Cardiovascular-Renal Drugs

Heart Failure
 DETERMINANTS OF VENTRICULAR FUNCTION

CONTRACTILITY

PRELOAD AFTERLOAD

STROKE
VOLUME

- Synergistic LV contraction HEART

- LV wall integrity RATE
- Valvular competence

CARDIAC OUTPUT
•Heart failure
is the pathophysiological state in which the heart is
unable to pump sufficient blood to satisfy the metabolic
demands of the body with enough preload.
 The Progressive Development
of Cardiovascular Disease

Risk Factors
Endothelial Dysfunction
Atherosclerosis
CAD
Myocardial Ischemia
Coronary Thrombosis

Myocardial Infarction
Arrhythmia & Loss of Muscle

Remodeling
Ventricular Dilation
Congestive Heart Failure

Endstage Heart Disease

HEART FAILURE
pathogenesis
 Cardiac injury

Increased load
Reduced systemic perfusion

Activation of RAS, SNS, and cytokines

Altered gene Growth and Ischemia and Direct

expression remodeling energy depletion toxicity

Apoptosis Necrosis

Cell death
Pathophysiology of heart failure

Impaired myocardium
↓
• Cardiac output ↓, heart failure
↓
• Neurohumoral stimulation
• RAS and sympathetic-adrenergic↑
↓ ↓
• Vasoconstriction increased heart rate
• Salt and water retention increased energy
• (augments preload) expenditure
• Hypertrophy
↓
• Leads to deterioration and death of cardiac cell
 Congestion in front
of the left ventricle
causes dyspnea and
pulmonary edema
Ankle edemas,
enlarged liver, and
ascites signal congestion
in front of the right
ventricle.
 stage A

Stage B

Stage C

Stage D
Class I

Class II

Class III

Class IV
Effects of Neurohormonal
Stimulation in Heart Failure
Heart
­Heart rate Peripheral Circulation
­Contractility ­Arterial vasoconstriction
­Stroke volume ­Venoconstriction
­Cardiac output ­Systemic vascular
resistance
­Conduction velocity
­Redistribution of blood
­Myocardial oxygen
flow
consumption
­Renal vasoconstriction
Øtachycardia

Øincreased peripheral vascular resistance;

Øretention of salt and water by the kidney

Øcardiomegaly
Øapoptosis
HEART FAILURE
compensatory mechanisms

1. sympathetic nerve system and of the

2. renin–angiotensin system.
 (nor)epinephrine, aldosterone,
and angiotensin II
Myocardial dysfunction Diminished
Diminished Cardiac output renal
blood flow

Increased Increased force Increased

cardiac and rate of Sympathetic
workload myocardial Activity Renin release
contraction

Increased Vasoconstriction
venous Renal
retention of Angiotensin II
return
sodium and water

Aldosterone
Edema
 ¯LV Function
Digoxin
Vasodialtors
ACE Inhibitors
¯Cardiac Output
­Peripheral vasoconstriction
¯Blood flow

Neurohormonal ACE Inhibitors

Salt and Water ß Blockers
Activation
Retention

Diuretics
Dyspnea
For progressive duration

• Congestive heart failure is

classified into acute and For anatomical type
chronic heart failure
• Congestive heart
failure is classified into
left side, right side and
biventricular heart
failure
Coronary artery disease Cardiomyopathic factors Atrial Fibrillation

Hypertension Diabetes Valvular disease

Left ventricular Pathologic Low ejection

injury Remodeling fraction

Death
 Heart Failure Clinical Stages

NORMAL
No symptoms
Normal exercise
Asymptomatic
Normal LV fxn LV Dysfunction
No symptoms
Normal exercise Compensated
Abnormal LV fxn
No symptoms
Exercise Decompensated
Abnormal LV fxn
Symptoms
Exercise Refractory
Abnormal LV fxn
Symptoms not
controlled
with treatment
Prevalence of Heart Failure
 SUCCESSFUL THERAPY OF CHRONIC CONGESTIVE
FAILURE IS BASED ON INHIBITION OF
COMPENSATION MECHANISMS

