Chapter 4

CV Pharmacology
2
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
Discuss important pre-administration &
ongoing assessment activities the nurse
should perform on the pt taking an
antihypertensive drug

3
Introduction

 Hypertension (HTN) is the most common CVD

 Left untreated, hypertension can lead to heart

disease, kidney disease, & stroke
 Effective lowering of BP with the use of
antihypertensive drugs has been shown to prevent
damage to blood vessels & to substantially reduce
morbidity & mortality rates

4
Introduction

 Basic considerations in HTN

Classification of BP based on values for

systolic & diastolic pressure
Types of HTN

The damaging effects of chronic HTN

5
 Introduction…
 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
• CO = HR × SV

6
Introduction…

 BP is controlled by the same MZMs in both

hypertensive & normotensive subjects; the only
difference is that the baroreceptors & the renal
blood volume-pressure control systems are ‘set’
at a higher level of BP in hypertensive pts

 All antihypertensive drugs act at one or more of

the 4 anatomic control sites by interfering with
normal regulatory MZMs of BP

7
Fig. Regulation of BP

8
9
Classification of antihypertensive drugs by
their primary site or MOA

A. Diuretics
Thiazides & related agents:
hydrochlorothiazide, chlorthalidone,
indapamide, metolazone

Loop diuretics: furosemide, torsemide,

ethacrynic acid

K+-sparing diuretics: amiloride, triamterene,

spironolactone

10
Classification of antihypertensive drugs…

B. Sympatholytic drugs
β-receptor antagonists: metoprolol, atenolol,
bisoprolol, propranolol
α receptor antagonists: prazosin, terazosin,
phentolamine (α1 sellective)
Mixed - receptor antagonists: labetalol,
carvedilol (block both α and β)
Centrally acting antiadrenergic agents:
methyldopa, clonidine, guanabenz, guanfacine
Adrenergic neuron blocking agents:
guanadrel, reserpine
11
Classification of antihypertensive drugs…

C. Ca2+ channel blockers: verapamil, diltiazem,

felodipine, amlodipine,, nifedipine
D. RAAS inhibitors
• Angiotensin-converting enzyme inhibitors:
captopril, enalapril, lisinopril
• Ang II receptor antagonists: losartan, candesartan
• Direct Renin Inhibitor: aliskirin
E. Direct Vasodilators
 Arterial: hydralazine, minoxidil, diazoxide,
fenoldopam
 Arterial and venous: nitroprusside

12
Fig. SOA of the major classes of antihypertensive drugs
13
A. Diuretics

 Pharmacodynamic Effects
Lower BP by depleting the body of Na &
reducing blood volume
Initially, diuretics reduce BP by decreasing
blood volume & CO (which may lead to an ↑
in PVR)
• After 6-8 wks of therapy, CO returns to
normal while PVR decreases

14
 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 ( opposes the down stream effect of post
ganglionic nerve firing) & vasodilator drugs to control the
retention of Na caused by these agents

15
 B. Sympathoplegic (sympatholytic)
agents
 Sympathoplegic drugs inhibit the function of the SNS

 Drugs that inhibit sympathetic function can cause compensatory

effects via MZMs that are not dependent on adrenergic nerves
 Thus, the use of these agents alone may cause retention of Na &
water by the kidneys & expansion of blood volume (via the RAAS
pathway)
 Consequently, sympathoplegic antihypertensive drugs are
most effective when used in combination with a diuretic
16
 Sympathoplegic agents: Beta blockers
 Examples of available b-blockers include:
Nonselective: Propranolol, Nadolol,
Carteolol,timolol,sotalol,pidolol, Carvedilol
β1-selective: Metoprolol, Atenolol, Betaxolol, Bisoprolol,
Esmolol, Nebivolol, Acebutalol
 Carvedolol & labetolo-block α and β receptors
 Nebivolol-sellective B1,induce release NO from p
 Betaxolol-also block CC
 Acebutalol & pindolol-intrinsic sympathomimetic effect
 They lower BP by decreasing HR, myocardial contractility &
renin activity
17
Beta Blockers: Adverse effects

