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Ischemic Heart Disease          -Angina PectorisCoronaryartery                                        Plaque              ...
Three types of angina  Stable angina/Classic angina/Effort angina  Unstable angina/Crescendo angina  Variant angina/Pri...
Causes  — Imbalances in myocardial oxygen demand and supply  Coronary Flow Reduction      Endothelial dysfunctionStable an...
Treatment strategy - correct the imbalance     Stable angina:         Decreasing cardiac work to reduce oxygen demand    ...
Determinants of oxygen demandWall stress     Intraventricular pressure     Ventricular radius (volume)   Arterial blood pr...
Drugs of modulating oxygen demand
Determinants of oxygen supply   Coronary blood flow     Aortic diastolic pressure     Duration of diastole                ...
Vascular tone                    Myocardial O2          Preload:                                Myocardial O2             ...
Sites of drugs action-Nitrates,                                   Calcium channel blockers                                ...
Sites of drugs action - Sildenafil                       Regulates blood                       flow in the penis          ...
Drugs used to treat angina   Nitrates  Calcium channel blockers                             Heart rate    blockers    ...
Nitrates        Nitroglycerin (NTG)         (glyceryl trinitrate) • Volatilization and adsorption to plastic surfaces • Ke...
Pharmacokinetics                                    Nitroglycerin   Organic nitrate reductase   Oral bioavailability LOW...
Mechanism of action - Nitrates                                 Nitroglycerin                                 Nitrates     ...
Experiment             Norepinephrine (NE)
Organ system effects of NTGDilation of peripheral           Mildly dilate arteriolar capacitance veins                resi...
Side effects of NTG• Orthostatic hypotension• Syncope• Artery pulsation and throbbing headache• Negative inotropic effect
Pseudocyanosis                                  Fe3+                     hemoglobin   methemoglobin  • Pseudocyanosis  • T...
Drugs for erectile dysfunction                                         Preventing apoptosis                               ...
Toxicity - Nitrates   Acute adverse effects       Orthostatic hypotension       Tachycardia       Throbbing headache   ...
Carcinogenicity               Nitrosamines   Animal studies show a powerful carcinogens  Strong epidemiologic correlatio...
Beneficial and deleterious effects of nitratesEffect                                                   ResultPotential ben...
Nitrate and nitrite drugs used in anginaDrug                                              Dose                         Dur...
Under investigation                         Activation of cardiac KATP channels        Nicorandil Reduces both preload and...
Which of the following is a common direct effect of nitroglycerin? A.   Increased heart rate B.   Increased afterload C.  ...
Calcium channel blocker   Nit                 Ca2+
Calcium channelsType   Channel Name    Where Found                  Properties of the calcium     Blocked by              ...
Chemistry – calcium channel blockers   High first-pass effect, high plasma binding, and extensive metabolism
Mechanism of action - calcium channel blockers              Verapamil              Diltiazem Nifedipine
Smooth muscle  Vascular           • Peripheral vascular resistance-effort angina  Bronchiolar        • Coronary artery t...
Cardiac muscle  Reduce SA and AV action potential  Reduce cardiac contractility  Reduce cardiac output  Nifedipine/dihydro...
Skeletal muscle  CCBs do not affect  skeletal muscle
Cerebral vasospasm        Nimodipine        Nicardipine                     Prevent cerebral vasospasm                    ...
Other aspects – Calcium channel blocker   Minimally affect glands and nerve due to calcium channel type   Verapamil inhi...
Toxicity – calcium channel blocker                             Cardiac arrest                             Bradycardia   C...
Clinical effects – calcium channel blocker                             Decrease myocardial contractile force              ...
Target selectivity – calcium channel blocker         Verapamil         DiltiazemTachycardiaDecreasing ventricular response...
Clinical pharmacology of calcium channel-blockerDrug               Oral                  Half-life   Indication           ...
Clinical considerations – calcium channel blocker     Low blood pressure         Verapamil/diltiazem are better than DHP ...
Which muscle may not be affected by calcium channel blockers?A.   Cardiac muscleB.   Bronchiolar smooth muscleC.   Skeleta...
 blockers Reduce oxygen demand by decreasing heart rate, blood pressure and contractility                            NE: ...
Clinical aspects -  blocker     Silent/ambulatory ischemia     Myocardial infarction     Hypertension     Stable angina
Side effects -  blocker   Increase in end-diastolic volume                                        Myocardial oxygen      ...
