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CARDIOVASCULAR
SYSTEM
DRUGS ACTING ON THE
CARDIOVASCULAR
SYSTEM
 TOPICS:
• Regulation of Blood Pressure
• Anti-hypertensive Drugs
• Diuretics
• Anti-arrhythmic drugs
• Drugs to Treat Heart Failure
• Vasodilators and Nitric Oxide Synthase
• PG and Related Autocoids
• Lipid-lowering Drugs
• Drugs to treat Blood Disorders
REGULATION OF BLOOD
PRESSURE
Hypertension
- most common cardiovascular disease.

• Sustained arterial hypertension damages

blood vessels in kidney, heart, and brain
and leads to an increased incidence of
renal failure, coronary disease, heart
failure, stroke, and dementia.
 Diagnosis
The diagnosis of hypertension is based on repeated,
reproducible measurements of elevated blood
pressure.

Even mild hypertension (blood pressure 140/90 mm

Hg) increases the risk of eventual end-organ damage.
 SYSTOLIC DIASTOLIC
• Heart contraction: the • Expansion of heart on
contraction of the each beat: the rhythmic
heart, during which expansion of the
blood is pumped into chambers of the heart
the arteries. at each heartbeat,
during which they fill
with blood.
Etiology of Hypertension
• Patients in whom no specific cause of
hypertension can be found are said to
have essential or primary hypertension.

• Patients with a specific etiology are said

to have secondary hypertension.
• In most cases, elevated blood pressure is associated
with an overall increase in resistance to flow of
blood through arterioles, whereas cardiac output is
usually normal.

• Elevated blood pressure is usually caused by a

combination of several (multifactorial)
abnormalities.
• Epidemiologic evidence points to genetic factors,
psychological stress, and environmental and
dietary factors (increased salt and decreased
potassium or calcium intake) as contributing to
the development of hypertension.
• According to the hydraulic equation

– arterial blood pressure (BP) is directly

proportionate to the product of the blood
flow (cardiac output, CO) and the
resistance to passage of blood through
precapillary arterioles (peripheral
vascular resistance, PVR):

BP = CO × PVR
 Regulation of cardiac output and peripheral
vascular resistance, exerted at three anatomic
sites:
arterioles
postcapillary venules (capacitance vessels)
heart
kidney
Normal Regulation of Blood Pressure
A. Short term
1. Baroreceptor Reflex
2. Chemoreceptor Reflex
3. Hormones: Epinephrine and
Norepinephrine
ANP
ADH
B. Long Term
1. Renin Angiotensin Aldosterone(RAA)
System
 Cardiovascular Center in Medulla
Oblongata
Control Center for Heart and Blood Vessels
A. Cardiac Center
Autonomic control of the Heart
-Cardioaccelatory center:
sympathetic
- Cardioinhibitory center:
parasympathetic
 B. Vasomotor Center

Autonomic control of blood vessels

Stimulation of vasomotor center

Sympathetic: Vasoconstriction

Inhibition of the vasomotor

Center: Vasodilation
Baroreceptor reflexes
• Pressure receptor

• Responsible for rapid, moment-to-

moment adjustments in blood pressure.

• Located in the Carotid sinus and the

Aortic arch.
 Chemoreceptors:
receptors that are
responding to Chemical
Changes in the Blood
Peripheral Chemoreceptors
in the aortic and carotid bodies
Monitor blood O2, CO2, and pH.

Central Chemoreceptors
in the medulla monitor mainly
pH of CSF (which is affected by CO2)
 EFFECT OF HORMONES

EPINEPHRINE AND
-produced by the Adrenal Gland NOREPINEPHRINE

When are they produced?

- Sympathetic stimulation to the brain and the nerves,

information is going to travel very quickly to the adrenal medulla
and INCREASE its secretion of those 2 hormones which will
INCREASE the cardiac output exactly like the sympathetic
stimulation.
Hormones: Atrial Natriuretic Peptide (ANP)
• Released by cells of atria in response to
high BP and high blood volume.