Therapeutic strategies for chronic heart failure

include:
a. reduction in physical activity;

b. low dietary intake of sodium (< 1500 mg/day);

c. treatment of comorbid conditions;

HEART FAILURE
Therapeutic strategies
Ø the removal retained salt and water with
diuretics;
Ø reduction of afterload and salt and water
retention by means of angiotensin-converting
enzyme (ACE) inhibitors;
Ø reduction of excessive sympathetic stimulation
by means of β – blockers;
Ø reduction of preload or afterload with
vasodilators;
Ø direct augmentation of depressed cardiac
contractility wi t h po si t i v e i no t ro pi c
dr ug s suc h as di g i t a l i s gl yc osi de s.
HEART FAILURE
Therapeutic strategies

should be avoided if possible.

HEART FAILURE
Therapeutic strategies

best
“digitalis”
 CARDIAC EFFECTS OF GLICOSIDES

1. positive inotropic effect (increased contractility);

2. positive batmotropic effect (increased automaticity);

3. negative dromotropic effect (decreased velocity in

atrioventricular conduction);

4. negative chronotropic effect (reduced heart rate

digoxin.
 the drugs
accumulate significantly in the body,
and dosing regimens must be carefully
designed and monitored.

do not require digoxin.

 However, careful clinical studies indicate that while digitalis
may improve functional status, it does not prolong life. Other
agents – diuretics, ACE inhibitors, vasodilators – may be equally
effective and less toxic, and some of these alternative therapies
do prolong life.
DIGOXIN`S MAJOR INDICATION IS HEART FAILURE
WITH ATRIAL FIBRILLATION
The major signs of digitalis toxicity are
• Cardiac arrhythmias - sinus bradycardia, AV-block, ventricular
extrasystoles, ventricular fibrillation (ECG),
Ø anorexia, nausea, vomiting, and diarrhea
ØCNS disturbances: characteristically, altered color
vision (xanthopsia), and also fatigue, disorientation,
hallucinations, confusion.
In general, decreased serum level of potassium
(hypokalemia) facilitates digoxin toxicity
 Increased automaticity (caused by calcium accumulation in cardiac
cells) may evoke extrasystoles, tachycardia, or fibrillation in any part of
the heart. In the ventricles, the extrasystoles are recognized as
premature ventricular beats (PVBs):
Premature ventricular beats - An abnormal beat arising from a
cell below the AV node - often from a Purkinje fiber, sometimes from a
ventricular fiber.
Rarely, confusion or hallucinations and visual aberrations may
occur. Central nervous system effects also include:
Ø Headache
Ø Fatigue
Ø Blurred vision
Ø Alteration of color perception
Ø Halos on dark objects.
The treatment of arrhythmias is important because this manifestation of
digitalis toxicity is common and dangerous.
Severe, acute intoxication caused by suicidal or accidental
extreme overdose results in cardiac depression leading to cardiac arrest
rather than tachycardia or fibrillation.
Ørenal
 PDE – inhibitors - phosphodiesterase inhibitors that
increase the intracellular concentration of cAMP. This results in an
increase of intracellular calcium, and therefore, cardiac
contractility. Short-term use of intravenous milrinone has some
symptomatic benefit when it is used in patients with refractory
heart failure. Examples: high concentrations of theophylline,
inamrinone.
Diuretics - are the first – line therapy for both systolic and
diastolic failure and are used in heart failure before digitalis.
Diuretics decrease plasma volume and, subsequently, decrease
venous return to the heart (preload). Loop diuretics are the most
commonly used diuretics in heart failure.
Furosemide is very useful agent for immediate reduction of
the pulmonary congestion and severe edema associated with acute
heart failure and for moderate or severe chronic failure. Thiazides
such as hydrochlorothiazide are sometimes sufficient for mild
chronic failure. Spironolactone (aldosterone antagonist diuretics)
have significant long-term benefits and can reduce mortality in
chronic failure.
Angiotensin II antagonists
 Beta – adrenoceptor agonists - Dobutamine (β1-
selective agonist) and dopamine are often useful in acute
failure. Dobutamine must be given by intravenous
infusion and is primarily used in the treatment of acute
heart failure in a hospital setting.
Beta – adrenoceptor antagonists - Carvedilol,
labetalol, metoprolol are useful to reduce progression of
chronic heart failure.
β – blockers are not of value in acute failure and may
be detrimental if systolic dysfunction is marked.
Carvedilol and metoprolol reduce morbidity and mortality
associated with heart failure. Treatment should be started
at low doses and gradually titrated to effective doses based
on patient tolerance.
 PDE-inhibitors - Inamrinone and milrinone are the major
representatives of this group. These drugs increase cyclic
adenosine monophosphate (cAMP) by inhibition its breakdown by
phosphodiesterase and cause an increase in cardiac intracellular
calcium. They also cause vasodilation.
Vasodilators - Vasodilators therapy with nitroprusside or
nitroglycerin is often used for acute severe failure with congestion.
Chronic heart failure sometimes responds favorably to oral
vasodilators such as hydralazine or isosorbide dinitrate or both.
Calcium channel blockers (eg, verapamil) should be avoided
in patients with heart failure.
 TREATMENT
Correction of aggravating factors

