Ischemic Heart Disease

-Angina Pectoris

The leading cause of mortality in the United States

More than 500,000 deaths per year

Coronary

artery

Enlarged view of

coronary artery

Plaque

Three types of angina

Stable angina/Classic angina/Effort angina

Variant angina/Prinzmetal angina

Unstable angina/Crescendo angina

Normal coronary artery

Atherosclerosis

Atherosclerosis

with blood clot

Coronary spasm

Normal

Stable angina

Unstable angina

Variant angina

— Imbalances in myocardial oxygen demand and supply

Coronary Flow Reduction Endothelial dysfunction

Causes

Stable angina Unstable angina Variant angina

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

Determinants of oxygen demand

Wall stress

Intraventricular pressure

Ventricular radius (volume)

Wall thickness

Heart rate

Contractility

Arterial blood pressure

Drugs of modulating oxygen demand

Determinants of oxygen supply

Coronary blood flow

Metabolic products

Autonomic activity

Pharmacological agents

Coronary vascular

bed resistance

Aortic diastolic pressure

Duration of diastole

Vascular tone

Afterload: systolic ventricular wall stress

Preload: end-diastolic ventricular wall

stress

Right coronary artery

Left anterior descending coronary artery

Left circumflex coronary artery

Vascular tone of the coronary arteries

Perfusion of the heart

Myocardial O2

SUPPLY

Veins (capacitance vessels) Arterioles (resistance vessels)

Capillaries

Heart(pump)

Arteriolar toneVenous tone

Preload Afterload

Ventricular wall stress

Myocardial O2

DEMAND

Peripheral vascular

resistanceArterial blood pressure

Sites of drugs action-Nitrates,

Calcium channel blockers

NO

Reduce heart rate, contractility

Stabilize depolarization

Sites of drugs action - Sildenafil

Sildenafil/Viagra

Regulates blood

flow in the penis

Drugs used to treat angina

Nitrates

Calcium channel blockers

blockers Heart rate

Ventricular volume

Blood pressure

Contractility

Nitrates

Nitroglycerin (NTG)

(glyceryl trinitrate)

• Keep it in tightly closed glass container

• Volatilization and adsorption to plastic surfaces

• Not sensitive to light

Pharmacokinetics

Organic nitrate reductase

Oral bioavailability LOW

Sublingual

Transdermal

Buccal

Nitroglycerin

Isosorbide dinitrates

Mechanism of action - Nitrates

Nitrates

Glutathione S-transferase

Nitroglycerin

Experiment

Norepinephrine (NE)

Dilation of peripheral

capacitance veins Mildly dilate arteriolar

resistance vessels

Organ system effects of NTG

Side effects of NTG

• Orthostatic hypotension

• Syncope

• Artery pulsation and throbbing headache

• Negative inotropic effect

Pseudocyanosis

Fe3+

• Pseudocyanosis

• Tissue hypoxia

• Death

hemoglobin methemoglobin

Drugs for erectile dysfunction

Sildenafil (Viagra)

Tadalafil

Vardenafil

Corpora cavernosa

Preventing apoptosis

and cardiac remodeling

after ischemia and

reperfusion

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)

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

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

Nitrate and nitrite drugs used in angina

Amyl nitrite Nitroglycerin

Isosorbide dinitrate

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

Under investigation

Nicorandil

Reduces both

preload and afterload

Activation of cardiac KATP channels

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

Calcium channel blocker Nitrates

Ca2+

Calcium channels

Type Channel Name Where Found Properties of the calcium

Current

Blocked by

L Cav1.1-Cav1.3 Cardiac, skeletal, smooth

muscle, neurons, endocrine

cells, bone

Long, large, high threshold Verapamil, DHPs, Cd2+, -aga-IIIA

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

Chemistry – calcium channel blockers

High first-pass effect, high plasma binding, and extensive metabolism

Mechanism of action - calcium channel blockers

Nifedipine

Verapamil

Diltiazem

Smooth muscle

Vascular

Bronchiolar

Gastrointestinal

Uterine

• Peripheral vascular resistance-effort angina

• Coronary artery tone-variant angina

Dihydropyridines

Diltiazem

Verapamil

Cardiac muscle

Reduce SA and AV action potential

Reduce cardiac contractility

Reduce cardiac output

Nifedipine/dihydropyridines

Verapamil

Diltiazem

Skeletal muscle

CCBs do not affect

skeletal muscle

Cerebral vasospasm

Nimodipine Nicardipine

Prevent cerebral vasospasm

associated with stroke

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

Toxicity – calcium channel blocker

Cardiac depression

Cardiac arrest

Bradycardia

Atrioventricular block

Heart failure

Immediate-acting Nifedipine increase the risk of MI

Flushing, dizziness, nausea, constipation, peripheral edema

Clinical effects – calcium channel blocker

Decrease myocardial contractile force

Decrease arterial and intraventricular pressure

Left ventricular wall stress declines

Decrease heart rate

Decrease myocardial

oxygen demand

Relieve and prevent the focal coronary artery spasm

-Variant angina

Most effective prophylactic treatment for variant angina

Target selectivity – calcium channel blocker

Verapamil

Diltiazem

Reflex tachycardia occurs with nifedipine

Tachycardia

Decreasing ventricular response in

atrial fibrillation of flutter

Clinical pharmacology of calcium channel-blocker

Drug Oral

Bioavailability (%)

Half-life

(hours)

Indication Dosage

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,

arrhythmias, migraine

75-150 mcg/kg IV; 80-160 mg orally every

8 hours

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

Which muscle may not be affected by calcium channel blockers?

