Congestive heart failure a path from conventional to aadvance therapy

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Congestive heart failure a path from conventional to aadvance therapy

  1. 1. 1
  2. 2. CONGESTIVE HEART FAILURE: A PATH FROM CONVENTIONAL TO ADVANCE THERAPY PRESENTED BY MOMIN ALTAMASH M PHARM 1 ST YEAR (PHARMACOLOGY) ROLL NO. 22 GUIDED BY http://www.freewebs.com MR VINOD GUPTA 2
  3. 3. Table of Contents : 1. INTRODUCTION 2. PATHOPHYSIOLOGY 3. PHARMACOLOGICAL TREATMENT OF CONGESTIVE HEART FAILURE 4. NEWER DRUGS UNDER RESEARCH 5. ADVANCES IN THE TREATMENT 6. NON PHARMACOLOGICAL TREATMENT 7. CONCLUSION 8. REFRENCES 3
  4. 4. 1 ) Introduction : CONGESTIVE HEART FAILURE Factors that may produce congestive heart failure Obstruction Inflammation Malnutrition Insufficiency Oxygen lack Anaemia Raised pressure Toxins Hyperthyroidism 4
  5. 5. SYMPTOMS • http:/www.nationdisease.com 5
  6. 6. 2) Pathophysiology of Congestive Heart Failure : • Congestive heart failure is the pathophysiologic state in which – • the heart is unable to pump blood at a rate commensurate with the requirements of metabolizing tissues, or can do so only from an elevated filling pressure (Braunwald and Bristow, 2000). • Heart failure is a complex of symptoms – • That is fatigue, shortness of breath, and congestion that are related to the inadequate perfusion of tissue during exertion and often to the retention of fluid. Its primary cause is an impairment of the heart's ability to fill or empty the left ventricle properly (Cohn, 1996). 6
  7. 7. 7 John Burton, MD- Albany Medical Center-Albany, New York
  8. 8. Preload is a passive stretching force exerted on the ventricular muscle at the end of diastole. Preload is caused by the volume of blood in the ventricle at the end of diastole. Afterload is the force resisting the contraction of the cardiac muscle fibers. Afterload can also be considered as the blood pressure exerted on the Atrial Valve during diastole John Burton, MD- Albany Medical CenterAlbany, New York Contractility refers to the ability of cardiac muscle fibers to shorten when stimulated (strength 8
  9. 9. PATHOPHYSIOLOGY PUMP FAILS COMPENSATORY MECHANISMS STROKE VOLUME MYOCARDIAL HYPERTROPHY SNS STIMULATION EPINEPHRINE/ NOR EPINEPHRINE WALLS THICKEN RENIN HORMONE RELEASE ANGIOTENSIN 1 ANGIOTENSIN 2 ALDOSTERONE HEART RATE CONTRACTILITY AFTERLOAD PERIPHERAL VASOCONSTRICTION 9
  10. 10. • Compensatory mechanisms may restore CO to near-normal. • But, if excessive the compensatory mechanisms can worsen heart failure because . . . • Vasoconstriction: ↑’s the resistance against which heart has to pump (i.e., ↑’s afterload), and may therefore ↓ CO • Na and water retention: ↑’s fluid volume, which ↑’s preload. If too much “stretch” ↓ strength of contraction and ↓’s CO • Excessive tachycardia → ↓’d diastolic filling time → ↓’d ventricular filling → ↓’d SV and CO 10
  11. 11. 3) PHARMACOLOGICAL TREATMENT CONGESTIVE OF HEART FAILURE : Drug Classes Used To Treat CHF : Cardiac Glycosides β blockers (ACE Inhibitors) and AT1 Receptor Antagonists Diuretics Vasodilators Aldosterone Antagonists 11
  12. 12. 3.1] The Cardiac Glycosides (Cardenolides): • Drug Members : i. Digitoxin (Crystodigin) ii. Digoxin (Lanoxin) iii. Deslanoside (Cedilanid-D) • Mechanisms of Action : http://cvpharmacology.com 12
  13. 13. • The net effect of the glycosides on the heart is as follows : a. heart rate is slowed b. contraction is greater due to increased filling volumes c. ejection fraction is improved d. increased ejection velocity • Adverse Side Effects Of The Glycosides : Fatigue, delirium, anorexia, headaches, hallucinations. 13
  14. 14. 3.2] Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) and AT1 Receptor Antagonists: • Drug Members: • Captopril (Capoten) • Enalapril (Vasotec) • Lisinopril (Prinivil) Mechanism: • AT1 receptor antagonists should at present be viewed as the preferred alternative when ACE inhibitors cannot be tolerated http://www.uspharmacist.com • Adverse Side Effects : GI distress, dizziness, skin rashes, hypotension 14
