Drugs for Treatment of Heart Failure Flashcards
What is congestive HF?
A condition in which the heart is unable to pump sufficient blood to meet the needs of the body
What are the 2 forms of congestive HF?
- Systolic dysfunction: impaired ventricular contraction
2. Diastolic dysfunction: impaired ventricular relaxation
What is chronic HF characterised by?
- Progressive cardiac dysfunction
- Breathlessness
- Tiredness
- Neurohormonal disturbances
- Sudden death
What are the cardiovascular consequences of HF?
- Decreased cardiac output
- Sympathetic activity
- Decreased BP
- RAAS to increase fluid volume
- Edema - Increased venous pressure (backpressure)
- Edema
What are the 3 broad classes of drugs used in the therapy of chronic HF?
- Positive inotropic drugs
- Vasodilators
- Misc. drugs
What do inotropic drugs do?
Increase heart contraction
Why is it that therapy for chronic heart failure involves positive inotropic drugs (increase heart contraction) and vasodilators (decrease CO)?
It’s therapy for different stages of heart failure
Early HF: decreased ventricular EF
- Therapy is to preserve this by decreasing cardiac load (vasodilators)
Late HF: further reduce in heart pumping will threaten life
- Therapy is not to maintain fn but to maximise survival (positive inotropic drugs)
What are the positive inotropic drugs?
Glycosides
Beta agonists
PDE inhibitors
What are the vasodilators?
PDE inhibitors
Nitroprusside, Nitrates, AT1R antagonist
Diuretics, ACE inhibitors
What are the misc. drugs?
Diuretics, ACE inhibitors
Beta blockers, aldosterone antagonists
What are the beta blockers specifically approved to treat HF?
‘Coffee Meets Bagel!!!’:
Carvedilol
Metoprolol
Bisoprolol
What is the pathophysiology of chronic HF?
- As the pump becomes less effective, more blood remains in the ventricles at the end of cycle
- End-diastolic volume (preload) increases
- Initially, increased preload may promote increased force of contraction, but further increase in preload causes heart to become overstretched and contract less forcefully
What is the MOA of nitrates?
Activates guanylyl cyclase
- Increase conversion of GTP to cGMP
- Inactivation of myosin-LC
- Vasorelaxation (venodilation decreases preload, arteriolar dilation decreases afterload)
- Decrease O2 consumption
What are the therapeutic effects of nitrates?
Vasorelaxation:
- Venodilation (decreases preload)
- Arteriolar dilation (decreases afterload TPR)
- Decrease cardiac load and BP
What is the specific nitrate used for chronic HF? What does it do?
Sodium nitroprusside (SNP)
SNP donates NO to become = NO + cyanide + methemoglobin
How is SNP administered?
IV infusion
What is the indication for SNP?
Chronic or refractory HF
What are the adverse effects of SNP?
- Hypotension
- Cyanide poisoning from cyanide side group
- Methemoglobin leading to cellular hypoxia bc of decreased O2 carrying capacity compared to Hb
What happens in the loop of Henle? What substances are absorbed at which part of the loop? (thin descending, loop, thick ascending)
Thin descending loop: Absorption of water only by osmosis
Loop of Henle: (point where urine is most concentrated)
Thick ascending loop: Absorption of NaCl by active transport. Impermeable to water unlike prox. tubule and thin limb
Where in the nephron is only water absorbed?
- Thin descending limb
2. Collecting duct
How is NaCl absorbed in the thick ascending limb? What transporter is involved? How does this affect the membrane potential?
Na/K/2Cl cotransporter
- Excess K+ accumulation within the cell bc of synergistic effect w basal N+/K+ ATPase
- Back diffusion of K+ into the tubular lumen via a K+ channel
- Development of lumen-positive electrical potential
- This electrical potential provides the driving force for the reabsorption of cations - including Mg2+ and Ca2+ via the paracellular pathway
What are the loop diuretics (sulfonamide derivatives)?
- Furosemide
- Bumetanide
- Ethacrynic acid
What are the MOAs of loop diuretics?
- Selectively inhibit the luminal Na+/K+/2Cl- transporter in the thick ascending limb of Henle’s loop
- Increase Mg2+ and Ca2+ excretion because of decreased membrane potential
- Induce renal PG synthesis
- (Furosemide) Increase renal blood flow
Which part of the loop does loop diuretics work on?
Thick ascending limb
Do loop diuretics have a fast or slow onset? What is the duration of effect of furosemide?