Pregnancy Endocarditis

Arrhythmias (AF) Obesity

Infections Hypertension

Hyperthyroidism Physical activity

Thromboembolism Dietary excess

MEDICATIONS
 PHARMACOLOGIC THERAPY

Improved Decreased Prevention Neurohumoral

symptoms mortality of CHF Control

DIURETICS yes ? ? NO

DIGOXIN yes = minimal yes

INOTROPES yes mort. ? no

Vasodil.(Nitrates) yes yes ? no

ACEI yes YES yes YES

Other neurohormonal
yes +/- ? YES
control drugs
 TREATMENT
Normal
Asymptomatic
LV dysfunction
EF <40%
Symptomatic CHF
ACEI NYHA II
Symptomatic CHF
NYHA - III
Diuretics mild
Neurohormonal Symptomatic CHF
inhibitors Loop NYHA - IV
Digoxin? Diuretics
Inotropes
Secondary prevention Specialized therapy
Modification of physical activity Transplant
 DIURETICS
Thiazides
Cortex Inhibit active exchange of Cl-Na
in the cortical diluting segment of the
ascending loop of Henle

K-sparing
Inhibit reabsorption of Na in the
distal convoluted and collecting tubule

Medulla Loop diuretics

Inhibit exchange of Cl-Na-K in
the thick segment of the ascending
loop of Henle

Loop of Henle
Collecting tubule
 THIAZIDES
MECHANISM OF ACTION

Excrete 5 - 10% of filtered Na+

Elimination of K

Inhibit carbonic anhydrase:

increase elimination of HCO3

Excretion of uric acid, Ca and Mg

No dose - effect relationship

 LOOP DIURETICS
MECHANISM OF ACTION

Excrete 15 - 20% of filtered Na+

Elimination of K+, Ca+ and Mg++

Resistance of afferent arterioles

- Cortical flow and GFR

- Release renal PGs
- NSAIDs may antagonize diuresis
 K-SPARING DIURETICS
MECHANISM OF ACTION

Eliminate < 5% of filtered Na+

Inhibit exchange of Na+ for K+ or H+

Spironolactone = competitive
antagonist for the aldosterone receptor

Amiloride and triamterene block

Na+ channels controlled by aldosterone
 DIURETIC EFFECTS

Volume and preload

Improve symptoms of congestion

No direct effect on CO, but excessive preload reduction may

Improves arterial distensibility

Neurohormonal activatio

Levels of NA, Ang II and ARP

Exception: with spironolactone

 DIURETICS
ADVERSE REACTIONS
Thiazide and Loop Diuretics
Changes in electrolytes:
Volume
Na+, K+, Ca++, Mg++
metabolic alkalosis
Metabolic changes:
glycemia, uremia, gout
LDL-C and TG
Cutaneous allergic reactions
 DIURETICS
ADVERSE REACTIONS
K-SPARING DIURETICS

