Transcript Hypertension - WordPress.com

Pharmacotherapy: A Pathophysiologic Approach
The McGraw-Hill Companies
Abbreviations
ACC: American College of Cardiology
ACEI: angiotensin-converting enzyme inhibitor
ACIP: Asymptomatic Cardiac Ischemia Pilot
AHA: American Heart Association
AV: arteriovenous
CABG: coronary artery bypass grafting
CAD: coronary artery disease
CASS: Coronary Artery Surgery Study
CHD: coronary heart disease
CT: computed tomography
CVD: cardiovascular disease
2
Abbreviations
DCA: directional coronary atherectomy
ECG: electrocardiogram
EDRF: endothelium-derived relaxing factor
ETT: exercise tolerance (stress) testing
GMP: guanosine monophosphate
HDL: high-density lipoprotein
HERS: Heart Estrogen/Progestin Replacement Study
IHD: ischemic heart disease
I Na: late sodium current
ISDN: isosorbide dinitrate
ISMN: isosorbide mononitrate
3
Abbreviations
LAD: left anterior descending
LDL: low-density lipoprotein
LV: left ventricle
MI: myocardial infarction
MVO2: myocardial oxygen demand
PCI: primary coronary intervention
PTCA: percutaneous transluminal angioplasty
R1: resistance 1-large epicardial or surface vessels
R2: resistance 2-intramyocardial arteries and arterioles
4
Key Concepts
 Ischemic heart disease (IHD): caused by coronary
atherosclerotic plaque formation which leads to
imbalance between O2 supply & demand
 results in myocardial ischemia
 Chest pain: cardinal symptom of myocardial ischemia
caused by coronary artery disease (CAD)
 Risk factor identification/modification important
interventions for patients with known/suspected IHD
5
Key Concepts
 Major risk factors that can be altered
 dyslipidemia



high total & low-density lipoprotein cholesterol
low high-density lipoprotein cholesterol
high triglycerides
 smoking
 glycemic control in DM
 HTN
 therapeutic lifestyle changes


exercise, weight reduction, reduced dietary cholesterol
reduction in inflammation may play an important role
6
Key Concepts
 Most CAD patients should receive antiplatelet therapy
 Manage chronic stable angina patients initially with β-
blockers for symptomatic control
 at least as well as nitrates or CCBs
 decrease risk of recurrent MI, CAD mortality
 Nitroglycerin, other nitrate products useful for angina
prophylaxis when patients undertake activities known
to provoke angina
 When angina occurs on a regular, routine basis
 institute chronic prophylactic therapy
7
Key Concepts
 CCBs: effective monotherapy
 generally used with β-blockers or as monotherapy for
patients intolerant to β-blockers
 most patients with moderate to severe angina require 2
drugs to control symptoms
 ranolazine: 2nd line drug

used with β-blockers & CCBs
8
Key Concepts
 Pharmacologic management as effective as
revascularization if 1 or 2 vessels involved
 no differences in survival
 recurrent MI
 other measures of effectiveness
 Multivessel involvement best managed with
revascularization
 left main coronary artery disease
 left main equivalent disease
 2- to 4-vessel involvement with significant left
ventricular dysfunction
9
Key Concepts
 Revascularization
 percutaneous transluminal coronary angioplasty
 coronary artery bypass graft (CABG)
 certain patients (e.g. diabetics) should have CABG
 Percutaneous transluminal coronary angioplasty &
CABG produce similar results
10
Key Concepts
 Clinical performance measures for chronic stable CAD
 American College of Cardiology, American Heart
Association




