ul><ul><li>anxiety </li></ul><ul><li>DOE </li></ul><ul><li>PND </li></u...
Review: Objective Data <ul><li>PA may reveal: </li></ul><ul><li>Left heart Failure </li></ul><ul><li>Tachypnea/SOB </li></...
FRAMINGHAM CRITERIA FOR DIAGNOSIS OF CHF: <ul><li>MAJOR CRITERIA </li></ul><ul><ul><li>PND </li></ul></ul><ul><ul><li>NECK...
NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSSIFICATION : <ul><li>CLASS I : no limitations on ordinary physical activities a...
<ul><li>CLASS III: results in no symptoms at rest, but fatigue with less than ordinary physical activity </li></ul><ul><li...
“ All the signs of CHF are the consequences of inadequate force of contraction&quot;
Potential Therapeutic Targets in Heart Failure  <ul><li>Preload   </li></ul><ul><li>Afterload  </li></ul><ul><li>Contracti...
CLINICAL MANAGEMENT OF CONGESTIVE HEART FAILURE <ul><li>OBJECTIVES: </li></ul><ul><ul><li>Increase cardiac contractility <...
<ul><li>Approaches : Reduce workload  of heart </li></ul><ul><li>1.Limit activity level reduce weight control hypertension...
<ul><li>4. Give  angiotensin-converting enzyme inhibitors (decreases afterload and retained salt and water) 5. Give  digit...
DRUGS COMMONLY USED IN HEART FAILURE
Positive Inotropic Agents   <ul><li>Cardiac Glycosides </li></ul><ul><li>Phosphodiesterase inhibitors </li></ul><ul><li> ...
Cardiac Glycosides <ul><li>digoxin  </li></ul><ul><li>digitoxin  </li></ul><ul><li>deslanoside  </li></ul><ul><li>ouabain ...
DIGITALIS <ul><li>Derived from foxglove plant  Digitalis lanata </li></ul><ul><li>Prototype – DIGOXIN </li></ul><ul><li>St...
BASIC PHARMACOLOGY OF DRUGS USED IN CONGESIVE HEART FAILURE : <ul><li>DIGITALIS </li></ul><ul><li>PHARMACOKINETICS: </li><...
PHARMACOKINETICS: <ul><li>T1/2  =  ( 40 hrs ) </li></ul><ul><li>Therapeutic plasma concentration:  </li></ul><ul><ul><li>0...
<ul><li>after intial dosages, digitalis is given in &quot;maintenance&quot; amounts sufficient to replace that which is ex...
METABOLISM & EXCRETION: <ul><li>Digoxin –  not extensively metabolized, 2/3 excreted unchanged in the kidneys </li></ul><u...
PROPERTIES OF CARDIAC GLYCOSIDES: OUABAIN DIGOXIN DIGITOXIN Lipid solubility (oil/water coefficient) Low Medium High Oral ...
MECHANICAL EFFECTS: <ul><li>Inhibit the monovalent cation transport enzyme coupled  Na+- K+ ATPase  & increased intracellu...
 
 
 
Mechanism of Digitalis Action: Molecular <ul><li>Inhibition of Na/K ATPase   </li></ul><ul><li>blunting of Ca 2+  extrusio...
ELECTRICAL EFFECTS: <ul><li>Produces alterations in the electrical properties of both contractile cells and the specialize...
Direct Electrophysiological Effects: Cellular Action Potential
Afterdepolarizations
TISSUE OR VARIABLE EFFECTS AT THERAPEUTIC DOSAGE EFFECTS AT TOXIC DOSAGE Sinus node    rate    rate Atrial muscle    Re...
EFFECTS IN HEART FAILURE: <ul><li>Stimulates myocardial contractility </li></ul><ul><li>Improves ventricular emptying </li...
 
Summary Direct Electrophysiological Effects <ul><li>Less negative membrane potential: decreased conduction velocity </li><...
Parasympathomimetic Effects  <ul><li>Decreased conduction velocity in the AV node  </li></ul><ul><li>increased effective r...
EKG Effects of Digitalis <ul><li>decrease in R-T interval  </li></ul><ul><li>inversion of T wave   </li></ul><ul><li>Uncou...
Therapeutic Uses of Digitalis <ul><li>Congestive Heart Failure   </li></ul><ul><li>Atrial fibrillation  </li></ul>
Overall Benefit of Digitalis to Myocardial Function   <ul><li>   cardiac output   </li></ul><ul><li>   cardiac efficienc...
Other Beneficial Effects  <ul><li>Restoration of baroreceptor sensitivity  </li></ul><ul><li>Reduction in sympathetic acti...
Adverse Effects  <ul><li>Cardiac  </li></ul><ul><ul><li>AV block  </li></ul></ul><ul><ul><li>Bradycardia  </li></ul></ul><...
INTERACTIONS: <ul><li>POTASSIUM </li></ul><ul><ul><li>HYPERKALEMIA: reduces enzyme inhibiting actions of digitalis, abnorm...
Serum Electrolytes Affect Toxicity <ul><li>K + </li></ul><ul><ul><li>Digitalis competes for K binding at Na/K ATPase </li>...
DIGITALIS INTOXICATION: <ul><li>Serious & potentially fatal complication </li></ul><ul><li>Anorexia, nausea & vomiting = e...
TREATMENT OF DIGITALIS INTOXICATION: <ul><li>Tachyarrythmias: withdrawal of the drug, treatment with beta blocker or lidoc...
Treatment of Digitalis Toxicity <ul><li>reduce dose:  1st degree heart block, ectopic beats </li></ul><ul><li>Atropine: ad...
PHOSPHODIESTERASE INHIBITORS <ul><li>BIPYRIDINES </li></ul><ul><ul><li>Inamrinone & Milrinone </li></ul></ul><ul><ul><li>L...
 
Phosphodiesterase Inhibitors: Therapeutic Use <ul><li>short term support in advanced cardiac failure   </li></ul><ul><li>l...
Adverse Effects of Phosphodiesterase Inhibitors <ul><li>Cardiac arrhythmias   </li></ul><ul><li>GI:  Nausea and vomiting  ...
 -Adrenoceptor and Dopamine Receptor Agonists   <ul><li>Dobutamine   </li></ul><ul><li>Dopamine   </li></ul>
BETA ADRENOCEPTOR STIMULANTS: <ul><li>DOBUTAMINE </li></ul><ul><ul><li>Increases cardiac output  </li></ul></ul><ul><ul><l...
 
Mechanism of Action:   Dobutamine   <ul><li>Stimulation of cardiac     adrenoceptors:    inotropy >    chronotropy   ...
Mechanism of Action:  Dopamine   <ul><li>Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors </li><...
Therapeutic Use   <ul><li>Dobutamine:   management of acute failure only  </li></ul><ul><li>Dopamine:   restore renal bloo...
Adverse Effects   <ul><li>Dobutamine   </li></ul><ul><ul><li>Tolerance   </li></ul></ul><ul><ul><li>Tachycardia </li></ul>...
DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS USED IN HEART FAILURE: <ul><li>DIURETICS </li></ul><ul><ul><li>Reduce salt & wate...
Diuretics:   Mechanism of Action in Heart Failure <ul><li>Preload reduction: reduction of excess plasma volume and edema f...
ACE Inhibitors in Heart Failure
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS: <ul><li>Reduce peripheral resistance     reduce afterload </li></ul><ul><li>Red...
Mechanism of Action   <ul><li>Afterload reduction   </li></ul><ul><li>Preload reduction   </li></ul><ul><li>Reduction of f...
ACE Inhibitors: Therapeutic Uses   <ul><li>Drugs of choice in heart failure (with diuretics) </li></ul><ul><li>Current inv...
 
VASODILATORS <ul><ul><li>Reduce the preload (through venodilatation), or reduction in afterload (through arteriolar dilata...
VASODILATORS: <ul><li>HYDRALAZINE, ISDN </li></ul><ul><ul><li>Reduction in preload  through venodilatation  </li></ul></ul...
VASODILATORS <ul><li>NESIRITIDE </li></ul><ul><ul><li>Brain natriuretic peptide (BNP) </li></ul></ul><ul><ul><li>Approved ...
VASODILATORS <ul><li>BOSENTAN </li></ul><ul><ul><li>Competitive inhibitor of endothelin </li></ul></ul><ul><ul><li>Oral </...
<ul><li>-Blockers in Heart Failure:     Mechanism of Action   </li></ul><ul><li>Standard   -blockers:  </li></ul><ul><ul>...
BETA-ADRENOCEPTOR BLOCKERS: <ul><li>BISOPROLOL, CARVEDILOL, METOPROLOL </li></ul><ul><ul><li>Reduction in mortality in pat...
DIURETICS
Principles important for understanding effects of diuretics <ul><li>Interference with Na +  reabsorption at one nephron si...
