Pharmacology–I

PHL-313

Drugs acting on the Cardiovascular

System

Dr. Hassan Madkhali

Assistant Professor
Department of Pharmacology
E mail: [email protected]
 Drugs acting on the CVS
• The drugs having their primary action on heart
or blood vessels, or those used primarily for
treatment of cardiovascular disorder.

• These drugs include:

– Cardiotonic Drugs
– Antihypertensive Drugs
– Diuretics Drugs
– Antiarrhythmic Drugs
 CVS
overview

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What is the Cardiovascular System (CVS)?

· The CVS (known also as the circulatory system or the

vascular system) is is an organ system that is consist of
three parts the heart, vessels , and the blood (~5
L/min).

· The heart works as a pump that pushes blood

through the vessels to the body’s organs, tissues, and
cells.

· The blood delivers nutrients (including amino acids

and electrolytes), oxygen, carbon dioxide, hormones,
and blood cells to and from the cells in the body.
 What are the functions of the CVS?

CVS
functions

Transportatio Protection &

Pump blood Regulation
n Hemostasis

The heart is Transport of Regulation include Clotting (protects

pump the substances including Hormonal (blood against
blood Respiratory (RBC, O2 carries hormones to blood loss) and
throughout the and CO2), Nutritive target tissues), and Immune (white
circulatory (absorbed products of Temperature (by blood cells
system.. digestion), and diversion of blood protect against
Excretory (Metabolic from deeper to more many pathogens
wastes such as urea, superficial that cause
excess water and ions, cutaneous vessels several disease.
and others) or vice versa).
Anatomy of the Heart
Blood
circulation:
HeartArteries Arterioles
 
VeinsVenules Capillaries
 What are cardiovascular diseases?
• Cardiovascular diseases (CVDs) are a group of diseases of the
heart and blood vessels including coronary heart disease,
cerebrovascular disease, peripheral arterial disease, rheumatic
heart disease, congenital heart disease and deep vein thrombosis
and pulmonary embolism.

• Statistically, CVDs considered as number 1 cause of death globally

(about 17.5 million people died from CVDs in 2012, representing
31% of all global deaths).

• Early detection and management of CVDs are needed for

individuals having these diseases or at high cardiovascular risk (due
to the presence of one or more risk factors such as coronary artery
disease, hypertension, obesity and diabetes).
 Prevalence of CVD in Saudi Arabia

Proportional mortality (% of total deaths,

Age-standardized death rates all ages, both sexes)

Source: World Health Organization - Noncommunicable Diseases (NCD) Country Profiles, 2014.
Cardiotonic Drugs
 Heart Failure (HF)
• Heart failure: it is the inability of the heart to meet the
metabolic requirements of the peripheral system due to an
inadequate contractility.
• Results in rise in venous blood pressures which then lead to
impair fluid drainage from the tissues and produce a variety
of serious clinical effects:
• Right side HF: causes lower limb edema. Blood pooling
in the lower extremities
• Left side HF: produces pulmonary edema and respiratory
distress
-There are two types of left-side heart failure:
• Systolic failure: The left ventricle loses its ability to contract normally.
The heart can't pump with enough force
• Diastolic failure: The left ventricle loses its ability to relax normally.
The heart can't properly fill with blood
Heart Failure Pathophysiology Comparison
 Heart Failure Manifestations Comparison
Manifestation of Left side HF Manifestation of right side HF
• External & nocturnal • Ascites
dyspnea • Gastrointestinal
• Blood-tinged sputum disorders
• Orthopnea • Liver & spleen
• Cough enlargement
• Cyanosis • Distended jugular veins
• Decrease urinary output • Elevated venous
• Rale (abnormal lung pressure
sound) • Dependent edema (?)
• Fatigue • Fatigue
 Chronic vs. Acute Heart Failure
• Chronic heart failure: symptoms appear slowly
over time and worsen gradually.
• Acute heart failure: develops suddenly and
symptoms are initially severe. It either follows a
heart attack that has caused damage to an area
of your heart or caused by a sudden lack of
ability by the body to compensate for chronic
heart failure.
• Compensation: adjust to the effects of heart
failure in the short term followed by enlargement
of the heart and reducing its pumping ability.
• Compensation by nervous system (increase sympathetic activity)
• Compensation by hormones release (increase release of renin,
angiotensin and aldosterone).
 Common HF Risk Factors
• Coronary Artery Disease (CAD): narrowed arteries may limit the heart
supply of oxygen-rich blood, resulting in weakened heart muscle.