 Dizziness/orthostasis  May prolong recovery

(esp. Alpha/beta from hypoglycemia (esp.
blockers) non-selectives)
 Bronchospasm (can  May blunt symptoms of
exacerbate hypoglycemia (esp. non
asthma/COPD) selectives)
 Bradycardia (HR<60bpm)  Other –fatigue, cold
 Hyperlipedimia (↓with β1 extremities
selectives)

18
Beta Blockers :Warnings

 Taper over 14 days  Renal impairment pts

No abrupt d/c, esp. if Caution with atenolol,
CAD nadolol
 Asthma/COPD
 Preexisting cardiac  1st pass metabolism with
conduction abnormalities propranolol, metoprolol
 Peripheral arterial Hepatic impairment
disease Drug interaction –CYP
 Uncontrolled DM (esp. 3A4/2D6
high dose non -
selectives)
19
Other Sympathoplegic agents

 Alpha (α1) Blockers

 Centrally Acting Sympathoplegic Drugs

 Ganglion-Blocking Agents

 Adrenergic Neuron–Blocking Agents

20
 Other Sympathoplegic agents: α-receptor
blockers
 Classified as non selective α1& α2 =phentolamine, phenoxybenzamine and
selectiveα1 blockers =Prazosin, terazosin, & doxazosin
 Block α1 on peripheral smooth muscles, bladder neck and prostate gland
 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 1 st
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

21
Other 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 & ↑ vagal tone
Chronic use results in Na & fluid retention
Other SEs may include depression, orthostatic
hypotension, dizziness, & anti-cholinergic effects

22
Other Sympathoplegic agents:
Central α2-agonists..

 Abrupt cessation may lead to rebound HTN

 Due to compensatory ↑ in NE release
 Methyldopa rarely may cause hepatitis or
hemolytic anemia
 Most common undesirable effect of methyldopa is
sedation, particularly at the onset of Tx

23
C. Calcium Channel Blockers

 Dihydropyridines (DHP)
Nifedipine, Amlodipine, Felodipine,
etc
 Nondihydropyridines
Diltiazem, Verapamil

24
 CCBs: Adverse Effects
DHP (eg. Amlodipine, Nifedipine) Verapamil or Diltiazem
 HA, dizziness, flushing (↑  GI- constipation (esp.
vasodilation)
Verapamil), N,GERD
 Peripheral edema (dose related)
 HA, dizziness, flushing
 Reflex tachycardia/palpitation
(less vasodilation Vs
 Gingival hyperplasia (esp.Nifed)
DHP)
 Less common- GI disturbances
 Less common
(N, constipation, anorexia,
GERD) • Peripheral edema
 Unlikely to cause AV • Cardiac conduction
conduction problems abnormalities
(bradycardia, AV
Block, HF)
25
CCBs: Warnings

 Concomitant β blockers (with non-DHP-CCBs)

Due to risk with additive (-) inotropic effects
 Pre-existing cardiac conduction abnormalities
 DHP with migraine
 Hepatic/Renal dysfunction
Amlodipine (hepatic), Diltiazem (renal),
Verapamil, Nifedipine (renal/hepatic)

26
CCBs: Warnings…

 Drug interaction
Verapamil, Diltiazem, & Nifedipine
• CYP450 Substrate/inhibitor
• Eg. Erythromycin (avoid
Diltiazem/verapamil
• Cause high Eryth. Level thereby ↑
risk of cardiac death up to 5 fold
• Digoxin ↑ level up to 50% with
Verapamil, Diltiazem, Nifedipine

27
D. Agents that block production/action
of angiotensin
i. ACE INHIBITORS
Includes:
• Lisnopril, Enalapril, Fosinopril, Quinapril,
Ramipril, Captopril, Benazepril, Moexipril,
Trandolapril
1st line agents for HTN
Block conversion of Ang I to II
Block degrdation of bradykinin & stimulate
synthesis of PGE2, Prostacycline

28
Fig. SOA of drugs that interfere with the renin-angiotensin-
aldosterone system. ACE, angiotensin-converting enzyme; ARBs,
angiotensin receptor blockers

29
ACEIs: Adverse Effects

 Non productive cough  Less common

 Hyperkalemia Rash (more common
 Dizziness/hypotension with Captopril,
 Enalapril)
Taste disturbance
Angieoedema
Neutropenia

