CV Pharmacology

1. Antihypertensive Agents
 Learning Objectives

• On completion of this topic, you will be able to:

– List the various types of drugs used to treat HTN
– Discuss the general drug actions, uses, ADRs, C/Is,
precautions, & interactions of the
antihypertensive drugs

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 Hypertension
 The most common chronic CV disease

 Is a sustained/persistent abnormal elevation of BP

[Systolic BP, Diastolic BP, or both] .
 Is the level of BP at which there is risk of

 CV morbidity & mortality

– The normal: <120/80 mm Hg
– Identified not based on symptoms
 B/c it is asymptomatic till overt end organ
damage occurred
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 Classifying Blood Pressure

Blood Pressure Systolic Diastolic

Category (mm Hg) (mm Hg)

Normal <120 <80

Prehypertension 120-139 80-89

High: Stage 1 140-159 90-99

High: Stage 2 160 + 100 +

Stage – 3 (severe) 180 or > 110

• Elevated readings must occur on multiple

occasions to be diagnosed
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 Types (forms) of HTN
1. Primary/Essential/Idiopathic HTN
 with no apparent cause (about 85 - 90 % of cases)

 It may be due to genetic inheritance, psychological stress,

environmental and dietary factors e.g., increased salt
intake
– Risk factors: Family history, race, age, salt, obesity, smoking,
alcohol & stress
Treatment is non-curative/symptomatic/emperical treatment
– Life long treatment
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 Types cont…
2. Secondary HTN
 secondary to some definite abnormalities
 Uncommon: Accounts for 10 – 15 % of hypertensive cases

 Due to comorbid diseases e.g. renal diseases, thyrotoxicosis,

Cushing’s disease
 Adrenal Disease
 Primary aldosteronism (Conn’s syndrome)
 phaeochromocytoma (toumor of epinephrine secreting cells)
 Due to drugs e.g. corticosteroids, Oral contraceptive, Sympathomimetics

 Others: Pregnancy

 Direct treatment of the underlying cause

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 Regulation of BP

– BP is directly proportionate to the product of the blood flow

(cardiac output, CO) & the resistance to passage of the blood
through pre-capillary arterioles (peripheral vascular resistance,
PVR):
BP = CO x PVR
– In both normal & hypertensive individuals, BP is maintained by
moment-to-moment physiologic regulation of CO & PVR,
exerted at 4 anatomic sites:
• Arterioles, Postcapillary venules, Heart, & Kidney

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Fig. Regulation of BP

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 Therapeutic interventions
 Healthy lifestyle modifications/non-
pharmacological treatment
 Cornerstone of mgt for preventing & treating
HTN
» Wt loss
» Salt restriction
» Healthy diet
» Alcohol restriction
» Aerobic exercise
» Smoking cessation
» Avoidance of stress, emotions
 Treatment of the underlining cause if present 9
 Antihypertensive Drugs
 Based on their principal mzms of action
classified as:
1. Diuretics
2. Sympatholytic agents
3. Angiotensin Converting Enzyme
inhibitors(ACEIs)
4. Angiotensin receptor blockers (ARBs)
5. Vasodilators (Calcium channel blockers,
direct vasodilators)

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Classification of antihypertensive drugs by their
primary site or MOA

1 Diuretics
– Thiazides & related agents:
hydrochlorothiazide, chlorthalidone,
indapamide, metolazone

– Loop diuretics: furosemide, torsemide,

ethacrynic acid

– K+-sparing diuretics: amiloride, triamterene,

spironolactone
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 MOA & Hemodynamic Effects of Diuretics

Diuretics lower BP
• Initially, diuretics reduce BP by
– Reducing blood vol. & CO;
– PVR may increase.
• After 6–8 weeks of Rx
– CO returns toward normal but BP remains low (b/c
of decline in PVR).

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 Diuretics…

• Diuretics are effective in lowering BP by 10-15 mm Hg

• Diuretics alone often provide adequate therapy for
mild or moderate essential HTN
• In severe HTN, diuretics are used in combination with
sympathoplegic & vasodilator drugs to control the
retention of Na caused by these agents

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 Diuretics cont…
Thiazide Diuretics
• Appropriate for mild or moderate HTN &
normal renal & cardiac function.

