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CVS_Lecture 2.pdf

  1. CV Pharmacol (PHL 322) Lecture-2 Heart Failure Drugs 1 Prof. Dr/ Gamal A. Soliman Pharmacy College
  2. █ Heart Failure (HF) ▪ Heart failure is the inability of the heart muscle to pumps sufficient blood to meet the needs of the tissues for oxygen and nutrients. ▪ Heart failure, also known as congestive heart failure. 2
  3. █ Types of heart failure 1- Left-sided heart failure: ▪ It is the inability of the left ventricle of the heart to pump an adequate amount of blood to the Aorta (as a result of high systemic BP). ▪ This result in , o Accumulation of blood in the left ventricle So causes hypertrophy and, as the condition continues, leads to dilatation. o Accumulation of blood in the pulmonary veins (pulmonary congestion) So increases the venous pressure that result in fluid outflow from the pulmonary capillaries into the pulmonary tissues and alveoli, causing pulmonary edema. o Pulmonary edema leads to tachypnea (rapid breathing) and dyspnea (difficult breathing). ▪ Over time, left-sided heart failure can lead to right-sided heart failure. NOTE ▪ Left-sided heart failure is more common than right-sided heart failure. 3
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  5. 2- Right-sided heart failure: ▪ It is the inability of the right ventricle of the heart to pump blood to the lungs (as a result of too weak ventricular M or pulmonary hypertension). ▪ This result in , o Accumulation of blood in the right ventricle causing hypertrophy and, as the condition continues, leads to dilatation. o Accumulation of blood in the vena cava So increases the systemic venous pressure that result in fluid outflow from the veins causing edema and ascites. ▪ Some organs like liver are enlarged because they are congested with blood. ▪ Some areas like the limbs develop pitting edema because fluid pools in these areas. ▪ Also, neck veins become distended and pulsating NOTE ▪ As the left-sided heart failure causes pulmonary congestion and the right-sided heart failure causes systemic venous congestion, so the disease is called congestive heart failure (CHF) when it affects both sides 5
  6. █ Symptoms of heart failure ❖ Symptoms include : ▪ Dyspnea ▪ Breathlessness ‫تنفس‬ ‫ضيق‬ ▪ Orthopnea ▪ Generalized lethargy ‫خمول‬ and fatigue ▪ Ankle swelling ❖ Signs include: ▪ Pulmonary edema ▪ High jugular pressure ▪ tachycardia _ due to Increased adrenergic activity ▪ Hepatomegaly (secondary to raised right-sided heart pressures) ▪ Ascites 6
  7. █ Consequences of heart failure ▪ In HF, COP decreases therefore, all tissues of the body suffer from ischemia and hypoxia ▪ Brain _ the brain respond to hypoxia by reflex sympathetic stimulation which result in tachycardia ▪ Kidneys _ the kidney respond to hypoxia by stimulation of RAAS o Angiotensin II: induces VC, so increases the systemic resistance (increase after load) o Aldosterone : induces salt and water retention, so increase edema (increase preload) 7
  8. █ The goal of therapy ▪ In case of the left-sided heart failure o The goal of therapy is to reduce afterload o This goal can be achieved by using a vasodilator to open the way to the left ventricle, so the left ventricle can pump blood easily ▪ In case of the right-sided heart failure o The goal of therapy is to reduce preload o This goal can be achieved by using a diuretic to remove extra fluids from the body, so the right ventricle can pump blood easily 8
  9. █ Treatment of heart failure ❖ Non-drug measures 1- Diet (reduce salt and fluid intake) 2- Stop smoking 3- Regular exercise 4- Maintain optimal weight ❖ Drug treatment 1- ACE inhibitors : Captopril, ramipril, enalapril 2- Diuretics o Loop diuretic (Furosemide) o Aldosterone antagonists (Spironolactone) 3- Vasodilators : Hydralazine, Nitrates 4- Positive inotropes : Digoxin 5- β blockers : Bisoprolol, Metoprolol, Carvedilol NOTE ▪ It is not preferable to start treatment with a digitalis group (digoxin) that increases COP in the presence of increased cardiac preload and afterload. o Cardiac preload and afterload must be reduced firstly. ▪ Therefore, it is preferable to start treatment with ACE inhibitors and diuretics 9