Contraindications -  blocker    Asthma and other bronchospastic conditions    Severe bradycardia    Atrioventricular b...
Complications -  blocker    Fatigue    Impaired exercise tolerance    Insomnia    Unpleasant dreams    Worsening of ...
New drugs  Drugs under investigation for use in angina  Metabolic modulators, eg, trimetazidine, ranolazine  Direct bradyc...
Trimetazidine
Ranolazine  Ranolazine was patented in 1986, and then approved for use in the US  in 2006 for angina patients who remain s...
Sodium channel blockersIvabradineInhibit thehyperpolarization-   Efficacy similar to that of calcium channel blockers anda...
Clinical pharmacology    Atherosclerotic disease of the coronaries (CAD)    Smoking, hypertension, hyperlipidemia, obesi...
Effort angina                    Nitrates Alone    -Blockers or Calcium Channel   Combined Nitrates with  blockers or   ...
Variant angina     Normal coronary artery     Nitrates           Atherosclerosis     Calcium channel blockers           ...
Unstable angina                  Unstable angina     Aspirin    Clopidogrel
Peripheral artery disease                                           Pentoxifylline                                        ...
SummarySubclass                Mechanism of action                     Effects                                 Clinical   ...
Which approach may not be used for variant angina?A.   NitratesB.   Calcium Channel blockersC.    blockersD.   Angioplasty
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Ischemic heart disease 2012 ji li

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Ischemic heart disease 2012 ji li

  1. 1. Ischemic Heart Disease -Angina PectorisCoronaryartery Plaque Enlarged view of coronary arteryThe leading cause of mortality in the United StatesMore than 500,000 deaths per year
  2. 2. Three types of angina  Stable angina/Classic angina/Effort angina  Unstable angina/Crescendo angina  Variant angina/Prinzmetal angina Normal coronary artery Normal Atherosclerosis Stable angina Atherosclerosis with blood clotUnstable angina Coronary spasm Variant angina
  3. 3. Causes — Imbalances in myocardial oxygen demand and supply Coronary Flow Reduction Endothelial dysfunctionStable angina  Unstable angina  Variant angina
  4. 4. Treatment strategy - correct the imbalance  Stable angina: Decreasing cardiac work to reduce oxygen demand  Unstable angina: Increasing oxygen delivery and decreasing oxygen demand  Variant angina: Spasm of coronary vessels reversed by nitrates, calcium channel blockers
  5. 5. Determinants of oxygen demandWall stress Intraventricular pressure Ventricular radius (volume) Arterial blood pressure Wall thicknessHeart rateContractility
  6. 6. Drugs of modulating oxygen demand
  7. 7. Determinants of oxygen supply Coronary blood flow Aortic diastolic pressure Duration of diastole Metabolic products Coronary vascular Autonomic activity bed resistance Pharmacological agents
  8. 8. Vascular tone Myocardial O2 Preload: Myocardial O2 SUPPLY DEMAND end-diastolic Perfusion of the heart ventricular wall Ventricular wall stress stress Vascular tone of the Preload Afterload Afterload: coronary arteries Heart systolic ventricular Venous tone (pump) Arteriolar tone wall stress Left circumflex Peripheral vascular coronary arteryRight coronary Capillaries resistanceartery Arterial blood pressure Left anterior descending coronary artery Veins (capacitance vessels) Arterioles (resistance vessels)
  9. 9. Sites of drugs action-Nitrates, Calcium channel blockers Stabilize depolarization NOReduce heart rate, contractility
  10. 10. Sites of drugs action - Sildenafil Regulates blood flow in the penis Sildenafil/Viagra
  11. 11. Drugs used to treat angina  Nitrates  Calcium channel blockers Heart rate   blockers Ventricular volume Blood pressure Contractility
  12. 12. Nitrates Nitroglycerin (NTG) (glyceryl trinitrate) • Volatilization and adsorption to plastic surfaces • Keep it in tightly closed glass container • Not sensitive to light
