1

CARDIOVASCULAR PHARMACOLOGY

BY:Wondemu E. (B.Pharm)
 Cardiovascular Drugs
2

 Antihypertensive Agents
 Treatment of Angina Pectoris
 Antiarrhythmic Drugs
 Drugs Used in Heart Failure
 Antihypertensive Agents
3

Hypertension (HTN)
 Refers to persistently elevated arterial blood pressure
(BP≥140/90 mmHg)
Etiology of hypertension
 Essential /primary hypertension (>90% of the cases).

 No specific cause/etiology can be identified or may be

genetic
 Secondary hypertension (<10% of the cases)

 Has got specific etiology → there are many potential

secondary causes (co-morbid/ concurrent diseases or
drugs)
 HTN…cont’d

Table: Classification of HTN on the basis of BP

 HTN…cont’d

Target-organ Damage
 As hypertension progresses, target-organ damage may

appear.
 The primary organs involved are the eye, brain, heart,

kidneys and peripheral blood vessels.

 Cardiovascular events, cerebrovascular accidents, and
kidney failure are the primary causes of morbidity and
mortality in patients with hypertension.
 HTN…cont’d
6

Normal Regulation of Blood Pressure

 Arterial blood pressure is due to combination of:

 Cardiac output (CO) and

 Peripheral vascular resistance (PVR)
BP = CO x PVR
 Physiologically BP is maintained by moment-to-moment
regulation of cardiac output and PVR, exerted at 4 anatomic
sites: arterioles, post-capillary venules (capacitance vessels),
heart and kidney (Figure below)
 HTN…Cont’d

Figure: Anatomic sites of BP regulation

 HTN…cont’d
8

 Cardiac output (CO)

 is in turn regulated by heart rate (HR) & stroke volume
(SV)
CO = HR x SV
 Heart rate is a function of:
 Sympathetic (SNS) and vagus nerve activities:

 SNS → ↑HR & ↑myocardial contractility (MC)

 Vagus nerve (PNS) → ↓HR & ↓MC
 Neurohormonal substances

 Angiotensin II
 Vasopressin (ADH)
 HTN…Cont’d
9

 Stroke volume is a function of:

 Venous return which in turn depends on

 Sympathetic activity (α1, α2 receptors)

 Circulating blood volume: depends on fluid intake, fluid
output, fluid distribution
 Myocardial contractility (MC) depends on:
 Sympathetic tone (β1 receptors)
 HTN…Cont’d
10

Peripheral vascular resistance (PVR)

 Is also called total peripheral resistance (TPR)

 is function of:

 Viscosity of blood (hematocrit)

 Length of blood vessels
 Luminal diameter of blood vessels (arterioles)
 From Poiseuille’s equation: for sum of all blood vessels

PVR/TPR = _L · Where, r = radius of blood vessel

η_ L = length of blood vessel
r4 η = viscosity of blood
(function of hematocrit)
 Treatment of hypertension (HTN)
11

Goal of therapy:
 The overall goal of treating hypertension is to reduce

hypertension-associated morbidity and mortality

 These morbidity and mortality are related to target-organ
damage: cardiovascular events, cerebrovascular accidents,
heart failure, and kidney disease
General Approach to Treatment
 Treatment involves:

 Nonpharmacologic therapy: Lifestyle modifications

 Pharmacologic therapy: Drug therapy
 Treatment of HTN…Cont’d
12

I.Nonpharmacologic therapy: Lifestyle modifications

 Prescribed for all patients with prehypertension and

hypertension
 Lifestyle modification involve:

 Weight reduction
 Adopt Dietary Approaches to Stop Hypertension (DASH)
eating plan: diet rich in fruits, vegetables, low-fat dairy
products, and food with ↓saturated & total fat
 Dietary sodium/salt restriction.
 Physical exercise
 Treatment of HTN…Cont’d
13

II. Pharmacologic therapy: Drug therapy

Antihypertensive drug classes
1. Diuretics
 Thiazides
 Loop diuretics
 Potassium sparing diuretics
2. Sympatholytics Drugs
 β-adrenoreceptor antagonists (β-blockers)
 α-adrenoreceptor antagonists (α-blockers)
 Central α2-adrenoreceptor agonists
 Adrenergic neuronal blockers
Treatment of HTN…Cont’d
14

