Outline

Management of Heart Failure

Diuretics VASODILATOR THERAPY IN HEART FAILURE

Angiotensin Converting Enzyme Inhibitors

VASODILATION DIURESIS REMODELING REGRESSION B- blockers Digoxin

1. 2. 3.

Diuretics Clinical Pharmacology & Usage

Diuretics can relieve peripheral & pulmonary edema within hours or days unlike other agents (ACEIs/-blockers) that require weeks to months

DIURETIC MONOTHERAPY IS NOT ALLOWED as they offer ineffective maintenance alone.

Diuretics Clinical Pharmacology & Usage

Diuretics are recommended when clinical evidence exists for volume overload Patients without peripheral/pulmonary edema can be treated WITHOUT OR INTERMITTANT diuretics As-needed diuretic depends on wt gain changes, neck vein distention (>0.5-1 kg/day or 2 kg/week wt gain/swollen legs) Otherwise, diuretic-free periods or week ends are applied

Diuretics Clinical Pharmacology & Usage

EFFICAY of diuretics depend on sodium load delivered to their site of action In HF, compromised GFR increases Na+ re-absorption, leading to minimal efficacy for thiazide & K+-sparing diuretics. Loop diuretics (furosemide, bumetanide & torsemide) are the preferred diuretics in HF They are effective even at creatinine Clcr is less than 5 mL/min Furosemide has addition vasodilating properties decreasing renal vascular resistance even before diuresis starts

Diuretics Adverse Effects

1- Azotemia

Normal BUN/creatinine=10-20
Increased both values: progressive renal damage

Increased BUN/creatinine ratio above 20 denotes prerenal azotemia caused by poor renal perfusion &/or overdiuresis
Proper diuretic therapy would improve HF, renal perfusion & helps lower BUN Prolonged over-diuresis & dehydration may cause decreased renal perfusion & renal damage, where creatinine will rise as well

Diuretics Adverse Effects

2- Hypokalemia

Definition: less than 3.5 mEq/L, HCTZ (50-100 mg/day), incidence is 15-40% At lower-dose HCTZ & accepting serum levels of <3 mEq/L as normal, incidence is much lower Initial serum K+ before therapy is considered HF patients have higher K+ levels than HTN patients, & hence incidence of hypokalemia is less Furosemide produces lower degree of hypokalemia than thiazides Patients on digoxin are more sensitive to hypokalemia (toxicity)

Diuretics Adverse Effects

3- Hypomagnesemia Severe hypomagnesemia can lead to muscle spasms, decreased seizure threshold & cardiac arrythmias Concurrent hypokalemia & hypomagnesemia can be seriously dangerous IV MgSO4 is administered to restore serum Mg2+

Diuretics Adverse Effects

4- Hyperuricemia

Usual increments in uric acid levels are1-2 mg/dL Asymptomatic hyperuricemic patients usually do not require treatments Persistent hyperuricemia >10 mg/dL, or history of gout, consider urate-lowering agents Hyperglycemia & glucose intolerance are side effects to thiazide & loop diuretics Family history & other risk factors are evaluated

5- Hyperglycemia

Potassium Supplementation

Serum K+ must be monitored frequently Hypokalemia can occur few hrs after first dose, & reaches max after a week Hypokalemia takes several weeks to go to normal after diuretic withdrawal K+ replacement: Only KCl should be used because all hypokalemic diuretics can cause hypochloremic alkalosis If hypochloremia was not corrected, hypokalemia & alkalosis persist K+-sparing diuretic or K+-containing food

Diuretic Therapy Monitoring

CHF symptoms Wt Loss (0.5-1 kg/day) and decreased edema Signs of volume depletion: hypotension, dizziness, weakness, decreased urine output & raised BUN Check serum K+, Mg2+, uric acid & glucose

Diuretic-Independent Effects of Spironolactone

o o o o

Both ANGII & aldosterone have direct CV detrimental effects: Vascular & myocardial hypertrophy & fibrosis, direct vascular & endothelial damage, increased oxidative stress Inhibition of NE uptake by the myocardium Spironolactone addition to maintenance HF therapy, significantly reduced mortality in severe HF (stage IV)

VASODILATOR THERAPY IN HEART FAILURE

Arterial vasodilation decreases afterload & venodilation lowers preload. Hydralazine (arterial dilator) & nitrates (venous dilator) combination reduces HF symptoms & have modest reduction of mortality. ACEIs reduce both preload & afterload and suppress cardiac remodelling. It was recommended the use of ACEIs to all systolic HF patients unless contraindicated or intolerated.