<ul><li>Diuretics act only if Na +  reaches their site of action.  The magnitude of the diuretic effect depends on the amo...
 
From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250 70% 20% 5% 4.5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excre...
 
 
RENAL TRANSPORT MECHANISM: <ul><li>PROXIMAL CONVOLUTED TUBULE: </li></ul><ul><ul><li>Carries out isosmotic reabsorption of...
LOOP OF HENLE: <ul><li>Pumps Na, K & Cl out of the lumen into the interstitium </li></ul><ul><li>Provides the concentratio...
DISTAL CONVOLUTED TUBULE: <ul><li>Actively pumps Na & Cl out of the lumen nephron </li></ul><ul><li>10 % Na reabsorbed </l...
COLLECTING TUBULE: <ul><li>Final site of NaCl reabsorption </li></ul><ul><li>Tight regulation of body fluid volume </li></...
<ul><li>Reabsorption of Na via the epithelial Na channel  (ENaC)  and its coupled K secretion is regulated by  aldosterone...
DIURETICS <ul><li>Drugs that increase the rate of urine flow </li></ul><ul><li>Increase the rate of Na & Cl excretion </li...
DIURETICS <ul><li>CLASSIFICATION: </li></ul><ul><li>CARBONIC ANHYDRASE INHIBITORS </li></ul><ul><li>OSMOTIC DIURETICS </li...
CARBONIC ANHYDRASE INHIBITORS: <ul><li>CLASSIFICATION & PROTOTYPES: ACETAZOLAMIDE (Diamox) – a sulfonamide derivative </li...
 
PHARMACOKINETICS: <ul><li>Well absorbed after oral administration </li></ul><ul><li>Onset of action: 30 minutes </li></ul>...
PHARMACODYNAMICS: <ul><li>Depresses the HC03 reabsorption in the PCT </li></ul><ul><li>Significant HC03 losses –  hyperchl...
CLINICAL USES: <ul><li>Treatment of glaucoma – major application </li></ul><ul><li>Urinary alkalinization </li></ul><ul><l...
TOXICITY: <ul><li>Hyperchloremic metabolic acidosis </li></ul><ul><li>Renal stones </li></ul><ul><li>Renal potassium wasti...
CONTRAINDICATIONS: <ul><li>HYPERAMMONEMIA </li></ul><ul><ul><li>Decrease urinary excretion of NH4 due to alkalinization of...
LOOP DIURETICS <ul><li>CLASSIFICATION & PROTOTYPES: Furosemide – prototype & sulfonamide derivative </li></ul><ul><li>Bume...
PHARMACOKINETICS: <ul><li>Rapidly absorbed  </li></ul><ul><li>Diuretic response is extremely rapid following IV injection ...
PHARMACOKINETICS: <ul><li>TORSEMIDE </li></ul><ul><li>Absorption: 1 hr </li></ul><ul><li>Duration: 4-6 hrs </li></ul><ul><...
MECHANISM OF ACTION: <ul><li>Inhibits the coupled Na+/K+/2Cl transport system  (NKCC2)  in the luminal membrane of the thi...
 
CLINICAL USES: <ul><li>Treatment of edematous states (CHF & ascites) </li></ul><ul><li>Acute pulmonary edema in w/c a sepa...
TOXICITY: <ul><li>Hypokalemic metabolic alkalosis </li></ul><ul><li>Hyperuricemia </li></ul><ul><li>Hypovolemia & cardiova...
THIAZIDE DIURETICS <ul><li>CLASSIFICATION & PROTOTYPE: </li></ul><ul><ul><li>HYDROCHLOROTHIAZIDE – sulfonamide derivative ...
 
MECHANISM OF ACTION: <ul><li>Inhibit NaCl transporter  (NCC)  in the early segment of the distal convoluted tubule  </li><...
EFFECTS: <ul><li>Urinary excretion </li></ul><ul><ul><li>Full doses – produce a moderate Na & Cl diuresis   hypokalemic m...
CLINICAL USE: <ul><li>Hypertension – major application, for w/c their long duration of action & moderate intensity of acti...
TOXICITY: <ul><li>Hypokalemic metabolic alkalosis &   hyperuricemia </li></ul><ul><li>Chronic therapy is often associated ...
CONRAINDICATIONS: <ul><li>HEPATIC CIRRHOSIS </li></ul><ul><li>BORDERLINE RENAL FAILURE </li></ul>
POTASSIUM SPARING DIURETICS: <ul><li>CLASSIFICATION & PROTOTYPES </li></ul><ul><ul><li>SPIRINOLACTONE, EPLERENONE– antagon...
CLINICAL USE: <ul><li>Hyperaldosteronism – important indication </li></ul><ul><li>Potassium wasting caused by chronic ther...
ADVERSE EFFECTS: <ul><li>Decrease K & H ion excretion and may cause  hyperchloremic metabolic acidosis </li></ul><ul><li>I...
TOXICITY: <ul><li>Hyperkalemia  – most important toxic effect </li></ul><ul><li>Metabolic acidosis in cirrhotic patients <...
CONTRAINDICATIONS: <ul><li>Oral K administration </li></ul><ul><li>Concomittant use of other agents that blunt the RAS (Be...
OSMOTIC DIURETICS <ul><li>CLASSIFICATION & PROTOTYPE: </li></ul><ul><ul><li>MANNITOL – prototype osmotic diuretic given in...
MECHANISM OF ACTION: <ul><li>Holds water in the lumen by virtue of its osmotic effect </li></ul><ul><li>Major location for...
EFFECTS: <ul><li>Volume or urine is increased </li></ul><ul><li>Most filtered solutes will be excreted in larger amounts u...
CLINICAL USES: <ul><li>Maintain high urine flow (when renal blood flow is reduced & in conditions of solute overload from ...
ANTIDIURETIC HORMONE AGONISTS <ul><li>VASOPRESSIN </li></ul><ul><li>DESMOPRESSIN </li></ul><ul><li>Treatment of central di...
TOXICITY: <ul><li>Nephrogenic Diabetes Insipidus </li></ul><ul><li>Renal failure </li></ul>
ANTIDIURETIC HORMONE ANTAGONISTS  <ul><li>CONIVAPTAN  </li></ul><ul><ul><li>Receptor antagonist </li></ul></ul><ul><li>LIT...
PHARMACODYNAMICS <ul><li>Inhibits the effects of ADH in the collecting tubule </li></ul><ul><li>Conivaptan – pharmacologic...
CLINICAL INDICATIONS: <ul><li>Syndrome of Inappropriate ADH Secretion (SIADH) </li></ul><ul><ul><li>When water restriction...
TOXICITY: <ul><li>Extracellular volume expansion </li></ul><ul><li>Dehydration </li></ul><ul><li>Hyperkalemia </li></ul><u...
Asymptomatic LV Dysfunction Mild to moderate CHF Moderate to severe CHF ACE inhibitor Digoxin Digoxin Beta blocker Diureti...
THANK YOU!!!
POST TEST <ul><li>1. Site of action of loop diuretics: </li></ul><ul><li>A. loop of henle  B. distal convoluted tubule </l...