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 Diuretics cont…
loop diuretics: Furosemide are necessary
• In severe HTN, when multiple drugs with Na+
retaining properties are used
• In renal insufficiency: GFR < 30 or 40 mL/min
(in which thiazide diurtics are inefficient) &In
cardiac failure or cirrhosis, in which sodium
retention is marked

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 Diuretics cont…
Potassium-sparing diuretic: useful both to
 Avoid excessive potassium depletion &
 Enhance the natriuretic effects of other
diuretics.

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 Toxicity of Diuretics
• Most common ADE of diuretics is potassium
depletion (hypokalemia) Except for potassium-
sparing diuretics.
• Increase serum [uric acid] & may precipitate
gout.
– Due to inhibition of urate excretion
• The use of low doses minimizes these adverse
metabolic effects without impairing the
antihypertensive action.
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 Toxicity of Diuretics cont…
• Diuretics may also cause
– Magnesium depletion
– Impair glucose tolerance
• Inhibition of insulin release due to K+ depletion
(proinsulin to insulin) – precipitation of diabetes
– Increase serum lipid concentrations.
• cause rise in total LDL level

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 K - Sparing diuretics
+

• May produce hyperkalemia

• Spironolactone (a steroid)
– Associated with Gynecomastia.

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2.Drugs that alter Sympathetic
Nervous System Function

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 Sympathoplegic agents
A. Centrally acting antihypertensive agents e.g. alpha methyl
dopa, clonidine.
B. Adrenergic neuron–blocking agents e.g. reserpine ,
guanethedine
C. Alpha adrenergic receptor blockers e.g. prazosin .
D. Beta adrenergic blockers e.g. propranolol , atenolol ,
nadolol ....... etc .
E. Ganglion blockers e.g trimetaphan
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 Beta-adrenergic blockers
• Non selective: Propranolol (others: nadolol, timolol, pindolol,
labetolol)

• Cardioselective: Metoprolol (others: atenolol, esmolol,

betaxolol)

• All beta-blockers have similar antihypertensive effects –

irrespective of additional properties

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 β-Adrenergic Blockers

Mechanism of Action-:
 Initially, they decrease COP without effective drop in BP due
to reflex vasospasm with early increase in TPR (total
peripheral resistance).
 Later, they decrease TPR and BP through:
 ↓ Renin release (beta-1 mediated)

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 Beta Blockers: Adverse effects
• Dizziness/orthostasis (esp. • May prolong recovery
Alpha/beta blockers) from hypoglycemia (esp.
• Bronchospasm (can non-selectives)
exacerbate asthma/COPD) • May blunt symptoms of
• Bradycardia (HR<60bpm) hypoglycemia (esp. non
• Hyperlipedimia (↓with β1 selectives)
selectives) • Other –fatigue, cold
extremities

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 Beta Blockers :Warnings
• Taper over 14 days
.
– No abrupt d/c,
• Asthma/COPD
• Preexisting cardiac conduction abnormalities
• Peripheral arterial disease
• Uncontrolled DM (esp. high dose non -selectives)

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 Sympathoplegic agents: α-receptor blockers

• Prazosin, terazosin, & doxazosin

– A potentially severe SE is a 1st -dose phenomenon
• Orthostatic hypotension accompanied by transient
dizziness or faintness, palpitations, & even syncope
within 1 - 3 hrs of the 1st dose or after later dosage ↑
– These episodes can be avoided
» By having the pt take the 1st dose, & subsequent 1st
↑ed doses, at bedtime
– Na & water retention can occur with chronic administration
– Should be reserved as alternative agents for unique situations,
such as men with BPH

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 Sympathoplegic agents: Central α2-agonists

• Clonidine, methyldopa
– Lower BP primarily by stimulating α2-
adrenergic receptors in the brain
• Reduces sympathetic outflow from the vasomotor
center
– Chronic use results in Na & fluid retention
– Other SEs may include depression, orthostatic
hypotension, dizziness, & anti-cholinergic
effects

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 Central α2-Agonists…

• Sedation and dry mouth are common side

effects that may diminish or disappear with
chronic low doses.
• Methyldopa rarely may cause hepatitis or
hemolytic anemia and choice of drug during
pregnancy
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 3. Angiotensin Converting Enzyme
Inhibitors(ACEI)

• They inhibit the conversion of angiotensin -I to angiotensin -II.