BP
lipid profile
drug therapy
hyperlipidemia
symptom & activity
assessment





smoking cessation
antiplatelet therapy
β-blocker therapy for prior
myocardial infarction
ACE inhibitor therapy
diabetes screening
11
Ischemic Heart Disease
 Caused by epicardial vessel atherosclerosis which leads
to coronary heart disease
 Presentation:
 acute coronary syndrome
 chronic stable exertional angina pectoris
 ischemia without clinical symptoms
 heart failure, arrhythmias
 cerebrovascular disease
 peripheral vascular disease
12
Epidemiology
 ~79 million American adults: > 1 type of cardiovascular
disease (CVD)
 ~2,400 Americans die of CVD each day
 average of 1 death every 33 seconds
 In 2004, CHD was responsible for 52% of CVD deaths
 Common initial presentation:
 women: angina
 men: myocardial infarction
Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: A report from the American Heart
Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:69–171.
13
Criteria for Determination of the Specific Activity
Scale Functional Class
Any Yes
1. Can you walk down a flight of steps without stopping (4.5 Go to 2
– 5.2 MET)?
2. Can you carry anything up a flight of 8 steps without
Go to 3
stopping (5 – 5.5 MET)? Or can you:
a. Have sexual intercourse without stopping (5 – 5.2 MET)
b. Garden, rake, weed (5.6 MET)
c. Roller skate, dance foxtrot (5 – 6 MET)
d. Walk at a 4-miles/hr rate on level ground (5 – 6 MET)
3. Can you carry at least 24 lb up 8 steps (10 MET)? Or can Class I
you:
a. Carry objects that weigh at least 80 lb (18 MET)
b. Do outdoor work, shovel snow, spade soil (7 MET)
c. Do recreational activities such as skiing, basketball,
touch football, squash, handball (7 – 10 MET)
d. Jog/walk 5 miles/h (9 MET)
No
Go to 4
Class III
Class II
MET, metabolic equivalents of activity.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
14
Criteria for Determination of the Specific Activity
Scale Functional Class
Any Yes
No
4. Can you shower without stopping (3.6 – 4.2 MET)? Or can Class III
you:
a. Strip and make bed (3.9 – 5 MET)
b. Mop floors (4.2 MET)
c. Hang washed clothes (4.4 MET)
d. Clean windows (3.7 MET)
e. Walk 2.5 miles/h (3 – 3.5 MET)
f. Bowl (3 – 4.4 MET)
g. Play golf, walk and carry clubs (4.5 MET)
h. Push a power lawnmower (4 MET)
Go to 5
5. Can you dress without stopping because of symptoms (2 – Class III
2.3 MET)?
Class IV
MET, metabolic equivalents of activity.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
15
Angina
 Classified by symptom severity, disability, specific
activity scale
 Number of vessels obstructed important determinate
of outcome
 Risk factors for increased mortality:
 heart failure
 smoking
 left main or left main equivalent CAD
 diabetes
 prior MI
16
Grading of Angina Pectoris by the Canadian
Cardiovascular Society Classification System
Class
Class I
Class II
Class III
Class IV
Description of Stage
Ordinary physical activity does not cause angina, such as walking,
climbing stairs. Angina occurs with strenuous, rapid, or prolonged
exertion at work or recreation.
Slight limitation or ordinary activity. Angina occurs on walking or
climbing stairs rapidly, walking uphill, walking or stair climbing after
meals, or in cold, or in wind, or under emotional stress, or only
during the few hours after wakening. Walking more than 2 blocks
on the level and climbing more than 1 flight of ordinary stairs at a
normal pace and in normal condition.
Marked limitations of ordinary physical activity. Angina occurs on
walking 1 to 2 blocks on the level and climbing 1 flight of stairs in
normal conditions and at a normal pace.
Inability to carry on any physical activity without discomfort—
anginal symptoms may be present at rest.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
17
Etiology/Pathophysiology
 Coronary atherosclerotic plaque formation leads to
imbalance between O2 supply & demand 
myocardial ischemia
 Ischemia: lack of O2, decreased or no blood flow in
myocardium
 Anoxia: absence of O2 to myocardium
18
Etiology/Pathophysiology
 Determinants of myocardial oxygen demand (MVO2)
 HR
 contractility
 intramyocardial wall tension during systole (most
important)
 Determinants of ischemia:
 resistance in vessels delivering blood to myocardium
 MVO2
19
Etiology/Pathophysiology
 Coronary blood flow
 inversely related to arteriolar resistance
 directly related to coronary driving pressure
 Extent of functional obstruction important limitation
of coronary blood flow
 severe stenosis (> 70%)

ischemia & symptoms at rest
20
21
Etiology/Pathophysiology
 Changes in O2 balance lead to rapid changes in
coronary blood flow
 Mediators that affect O2 balance:
 adenosine
 other nucleotides
 nitric oxide
 prostaglandins
 CO2
 H+
22
Etiology/Pathophysiology
 Extrinsic factors
 alterations in intramyocardial wall tension throughout
the cardiac cycle
 phasic systolic vascular bed compression
 factors that favor reduction in blood flow
 Intrinsic factors
 myogenic control

Bayliss effect
 neural components

parasympathetic nervous system, sympathetic nervoussystem,
coronary reflexes
23
Etiology/Pathophysiology
 Factors limiting coronary perfusion:
 coronary reserve diminished at ~85% obstruction
 critical stenosis occurs when obstructing lesion
encroaches on the luminal diameter & exceeds 70%
24
Short-Term Risk of Death or Nonfatal Myocardial Infarction in
Patients with Unstable Angina
Feature
High Risk (At least 1 of the
following features must be
present)
Accelerating tempo of ischemic
symptoms in preceding 48 h
Intermediate Risk (No
high-risk feature but must
have 1 of the following)
History
Prior Ml, peripheral or
cerebrovascular disease, or
CABG, prior aspirin use
Character of pain Prolonged ongoing (> 20 min), Prolonged (> 20 min), rest
rest pain
angina, now resolved, with
moderate or high likelihood
of CAD
Low Risk (No high- or
intermediate-risk feature but
may have any of the following)
New-onset CCS class III or IV
angina in the past 2 weeks
without prolonged (> 20 min)
rest pain but with moderate or
high likelihood of CAD
Clinical findings
Pulmonary edema, most likely
caused by ischemia
New or worsening MR murmur
S3 or new/worsening rales
Hypotension, bradycardia,
tachycardia
Age > 75 y
ECG
Angina at rest with transient ST- T-wave inversions > 0.2 mV Normal or unchanged ECG
segment changes > 0.05 mV
Pathologic Q waves
during an episode of chest
Bundle-branch block, new or
discomfort
presumed new
Cardiac markers Markedly elevated (e.g., TnT or Slightly elevated (e.g., TnT > Normal
TnI > 0.1 ng/mL)
0.01 but < 0.1 ng/mL)
CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; ECG,
electrocardiogram; Ml, myocardial infarction; MR, mitral regurgitation; Tnl, troponin; TnT, troponin T.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
25
Clinical Presentation of Angina
 Many ischemia episodes are silent (no symptoms)
 Patients often have reproducible pattern, pain, other
symptoms
 Increased frequency, severity, duration, symptoms at
rest suggests unstable angina
26
Clinical Presentation of Angina
 Symptoms
 sensation of pressure/burning over or near sternum;
often but not always radiating