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  • S
  • WHILE INCREASED PRELOAD, FORCE AND HR INTITIALLY INCREASE CARDIAC OUTPUT, INCREASED ARTERIAL TONERESULTS IN INCREASED AFTERLOAD &amp; DECREASED EJEX
  • EJECTION FRACTION IS THE RATIO OF THE STROKE VOLUME TO END-DIASTOLIC VOLUME WHICH MAY BE ESTIMATED BY RADIOCONTRAST OR RADIONUCLIDE ANGIOGRAPHY OR ECHOCARDIOGRAPHY THAT IS DEPRESSED IN SYSTOLIC hf EVEN WHEN THE STROKE VOLUME ITSELF IS NORMAL
  • Elevation in LVEDP (left ventricular end-diastolic pressure) Increases left atrial pressure Backs into the pulmonary vascular bed &amp;quot;Pulmonary edema&amp;quot; is water on the lungs.  Fluid is not only in the lung tissues, but actually in the air spaces as well.  This is a severe degree of heart failure, and requires immediate and aggressive management. When the heart&apos;s output decreases, the body does many things to try and compensate for it. It will release hormones to make the heart beat stronger. The heart will beat faster. Many of these reflexes however, only create a short term gain, and may ultimately hurt the heart&apos;s function. When the kidneys sense a decrease in flow, they release hormones which cause the body to hold sodium and water.  In the short term, this will lead to an increase in the volume of blood which is circulating, and provide the kidneys with the blood volume they are looking for.  However, this extra volume of fluid is more than can be held in the blood vessels, and it will start to exude out into the tissues of the bo Develops when the imbalance in pump function causes an increase in lung fluid secondary to leakage from pulmonary capillaries into the interstitium and alveoli of the lung. Life threatening situation in which the lung alveoli become filled with serosanguinous fluid. Most common cause is acut L venricular failure secondary to CAD –thus producing the cymptom of pink frothy sputum---
  • CONTROL OF CARDIAC CONTRACTILITY: CONTROL OF NORMAL CARDIAC CONTRACTILILITY CONTROL OF NORMAL CARDIAC CONTRACTILITY : SENSITIVITY OF THE CONTRACTILE PROTEINS TO CALCIUM, AMOUNT OF CALCIUM RELEASED FROM THE SR, AMOUNT OF CALCIUM STORED IN THE SR, AMOUNT OF TRIGGER CALCIUM &amp; ACTVITY OF SODIUM-CALCIUM EXCHANGER, INTRACELLULAR SODIUM CONCERTRATION &amp; ACTIVITY OF Na-K ATPase
  • Transcript of "Congestive hf lect"

    1. 1. CONGESTIVE HEART FAILURE DR. MA. LENY ALDA G. JUSAYAN INTERNAL MEDICINE, FPSECP, RN, RMT Department of Pharmacology
    2. 2. COURSE OBJECTIVES: <ul><li>Explain the pathophysiology of heart failure </li></ul><ul><li>Discuss the different drugs used in the treatment of heart failure as to its pharmacokinetics, pharmacodynamics, drug interactions, adverse effects </li></ul><ul><li>Clinical application of the use of drugs in acute and chronic types of heart failure </li></ul>
    3. 3. HEART FAILURE <ul><li>Inability of the heart to pump an adequate amount of blood to the body’s needs </li></ul><ul><li>CONGESTIVE HEART FAILURE – refers to the state in which abnormal circulatory congestion exists a result of heart failure </li></ul>
    4. 4. Heart Failure (Pump Failure) <ul><li>A disorder in which the heart loses its ability to pump blood efficiently throughout the body </li></ul><ul><li>Affects Cardiac Output </li></ul><ul><ul><li>SV X HR </li></ul></ul><ul><li>End result: </li></ul><ul><li>↓ Cardiac Output </li></ul>
    5. 5. PATHOPHYSIOLOGY: <ul><ul><li>Heart failure results in DEPRESSION of the ventricular function curve </li></ul></ul><ul><ul><li>COMPENSATION in the form of stretching of myocardial fibers </li></ul></ul><ul><ul><li>Stretching leads to cardiac dilatation which occurs when the left ventricle fails to eject its normal end diastolic volume </li></ul></ul>
    6. 6. Heart Failure Pathophysiology: Impaired Cardiac Function <ul><li>Failure to pump: </li></ul><ul><li>Failure to empty ventricles </li></ul><ul><li>& reduced delivery of blood into circulation (↓ CO) </li></ul><ul><li>Increased ventricular pressures </li></ul><ul><li>Elevated pulmonary and systemic pressures </li></ul><ul><li>further ↓ CO </li></ul><ul><li>Series of compensatory mechanisms </li></ul>
    7. 7. Heart Failure Compensatory mechanisms of low CO… <ul><li>1. SNS stimulation… ↑ HR and </li></ul><ul><li>cardiac contractility… ↑ CO </li></ul><ul><li>3. Ventricular hypertrophy … cardiac contractility… ↑ CO </li></ul><ul><li>2. Starling’s Law/… </li></ul><ul><li>Ventricular dilation : ↑ CO </li></ul>4 . Decreased renal blood flow…increasing Na & H20 retention…increases blood volume, ↑ HR & CO.
    8. 8. Heart Failure Compensatory mechanisms of low CO… <ul><li>1. SNS stimulation… ↑ HR and </li></ul><ul><li>cardiac contractility… ↑ CO </li></ul><ul><li>3. Ventricular hypertrophy … cardiac contractility… ↑ CO </li></ul><ul><li>2. Starling’s Law/… </li></ul><ul><li>Ventricular dilation : ↑ CO </li></ul>4 . Decreased renal blood flow…increasing Na & H20 retention…increases blood volume, ↑ HR & CO.
    9. 9. Compensatory Mechanisms in Heart Failure <ul><li>Mechanisms designed for acute loss in cardiac output </li></ul><ul><li>Chronic activation of these mechanisms worsens heart failure </li></ul>
    10. 10. PATHOPHYSIOLOGY: <ul><li>STARLING’S LAW </li></ul><ul><ul><li>“ Within limits, the force of ventricular contraction is a function of the end-diastolic length of the cardiac muscle, which in turn is closely related to the ventricular end-diastolic volume.” </li></ul></ul>
    11. 11. CARDIAC FAILURE  VENOUS PRESSURE  CARDIAC OUTPUT  BLOOD PRESSURE  SYMPATHETIC ACTIVITY  RENAL BLOOD FLOW  RENIN ANGIOTENSIN II  ALDOSTERONE  SODIUM RETENTION  CAPILLARY FILTRATION EDEMA
    12. 12. NEUROHUMORAL ACTIVATION DURING MYOCARDIAL FAILURE MYOCARDIAL FAILURE  CARDIAC OUTPUT  BLOOD PRESSURE/TISSUE PERFUSION ACTIVATION OF ADRENERGIC SYSTEM ARTERIOLAR CONSTRICTION INCREASED SYSTEMIC VASCULAR RESISTANCE INCREASED RESISTANCE TO EJECTION
    13. 13. COMPENSATORY RESPONSES DURING HEART FAILURE:  CARDIAC OUTPUT  CAROTID SINUS FIRING  RENAL BLOOD FLOW  SYMPATHETIC DISCHARGE  RENIN RELEASE  FORCE  RATE  PRELOAD  AFTERLOAD REMODELING <ul><li>CARDIAC OUTPUT </li></ul><ul><li>(VIA COMPENSATION) </li></ul>
    14. 14. Pathophysiology of Cardiac Performance Factor Mechanism Therapeutic Strategy 1. PRELOAD (work or stress the heart faces at the end of diastole) increased blood volume and increased venous tone--->atrial filling pressure -salt restriction -diuretic therapy -venodilator drugs 2. AFTERLOAD (resistance against which the heart must pump) increased sympathetic stimulation & activation of renin-angiotensin system ---> vascular resistance ---> increased BP - arteriolar vasodilators -decreased angiotensin II (ACE inhibitors) 3. CONTRACTILITY decreased myocardial contractility ---> decreased CO -inotropic drugs (cardiac glycosides) 4. HEART RATE decreased contractility and decreased stroke volume ---> increased HR (via activation of  adrenoceptors)
    15. 18. EFFECTS: <ul><li>DOWN-REGULATORY CHANGES IN THE β 1-ADRENOCEPTOR-G PROTEIN EFFECTOR SYSTEM </li></ul><ul><li>BETA 2 RECEPTORS ARE NOT DOWN REGULATED – COUPLING WITH IP3-DAG CASCADE </li></ul><ul><li>BETA 3 RECEPTORS ARE NOT DOWN REGULATED – MEDIATE NEGATIVE INOTROPHIC EFFECTS </li></ul>
    16. 19. <ul><li>EXCESSIVE BETA ACTIVATION: </li></ul><ul><ul><li>LEAKAGE OF CALCIUM FROM THE SR VIA RyR2 CHANNELS – VENTRICULAR STIFFENING & ARRYHTHMIAS </li></ul></ul><ul><li>INCREASED ANGIOTENSIN II PRODUCTION LEADS </li></ul><ul><ul><li>INCREASED ALDOSTERONE SECRETION </li></ul></ul><ul><ul><li>INCREASED AFTERLOAD </li></ul></ul><ul><ul><li>REMODELLING </li></ul></ul>