30
 ACEIs: Warning
 Start low dose with
 Avoid with history of
Elderly, particularly with
ACEI diuretic therapy
angioedema/hyper- Renal impairment or CHF
sensetivity  Drug-Drug interaction
 Preexisting or risk of
With K- sparing diuretics,
hyperkalemia aldosterone antagonists,
 Dehydration/acute KCl supplements, ARBs,
hypotension/high dose DRIs
diuretic • Risk of ↑K level
 Pregnancy & lactation High dose Aspirin
Avoid use • May blunt BP effects of
ACEIs
31
ii. ARBs

 Includes:
Losartan, valsartan, irbesartan, candesartan,
telmisartan, olmesartan
Combinations: ARBs/Hydrochlorothiazide
 1st line agents for HTN (Alternative to ACEIs)
 Block Ang II from all sources
 Block the Ang type1 rp that mediates effects of
angiotensin II
Vasoconstriction, aldosterone release, sympathetic
activation, ADH release, & constriction of the efferent
arterioles of the glomerulus
32
 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

33
ARBs: Warnings

 Precautions  Drug interactions

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

34
Last line HTN drugs & Adverse effects

 α1-Receptor Blockers
 Direct Renin Inhibitor
 Central α2-Agonists
 Sympathetic nerve terminal blockers
 Direct Arterial Vasodilators

35
E. 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
36
Direct arterial vasodilators …

 Direct vasodilators can precipitate angina in pts with

Underlying CAD, unless the baroreceptor reflex
MZM is completely blocked with a β-blocker
 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

37
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
38
Parenteral Antihypertensive Agents for Hypertensive
Emergency

39
 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 important pre-administration and ongoing
assessment activities the nurse should perform on
the pt taking these drug
 Identify the symptoms of digitalis toxicity.
Discuss ways to promote an optimal response to
therapy, how to manage common adverse reactions

41
Introduction

 Heart failure, often called congestive heart

failure (CHF), is a common, usually
progressive condition with a poor prognosis

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

42
Introduction…

 It can appear during the end stage of many forms

of chronic heart disease
In this setting, it most often develops
insidiously due to
• The cumulative effects of
• Chronic work overload (due to valve
disease or HTN) or
• Ischemic heart disease (e.g., following
MI with extensive heart damage)

43
Introduction…

 However, acute hemodynamic

stresses can cause CHF to appear
suddenly, such as
Fluid overload
Acute valvular dysfunction, or
A large MI

44
Introduction…

 When cardiac function is impaired or the work

load ↑es, several physiologic MZMs maintain
arterial pressure & perfusion of vital organs

 The most important of these are the following:

The Frank-Starling MZM
Myocardial adaptations, including
hypertrophy with or without cardiac chamber
dilation
Activation of Neurohumoral systems
45
Fig. Some compensatory responses that occur during CHF. In
addition to the effects shown, sympathetic discharge facilitates renin
release, & angiotensin II increases NE release by sympathetic nerve
endings (dashed arrows).
46
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

47
Introduction (6)

 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

48
 The Donkey Analogy
Ventricular dysfunction limits a patient's ability to perform the
routine activities of daily living…

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

49
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
50
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

51
A.Positive inotropic drugs
Digoxin

53
1. Digoxin
Digitalis Compounds

Like the carrot placed in front of the donkey

• Pharmacokinetic properties
– Absorption & distribution
• 65-80% absorbed after oral administration
• It is widely distributed to tissues, including the CNS
– Metabolism & excretion
• It is not extensively metabolized in humans
• 2/3 is excreted unchanged by the kidneys
• Renal Cl ~Cr Cl
• t1/2: 36–40 hrs in pts with normal renal
function

54
Digoxin: Pharmacodynamics

 Digoxin has two mechanisms of action:

a) Inotropic action:
• Through the action of Na/K/ATP ion pump
blockade, the following sequence of ionic events
occurs:
• ↓ Na exits the cell
• ↑ Intracellular Na
• ↓ Na electrochemical gradient for Na-Ca
exchanger
• ↓ Ca exits the cell
• ↑ Intracellular Ca