• Cardiomyopathy: heart muscle diseases.

• Myocardial Infarction: irreversible death (necrosis) of heart muscle

secondary to prolonged lack of oxygen supply (ischemia)

• Hypertension: the heart works harder than it has to.

• Diabetes: high blood glucose can damage parts of the body such as the
heart and blood vessels. This damage weakens the heart, often leading to
heart failure).

• Obesity: people who are obese have a higher risk of developing heart
failure (heart can't pump enough blood to meet your body's needs).
 Cardiotonic Drugs

• Drugs that increase force of contraction of heart

• The cardiotonics are drugs used to increase the

efficiency & improve the contraction of the heart
muscle, which leads to improved blood flow to all
tissues of the body
 Drug groups commonly used in
management of Heart Failure
• Cardiac Glycosides
• Digitoxin, Gitoxin, Digoxin
• Phosphodiesterase 3–Inhibitors
• Milrinone (Primacor), Amrinone (Inocor)
• β1-adrenoceptors agonists
• Dobutamine, dopamine, Epinephrine
• Diuretics
• Carbonic anhydrase inhibitors: Acetazolamide
• Loop diuretics: Furosemide
• Thiazides: Hydrochlorothiazide
• Potassium Sparing Diuretics: Amiloride,
Spironolactone
 Drug groups commonly used in
management of Heart Failure
• ACE inhibitors:
Captopril (Capoten), Enalapril (Vasotec), ?
Enalaprilat (Vasotec IV)
Fosinopril, Monopril, Ramipiril (Altace)
• AT-II antagonists [Angiotensin II receptor blockers (ARBs) ]
Losartan (Cozaar), Valsartan (Diovan)
• β-adrenergic receptor antagonists
Propranolol, carvedilol
• Aldosterone antagonists
Spironolactone, Eplerenone
• Vasodilators
Nitrates/Nitrites: Nitroglycerin, Hydralazine (Apresoline),
Sodium Nitroprusside (Nipride)
 HF Treatment
A) Drug
Chronic heart failure Acute heart failure
• Digoxin • Diuretics
• Beta-agonists • PDE3 inhibitors
• Diuretics • vasodilators
• ACE inhibitors
• AT-II antagonists
• Aldosterone antagonists

B) Lifestyle modifications
• Reduce cardiac work (Generally)
• Exercise-based program of cardiac
rehabilitation
• Smoking cessation
• Rest
• Weight loss
• low Na+ diet
 Cardiac Glycosides
• Cardiac glycosides slow the heart rate and increase the force
of contraction (=positive inotrope)
• Digitalis is the drug of choice for heart failure associated with
atrial fibrillation
• Increases cardiac output, Increase urine output, Decreased
renin release

Sources: Glycosides:
1. D. purpurea - Digitoxin, Gitoxin, Gitalin
2. D. lanata - Digitoxin, Gitoxin, Digoxin
Cardiac glycosides

The cardiac glycosides

inhibit the Na+/K+-
ATPase pump, which
causes an increase in
intracellular Na+ leading
to slowing of
the Na+/Ca++-exchanger
and ultimately increase in
intracellular Ca++.
 Pharmacological Action

