Drugs for Treatment of Heart Failure

Question 1

What is congestive HF?

Answer 1

A condition in which the heart is unable to pump sufficient blood to meet the needs of the body

Question 2

What are the 2 forms of congestive HF?

Answer 2

1. Systolic dysfunction: impaired ventricular contraction

2. Diastolic dysfunction: impaired ventricular relaxation

Question 3

What is chronic HF characterised by?

Answer 3

• Progressive cardiac dysfunction
• Breathlessness
• Tiredness
• Neurohormonal disturbances
• Sudden death

Question 4

What are the cardiovascular consequences of HF?

Answer 4

1. Decreased cardiac output
   - Sympathetic activity
   - Decreased BP
   - RAAS to increase fluid volume
   - Edema
2. Increased venous pressure (backpressure)
   - Edema

Question 5

What are the 3 broad classes of drugs used in the therapy of chronic HF?

Answer 5

1. Positive inotropic drugs
2. Vasodilators
3. Misc. drugs

Question 6

What do inotropic drugs do?

Answer 6

Increase heart contraction

Question 7

Why is it that therapy for chronic heart failure involves positive inotropic drugs (increase heart contraction) and vasodilators (decrease CO)?

Answer 7

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)

Question 8

What are the positive inotropic drugs?

Answer 8

Glycosides
Beta agonists
PDE inhibitors

Question 9

What are the vasodilators?

Answer 9

PDE inhibitors
Nitroprusside, Nitrates, AT1R antagonist
Diuretics, ACE inhibitors

Question 10

What are the misc. drugs?

Answer 10

Diuretics, ACE inhibitors

Beta blockers, aldosterone antagonists

Question 11

What are the beta blockers specifically approved to treat HF?

Answer 11

‘Coffee Meets Bagel!!!’:
Carvedilol
Metoprolol
Bisoprolol

Question 12

What is the pathophysiology of chronic HF?

Answer 12

• 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

Question 13

What is the MOA of nitrates?

Answer 13

Activates guanylyl cyclase

• Increase conversion of GTP to cGMP
• Inactivation of myosin-LC
• Vasorelaxation (venodilation decreases preload, arteriolar dilation decreases afterload)
• Decrease O2 consumption

Question 14

What are the therapeutic effects of nitrates?

Answer 14

Vasorelaxation:

1. Venodilation (decreases preload)
2. Arteriolar dilation (decreases afterload TPR)

• Decrease cardiac load and BP

Question 15

What is the specific nitrate used for chronic HF? What does it do?

Answer 15

Sodium nitroprusside (SNP)

SNP donates NO to become = NO + cyanide + methemoglobin

Question 16

How is SNP administered?

Answer 16

IV infusion

Question 17

What is the indication for SNP?

Answer 17

Chronic or refractory HF

Question 18

What are the adverse effects of SNP?

Answer 18

1. Hypotension
2. Cyanide poisoning from cyanide side group
3. Methemoglobin leading to cellular hypoxia bc of decreased O2 carrying capacity compared to Hb

Question 19

What happens in the loop of Henle? What substances are absorbed at which part of the loop? (thin descending, loop, thick ascending)

Answer 19

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

Question 20

Where in the nephron is only water absorbed?

Answer 20

1. Thin descending limb

2. Collecting duct

Question 21

How is NaCl absorbed in the thick ascending limb? What transporter is involved? How does this affect the membrane potential?

Answer 21

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

Question 22

What are the loop diuretics (sulfonamide derivatives)?

Answer 22

• Furosemide
• Bumetanide
• Ethacrynic acid

Question 23

What are the MOAs of loop diuretics?

Answer 23

1. Selectively inhibit the luminal Na+/K+/2Cl- transporter in the thick ascending limb of Henle’s loop
2. Increase Mg2+ and Ca2+ excretion because of decreased membrane potential
3. Induce renal PG synthesis
4. (Furosemide) Increase renal blood flow

Question 24

Which part of the loop does loop diuretics work on?

Answer 24

Thick ascending limb

Question 25

Do loop diuretics have a fast or slow onset? What is the duration of effect of furosemide?