55
Digoxin: Pharmacodynamics…

 The ↑ in intracellular Ca results in ↑ed

contractility, SV, & CO
 In heart failure, sympathetic tone is ↑ed as a
compensatory mechanism to↓CO
Digoxin increases contractility & hence SV &
CO, therefore reducing the need for sympathetic
compensation; thus digoxin reduces the
sympathetic tone in heart failure

56
Digoxin: Pharmacodynamics…

b) ↑ed parasympathetic nervous system activity:

 In addition to the indirect reduction of the SNS, there is
a direct ↑ in the PSNS
 Digoxin sensitizes arterial baroreceptors in the carotid
sinus & activates the vagal nuclei (in the brainstem)
• These baroreceptors induce a response via the
vagus nerve that decreases HR & causes
vasodilation when the receptors are stretched
(which occurs with high BP)
• HR decreases owing to increased parasympathetic
tone of the SA and AV nodes
• By this mechanism on the AV node, digoxin is
useful in patients with atrial fibrillation
57
 Digoxin: Interactions with K, Ca, & Mg

 Digoxin Interaction with K

K & digoxin interact in 2 ways
• They inhibit each other's binding to Na+/K+
ATPase
• Hyperkalemia ↓ the enzyme-inhibiting actions
• Hypokalemia facilitates these actions
• Abnormal cardiac automaticity is (-) by
hyperkalemia
• Moderately ↑ed extracellular K+ →reduces
the effects of digitalis, esp. the toxic effects

58
Digoxin: Interactions with K, Ca, & Mg …

 Digoxin Interactions with Ca & Mg

Ca facilitates the toxic actions of digoxin by
accelerating the overloading of intracellular Ca
stores
• Responsible for digitalis-induced abnormal
automaticity
• Hypercalcemia therefore ↑ the risk of a digitalis-
induced arrhythmia
Effects of Mg appear to be opposite to those of Ca

59
Clinical Uses of Digoxin

 Digoxin does not improve survival in pts with HF

but does provide symptomatic benefits
 Digoxin is indicated In pts with
HF & Atrial fibrillation
Continued symptoms of HF despite optimal
doses of diuretics & ACEIs
Severe LV systolic dysfunction with dilated
heart
Recurrent hospital admissions for HF

60
Clinical Uses of Digoxin …

 Doses should be adjusted to achieve plasma digoxin

conc. of 0.6 to 0.9 μg/L
 Methods of dosing (digitalization)
Slow loading dose: 0.125-0.25 mg/day
Rapid method: 0.5-0.75 mg tid for 3 doses,
followed by 0.125-0.25 mg/day
• NB: When symptoms are mild ,slow loading
dose is safer & just as effective as the rapid
method

61
Clinical Uses of Digoxin …

 Higher plasma levels are not associated with

additional benefits but may ↑ the risk of toxicity

Most pts with normal renal function can achieve

this level with a dose of 0.125 mg/day
 Pts with ↓ed renal function, the elderly, or
those receiving interacting drugs should receive
0.125 mg every other day

62
Digoxin Toxicity

 Divided into extra-cardiac & cardiac manifestations

Extra-cardiac symptoms
• Visual disturbances such as flashing lights,
halos, & color disturbances (green-yellow
patterns)
• Acute fatigue, hallucinations, Anorexia & N

One sign of serious digoxin toxicity that clinicians

should always specifically target is hyperkalemia
i.e. serum K+ conc. >5.0 mmol/L

63
Digoxin Toxicity …

 Digoxin cause nearly every rhythm disturbance

 It is sometimes difficult to diagnose digoxin toxicity
b/c many of the more common signs or symptoms
are relatively non-specific
• e.g. anorexia, premature ventricular complexes
 Determination of digoxin conc. is very useful
Toxic symptoms are clearly more common above
1.5 μg/L

64
Management of Digoxin Toxicity

 Mild to moderate toxicity without serious

arrhythmia
• Withdrawal of digoxin
• Correction of electrolyte disturbance
 Moderate to severe toxicity with arrhythmia
Withdrawal of digoxin
Correction of electrolyte disturbance
Cardiac pacing for bradyarrhythmias
• Antiarrthymic drugs: e.g. lidocaine
• Digitalis antibodies(digoxin immune fab)
65
2. 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
during the AP
May also alter the intracellular movements of Ca
by influencing the SR
Have an important arterio & veno-dilating effects
66
3. 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