• Cardiac Effects: Digitalis direct affects on myocardial contractility &

electrophysiological properties.
• Positive inotropic effect: increase the force of contraction of the
normal and failing myocardium.
• Negative chronotropic effect: cardiac glycosides slow down the heart
rhythm.
• Positive tonotropic effect: reduce the size of the heart.
• Positive bathmotropic effect: increase the excitability of the
myocardium, which can cause arrhythmias (extrasystole, ventricular
fibrillation).
• Other Effects:
• Indirect vasodilation (little effect on the BP)
• Increase diuresis, secondary to improved circulation.
• Induce contractions of intestinal muscles
 Pharmacokinetic of Digoxin

• Amongst various cardiac glycosides used, digoxin &

digitoxin are very common.
– Available IV & Orally
– Oral ABS: Depend on formulation (Soft Gelatin Caps > Elixir >
Tablets )
• Absorption is confined to small intestine.
• Digoxin absorption is variable (60-80%), digitoxin is
absorbed almost (100%).
• Digitoxin is the most lipid soluble, digoxin is relatively polar.
• Digitoxin metabolized in liver, partly to digoxin & undergoes
some enterohepatic circulation.
• Digoxin excreted by kidney
 ADRs of Digoxin
• Central nervous system reaction:
Headache; weakness; drowsiness; visual
disturbance,
• Cardiovascular and gastrointestinal reactions:
Arrhythmias; gastrointestinal upset; anorexia,
Nausea, Vomiting,
• Rare ADR
Eosinofilia, skin rashes, gynecomastia
 Preparation
Digoxin
0.25 mg tab,
0.05 mg/ml pediatric elixir,
0.5 mg/2ml inj.
Digitoxin
0.1 mg tab

Uses
• Chronic heart failure
• Atrial fibrillation (will discussed in antiarrhythmic drugs
lecture)
 PDE3 Inhibitor: MOA

Inhibition of type III

phosphodiesterase

↑ intracellular cAMP

activation of protein kinase A

Ca2+ entry Inhibition of Ca2+

through L type sequestration by
Ca channels SR

PDE3 Inhibitor
×
↑ contractility
↑ cardiac output and
↓ peripheral vascular resistance
SR: sarcoplasmic reticulum
 PDE III Inhibitor
• Drug – Amrinone (Inocor) , Milrinone (Primacor)
• Have a positive inotropic effect.
• Cause vasodilatation, decrease BP & decrease preload &
afterload
• ROA: IV
• Effective in patients taking Beta-blockers
• Indications: Used only for short term in acute heart failure and
Unresponsive CHF to other treatment
• ADRs: Arrhythmia, hypotension, thrombocytopenia, GI
Complaint (pain, nausea, vomiting), Liver dysfunction, allergy.
• Long-term use increases the risk of mortality.
• Sudden death secondary to ventricular arrhythmia
 β1 – Agonist
• MOA: Adrenergic stimulation of β1-adrenergic receptors
produces positive inotropic effect.
• Drugs: Dobutamine, Dopamine, Epinephrine
• ROA: IV
• Most widely used, but limited to emergency case due to
cardiogenic, traumatic & hypovolemic shock.
• SE: Restlessness, tremor, headache, cerebral hemorrhage,
cardiac arrhythmias,
• used with caution in patients taking β-blockers, can develop
dobutamine tolerance
• Long-term use increases risk of cardiac arrhythmias,
hypertension and the risk of mortality
 Diuretics: MOA & ADRs
• Diuretics decreases Failing heart pumping function
preload through several
mechanisms: Sodium and water
– diuresis (excretion of retention
water and
electrolytes) Increased intravascular
– vasodilation (loop volume
diuretic: furosemide)

