-As mentioned in the pathophysiology lecture, renin-angiotensin-aldosterone system (RAAS) is highly activated in CHF.
-In CHF patients, plasma concentrations of plasma aldosterone can be as high as 20 times the normal level.
What is aldosterone?
-Main endogenous mineralocorticoid (steroid) with almost total sodium retention activity and minimal anti-inflammatory activity.
-It is produced in the zona-glomerulosa of the adrenal medulla
-Its main function is to INCREASE SODIUM REABSORPTION in the collecting tubules of the kidneys.
-Associated with it is an INCREASE IN POTASSIUM AND PROTON IONS
∴Overall effect is to increase fluid retention and increase blood pressure.
Two factors control the levels of aldosterone:
-The aldosterone secretion is dependent upon the electrolyte composition of plasma and the renin-angiotension system –
Decreased plasma sodium ions or increased potassium ions cause zona glomerulosa cells to release aldosterone.
-Since it is a steroid, it will bind to intracellular receptors
-Aldosterone specifically alters DNA regulatory regions to increase expression of genes for sodium channels as well as those for Na+/K+ ATPase molecules.
- Potential roles of Aldosterone in CHF
1. Increased sodium and water retention Edema, elevated cardiac filling pressures
2. K+ and Mg2+ loss Arrhythmogenesis (generating arrhythmias) and risk of sudden cardiac death
3. Reduced myocardial NAdr uptake Potentiation of NAdr effects, myocardial remodelling and arrhythmogenesis 4. Reduced Baroreceptor sensitivity Reduced parasympathetic activity and risk of sudden cardiac death
5. Myocardial fibrosis, fibroblast proliferation. Remodelling and ventricular dysfunction 6. Alterations in sodium channel expression. Increased excitability and contractility of cardiac myocytes
*Aldosterone has biological effects beyond salt retention and antagonism of aldosterone’s action is beneficial in patients with heart failure. *These beneficial effects are additive to those of ACE inhibitors and B-Blockers.
-As a steroid, aldosterone binds intracellular receptors which specifically alters DNA regulatory regions to increase the expression of genes for sodium channels as well as those for Na+/K+ ATPase molecules.
-Increase in sodium channels present in the Collecting Tubule (CT) which facilitates sodium reabsorption.
1.1 Drug Class: Aldosterone Receptor Antagonists
1 (a) Spironolactone
-competitive antagonist of aldosterone, prevents aldosterone from binding, thus reducing no. of Na+ channels present in the DT. Na+ not reabsorbed, water loss.
Note: Since it is a renal drug (or any renal drug), caution must be taken when significant renal impairment is present.
1. Gynaecomastia (Spironolactone has cross-specificity with androgen and progesterone receptors, thus being able to stimulate secondary sex characteristics)
*Other important clinical indications: Hirsutism (in females)
Mechanism of action (hirusutism): Inhibits binding of Dihydrotestosterone and the intracellular androgen receptor. It also inhibits ovarian steroidogenesis, resulting in lowered plasma levels of testosterone.
Dosage: Initiated at 12.5 or 25mg daily (Higher doses may lead to hyperkalemia-K+ sparing especially in patients receiving on an ACE inhibitor)
Note: Serum K+ levels and electrolytes should be checked after initiation (K+ sparing diuretic)
-Drug interactions and medical disorders may elevate serum K+ concentration (e.g. potassium supplements, ACE-inhibitors, worsened renal function
-more recent drug and reportedly lower impact on sex hormones.
Note: It is a substrate of CYP3A4, which potentially will be affected by drugs that inhibit or induce this system.
2. B-blockers (for CHF)
-As mentioned previously (in the pathophysiology notes), heart failure is characterized by sympathetic hyperactivation (heart pumps faster/harder to increase cardiac output etc)
-The body has these compensatory mechanisms to (a) enhance inotropy (b) Augment ventricular relaxation and filling (lusitropy-myocardial relaxation) (c) Increase rate (chronotropy) which worsens CHF
–For many years (in the past), treatment of heart failure involved drugs that furthur stimulated responses (e.g. digoxin-positive inotrophy)
-The rationale for that was CHF main pathological cause was a drop in CO/SV as a result of myocardial dysfunction.