• Lowers blood pressure by causing

vasodilation and promoting loss of
sodium and water in urine.
Hormones: Antidiuretic Hormone (Vasopressin)
• Produced by hypothalamus. Stored in
Posterior pituitary gland.

• Increased release by posterior pituitary

gland in response to decreased BP and
decreased blood volume.
• Promotes water reabsorption by
kidneys

• Vasoconstriction of vessels

• Will result in restoring BP back to

normal.
 Renal Response to
Decreased Blood
Pressure

Kidney
-Primarily responsible for long-term blood
pressure control.
Drugs to Treat Heart Failure
HEART FAILURE

- occurs when cardiac output

is inadequate to provide the
oxygen needed by the body.
2 types of Heart Failure:

• Systolic – reduced pumping action

(decrease contractility)

• Diastolic – stiffening and loss of

relaxation (decrease amount of blood
entering the heart)
Signs and symptoms of heart failure:
• Tachycardia
• Decreased exercise tolerance
• Shortness of breath
• Cardiomegaly (abnormal
enlargement of the heart)
Goals of treatment:

• Reduce symptoms and slow

progression

• Manage acute episodes

Control of Normal Cardiac Contractility
• Calcium is needed for muscle contraction.

• Contraction results from the interaction of

activator calcium (during systole) with the
actin-troponin-tropomyosin system, thereby
releasing the actin-myosin interaction.

• Activator Calcium is released from

sarcoplasmic reticulum(SR).
Pathophysiology of Heart Failure
• Cardiac output is usually below the
normal range (“low-output” failure).

• Systolic dysfunction, with reduced

cardiac output and significantly
reduced ejection fraction is typical
of acute failure.
• Diastolic dysfunction often occurs as a
result of hypertrophy and stiffening of
the myocardium, and although cardiac
output is reduced, ejection fraction may
be normal.
• “High-output” failure is a rare form
of heart failure.
- can result from
hyperthyroidism, beriberi, anemia,
and arteriovenous shunts.
• Decreased exercise tolerance with rapid
muscular fatigue is the major direct
consequence of diminished cardiac
output.

• Neurohumoral (extrinsic) compensation

involves two major mechanisms the
sympathetic nervous system and the
renin-angiotensin-aldosterone hormonal
response.
• The baroreceptor reflex appears to be
reset, with a lower sensitivity to arterial
pressure, in patients with heart failure.

• Vascular tone is further increased by

angiotensin II and endothelin.

• Vasoconstriction increases afterload,

which further reduces ejection fraction
and cardiac output.
• Excessive β activation can lead to leakage
of calcium from the SR via RyR channels
and contributes to stiffening of the
ventricles and arrhythmias.

• Increased angiotensin II production

leads to increased aldosterone secretion
(with sodium and water retention), to
increased afterload, and to remodeling of
both heart and vessels.
• The most obvious intrinsic compensatory
mechanism is myocardial hypertrophy. The
increase in muscle mass helps maintain
cardiac performance.

• Remodeling is the term applied to dilation

(other than that due to passive stretch) and
other slow structural changes that occur in
the stressed myocardium.
Pathophysiology of Cardiac Performance
Cardiac performance is a function of four
primary factors:
1) Preload – amount of stretching of the
ventricles
2) Afterload – resistance offered by the artery
3) Contractility – strength of muscle
contraction
4) Heart rate – major determinant of cardiac
output
DIGITALIS
Cardiac glycoside: Digoxin (Lanoxin)