left jaw, shoulder, arm
 chest tightness, shortness of breath
 visceral pain: lasts 0.5 to 30 min
 precipitating factors: exercise, cold environment,
walking after a meal, emotional upset, fright, anger,
coitus
 relief with rest, nitroglycerin
27
Clinical Presentation of Angina
 Signs
 abnormal precordial systolic bulge
 abnormal heart sounds
 Typically no abnormal laboratory tests
 Likely to have abnormal tests for IHD risk factors
 History of chest pain
28
Differential Diagnosis of Episodic Chest Pain
Resembling Angina Pectoris
Effort angina
Duration
Quality
5 – 15 min
Visceral
(pressure)
Visceral
(pressure)
Provocation Relief
During effort Rest, NTG
or emotion
Rest angina
5 – 15 min
Spontaneous NTG
(? with
exercise)
Mitral prolapse Min – hours Superficial Spontaneous Time
(rarely
(no pattern)
visceral)
Esophageal
10 min – 1 h Visceral
Spontaneous, Foods,
reflux
cold liquids, antacids, H2
exercise,
blockers,
lying down proton pump
inhibitors,
NTG
Peptic ulcer
Hours
Visceral,
burning
Location
Comment
Substernal,
radiates
Substernal,
radiates
First episode
vivid
Often
nocturnal
Left anterior No pattern,
variable
Substernal,
radiates
Mimics
angina
Lack of food, Foods,
Epigastric,
"acid" foods antacids, H2 substernal
blockers,
proton pump
inhibitors
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
29
Differential Diagnosis of Episodic Chest Pain
Resembling Angina Pectoris
Duration Quality
Location
Comment
Epigastric,
radiates
Colic
Head and
Time,
neck,
analgesia
movement
and palpation
Arm, neck
Not relieved
by rest
Hyperventilation 2 – 3 min Visceral
Emotion,
tachypnea
Stimulus
removed
Substernal
Facial
paraesthesia
Musculoskeletal Variable
Superficial
Movement,
palpation
Time,
analgesia
Multiple
Tenderness
Pulmonary
Visceral
(pressure)
Often
Rest, time
spontaneous bronchodilator
Substernal
Dyspneic
Biliary disease
Hours
Cervical disk
Variable Superficial
(gradually
subsides)
30 min
Provocation Relief
Visceral (wax Spontaneous, Time,
and wane)
food
analgesia
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
30
Cardiac Findings in CAD Patients
Sign
Abnormal precordial systolic bulge
Decreased intensity of S1
Clinical Significance
Left ventricular wall
motion abnormality
Frequency
Not usually present unless patient has
sustained a prior Ml (especially anterior
wall) or is experiencing angina at time of
examination
Decrease in left
Difficult to evaluate in resting state, but can
ventricular contractility be commonly demonstrated during angina
Paradoxical splitting of S2
Left ventricular wall
Very uncommon but occasionally noted
motion abnormality
during angina
S3 (ventricular gallop)
Increased left
Not usually present unless patient sustained
ventricular diastolic
extensive Ml; may occasionally be present
pressure, with or
during angina
without clinical CHF
S4 (atrial gallop)
Reduced ventricular
Common; very common in patients who
compliance ("stiff
have sustained a prior Ml as well as during
heart")
angina
Apical systolic murmur (in absence Papillary muscle
Not usually present unless patient has
of rheumatic mitral regurgitation or dysfunction
sustained prior Ml
Barlow syndrome)
Diastolic murmur (in absence of
Coronary artery stenosis Rare
aortic regurgitation)
CHF, congestive heart failure; MI, myocardial infarction; S1, first heart sound; S2, second heart sound; S3,
third heart sound; S4, fourth heart sound
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
31
32
Diagnostic Tests
 Electrocardiogram (ECG)
 normal in ½ of patients with angina not experiencing an
acute attack
 ST-T wave changes



depression
T-wave inversion
ST-segment elevation
 significant ischemia



ST-segment depression > 2 mm
exertional hypotension
reduced exercise tolerance
33
Lead V4 at rest (top) and
after 4½ min of exercise
(bottom).
There is 3 mm (0.3 mV)
of horizontal STsegment depression,
indicating a positive
test for ischemia.
34
Diagnostic Tests
 Exercise Tolerance Testing (ETT)
 recommended for patients with intermediate pretest
probability of CAD based on age, gender, symptoms
 insensitive for predicting coronary artery anatomy but
correlates well with outcome
 Echocardiography
 useful if physical examination suggests valvular,
pericardial disease, ventricular dysfunction
35
45-year-old avid jogger who began
experiencing classic substernal chest
pressure underwent an exercise echo
study.
With exercise the patient's heart rate
increased from 52 to 153 bpm. The left
ventricular chamber dilated with
exercise, and the septal and apical
portions became akinetic to dyskinetic
(red arrow).
These findings are strongly suggestive of
a significant flow limiting stenosis in the
proximal left anterior descending
coronary artery, which was confirmed at
coronary angiography.
36
Diagnostic Tests
 Cardiac imaging
 radionucleotide angiocardiography
 technetium pyrophosphate scans
 positron emission tomography
 ultrarapid computerized tomography