-However many of these sympathetic mimicking drugs increased mortality (death rate) in CHF patients whereas an unexpected decrease in mortality has been observed in administration of B-blockers.
-Now, it is accepted that sustained activation of sympathetic nerves in the myocardial injury contributes to progression of contractile dysfunction.
-This is supported by the adverse consequences of long-term sympathetic stimulation.
1. Proliferation in the myocardium (Hyperplasia)
2. Direct Cardiomyocyte toxicity
3. Myocyte apoptosis
4. Increase in renin production (B1 receptors on JGA)
2.1 Mechanisms of action of B-Blockers
-Improve heart failure symptoms
-Improve exercise tolerance
-Improves ventricular function (over a peroid of several months in patients with CHF)
*However, a decrease in systolic pressure (afterload) would be expected immediately after administration of B-blocker in a CHF patient.
-Systolic function will recover and improve beyond baseline levels within the next 2-4 months.
-B-blockers ameliorate symptoms, reduce hospitalisation and decrease mortality in patients (mild to moderate cases of CHF)
Why does B-blockers decrase mortality?
1. This suggests a decrease in malignant ventricular arrhythmias (anti-arrhythmia benefits)
2. This might also suggest reduced hypokalemia following B-adrenergic blockade (renin-production inhibited, K+ reabsorbed into blood).
-Sympathomimetic stimulation (via adrenaline) also results in hypokalemea, which may cause cardiac arrhythmias.
3. Could also be a direct consequence of the anti-ischemic effects of B-blockers
4. B-blockers also improve left ventricular structure and function by (a) decreasing chamber size (b) increase in ejection fraction (Due to reduced signalling for cardiac remodelling)
Caution! (Counter-productive effects)
*Note: We cannot assume that all B-blockers will exert similar effects.
1. Since B-blockers have the potential to worsen both ventricular function and symptoms in patients with CHF, they should be used cautiously in this disease.
–They should be initiated at very low doses (generally less than 1/10th of the desired therapeutic dose)
-The doses should be increased slowly, over the course of weeks (until maximum dose is reached) under careful supervision.
B-blockers: Start low, Go slow,
2. Using B-blocker at doses used for hypertension or coronary artery disease may cause decompensation.
-Cardiac function is reduced is already reduced in hypertension or CAD.
-If sympathetic baroreceptor reflex is blocked as well, dyspnea, edema and venous pooling occurs.
-Even when therapy is initiated with low doses of B-blockers, there may be fluid retention requiring adjustments in diuretic regimen.
2.2 Side effects (Refer to anti-hypertensive notes): Worsen or futhur aggravates arrhythmias, Raynaud’s syndrome, Decreased sensitivity to hypoglycemia, Increased responsiveness upon abrupt cessation of B-blockers, depression.
3. Phosphodiesterase inhibitors
3.1Mechanism of action:
1. cAMP Phosphodiesterase (PDE) inhibitors reduce the degradation of cellular cAMP.
-This leads to elevated cAMP which leads to increase PKA levels which phosphorylate PRIDES (Increase calcium levels eventually)
2. Decreased arteriole resistance.
-In the peripheral vasculature, the result is the dilation of vessels of arterioles and arteries, which increases supply Oxygen to organs.
-The vasculature can now respond to neuronal and humoral signals to regulate blood flow.
-Venous capacitance, capillary capacitance increases (esp. veins since majority of blood volume is located, regional blood volume modulated)
-Leads to reduction in afterload and preload.
*These combined effects on the myocardium and in the periphery underlie classification of these drugs as “inodilators“ (dilates arterioles and positive inotropic)
Drug examples: Milrinone
-Approved fo the short-term support circulation in advanced heart failure.
-It is a bi-pyridine derivative
Mechanism of action:
- Relatively selective inhibitor of Phosphodiesterase 3 which cGMP-inhibited cAMP phosphodiesterase
- It causes direct stimulation of myocardial contractility
- Accelerates myocardial relaxation (reduce preload)
- Causes balanced arterial and venous dilation with fall in systemic and pulmonary vascular resistance and left and right heart filling pressures (Decreased afterload and preload)
∴Cardiac output increases due to stimulation of myocardial contractility and decrease in left ventricular preload.