3. Vasodilators
 Hydralazine
 Minoxidil
 Sodium nitroprusside
 Calcium channel blockers (CCBs)
 Diazoxide
 Fenoldopam
4. Drugs affecting the renin angiotensin aldosterone system
(RAAS)
 Angiotensin converting enzyme inhibitors (ACEIs)
 Angiotensin receptor blockers (ARBs)
 Treatment of HTN…Cont’d
15

1. Diuretics
 Affect blood volume by altering sodium & water balance
I. Thiazides: hydrochlorothiazide, metolazone, indapamide,
etc.
II. Loop diuretics: Furosemide, torsemide, bumetadine, etc.
III. Potassium sparing diuretics: amiloride, triamterene,
spironolactone, eplerenone
 Treatment of HTN…Cont’d

16

2. Sympatholytics Drugs
2.1. β-adrenoreceptor antagonists (β-blockers)
A. Non-selective β-blockers: propranolol, nadolol, carteolol
 Inhibit both β1- & β2- adrenergic receptors

 MOA:

 Blockade of β1 in the heart → ↓Heart rate & force

of contraction →↓Cardiac output (CO) →↓BP
 Blockade of β1 in the kidney (juxtaglomerular cells)
→ ↓renin release → ↓angiotensin II
↓PVR
↓BP← CO↓←↓Blood volume ← ↓Aldosterone
 Treatment of HTN…Cont’d
17

Blockade of β2 in vascular smooth muscle →



vasoconstriction (not important for HTN)

 Blockade of β2 in the bronchi of the lung →

bronchoconstriction → aggravation of asthma in asthmatic

patient (not desirable)
 Are contraindicated in patient with asthma

B. Selective β1 blockers: metoprolol, atenolol, bisprolol,

esmolol
 Are selective antagonists of β1-adrenergic receptors
 MOA: Selectively block β1-adrenergic receptors in the heart
& kidney
 Can be used in patient with asthma
 Treatment of HTN…Cont’d
18

2.2. α1-adrenergic receptor antagonists (α1-blockers)

 Include: prazocin, terazocin, doxazocin

 ADRs: postural hypotension, dizzness

2.3. Centrally acting α2-adrenergic receptor agonists

A. Methyldopa (α-methyldopa)

 Clinical Uses:

 Hypertension during pregnancy

B. Clonidine

Clinical Uses:
 Hypertension complicated by renal diseases
ADRs:
 Sedation, postural hypotension, dry mouth
 Treatment of HTN…Cont’d
19

2.4. α/β adrenorececeptor blocking agents: Labetalol,

carvedilol
 MOA: blockade of α1, β1 & β2 adrenoreceptors

 Clinical Uses:

 Labetalol: hypertension of pheochromocytoma &

hypertensive emergency
 Carvedilol: both hypertension and heart failure
 Treatment of HTN…Cont’d
20

2.5. Adrenergic neuron blocking agents: guanethidine,

reserpine
 Prevent release of norepinephrine from the postganglionic
sympathetic neurons
 MOA:
 Guanethidine: taken up by NET & stored in the synaptic
vesicle → leading to depletion of norepinephrine
 Reserpine: inhibition of VMAT → depletion of
norepinephrine store
 Treatment of HTN…Cont’d
21

3. Vasodilators
Directly relax vascular smooth muscles

Used for long-term outpatient therapy of HTN

I. Oral vasodilators: Hydralazine, Minoxidil

A.Hydralazine
Administered orally

Primarily act on arteries and arterioles

Adverse effects: Reflex tachycardia, Nacl & water

retension (via renin release), lupus-like syndrome

 Treatment of HTN…Cont’d
22

B. Minoxidil
 Prodrug & administered orally
 Potent arteriolar dilator
 Adverse effects
 Tachycardia
 Water & salt retention
 Hirsutism
 Treatment of HTN…Cont’d
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II. Parentral vasodilators

 Include: sodium nitroprusside, diazoxide, fenoldopam
A. Nitoprusside: sodium nitroprusside
 Available as parentral preparation(IV)
 Act equally on arterial and venous smooth muscles
Clinical uses:
• Hypertension emergency, cardiac decompensation in acute
myocardiac infarction (MI).
Adverse effects
• Hypotension, tachycardia,