  10. [1] ACE inhibitors ▪ Ex: Captopril, ramipril, enalapril ▪ ACE inhibitors are widely used in the treatment of heart failure and hypertension. ▪ These drugs block the ACE so inhibits the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. o So, these drugs act as vasodilators, reducing load on the heart and making it easier to pump blood around the body i.e decreasing both cardiac preload and afterload ▪ Also, ACE inhibitors reduce the secretion of aldosterone, resulting in excretion of salts and water (diuresis) i.e . decreasing cardiac preload 10 Renin ACE Angiotensinogen Inactive Angiotensin I Active Angiotensin-II
  11. [2] Diuretics ▪ Drugs that used to remove salts and extra-fluid (edema) from the body through urine. ▪ Their major mechanism of action in heart failure is to reduce blood volume, venous pressure and consequently cardiac preload. ▪ Increased excretion of salt and water by diuretics result in : o Reduction in the volume of blood that the heart must pump and help lower venous pressure and consequently cardiac preload. o Reduction in the pulmonary edema so relieve dyspnea and improve oxygenation o Reduction in edema in other parts of the body such as Ankle edema and ascites ▪ Diuretics have no direct effect on the cardiac contractility 11
  12. Ex: 1- Loop diuretic (Furosemide) ▪ Furosemide is the most widely used diuretic in case of heart failure ▪ It help the excretion of NaCl, KCl and water in the urine causing diuresis So ….. o decrease cardiac preload. o improves the symptoms secondary to fluid overload as edema and ascites. ❖ Common side effects include: ▪ Hyponatraemia ▪ Hypokalaemia 2- Aldosterone antagonists (Spironolactone) ▪ The most serious side effect of spironolactone is that it can elevates the level of potassium in the blood to become dangerously high (hyperkalemia). o Therefore, regular blood tests should be done to check the potassium level. ▪ Although spironolactone belongs to a weak class of diuretics, it reduces the mortality rate in patients with heart failure who are also receiving ACE inhibitors and other standard therapy. 12
  13. [3] Vasodilators ▪ Vasodilators can help relax and dilate the blood vessels. ▪ Vasodilators are effective in acute heart failure because they provide a reduction of cardiac preload (through venodilation), and reduction of cardiac afterload (through arteriolar dilation). ❖ Ex: Hydralazine, Nitrates ▪ Hydralazine causes vasodilation by acting mainly on arteries and arterioles but not veins so reduces the cardiac afterload . ▪ Nitrates dilate veins more than arteries so decrease the cardiac preload. o Therefore, it is preferable to use hydralazine and nitrates together. 13
  14. █ Cardiac myocytes (Heart cell) 14
  15. [4] Positive inotropes (Digitalis, Cardiac glycosides) ▪ Positive inotropes or cardiotonic drugs are drugs that increase the force of heart muscle contractions, increase COP and pump blood more effectively to all tissues of the body in patients with HF. Ex: Digitalis or cardiac glycosides ▪ Cardiac glycosides represent a family of compounds derived from the foxglove plant (Digitalis purpurea). ▪ Cardiac glycosides include digoxin, digitoxin and Ouabain ▪ The 3 compounds are chemically similar 15
  16. ❖ Chemical structure 16 1- Steroid nucleus with 4 fused rings 2- Lactone ring 3- Sugar molecules ❖ Each cardiac glycoside compound consists of two parts : 1- Non sugar part (Aglycon or genin) _ part that contain steroid nucleus and lactone ring , o It is found in all members of cardiac glycosides o It is the part that is responsible for the pharmacological activities of the glycosides 2- Sugar part (Glycon) _ the sugar part o It is the part that is responsible for pharmacokinetic of the glycoside –Glycon part differs from one glycoside to another ▪ All glycosides have the same MOA because the MOA depends on Aglycon part which is fixed and constant in the 3 compounds
