2. Learning Objectives
• Analyze the pathophysiologic conditions associated with Heart
failure, hypertension and angina pectoris
• List classes of drugs used in the treatment of CHF
• Classify Antihypertensive medications
• Drugs used in treatment of Ischemic heart disease
4. Introduction
• Hypertension is defined by persistent elevation of arterial blood
pressure (BP).
• Patients with diastolic blood pressure (DBP) values <90 mm Hg
and systolic blood pressure (SBP) values ≥140 mm Hg have
isolated systolic hypertension.
6. Introduction …
• Because increased risk is associated with pressures sometimes
regarded as normal, an ‘optimal’ grade has been proposed.
• SBP is inversely proportional to arterial compliance, which declines
with age owing to smooth muscle fibrosis and calcification
(arteriosclerosis).
• DBP by contrast reflects the peripheral resistance, a measure of the
average size of blood vessel lumens throughout the body, against
which the heart has to develop and maintain a pressure.
7. Introduction ….
• A hypertensive crisis (BP >180/120 mm Hg) may be categorized
as either
• a hypertensive emergency (extreme BP elevation with acute
or progressing target organ damage) or
• a hypertensive urgency (severe BP elevation without acute or
progressing target organ injury).
8. Pathophysiology
• Primary or essential hypertension
• Hypertension is a heterogeneous disorder that may result
either from a specific cause (secondary hypertension) or
from an underlying pathophysiologic mechanism of unknown
etiology (primary or essential hypertension).
9. Pathophysiology…
• Secondary hypertension
• accounts for fewer than 10% of cases, and most of these are
caused by chronic kidney disease or renovascular disease.
• Other conditions causing secondary hypertension include
pheochromocytoma, Cushing’s syndrome, hyperthyroidism,
hyperparathyroidism, primary aldosteronism, pregnancy,
obstructive sleep apnea, and coarctation of the aorta.
11. Pathophysiology…
• The main causes of death in hypertensive subjects are
cerebrovascular accidents, cardiovascular (CV) events, and
renal failure.
• The probability of premature death correlates with the severity
of BP elevation.
12. Potential Mechanisms of Pathogenesis
• Blood pressure is the mathematical product of cardiac output and peripheral resistance.
Increased blood pressure can result from increased cardiac output and/or increased total
peripheral resistance.
• Increased cardiac output
• Increased cardiac preload:
• Increased fluid volume from excess sodium intake or renal sodium retention
(from reduced number of nephrons or decreased glomerular filtration)
• Venous constriction:
• Excess stimulation of the RAAS
• Sympathetic nervous system overactivity
13. Potential Mechanisms of Pathogenesis…
• Increased peripheral resistance
• Functional vascular constriction:
• Excess stimulation of the RAAS
• Sympathetic nervous system overactivity
• Genetic alterations of cell membranes
• Endothelial-derived factors
• Structural vascular hypertrophy:
• Excess stimulation of the RAAS
• Sympathetic nervous system over activity
• Genetic alterations of cell membranes
• Endothelial-derived factors
• Hyperinsulinemia resulting from obesity or the metabolic syndrome
16. Treatment Desired Outcome
• The overall goal of treating hypertension is to reduce
hypertension-associated morbidity and mortality.
17. Treatment Desired Outcome …
• Most patients < 140/90 mm Hg
• Patients with diabetes < 130/80 mm Hg
• Patients with chronic kidney disease < 130/80 mm Hg
• (estimated GFR<60 mL/min, serum creatinine > 1.3 mg/dL in
women or>1.5 mg/dL in men, or albuminuria > 300 mg/ day or
≥ 200 mg/g creatinine)
18. Treatment Desired Outcome …
• SBP is a better predictor of CV risk than DBP and must be used
as the primary clinical marker of disease control in
hypertension.
19. Non Pharmacologic treatment ….
• DASH eating plan is a diet that is rich in fruits, vegetables, and low-fat dairy products with a reduced
content of saturated and total fat.
Dietary approaches to stop hypertension
23. Algorithm for treatment of hypertension when patients are not at their goal blood pressure
PHARMACOLOGIC THERAPY
24. Recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 7)
25. Principles of drug therapy in hypertension
• As few drugs as possible
• As few daily doses as possible
• Start with most suitable initial drug(a)
• Increase the dose gradually until adequate effect achieved
• If primary failure, substitute another suitable drug from different group
• If effectiveness declines, add another agent rather than substitute
• Combine agents acting by different mechanisms
• Combine agents tending to reduce each other’s adverse actions
• Monitor adverse reactions and patient compliance regularly
27. Introduction
• Heart failure (HF)
• is a clinical syndrome caused by the inability of the heart to pump
sufficient blood to meet the metabolic needs of the body.