Angiotensin Converting Enzyme Inhibitors (ACEIs)

VASODILATION, DIURESIS & REMODELING REGRESSION are the beneficial triad for ACE
inhibition Vasodilation: decreased ANG II & NE and increased bradykinin (BK) & substance P Bradykinin stimulates B1 receptors leading to increased PGI2, NO & EDRF BK increases natriuresis via direct tubular effect

Angiotensin Converting Enzyme Inhibitors (ACEIs)

Mild diuresis:
Reduction of aldosterone & vasopressin secretion Enhanced renal blood flow, via increased CO & locally through efferent arteriolar vasodialtion

Cardiac & Vascular Remdelling inhibition by lowering

ANGII type-1 R - hypertrophic effects

Angiotensin Converting Enzyme Inhibitors (ACEIs)

FDA-labeled ACEIs for HF: captopril, enalpril, fosinopril, lisinopril, quinapril, ramipril. No drug is preferred to another Efficacy: ACEIs are effective in ischemic/nonischemic HF & all HF stages (I-IV) Produce relative reduction of 20-30% HF mortality, superior to hydralazine-nitrate or ARBs ACEIs showed better cardiac remodeling inhibitory effect over ARBs

Various ACEIs

It was recommended captopril, enalpril, lisinopril & ramipril Captopril & lisinopril have no active metabolites All other agents are PRODRUGS requiring enzymatic conversion to active metabolites Captopril has shorter onset and duration of action, administered frequently/day Captopril is better for initiating ACEI therapy for 2 days followed by longer-acting ones in good responders

ACE Inhibitors-Induced Cough

ALL ACEIs can induce cough in 3-15% of patients It occurs within few weeks to months of treatment & persist 1-2 weeks after drug withdrawal Changing an ACEI to another or dose reduction do not stop cough because of the Pharmacologic mechanism (increased Bradykinin & substance P) Withdrawal of the ACEI drug is the only way to stop ACEI-induced cough If cough persists, shift to another vasodilator: ARB or hydralazine-nitrate combination

Angiotensin II Type-1 (AT1) Receptor Antagonists (ARBs)

They preferentially block AT-1 receptors They improve HF symptoms: increased exercise tolerance & ejection fraction ARBs were not superior to ACEIs in reduction of all-cause mortality, but cough-free FDA approved valsartan for HF Triple combination: ACEI-ARB--blocker should not be used

Adverse Effects of ACEIs & ARBs

1- Hyperkalemia ANG II-induced aldosterone secretion is decreased by ACEI/ARB leading to K+ retention Significant hyperkalemia occurs in o Renal compromised patients o K+ supplementation & K+-sparing diuretics K+-losing (thiazide & loop) diuretics concurrent use leads to either normokalemia or hypokalemia

Adverse Effects of ACEIs & ARBs Angioedema (Angioneurotic edema)

It consists of facial/neck edema with airway obstruction (laryngeal& bronchial edema) Mechanism is unknown but thought to be related to kinins accumulation Though kinin-related, case reports exist for angioedema induced by losartan & valsartan ARBs are an option whenever ACE-induced angioedema occurs Hydralazine-nitrate combination is another alternative African Americans & females are more vulnerable

Effects of ACEIs & ARBs on Kidney Function HF Patients

Beneficial Effect: ACEI/ARB decrease pre- & afterload increase CO improve renal blood flow. Non-beneficial Effect: Initial therapy rapid BP fall slow CO response worsening of renal function Prediction of which event to occur is impossible ACEI/ARB therapy initiated with low dose, slow increase in dose/careful BP & renal function monitor Diuretic dose is adjusted to avoid volume depletion & hypotension

ACEIs in Asymptomatic Patients

HF patients in Stage A-B, with LVH or decreased EF but NO signs benefits from ACEI therapy. Possibly ACEI retards cardiac remodelling -blockers may be added to ACEI for asymptomatic HF patients whenever compelling indication exists (e.g., MI)

-Blockers in Systolic Heart Failure

EVIDENCE: -blockers reduce mortality (30%) & hospitalization (40%) Metoprolol & carvedilol reduce HF symptoms & mortality They are added to diuretic-ACEI & often digoxin They should not be delayed till refractoriness to HF therapy occurs Addition to low-dose ACEI produces better improvement of symptoms & mortality

-Blockers in Systolic Heart Failure

Contraindication: Unstable HF hospialized patients, symptomatic bradycardia/heart block, resistant asthma

DOSE: Initial low dose, gradual increase every 1-2 weeks according to patient tolerance Transient bradycardia, heart block, hypotension often are asymptomatic, no treatment, but patients advised to stand slowly from lying position If symptoms (dizziness, blurred vision) occur dose reduction &/or lower dose titration

Metoprolol, Bisoprolol & Carvedilol

They are FDA approved for HF Metporolol & bisoprolol are cardioselective showing myocardial 2-receptor upregulation Carvedilol is mixed ,-blocker with additional antioxidant activity Approved for stages II & III and now IV HF Carvedilol is possibly associated with more hypotension & dizziness

DIGOXIN

Digoxin Intervention Group (DIG) trial HF patients Class II/III on digoxin (2-5 years) moderate decrease of combined mortality/hospitalization but little effect on survival Digoxin started early to reduce symptoms of HF patients on ACEI or -blocker but not yet with improved symptoms Digoxin is routinely advised for HF patients with chronic atrial fibrilation Digoxin is avoided in patients with appreciable sinus/AV block It is not indicated as 1ry therapy for acute decompensated HF

Digoxin

Digoxin therapy can be delayed till response to ACEI or -blocker is evident and given to the still symptomatic patients Digoxin monotherapy or digoxin-diuretic therapy is no longer recommended Usual maintenace dose is 0.125-0.25 mg/day