A. Cardiac muscle

B. Bronchiolar smooth muscle

C. Skeletal muscle

D. Gastrointestinal smooth muscle

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

Clinical aspects - blocker

Silent/ambulatory ischemia

Myocardial infarction

Hypertension

Stable angina

Side effects - blocker

Increase in end-diastolic volume

Increase in ejection time

Myocardial oxygen

requirement

Propranolol Nitroglycerin

Asthma and other bronchospastic conditions

Severe bradycardia

Atrioventricular blockade

Bradycardia-tachycardia syndrome

Unstable left ventricular failure

Contraindications - blocker

Complications - blocker

Fatigue

Impaired exercise tolerance

Insomnia

Unpleasant dreams

Worsening of claudication

Erectile dysfunction

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

Trimetazidine

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

Ranolazine

Sodium channel blockers

Ivabradine

Efficacy similar to that of calcium channel blockers and

Beta blockers, but lack of effect on gastrointestinal and

bronchial smooth muscle

Inhibit the

hyperpolarization-

activated sodium

channel in the

sinoatrial node

Clinical pharmacology

Atherosclerotic disease of the coronaries (CAD)

Smoking, hypertension, hyperlipidemia, obesity

Antiplatelet agents/Aspirin, clopidogrel

Lipid-lowering agents/statins

Aspirin

Clopidogrel Statins

Effort angina Nitrates Alone -Blockers or Calcium Channel

Blockers

Combined Nitrates with blockers or

Calcium Channel Blockers

Heart rate Reflex increase Decrease Decrease

Arterial pressure Decrease Decrease Decrease

End-diastolic

volume

Decrease Increase None or decrease

Contractility Reflex increase Decrease None

Ejection time Decrease Increase None

Variant angina

Nitrates

Calcium channel blockers

No surgical revascularization and angioplasty

Normal coronary artery

Atherosclerosis

Atherosclerosis

with blood clot

Coronary spasm

Variant angina

Unstable angina

Aspirin

Clopidogrel

Unstable angina

Peripheral artery disease

Pentoxifylline

Cilostazol

Physical therapy and exercise training

is of proven benefit.

Summary Subclass Mechanism of action Effects Clinical

applications

Pharmacokinetics,

toxicities, interactions

NITRATES

Nitroglycerin

Releases NO in smooth muscle Smooth muscle relaxation,

especially in vessels

Angina: Sublingual form for

acute episodes oral and

transdermal form for

prophylaxis IV form for acute

coronary syndrome

Very high first-pass effect, so

sublingual dose is much smaller than

oral high lipid solubility ensures

rapid absorption Toxicity:

Orthostatic hypotension, tachycardia,

headache Interactions: Synergistic

hypotension with phosphodieasterase

type 5 inhibitors (sildenafil)

BETA BLCKERS

Propranolol

Nonselective competitive

antagonist at adrenoceptors

Decreased heart rate, cardiac output,

and blood pressure decrease

myocardial oxygen demand

Prophylaxis of angina Oral and parenteral, 4-6 h duration of

action Toxicity: Asthma,

atrioventricular block, acute heart

failure, sedation Interactions:

Additive with all cardiac depressants

CALCIUM CHANNEL

BLOCKERS

Verapamil, diltiazem

Nifedipine

(a dihydropyridine)

Nonselective block of L-type

calcium channels in vessels and

heart

Block of vascular L-type calcium

channels>cardiac channels

Reduced vascular resistance, cardiac

rate, and cardiac force results in

decreased oxygen demand

Like verapamil and diltiazem; less

cardiac effect

Prophylaxis of angina,

hypertension

Prophylaxis of angina,

hypertension

Oral, IV, duration 4-8 h Toxicity:

atrioventricular block, acute heart

failure, constipation, edema

Interactions: Additive with other

cardiac depressants and hypotensive

drugs

Oral, duration 4-6 h Toxicity:

Excessive hypotension Interactions:

Additive with other vasodilators

MISCELLANEOUS

Ranolazine

Inhibits late sodium current in heart

also may modify fatty acid

oxidation

Reduces cardiac oxygen demand

fatty acid oxidation modification may

improve efficiency of cardiac oxygen

utilization

Prophylaxis of angina Oral, duration 6-8 h Toxicity: QT

interval prolongation, nausea,

constipation, dizziness Interactions:

inhibitors of CYP3A increase

ranolazine concentration and duration

of action

Which approach may not be used for variant angina?

A. Nitrates

B. Calcium Channel blockers

C. blockers

D. Angioplasty