12.4 Pharmacology of Heart failure Flashcards
What is left & right-sided heart failure known as (when co-exist)?
Biventricular failure
What is heart failure?
- Heart failure is where the heart is unable to pump blood around the body properly and needs treatment to help it work
- Symptoms of heart disease include shortness of breath (dyspnoea), tiredness and swelling in your ankles or legs (**oedema)
- Also known as chronic heart failure (CHF), congestive heart failure (CHF)
What would you first prescribe someone with CHF?
Offer diuretics & then depends if CHF with or without reduced ejection fraction
What is the percentage reabsorption of Na+ in different areas of the nephron?
For the average 70kg male what is the:
- Cardiac output
- Renal blood flow (rate)
- Renal plasma flow (rate)
- Glomerular filtration rate
- Urinary flow rate
Explain the class, pharmacology, physiology, clinical of acetazolamide
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CLASS:
- Carbonic Anhydrase Inhibitor
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PHARMACOLOGY
- Target: carbonic anhydrases
- Activity: Competitive inhibitor
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PHYSIOLOGY
- ↓Na⁺ reabsorption in PCT → ↑urine flow
- ~⅓ PCT Na⁺ reabsorption is through Na⁺/H⁺ antiporter
- Diuretic effect is mild and self-limiting
- → ↓ preload → ↓ venous congestion → symptomatic relief
- Heavy loss of HCO₃⁻ → alkaline urine/metabolic acidosis → ↓diuresis
- ↑Na⁺ at DCT → ↑K⁺ loss → hypokalaemia
-
CLINICAL
- Diuretic
- Still in use for glaucoma
How is CO2 carried in blood?
- 10% dissolved in plasma
- 20% bound to Hb
- 70% converted to H₂CO₃
Explain how carbonic anhydrase is involved in the PCT (nephron)
Primary function in the kidneys is for reabsorption of HCO3-
Explain the class, pharmacology, physiology, clinical of hydrochlorothiazide
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CLASS:
- Thiazide diuretic
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PHARMACOLOGY
- Target: Na⁺-Cl⁻ symporter
- Activity: Inhibitor
-
PHYSIOLOGY
- ↓Na⁺ reabsorption in DCT → ↑urine flow
- Mild diuretic action
- Some loss of HCO₃⁻ → metabolic alkalosis
- ↑K⁺ loss → hypokalaemia
- Secreted by OATs (organic anion transporters) into PCT → ↑concentration in tubule lumen
- ↓uric acid secretion (competes for OATs) → uricaemia → ↑risk of gout
-
CLINICAL
- Hypertension; oedema
Explain the class, pharmacology, physiology, clinical of furosemide
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CLASS:
- Loop diuretic
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PHARMACOLOGY
- Target: Na⁺-K⁺-Cl⁻ symporter
- Activity: Inhibitor
-
PHYSIOLOGY
- ↓Na⁺ reabsorption in thick ascending Loop of Henle → ↑urine flow
- Potent diuretic action
- ↑↑ K⁺ loss → hypokalaemia (& metabolic alkalosis)
- Secreted by OATs (organic anion transporters) in PCT → ↑↑ concentration in tubules
- ↓uric acid secretion (competes for OATs) → uricaemia → ↑risk of gout
-
CLINICAL
- Hypertension; oedema; heart failure
Explain the class, pharmacology, physiology, clinical of spironolactone
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CLASS:
- K⁺-sparing diuretic
-
PHARMACOLOGY
- Target: Mineralocorticoid Receptor
- Activity: competitive antagonist
-
PHYSIOLOGY
- Antagonises action of aldosterone in late DCT/CD
- ↓ expression of ENaCs and Na⁺/K⁺-ATPase
- Weak diuretic effect (most Na⁺ already reabsorbed)
- K⁺ retention → hyperkalaemia
-
CLINICAL
- Often used with thiazide/loop to offset K⁺ loss
- Hypertension; oedema; heart failure
Explain the class, pharmacology, physiology, clinical of amiloride
-
CLASS:
- K⁺-sparing diuretic
-
PHARMACOLOGY
- Target: Epithelial Na channel (ENaCs)
- Activity: channel blocker
-
PHYSIOLOGY
- ↓ Na⁺ entry from lumen of DCT into cell
- Rate-limiting step of Na⁺ reabsorption
- Weak diuretic effect (most Na⁺ already reabsorbed)
- K⁺ retention → hyperkalaemia
-
CLINICAL
- Used with thiazide/loop to offset K⁺ loss
- Hypertension; oedema; heart failure – not often used in CHF
Draw the effect of spironolactone & amiloride on the nephron
In the DCT
K+ can leave to apical lumen through the apical membrane via ROMK (renal outer medullary K channel) - K+ leaves cell to balance charge associated with Na+ entry
Briefly explain mineralcorticoid receptors (MR) in the DCT
- Activation by aldosterone →
- ↑ENaC (epithelial sodium channel) - (apical membrane of DCT) and Na⁺/K⁺-ATPase expression (basement membrane of DCT)
Explain the class, pharmacology, physiology, clinical of mannitol
-
CLASS:
- Osmotic diuretic
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PHARMACOLOGY
- Target: NONE !!!!!!!
- Activity: NONE !!!!!!!
-
PHYSIOLOGY
- Does not cross membranes
- Raises osmotic pressure → draws fluid to itself
- Response proportional to concentration
- Very potent diuretic
- Substantial K⁺ loss
-
CLINICAL
- IV injection
- Used ACUTELY → rapid loss of fluid, e.g., cerebral oedema
- NOT used in chronic hypertension; congestive heart failure
What is the class, pharmacology, physiology, clinical of dapaglifozin?
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CLASS:
- SGLT2 inhibitor
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PHARMACOLOGY
- Target: SGLT2 Sodium/glucose co-transporter 2 (expressed in early PCT, have low affinity & high capacity, 1 Na+:1 glucose)
- Activity: Competitive inhibitor
-
PHYSIOLOGY
- ↓ glucose reabsorption in PCT → glycosuria → osmotic diuresis
- ↓ Na⁺ reabsorption in PCT → natriuresis
- ↓ blood glucose
-
CLINICAL
- Diabetes mellitus (mostly Type II)
- Congestive heart failure
Using a diagram show how different diuretics can target different areas of the nephron
Explain the class, pharmacology, physiology, clinical of digoxin
-
CLASS:
- Cardiac glycoside
-
PHARMACOLOGY
- Target: Na⁺/K⁺-ATPase (sodium pump)
- Activity: Competitive inhibitor (K⁺ binding site)
-
PHYSIOLOGY
- Na⁺/Ca²⁺(3Na+ in : 1 Ca2+ out) exchanger (NCX) removes Ca²⁺ from cytoplasm during diastole
- ↑ [Na⁺]ᵢ → ↓ driving force for Ca²⁺ extrusion →
- ↑ [Ca²⁺]ᵢ → ↑ force of contraction +ve inotropic effect)
- ↓ oedema (dropsy)
- TOXIC – low therapeutic index (interaction with diuretics)
-
CLINICAL
- Atrial fibrillation: ↓AV node conduction
- Congestive heart failure