  15. 15. 3.3) BETA-BLOCKERS: http://www.cardiachealth.org Beta-blockers may work by slowing the heart rate, which allows the left ventricle (the main pumping chamber of the heart) to fill more completely. some of these medicines may also help open or widen blood vessels in the body. this makes them especially useful in some people with certain forms of heart failure who may also have high blood pressure 15
  16. 16. 3.4] Diuretics : Classes High Ceiling of Loop Diuretics Diuretics Furosemide (Lasix) 20,40 & 80 mg Ethacrynic Acid (Edecrin) Bumetanide (Bumex) Benzothiadiazide Diuretics Hydrochlorothiazide (Hydrodiuril) Potassium Sparing Diuretics Triamterene (Dyrenium) Osmotic Diuretics Mannitol (Osmitrol) Clorthalidone (Hygroton) Chlorothiazide (Diuril)10-20mg/kg Amiloride (Midamor) spironolactone (Aldactone)100-200mg 16
  17. 17. http://pharmacologycorner.com 17
  18. 18. • Side effects • Low plasma ion concentrations : • Hypokalemia (low blood Potassium) • Hyponatremia (low blood Sodium) • Hypocalcemia (low blood Calcium) • Hypomagnesemia (low blood Magnesium • diarrhoea, • drowsiness, • headaches, • impotence, • mental confusion 18
  19. 19. 4) NEWER DRUGS UNDER RESEARCH • 4.1) Coenzyme Q10 : • occurs naturally in the body and is essential to survival. • Acts as an electron carrier in the mitochondria, http://www.netrition.com • CoQ10 levels are decreased in the heart muscle of patients with heart failure, • Double blind controlled trials have shown that CoQ10 improves symptoms, functional capacity and quality of life in patients with heart failure with no side effects • "Other heart failure medications block rather than enhance cellular processes and may have side effects. • Supplementation with CoQ10, which is a natural and safe 19
  20. 20. • It corrects a deficiency in the body and blocks the vicious metabolic cycle in chronic heart failure called the energy starved heart.“ • sources-Q10 is present in food, including red meat, plants and fish, but levels are insufficient to impact on heart failure. • CoQ10 is also sold over the counter as a food supplement. • Coenzyme Q10 decreases all cause mortality by half. • It is the first drug to improve heart failure mortality in over a decade and can be added to standard treatment . http://www.vitacost.com 20
  21. 21. •4.2) Bromodomain and extraterminal domain (BET) protein inhibitors : Current therapies are not adequately effective at improving health and preventing deaths. Bromodomain and extraterminal domain (BET) proteins activates genes that contribute to heart failure. Heart failure may be triggered by the activation of a large set of genes that cause the walls of the heart to thicken and develop scar tissue, impairing the organ's ability to pump blood normally. 21
  22. 22. BET proteins can have a huge impact on gene activity because they belong to a class of molecules called epigenetic readers, which recognize special marks on DNAprotein complexes and attract gene-activating proteins to those spots. BET inhibitor called JQ1 shows promise in treating heart failure. JQ1 protect against heart-wall thickening, the formation of scar tissue, and pump failure 22
  23. 23. 5) Advances in treatment of CHF Stem cell therapy Gene therapy 23
  24. 24. 5.1) Stem cell therapy. • Stem cells - These are undifferentiated cells that can differentiate into specialized cell types. stem cells come from 3 main sources: i. Embryonic stem cells, ii. Adult tissue (adult stem cells). iii. Endometrial stem cells. 24