spiral CT
ultrafast CT
electron-beam CT
 Cardiac catheterization & angiography
37
Stress and rest myocardial perfusion
PET images obtained with rubidium-82
in a patient with chest pain on exertion.
The images demonstrate a large and
severe stress perfusion defect
involving the mid and apical anterior,
anterolateral, and anteroseptal walls,
and the LV apex, showing complete
reversibility, consistent with extensive
and severe ischemia in the mid left
anterior descending coronary artery
territory (red arrows).
38
39
40
IHD Treatment
 Short term goals:
 reduce/prevent angina symptoms that limit exercise
capability & impair quality of life (QOL)
 Long-term goals:
 prevent CHD events



MI
arrhythmias
heart failure
 extend the patient’s life
41
42
IHD Treatment
 Risk factor identification/modification
 risk factors play a major role in determining occurrence
& severity of IHD
 risk factors are additive

classified as alterable or unalterable
43
IHD Treatment
 Unalterable risk factors:
 gender
 age
 family history
 environmental influences

climate, air pollution, trace metals in drinking water
 diabetes mellitus
44
IHD Treatment
 Alterable risk factors:
 smoking
 HTN
 hyperlipidemia
 obesity, sedentary lifestyle
 hyperuricemia
 psychosocial factors (stress, type A behavior)
 medications



progestins
corticosteroids
cyclosporine
45
The American College of Cardiology and American
Heart Association Evidence Grading System
Recommendation Class
Level of Evidence
I Conditions for which there is evidence or A Data derived from multiple randomized
general agreement that a given
clinical trials with large numbers of
procedure or treatment is useful and
patients
effective
II Conditions for which there is conflicting B Data derived from a limited number of
evidence or a divergence of opinion
randomized trials with small numbers of
about the usefulness/efficacy of a given
patients, careful analyses of
procedure or treatment is useful and
nonrandomized studies, or observational
effective
registries
IIa Weight of evidence/opinion is in favor or C Expert consensus was the primary basis
usefulness/efficacy
for the recommendation
IIb Usefulness/efficacy is less-well
established by evidence/opinion
III Conditions for which there is evidence or
general agreement that a given
procedure or treatment is not
useful/effective and in some cases may
be harmful
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
46
Stable Exertional Angina Pectoris
 ASA (Class I, Level A)
 β-blockers with prior MI (Class I, Level A)
 ACE inhibitors for patients with CAD & diabetes or LV
systolic dysfunction (Class I, Level A)
 LDL-lowering therapy with CAD & LDL > 130 mg/dL
(Class I, Level A)
 target LDL < 100 mg/dL
 < 70 mg/dL in patients with CHD & multiple risk factors
 Sublingual nitroglycerin for immediate angina relief
(Class I, Level B)
47
Stable Exertional Angina Pectoris
 Calcium antagonists or long-acting nitrates for
symptom reduction when β-blockers contraindicated
(Class I, Level B)
 Calcium antagonists or long-acting nitrates in
combination with β-blockers when initial β-blocker
treatment is inadequate (Class I, Level C)
 Calcium antagonists or long-acting nitrates as
substitutes for β-blockers if initial β-blocker treatment
leads to intolerable side effects (Class I, Level A)
48
Stable Exertional Angina Pectoris
 May substitute clopidogrel when ASA contraindicated
(Class IIa, Level B)
 Use of long-acting nondihydropyridine calcium
antagonists instead of β-blockers as initial therapy
(Class IIa, Level B)
 Therapies to avoid:
 dipyridamole (Class III, Level B)
 chelation therapy (Class III, Level B)
49
Effect of Drug Therapy on Myocardial O2 Demand
Nitrates
LV Wall Tension
Heart Rate Myocardial
Systolic
LV Volume
Contractility Pressure
↓
0
↓
↓↓
β-Blockers
↓↓
↓
↓
↓
Nifedipine
↓
0 or ↓
↓↓
0 or ↓
Verapamil
↓
↓
↓
0 or ↓
Diltiazem
↓↓
0 or ↓
↓
0 or ↓
Calcium channel antagonists and nitrates also may increase myocardial oxygen supply through
coronary vasodilation. Diastolic function may be improved with verapamil, nifedipine, and
perhaps, diltiazem. These effects may vary from those indicated in the table depending on
individual patient baseline hemodynamics.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
50
Stable Exertional Angina Pectoris
 β-blocker place in therapy:
 effective in chronic exertional angina as monotherapy
and in combo with nitrates and/or CCBs
 1st line in chronic angina that requires daily maintenance
therapy
 ideal candidates:




physical activity figures prominently in anginal attacks
coexistent hypertension
history of supraventricular arrhythmias or post-MI angina
anxiety associated with angina
51
Stable Exertional Angina Pectoris
 β-blockers
 symptom control
 reduce risk of recurrent MI, CAD mortality
 may be used for chronic prophylaxis in patients with > 1
angina episodes/day
 smokers have reduced anti-anginal efficacy