• Includes:
– Captopril, Enalapril, Lisinopril

– Benazepril, Fosinopril

– Trandolapril, Quinapril, Ramipril

– Moexipril, Perindopril

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 ACEIs: Adverse Effects
• Non productive cough • Less common
• Hyperkalemia – Rash (more common
• Dizziness/hypotension with Captopril, Enalapril)
• Taste disturbance – Angieoedema
– Neutropenia

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 ACEIs: Warning
• Start low dose with
• Avoid with history of – Elderly, particularly with
ACEI angioedema/hyper- diuretic therapy
sensetivity – Renal impairment or CHF
• Preexisting or risk of • Drug-Drug interaction
hyperkalemia – With K- sparing diuretics,
• Dehydration/acute aldosterone antagonists, KCl
hypotension/high dose supplements, ARBs, DRIs
diuretic • Risk of ↑K level
• Pregnancy & lactation – High dose Aspirin
– Avoid use • May blunt BP effects of
ACEIs

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4.Angiotensin Receptor Blockers (ARBs)

Angiotensin Receptors:
• Specific angiotensin receptors have been discovered,
grouped and abbreviated as – AT1 and AT2
• Most of the physiological actions of angiotensin are
mediated via AT1 receptor
– AT1 receptor: vascular and visceral smooth muscle -
contraction.
– AT2 receptor: vasodilator action.

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Angiotensin Receptor-Blocking Agents

• Losartan, valsartan, candesartan, eprosartan, irbesartan

• They have no effect on bradykinin metabolism.
• have the potential for more complete inhibition of angiotensin
action compared with ACEI
– b/c there are enzymes other than ACE that are capable of generating
angiotensin II.

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 ARBs
• Blocks all the actions of A-II:
– vasoconstriction, sympathetic stimulation,
aldosterone release and renal actions of salt and
water reabsorption
• No inhibition of ACE

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 ARBs: Adverse Effects
• Fatigue
• Dizziness/Hypotension
– Increased risk with diuretics, elderly, HF
• Hyperkalemia (less likely Vs ACEIs)
• Rare
– Neuropenia, nephrotoxicity

Note : cough is not expected with these agents

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 ARBs: Warnings
• Precautions • Drug interactions
– Angioedema (history or – Avoid concomitant K
Hypersensetivity) supplements or K-
– Pregnancy or lactation sparing diuretics,
– Excessive volume aldosterone antagonists,
depletion/hypotension KCl supplements, ARBs,
DRIs - risk of ↑K
– Hepatic or renal
impairment
– Hyperkalemia
– Severe HF

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 Advantages of ARBs over ACEIs
1. Antagonize AG II formed by both ACE & non-ACE pathway (e.g.
chymase).
2 No accumulation of bradykinin which may be responsible for
angioedema and cough seen with ACEIs.

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5.Vasodilators
.

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Calcium Channel Blockers - Classification

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 Calcium channel blockers

 Chemically, they are classified into 3 classes:

 Phenylalkylamines e.g. verapamil.

 Benzothiazepines e.g., diltiazem

 Dihydropyridines e.g. nifedipine, nicardipine &

nimodipine, amlodipin

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 Calcium channel blockers

MOA
• Block L-type Ca2+ channels in both cardiac and
vascular tissues and cause relaxation of arterial
smooth muscle
– by blocking influx of calcium which is essential for
initiation of the process of contraction.