  25. 25. CLASSIFICATION 1 Adult stem cells 2 Embryionic stem cells 3 Endometrial stem cells Exist throughout the body after embryonic development. found in tissues such as the brain, bone marrow, blood, blood vessels, skeletal muscles, skin, and the liver. Derived from a four- or five-day-old human embryo that is in the blastocyst phase of development. in IVF (in vitro fertilization) clinics there are extra embryos. only one is implanted into a woman from several eggs fertilized in a test tube. It involves extraction of a small amount of menstrual blood from young healthy donors that is called as endometrial stem cells. 25
  26. 26. Fig: pictorial representation of injecting stem cells in cardiac tissue http:/www.trialx.com 26
  27. 27. • Possible mechanisms of recovery include: • Generation of heart muscle cells, • Stimulation of growth of new blood vessels to repopulate damaged heart tissue, • Secretion of growth factors, • Assistance via some other mechanism, 27
  28. 28. • PROCEDURE OF STEM CELL THERAPY 1. COLLECTION 2. PROCESSING AND CRYOPRESRVATION 3. INFUSION 4. ENGRAFMENT AND RECOVERY 28
  29. 29. 5.2) GENE THERAPY : • Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. Gene therapy is a technique that uses genes to treat or prevent disease. • Researchers are testing several approaches to gene therapy, including: • Replacing a mutated gene that causes disease with a healthy copy of the gene. • Inactivating, or “knocking out,” a mutated gene that is functioning improperly. • Introducing a new gene into the body to help fight a disease . 29
  30. 30. http:/www.wikipedia.org 30
  31. 31. • SARCOENDOPLASMIC RETICULUM (SER): • Sarcoplasmic reticulum activated by Ca2+ leads to contraction. • In heart failure, decrease expression of Ca2+ causes impairment of SER. • widely used viruses for gene delivery to heart are recombinant AAVs (adeno associated virus).They are relatively sective for cardiac myocites • There is high diastolic and low systolic Ca2+ levels when SER is impaired. Studies has shown that by increasing SER Ca2+ expression by viral transduction of SER Ca2+ transgene, heart failure can be treated . 31
  32. 32. • OTHER TARGETS a) PHOSPHOLAMBAN: • It is a protein that regulates the calcium pump in cardiac muscle. • This protein is a potent inhibitor of sarcoplasmic reticulum ca 2+ ATPase in unphosphorylated state, but inhibition is relieved upon phosphorylation. • Inhibitory phospholamban, antisense and psuedophosphorylated state mutant is used in heart failure by viral delivery. 32
  33. 33. b) ADENYLYL CYCLASE 6 protein kinase a phosphorylates phospholamban and SERCA2A activity is enhanced. FIG: ROLE OF ADENYLYL CYCLASE (AC6) IN HEART CONTRACTION http:/www.sciencedirect.com Symptoms of heart failure is alleviated by viral delivery of AC6 transgene as result of SERCA2a function. 33
  34. 34. c) PROTEIN PHOSPHATASE 1 • It is involved in the regulation of a variety of cellular processes,. • Increased PP1 activity has been observed in the end stage of heart failure • SR ca2+ upake is suppressed by the (ppi) because it dephosphorylates the phospholamban. • Pp1 is reduced using (sh)RNA and has showed improved cardiac function and reduced interstitial fibrosis in mouse model of heart failure. 34
  35. 35. d) SMALL UBIQUITINE LIKE MODIFIER (SUMO 1 ) : • SUMO 1 is a key component in cardiac function . • The interaction between SUMO 1 and SERCA2A is crucial for regulating calcium levels inside cardiac myocytes. • Reduction in SUMO 1 protein reduces SERCa2+, and thus efficient calcium handling in patients with failing hearts . • Introduction of SUMO 1 through gene therapy is associated with improved activity of SERCA2A, which resulted in improved cardiac function through an augmentation of cardiac contractility. 35
  36. 36. FIG : GENE THERAPY PROCEDURE http://www.trip2medi.com 36
  37. 37. • GENE DELIVERY METHODS ; A) Transvascular intracoronary antegrade and retrograde delivery : B) Direct intramyocardial delivery : http://www.sciencedirect.com 37