  13. 13. Pharmacokinetics Nitroglycerin  Organic nitrate reductase  Oral bioavailability LOW  Sublingual  Transdermal  Buccal Isosorbide dinitrates
  14. 14. Mechanism of action - Nitrates Nitroglycerin Nitrates Glutathione S-transferase
  15. 15. Experiment Norepinephrine (NE)
  16. 16. Organ system effects of NTGDilation of peripheral Mildly dilate arteriolar capacitance veins resistance vessels
  17. 17. Side effects of NTG• Orthostatic hypotension• Syncope• Artery pulsation and throbbing headache• Negative inotropic effect
  18. 18. Pseudocyanosis Fe3+ hemoglobin methemoglobin • Pseudocyanosis • Tissue hypoxia • Death
  19. 19. Drugs for erectile dysfunction Preventing apoptosis and cardiac remodeling Sildenafil (Viagra) after ischemia and reperfusion Corpora cavernosa Tadalafil Vardenafil
  20. 20. Toxicity - Nitrates Acute adverse effects  Orthostatic hypotension  Tachycardia  Throbbing headache Tolerance  Sulfhydryl group  Reactive oxygen species (ROS)  Calcitonin gene-related peptide (CGRP) ( a potent vasodilator)
  21. 21. Carcinogenicity Nitrosamines  Animal studies show a powerful carcinogens Strong epidemiologic correlation between the incidence of esophageal and gastric carcinoma and the nitrates content of food
  22. 22. Beneficial and deleterious effects of nitratesEffect ResultPotential beneficial effects Decreased ventricular volume Decreased myocardial oxygen requirement Decreased arterial pressure Decreased ejection time Vasodilation of epicardial coronary arteries Relief of coronary artery spasm Increased collateral flow Improved perfusion to ischemic myocardium Decreased left ventricular diastolic pressure Improved subendocardial perfusionPotential deleterious effects Reflex tachycardia Increased myocardial oxygen requirement Reflex increase in contractility Decreased diastolic perfusion time due to tachycardia Decreased coronary perfusion
  23. 23. Nitrate and nitrite drugs used in anginaDrug Dose Duration of ActionShort-acting Nitroglycerin, sublingual 0.15-1.2 mg 10-30 min Isosorbide dinitrate, sublingual 2.5-5 mg 10-60 min Amyl nitrite, inhalant 0.18-0.3 mL 3-5 minLong-acting Nitroglycerin, oral sustained-action 6.5-13 mg per 6-8 hours 6-8 hrs Nitroglycerin, 2% ointment, transdermal 1-1.5 inches per 4 hours 3-6 hrs Nitroglycerin, slow-release, buccal 1-2 mg per 4 hours 3-6 hrs Nitroglycerin, slow-release patch, transdermal 10-25 mg per 24 hours 8-10 hrs Isosorbide dinitrate, sublingual 2.5-10 mg per 2 hours 1.5-2 hrs Isosorbide dinitrate, oral 10-60 mg per 2-4 hours 4-6 hrs Isosorbide dinitrate, chewable oral 5-10 mg per 2-4 hours 2-3 hrs Isosorbide mononitrate, oral 20 mg per 12 hours 6-10 hrs Isosorbide dinitrate Amyl nitrite Nitroglycerin
  24. 24. Under investigation Activation of cardiac KATP channels Nicorandil Reduces both preload and afterload
  25. 25. Which of the following is a common direct effect of nitroglycerin? A. Increased heart rate B. Increased afterload C. Increased venous capacitance D. Increased preload
  26. 26. Calcium channel blocker Nit Ca2+
  27. 27. Calcium channelsType Channel Name Where Found Properties of the calcium Blocked by CurrentL Cav1.1-Cav1.3 Cardiac, skeletal, smooth Long, large, high threshold Verapamil, DHPs, Cd2+, -aga-IIIA muscle, neurons, endocrine cells, boneT Cav3.1-Cav3.3 Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni2+, mibefradilN Cav2.2 Neurons, sperm Short, high threshold Ziconotide, gabapentin, Cd2+P/Q Cav2.1 Neurons Long, high threshold -CTX-MVIIC, -aga-IVAR Cav2.3 Neurons, sperm Pacemaking SNX-482, -aga-IIIA
  28. 28. Chemistry – calcium channel blockers High first-pass effect, high plasma binding, and extensive metabolism
  29. 29. Mechanism of action - calcium channel blockers Verapamil Diltiazem Nifedipine
  30. 30. Smooth muscle  Vascular • Peripheral vascular resistance-effort angina  Bronchiolar • Coronary artery tone-variant angina  Gastrointestinal  Dihydropyridines  Uterine  Diltiazem  Verapamil