some have reduced efficacy based on lipid solubility
 propranolol: lipid soluble, inducible metabolism
52
Stable Exertional Angina Pectoris
 β-blockers
 overall effect of β-blockers in patients with effortinduced angina  reduction in O2 demand
 do not improve O2 supply
 can blunt reflex tachycardia from nitrate therapy
 may decrease exercise capacity in healthy individuals or
those with HTN
 may improve exercise tolerance in angina patients
53
Stable Exertional Angina Pectoris
 β-blockers
 dosing based on t½

disparity between t½ & duration of action for several BBs
 renal/hepatic dysfunction affect disposition

route of elimination not major consideration in drug selection
54
Stable Exertional Angina Pectoris
 β-blocker adverse effects
 abrupt withdrawal associated with increased severity &
number of pain episodes & myocardial infarction
 pharmacologic effects



hypotension
decompensated heart failure
bradycardia



heart block
bronchospasm
altered glucose metabolism
 CNS effects



fatigue
malaise
depression
55
Stable Exertional Angina Pectoris
 Nitrate place in therapy
 terminate acute anginal attack
 prevent effort/stress-induced attacks
 long-term prophylaxis
 usually in combination with β-blockers or CCBs
 formulations:
 chewable


oral
transdermal



ointments
spray
IV
56
Stable Exertional Angina Pectoris
 Nitrate therapy for acute attacks
 sublingual
 buccal
 spray products
 Symptom prophylaxis when undertaking activities that
precipitate attacks
 oral or transdermal products
 0.3 to 0.4 mg SL ~5 min prior to activity
 Chronic prophylaxis with long-acting forms
 tolerance: limiting factor
57
Stable Exertional Angina Pectoris
 Nitrate therapy
 reduces MVO2 2 to venodilation & arterial-arteriolar
dilation  reduction in wall stress from reduced
ventricular volume & pressure
 systemic venodilation increases flow to deep myocardial
tissue
 dilation of large & small intramural coronary arteries,
collateral dilation, coronary artery stenosis dilation,
abolition of normal tone in narrowed vessels, relief of
spasms
58
Stable Exertional Angina Pectoris
 Nitrate therapy
 large 1st-pass effect
 short t½ (except isosorbide mononitrate)

see Nitrate Products chart on slide 61
 large volume of distribution
 high clearance rates
 large interindividual variation in plasma/blood
concentrations
 saturable metabolism
 accumulation of metabolites with multiple doses
 drug adsorption to PVC tubing, syringes
59
Stable Exertional Angina Pectoris
 Nitrate therapy adverse effects
 extension of pharmacologic effects


postural hypotension with CNS symptoms, headaches,
flushing 2 to vasodilation
occasional nausea from smooth muscle relaxation
 reflex tachycardia, but bradycardia has been reported
 rash with all products (particularly with patches)
 production of methemoglobinemia with high doses for
extended periods
 measurable ethanol & propylene glycol concentrations
with IV nitroglycerin
 tolerance
60
Nitrate Products
Product
Nitroglycerin
IV
Sublingual/lingual
Oral
Ointment
Patch
Erythritol tetranitrate
Pentaerythritol tetranitrate
Isosorbide dinitrate
Sublingual/chewable
Oral
Isosorbide mononitrate
a
Onset (min)
1–2
1–3
40
20 – 60
40 – 60
5 – 30
30
2–5
20 – 40
30 – 60
Duration
Initial Dose
3 – 5 min
5 mcg/min
30 – 60 min
0.3 mg
3–6h
2.5 – 9 mg tid
2–8h
0.5 – 1 in
>8h
1 patch
4–6h
5 – 10 mg tid
4–8h
10 – 20 mg tid
1–2h
4–6h
6–8h
2.5 – 5 mg tid
5 – 20 mg tid
a
20 mg daily, bid
Product dependent
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
61
Stable Exertional Angina Pectoris
 Calcium channel blockers (CCBs)
 effective monotherapy (usually used if patients are
intolerant of β-blockers)

generally used in combination with β-blockers
 improve coronary blood flow through coronary artery
vasodilation, decrease MVO2
 provide better skeletal muscle oxygenation than βblockers  decrease fatigue, improve exercise tolerance
 CCBs have similar efficacy

differences in electrophysiology, peripheral/central
hemodynamic effects, ADR profiles useful in selecting
appropriate agent
62
Stable Exertional Angina Pectoris
 Calcium channel blockers (CCBs)
 ideal candidates






contraindications/intolerance to β-blockers
coeixting conduction system disease (except verapamil,
diltiazem)
Prinzmetal angina
peripheral vascular disease
severe ventricular dysfunction (amlodipine drug of choice)
concurrent HTN
63
Stable Exertional Angina Pectoris
 Calcium channel blockers (CCBs)
 vasodilation of systemic arterioles & coronary arteries


reduction of arterial pressure and coronary vascular resistance
depression of myocardial contractility & conduction velocity of
the SA/AV nodes
 MVO2 reduction due to reduced wall tension 2 to reduced
arterial pressure
 may improve coronary blood flow through areas of fixed
coronary obstruction

inhibits coronary artery vasomotion/vasospasm
 non-dihydropyridine products affect AV conduction and
contractility
64
Stable Exertional Angina Pectoris
 Calcium channel blockers (CCBs)
 large, variable, 1st-pass metabolism