  38. 38. 6) Device therapy : • Damage to the heart muscle can cause changes in the electrical system of the heart. • There are three different types of devices that can be used in the treatment of heart failure to correct an abnormal heartbeat. 38
  39. 39. I. Pacemakers : • The traditional pacemaker has two parts: lead wires and a pulse generator, which houses a battery and a tiny computer. • The lead wires sense the heart's electrical activity, and when the computer determines that the heart rhythm is off, it responds by sending electrical impulses to the heart muscle to correct its rate. • Pacemakers are usually used to treat heart rhythms that are too slow. But they can also be used to treat fast rhythms or to increase the heart rate in response to changes in the patient's activity level 39
  40. 40. 2. Biventricular (cardiac resynchronisation therapy) : 40
  41. 41. 3) Internal cardioverter defibrillator (ICD): ICD senses electrical activity and sends a shock to the heart if it detects a dangerous heart rhythm implantable cardiac defibrillators reduce the risk of death from sudden cardiac arrest by 23 percent in patients with heart failure 41
  42. 42. • Continuous positive airway pressure(CPAP): • To improve the prognosis of CHF, additional novel approaches to its therapy are required. One promising approach is the use of continuous positive airway pressure (CPAP ). • When applied via a nasal mask, CPAP provides a noninvasive mechanical assist to the failing heart by increasing intrathoracic pressure and augmenting stroke volume and cardiac output,CPAP improves the mechanical efficiency of the failing heart possibly through reverse ventricular remodeling. 42
  43. 43. 7) Conclusion Heart failure is a major health issue with a high rate of morbidity and mortality Thus, there is a substantial need for new strategies to prevent the progression of heart failure. Until now, heart failure was seen as an incurable disease. However, gene therapy approach have offered the promise of an effective therapy for reversing systolic heart failure Great advances in understanding the pathobiology of HF and their application to further improvements of patient care are withun reach 43
  44. 44. Time will tell whether a single target approach is sufficient to restore heart function and prevent deterioration or whether multiple gene targets are needed along with stem cell therapy to eventually replace the injured myocardium. Using a viral-delivery gene therapy approach to treat heart failure by enhancing contractility is not yet a reality, but substantial progress in that direction has been made in the last few years. Great advances in understanding the pathobiology of HF and their application to further improvements of patient care are within reach 44
  45. 45. • Refrences • 1. Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., Nadal-Ginard, B., Silvestri, F., Leri, A., Beltrami, C.A., and Anversa, P. (2001). Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 344, 1750–1757. • 2 . Itskovitz-Eldor, J., Schuldiner, M., Karsenti, D., Eden, A., Yanuka, O., Amit, M., Soreq, H., and Benvenisty, N. (2000). Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol. Med. 6, 88–95. • 3. Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K., and Goodell, M.A. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1–8. • 4. Kehat, I., Kenyagin-Karsenti, D., Druckmann, M., Segev, H., Amit, M., Gepstein, A., Livne, E., Binah, O., Itskovitz-Eldor, J., and Gepstein, L. (2001). Human embryonic stem cells can differentiate into myocytes portraying cardiomyocytic structural and functional properties. J. Clin. Invest. (in press) • 5. Kessler, P.D. and Byrne, B.J. (1999). Myoblast cell grafting into heart muscle: cellular biology and potential applications. Annu. Rev. Physiol. 61, 219–242. 45
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