  31. 31. Cardiac muscle Reduce SA and AV action potential Reduce cardiac contractility Reduce cardiac output Nifedipine/dihydropyridines Verapamil Diltiazem
  32. 32. Skeletal muscle CCBs do not affect skeletal muscle
  33. 33. Cerebral vasospasm Nimodipine Nicardipine Prevent cerebral vasospasm associated with stroke
  34. 34. Other aspects – Calcium channel blocker  Minimally affect glands and nerve due to calcium channel type  Verapamil inhibit insulin release  Interfere with platelet aggregation  Block P-glycoprotein  Reverse the resistance of cancer cells  Osteoporosis, fertility disorders, male contraception, immune modulation, schistosomiasis
  35. 35. Toxicity – calcium channel blocker Cardiac arrest Bradycardia  Cardiac depression Atrioventricular block Heart failure  Immediate-acting Nifedipine increase the risk of MI  Flushing, dizziness, nausea, constipation, peripheral edema
  36. 36. Clinical effects – calcium channel blocker Decrease myocardial contractile force Decrease arterial and intraventricular pressure Decrease myocardial oxygen demand Left ventricular wall stress declines Decrease heart rate  Relieve and prevent the focal coronary artery spasm -Variant angina  Most effective prophylactic treatment for variant angina
  37. 37. Target selectivity – calcium channel blocker Verapamil DiltiazemTachycardiaDecreasing ventricular response inatrial fibrillation of flutter Reflex tachycardia occurs with nifedipine
  38. 38. Clinical pharmacology of calcium channel-blockerDrug Oral Half-life Indication Dosage Bioavailability (%) (hours)Dihydropyridines Amlodipine 65-90 30-50 Angina, hypertension 5-10 mg orally once daily Felodipine 15-20 11-16 Hypertension 5-10 mg orally once daily Isradipine 15-25 8 Hypertension 2.5-10 mg orally once daily Nicardipine 35 2-4 Angina, hypertension 20-40 mg orally every 8 hours Nifedipine 45-70 4 Angina, hypertension 3-10 mcg/kg IV; 20-40 orally every 8 hours Nimodipine 13 1-2 Subarachnoid hemorrhage 40 mg orally every 4 hours Nisoldipine <10 6-12 Hypertension 20-40 mg orally once daily Nitrendipine 10-30 5-12 Investigational 20 mg orally once or twice dailyMiscellaneous Diltiazem 40-65 3-4 Angina, hypertension 75-150 mcg/kg IV; 30-80 mg orally every 6 hours Verapamil 20-35 6 Angina, hypertension, 75-150 mcg/kg IV; 80-160 mg orally every 8 hours arrhythmias, migraine
  39. 39. Clinical considerations – calcium channel blocker  Low blood pressure Verapamil/diltiazem are better than DHP  Atrial tachycardia, flutter, fibrillation Verapamil/diltiazem are better due to the antiarrhymic effects  Unstable angina Immediate-release short-acting CCBs increase the risk of adverse cardiac events
  40. 40. Which muscle may not be affected by calcium channel blockers?A. Cardiac muscleB. Bronchiolar smooth muscleC. Skeletal muscleD. Gastrointestinal smooth muscle
  41. 41.  blockers Reduce oxygen demand by decreasing heart rate, blood pressure and contractility NE: norepinephrine Gs: G-stimulatory protein AC: adenylyl cyclase PK-A: cAMP-dependent protein kinase SR: sarcoplasmic reticulum
  42. 42. Clinical aspects -  blocker  Silent/ambulatory ischemia  Myocardial infarction  Hypertension  Stable angina
  43. 43. Side effects -  blocker Increase in end-diastolic volume Myocardial oxygen requirement Increase in ejection time Propranolol Nitroglycerin
  44. 44. Contraindications -  blocker  Asthma and other bronchospastic conditions  Severe bradycardia  Atrioventricular blockade  Bradycardia-tachycardia syndrome  Unstable left ventricular failure
  45. 45. Complications -  blocker  Fatigue  Impaired exercise tolerance  Insomnia  Unpleasant dreams  Worsening of claudication  Erectile dysfunction
  46. 46. New drugs Drugs under investigation for use in angina Metabolic modulators, eg, trimetazidine, ranolazine Direct bradycardic agents, eg, ivabradine Potassium channel activators, eg, nicorandil Rho-kinase inhibitors, eg, fasudil Protein kinase G facilitators, eg, detanonoate Sulfonylureas, eg, glybenclamide Thiazolidinediones Vasopeptidase inhibitors Nitric oxide donors, eg, L-arginine Capsaicin Amiloride