• HF can result from any disorder that reduces ventricular filling
(diastolic dysfunction) and/or myocardial contractility (systolic
dysfunction).
28. Introduction ….
• To understand the pathophysiologic processes in heart failure, a
basic understanding of normal cardiac function is necessary.
29. Introduction …
• Cardiac output (CO) is defined as the volume of blood ejected per
unit time (L/min) and is the product of heart rate (HR) and stroke
volume (SV):
• CO = HR × SV
• The relationship between CO and mean arterial pressure (MAP) is
• MAP = CO × systemic vascular resistance (SVR)
30. Introduction …
• Heart rate is controlled by the autonomic nervous system.
• Stroke volume, or the volume of blood ejected during systole,
depends on preload, afterload, and contractility.
• As defined by the Frank-Starling mechanism, the ability of the
heart to alter the force of contraction depends on changes in
preload.
31.
32.
33.
34. Pathophysiology
• Causes of systolic dysfunction (decreased contractility) are
• reduction in muscle mass (e.g., myocardial infarction [MI]),
• dilated cardiomyopathies,
• ventricular hypertrophy
• Pressure overload (e.g., systemic or pulmonary hypertension, aortic or
pulmonic valve stenosis)
• Volume overload (e.g., valvular regurgitation, shunts, high-output
states)
35. Pathophysiology…
• Causes of diastolic dysfunction (restriction in ventricular filling) are
• Increased ventricular stiffness,
• Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy)
• Infiltrative myocardial diseases e.g., amyloidosis, sarcoidosis,
endomyocardial fibrosis)
• Myocardial ischemia and infarction,
• Mitral or tricuspid valve stenosis, and
• Pericardial disease (e.g., pericarditis, pericardial tamponade).
36. Pathophysiology…
• As cardiac function decreases after myocardial injury, the heart relies
on the following compensatory mechanisms:
• (1) tachycardia and increased contractility through sympathetic
nervous system activation;
• (2) the Frank-Starling mechanism, whereby increased preload increases
stroke volume;
• (3) vasoconstriction; and
• (4) ventricular hypertrophy and remodeling.
• Although these compensatory mechanisms initially maintain cardiac
function, they are responsible for the symptoms of HF and contribute to
disease progression.
37. Pathophysiology (Cont’d)
• Increased preload
• The kidney interprets the reduced perfusion as an ineffective
blood volume, resulting in activation of the renin-angiotensin-
aldosterone (RAA) system.
• Reduced renal perfusion and increased sympathetic tone also
stimulate renin release from juxtaglomerular cells in the kidney
38.
39. Pathophysiology (Cont’d)
• Ventricular hypertrophy and remodeling
• Cardiac remodeling is a complex process that affects the
heart at the molecular and cellular levels.
• Collectively, these events result in progressive changes in
myocardial structure and function, such as cardiac
hypertrophy, myocyte loss, and alterations in the
extracellular matrix.
40.
41.
42. Drugs that May Precipitate or Exacerbate Heart
Failure
• Negative Inotropic Effect
• Antiarrhythmics (e.g., disopyramide, flecainide, and others), β-Blockers (e.g.,
propranolol, metoprolol, atenolol, and others), Calcium channel blockers (e.g.,
verapamil and others), Itraconazole, Terbinafine
• Cardiotoxic
• Doxorubicin, Daunomycin, Cyclophosphamide
• Sodium and Water Retention
• NSAIDs, COX-2 inhibitors, Rosiglitazone and pioglitazone, Glucocorticoids, Androgens,
Estrogens, Salicylates (high dose)
• Sodium-containing drugs (e.g., carbenicillin disodium, ticarcillin disodium)
45. Treatment Desired Outcome
• The therapeutic goals for chronic HF are to
•improve quality of life,
•relieve or reduce symptoms,
•prevent or minimize hospitalizations,
•slow disease progression, and
• prolong survival.
46. Treatment…
• The first step in managing chronic HF is to determine the
etiology or precipitating factors.
• Treatment of underlying disorders (e.g., anemia,
hyperthyroidism) may obviate the need for treating HF.
47. Treatment…
• Non-pharmacologic interventions include
• cardiac rehabilitation and
• restriction of fluid intake (maximum 2 L/day from all sources)
and
• Dietary sodium (approximately 2 to 3 g of sodium per day).
48.
49.
50.
51. Pharmacologic therapy
• Standard First line therapies
• Diuretics
• ACE Inhibitors
• B-Blockers
• Other HF Therapies (Drug
therapies to consider for
selected patients)
• Angiotensin II receptor blockers
• Aldosterone Antagonists
• Digoxin
• Nitrates and Hydralazine
54. Introduction
• Ischemic heart disease (IHD) is defined as a lack of oxygen and
decreased or no blood flow to the myocardium resulting from
coronary artery narrowing or obstruction.
