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IVMS-CV -Cardiovascular Pharmacology Global Review

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IVMS-CV -Cardiovascular Pharmacology Global Review

  1. 1. Cardiovascular Pharmacology Global Overview/Review Topics discussed: Autonomic Nervous System and Blood Pressure Control Antihypertensive Drugs Drugs for Angina ACE Inhibitors Calcium Channel Blockers Adrenergic Blockers Cardiac Glycosides Prepared and presented by: Marc Imhotep Cray, M.D. eNotes: Cardiovascular Pharmacology
  2. 2. 2 Blood Pressure
  3. 3. Blood Pressure(2) 3
  4. 4. 4 Autonomic Nervous System and Blood Pressure Control • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles • (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO)
  5. 5. 5 Spinal Cord Brain Stem Carotid Sinus Parasympathetic (Vagus) Sympathetic -Adrenoceptor -Adrenoceptor Vasomotor Center Higher Centers Neural Control of the CVS: Autonomic Nervous System Arteriole
  6. 6. 6 Parasympathetic Sympathetic Baroreceptor Reflexes in BP Control  BP1
  7. 7. 7 Carotid sinus senses  BP Parasympathetic Sympathetic 2 Baroreceptor Reflexes in BP Control  BP1
  8. 8. 8 Carotid sinus senses  BP Parasympathetic Sympathetic Vasomotor Center responds with  Symp. NS activity and  Parasymp. activity 2 3 Baroreceptor Reflexes in BP Control  BP1
  9. 9. 9 Carotid sinus senses  BP Parasympathetic Sympathetic  PVR  Heart rate and contractility Vasomotor Center responds with  Symp. NS activity and  Parasymp. activity 2 3 4 4 Baroreceptor Reflexes in BP Control  BP1
  10. 10. 10 Carotid sinus senses  BP Parasympathetic Sympathetic  PVR  Heart rate and contractility Vasomotor Centre responds with  Symp. NS activity and  Parasymp. activity Baroreceptor Reflexes in BP Control  BP 2 3 4 4 5  BP1
  11. 11. 11 • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO) Blood Pressure Control: Control of Stroke Volume
  12. 12. 12 Stroke volume (SV) • Stroke volume (SV) is volume of blood pumped by right/left ventricle of heart in one contraction • Specifically, it is volume of blood ejected from ventricles during systole • SV is not all of blood contained in left ventricle • Normally, only about two- thirds of blood in ventricle is put out with each beat • What blood is actually pumped from left ventricle is stroke volume and it, together with heart rate, determines the cardiac output Calculation Its value is obtained by subtracting end-systolic volume (ESV) from end-diastolic volume (EDV) for a given ventricle: SV = EDV − ESV In a healthy 70-kg man, the left ventricular EDV is 120 ml and the corresponding ESV is 50 ml, giving a stroke volume of 70 ml.
  13. 13. 13 Factors Determining Stroke Volume • Contractility –  sympathetic activity increases contractility • End-diastolic volume – Determined by venous filling pressure (distensible ventricle) Blood Pressure Control: Control of Stroke Volume
  14. 14. 14 Venous filling pressure and stroke volume • The Frank-Starling relationship StrokeVolume End diastolic volume (filling pressure) Output increases with increased filling pressure Overdistended, output falls Blood Pressure Control: Control of Stroke Volume
  15. 15. 15 What determines venous filling pressure? • Blood volume, mostly contained in a distensible venous circulation! Blood Pressure Control: Control of Stroke Volume
  16. 16. 16 • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO) Blood Pressure Control: Renin-Angiotensin
  17. 17. 17 Renin-Angiotensin System Renin (Circulating) Liver Angiotensin Precursor (Circulating) Angiotensin I AT1 Receptor Aldosterone from adrenal cortex SENSOR IN KIDNEY Vasoconstriction Na+ Retention K+ Excretion Angiotensin II OUTCOMES
  18. 18. 18 BP Control Mechanisms Summary
  19. 19. Antihypertensive Drugs See Antihypertensive Agents