Increased preload
• ADRs :
• Skin rashes
• Hepatic dysfunction
Renin-Angiotensin-Aldosterone system antagonists
Angiotensin Converting Enzyme Inhibitors
• Examples: Quinipril, captopril, enalapril, benaepril
• MOA: Block the conversion of angiotensin I to
angiotensin II, a potent vasoconstrictor. There will be
reduction in blood pressure by vasodilation. This
results in decreased PVR.
• Decreased preload & decreased afterload
• Adverse Effects: Dry cough, hyperkalemia,
Angioedema, Hypotension, Renal insuffiency, Rashes
• Contraindications: Pregnancy – renal failure in
infants, renal impairment.
 Angiotensin II receptor blockers
• They block angiotensin II effect at the angiotensin type 1
receptors. Thus, there is vasodilatation and blood pressure
lowering.
• Has comparable effect to ACE I
• Can be used in certain conditions when ACE I are
contraindicated (angioneurotic edema, cough)
 Therapeutic uses:
• Hypertension, Heart failure,
• Diabetic nephropathy, Myocardial infarction,
• Stroke prevention, Migraine headache
 Adverse effects: Angioedema, Fetal harm, Renal failure
 Examples: Losartan (Cozaar), Valsartan (Diovan), Irbesartan,
Candesartan, Telmisartan, Olmesartan
 Aldosterone Antagonists
Elevated Angiotensin II levels increase production of
aldosterone in the adrenal cortex (~20X increase)
Aldosterone activates mineralocorticoid receptors in
epithelial cells in kidney
aldosterone promotes
Na+ retention, water retention, Mg2+ and K+ loss
increased SNS activity
decreased PSNS activity
myocardial/vascular fibrosis
 Therapeutic Use

• Goal: inhibit aldosterone negative effects in CHF

• Aldosterone receptor antagonists
– spironolactone
– eplerenone
• Reduce mortality in patients with moderate to severe
CHF
• Only use in patients with normal renal function and K+
levels
• Use with K+ sparing diuretic
 Side Effects
hyperkalemia
agranulocytosis
anaphylaxis
hepatotoxicity
renal failure
Spironolactone: gynecomastia, sexual dysfunction
Eplerenone: arrhythmia, myocardial infarct/ischemia
 Vasodilators
• Examples: Hydralazine (Apresoline), Nitroprusside
(Nipride), Nitroglycerine.
• MOA: Vasodilators cause a direct relaxation of vascular
smooth muscle to decrease PVR and lower BP. There are
two types: atreriolar dilators and venous dilators.
• They are usually given with a beta blocker.
• Reduction of afterload by arteriolar vasodilatation
(hydralazine)  reduce LVEDP, O2 consumption, improve
myocardial perfusion,  stroke volume and CO
• Reduction of preload By venous dilation (Nitrate)  ↓ the
venous return ↓ the load on both ventricles.
• Usually the maximum benefit is achieved by using agents
with both action.
 Vasodilators
Nitrovasodilators

NO release

Activate guanylyl cyclase and ↑cGMP

↓Intracellular calcium

Smooth muscle relaxation

-5
Vasodilation

Preload and afterload reduction

Improved cardiac function

 β-adrenergic receptor antagonists
β- blockers were once contraindicated in CHF, as they have the
potential to worsen the condition, studies in the late 1990s showed
their efficacy at reducing morbidity and mortality in CHF.

Carvedilol and sustained-release metaprolol are specifically

indicated as adjuncts to standard ACEIs and diuretic therapy in CHF.

reduce sudden death caused by other drugs

Propranolol: prototype

Carvedilol: combination effects

 Mechanism of Action
β-blockers, in addition to their sympatholytic β1 activity in the
heart, influence the renin/angiotensin system at the kidneys. β
blockers cause a decrease in renin secretion, which in turn reduce
the heart oxygen demand by lowering extracellular volume and
increasing the oxygen carrying capacity of blood.
Prevents development of arrhythmias
 Therapeutic Use
Administered orally
Effective in patients with chronic systolic heart failure
Prevents remodeling and cardiac damage

Side Effects
Cardiac decompensation
Bradycardia
Hypoglycemia
Cold extremities
Fluid retention
Fatigue
Thank you
?