    17. 20. INTRINSIC COMPENSATORY RESPONSE: <ul><li>MYOCARDIAL HYPERTROPHY </li></ul><ul><ul><li>Increase in muscle mass to help maintain cardiac performance </li></ul></ul><ul><ul><li>Ischemic changes, impairment of diastolic filling, alterations in ventricular geometry </li></ul></ul><ul><li>REMODELLING </li></ul><ul><ul><li>Dilatation & other slow structural changes that occur in the stressed myocardium </li></ul></ul><ul><ul><li>Proliferation of connective tissue cells & myocardial cells </li></ul></ul><ul><ul><li>Accelerated apoptosis </li></ul></ul>
    18. 21. Causes of Heart Failure <ul><li>Acute/Chronic ♥ Problems </li></ul><ul><li>HTN -#1 </li></ul><ul><li>CAD </li></ul><ul><li>MI </li></ul><ul><li>Valvular ♥ Disease </li></ul>
    19. 22. CAUSES OF HEART FAILURE: <ul><li>Final common pathway of many kinds of heart diseases </li></ul><ul><ul><li>Ischemic, alcoholic, restrictive, hypertrophic </li></ul></ul><ul><ul><li>Optimal treatment requires identification of primary & secondary factors leading to CHF </li></ul></ul><ul><ul><li>HELPFUL RESULT of dilatation: increases cardiac output </li></ul></ul><ul><ul><li>HARMFUL RESULT of dilation: more wall tension, more oxygen is needed to produce any given stroke volume </li></ul></ul>
    20. 23. CLASSIFICATION: <ul><li>SYSTOLIC DYSFUNCTION: </li></ul><ul><ul><li>Inadequate force is generated to eject blood normally </li></ul></ul><ul><ul><li>Reduce cardiac output, ejection fraction </li></ul></ul><ul><ul><li>(< 45%) </li></ul></ul><ul><ul><li>Typical of acute heart failure </li></ul></ul><ul><ul><li>Secondary to AMI </li></ul></ul><ul><ul><li>Responsive to inotropics </li></ul></ul>
    21. 24. CLASSIFICATION: <ul><li>DIASTOLIC DYSFUNCTION </li></ul><ul><ul><li>Inadequate relaxation to permit normal filling </li></ul></ul><ul><ul><li>Hypertrophy and stiffening of myocardium </li></ul></ul><ul><ul><li>Cardiac output may be reduced </li></ul></ul><ul><ul><li>Ejection fraction may be normal </li></ul></ul><ul><ul><li>Do not respond optimally to inotropic agents </li></ul></ul>
    22. 25. CLASSIFICATION: <ul><li>HIGH OUTPUT FAILURE </li></ul><ul><ul><li>Increase demand of the body with insufficient cardiac output </li></ul></ul><ul><ul><li>Hyperthyroidism, beri-beri, anemia, AV shunts </li></ul></ul><ul><ul><li>Treatment is correction of underlying cause </li></ul></ul>
    23. 26. CLASSIFICATION: <ul><li>ACUTE HEART FAILURE </li></ul><ul><ul><li>Sudden development of a large myocardial infarction or rupture of a cardiac valve in a patient who previously was entirely well, usually predominant systolic dysfunction </li></ul></ul>
    24. 27. CLASSIFICATION: <ul><li>CHRONIC HEART FAILURE </li></ul><ul><ul><li>Typically observed in patients with dilated cardiomyopathy or multivalvular heart diseases that develops or progresses slowly </li></ul></ul>
    25. 29. PRECIPITATING CAUSES OF HEART FAILURE: <ul><li>Infection </li></ul><ul><li>Anemia </li></ul><ul><li>Thyrotoxicosis & pregnancy </li></ul><ul><li>Arrythmias </li></ul><ul><li>Rheumatic, viral & other forms of myocarditis </li></ul><ul><li>Infective endocarditis </li></ul><ul><li>Systemic hypertension </li></ul><ul><li>Myocardial infarction </li></ul><ul><li>Physical, dietary, fluid, environmental & emotional excesses </li></ul><ul><li>Pulmonary embolism </li></ul>
    26. 30. CLINICAL MANIFESTATIONS:
    27. 31. LEFT HEART FAILURE
    28. 32. Pulmonary Edema The most severe manifestation of Left Heart Failure Fluid leak into the pulmonary interstitial spaces (Pulmonary congestion/edema) Hypoxia and poor 02 exchange
    29. 33. PULMONARY CONGESTION & RESPIRATORY SYMPTOMS: <ul><li>Result of dilatation & increasing left ventricular end diastolic pressure, left atrial pressure & capillary pressures </li></ul><ul><ul><li>Results to pulmonary vascular congestion & symptoms associated with cough with blood tinged sputum </li></ul></ul>
    30. 37. Clinical picture… Left Heart Failure <ul><li>Dyspnea/Dyspnea on exertion (most sensitive: absence indicates Tx effective) </li></ul><ul><li>Cough orthopnea </li></ul><ul><li>Paroxysmal nocturnal dyspnea (PND) </li></ul><ul><li>Productive cough with pink frothy sputum </li></ul><ul><li>Tachypnea </li></ul><ul><li>Pale, possible cyanotic </li></ul><ul><li>Clammy and cold skin </li></ul><ul><li>Crackles/Wheezes </li></ul><ul><li>Extra heart sounds – S3, S4 </li></ul><ul><li>Heart murmur </li></ul>
    31. 38. Cont. <ul><li>EDEMA OF THE BRONCHIAL MUCOSA </li></ul><ul><ul><li>Increases resistance to airflow producing respiratory distress similar to asthma (cardiac asthma) </li></ul></ul>
    32. 39. Cont: <ul><li>DYSPNEA </li></ul><ul><ul><li>Results from reflexes initiated by vascular distention </li></ul></ul><ul><ul><li>Increased rigidity of lungs & impaired gas exchange resulting from interstitial edema </li></ul></ul><ul><ul><li>Accumulation of fluid in ALVEOLARS SACS (pulmonary edema) </li></ul></ul>
    33. 40. Cont. <ul><li>TACHYCARDIA </li></ul><ul><ul><li>An early compensatory response mediated by increased sympathetic tone </li></ul></ul><ul><ul><li>EDEMA </li></ul></ul><ul><ul><li>compensatory response mediated by the renin angiotensin aldosterone system & by increased sympathetic outflow </li></ul></ul><ul><ul><li>CARDIOMEGALY </li></ul></ul><ul><ul><li>a compensatory structural response </li></ul></ul>
    34. 41. Right Heart Failure <ul><li>Clinical picture…( Congestion ) </li></ul><ul><ul><li>JVD, hepatomegaly and dependent edema (LEs, thighs, abdomen-ascites ) </li></ul></ul>
    35. 42. Heart Failure Clinical manifestations : Pulmonary Congestion (L) and Systemic Congestion (R) Right Heart Failure Left Heart Failure Pulmonary fluid overload Peripheral fluid overload
    36. 43. PHYSICAL EXAM: <ul><li>Jugular venous distention </li></ul><ul><li>S3 </li></ul><ul><li>Rales </li></ul><ul><li>Pleural effusion </li></ul><ul><li>Edema </li></ul><ul><li>Hepatomegaly </li></ul><ul><li>Ascites </li></ul>
    37. 45. Review: Subjective Data <ul><li>Pt. may c/o </li></ul><ul><li>anxiety </li></ul><ul><li>DOE </li></ul><ul><li>PND </li></ul><ul><li>orthopnea </li></ul><ul><li>productive cough with pink frothy sputum </li></ul><ul><li>Fatigue and weakness </li></ul>
    38. 46. Review: Objective Data <ul><li>PA may reveal: </li></ul><ul><li>Left heart Failure </li></ul><ul><li>Tachypnea/SOB </li></ul><ul><li>Use of accessory muscles </li></ul><ul><li>Wheezes/Crackles </li></ul><ul><li>skin </li></ul><ul><ul><li>Clammy/cold </li></ul></ul><ul><ul><li>pale/cyanotic </li></ul></ul><ul><li>Right Heart Failure </li></ul><ul><li>peripheral edema </li></ul><ul><li>JVD </li></ul><ul><li>Ascites, enlarged spleen/liver </li></ul>
    39. 47. FRAMINGHAM CRITERIA FOR DIAGNOSIS OF CHF: <ul><li>MAJOR CRITERIA </li></ul><ul><ul><li>PND </li></ul></ul><ul><ul><li>NECK VEIN ENGORGEMENT </li></ul></ul><ul><ul><li>RALES </li></ul></ul><ul><ul><li>CARDIOMEGALY </li></ul></ul><ul><ul><li>ACUTE PULMONARY EDEMA </li></ul></ul><ul><ul><li>S3 GALLOP </li></ul></ul><ul><ul><li> VENOUS PRESSURE (>16 cmH2O) </li></ul></ul><ul><ul><li>(+) HEPATOJUGULAR REFLUX </li></ul></ul><ul><li>MINOR CRITERIA </li></ul><ul><ul><li>EXTREMITY EDEMA </li></ul></ul><ul><ul><li>NIGHT COUGH </li></ul></ul><ul><ul><li>DYSPNEA ON EXERTION </li></ul></ul><ul><ul><li>HEPATOMEGALY </li></ul></ul><ul><ul><li>PLEURAL EFFUSION </li></ul></ul><ul><ul><li>VITAL CAPACITY REDUCED BY 1/3 </li></ul></ul><ul><ul><li>TACHYCARDIA </li></ul></ul><ul><li>ONE MAJOR + 2 MINOR </li></ul>
    40. 48. NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSSIFICATION : <ul><li>CLASS I : no limitations on ordinary physical activities and symptoms that occur only with greater than ordinary exercise </li></ul><ul><li>CLASS II: slight limitation of ordinary activities, which result in fatigue & palpitations with ordinary physical activity </li></ul>