- Rapidly absorbed
- Extremely rapid onset after IV injection
- Furosemide duration of effect: 2-3h
How are loop diuretics excreted?
Eliminated by tubular secretion & glomerular filtration
What are the clinical uses of loop diuretics?
- Acute pulmonary edema and other edema
- Acute hyperkalemia
- Acute renal failure
- Anion overdose: toxic ingestions of bromide, fluoride, and iodide
What are the adverse effects of loop diuretics?
- Hypokalemic metabolic alkalosis
- Ototoxicity leading to deafness
- Hyperuricemia (ion imbalance)
- Hypomagnesemia
What is the contraindication for loop diuretics?
Avoid using together w aminoglycosides if possible
What happens in the distal convoluted tubule? What substances are absorbed and by what transporters? How is it different from in the thick ascending limb?
- Relatively impermeable to water
- NaCl reabsorption by electrically neutral Na+ and Cl- cotransporter (vs. Na/K/Cl cotransporter in the thick ascending limb), further dilutes the tubular fluid
- Active reabsorption of Ca2+ by apical Ca2+ channel and basolateral Na+/Ca2+ exchanger
What are the thiazide diuretics?
- Hydrochlorothiazide
- Indapamide
- Chlorthalidone
What are the MOAs of thiazide diuretics?
- Inhibit Na+/Cl- transporter in the distal convoluted tubule
- Inhibit NaCl reabsorption
- Decrease H2O reabsorption, more excreted - Enhance Ca2+ reabsorption
- Action is dependent on renal PG synthesis
!!! NSAIDs interfere w this by reducing PG synthesis
What are the clinical uses of thiazide diuretics?
- Hypertension
- Congestive heart failure
- Nephrolithiasis due to idiopathic hypercalciuria
- Nephrogenic diabetes insipidus
What are the adverse effects of thiazide diuretics?
- Hypokalemic metabolic alkalosis
- Hyperuricemia (ion imbalance)
- Hyperglycemia
- Hyperlipidemia
- Hyponatremia
In what group of individuals are thiazide diuretics less unsuitable for?
Diabetics (bc an adverse effect is hyperglycemia)
What are the functions of the collecting tubule?
- Final site of NaCl reabsorption
- Responsible for volume regulation and for determining final Na+ conc. of the urine
- Site at which mineralocorticoids (eg. aldosterone) exert a significant influence
- Site of potassium secretion
What cells are in the collecting tubule? What are their significance?
Principal cells: Major sites of Na+, K+, H2O transport
Intercalated cells: Primary sites of proton (H+) secretion
What happens in the collecting tubule? What substances are absorbed and what hormones have effects in this area?
- Na+, K+, H2O transport (principal cells) and H+ proton secretion (intercalated cells)
- Na+ reabsorption via epithelial Na+ channel is coupled w K+ secretion - regulated by aldosterone
- Membrane water permeability regulated by ADH-induced fusion of vesicles containing performed water channels w the apical membranes
What are the potassium sparing diuretics? What are they also known as?
- Spironolactone
- Triamterene
- Amiloride
- Eplerenone
Mineralocorticoids antagonists
What is the MOA of spironolactone and triamterene?
Downregulate the aldosterone receptor
- Decrease Na+ reabsorption, H2O reabsorption, more H2O excretion
- Decrease K+ secretion “potassium sparing”
What is the MOA of amiloride and eplerenone?
Downregulate the Na+ channel expression
- Decrease Na+ reabsorption, H2O reabsorption, more H2O excretion
- Decrease K+ secretion “potassium sparing”
Do potassium-sparing diuretics have a fast or slow onset?
Spironolactone has a slow onset (vs. loop diuretics), requires several days before full therapeutic effect is achieved
How are triamterene and amiloride metabolised? How are they different in terms of duration of onset?
Triamterene: Liver
- Shorter half life, must be given more frequently
Amiloride: Not metabolised at all, excreted unchanged
What are the clinical uses of potassium-sparing diuretics?
- Diuretic
2. Hyperaldosteronism
What are the adverse effects of potassium-sparing diuretics? How is it different from loop diuretics & thiazides?
- Hyperkalemia
* **DOES NOT CAUSE hypokalemia unlike loop diuretics & thiazides - Metabolic acidosis
- Gynecomastia (except eplerenone)
- Acute renal failure (triamterene + indomethacin)
- Kidney stones (triamterene)