Answer 25

- Rapidly absorbed - Extremely rapid onset after IV injection - Furosemide duration of effect: 2-3h

Question 26

How are loop diuretics excreted?

Answer 26

Eliminated by tubular secretion & glomerular filtration

Question 27

What are the clinical uses of loop diuretics?

Answer 27

1. Acute pulmonary edema and other edema 2. Acute hyperkalemia 3. Acute renal failure 4. Anion overdose: toxic ingestions of bromide, fluoride, and iodide

Question 28

What are the adverse effects of loop diuretics?

Answer 28

1. Hypokalemic metabolic alkalosis 2. Ototoxicity leading to deafness 3. Hyperuricemia (ion imbalance) 4. Hypomagnesemia

Question 29

What is the contraindication for loop diuretics?

Answer 29

Avoid using together w aminoglycosides if possible

Question 30

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?

Answer 30

- 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

Question 31

What are the thiazide diuretics?

Answer 31

- Hydrochlorothiazide - Indapamide - Chlorthalidone

Question 32

What are the MOAs of thiazide diuretics?

Answer 32

1. Inhibit Na+/Cl- transporter in the distal convoluted tubule - Inhibit NaCl reabsorption - Decrease H2O reabsorption, more excreted 2. Enhance Ca2+ reabsorption 3. Action is dependent on renal PG synthesis !!! NSAIDs interfere w this by reducing PG synthesis

Question 33

What are the clinical uses of thiazide diuretics?

Answer 33

1. Hypertension 2. Congestive heart failure 3. Nephrolithiasis due to idiopathic hypercalciuria 4. Nephrogenic diabetes insipidus

Question 34

What are the adverse effects of thiazide diuretics?

Answer 34

1. Hypokalemic metabolic alkalosis 2. Hyperuricemia (ion imbalance) 3. Hyperglycemia 4. Hyperlipidemia 5. Hyponatremia

Question 35

In what group of individuals are thiazide diuretics less unsuitable for?

Answer 35

Diabetics (bc an adverse effect is hyperglycemia)

Question 36

What are the functions of the collecting tubule?

Answer 36

1. Final site of NaCl reabsorption 2. Responsible for volume regulation and for determining final Na+ conc. of the urine 3. Site at which mineralocorticoids (eg. aldosterone) exert a significant influence 4. Site of potassium secretion

Question 37

What cells are in the collecting tubule? What are their significance?

Answer 37

Principal cells: Major sites of Na+, K+, H2O transport Intercalated cells: Primary sites of proton (H+) secretion

Question 38

What happens in the collecting tubule? What substances are absorbed and what hormones have effects in this area?

Answer 38

- 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

Question 39

What are the potassium sparing diuretics? What are they also known as?

Answer 39

- Spironolactone - Triamterene - Amiloride - Eplerenone Mineralocorticoids antagonists

Question 40

What is the MOA of spironolactone and triamterene?

Answer 40

Downregulate the aldosterone receptor - Decrease Na+ reabsorption, H2O reabsorption, more H2O excretion - Decrease K+ secretion “potassium sparing”

Question 41

What is the MOA of amiloride and eplerenone?

Answer 41

Downregulate the Na+ channel expression - Decrease Na+ reabsorption, H2O reabsorption, more H2O excretion - Decrease K+ secretion “potassium sparing”

Question 42

Do potassium-sparing diuretics have a fast or slow onset?

Answer 42

Spironolactone has a slow onset (vs. loop diuretics), requires several days before full therapeutic effect is achieved

Question 43

How are triamterene and amiloride metabolised? How are they different in terms of duration of onset?

Answer 43

Triamterene: Liver - Shorter half life, must be given more frequently Amiloride: Not metabolised at all, excreted unchanged

Question 44

What are the clinical uses of potassium-sparing diuretics?

Answer 44

1. Diuretic | 2. Hyperaldosteronism

Question 45

What are the adverse effects of potassium-sparing diuretics? How is it different from loop diuretics & thiazides?

Answer 45

1. Hyperkalemia * **DOES NOT CAUSE hypokalemia unlike loop diuretics & thiazides 2. Metabolic acidosis 3. Gynecomastia (except eplerenone) 4. Acute renal failure (triamterene + indomethacin) 5. Kidney stones (triamterene)