~20 to 50% bioavailability for diltiazem, nicardipine,
nifedipine, verapamil, felodipine, isradipine
amlodipine bioavailability ~60 to 80%
 most CCBs eliminated via CYP 3A4 & other CYP
isoenzymes
65
Stable Exertional Angina Pectoris
 Ranolazine
 reduces Ca2+ overload in ischemic myocytes through
selective inhibition of late Na+ current (INa)

does not affect HR, inotropic state, hemodynamic state or
increase coronary blood flow
 indicated for chronic angina treatment


prolongs QT interval
reserved for patients who have not achieved adequate
response with other antianginal agents
66
Stable Exertional Angina Pectoris
 Ranolazine
 dose: 500 mg BID then 1000 mg BID
 contraindications


preexisting QT interval prolongation
hepatic impairment
 drug interactions


other QT interval-prolonging medications
cytochrome P450 3A inhibitors decrease ranolazine clearance
67
Clinical Controversy
 MERLIN-TIMI 36
 Metabolic Efficiency With Ranolazine for Less
Ischemia in Non−ST-Elevation Acute Coronary
Syndromes
 Randomized, double-blind, controlled trial (n=6560)
 2 groups
 ranolazine 1000 mg BID
 placebo
Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients
with non-ST-elevation acute coronary syndromes: the MERLIN TIMI 36 randomized trial. JAMA 2007;297:1775– 83.
Evaluation of the Glycometabolic Effects of Ranolazine in Patients With and Without Diabetes Mellitus in the
MERLIN-TIMI 36 Randomized Controlled Trial Circulation, 2009; 119: 2032 - 2039.
68
Clinical Controversy
 MERLIN-TIMI 36 results
 NSTEMI angina symptom relief
 6.2% HbA1c reduction at 4 months: ranolazine group
 5.9% HbA1c reduction at 4 months: placebo

0.30 versus 0.04 (p<0.001) – clinical significance?
 no significant reduction in composite 1˚ outcome at
(median follow-up 348 days)


CV death
MI, recurrent ischemia
Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients
with non-ST-elevation acute coronary syndromes: the MERLIN TIMI 36 randomized trial. JAMA 2007;297:1775– 83.
Evaluation of the Glycometabolic Effects of Ranolazine in Patients With and Without Diabetes Mellitus in the
MERLIN-TIMI 36 Randomized Controlled Trial Circulation, 2009; 119: 2032 - 2039.
69
70
71
Stable Exertional Angina Pectoris
 Nonpharmacologic therapy
 revascularization
 coronary artery bypass grafting
 percutaneous transluminal coronary angioplasty
72
Recommended Mode of Coronary Revascularization
Extent of Disease
Left main disease, not a candidate for CABG
CABG
PCI
PCI
Class/Level of
Evidence
I/A
III/C
IIb/C
Three-vessel disease with EF < 0.50
Multivessel disease including proximal LAD with EF
CABG
CABG
I/A
I/A
PCI
PCI
IIb/B
I/A
One- or two-vessel disease without proximal LAD but with large
areas of myocardial ischemia or high-risk criteria on noninvasive
testing
CABG or PCI
I/B
One-vessel disease with proximal LAD
CBAG or PCI
IIa/B
One- or two-vessel disease without proximal LAD with small area CABG or PCI
of ischemia or no ischemia on noninvasive testing
Insignificant coronary stenosis
CABG or PCI
III/C
a
Left main disease, candidate for CABG
< 0.50 or treated diabetes
Multivessel disease with EF > 0.50 and without diabetes
Treatment
III/C
CABG, coronary artery bypass grafting; EF, ejection fraction; LAD, left anterior descending coronary
artery; PCI, percutaneous coronary intervention. a50% diameter stenosis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
73
74
Stable Exertional Angina Pectoris
 Revascularization
 based on extent of coronary disease (# of vessels,
location/amount of stenosis) & ventricular function
 complications: coronary artery spasm, intraluminal
thrombus

combination therapy with acetylsalicylic acid, unfractionated
heparin, or low-molecular-weight heparin, glycoprotein
IIb/IIIa receptor antagonists & stents have reduced occurrence
of reocclusion & late restenosis
75
Stable Exertional Angina Pectoris
 Coronary artery bypass grafting (CABG)
 reduces symptomatic angina not controlled by medical
management or PCI
 improves patient lifestyle
 reduces CAD mortality
 reduces need for nitrates, β-blockers
76
Stable Exertional Angina Pectoris
 Percutaneous transluminal coronary angioplasty
(PTCA)
 reduced stenosis due to




compression, redistribution of plaque
embolization of plaque contents
aneurysm formation
disruption of plaque & arterial wall
 patients usually heparinized during PTCA to prevent
immediate thrombus formation at site of arterial injury

anticoagulation up to 24 hrs
77
Stable Exertional Angina Pectoris
 Percutaneous transluminal coronary angioplasty
(PTCA)
 prevention of restenosis:



