Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

1

Impaired cardiac pumping such that heart isunable to pump adequate amount of blood tomeet metabolic needsNot a disease but a “syndrome” associated withlong-standing HTN and CAD

Pulmonary edemaAgitationPale or cyanoticCold, clammy skinSevere dyspneaTachypneaPink, frothy sputumFatigueDyspneaParoxysmal nocturnal dyspnea (PND)TachycardiaEdema – (lung, liver, abdomen, legs)Nocturia

Coronary Artery Disease -CADAgeSmokingHTNObesityHeart valve diseaseDiabetes mellitusCardiomyopathy-dialated,Hypertropic, restrictive

Chronic AcuteCADHypertensive HDRheumatic Heart DisCongenital Heart DisCor pulmonaleCardiomyopathyAnemiaBacterial endocarditisValvular disorders

Acute MIDysrhythmiasPulmonary emboliThyrotixicosisHypertensive crisisRupture of papillarymuscleVSDMyocarditis

Cardiac Output

Preload

Afterload Contractility

Heart Rate Stroke Volume= X

Pathologicremodeling

Low ejectionfraction Death

Symptoms:DyspneaFatigueEdema

Chronicheart

failure

•Neurohormonalstimulation

•Myocardialtoxicity

SuddenDeath

Pumpfailure

Coronary arterydisease

Hypertension

Cardiomyopathy

Valvular disease

Myocardialinjury

Diabetes

Renin + Angiotensinogen

Angiotensin I

Angiotensin II

PeripheralVasoconstriction

Afterload

Cardiac Output

Heart Failure

Cardiac Workload

Preload

Plasma Volume

Salt & Water Retention

Edema

Aldosterone Secretion

ACE

Kaliuresis

BetaStimulation

• CO• Na+

Fibrosis

Vasoconstric on: ↑’s the resistance against whichheart has to pump (i.e., ↑’s a erload), and maytherefore ↓ CO

Na and water reten on: ↑’s fluid volume, which ↑’spreload. If too much “stretch” (d/t too much fluid) →↓ strength of contrac on and ↓’s CO

Excessive tachycardia → ↓’d diastolic filling me → ↓’dventricular filling → ↓’d SV and CO

ACC/AHA HF Stage NYHA Functional Class

A At high risk for heart failure but withoutstructural heart disease or symptomsof heart failure (eg, patients withhypertension or coronary artery disease)

B Structural heart disease but withoutsymptoms of heart failure

C Structural heart disease with prior orcurrent symptoms of heart failure

D Refractory heart failure requiringspecialized interventions

I Asymptomatic

II Symptomatic with moderate exertion

IV Symptomatic at rest

III Symptomatic with minimal exertion

None

Relief from congestionIonotropic drugs-DIGOXIN, DOBUTAMINE, DOPAMINE

AMRINONE, MIRINONEDiuretics- FUROSEMIDE, THIAZIDESRAS inhibitors-ACE INHIBITORS/ ARBs- ENALAPRIL,

VALSARTANVasodialators- HYDRALAZINE, NITRATE, NITROPRUSSIDEBeta blockers-METARPOLOL, BISOPROLOL, CARVEDILOL

NEBIVOLOLReversal of progressionACE inhibitors, ARBs, Beta blockers, spironolactone,eplerenone

D ig ita lis p u rp u re a (F o x g lo v e ) W . W ith e r in g (1 7 8 5 )

F ra n c e , U K N a tiv e lle(1 8 6 9 )•D ig ito x in

Inhibits NaK/ATPase pumpContractility increases as intracellular Ca, Na increases andloss of intracellular K+• Positive inotropic effect- increases force of contraction

without increasing of oxygen consumption• Positive bathmotropic effect-Modifying degree of

excitability• Negative chronotropic effect-rate of heart is decreased• Negative dromotropic effect-conduction speed of AV

node• CGs are effective in CHF, occurring with normal or

accelerated heart rhythm, especially in cases of atrialfibrillation

ARs: bradycardia, AV block,Extra-systoles arrhythmias,accumulation and intoxication.Digoxin toxicity- renal insufficiency, ischemia, hypokalemiacalcium channel blockers, beta blockers, cyclosporine andfurosemideNormal levels- 0.5-2ng/mlTreatment of toxicity-charcoal. Correct potassium, calciumIV, DIGIBIND antibodies

Preparations of Digitalis (foxglove)Digitoxin (t1/2 168 h)Digoxin (t1/2 40 h): p.o. or i.v.Semisynthetic derivatives of Digoxin

– Acetyldigoxin (Lanatilin): p.o.– Methyldigoxin (Lanitop): p.o.

Preparations of Strophanthus gratus– Strophanthin G (Ouabain) – i.v.

ATP 3’,5’-AMPAC PDE III

AmrinoneEnoximoneMilrinone

(–)cAMP

Amrinone, Enoximone, MilrinoneThese agents are indicated in severe congestiveAHF, resistant to other drugs; usually for shorti.v. treatment. They have positive inotropic effect,but they increase oxygen consumption.ARs: ventricular and SV arrhythmias, angina,hypotension, headache, hypokalemia.

In AHF with cardiogenic shock Dobutamine (β1-agonist)and Dopamine are administered by i.v. infusion.In high doses dopamine may increase peripheral vascularresistance, while dobutamine does not influence it.