55. Introduction …
• IHD may present as an acute coronary syndrome (ACS), which includes
• unstable angina and
• non–ST-segment elevation or ST-segment elevation myocardial
infarction [MI]),
• chronic stable exertional angina,
• ischemia without symptoms, or
• ischemia due to coronary artery vasospasm (variant or Prinzmetal
angina).
57. Classification…
• 1. Stable angina or typical or exertional or classical angina:
• induced by effort, relieved by rest.
• 2. Unstable angina or descendo angina:
• rapidly worsening angina or angina at rest.
• 3. Post –infraction angina
• 4. Prinzmetal’s or vasospastic angina or variant, angina:
• occurs without provocation, usually at rest as a result of coronary artery spasm.
• 5. Nocturnal angina:
• angina that occurs during sleep at night due to coronary ostial stenosis (narrowing of the mouths of the coronary
arteries as a result of syphilitic aortitis or atherosclerosis).
• 6. Variant angina
• results from reduced blood flow (a consequence of transient localized vasoconstriction) rather than increased O2
demand.
58. Pathophysiology
• The major determinants of myocardial oxygen demand (MVO2)
are
• Heart rate (HR),
• Contractility, and
• Intramyocardial wall tension during systole.
59. Pathophysiology….
• Wall tension is thought to be the most important factor.
• Because the consequences of IHD usually result from increased
demand in the face of a fixed oxygen supply, alterations in MVO2 are
important in producing ischemia and for interventions intended to
alleviate it.
• A clinically useful indirect estimate of MVO2 is the double product (DP),
which is HR multiplied by systolic blood pressure (SBP) (DP = HR× SBP).
60. Grading of Angina Pectoris by the Canadian
Cardiovascular Society Classification System
61. Conditions that exacerbate or provoke angina
• Medications:
• Vasodilators
• Excessive thyroid
replacement
• Vasoconstrictors
• Other medical problems:
• Profound anemia
• Uncontrolled
hypertension
• Hyperthyroidism
• Hypoxemia
• Other cardiac problems:
• Tachyarrhythmias
• Bradyarrhythmias
• Valvular heart disease
(espec. AS)
• Hypertrophic
cardiomyopathy
62. Treatment desired outcome/goal
• The short-term goals of therapy for IHD are to reduce or
prevent angina symptoms that limit exercise capability and
impair quality of life.
• Long term goals are to prevent CHD events such as MI,
arrhythmias, and heart failure and to extend the patient’s life.
63. Treatment desired outcome/goal…
• 1. To abolish the symptoms of an acute attack.
• 2. To prevent or minimize the frequency of symptomatic or
silent myocardial ischaemia.
• 3. To halt or reduce the progression of the underlying
atherosclerosis.
64. Risk-factor modification
• Primary prevention through the modification of risk factors
should significantly reduce the prevalence of IHD.
• Secondary intervention is effective in reducing subsequent
morbidity and mortality.
65. Risk-factor modification…
• Risk factors that can be altered include
• smoking, hypertension, hyperlipidemia, obesity, sedentary
lifestyle, hyperuricemia,
• psychosocial factors such as stress and type A behavior patterns,
and
• the use of certain drugs that may be detrimental, including
progestins, corticosteroids, and cyclosporine.
Because the vasculature is exposed to diastolic pressure for the greater part of the cardiac cycle, it was formerly assumed that DBP was the main marker for the vascular damage that is the main complication of hypertension.
Thus most early trials monitored DBP and aimed to reduce it.
However, following more recent trials (e.g. Syst-Eur), systolic pressure is increasingly being accepted as an equally or more important prognostic indicator. Because both tend to be elevated in hypertension this is not so important.
Factors that may contribute to the development of primary hypertension, include
Humoral abnormalities involving the renin-angiotensin-aldosterone system, natriuretic hormone, or hyperinsulinemia;
A pathologic disturbance in the CNS, autonomic nerve fibers, adrenergic receptors, or baroreceptors;
Abnormalities in either the renal or tissue autoregulatory processes for sodium excretion, plasma volume, and arteriolar constriction;
A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I;
A high sodium intake and increased circulating natriuretic hormone inhibition of intracellular sodium transport, resulting in increased vascular reactivity and a rise in BP; and
Increased intracellular concentration of calcium, leading to altered vascular smooth muscle function and increased peripheral vascular resistance.
Risk factors and aetiological influences in hypertension
catecholamine-secreting tumor derived from chromaffin cells
tumors arising from chromaffin cells of the adrenal medulla
In primary aldosteronism, your adrenal glands produce too much aldosterone, causing you to lose potassium and retain sodium. The excess sodium in turn holds on to water, increasing your blood volume and blood pressure.