• Cyanide toxicity (antidote → sodium thiosulfate)

 Treatment of HTN…Cont’d
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B) Diazoxide
 Is arteriolar dilator

 Available as parentral prepaation (IV)

C) Fenaldopam:
 Is peripheral dopamine (D1) receptor agonists

 Available as parentral preparation (IV)

Clinical uses
 Hypertensive emergencies (is a rare but life threatening

situation in which the BP>210/150)

 ADRs: Reflex tachycardia, headache & flushing
 Treatment of HTN…Cont’d
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III) Calcium channel blockers (CCBs):

 Besides antihypertensive effects they have also antianginal

and antiarrhythemic effects

 MOA: inhibition of calcium influx into arterial smooth

muscle → relaxation of arteriolar smooth muscle →↓PVR

→↓BP
 Contraction of vascular smooth muscle is dependent on the

free intracellular Ca2+, inhibition of transmembrane

movement of Ca2+ through voltage sensitive Ca2+ channels
by CCBs can decrease the total amount of Ca2+ that reaches
intracellular sites.
 Treatment of HTN…Cont’d
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Classes of CCBs
 CCBs fall into two classes

 Non dihydropyridines

A. Verapamil
 Verapamil : affects both cardiac & vascular smooth muscle (the

least selective of any CCB)

B. Diltiazem
 Diltiazem: affects both cardiac and vascular smooth muscle cells

 Dihydropyridines:

 First-generation: nifedipine
 Second-generation agents: amlodipine, felodipine, isradipine,

nicardipine , and nisoldipine

 Treatment of HTN…Cont’d
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 All dihydropyridines have greater affinity for vascular

calcium channels than for calcium channels in the heart
→are attractive in treating HTN compared to other CCBs
ADRs:
 Peripheral edema and headache with DHCCB

 Constipation with Diltiazem, Headache with Verapamil and

tachycardia with both

Clinical uses
 Treatment of HTN, angina & cardiac arrythemia
 Treatment of HTN…Cont’d
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NB:
 Vasodilators work best in combination with other

antihypertensive drugs that oppose the compensatory

cardiovascular responses.
 Vasodilators are usually used in combination with
diuretics and β-blockers
 Treatment of HTN…Cont’d
29

4) Drugs affecting the renin angiotensin aldosterone

system (RAAS)
 Fall into three classes
 Angiotensin converting enzyme inhibitors (ACEIs)
 Angiotensin receptor blockers (ARBs)
 Renin antagonists: aliskerin
30

Figure: sites of action of drugs interfering with the RAAS

 Treatment of HTN…Cont’d
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4.1. Angiotensin converting enzyme inhibitors (ACEIs)

 Include: enalapril, lisinopril, captopril, quinapril

Clinical uses
 Hypertension (complicated by diabetes mellitus)

 Heart failure

 MI

ADR/toxicity
 Hypotension, acute renal failure, hyperkalemia, angioedema

Drug interaction
 Potassium supplement & potassium sparing diuretics → aggravate

hyperkalemia
 NSAIDs → block bradykinin-mediated vasodilation
 Treatment of HTN…Cont’d
32

Contraindication
 Avoid use with use with potassium sparing diuretics →

exacerbates hyperkalemic toxicity

 Avoid use during the 2nd and 3rd trimesters → leads to fetal

hypotension
4.2. Angiotensin II receptor blockers (ARBs)
 Are alternative to ACEIs

 Include: losartan, valsartan, candesartan, irbesartan,

telmisartan, olmesartan & eprosartan

 MOA: block angiotensin II type 1 (AT1) receptor

Arteriolar & venules dilation ↓aldosterone secretion

 Treatment of HTN…Cont’d
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 ADRs: Hypotension, hyperkalemia, nephrotoxicity,

 Drug interaction: avoid concurrent use with K+-sparing

diuretics
 Contraindication: pregnancy

4.3. Renin inhibitor: aliskiren

MOA: blockade of conversion of angiotensinogen into
angiotensin I by inhibiting renin
ADRs
 Angioedema, hypotension

Contraindication
 Pregnancy
34

Antianginal Drugs
 Angina pectoris

35

 Angina pectoris is the severe chest pain that occurs when coronary

blood flow is inadequate to supply the oxygen required by the heart

 The primary cause of angina pectoris is an imbalance between the

oxygen requirements of the heart and the oxygen supplied to it via

the coronary vessels.