Dopamine in low doses activates D2-receptors in renal andmesenterial vessels and in coronaries. It causes arterialvasodilation, activates D5-receptors in myocardium andincreases myocardial contractility.Used in low doses (2 to 5 mcg/kg/min i.v.) dopaminedoes not increase blood pressure.In high doses (> 5 mcg/kg/min i.v.) its α- and β-effectsdominate.

They increase salt and water loss,reduce blood volumeand lower excessive venous filling pressure,reduce circulating blood volume and preload.The congestive features of oedema, in the lungsand periphery, are alleviated,cardiac output is also increased.

Diuretics are administered together withACE inhibitors and other drugs.

RENAL TUBULARINTERSTITIUM LUMEN

Na+K+Cl-

TPC

Na+

H+

Na+

K+

PARACELLULAR DIFFUSIONNa+ K+Mg++ Ca++

Cl-

+8 mV

RENAL TUBULARINTERSTITIUM LUMEN

Na+K+Cl-

TPC

Na+

H+

Na+

K+

PARACELLULAR DIFFUSIONNa+ K+Mg++ Ca++

Cl-

+8 mV

THICK ASCENDING LOOP

LOOP DIURETICS

Early DCT Late DCT

Na+

Cl-

LUMEN

K+

Na+

Cl-

THIAZIDES

Spironolactone is a weak diuretic.

In cases of severe heart failure low doses ofSpironolactone are added to the therapy while regularlychecking creatinine and electrolyte levels.

It blocks aldosterone receptors in the distal renal tubulesand reduces increased aldosterone levels in CHF.

In low doses (25 mg/24 h) Spironolactonepotentiates the effects of ACE inhibitors.

It also saves K+ and Mg2+ and has antiarrhythmic activity.Spironolactone prevents myocardial fibrosis, caused byaldosterone, and in this way increases myocardialcontractility.Similar to spironolactone is another aldosteroneantagonist – Eplerenone.

ACE inhibitors reduce pre- and afterload.They are administered in lower doses aloneor together with diuretics, cardiac glycoside,antiischemic agents in all stages of CHF,due to systolic dysfunction.

In preparations with t1/2 ≥ 24 h (Perindopril,Ramipril) the risk of lowering blood pressure afterthe first dose is avoided.

VasoconstrictionArt+venous

Na+ & waterretention

(Adrenal cortex)

Kidney

IncreasedBlood Vol.

Rise in BPIncreasedveonousreturn, EDV

Competitive antagonist and inverse agonist of AT1receptor Complete inhibition of AT1 – alternativeremains with ACEsResult in indirect activation of AT2 – vasodilatation(additional benefit)

Does not interfere with other receptors except TXA2Blocks all the actions of A-II - vasoconstriction,sympathetic stimulation, aldosterone release and renalactions of salt and water reabsorptionNo inhibition of ACE

Organic nitrates dilate capacity vessels, reduce preloadand myocardium oxygen needs.They connect with thiol groups (-SH) and release nitricoxide (NO). NO combines with new thiol groups in vascularendothelium to form nitrosothiol (R-SNO).Nitrosothiols activates guanylate cyclase which raises theconcentration of cyclic GMP.This reduces the bioavailability of intracellular calcium andproduces vasodilationGlyceryl trinitrate is prescribed sublingually at 18–20 minintervals in acute left-ventricular heart failure

Trimetazidine has prolonged concentration plateau lastingup to 11 h.It increases ATP synthesis and decreases acidosis inischemic tissues.It supplies energy for Na+/K+ transmembrane pump,

but can cause parkinsonism.

Carvedilol is a blocker of β- and α-receptors. It also hasantioxidant, vasodilating and cardioprotective effects.It decreases cardiac output, peripheral vascular resistanceand afterload.Carvedilol lowers mortality with 25–67%, but it iscontraindicated in CHF, occuring with cor pulmonale. Thetreatment begins with low doses (3.125 mg/12 h).

Cardioselective beta-blockers Bisoprolol andMetoprolol decrease with 31% mortality inpatients with CHF, if used in combination withdiuretics, ACE inhibitors and Digoxin.

Levocarnitine is a N-containing aminoacid in muscle, which has antioxidant activity.It is indicated in cardiomyopathy and muscledystrophy caused by carnitine deficiency.

Preparations containing Coenzyme Q10(a part of the mitochondrial redox system),stimulate ATP synthesis and improvemyocardial contractility in CHF.

Levosimendan increases sensitivity of troponin in theheart to calcium.This results in increased myocardial contractility.It is infused i.v. for short treatment of severe heartfailure.

ACE inhibitor (angiotensin-converting enzyme)

ARB (angiotensin receptorblockers)

Beta-blocker

Digoxin

Diuretic

Aldosterone blockade

Type What it doesExpands blood vessels which lowers bloodpressure, neurohormonal blockade

Similar to ACE inhibitor—lowersblood pressure

Reduces the action of stress hormonesand slows the heart rate

Slows the heart rate and improves the heart’spumping function (EF)

Filters sodium and excess fluid from the bloodto reduce the heart’s workload

Blocks neurohormal activation and controlsvolume

EBM Therapies Relative RiskReduction

Mortality2 year

ACE-I 23% 27%

Β-Blockers 35% 12%

AldosteroneAntagonists

30% 19%

ICD 31% 8.5%