Cushing syndrome occurs when your body is exposed to high levels of the hormone cortisol for a long time. Cushing syndrome, sometimes called hypercortisolism, may be caused by the use of oral corticosteroid medication. The condition can also occur when your body makes too much cortisol on its own.
Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between your shoulders, a rounded face, and pink or purple stretch marks on your skin. Cushing syndrome can also result in high blood pressure, bone loss and, on occasion, type 2 diabete
This morbidity and mortality are related to target-organ damage (e.g., cardiovascular events, cerebrovascular events, heart failure, and kidney disease).
Reducing risk remains the primary purpose of hypertension therapy, and the choice of drug therapy is influenced significantly by evidence demonstrating such risk reduction.
Patients with LV dysfunction have a BP goal of <120/80 mm Hg.
Dietary approaches to stop hypertension
Compelling indications for individual drug classes. Compelling indications for specific drugs are
evidenced-based recommendations from outcome studies or existing clinical guidelines. The order of drug therapies
serves only as a general guidance that should be balanced with clinical judgment and patient response. Blood pressure
control should be managed concurrently with the compelling indication.
Ventricular hypertrophy can be caused by pressure overload (e.g., systemic or pulmonary hypertension, aortic or pulmonic valve stenosis) or volume overload (e.g., valvular regurgitation, shunts, high-output states).
Diastolic Dysfunction (Restriction in Ventricular Filling)
Increased ventricular stiffness
Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy,
other examples above)
Infiltrative myocardial diseases (e.g., amyloidosis, sarcoidosis,
endomyocardial fibrosis)
Myocardial ischemia and infarction
Mitral or tricuspid valve stenosis
Pericardial disease (e.g., pericarditis, pericardial tamponade)
FIGURE 14–2. Physiology of the renin-angiotensinaldosterone system. Renin produces angiotensin I from angiotensinogen. Angiotensin I is cleaved to angiotensin
II by angiotensin-converting enzyme (ACE). Angiotensin II has a number of physiologic actions that are detrimental in heart failure. Note that angiotensin II can be
produced in a number of tissues, including the heart, independent of ACE activity. ACE is also responsible for the breakdown of bradykinin. Inhibition of ACE results
in accumulation of bradykinin, which, in turn, enhances the production of vasodilatory prostaglandins.
Angiotensin II, NE, endothelin, aldosterone, vasopressin, and numerous inflammatory cytokines, as well as substances under investigation, that are activated both systemically and in the heart play an important role in initiating the signal-transduction cascade responsible for ventricular remodeling.
FIGURE 14–4. Key components of the pathophysiology of cardiac remodeling. Myocardial injury (e.g., myocardial infarction) results in the activation of a number of hemodynamic and neurohormonal compensatory responses in an attempt to maintain circulatory homeostasis. Chronic activation of the neurohormonal systems results in a cascade of events that affect the myocardium at the molecular and cellular levels. These events lead to the changes in ventricular size, shape, structure, and function known as ventricular remodeling. The alterations in ventricular function result in further deterioration in cardiac systolic and diastolic function, which further promotes the remodeling process.
Relieve symptoms of central and peripheral circulatory congestion
Improve quality of life
Reduce neurohormonal activation
Prevent CHF
Minimize or prevent acute CHF exacerbations
Slow progression of CHF
Increase survival
New therapies should neither worsen symptoms nor shorten life.
Other general measures include moderate sodium restriction, daily weight measurement, immunization against influenza and pneumococcus, modest physical activity, and avoidance of medications that can exacerbate HF.
The DP does not consider changes in contractility (an independent variable), and because only changes in pressure are considered, volume loading of the left ventricle and increased MVO2 related to ventricular dilation are underestimated.
The caliber of the resistance vessels delivering blood to the myocardium and MVO2 are the prime determinants in the occurrence of ischemia.
The normal coronary system consists of large epicardial or surface vessels (R1) that offer little resistance to myocardial flow and intramyocardial arteries and arterioles (R2), which branch into a dense capillary network to supply basal blood flow.
Under normal circumstances, the resistance in R2 is much greater than that in R1. Myocardial blood flow is inversely related to arteriolar resistance and directly related to the coronary driving pressure
Trigger factors, symptoms and signs of an angina attack
Pain is not usually brought on by exertion or emotional stress nor is it relieved by rest; the electrocardiogram (ECG) pattern is that of current injury with ST-segment elevation rather than depression
Primary prevention of ischemic heart disease through the identification and modification of risk factors prior to the initial morbid event would be the optimal management approach and should result in a significant impact on the prevalence of IHD.
ype A and Type B personality theory. ... In this hypothesis, personalities that are more competitive, highly organized, ambitious, impatient, highly aware of time management and/or aggressive are labeled Type A, while more relaxed, less 'neurotic', 'frantic', 'explainable', personalities are labeled Type B