MOA: Inhibit Na+/K+-ATPase

Primary Indications:
Control the rate of Ventricular
response in atrial fibrillation
Useful in Pregnant patient with CHF
• Mechanical EFFECTS:
(Ϯ) Inotropism
(contraction of heart muscles)
Intracellular Ca dromotism
Decrease conduction
velocity in the AV node
• Electrical EFFECTS:
Decrease in the refractory period
of atrial muscles
Increase in the refractory period
of the AV node
Increase in the automaticity of
atrial tissues and the AV node
Conditions that may augment the
Effects of Digitalis Glycosides:
• Hypokalemia
• Hypomagnesemia
• Hypercalcemia (concurrent administration
of calcium gluconate)
• Hypoxia (reduced oxygenation of
myocardial tissues)
SIDE EFFECTS
HEART:
Bradycardia, Arrhythmia
NON-CARDIAC:
Nausea, Vomiting, Ophthalmic effect
(blurring of vision)
or Xanthopsia
TOXICITY
• GI: Most common site of Digitalis Toxicity
Digitalis binding antibodies
 K Supplements- are given if the patient is
hypokalemic
 Cholestyramine- capable to bind to
digitalis glycosides
 Fab-Fragment- for suicidal overdose with
Digoxin
DRUG INTERACTION
• Quinidine
- decrease the renal clearance of Digoxin
• Na-K pump
- affected by Digitalis Glycosides and
Oabain
• Contraindicated in patients with Wolff-
parkinson- white syndrome and atrial
fibrillation
Other Positive Inotropic Drugs Used
In Heart Failure
• Bipyridines:
Inamrinone and Milrinone
- Phosphodiesterase isozyme 3 (PDE-3)
inhibitors.
* inhibition of phosphodiesterase =
cAMP
contractility
vasodilation
SIDE EFFECTS:
Arrhythmia, Hypersensitivity, Thrombocytopenia
 TOXICITY: Arrhythmias
Interaction: Additive with
• Beta1 Agonist:
other sympathomimetics
Dobutamine
- parenteral drug
cardiac output with a ventricular filling
pressure
Dopamine
-3, 4- dihydroxyphenylethylamine
- acts directly as Alpha and Beta receptors
- used to treat Hypotension
INVESTIGATIONAL POSITIVE
INOTROPIC DRUGS
• Istaroxime – a steroid derivative that
increases contractility by inhibiting Na+/K+-
ATPase.
• Levosimendan – phosphodiesterase
inhibitor/calcium sensitizer.
• Omecamtiv mecarbil - an investigational
parenteral agent that activates cardiac myosin
and prolongs systole without increasing
oxygen consumption of the heart.
 Drugs without positive inotropic
effects used in heart failure
• * These agents are the first-line
therapies for chronic heart failure
Diuretics (preload unloaders)
MOA: reduce venous pressure & ventricular
TOXICITY: Hypovolemia, Hypokalemia, preload.
Orthostatic Hypotension, Ototoxicity,
Sulfonamide allergy Furosemide
- Drug of choice in Heart Failure
TOXICITY: Hyperkalemia, Spironolactone & Eplerenone
antiandrogen actions - aldosterone antagonist
 TOXICITY:
Cough, Hyperkalemia, • ACE inhibitors
Angioneurotic edema
Captopril = peripheral
resistance, afterload
INTERACTION:
ADDITIVE with other = salt and water retention,
angiotensin preload
antagonists
 TOXICITY:
Hyperkalemia and • Angiotensin receptor blockers
Angioneurotic edema
- should be considered
INTERACTION: inpatients intolerant of ACE inhibitors
ADDITIVE with other because of incessant cough.
angiotensin antagonists Candesartan – was beneficial when
added to an ACE inhibitor.
TOXICITY: • Renin Inhibitor
Angioedema, Renal Aliskiren – for hypertension and
impairment, Dry cough heart failure
and rashes
-add on to ACE-Inhibitors/ ARB
• Vasodilators
- provide a reduction in preload
or reduction in afterload, or both.

- long term use of Hydralazine

(afterload) and Isosorbide Dinitrate
(preload) can also reduce damaging
remodeling of the heart.
 TOXICITY:
Renal Damage and • Nesiritide –Activates BNP receptors,
Hypotension
cGMP, causes diuresis.

• Sacubitril- a prodrug that is metabolized

to an active neprilysin inhibitor plus an
ARB.
• Bosentan &Tezosentan – orally active
competitive inhibitors of endothelin.
 TOXICITY:
• Bronchospasm
• Beta-Adrenoceptor Blockers: • Bradycardia
Bisoprolol, Carvedilol, • Atrioventricular
shock
Metropolol and Nebivolol
• Acute cardiac
Slows heart rate and Decompensation
Allow more time to fill with blood
Reduces blood pressure
Reduces heart failure
mortality