  17. ▪ Digoxin is the only cardiac glycoside used now for medicinal purposes. ❖ Pharmacokinetics ▪ Digoxin is 65–80% absorbed after oral administration. ▪ Once present in the blood, digoxin is widely distributed to tissues, including the heart and CNS. ▪ Digoxin is not extensively metabolized; almost two thirds is excreted unchanged by the kidneys. ▪ The half-life of digoxin in patients with normal renal function is long (40 hours) ▪ Digoxin is eliminated by the kidneys. 17
  18. ❖ The sodium-potassium pump ▪ The of Na+ /K+ -ATPase (also known as the sodium-potassium pump) is the enzyme responsible for pumping sodium ions out of the cell and potassium ions into the cell. ▪ This transport function is necessary for the normal function of the cell ❖ The mechanism of action A. Cardiac Effects ▪ Cardiac glycosides act by inhibiting the activity of Na+ /K+ -ATPase enzyme so inhibit cell membranes from pumping sodium out. ▪ This leads to the accumulation of Na+ inside the heart cells 18
  19. ▪ The accumulation of sodium ions inside the heart cells allows more calcium to accumulate in the cells. ▪ This is because: o The release of ca from ca-binding stores at the inner aspect of cell membrane o Opening Ca channels in the cell membrane o Decreasing the ability of the Na/ Ca transporter to push calcium out of the cells. ▪ The accumulated calcium creates stronger heart muscle contractions (positive inotropic effect), meaning the heart pumps more blood with each heartbeat, i.e increases the cardiac output. ▪ The increased COP result in improvement of renal blood flow causing diuresis so edema starts to disappear ▪ Further, the diuresis decreases blood volume. o A decrease in blood volume relieve the workload of the heart. 19
  20. B. Extracardiac effects— ▪ Digoxin induce vagal stimulation so decrease the heart rate i.e bradycardia (negative chronotropic effect) ▪ Due to bradycardia : o The diseased cardiac muscle takes more time of rest o The ventricle take more chance for good filling with blood ❖ Indications ▪ Digoxin is mostly used to treat serious heart failure when other medicines do not help improve the symptoms. 20
  21. ❖ Side effects ▪ Digoxin has a relatively narrow safety margin. o The therapeutic plasma concentration range for digoxin is 0.5 - 1.5 ng/ml. o Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity ▪ If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life. 1- Cardiac symptoms ▪ Bradycardia ▪ The most significant side effect of digoxin is cardiac arrhythmias, some of which may be life-threatening. 2- Extra cardiac symptoms ▪ GI symptoms: anorexia, diarrhea ▪ Neurologic symptoms: confusion, fatigue, yellow vision (xanthopsia) 21
  22. ❖ Treatment of toxicity ▪ Stope the drug ▪ Potassium supplementation can reverse the toxic effects of digoxin if the toxicity is related to hypokalemia. ▪ Antiarrhythmic drugs as lidocaine ▪ Atropine _ in case of severe bradycardia ▪ Fab (Fractionated Antibodies) _ it is the most specific treatment that can be used to rapidly reduce plasma digoxin levels. o These antibodies combine with excess digoxin forming complex which excreted through urine 22
  23. [5] Beta blockers ▪ Beta blockers work by protecting the heart against the effects of sympathetic overactivity produced by the brain. o So protect against tachycardia ▪ They decrease the release of renin in the kidneys _ so help ACE inhibitors ▪ These drugs slow the heart rate and reduce blood pressure which allows the heart to pump more efficiently. ▪ Most patients with chronic heart failure respond favorably to certain β blockers (Bisoprolol, Metoprolol, Carvedilol). NOTES ▪ Beta blockers should be used in small doses ▪ They should be used once patients are clinically stable ▪ Beta-blockers are contraindicated in patients with Asthma. 23
  24. 24 The lecture end Thank you