    41. 49. <ul><li>CLASS III: results in no symptoms at rest, but fatigue with less than ordinary physical activity </li></ul><ul><li>CLASS IV: associated with symptoms even when the patient is at rest </li></ul>
    42. 50. “ All the signs of CHF are the consequences of inadequate force of contraction&quot;
    43. 51. Potential Therapeutic Targets in Heart Failure <ul><li>Preload </li></ul><ul><li>Afterload </li></ul><ul><li>Contractility </li></ul>
    44. 52. CLINICAL MANAGEMENT OF CONGESTIVE HEART FAILURE <ul><li>OBJECTIVES: </li></ul><ul><ul><li>Increase cardiac contractility </li></ul></ul><ul><ul><li>Decrease preload ( left ventricular pressure) </li></ul></ul><ul><ul><li>Decrease afterload (systemic vascular resistance) </li></ul></ul><ul><ul><li>Normalize heart rate and rhythm </li></ul></ul>
    45. 53. <ul><li>Approaches : Reduce workload of heart </li></ul><ul><li>1.Limit activity level reduce weight control hypertension </li></ul><ul><li>2. Restrict sodium (low salt diet) 3. Give diuretics (removal of retained salt and water) </li></ul>
    46. 54. <ul><li>4. Give angiotensin-converting enzyme inhibitors (decreases afterload and retained salt and water) 5. Give digitalis (positive inotropic effect on depressed heart) 6. Give vasodilators (decreases preload & afterload) </li></ul>
    47. 55. DRUGS COMMONLY USED IN HEART FAILURE
    48. 56. Positive Inotropic Agents <ul><li>Cardiac Glycosides </li></ul><ul><li>Phosphodiesterase inhibitors </li></ul><ul><li> -adrenoceptor agonists and dopamine receptor agonists </li></ul>
    49. 57. Cardiac Glycosides <ul><li>digoxin </li></ul><ul><li>digitoxin </li></ul><ul><li>deslanoside </li></ul><ul><li>ouabain </li></ul>
    50. 58. DIGITALIS <ul><li>Derived from foxglove plant Digitalis lanata </li></ul><ul><li>Prototype – DIGOXIN </li></ul><ul><li>Steroid nucleus linked to a lactone ring at the 17 position and series of sugars at carbon 3 of the nucleus </li></ul>
    51. 59. BASIC PHARMACOLOGY OF DRUGS USED IN CONGESIVE HEART FAILURE : <ul><li>DIGITALIS </li></ul><ul><li>PHARMACOKINETICS: </li></ul><ul><li>DIGOXIN DIGITOXIN </li></ul><ul><li>LIPID SOLUBILITY MEDIUM HIGH </li></ul><ul><li>ORAL AVAILABILITY 75% >90% </li></ul><ul><li>HALF-LIFE 40 HRS 168 HRS </li></ul><ul><li>PLASMA PROTEIN BINDING 20-40 HRS >90 HRS </li></ul><ul><li>PERCENTAGE METABOLIZED <20 >80 </li></ul><ul><li>VOLUME OF DISTRIBUTION 6.3 L/KG 0.6 L/KG </li></ul>
    52. 60. PHARMACOKINETICS: <ul><li>T1/2 = ( 40 hrs ) </li></ul><ul><li>Therapeutic plasma concentration: </li></ul><ul><ul><li>0.5-2 ng/ml </li></ul></ul><ul><li>Toxic plasma concentration: >2 ng/ml </li></ul><ul><li>*digitalis must be present in the body in certain &quot;saturating&quot; amount before any effect on congestive failure is noted </li></ul><ul><li>this is achieved by giving a large initial dose in a process called &quot; digitalization &quot; </li></ul>
    53. 61. <ul><li>after intial dosages, digitalis is given in &quot;maintenance&quot; amounts sufficient to replace that which is excreted </li></ul><ul><li>to avoid exceeding therapeutic range during digitalization: - the loading dose should be adjusted according to the health of the patient - slow digitalization (over 1 week) is the safest technique </li></ul><ul><li>plasma digoxin levels should be monitored </li></ul>
    54. 62. METABOLISM & EXCRETION: <ul><li>Digoxin – not extensively metabolized, 2/3 excreted unchanged in the kidneys </li></ul><ul><li>Digitoxin – metabolized in the liver and excreted into the gut via the bile </li></ul>
    55. 63. PROPERTIES OF CARDIAC GLYCOSIDES: OUABAIN DIGOXIN DIGITOXIN Lipid solubility (oil/water coefficient) Low Medium High Oral availability (% absorbed) 0 75 > 90 Half-life in the body (hrs) 21 40 168 Plasma protein binding (% bound) 0 <20 >80 Volume of distribution 18 6.3 0.6
    56. 64. MECHANICAL EFFECTS: <ul><li>Inhibit the monovalent cation transport enzyme coupled Na+- K+ ATPase & increased intracellular Na+ content  increases intracellular Ca2+ through a Na+ - Ca2+ exchange carrier mechanism </li></ul><ul><li>Increases myocardial uptake of Ca2+ augments Ca2+ release to the myofilaments during excitation  invokes a positive inotropic response </li></ul>
    57. 68. Mechanism of Digitalis Action: Molecular <ul><li>Inhibition of Na/K ATPase </li></ul><ul><li>blunting of Ca 2+ extrusion </li></ul><ul><li> Ca 2+ i </li></ul><ul><li> sarcomere shortening </li></ul>
    58. 69. ELECTRICAL EFFECTS: <ul><li>Produces alterations in the electrical properties of both contractile cells and the specialized automatic cells  increased automaticity & ectopic impulse activity </li></ul><ul><li>Prolongs the effective refractory period of the AV node  slow ventricular rate in atrial flutter & fibrillation </li></ul>
    59. 70. Direct Electrophysiological Effects: Cellular Action Potential
    60. 71. Afterdepolarizations
    61. 72. TISSUE OR VARIABLE EFFECTS AT THERAPEUTIC DOSAGE EFFECTS AT TOXIC DOSAGE Sinus node  rate  rate Atrial muscle  Refractory period  Refractory period, arrhythmias Atrioventricular node  Conduction velocity,  refractory period  Refractory period, arrhythmias Purkinje system, ventricular muscle Slight  refractory period Extrasystoles, tachycardia, fibrillation Electrocardiogram  PR interval,  QT interval Tachycardia, fibrillation, arrest at extremely high dosage
    62. 73. EFFECTS IN HEART FAILURE: <ul><li>Stimulates myocardial contractility </li></ul><ul><li>Improves ventricular emptying </li></ul><ul><li>Increase cardiac output </li></ul><ul><li>Augments ejection fraction </li></ul><ul><li>Promotes diuresis </li></ul><ul><li>Reduces elevated diastolic pressure & volume & end –systolic volume </li></ul><ul><li>Reduces symptoms resulting from pulmonary vascular congestion & elevated systemic venous pressure </li></ul>
    63. 75. Summary Direct Electrophysiological Effects <ul><li>Less negative membrane potential: decreased conduction velocity </li></ul><ul><li>Decreased action potential duration: decreased refractory period in ventricles </li></ul><ul><li>Enhanced automaticity due to </li></ul><ul><ul><li>Steeper phase 4 </li></ul></ul><ul><ul><li>Afterdepolarizations </li></ul></ul>
    64. 76. Parasympathomimetic Effects <ul><li>Decreased conduction velocity in the AV node </li></ul><ul><li>increased effective refractory period in the AV </li></ul><ul><li>Heart block (toxic concentrations) </li></ul>
    65. 77. EKG Effects of Digitalis <ul><li>decrease in R-T interval </li></ul><ul><li>inversion of T wave </li></ul><ul><li>Uncoupled P waves (Toxic concentrations) </li></ul><ul><li>Bigeminy (toxic concentrations) </li></ul>
    66. 78. Therapeutic Uses of Digitalis <ul><li>Congestive Heart Failure </li></ul><ul><li>Atrial fibrillation </li></ul>
    67. 79. Overall Benefit of Digitalis to Myocardial Function <ul><li> cardiac output </li></ul><ul><li> cardiac efficiency </li></ul><ul><li> heart rate </li></ul><ul><li> cardiac size </li></ul><ul><li>NO survival benefit </li></ul>
    68. 80. Other Beneficial Effects <ul><li>Restoration of baroreceptor sensitivity </li></ul><ul><li>Reduction in sympathetic activity </li></ul><ul><li>increased renal perfusion, with  edema formation </li></ul>
    69. 81. Adverse Effects <ul><li>Cardiac </li></ul><ul><ul><li>AV block </li></ul></ul><ul><ul><li>Bradycardia </li></ul></ul><ul><ul><li>Ventricular extrasystole </li></ul></ul><ul><ul><li>Arrhythmias </li></ul></ul><ul><li>CNS </li></ul><ul><li>GI </li></ul>Therapeutic index is ~ 2!