 The myocardial oxygen demand increases when there is an increase

in heart rate, contractility, arterial pressure, or ventricular volume

 Cont…

36

 Is a characteristic sudden, severe, pressing chest pain

 Radiate to the neck, jaw, back, and arms.
 It is caused by insufficient coronary blood flow to meet the
oxygen demands of the myocardium, leading to ischemia.

Types of Angina

1. Stable or typical angina,

2. Unstable angina, and

 Cont…
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A. Stable angina (typical angina pectoris)

 Is the most common form of angina
 Caused by the reduction of coronary perfusion
 Due to a fixed obstruction produced by coronary atherosclerosis.
 Symptoms precipitated by
 Physical activity,
 Emotional excitement, or
 Any other cause of increased cardiac workload.
 It is promptly relieved by rest or nitroglycerin (vasodilators)
 Cont…
38

Drug Treatment
 Organic nitrates, β-blockers, and Calcium-channel blockers.
 They Lower oxygen demand of the heart by affecting:
 Blood pressure,
 Venous return,
 Heart rate, and contractility
 Cont…
39

B. Unstable angina
 Chest pains occur with increased frequency and
 The symptoms are not relieved by rest or nitroglycerin.
 Unstable angina requires hospital admission and More
aggressive therapy to prevent death and progression to
myocardial infarction
 Cont…
40
C. Prinzmetal's or variant or vasospastic angina
 Is an uncommon pattern of episodic angina
 Occurs at rest and is due to coronary artery spasm
 Angina attacks are unrelated to Physical activity, Heart rate, or Blood
pressure
 Responds promptly to coronary vasodilators, such as

 Nitroglycerin and
 Calcium-channel blockers.
N.B. Beta blockers cannot be used in Prinzmetal's type of
angina pain.
 Cont…
41

Organic Nitrates:

Examples- Iosorbide dinitrate and Iosorbide mononitrate

Nitroglycerine - sublingual tablet

 They cause:

 Rapid reduction in myocardial oxygen demand

 Followed by rapid relief of symptoms.

 Effective in the treatment of all types of angina

 Cont…
42

Adverse effects

 Headache- the most common

 Postural hypotension( High dose),

 Facial flushing, and tachycardia.

 Sildenafil potentiates the action of the nitrates

(Contraindicated because of drug interaction)

 Cont…
43

β-Adrenergic Blockers:
 Decrease the oxygen demands of the myocardium
 Reduce the work of the heart by decreasing:
Heart rate, Contractility, Cardiac output, and BP
E.g. Propranolol –Prototype
Metoprolol or Atenolol
 Contraindicated in:

Patients with asthma,

Severe bradycardia,

Peripheral vascular disease, or

 Cont…
44

Calcium-Channel Blockers:

 Verapamil- Mainly affects the myocardium,

 Nifedipine- Exerts a greater effect on smooth
muscle

in the peripheral vasculature.

 Diltiazem -Intermediate in its actions
45

ANTI ARRHYTHMIC
DRUGS
Anti Arrhythmic drugs
46

Def: Arrhythmia is defined as loss of cardiac rhythm,

especially irregularity of heart beat.

Supraventricular Arrhythmias

Atrial fibrillation: is an extremely rapid (400 to 600 atrial

beats/min) and disorganized atrial activation.  

Atrial flutter: is characterized by rapid (270 to 330 atrial

beats/min) but regular atrial activation.

 Cont…

47

 Patients may experience dizziness or acute syncopal episodes;

 Symptoms of heart failure;
 Anginal chest pain; or, pressure sensation during the tachycardia
episode

Bradyarrhythmias
 Heart rate less than 60 beats/min

 Patients experience symptoms associated with hypotension

such as dizziness, syncope, fatigue, and confusion

 Pharmacotherapy of cardiac arrhythmias
48

 Antiarrhythmic drugs are used to:

Prevent or
Correct cardiac arrhythmias (tachyarrhythmia)
Classified into:
Class (I):
 Sodium channel blockers, include:
Quinidine, Lidocaine, Phenytion, Flecainide, etc.
 Slow conduction velocity,
 Prolong refractoriness, and
 Decrease the automatic properties of sodium-dependent conduction tissue.
 Cont…
49

Class (II):

 Beta adrenergic blockers,include:Propranolol, Atenolol, etc.