  47. 47. Trimetazidine
  48. 48. Ranolazine Ranolazine was patented in 1986, and then approved for use in the US in 2006 for angina patients who remain symptomatic despite being on one or more of the standard treatments Ranolazine acts by shifting ATP production away from fatty acid oxidation in favor of glucose oxidation Ranolazine
  49. 49. Sodium channel blockersIvabradineInhibit thehyperpolarization- Efficacy similar to that of calcium channel blockers andactivated sodium Beta blockers, but lack of effect on gastrointestinal andchannel in the bronchial smooth musclesinoatrial node
  50. 50. Clinical pharmacology  Atherosclerotic disease of the coronaries (CAD)  Smoking, hypertension, hyperlipidemia, obesity Antiplatelet agents/Aspirin, clopidogrel Aspirin Lipid-lowering agents/statins Statins Clopidogrel
  51. 51. Effort angina Nitrates Alone -Blockers or Calcium Channel Combined Nitrates with  blockers or Blockers Calcium Channel BlockersHeart rate Reflex increase Decrease DecreaseArterial pressure Decrease Decrease DecreaseEnd-diastolic Decrease Increase None or decreasevolumeContractility Reflex increase Decrease NoneEjection time Decrease Increase None
  52. 52. Variant angina Normal coronary artery  Nitrates Atherosclerosis  Calcium channel blockers Atherosclerosis  No surgical revascularization with blood clot and angioplasty Variant angina Coronary spasm
  53. 53. Unstable angina Unstable angina Aspirin Clopidogrel
  54. 54. Peripheral artery disease Pentoxifylline Cilostazol Physical therapy and exercise training is of proven benefit.
  55. 55. SummarySubclass Mechanism of action Effects Clinical Pharmacokinetics, applications toxicities, interactionsNITRATES Releases NO in smooth muscle Smooth muscle relaxation, Angina: Sublingual form for Very high first-pass effect, so Nitroglycerin especially in vessels acute episodes  oral and sublingual dose is much smaller than transdermal form for oral  high lipid solubility ensures prophylaxis  IV form for acute rapid absorption  Toxicity: coronary syndrome Orthostatic hypotension, tachycardia, headache  Interactions: Synergistic hypotension with phosphodieasterase type 5 inhibitors (sildenafil)BETA BLCKERS Nonselective competitive Decreased heart rate, cardiac output, Prophylaxis of angina Oral and parenteral, 4-6 h duration of Propranolol antagonist at  adrenoceptors and blood pressure  decrease action  Toxicity: Asthma, myocardial oxygen demand atrioventricular block, acute heart failure, sedation  Interactions: Additive with all cardiac depressantsCALCIUM CHANNELBLOCKERS Verapamil, diltiazem Nonselective block of L-type Reduced vascular resistance, cardiac Prophylaxis of angina, Oral, IV, duration 4-8 h  Toxicity: calcium channels in vessels and rate, and cardiac force results in hypertension atrioventricular block, acute heart heart decreased oxygen demand failure, constipation, edema  Interactions: Additive with other cardiac depressants and hypotensive drugs Nifedipine Block of vascular L-type calcium Like verapamil and diltiazem; less Prophylaxis of angina, Oral, duration 4-6 h  Toxicity: (a dihydropyridine) channels>cardiac channels cardiac effect hypertension Excessive hypotension  Interactions: Additive with other vasodilatorsMISCELLANEOUS Inhibits late sodium current in heart Reduces cardiac oxygen demand  Prophylaxis of angina Oral, duration 6-8 h  Toxicity: QT Ranolazine also may modify fatty acid fatty acid oxidation modification may interval prolongation, nausea, oxidation improve efficiency of cardiac oxygen constipation, dizziness  Interactions: utilization inhibitors of CYP3A increase ranolazine concentration and duration of action
  56. 56. Which approach may not be used for variant angina?A. NitratesB. Calcium Channel blockersC.  blockersD. Angioplasty

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