Changes in electrolytes

Na+, K+, acidosis

Musculoskeletal:

Cramps, weakness

Cutaneous allergic reactions :

DIGOXIN
Na-K ATPase
Na-Ca Exchange
Na+ K+ Na+ Ca++

Myofilaments Ca++
K+ Na+

CONTRACTILITY
 DIGOXIN
PHARMACOKINETIC PROPERTIES
Oral absorption (%) 60 - 75
Protein binding (%) 25
Volume of distribution (l/Kg) 6 (3-9)
Half life 36 (26-46) h
Elimination Renal
Onset (min)
i.v. 5 - 30
oral 30 - 90
Maximal effect (h)
i.v. 2-4
oral 3-6
Duration 2 - 6 days
Therapeutic level (ng/ml) 0.5 - 2
 DIGOXIN
DIGITALIZATION STRATEGIES

Maintenance
Loading dose (mg) Dose
i.v oral 12-24 h oral 2-5 d (mg)
0.5 + 0.25 / 4 h 0.75 + 0.25 / 6 h 0.25 / 6-12 h 0.125-0.5 / d

ILD: 0.75-1 1.25-1.5 1.5-1.75 0.25 / d

ILD = average INITIAL dose required for digoxin loading

 DIGOXIN
HEMODYNAMIC EFFECTS

Cardiac output
LV ejection fraction
LVEDP
Exercise tolerance
Natriuresis
Neurohormonal activation
 DIGOXIN
NEUROHORMONAL EFFECTS

Plasma Noradrenaline

Peripheral nervous system activity

RAAS activity

Vagal tone
 DIGOXIN
EFFECT ON CHF PROGRESSION

30
Placebo n=93
DIGOXIN
Withdrawal
WORSENING OF CHF %
20

DIGOXIN: 0.125 - 0.5 mg /d p = 0.001

(0.7 - 2.0 ng/ml) 10
EF < 35%
Class I-III (digoxin+diuretic+ACEI)
Also significantly decreased exercise
DIGOXIN n=85
time and LVEF. 0
RADIANCE
N Engl J Med 1993;329:1
0 20 40 60 80 100
Days
 OVERALL MORTALITY
50

40

30
% Placebo
20 n=3403 p = 0.8

10 DIGOXIN
n=3397

0
DIG 0 12 24 36 48 Months
N Engl J Med 1997;336:525
 DIGOXIN
LONG TERM EFFECTS

Survival similar to placebo

Fewer hospital admissions

More serious arrhythmias

More myocardial infarctions

 DIGOXIN
CLINICAL USES

AF with rapid ventricular response

CHF refractory to other drugs

Other indications?

Can be combined with other drugs

 DIGOXIN
CONTRAINDICATIONS
ABSOLUTE:
- Digoxin toxicity

RELATIVE
- Advanced A-V block without pacemaker
- Bradycardia or sick sinus without PM
- PVC’s and TV
- Marked hypokalemia
- W-P-W with atrial fibrillation
 DIGOXIN TOXICITY
CARDIAC MANIFESTATIONS

ARRHYTHMIAS :
- Ventricular (PVCs, TV, VF)
- Supraventricular (PACs, SVT)

BLOCKS:
- S-A and A-V blocks

CHF EXACERBATION
 DIGOXIN TOXICITY
EXTRACARDIAC MANIFESTATIONS

GASTROINTESTINAL:
- Nausea, vomiting, diarrhea

NERVOUS:
- Depression, disorientation, paresthesias

VISUAL:
- Blurred vision, scotomas and yellow-green vision
 POSITIVE INOTROPES
CARDIAC GLYCOSIDES

SYMPATHOMIMETICS
Catecholamines
ß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS
Amrinone Milrinone
Enoximone Piroximone
Others
 ß-ADRENERGIC STIMULANTS
CLASSIFICATION

B1 Stimulants
Increase contractility
DobutamineDoxaminol Xamoterol
ButopaminePrenalterol Tazolol