67
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

68
B.Drugs without positive
inotropic effects
 ß-Blockers

Limit the donkey’s speed, thus saving energy

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
70
 Diuretics, ACE Inhibitors

2. RAASIs
Reduce the number of sacks on the wagon

• 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

71
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
 But can not replace digoxin in pts already
receiving the drug
B/c pts withdrawn from Digoxin deteriorate
while on ACEI therapy
72
 Diuretics, ACE Inhibitors

3. Diuretics
Reduce the number of sacks on the wagon

• 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
73
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

74
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
 Remember: Excessive use of diuretics may
diminish VR & further impair CO

75
Diuretics …

 Na+ loss causes secondary loss of K+

Hypokalemia can exacerbate underlying cardiac
arrhythmias & contribute to digitalis toxicity
Hypokalemia can usually be avoided by
• Having the pt reduce Na+ intake, thus ↓ing
Na+ delivery to the K+-secreting collecting
tubule
Pts who are noncompliant with a low Na+ diet
must take oral KCl supplements or a K+-sparing
diuretics or through the addition of ACEI

76
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

77
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
78
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

79
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

80
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

81
 CV pharmacology…

3. Antianginal drugs
Learning Objectives

 On completion of this chapter, you should be able

to :
 List the two types of antianginal drugs
 Discuss the general actions, uses, ADRs, C/Is,
precautions, & interactions of antianginal drugs
 Discuss important preadministration & ongoing
assessment activities the nurse should perform on the pt
taking an antianginal drugs
 Discuss ways to promote an optimal response to
therapy, how to manage common ADRs, & important
points to keep in mind when educating pts about the use
of antianginal drugs

83
Angina Pectoris

 Angina pectoris ( literally, chest pain)

Characterized by paroxysmal & usually
recurrent attacks of substernal or
precordial chest discomfort
• Variously described as constricting,
squeezing, choking, or heaviness
Caused by transient (15 sec – 15 min)
myocardial ischemia that falls short of
inducing myocyte necrosis
84
Angina Pectoris …

 The 3 overlapping patterns of angina

pectoris are:
Stable (typical), Prinzmetal /variant
angina & Unstable (crescendo angina)

Caused by varying combinations of ↑ed

myocardial demand, ↓ed myocardial
perfusion, & coronary arterial pathology

85
Angina Pectoris …

 Stable angina
The most common form
Caused by an imbalance in coronary
perfusion (due to chronic stenosing coronary
atherosclerosis) relative to demand
• Produced by physical activity, emotional
excitement or any other cause of ↑ed
cardiac workload
Relieved by rest or nitroglycerin

86
Angina Pectoris …

 Prinzmetal /variant angina

Uncommon form of episodic myocardial
ischemia
Caused by coronary artery spasm
Unrelated to physical activity, HR, or BP
Responds promptly to vasodilators
(CCBs, nitroglycerin)
87
Angina Pectoris …
 Unstable angina
A pattern of increasingly frequent pain, often of
prolonged duration, that precipitated by
progressively lower levels of physical activity or
that even occur at rest
Caused by plaque rupture complicated by
partially occlusive thrombosis & vasoconstriction
• This lead to severe but transient reductions in
coronary blood flow
Sometimes referred as pre-infarction angina

88
General principles

 Tx of angina is aimed at ↓ O2 demand &/or ↑ O2

supply
 Myocardial oxygen demand varies with:

• Heart rate

• Systolic blood pressure (afterload)

• Contractility

• LV wall stress, which is proportional to LV end-

diastolic volume (preload) & myocardial mass
89
Drug action in angina

 The 3 drug groups traditionally used in

angina (organic nitrates, CCBs, & β
blockers)

↓Myocardial O2 requirement by ↓ the

determinants of O2 demand (HR,

ventricular volume, BP, & contractility)