    70. 82. INTERACTIONS: <ul><li>POTASSIUM </li></ul><ul><ul><li>HYPERKALEMIA: reduces enzyme inhibiting actions of digitalis, abnormal cardiac automaticity is inhibited </li></ul></ul><ul><ul><li>HYPOKALEMIA: facilitates enzyme inhibiting actions </li></ul></ul><ul><li>CALCIUM </li></ul><ul><ul><li>Facilitates the toxic actions digitalis by accelerating the overloading of intracellular calcium stores that appears to be responsible for abnormal automaticity </li></ul></ul><ul><ul><li>HYPERCALCEMIA: increases the risk of digitalis induced arryhythmia </li></ul></ul><ul><li>MAGNESIUM </li></ul><ul><ul><li>Opposite to those of calcium </li></ul></ul>
    71. 83. Serum Electrolytes Affect Toxicity <ul><li>K + </li></ul><ul><ul><li>Digitalis competes for K binding at Na/K ATPase </li></ul></ul><ul><ul><li>Hypokalemia: increase toxicity </li></ul></ul><ul><ul><li>Hyperkalemia: decrease toxicity </li></ul></ul><ul><li>Mg 2+ </li></ul><ul><ul><li>Hypomagnesemia: increases toxicity </li></ul></ul><ul><li>Ca 2+ </li></ul><ul><ul><li>Hypercalcemia: increases toxicity </li></ul></ul>
    72. 84. DIGITALIS INTOXICATION: <ul><li>Serious & potentially fatal complication </li></ul><ul><li>Anorexia, nausea & vomiting = earliest signs of digitalis intoxication </li></ul><ul><li>Arrythmias: ventricular premature beats, bigeminy, ventricular & atrial tachycardia w/ variable AV block </li></ul><ul><li>Chronic digitalis intoxication = exacerbations of heart failure, weight loss, cachexia, neuralgias, gynecomastia, yellow vision, delirium </li></ul>
    73. 85. TREATMENT OF DIGITALIS INTOXICATION: <ul><li>Tachyarrythmias: withdrawal of the drug, treatment with beta blocker or lidocaine </li></ul><ul><li>Hypokalemia: potassium administration by the oral route </li></ul><ul><li>Digitoxin Ab (Fab fragments) </li></ul>
    74. 86. Treatment of Digitalis Toxicity <ul><li>reduce dose: 1st degree heart block, ectopic beats </li></ul><ul><li>Atropine: advanced heart block </li></ul><ul><li>KCl: increased automaticity </li></ul><ul><li>Antiarrythmics: ventricular arrhythmias </li></ul><ul><li>Fab antibodies: toxic serum concentration; acute toxicity </li></ul>
    75. 87. PHOSPHODIESTERASE INHIBITORS <ul><li>BIPYRIDINES </li></ul><ul><ul><li>Inamrinone & Milrinone </li></ul></ul><ul><ul><li>Levosimendan </li></ul></ul><ul><ul><li>Parenteral forms only </li></ul></ul><ul><ul><li>Half-life: 2-3 hrs </li></ul></ul><ul><ul><li>10-40% excreted in the urine </li></ul></ul><ul><ul><li>MOA: increase inward calcium influx in the heart during action potential & inhibits phosphodiesterase </li></ul></ul><ul><ul><li>ADVERSE EFFECTS: nausea, vomiting, thrombocytopenia, liver enzyme changes </li></ul></ul>
    76. 89. Phosphodiesterase Inhibitors: Therapeutic Use <ul><li>short term support in advanced cardiac failure </li></ul><ul><li>long term use not possible </li></ul>
    77. 90. Adverse Effects of Phosphodiesterase Inhibitors <ul><li>Cardiac arrhythmias </li></ul><ul><li>GI: Nausea and vomiting </li></ul><ul><li>Sudden death </li></ul>
    78. 91.  -Adrenoceptor and Dopamine Receptor Agonists <ul><li>Dobutamine </li></ul><ul><li>Dopamine </li></ul>
    79. 92. BETA ADRENOCEPTOR STIMULANTS: <ul><li>DOBUTAMINE </li></ul><ul><ul><li>Increases cardiac output </li></ul></ul><ul><ul><li>Decrease in ventricular filling pressure </li></ul></ul><ul><ul><li>Given parenterally </li></ul></ul><ul><ul><li>CONTRAINDICATIONS: pheochromocytoma, tachyarrythmias </li></ul></ul><ul><ul><li>ADVERSE EFFECTS: precipitation or exacerbation of arrythmia </li></ul></ul><ul><li>DOPAMINE </li></ul><ul><ul><li>Raise blood pressure </li></ul></ul>
    80. 94. Mechanism of Action: Dobutamine <ul><li>Stimulation of cardiac    adrenoceptors:  inotropy >  chronotropy </li></ul><ul><li>peripheral vasodilatation </li></ul><ul><li> myocardial oxygen demand </li></ul>
    81. 95. Mechanism of Action: Dopamine <ul><li>Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors </li></ul><ul><li>Splanchnic and renal vasodilatation </li></ul>
    82. 96. Therapeutic Use <ul><li>Dobutamine: management of acute failure only </li></ul><ul><li>Dopamine: restore renal blood in acute failure </li></ul>
    83. 97. Adverse Effects <ul><li>Dobutamine </li></ul><ul><ul><li>Tolerance </li></ul></ul><ul><ul><li>Tachycardia </li></ul></ul><ul><li>Dopamine </li></ul><ul><ul><li>tachycardia </li></ul></ul><ul><ul><li>arrhythmias </li></ul></ul><ul><ul><li>peripheral vasoconstriction </li></ul></ul>
    84. 98. DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS USED IN HEART FAILURE: <ul><li>DIURETICS </li></ul><ul><ul><li>Reduce salt & water retention  reduce ventricular preload </li></ul></ul><ul><ul><li>Reduction in venous pressure  reduction of edema & its symptoms, reduction of cardiac size  improved efficiency of pump function </li></ul></ul>
    85. 99. Diuretics: Mechanism of Action in Heart Failure <ul><li>Preload reduction: reduction of excess plasma volume and edema fluid </li></ul><ul><li>Afterload reduction: lowered blood pressure </li></ul><ul><li>Reduction of facilitation of sympathetic nervous system </li></ul>
    86. 100. ACE Inhibitors in Heart Failure
    87. 101. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS: <ul><li>Reduce peripheral resistance  reduce afterload </li></ul><ul><li>Reduce salt & water retention ( by reducing aldosterone secretion)  reduce preload </li></ul><ul><li>Reduce the long term remodelling of the heart vessels ( maybe responsible for the observed reduction in the mortality & morbidity) </li></ul>
    88. 102. Mechanism of Action <ul><li>Afterload reduction </li></ul><ul><li>Preload reduction </li></ul><ul><li>Reduction of facilitation of sympathetic nervous system </li></ul><ul><li>Reduction of cardiac hypertrophy </li></ul>
    89. 103. ACE Inhibitors: Therapeutic Uses <ul><li>Drugs of choice in heart failure (with diuretics) </li></ul><ul><li>Current investigational use : Acute myocardial infarction </li></ul><ul><li>ATII antagonists </li></ul>
    90. 105. VASODILATORS <ul><ul><li>Reduce the preload (through venodilatation), or reduction in afterload (through arteriolar dilatation) or both </li></ul></ul><ul><ul><li>Decrease the load of the myocardium </li></ul></ul>
    91. 106. VASODILATORS: <ul><li>HYDRALAZINE, ISDN </li></ul><ul><ul><li>Reduction in preload through venodilatation </li></ul></ul><ul><ul><li>Reduction in afterload through arteriolar dilation </li></ul></ul>
    92. 107. VASODILATORS <ul><li>NESIRITIDE </li></ul><ul><ul><li>Brain natriuretic peptide (BNP) </li></ul></ul><ul><ul><li>Approved for acute heart failure </li></ul></ul><ul><ul><li>Increases cGMP in smooth muscle cells & reduces venous & arteriolar tone </li></ul></ul><ul><ul><li>Causes diuresis </li></ul></ul><ul><ul><li>T ½ = 18 minutes </li></ul></ul><ul><ul><li>Intrvenous dose </li></ul></ul>
    93. 108. VASODILATORS <ul><li>BOSENTAN </li></ul><ul><ul><li>Competitive inhibitor of endothelin </li></ul></ul><ul><ul><li>Oral </li></ul></ul><ul><ul><li>Approved for use in pulmonary hypertension </li></ul></ul><ul><ul><li>Teratogenic & hepatotoxic effects </li></ul></ul>