  20. 20. 20 Antihypertensive Drug Strategies • Reduce cardiac output – -adrenergic blockers – Ca2+ Channel blockers • Dilate resistance vessels – Ca2+ Channel blockers – Renin-angiotensin system blockers – 1 adrenoceptor blockers – Nitrates** • Reduce vascular volume – diuretics
  21. 21. (Also have uses in treating cardiac rhythm disturbances & angina) Calcium Channel Blocking Drugs Calcium-channel blockers (CCBs)
  22. 22. 22 Membrane Ca2+ Channels • All cells, voltage or ligand-gated, several types • [Ca2+]e  2.5mM • [Ca2+]i  100nM (maintained by Na+/Ca2+ antiport) • [Ca2+]i  Signaling Actin-myosin interaction Myocardial membrane depolarization (Phase 2)
  23. 23. 23 Effect of Ca2+ Influx: Muscle Contraction Ca2+ Channel Sarcoplasmic Reticulum Actin & Myosin Ca2+ Ca2+ “Trigger”  contraction (myocardial or vascular) Plasma Membrane Ca2+
  24. 24. 24 Ca2+ Channel Blockers • Cardioselective – verapamil • Vascular selective – dihydropyridines • nifedipine • felodipine • amlodipine • Non-selective – diltiazem
  25. 25. 25 Ca2+ Channel Blockers • Myocardial selective: – Reduce cardiac contractility – Also reduce heart rate (action on heart rhythm) •  BP,  heart work • Vascular smooth muscle selective – Reduce vascular resistance •  BP,  heart work
  26. 26. 1 Adrenoceptor Antagonists Beta-adrenoceptor antagonists (beta-blockers)
  27. 27. 27 Cardiac 1 Adrenoceptor Stimulation •  Heart rate •  contractility  blood pressure  heart work
  28. 28. 28 Cardiac 1 Adrenoceptor Blockade •  Heart rate •  contractility   blood pressure   heart work
  29. 29. 29 Cardiac 1 Adrenoceptor Blockers • Metoprolol • Atenolol
  30. 30. 30 Cardiac 1 Adrenoceptor Blockers: Clinical Uses • Antiarrhythmic (slows some abnormal fast rhythms) • Antihypertensive • Antiangina: via reduced heart work
  31. 31. 31 Blockade of Renin-Angiotensin- Aldosterone System (RAAS) 1. Angiotensin converting enzyme (ACE) inhibitors 2. Angiotensin II receptor (AT1) antagonists
  32. 32. 32 Renin-angiotensin system Renin Liver Angiotensin Precursor Angiotensin I Angiotensin II Angiotensin Converting Enzyme AT1 Receptor Renal Blood Flow Na+ load Aldosterone Vasoconstriction Na+ Retention K+ Excretion
  33. 33. 33 Angiotensin Converting Enzyme (ACE) Inhibitors • Captopril • Enalapril • anything else ending in -pril – (lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc)
  34. 34. 34 AT1 Blockers (ARB’s) • Candesartan, • irbesartan, • others ending in -sartan
  35. 35. 35 ACE-Inhibitors & AT1 Blockers: Clinical Uses •  reduced vascular resistance •  aldosterone   salt & H2O retention Uses • Antihypertensive • Heart failure
  36. 36. 36 1 Adrenoceptor Blockers Alpha-adrenoceptor antagonists (alpha-blockers)
  37. 37. 37 Neural Control of Circulation: Autonomic NS Spinal Cord Brain Stem Carotid Sinus Parasympathetic (Vagus) Sympathetic 1-Adrenoceptor -Adrenoceptor Vasomotor Center Higher Centers
  38. 38. 38 1 Adrenoceptor Blockers • Peripheral vasodilator   vascular resistance • Agents: – Prazosin
  39. 39. 39 Volume Reduction • Reduces cardiac filling pressure (LVEDV/P) • Thus reduces stroke volume and cardiac output • Independent vascular relaxation with long term use See Diuretics eNotes
  40. 40. 40 Clinical Use of Antihypertensives • Consequences of chronic high blood pressure – heart failure – arterial disease • kidney failure • strokes • myocardial infarction (heart attack) • Aim of treatment – prevent consequences of high BP
  41. 41. Drug Treatment of Angina Antianginal Agents
  42. 42. 42 • Oxygen demand depends on heart work • Coronary artery partial obstruction (due to atherosclerosis) limits blood supply to part of the myocardium • Coronary circulation can meet oxygen demands of myocardium at rest, but not when heart work increased by exercise, etc. – Ischemia (O2 deficiency) causes pain: “angina” What is Angina and Why Does it Happen?