90
Drug action in angina…

 In some pts, the nitrates & the CCBs may

cause a redistribution of coronary flow &↑ O2

delivery to ischemic tissue
In variant angina, these 2 drug groups also

↑ myocardial O2 delivery by reversing

coronary artery spasm

91
1. Nitrates & Nitrites

 These agents are simple nitric & nitrous acid esters

of polyalcohols
Nitroglycerin (Glyceryl trinitrate, GTN), Isosorbide
dinitrate (ISDN), Isosorbide mononitrate (ISMN)
 All therapeutically active agents in the nitrate group
appear to have identical MOA & similar toxicities,
although susceptibility to tolerance may vary
Therefore, PK factors govern the choice of agent
& mode of therapy when using the nitrates

92
Organ system effects: Effect on vascular smooth
muscle

 All segments of the vascular system from large

arteries through large veins relax in response to
GTN
Veins responding at the lowest conc.s, arteries
at slightly higher ones
Arterioles & precapillary sphincters are dilated
least

93
Nitrates & Nitrites: Toxicity & Tolerance

A. Acute Adverse Effects

The major acute toxicities of organic nitrates
are direct extension of therapeutic vasodialation
• Throbbing Headache, Flushing, Orthostatic
hypotension, palpitation
• Presyncope or syncope

94
Nitrates & Nitrites: Toxicity & Tolerance…

B. Tolerance
Tolerance has been a major problem with the
use of nitrates as chronic antianginal therapy
• It occurs when long-acting preparations or
continuous IV infusions are used for more
than a few hrs without interruption

95
Nitrates & Nitrites: Toxicity & Tolerance…

• Prevention of Tolerance

• Use smallest effective dose

• Administer the fewest possible doses per day

• Avoid continuous exposure to nitrates

• Provide a nitrate-free interval of 8-12 hrs/day

96
Nitrates & Nitrites: Clinical use

 Immediate treatment of angina

Sublingual nitroglycerin

• DOC for an acute anginal attack or for prophylaxis

prior to activities known to exacerbate angina

 IV nitroglycerin is restricted to the treatment of

severe, recurrent rest angina

i.e. in the setting of unstable angina or acute MI

97
Nitrates & Nitrites: Clinical use…

 Chronic nitrate therapy

Slowly absorbed preparations of nitroglycerin

like; buccal form, oral preparations & several
transdermal forms
Reserve chronic nitrate therapy for 2nd line
therapy
• B/c of the problems with tolerance & rebound
angina in the nitrate-free interval
98
Nitrates & Nitrites: Clinical use…

 Allowing for a sufficient nitrate-free interval

In pts with primarily exertional angina,
nitrates are given during the day when the pt
is more active
In pts with nocturnal angina, therapy at night
may be more beneficial
Remember
The hemodynamic effects of sublingual or
chewable ISDN & the oral organic nitrates are
similar to those of nitroglycerin given by the
same route
99
Nitrates & Nitrites: Contraindications

 Hypotension

 Coadministration of PDE5 inhibitors

 Elevated intracranial pressure (ICP)

Vasodilation of cerebral arteries increases

cerebral blood volume, which further increases
ICP

100
3. Calcium channel blockers

 Mechanism of clinical effects

Reduces myocardial O2 requirements by
• ↓ myocardial contractile force ?
• Arteriodialation →↓afterload
• ↓ HR ?

CCBs relieve & prevent the focal coronary

artery spasm involved in variant angina
• Most effective prophylactic Tx for this form of
angina pectoris

101
Calcium channel blockers …

 For stable angina:

CCBs are used as 2nd -line therapy when β-

blockers are genuinely C/I
Verapamil is a more effective antianginal agent
than diltiazem or DHPs & is considered a 1st
choice
• But the drug must be used with caution & must not be
combined with a β- blocker
102
Calcium channel blockers …

 Stable angina (2)

DHP, may aggravate anginal symptoms in some
pts when used without a β- blocker
Amlodipine produces less reflex tachycardia
than does nifedipine probably b/c of a flatter
plasma conc. profile
 Prinzmetal /variant angina
All presently available CCBs appear to be
equally effective
• Choice of a particular drug should depend on
the pt ???
103
4. Beta-blocking drugs

 Beneficial effects of β-blockers

↓HR, BP & contractility → ↓myocardial O2

requirements at rest & during exercise
Note: ↓HR → ↑ diastolic perfusion time → ↑
coronary perfusion

104
β-blockers …

 β-blockers are standard 1st -line therapy for

stable & unstable angina

 β-blockers are C/I for variant angina ?

105