    94. 109. <ul><li>-Blockers in Heart Failure: Mechanism of Action </li></ul><ul><li>Standard  -blockers: </li></ul><ul><ul><li>Reduction in damaging sympathetic influences in the heart (tachycardia, arrhythmias, remodeling) </li></ul></ul><ul><ul><li>inhibition of renin release </li></ul></ul><ul><li>Carvedilol: </li></ul><ul><ul><li>Beta blockade effects </li></ul></ul><ul><ul><li>peripheral vasodilatation via  1 -adrenoceptor blockade (carvedilol) </li></ul></ul>
    95. 110. BETA-ADRENOCEPTOR BLOCKERS: <ul><li>BISOPROLOL, CARVEDILOL, METOPROLOL </li></ul><ul><ul><li>Reduction in mortality in patients with stable Class II & Class III heart failure </li></ul></ul><ul><ul><li>Attenuation of the adverse effects of cathecolamines (apoptosis) </li></ul></ul><ul><ul><li>Up regulation of Beta receptors </li></ul></ul><ul><ul><li>Decreased HR, & remodelling </li></ul></ul>
    96. 111. DIURETICS
    97. 112. Principles important for understanding effects of diuretics <ul><li>Interference with Na + reabsorption at one nephron site interferes with other renal functions linked to it </li></ul><ul><li>It also leads to increased Na + reabsorption at other sites </li></ul><ul><li>Increased flow and Na + delivery to distal nephron stimulates K + (and H + ) secretion </li></ul>
    98. 113. <ul><li>Diuretics act only if Na + reaches their site of action. The magnitude of the diuretic effect depends on the amount of Na + reaching that site </li></ul><ul><li>Diuretic actions at different nephron sites can produce synergism </li></ul><ul><li>All, except spironolactone, act from the lumenal side of the tubular cellular membrane </li></ul>Principles important for understanding effects of diuretics
    99. 115. From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250 70% 20% 5% 4.5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day CA Inhibitors Proximal tubule Loop Diuretics Loop of Henle Thiazides Distal tubule Antikaliuretics Collecting duct Thick Ascending Limb
    100. 118. RENAL TRANSPORT MECHANISM: <ul><li>PROXIMAL CONVOLUTED TUBULE: </li></ul><ul><ul><li>Carries out isosmotic reabsorption of amino acids, glucose and cations </li></ul></ul><ul><ul><li>Bicarbonate reabsorption </li></ul></ul><ul><ul><li>40-50% Na reabsorption </li></ul></ul><ul><ul><li>Via specific transport systems: </li></ul></ul><ul><ul><ul><li>NaHCO3 – Na/H exchanger (NHE3) </li></ul></ul></ul>
    101. 119. LOOP OF HENLE: <ul><li>Pumps Na, K & Cl out of the lumen into the interstitium </li></ul><ul><li>Provides the concentration gradient for the countercurrent concentrating mechanism </li></ul><ul><li>Diluting segment – thick ascending limb of the loop of henle </li></ul><ul><li>Ca & Mg reabsorption </li></ul><ul><li>Na/K/2Cl cotransporter (NKCC2) </li></ul>
    102. 120. DISTAL CONVOLUTED TUBULE: <ul><li>Actively pumps Na & Cl out of the lumen nephron </li></ul><ul><li>10 % Na reabsorbed </li></ul><ul><li>Impermeable to water </li></ul><ul><li>Ca & Mg reabsorption </li></ul><ul><li>Na/Ca exchanger (NCC) </li></ul>
    103. 121. COLLECTING TUBULE: <ul><li>Final site of NaCl reabsorption </li></ul><ul><li>Tight regulation of body fluid volume </li></ul><ul><li>Determines the final Na concentration of the urine </li></ul><ul><li>Influenced by mineralocorticoids </li></ul><ul><li>Important site of K secretion by the kidney </li></ul><ul><li>Principal cells are the major sites of Na, K and H20 transport </li></ul><ul><li>Intercalated cells are the primary sites of H secretion </li></ul><ul><li>Do not contain cotransport system for Na </li></ul>
    104. 122. <ul><li>Reabsorption of Na via the epithelial Na channel (ENaC) and its coupled K secretion is regulated by aldosterone </li></ul><ul><li>ADH/AVP controls the permeability of the segment to water </li></ul>
    105. 123. DIURETICS <ul><li>Drugs that increase the rate of urine flow </li></ul><ul><li>Increase the rate of Na & Cl excretion </li></ul><ul><li>Decrease reabsorption of K, Ca & Mg </li></ul>
    106. 124. DIURETICS <ul><li>CLASSIFICATION: </li></ul><ul><li>CARBONIC ANHYDRASE INHIBITORS </li></ul><ul><li>OSMOTIC DIURETICS </li></ul><ul><li>LOOP DIURETICS </li></ul><ul><li>THIAZIDE DIURETICS </li></ul><ul><li>POTASSIUM SPARING DIURETICS </li></ul><ul><li>SITE OF ACTION: </li></ul><ul><li>Proximal tubule </li></ul><ul><li>Proimal tubule, Loop of Henle, Collecting tubule </li></ul><ul><li>Ascending limb of the loop of Henle </li></ul><ul><li>Distal convoluted tubule </li></ul><ul><li>Collecting tubule </li></ul>
    107. 125. CARBONIC ANHYDRASE INHIBITORS: <ul><li>CLASSIFICATION & PROTOTYPES: ACETAZOLAMIDE (Diamox) – a sulfonamide derivative </li></ul><ul><li>MECHANISM OF ACTION: </li></ul><ul><ul><li>Inhibit carbonic anhydrase w/c slows the ff. rxn: </li></ul></ul><ul><ul><li>H + HCO3  H2O + CO2 </li></ul></ul><ul><ul><li>Inhibit the dehydration of H2C03 </li></ul></ul><ul><ul><li>Drug effect occurs throughout the body </li></ul></ul><ul><ul><li>Block NaHCO3 reabsorption </li></ul></ul><ul><ul><li>HCO3 diuresis </li></ul></ul>
    108. 127. PHARMACOKINETICS: <ul><li>Well absorbed after oral administration </li></ul><ul><li>Onset of action: 30 minutes </li></ul><ul><li>Duration: 12 hrs </li></ul><ul><li>Excretion: proximal tubule </li></ul>
    109. 128. PHARMACODYNAMICS: <ul><li>Depresses the HC03 reabsorption in the PCT </li></ul><ul><li>Significant HC03 losses – hyperchloremic metabolic acidosis </li></ul>
    110. 129. CLINICAL USES: <ul><li>Treatment of glaucoma – major application </li></ul><ul><li>Urinary alkalinization </li></ul><ul><li>Epilepsy </li></ul><ul><li>Acute mountain sickness </li></ul><ul><li>Correction of metabolic alkalosis </li></ul>
    111. 130. TOXICITY: <ul><li>Hyperchloremic metabolic acidosis </li></ul><ul><li>Renal stones </li></ul><ul><li>Renal potassium wasting </li></ul><ul><li>Drowsiness & paresthesias – large doses </li></ul>
    112. 131. CONTRAINDICATIONS: <ul><li>HYPERAMMONEMIA </li></ul><ul><ul><li>Decrease urinary excretion of NH4 due to alkalinization of the urine </li></ul></ul><ul><li>HEPATIC ENCEPHALOPATHY </li></ul>
    113. 132. LOOP DIURETICS <ul><li>CLASSIFICATION & PROTOTYPES: Furosemide – prototype & sulfonamide derivative </li></ul><ul><li>Bumetanide- sulfonamide </li></ul><ul><li>Ethacrynic Acid – phenoxyacetic acid </li></ul>
    114. 133. PHARMACOKINETICS: <ul><li>Rapidly absorbed </li></ul><ul><li>Diuretic response is extremely rapid following IV injection </li></ul><ul><li>Duration of effect: 2-3 hrs </li></ul><ul><li>Half life: dependent on renal function </li></ul><ul><li>Excreted in the kidney </li></ul>
    115. 134. PHARMACOKINETICS: <ul><li>TORSEMIDE </li></ul><ul><li>Absorption: 1 hr </li></ul><ul><li>Duration: 4-6 hrs </li></ul><ul><li>FUROSEMIDE </li></ul><ul><li>Absorption: 2-3 hrs </li></ul><ul><li>Duration: 2-3 hrs </li></ul>
    116. 135. MECHANISM OF ACTION: <ul><li>Inhibits the coupled Na+/K+/2Cl transport system (NKCC2) in the luminal membrane of the thick ascending limb of the loop of henle  reduce NaCl reabsorption </li></ul><ul><li>Increases Mg & Ca+ excretion </li></ul><ul><li>Induces synthesis of renal prostaglandins </li></ul><ul><li>Increases renal blood flow </li></ul><ul><li>Reduces pulmonary congestion & left ventricular filling pressures </li></ul>
    117. 137. CLINICAL USES: <ul><li>Treatment of edematous states (CHF & ascites) </li></ul><ul><li>Acute pulmonary edema in w/c a separate pulmonary vasodilating action may play a useful additive role </li></ul><ul><li>Sometimes used in hypertension if response to thiazide is inadequate but their short duration of action is a disadvantage </li></ul><ul><li>Treatment of severe hypercalcemia induced by a carcinoma – less common </li></ul><ul><li>Acute renal failure </li></ul><ul><li>Hyperkalemia </li></ul>
