1. Drug Therapy of Angina Pectoris

2. Definition of Angina Pectoris
Angina Pectoris is defined as sudden pain beneath the sternum, often radiating to the left shoulder and arm.
Shortness of breath, last for 5-15mins, if pain longer than that => myocardial infarction, due to coronary vascular disease, partial block of coronary artery

3. Pathophysiology of Angina Pectoris
Anginal pain is precipitated when the oxygen supply to the heart is insufficient to meet oxygen demand.
Most often, Anginal pain occurs secondary to atherosclerosis of the coronary arteries.
Shortness of breath, may follow exercise, emotional upset, exposure to cold or may occur after meals or smoking, due to coronary vascular disease, partial block of coronary artery.

4. Angina Pectoris

5. Effect of exertion on the balance between oxygen supply and oxygen demand in the healthy heart and the heart with CAD
Healthy heart = coronary arteries are good
Supply => how much cor arteries can delivery
Demand => how much blood the heart needs to operate
During exertion, arteries dilate to supply more blood to heart b/c demand in heart is also increased
If cor arteries blocked, cannot dilate => cannot increase O2 supply despite demanding increasing.

6. Determinants Of Cardiac Oxygen Demand And Oxygen Supply
Oxygen Demand: the principle determinants of cardiac oxygen demand are:
(1) Heart Rate
(2) Myocardial Contractility
(3) Intramyocardial wall tension.
Oxygen Supply: Cardiac oxygen supply is determined by myocardial blood flow.
The imbalance between oxygen delivery and utilization may result from a spasm of the vascular smooth muscle or from obstruction of blood vessels caused by atherosclerotic lesions.

7. Factors of oxygen demand
Four major factors of oxygen demand (heart can relax, and it’s ok that it’s partially blocked….):
(1) Heart Rate
(2) Contractility
(3) After load
(4) Preload

8. Types of Angina Pectoris
Classic Angina Pectoris (Exertional Angina).
Variant Angina Pectoris (Prinzmetal’s Angina, Vasospastic Angina).

9. Treatment Strategy Two possible remedies are:
increase cardiac oxygen supply
decrease oxygen demand

10. Classic Angina Pectoris (Exertional Angina)
Exertional angina => due to emotional stress, exercise
Controlling oxygen supply is limited if artery is blocked secondary to atherosclerosis of the coronary arteries.

11. Classic Angina Pectoris (Exertional Angina)
. Classic angina => blockage of coronary artery => not much drugs can do, so they decrease DEMAND to balance things out

12. oxygen supply to the heart is insufficient to meet oxygen demand.
Classic Angina Pectoris

13. Classic Angina Pectoris (Exertional Angina)
Treatment Strategy: the goal of therapy is to reduce the intensity and frequency of Anginal attacks.
The principle way to relieve the pain of classic angina is to decrease cardiac oxygen demand.
Exertional angina => due to emotional stress, exercise
Controlling oxygen supply is limited if artery is blocked. Classic angina => blockage of coronary artery => not much drugs can do, so they decrease DEMAND to balance things out

14. Treatment Strategy. Classic Angina Pectoris
supply o2
demand
decrease cardiac oxygen demand

15. Variant Angina Pectoris
Variant Angina Pectoris caused by spontaneous coronary spasm, either at work or at rest, rather than by increases in myocardial oxygen requirements, Due to vasospasm => coronary arteries undergo spasm, can occur any time . No blockage in artery.
Spasm => narrow down vessel => still feel pain

16. oxygen supply to the heart is insufficient to meet oxygen demand.
Variant Angina Pectoris

17. Variant Angina Pectoris (Prinzmetal’s Angina, Vasospastic Angina)
Treatment Strategy: the goal of therapy is to reduce the incidence and severity of attacks.
Variant angina is treated by increasing cardiac oxygen supply.
Variant Angina Pectoris caused by spontaneous coronary spasm, either at work or at rest, rather than by increases in myocardial oxygen requirements, Due to vasospasm => coronary arteries undergo spasm, can occur any time . No blockage in artery.
Spasm => narrow down vessel => still feel pain

18. Treatment Strategy. Variant Angina Pectoris
supply o2
demand
Increasing cardiac oxygen supply

19. ANGINA PECTORIS: AND THERAPEUTIC STRATEGY
ORGANIC NITRATES
Nitroglycerin
Isosorbide dinitrates
Amyl Nitrite
β-ADRENERGIC BLOCKING AGENTS
CALCIUM CHANNEL BLOCKING AGENTS
Drugs can be used to relax artery to open up artery => can increase O2 supply
Diff treatment approach from classic angina

20. Biochemistry of Nitrate-induced Vasodilation
Nitrate (extra cellular)
Nitrate (within vascular smooth muscle)
sulfhydryl groups
Breakdown to nitric oxide
Activation of guanylate cyclase
Cyclic GMP
Decreased intracellular calcium
Vasodilation
NO => vasodilator

