1. Ischemic Heart Disease
-Angina Pectoris
Coronary
artery
Plaque
Enlarged view of
coronary artery
The leading cause of mortality in the United States
More than 500,000 deaths per year

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 clot
Unstable angina
Coronary spasm
Variant angina

3. Causes
— Imbalances in myocardial oxygen demand and supply
Coronary Flow Reduction Endothelial dysfunction
Stable angina  Unstable angina  Variant angina

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. Determinants of oxygen demand
Wall stress
Intraventricular pressure
Ventricular radius (volume) Arterial blood pressure
Wall thickness
Heart rate
Contractility

6. Drugs of modulating oxygen demand

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. 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 artery
Right coronary
Capillaries resistance
artery Arterial blood
pressure
Left anterior descending
coronary artery Veins (capacitance vessels) Arterioles (resistance vessels)

9. Sites of drugs action-Nitrates,
Calcium channel blockers
Stabilize depolarization
NO
Reduce heart rate, contractility

10. Sites of drugs action - Sildenafil
Regulates blood
flow in the penis
Sildenafil/Viagra

11. Drugs used to treat angina
 Nitrates
 Calcium channel blockers
Heart rate
  blockers
Ventricular volume
Blood pressure
Contractility

12. Nitrates
Nitroglycerin (NTG)
(glyceryl trinitrate)
• Volatilization and adsorption to plastic surfaces
• Keep it in tightly closed glass container
• Not sensitive to light

13. Pharmacokinetics
Nitroglycerin
 Organic nitrate reductase
 Oral bioavailability LOW
 Sublingual
 Transdermal
 Buccal Isosorbide dinitrates

14. Mechanism of action - Nitrates
Nitroglycerin
Nitrates
Glutathione S-transferase

15. Experiment
Norepinephrine (NE)

16. Organ system effects of NTG
Dilation of peripheral Mildly dilate arteriolar
capacitance veins resistance vessels

17. Side effects of NTG
• Orthostatic hypotension
• Syncope
• Artery pulsation and throbbing headache
• Negative inotropic effect

18. Pseudocyanosis
Fe3+
hemoglobin methemoglobin
• Pseudocyanosis
• Tissue hypoxia
• Death

19. Drugs for erectile dysfunction
Preventing apoptosis
and cardiac remodeling
Sildenafil (Viagra)
after ischemia and
reperfusion
Corpora cavernosa
Tadalafil
Vardenafil

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. 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. Beneficial and deleterious effects of nitrates
Effect Result
Potential 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 perfusion
Potential deleterious effects
Reflex tachycardia Increased myocardial oxygen requirement
Reflex increase in contractility
Decreased diastolic perfusion time due to tachycardia Decreased coronary perfusion

23. Nitrate and nitrite drugs used in angina
Drug Dose Duration of Action
Short-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 min
Long-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. Under investigation
Activation of cardiac KATP channels
Nicorandil
Reduces both
preload and afterload

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. Calcium channel blocker Nit
Ca2+

27. Calcium channels
Type Channel Name Where Found Properties of the calcium Blocked by
Current
L Cav1.1-Cav1.3 Cardiac, skeletal, smooth Long, large, high threshold Verapamil, DHPs, Cd2+, -aga-IIIA
muscle, neurons, endocrine
cells, bone
T Cav3.1-Cav3.3 Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni2+, mibefradil
N Cav2.2 Neurons, sperm Short, high threshold Ziconotide, gabapentin, Cd2+
P/Q Cav2.1 Neurons Long, high threshold -CTX-MVIIC, -aga-IVA
R Cav2.3 Neurons, sperm Pacemaking SNX-482, -aga-IIIA

28. Chemistry – calcium channel blockers
High first-pass effect, high plasma binding, and extensive metabolism

29. Mechanism of action - calcium channel blockers
Verapamil
Diltiazem
Nifedipine

30. Smooth muscle
 Vascular • Peripheral vascular resistance-effort angina
 Bronchiolar • Coronary artery tone-variant angina
 Gastrointestinal
 Dihydropyridines
 Uterine
 Diltiazem
 Verapamil

31. Cardiac muscle
Reduce SA and AV action potential
Reduce cardiac contractility
Reduce cardiac output
Nifedipine/dihydropyridines
Verapamil
Diltiazem

32. Skeletal muscle
CCBs do not affect
skeletal muscle

33. Cerebral vasospasm
Nimodipine Nicardipine
Prevent cerebral vasospasm
associated with stroke

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. 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. 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. Target selectivity – calcium channel blocker
Verapamil
Diltiazem
Tachycardia
Decreasing ventricular response in
atrial fibrillation of flutter Reflex tachycardia occurs with nifedipine

38. Clinical pharmacology of calcium channel-blocker
Drug 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 daily
Miscellaneous
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. 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. Which muscle may not be affected by calcium channel blockers?
A. Cardiac muscle
B. Bronchiolar smooth muscle
C. Skeletal muscle
D. Gastrointestinal smooth muscle

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. Clinical aspects -  blocker
 Silent/ambulatory ischemia
 Myocardial infarction
 Hypertension
 Stable angina

43. Side effects -  blocker
Increase in end-diastolic volume
Myocardial oxygen
requirement
Increase in ejection time
Propranolol Nitroglycerin

44. Contraindications -  blocker
 Asthma and other bronchospastic conditions
 Severe bradycardia
 Atrioventricular blockade
 Bradycardia-tachycardia syndrome
 Unstable left ventricular failure

45. Complications -  blocker
 Fatigue
 Impaired exercise tolerance
 Insomnia
 Unpleasant dreams
 Worsening of claudication
 Erectile dysfunction

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. Trimetazidine

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. Sodium channel blockers
Ivabradine
Inhibit the
hyperpolarization- Efficacy similar to that of calcium channel blockers and
activated sodium Beta blockers, but lack of effect on gastrointestinal and
channel in the bronchial smooth muscle
sinoatrial node

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. Effort angina
Nitrates Alone -Blockers or Calcium Channel Combined Nitrates with  blockers or
Blockers Calcium Channel Blockers
Heart rate Reflex increase Decrease Decrease
Arterial pressure Decrease Decrease Decrease
End-diastolic Decrease Increase None or decrease
volume
Contractility Reflex increase Decrease None
Ejection time Decrease Increase None

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. Unstable angina
Unstable angina
Aspirin
Clopidogrel

54. Peripheral artery disease
Pentoxifylline
Cilostazol
Physical therapy and exercise training
is of proven benefit.

55. Summary
Subclass Mechanism of action Effects Clinical Pharmacokinetics,
applications toxicities, interactions
NITRATES 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 depressants
CALCIUM CHANNEL
BLOCKERS
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 vasodilators
MISCELLANEOUS 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. Which approach may not be used for variant angina?
A. Nitrates
B. Calcium Channel blockers
C.  blockers
D. Angioplasty