 Are most useful in Ventricular tachycardias

 Also helpful in slowing ventricular response in

Atrial tachycardias (E.g.,atrial fibrillation) by their effects

on the AV node.
 Cont…
50

Class (III):
 Potassium channel blockers E.g. Amiodarone,
Bretylium.
 Specifically prolong refractoriness in atrial and
ventricular fibers
 Common effect of delaying repolarization by
blocking potassium channels
 Cont…
51

Class (IV):
 Calcium channel blockers E.g. Verapamil, Diltiazem etc.
 Inhibit calcium entry into the cell,
 Slows conduction,
 Prolongs refractoriness, and
 Decreases SA and AV nodal automaticity
 52

DRUGS USED IN HEART FAILURE

 Drugs Used in Heart Failure
53

Heart failure is a complex clinical syndrome resulting from



structural or functional disorders that impair the ventricles

ability to fill with or eject blood
May involve either ventricle or both


Cardiac output (CO) is usually below the normal range



Pathophysiology of Heart Failure

Systolic dysfunction: results from myocardial infarction


 ↓CO and ↓ejection fraction (< 45%)

Diastolic dysfunction: often occurs due to hypertrophy and



stiffening of the myocardium

↓CO but normal ejection fraction
 Cont....
54

Heart Failure and Compensatory mechanisms

 Compensation involves two major mechanisms:

 The sympathetic nervous system →the baroreceptor

reflex
 The renin-angiotensin-aldosterone system

Effects of intrinsic compensation

 ↑Contractility

 ↑heart rate

 ↑preload

 ↑afterload


 55

Figure: Some compensatory responses that occur during congestive heart failure
Principles of treatment of CHF
56

1. Increased pumping capacity: using positive inotropes like

cardiac glycosides
2. Reduction of preload and afterload: using vasodilators,
ACEI
3. Reduce volume overload: using diuretics, ACEI
 I. Cardiac glycosides
57

Digoxin & digitoxin

 Are first line therapy for CHF with atrial fibrillation
 ↑myocardial contractility (+ve inotrope) & ↓heart rate (-ve
chronotrope)
MOA:
 Indirect effect: enhances vagal tone
 ↑ vagal tone → ↑Ach release → opening of K+ channel
→ closing of L-type Ca2+ channel → ↓Heart rate (-ve
chronotropic effect)
 Cont....
58

Clinical uses
 Heart failure with atrial fibrillation

ADRs/toxicity
 Has narrow therapeutic index

 Nausia, vomiting & anorexia

 Cardiac toxicity
II. Vasodilators for CHF
59

A. Nitrates
 Indirect vasodilators: e.g. nitric oxide, nitroglycerine
 Dilation of coronary arteries => improved coronary

circulation
ADRs/toxicity
 Hypotension

 Tachycardia

 Peripheral edema
 Cont....
60

B. Direct vasodilators
e.g. hydralazine, nitroprusside
MOA:
 Relaxes smooth muscle of arterioles and sometimes veins

→ ↓peripheral vascular resistance →↓afterload (mainly) &

↓preload
ADRs/toxicity
 Edema =>should be given with diuretics

 Tachycardia => should be given with β-blockers

III. ACEI/ARB
61

 ↓afterload by reducing peripheral resistance

 ↓preload by reducing salt and water retention via inhibition
of aldosterone secretion
 ACEI: enalapril, lisinopril, captopril, quinapril
 ARB: losartan, valsartan, candesartan, etc
IV. Diuretics
62

 Thiazides
 Loop diuretics
 Potassium sparing diuretics
 Thiazides

63

 Differ from each other in potency & duration of action

 Prototype: hydrochlorothiazide
 Other thiazides: bendroflumethiazide, chlorothiazide,
hydroflumethiazide, etc.
 Thiazide-like diuretics: chlorthalidone, indapamide,
metolazone
 Thiazides…Cont’d
64