combination therapy with acetylsalicylic acid, heparin, GP
IIa/IIIa receptor antagonists
bivalirudin
drug-eluting & bare metal stents
78
Stable Exertional Angina Pectoris
 PTCA vs CABG
 low-risk patients have greater alleviation of symptoms
with PTCA
 moderate-risk patients had equal mortality & MI rates
with PTCA or CABG
 high-risk patients showed improved survival with CABG
than medical therapy
79
Stable Exertional Angina Pectoris
 Drug-eluting stents
 sirolimus (Cypher®)
 paclitaxel (Taxus®)
 zotarolimus (Endeavor®)
 target revascularization needed less often than bare
stents
 combination antiplatelet therapy (ASA + clopidogrel)
for > 1 yr following implantation
Eisenberg MJ; Richard PR, BSc; Libersan D; Filion KB. Safety of Short-Term Discontinuation of Antiplatelet Therapy in Patients
80
With Drug-Eluting Stents. Circulation. 2009; 119: 1634-1642.
Drug-eluting stents
 Antiplatelet therapy often discontinued in surgical
patients with drug-eluting stents
 risk factor for late stent thrombosis
 Medline search for late & very late stent thrombosis
cases Jan 2001 to July 2008
 When patients stopped antiplatelet agents
simultaneously, median time to event: 7 days
 If the thienopyridine was stopped & ASA continued,
median time to event: 122 days
Eisenberg MJ; Richard PR, BSc; Libersan D; Filion KB. Safety of Short-Term Discontinuation of Antiplatelet Therapy in Patients
81
With Drug-Eluting Stents. Circulation. 2009; 119: 1634-1642.
Variant Angina Pectoris
 Prinzmetal angina
 associated with ST-segment elevation
 commonly resolves without progression to MI
 usually younger patients
82
Variant Angina Pectoris
 Causes
 imbalance between endothelium-produced vasodilator
factors (prostacyclin, nitric oxide) & vasoconstrictor
factors (endothelin, angiotensin II)
 imbalance of autonomic control characterized by
parasympathetic dominance of inflammation
 adrenoreceptor polymorphisms may predispose patients
to developing vasospasm
83
Variant Angina Pectoris
 Precipitating factors
 hyperventilation
 exercise
 exposure to cold
 May have no apparent precipitating cause
84
Coronary Artery Spasm
 Diagnosis
 ST-segment elevation during transient chest discomfort
(usually at rest) that resolves when chest discomfort
diminishes in patients with normal or non-obstructive
lesions
 In absence of ST-segment elevation, may use
provocative tests to precipitate coronary artery spasm
 ergonovine, acetylcholine, methacholine
 withdraw nitrates & CCB prior to testing
85
Coronary Artery Spasm
 Treatment
 optimization of therapy includes dose titration
 treat all patients for acute attacks
 maintain prophylactic treatment 6 to 12 months
following initial episode
 eliminate aggravating factors



alcohol
cocaine
cigarette smoking
86
Coronary Artery Spasm
 Treatment
 nitrates for acute attacks
 CCBs



nifedipine, verapamil, diltiazem equally effective single agents
for initial treatment
dose titration needed
combination therapy with nifedipine-diltiazem or nifedipineverapamil useful for patients unresponsive to single-drug
regimens
 β-blockers have little or no role
87
Silent Ischemia
 Associated with ST-segment elevation, depression
 Frequently occurs without antecedent HR, BP changes
 ischemia from reduction in O2 supply
 2 classes
 Class I: patients do not experience angina
 Class II: patients have both asymptomatic &
symptomatic ischemia
 Associated with reduced survival, increased need for
PTCA/CABG, increased risk of acute MI
88
Silent Ischemia
 Causes
 increased physical activity
 sympathetic nervous system activation
 ↑ cortisol secretion
 ↑ coronary artery tone
 enhanced platelet aggregation due to endothelial
dysfunction leading to intermittent coronary
obstruction
89
Silent Ischemia
 Diagnosis: ambulatory ECG
 Initial management
 modify IHD risk factors



HTN
hypercholesterolemia
smoking
 Treatment goal
 reduce number of ischemic episodes (symptomatic &
asymptomatic), regardless of direction of ST-segment
shift
90
Silent Ischemia
 Pharmacologic treatment
 β-blockers

most useful for post-MI patients or those with high level of
sympathetic nervous system activity
 CCBs alone or in combination effective in reducing
symptomatic & asymptomatic ischemia