B2 Stimulants
Produce arterial vasodilatation and reduce SVR
Pirbuterol Rimiterol Tretoquinol Terbutaline Soterenol
Carbuterol Fenoterol Salbutamol Salmefamol Quinterenol

Mixed
Dopamine
 DOPAMINE AND DOBUTAMINE
EFFECTS

DA (µg / Kg / min) Dobutamine

<2 2-5 >5
Receptors DA1 / DA2 ß1 ß1 + a ß1
Contractility ± ++ ++ ++
Heart Rate ± + ++ ±
Arterial Press. ± + ++ ++
Renal perfusion ++ + ± +
Arrhythmia - ± ++ ±
 POSITIVE INOTROPES
CONCLUSIONS

May increase mortality

Safer in lower doses

Use only in refractory CHF

NOT for use as chronic therapy

 VASODILATORS
CLASSIFICATION
Venous
VENOUS Vasodilatation
Nitrates
Molsidomine

MIXED
Calcium antagonists
a-adrenergic Blockers
ACEI
Angiotensin II inhibitors
K+ channel activators
Arterial Nitroprusside
Vasodilatation
ARTERIAL
Minoxidil
Hydralazine
 NITRATES
HEMODYNAMIC EFFECTS

1- VENOUS VASODILATATION
Pulmonary congestion
Ventricular size
Preload Vent. Wall stress
MVO2

2- Coronary vasodilatation
Myocardial perfusion

3- Arterial vasodilatation • Cardiac output

Afterload • Blood pressure

4- Others
 NITRATES
TOLERANCE

Can be avoided or minimized

- Intermittent administration

- Use the lowest possible dose

 NITRATES
CONTRAINDICATIONS
Previous hypersensitivity

Hypotension ( < 80 mmHg)

AMI with low ventricular filling pressure

1st trimester of pregnancy

WITH CAUTION:
Constrictive pericarditis
Intracranial hypertension
Hypertrophic cardiomyopathy
 NITRATES
CLINICAL USES

Pulmonary congestion

Orthopnea and paroxysmal nocturnal dyspnea

CHF with myocardial ischemia

In acute CHF and pulmonary edema: NTG s.l. or i.v.

ACE-i. Mechanism of Action

VASOCONSTRICTION VASODILATATION
ALDOSTERONE PROSTAGLANDINS
VASOPRESSIN Kininogen tPA
SYMPATHETIC
Kallikrein
Angiotensinogen
RENIN
BRADYKININ
Angiotensin I

A.C.E. Inhibitor Kininase II

ANGIOTENSIN II Inactive Fragments

 ACEI
HEMODYNAMIC EFFECTS
Arteriovenous Vasodilatation
- PAD, PCWP and LVEDP

- SVR and BP
- CO and exercise tolerance

No change in HR / contractility

Renal, coronary and cerebral flow

 ACEI
FUNCTIONAL CAPACITY
100

No 95 Quinapril
Additional continued
n=114
Treatment 90
p<0.001
Necessary
(%) 85

Quinapril
80 stopped
Placebo
Class II-III
n=110
75
2 4 6 8 10 12 14 16 18 20
Quinapril Heart Failure Trial
JACC 1993;22:1557 Weeks
 ACEI
ADVANTAGES
Inhibit LV remodeling post-MI
Modify the progression of chronic CHF
- Survival
- Hospitalizations
- Improve the quality of life
In contrast to others vasodilators,
do not produce neurohormonal activation
or reflex tachycardia
 ACEI
SURVIVAL POST MI

ACEI Benefit Pt Selection

ISIS-4 Captopril 0.5 / 5 wk All with AMI

GISSI-3 Lisinopril 0.8 / 6 wk All with AMI

SAVE Captopril 4.2 / 3.5 yr EF < 40

asymptomatic

SMILE Zofenopril 4.1 / 1 yr Ant. AMI, No TRL

TRACE Trandolapril 7.6 / 3 yr Vent Dysfx / Clinical CHF

EF < 35

AIRE Ramipril 6 / 1 yr Clinical CHF

 ACEI
INDICATIONS

Clinical cardiac insufficiency

- All patients

Asymptomatic ventricular
dysfunction
- LVEF < 35 %
 ACEI
UNDESIRABLE EFFECTS
Inherent in their mechanism of action