21. vascular smooth muscle
NO3-
Nitrate
NO2- NO
Nitrite
RSH +
guanylate cyclase
Tissue thioles
Cyclic GMP Cyclic GMP
GTP
C GMP
Bound Ca2+
Vasodilation
Ca2+

22. Organic Nitrates Nitroglycerin Glyceryl trinitrate
Isosorbide dinitrates
Amyl Nitrite

23. Nitroglycerin ( Glyceryl trinitrate)
Vasodilator Actions
Nitroglycerin acts directly on vascular smooth muscle (VSM) to promote vasodilation.
At usual therapeutic doses. The drug acts primarily on veins (PRELOAD); dilation of arteriole is only modest.
These compounds cause a rapid reduction in myocardial oxygen demand followed by rapid relief of symptoms. NG = put under the tongue, patches, etc.
Tolerance due to lowered SH groups (depleted), therefore drug would lose effect.

24. Nitroglycerin( Glyceryl trinitrate)
Significant first-pass metabolism of nitroglycerin occurs in the liver.
Sublingual tablet or spray acts for about 30 minutes.
Transdermal patches have a long duration of action(24 hours).

25. Therapeutic uses
It is more useful in preventing attacks than in stopping them once they have begun.

26. Adverse Effects Due to vasodilation, vessels relaxed Headache.
Facial flushing
Orthostatic Hypotension
Reflex Tachycardia (lowered Bp => reflex to increase Bp)

27. Tolerance
If tolerance develops, it can be reversed by withholding nitrates (nitrates free interval).
until the sulfhydryl content of VSM has been replenished.
Tolerance to the actions of nitrates develops rapidly.
It can be overcome by provision of a daily “nitrate-free interval” to restore sensitivity to the drug.

28. vascular smooth muscle
NO3-
Nitrate
NO2- NO
Nitrite
RSH +
guanylate cyclase
Tissue thioles
Cyclic GMP Cyclic GMP
GTP
C GMP
Bound Ca2+
Vasodilation
Ca2+

29. lsosorbide dinitrate lsosorbide dinitrate is an orally active nitrate.
The drug is not readily metabolized by the liver or smooth muscle
It has a lower potency than nitroglycerin in relaxing vascular smooth muscle.

30. amyl nitrate
Amyl nitrate is extremely volatile.
High chance of abuse.

31. Beta-adrenergic Blocking Agents
Beta blockers reduce Anginal pain by decreasing cardiac oxygen demand (lowers HR, lowers contractility, lowers heart’s workload).

32. Beta-adrenergic Blocking Agents
This is accomplished primarily through blockade of β1 receptors in the heart, which decreases heart rate and contractility.
Beta blockers can reduce oxygen demand further by causing a modest reduction in arterial pressure (afterload).

33. Commonly Used Beta-Adrenergic Blockers
Propranolol is the prototype of this class of compounds, but other β-blockers, such as metoprolol and atenolol are equally effective.
However, agents with intrinsic sympathomimetic activity (for example, pindolol and acebutolol) are less effective and should be avoided.

34. Adverse effects Bronchoconstriction (nonselective).
Hypoglycemia (nonselective).
Sever myocardial depression & heart failure.

35. contraindication They are contraindicated in patients with: Diabetes,
Peripheral vascular disease,
Chronic obstructive pulmonary disease.

36. Calcium Channel Blockers
Verapamil mainly affects the myocardium => heart rate and contractility.
Nifedipine exerts a greater effect on smooth mus­cle in the peripheral vasculature and Diltiazem is intermediate in its actions, => afterload

37. Mechanisms of action Arteriolar dilation.
Block Ca entry into cell which is important for contractile action in heart, main effect is vasodilator on arteries.

38. by decreasing cardiac oxygen demand.
Decrease heart rate and contractility
Decrease arterial pressure (afterload)

39. In variant angina, calcium channel blockers promote relaxation of coronary artery spasm, thereby increasing cardiac oxygen supply.

40. Nifedipine: functions mainly as an arteriolar vasodilator.
This drug has minimal effect on cardiac conduction or heart rate.
Nifedipine is administered orally and has a short half-life (about 4 hours) requiring multiple dosing.

41. Uses
nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.

42. Side Effect
Can cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity.
may cause reflex tachycardia if peripheral vasodilation is marked resulting in a substantial decrease in blood pressure.

43. Verapamil
Verapamil slows cardiac conduction directly and thus decreases heart rate and oxygen demand, but it is a weaker vasodilator.

44. Side Effect
Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities.
It also causes constipation. Verapamil should be used with cau­tion in digitalized patients, since it increases digoxin levels.

45. Diltiazem
Diltiazem has cardiovascular effects that are similar to those of verapamil.
It reduces the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure.