Indications
1) Hypertension

2) Heart failure

3) Nephrolithiasis (kidney stones) → hypercalciuria

4) Nephrogenic diabetes insipidus

5) osteoporosis

Toxicity
 Hypokalemic Metabolic Alkalosis

 Hyperuricemia

 Hyponatremia

Contraindications
 Cirrhosis, borderline renal failure & heart failure
 Loop Diuretics
65

 Are the most efficacious diuretic agents currently available

 Prototypical drugs: furosemide & ethacrynic acid
 Other loop diuretics: bumetanide and torsemide
 Loop diuretics selectively inhibit NaCl reabsorption in the
thick ascending LH
 Loop Diuretics…Cont’d
66

 Pharmacological effects.
 ed urinary excretion of Na+ & Cl- (25% of filtered)
 ed excretion of Ca++ and Mg++
 ed excretion of HCO3- & Phosphate – Furosemide
 Some carbonic anhydrase inhibition activity
 ed excretion of K+
 Pharmacokinetics
 All are orally effective (bioavailability 60-100%)
 All are highly protein bound: eliminated in the urine by both glomerular
filtration and tubular secretion (organic acid secretory system in proximal
tubule)
 Elimination: metabolism and also renal as unchanged
 Adverse effects
67

 Most adverse effects are due to abnormalities of fluid

and electrolyte balance
 Hyponatremia and/or
hypovolemia—hypotentension/circulatory collapse
 Hypokalemic, hypochloremic alkalosis—cardiac
arrhythmias if K+ is not supplemented
 Hypomagnesemia

 Hypocalcemia
 Ototoxicity
 Contd

68

 Hyperuricemia—rarely leading to gout

 Hyperglycemia —rarely precipitating DM
 Hyperlipidemia --↑LDL, ↑triglycerides, ↓HDL
 Hypersensitivity reactions
 GI disturbances
 Bone marrow depression
 Drug interactions
69

 Aminoglycosides (synergism of ototoxicity caused by

both drugs)
 Anticoagulants (increased anticoagulant activity)
 Digitalis glycosides (increased digitalis induced
arrhythmias
 Lithium (increased plasma level of lithium)
 Propranolol (increased plasma level of propranolol)
 cont.
70

 Sulfonylureas (hyperglycemia)
 Cisplatin (increased risk of diuretic induced
ototoxicity)
 NSAIDs (blunted diuretic response)
 Thiazide diuretics (synergism of diuretic activity)
 Therapeutic uses
71

 Acute pulmonary edema

 Chronic congestive heart failure
 Hypertension (reserve drugs)
 Edema of nephrotic syndrome
 Management of poisoning (forced diuresis)
 Treatment of hypercalcemia (combined with saline to
prevent volume depletion)
 Potassium Sparing Diuretics
72

 Spironolactone and eplerenone:

 Are competitive antagonist of aldosterone
 eplerenone has greater selectivity for the
mineralocorticoid /aldosterone receptor than
spironolactone → has considerably fewer adverse effects.
 Amiloride and triamterene:
 are direct inhibitors of Na+ influx
 Triamterene is extensively metabolized in the liver → has
a shorter half-life → warranting more frequent dosing
 Amiloride is not metabolized → less frequent dosing
 Cont’d…
73

Clinical Indications
 As adjunct therapy with thiazides or loop diuretics (wastage

of K+)
 Ascites

 Heart failure

Toxicity
 Hyperkalemia

 Hyperchloremic metabolic acidosis

 Gynecomastia

 Kidney Stones
 Cont’d…
74

Contraindications
 Oral K+ administration

 Chronic renal insufficiency

 Concomitant use with agents blunting the RAAS

(ARB/ACEI)
 Exacerbates hyperkalemia

 Liver disease → carefully dose adjustment

 V. Beta-adrenoceptor blockers (β-blockers)
75

 Include: carvedilol, metoprolol, atenolol

 Importance in heart failure: prevent the changes due
to chronic activation of the sympathetic nervous
system
 decrease the heart rate and inhibiting the release of
renin
 Decrease cardiac remodeling, hypertrophy & cell
death