- Hypotension - Dry cough

- Hyperkalemia - Renal Insuff.
- Angioneurotic edema
 ACEI
CONTRAINDICATIONS

Renal artery stenosis

Renal insufficiency
Hyperkalemia
Arterial hypotension
Intolerance (due to side effects)
 ANGIOTENSIN II INHIBITORS （ARB)
MECHANISM OF ACTION

RENIN

Angiotensinogen Angiotensin I
ACE
Other paths ANGIOTENSIN II
AT1
RECEPTOR
BLOCKERS
AT1 RECEPTORS AT2

Vasoconstriction Proliferative Vasodilatation Antiproliferative

Action Action
AT1 RECEPTOR BLOCKERS
DRUGS

Losartan
Valsartan
Irbersartan
Candersartan
Competitive and selective
blocking of AT1 receptors
 ALDOSTERONE INHIBITORS

Spironolactone ALDOSTERONE

Competitive antagonist of the

aldosterone receptor
(myocardium, arterial walls, kidney)

Retention Na+ Collagen

Edema deposition
Retention H2O

Fibrosis
Excretion K+ - myocardium
Arrhythmias
Excretion Mg2+ - vessels
 ALDOSTERONE INHIBITORS
INDICATIONS
FOR DIURETIC EFFECT

• Pulmonary congestion (dyspnea)

• Systemic congestion (edema)

FOR ELECTROLYTE EFFECTS

• Hypo K+, Hypo Mg+

• Arrhythmias
• Better than K+ supplements

FOR NEUROHORMONAL EFFECTS

• Please see RALES results, N Engl J

Med 1999:341:709-717
 ALDOSTERONE INHIBITORS
CONTRAINDICATIONS

• Hyperkalemia
• Severe renal insufficiency

• Metabolic acidosis
 ß-ADRENERGIC BLOCKERS
POSSIBLE BENEFICIAL EFFECTS

Density of ß1 receptors
Inhibit cardiotoxicity of catecholamines
Neurohormonal activation
HR
Antihypertensive and antianginal
Antiarrhythmic
Antioxidant
Antiproliferative
 ß BLOCKERS
CARVEDILOL

4 studies in U.S.;
p < 0.0001
1 in Australia/New Zealand

U.S. studies with control group

Mortality with Placebo 8.2%

Mortality with Carvedilol2.9%

Initial low doses, progressive

ß-ADRENERGIC BLOCKERS
INDICATIONS and UTILIZATION

Begin with very low doses

Slow augmentation of dose

Slow withdrawal ?
 ß-ADRENERGIC BLOCKERS
IDEAL CANDIDATE?

Suspected adrenergic activation

Arrhythmias

Hypertension

Angina
 ß-ADRENERGIC BLOCKERS
CONTRAINDICATIONS

Hypotension: BP < 100 mmHg

Bradycardia: HR < 50 bpm

Clinical instability

Chronic bronchitis, ASTHMA

Severe chronic renal insufficiency

CALCIUM ANTAGONISTS
POTENTIAL EFFECTS

Antiischemic

Peripheral Vasodilatation

Inotropy
 CALCIUM ANTAGONISTS
POSSIBLE UTILITY

Diltiazem contraindicated
Verapamil and Nifedipine
not recommended

Vasoselective (amlodipine, nisoldipine),

may be useful in ischemia + CHF
 ANTICOAGULANTS

PREVIOUS EMBOLIC EPISODE

ATRIAL FIBRILLATION

Identified thrombus

LV Aneurysm (3-6 mo post MI)

Class III-IV in the presence of:

- EF < 30

- Aneurysm or very dilated LV

 ANTIARRHYTHMICS

Sustained VT, with/without symptoms

- ß Blockers
- Amiodarone
Sudden death from VF
- Consider
implantable
defibrillator
 angiotensin
converting enzyme (ACE) inhibitor
-
Positive Inotropic Mechanism of Digoxin