• i.e. → ↓Intracellular Ca2+ → ↓ contractility

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 Calcium channel blockers
• Dihydropyridines (DHP)
– Nifedipine, Amlodipine, Felodipine,
etc
• Nondihydropyridines
– Diltiazem, Verapamil

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 Direct arterial vasodilators
• Hydralazine
– Cause direct arteriolar smooth muscle
relaxation
• Compensatory activation of baroreceptor reflexes
– Results in ↑ed sympathetic outflow from the vasomotor
center, producing ↑ HR, CO, & renin release
» The effectiveness of direct vasodilators diminishes
over time unless the pt is also taking a sympathetic
inhibitor & a diuretic
– All pts taking these drugs for long-term HTN
therapy should 1st receive both a diuretic & β-
blocker
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 Direct arterial vasodilators …
• Hydralazine may cause a dose-related, reversible lupus-
like syndrome,
– More common in slow acetylators
– Lupus-like reactions can usually be avoided by
using total daily doses of less than 200 mg
• Other hydralazine SEs include:
– Dermatitis, PNP, hepatitis, & vascular
headaches

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 Direct Arterial Vasodilators …
• Minoxidil
– Is a more potent vasodilator than
hydralazine
• The compensatory ↑es in HR, CO, renin release, & Na
retention are more dramatic
– Severe Na & water retention may precipitate CHF
• Minoxidil also causes reversible hypertrichosis on the
face, arms, back, & chest
– Minoxidil is reserved for
• Very difficult to control HTN
• In pts requiring hydralazine who experience drug-induced
lupus
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 CV Pharmacology…

2. Drugs Used in Heart Failure

 Learning objectives

· On completion of this topic, you should be able to:

 Discuss the uses, general drug action, general ADRs, C/Is,
precautions, & interactions of drugs used for HF
management
Discuss ways to promote an optimal response to therapy,
how to manage common adverse reactions

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Introduction

· Heart failure, Occurs when the heart is unable to

pump blood at a rate sufficient to meet the
metabolic demands of the tissues or can do so
only at an elevated filling pressure

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Introduction…

· Most frequently, HF results from progressive

deterioration of myocardial contractile
function → Systolic dysfunction
 This may be attributable to
• Ischemic injury
• Pressure or vol. overload
• Due to valvular disease or HTN, or
dilated cardiomyopathy

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Introduction

· Sometimes, failure results from an inability

of the heart chamber to expand & fill
sufficiently during diastole →Diastolic
dysfunction
· The primary signs & symptoms of HF
Tachycardia, ↓ed exercise tolerance,
SOB, peripheral & pulmonary edema &
cardiomegaly

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Drugs for Heart failure

· Pharmacotherapy aimed at:

↓ Preload
• Diuretics, ACEIs, ARBs & Venodialators
↓ Afterload
• ACEIs, ARBs, & Arteriodialators
↑ Contractility
• Digoxin, β1 –agonists, PDE3 Inhibitors
↓ Remodeling of cardiac muscle
• ACEIs, ARBs, Aldostrone receptor antagonists

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Classification of drugs for Heart failure

1. Based on Aims of HF management

To achieve improvement in symptoms
- Diuretics - ACEIs/ARBs - Digitalis

To achieve improvement in survival

- ACEIs/ARBs - Aldostrone rp antagonists
- β blockers (eg. Carvedilol & Bisoprolol)
- Oral nitrates plus hydralazine
The mgt of HF should be aimed at improving both quality
of life & survival

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Classification of drugs for HF…

2. Based on mechanism of action

i. Positive inotropic drugs
• Cardiac glycosides: Digoxin
• PDE3 Inhibitors: Inamrinone, Milrinone
• β-adrenoceptor stimulants: dobutamine,
dopamine
ii. Drugs without positive inotropic effects
• Diuretics, ACEIs, ARBs, Vasodilators, β-
blockers

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A.Positive inotropic drugs
1. Bipyridines
Includes: Inamrinone & milrinone
· MOA: inhibit PDE-3
· Only available as parenteral forms
· t1/2: 3-6 hrs, with 10-40% being excreted in the
urine
· Pharmacodynamics
↑ Contractility by ↑Ca flux in the Cardiac myocytes
May also alter the intracellular movements of Ca
by influencing the SR
Have an important arterio & veno-dilating effects

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2. β -adreneregic & Dopaminergic agonists

i. Dobutamine
 It ↑ cardiac contractility but HR does not
rise much in usual dose