  43. 43. 43 Determinants of Heart Work • Heart work determined by: 1. Heart rate 2. Cardiac contractility 3. Peripheral resistance See: Antihypertensive Agents Physiological Factors Influencing Arterial Pressure for full discussion
  44. 44. 44 • Reduce heart rate and contractility –  adrenoceptor blockers – Ca2+ channel blockers (verapamil and diltiazem) • Dilate resistance vessels – Ca2+ channel blockers (nifedipine, felodipine, amlodipine) – Nitrates Drug Treatment of Angina: Limiting Heart Work
  45. 45. 45 Nitrates • Glyceryl trinitrate (GTN) • Isosorbide (di)nitrate
  46. 46. 46 GTN NO2 - OrganicNitrate Ester Reductase R-SH R-SH NO Nitrosothiols (R-SNO) Guanylate Cyclase + GTPcGMP Protein Kinase GRELAXATION Vascular Smooth Muscle Cell See : Nitrates, Digoxin and Calcium Channel Blockers Dr. Paul Forrest Royal Prince Alfred Hospital
  47. 47. 47 Nitric Oxide and Vasodilation After receptor stimulation, L- arginine-dependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle. EDRF=endothelium-derived relaxing factor. From: Inhaled Nitric Oxide Therapy ROBERT J. LUNN, M.D. http://www.mayoclinicproceedings.com/inside. asp?ref=7003sc
  48. 48. 48 Use of Nitrates • Very fast, short-lived vascular dilatation (Greater in venules than arterioles) • lower vascular resistance means less heart work • less heart work means less need for coronary artery blood flow – therefore, nitrates help chest pain (angina) that happens during exercise when there is coronary artery obstruction. • Not used for managing chronic high blood pressure
  49. 49. 49 Digitalis purpurea (Foxglove) Cardiostimulatory Medicines from foxgloves are called "Digitalin". The use of Digitalis purpurea extract containing cardiac glycosides for the treatment of heart conditions was first described in the English speaking medical literature by William Withering, in 1785. It is used to increase cardiac contractility (it is a positive inotrop) and as an antiarrhythmic agent to control the heart rate, particularly in the irregular (and often fast) atrial fibrillation. It is therefore often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with heart failure. From: http://en.wikipedia.org/wiki/Digitalis
  50. 50. 50 Cardiac Glycosides: Digoxin
  51. 51. 51 Digoxin Mechanism of Action Outside Inside Na+ K+ Na+ Ca2+ Na+ Pump ExchangerChannels Ca2+ K+ Na+/K+ ATPase
  52. 52. 52 Digoxin blocks Na+/K+ ATP’ase ATP’ase P Mg2+ K+ ATP’ase P Mg2+ Dig  less efficient Na+/K+ exchange  diminished Na+ gradient  diminished K+ gradient
  53. 53. 53 Digoxin increases intracellular Ca2+ Na+ K+ Na+ Ca2+ Pump Exchanger diminished Na+ gradient   intracellular Ca2+
  54. 54. 54 Effect of  [Ca2+]i Na+/K+ ATP’ase Ca2+ channel Sarcoplasmic Reticulum Actin & Myosin Na+/Ca2+ antiporter   contractility Na+K+ Ca2+ Ca2+ “Trigger” Na+ Na+ K+ Ca2+ Ca2+
  55. 55. 55 Digoxin Effects on Rhythm Therapeutic •  Vagus nerve activity – Slower heart rate – Slower AV conduction Toxic • Various abnormal rhythms
  56. 56. 56 Uses of Digoxin • Atrial fast arrhythmias: slows rate • Heart Failure: increases contractile strength
  57. 57. 57 Reference Resource Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Cairo CW, Simon JB, Golan DE. (Eds.); LLW 2012

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