    118. 138. TOXICITY: <ul><li>Hypokalemic metabolic alkalosis </li></ul><ul><li>Hyperuricemia </li></ul><ul><li>Hypovolemia & cardiovascular complications </li></ul><ul><li>Ototoxicity – important toxic effect of the loop agents </li></ul><ul><li>hypomagnesemia </li></ul>
    119. 139. THIAZIDE DIURETICS <ul><li>CLASSIFICATION & PROTOTYPE: </li></ul><ul><ul><li>HYDROCHLOROTHIAZIDE – sulfonamide derivative </li></ul></ul><ul><ul><li>INDAPAMIDE – new thiazide like agent with a significant vasodilating effect than Na diuretic effect </li></ul></ul>
    120. 141. MECHANISM OF ACTION: <ul><li>Inhibit NaCl transporter (NCC) in the early segment of the distal convoluted tubule </li></ul>REDUCE THE DILUTING CAPACITY OF THE NEPHRON
    121. 142. EFFECTS: <ul><li>Urinary excretion </li></ul><ul><ul><li>Full doses – produce a moderate Na & Cl diuresis  hypokalemic metabolic alkalosis </li></ul></ul><ul><ul><li>Reduced the blood pressure by reduction of the blood volume but with continued use these agents appear to reduce vascular resistance </li></ul></ul>
    122. 143. CLINICAL USE: <ul><li>Hypertension – major application, for w/c their long duration of action & moderate intensity of action are useful </li></ul><ul><li>Chronic therapy for edematous conditions (CHF) another common application </li></ul><ul><li>Recurrent renal calcium stone formation can sometimes be controlled with thiazides </li></ul><ul><li>Nephrogenic diabetes insipidus </li></ul>
    123. 144. TOXICITY: <ul><li>Hypokalemic metabolic alkalosis & hyperuricemia </li></ul><ul><li>Chronic therapy is often associated with potassium wasting </li></ul><ul><li>Hyperlipidemia </li></ul><ul><li>Hyponatremia </li></ul><ul><li>Allergic reactions </li></ul>
    124. 145. CONRAINDICATIONS: <ul><li>HEPATIC CIRRHOSIS </li></ul><ul><li>BORDERLINE RENAL FAILURE </li></ul>
    125. 146. POTASSIUM SPARING DIURETICS: <ul><li>CLASSIFICATION & PROTOTYPES </li></ul><ul><ul><li>SPIRINOLACTONE, EPLERENONE– antagonist of aldosterone in the collecting tubules </li></ul></ul><ul><ul><ul><li>Has a slow onset & offset of action (24-72 hrs) </li></ul></ul></ul><ul><ul><li>TRIAMTERENE & AMILORIDE – inhibitors of Na flux in the collecting tubule </li></ul></ul>
    126. 147. CLINICAL USE: <ul><li>Hyperaldosteronism – important indication </li></ul><ul><li>Potassium wasting caused by chronic therapy with loop diuretic or thiazide if not controlled by dietary K supplements </li></ul><ul><li>Most common use is in the form of products that combine a thiazide with a K sparing agent </li></ul>
    127. 148. ADVERSE EFFECTS: <ul><li>Decrease K & H ion excretion and may cause hyperchloremic metabolic acidosis </li></ul><ul><li>Interfere with steroid biosynthesis </li></ul>
    128. 149. TOXICITY: <ul><li>Hyperkalemia – most important toxic effect </li></ul><ul><li>Metabolic acidosis in cirrhotic patients </li></ul><ul><li>Gynecomastia & antiandrogenic effects </li></ul><ul><li>Hyperchloremic metabolic acidosis </li></ul><ul><li>Acute renal failure </li></ul><ul><li>Kidney stones - triamterene </li></ul>
    129. 150. CONTRAINDICATIONS: <ul><li>Oral K administration </li></ul><ul><li>Concomittant use of other agents that blunt the RAS (Beta blockers, ACE inhibitors) – HYPERKALEMIA </li></ul><ul><li>Liver disease </li></ul><ul><li>CYP3A4 inhibitors (ketoconazole, itraconazole) – increase blood levels of EPLERENONE </li></ul>
    130. 151. OSMOTIC DIURETICS <ul><li>CLASSIFICATION & PROTOTYPE: </li></ul><ul><ul><li>MANNITOL – prototype osmotic diuretic given intravenously </li></ul></ul>
    131. 152. MECHANISM OF ACTION: <ul><li>Holds water in the lumen by virtue of its osmotic effect </li></ul><ul><li>Major location for this action is the proximal convoluted tubule , where the bulk of isosmotic reabsorption takes place </li></ul><ul><li>Reabsorption of H2O is also reduced in the descending limb of the loop of henle & the collecting tubule </li></ul>
    132. 153. EFFECTS: <ul><li>Volume or urine is increased </li></ul><ul><li>Most filtered solutes will be excreted in larger amounts unless they are actively reabsorbed </li></ul>
    133. 154. CLINICAL USES: <ul><li>Maintain high urine flow (when renal blood flow is reduced & in conditions of solute overload from severe hemolysis or rhabdomyolysis) </li></ul><ul><li>Useful in reducing intraocular pressure in acute glaucoma & increase intracranial pressure in neurologic conditions </li></ul><ul><li>Removal of renal toxins </li></ul>
    134. 155. ANTIDIURETIC HORMONE AGONISTS <ul><li>VASOPRESSIN </li></ul><ul><li>DESMOPRESSIN </li></ul><ul><li>Treatment of central diabetes insipidus </li></ul>
    135. 156. TOXICITY: <ul><li>Nephrogenic Diabetes Insipidus </li></ul><ul><li>Renal failure </li></ul>
    136. 157. ANTIDIURETIC HORMONE ANTAGONISTS <ul><li>CONIVAPTAN </li></ul><ul><ul><li>Receptor antagonist </li></ul></ul><ul><li>LITHIUM </li></ul><ul><li>DEMECLOCYLINE </li></ul><ul><li>Oral administration </li></ul><ul><li>T ½ = 5-10 hrs </li></ul>
    137. 158. PHARMACODYNAMICS <ul><li>Inhibits the effects of ADH in the collecting tubule </li></ul><ul><li>Conivaptan – pharmacologic antagonist at V1a & V2 receptors </li></ul><ul><li>Lithium & Demeclocyline – reduce the formation of cAMP in response to ADH, interfere with the actions of cAMP in the collecting tubule cells </li></ul>
    138. 159. CLINICAL INDICATIONS: <ul><li>Syndrome of Inappropriate ADH Secretion (SIADH) </li></ul><ul><ul><li>When water restriction is not effective </li></ul></ul><ul><li>Other elevations of ADH </li></ul>
    139. 160. TOXICITY: <ul><li>Extracellular volume expansion </li></ul><ul><li>Dehydration </li></ul><ul><li>Hyperkalemia </li></ul><ul><li>Hypernatremia </li></ul>
    140. 161. Asymptomatic LV Dysfunction Mild to moderate CHF Moderate to severe CHF ACE inhibitor Digoxin Digoxin Beta blocker Diuretics Diuretics   ACE inhibitor ACE inhibitor   Beta blocker Beta blocker   Spironolactone  
    141. 162. THANK YOU!!!
    142. 163. POST TEST <ul><li>1. Site of action of loop diuretics: </li></ul><ul><li>A. loop of henle B. distal convoluted tubule </li></ul><ul><li>2. Site of action of thiazide diuretics: </li></ul><ul><li>A. Loop of henle B. distal convoluted tubule </li></ul><ul><li>3. Site of action of K sparing diuretics: </li></ul><ul><li>A. Collecting tubule B. loop of henle </li></ul><ul><li>4. Toxic level of digitalis: </li></ul><ul><li>A. .2 ng/ml B. 2.0 ng/ml </li></ul><ul><li>5. Prevents early remodelling of the heart: </li></ul><ul><li>A. ACE inhibitors B. diuretics </li></ul><ul><li>6. A vasodilator: </li></ul><ul><li>A. Nitrates B. furosemide </li></ul><ul><li>7. Decreases intracranial pressure: </li></ul><ul><li>A. Digitalis B. Mannitol </li></ul><ul><li>8. Decreases intraocular pressure: </li></ul><ul><li>A. acetazolamide B. furosemide </li></ul><ul><li>9. Potent vasoconstrictor: </li></ul><ul><li>A. bradykinin B. angiotensin II </li></ul><ul><li>10. Early compensatory response of the heart to a decrease cardiac output: </li></ul><ul><li>A. tacchycardia B. cardiomegaly </li></ul>
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