Indicated for acute decompensated HF

Intermittent infusion may benefit some pts

with chronic HF

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Beta-adrenoceptor stimulants…

ii. Dopamine
Its pharmacologic actions may be preferable to
dobutamine or milrinone in pts with
• Marked systemic hypotension or cardiogenic
shock in the face of elevated ventricular filling
pressures

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B.Drugs without positive
inotropic effects
1. Beta Blockers

· Mechanisms include
Attenuation of the adverse effects of high
conc.s of catecholamines, up-regulation
of rps, ↓ed HR, & reduced remodeling
through (-) of the mitogenic activity of
catecholamines
· Bisoprolol, carvedilol, & metoprolol showed a
reduction in mortality in pts with stable severe
HF
· Note: β- blockers can precipitate acute
decompensation of cardiac function

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2. RAASIs
• Activation of the RAAS is an early manifestation of
HF
• ACEIs or ARBs
• Reduce peripheral resistance →↓afterload
• Reduce salt & water retention →↓preload

• ARBs should be considered in pts intolerant of

ACE inhibitors because of incessant cough

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RAASIs …
· Reduce the long-term remodeling of the heart &
vessels
An effect that may be responsible for the
observed reduction in mortality & morbidity
· Beneficial in all subsets of pts—from those who
are asymptomatic to those in severe chronic
failure

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3. Diuretics

• Reduce venous pressure & ventricular preload

• Results in reduction of Na & water retention
& edema & its symptoms
• Reduction of cardiac size → improved pump
efficiency
• Aldosterone antagonist diuretics
• Have additional benefit of ↓ing morbidity &
mortality in pts with severe HF who are also
receiving ACEIs & other standard therapy
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Diuretics …

· Aldosterone antagonist diuretics

· Spironolactone or Eplerenone should probably
be considered in all pts with moderate or
severe HF, since both appear to reduce both
morbidity & mortality

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Diuretics …

· Loop & Thiazide diuretics

Edema associated with HF is generally
managed with loop diuretics (eg.
Furosemide)
• In some instances, salt & H2O retention
may become so severe that a combination
of Thiazides & Loop diuretics is necessary

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4. Vasodilators

· Effective in acute HF b/c they provide reduction in

Preload (through venodilation), or afterload
(through arteriolar dilation), or both

• Venodilators: Organic nitrates

• Arteriolar dilators: Hydralazine
• Combined arteriolar & venodilators:
• Nitroprusside, Nesritide

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Vasodilators …

· The choice of the agent should be based on the pt’s

Signs & symptoms
Hemodynamic measurements
• In pts with High filling pressure in whom the
principal symptom is dyspnea→???
• In pts in whom fatigue due to low ventricular out
put is the principal symptom →???
• In most pts with severe chronic failure that
responds poorly to other therapy, the problem
usually involves both elevated filling pressures &
reduced CO →???
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i. Nesiritide
· Manufactured using recombinant techniques
· Identical to the endogenous B-type natriuretic
peptide secreted by the ventricular myocardium in
response to volume overload
Mimics the vasodilatory & natriuretic actions of
the endogenous peptide
• Resulting in venous & arterial vasodilation; ↑es in
CO; Natriuresis & diuresis & ↓ed cardiac filling
pressures, SNS activity, & RAAS activity
Approved for use in acute (not chronic) HF

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ii. Oral nitrates & hydralazine

· Long-acting Nitrates (venous dilators) eg. ISDN

In pts with high filling pressures in whom the
principal symptom is dyspnea
• Most helpful in reducing filling pressures &
the symptoms of pulmonary congestion
Should be considered in pts with angina
· Hydralazine (arteriolar dilator)
In pts in whom fatigue due to low LV-output is
a primary symptom,
• May be helpful in increasing forward CO

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Oral nitrates & hydralazine …

• The combination of nitrates & hydralazine is an

alternative regimen
– In pts with severe renal impairment, in whom
ACEIs & ARBs are contraindicated
• It is rational to consider the addition of a
combination of nitrates & hydralazine:
• In pts who continue to have severe symptoms
despite optimal doses of ACEIs

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