46. Diltiazem
In addition, diltiazem can relieve coronary artery spasm and is therefore particularly useful in patients with variant angina.
The incidence of adverse side effects is low.

47. If step 1 doesn’t work, do step 2, etc….
Step 4 = surg
CABG = cor artery bypass

48. Anti-arrythmia drugs

49. Impulse Conduction Pathways
SA node => gives regular heart beat
Travels along internodal pathways to AV node, to bundle of His to purkinje fibres
Ventricular arrythmias vs superventricular arr.
Any place in heart can generate impulse

50. Ion Fluxes During Cardiac Action Potentials and Effects of Antidysrhythmic Drugs (A)
Graph of action potential (fast AP)
Diff drugs acting at diff phases
Quinidine => on Na entry

51. Ion Fluxes During Cardiac Action Potentials and Effects of Anti-dysrhythmic Drugs (B)

52. The Electrocardiogram
ECG – summary of all action potentials in the heart
PR – impulse from SA node to ventricle, some drugs can prolong this interval => anti-arr
QRS – how fast ventricle gets excited, some drugs can prolong this to prolong PR
QT – impulse from AV node to excite ventricles + repol’z of ventricles, drugs can prolong this interval.

53. Sodium Channel Blockers Class IA Agents---Quinidine
Effects on the Heart
1. Slows impulse conduction in atria, ventricles and His-Purkije system.
2. Delays repolarization in atria, ventricles and His-Purkije system.
3. Anticholinergic effect (symp), increase S-A nodal automaticity, increase HR. Use with beta blockers or verapamil.
Effects on EKG (time of impulse from A to V is prolonged)
1. Widens QRS complex.
2. Prolongs QT interval.
Therapeutic Use
Broad spectrum antiarrhythmic agent.
Supraventricular and ventricular arrhythmias
Slows conduction in whole heart
Cholinergic => PS effect, slow hr
Anti-chol => increase hr

54. Sodium Channel Blockers Class IB Agents--- Lidocaine (local anaes.)
Effects on the Heart (if used intravenously)
1. Reduces automaticity in ventricles and His-Purkije system.
2. Accelerates repolarization in ventricles and His-Purkije system (don’t see prolonged QRS or QT).
3. No anticholinergic effect. => doesn’t increase hr
Effects on EKG
1. No widening of QRS complex.
2. QT interval: a small reduction or no change.
Therapeutic Use
1. Intravenous use only.
2. Ventricular arrhythmias

55. Sodium Channel Blockers Class IC Agents---Propafenone
Effects on the Heart
1. Slows impulse conduction in ventricles and His-Purkije system. => same as lidocaine
2. Decreases automaticity in S-A node, ventricles and His-
Purkije system.
Effects on EKG
1. Widening of QRS complex. => slows conduction
2. Prolongation of P-R interval. => decrease of automaticity
3. QT interval: a small increase or no change.
Therapeutic Use
1. Life-threatening ventricular tachyarrhythmias

56. Class II. Beta Blockers---Propranolol (b1 & b2-blocker
Effects on the Heart
1. Decreases S-A node automaticity
2. Decreases A-V node conduction velocity
3. Decreases myocardial contractility
Effects on EKG
1. Prolong P-R interval (due to decreased AV node conduction to ventricle)
Therapeutic Use
Supraventricular tachycardia (above the AV node)
Contraindication: asthma b/c it blocks b2 receptors => airways constriction)

57. Class III. Drugs that delay Repolarization => Bretylium
Effects on the Heart
1. Delays repolarization (increase depol to repol)
2. Prolongs action potential duration
3. Prolongs effective refractory period (ERP, in between impulses cardiac muscle will not respond, impulse will only be generated throughout heart after this period, prolonging this can reduce chance of arrythmia)
Effects on EKG
1. Prolongs QT interval
Therapeutic Use
Ventricular tachycardia and fibrillation (life-threatening, heart isn’t pumping enough blood, patient can die w/in mins)
Amiodarone
Indication: Life-threatening ventricular tachyarrhythmias
when other drugs are ineffective or are not tolerated. Major –ve effect on thyroid gland.

58. Class IV: Calcium Channel Blockers Verapamil
Effects on the Heart
1. Reduction of S-A node automaticity ( lowers hr)
2. Reduction of A-V node conduction velocity (prolonged PR interval)
3. Reduction of myocardial contractility (less Ca)
Effects on EKG
1. Prolongs PR interval
Therapeutic Use
Supraventricular tachycardia arrythmias

59. Other Antiarrhythmic Drugs---Digoxin
Effects on the Heart
1. Reduction of S-A node automaticity
2. Reduction of A-V node conduction velocity
Effects on EKG
1. Prolongs PR interval
2. QT interval may be shortened.
3. Depression of S-T segment => *
4. T wave may be depressed or inverted
5. No change in QRS complex
Therapeutic Use
Supraventricular tachycardia.
Increases contractility in heart, inhibits Na/K ATPase