do not interrupt diurnal surge in ischemia
less effective than β-blockers
 combination β-blockers & CCBs: better response than
CCBs & nitrates or CCB monotherapy
91
Therapeutic Outcomes
 Angina symptom improvement
 Improved cardiac performance
 Risk factor reduction
 Increased exercise capacity
 May use coronary angiography to assess extent of
stenosis or restenosis after angioplasty or CABG
92
Clinical Controversy
 Many long-term trials compare β-blockade vs CCBs to
determine superior survival benefit
 β-blockers recommended 1st line prophylactic therapy
for symptomatic angina patients requiring daily
pharmacologic therapy
 effective in post-MI patients
 favorable adverse effect profile
 Stable CAD: medical management produces outcomes
similar to revascularization
 may impact future use of healthcare resources
93
Clinical Controversy
 Recent developments in understanding organic
nitrates bioactivation raise concern over endothelial
dysfunction induced by long-term nitrate
administration
 Nitrate products activated via different mechanisms
 impacts long-term effectiveness of individual drugs
94
American College of Cardiology, American Heart Association, and Physician
Consortium for Performance Improvement Chronic Stable Coronary Artery
Disease Core Physician Performance Measurement Seta
Clinical Recommendations
Blood pressure
measurement
A blood pressure ready is recommended at every visit.
Recommended blood pressure management targets are 130 mm
Hg systolic (Class I Recommendation, Level A Evidence) and 85
mm Hg diastolic in patient with CAD coexisting condition (e.g.,
diabetes, heart failure, or renal failure) and <140/90 mm Hg in
patient with CAD and no coexisting condition.
Lipid profile
A lipid profile is recommended and should include total
cholesterol, high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), and triglycerides. (Class
I Recommendation, Level C Evidence)
Symptom and activity
Regular assessment of patients' anginal symptoms and levels of
assessment
activity is recommended. (Serves as a basis for treatment
modification.)
Smoking cessation
Smoking status should be determined and smoking cessation
counseling and interventions are recommended. (Class I
Recommendation, Level B Evidence)
Screening for diabetes
Screening for diabetes is recommended in patients who are
Denominator exclusion:
considered high risk (e.g., CAD) (Class I Recommendation, Level
patients with documented DM A Evidence)
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
95
American College of Cardiology, American Heart Association, and Physician
Consortium for Performance Improvement Chronic Stable Coronary Artery
Disease Core Physician Performance Measurement Seta
Clinical Recommendations
Antiplatelet therapy
Routine use of aspirin is recommended in the
Denominator exclusion: Documentation of medical absence of contraindications. If
reason(s)b for not prescribing antiplatelet therapy; contraindications exist, other antiplatelet
documentation of patient reason(s)c for not
therapies may be substituted. (Class I
prescribing antiplatelet therapy
Recommendation, Level A Evidence)
ACE inhibitor therapy
ACE inhibitor use is recommended in all
Denominator inclusion: Patient with CAD who also patients with CAD who also have diabetes
has diabetes and/or left ventricular systolic
and/or LVSD (Class I Recommendation, Level
dysfunction (LVSD) (left ventricular ejection
A Evidence)
fraction [LVEF] < 40% or moderately or severely
ACE inhibitor use is also recommended in
depressed left ventricular systolic function)
patients with CAD or other vascular disease
Denominator exclusion: Documentation that ACE
(Class IIa Recommendation, Level B
inhibitor was not indicated (e.g., patients on
Evidence)
angiotensin receptor blockers [ARB]);
documentation of medical reason(s)b for not
prescribing ACE inhibitor; documentation of patient
reason(s)c for not prescribing ACE inhibitor
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
96
American College of Cardiology, American Heart Association, and Physician
Consortium for Performance Improvement Chronic Stable Coronary Artery
Disease Core Physician Performance Measurement Seta
Clinical Recommendations
β-Blocker therapy—prior myocardial infarction
(MI)
Denominator inclusion: Prior MI
Denominator exclusion: Documentation that a βblocker was not indicated; documentation of
medical reason(s)b for not prescribing a β-blocker;
documentation of patient reason(s)c for not
prescribing a β-blocker
Drug therapy for lowering LCL-cholesterol
Denominator exclusion: Documentation that a
statin was not indicated;e documentation of medical
reason(s)b for not prescribing a statin;
documentation of patient reason(s)c for not
prescribing statin
β-Blocker therapy is recommended for all
patients with prior MI in the absence of
contraindications. (Class I Recommendation,
Level A Evidence)
The LCL-C treatment goal is <100 mg/dL.
Persons with established coronary heart
disease (CHD) who have a baseline LCL-C
130 mg/dL should be started on a
cholesterol-lowering drug simultaneously
with therapeutic lifestyle changes and
control of nonlipid risk factors. (Class I
Recommendation, Level A Evidence)
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
97
Table Footnotes










aRefers
to all patients diagnosed with CAD
bMedical reasons for not prescribing antiplatelet therapy (aspirin, clopidogrel, or
combination of aspirin and dipyridamole): active bleeding in the previous 6 months with
required hospitalization and/or transfusion(s), patient on other antiplately therapy, etc.
Medical reasons for not prescribing a statin: clinical judgement, documented LCL-C < 130
mg/dL, etc.
Medical reasons for not prescribing a β-blocker: bradycardia (defined as heart rate < 50
beats/min without β-blocker therapy), history of class IV (congestive) heart failure, history of
second- or third-degree atrioventricular block without permanent pacemaker, etc.
Medical reasons for not prescribing ACE inhibitor (ACEI): allergy, angioedema caused by
ACEI, anuric rental failure caused by ACEI, pregnancy, moderate or severe aortic stenosis, etc.
cPatient reasons for not prescribing antiplatelet therapy, statin, -blocker, or ACEI: economic,
social, and/or religious, etc.
dAntiplatelet therapy may include aspirin, clopidogrel, or combination of aspirin and
dipyridamole.
eNot indicated for a statin refers to LCL-C < 100 mg/dL.
fTest measure.
gScreening for diabetes is usually done by fasting blood glucose or 2-hour glucose tolerance
testing. Clinical recommendations indicate screening should be considered at 3-year
intervals.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
98
Acknowledgements
Prepared By: Amy Pai, Pharm.D.
Series Editor: April Casselman, Pharm.D.
Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA
Chapter Author/Section Editor:
Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA
99