Metformin mechanism of action – inhibition of gluconeogenesis and activation of AMPK

Furosemide – Mechanism of Action

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Introduction

Furosemide, also known by its brand name Lasix, is a potent loop diuretic widely used in clinical practice to manage edema and hypertension. It acts quickly and effectively, making it a drug of choice in emergency settings like acute pulmonary edema or congestive heart failure (CHF).

It is a cornerstone medication in:

  • Congestive heart failure
  • Acute pulmonary edema
  • Chronic kidney disease with volume overload
  • Hypertension (especially with volume excess)
  • Hypercalcemia (off-label)

Furosemide’s rapid onset, short duration, and high efficacy make it a must-know drug for medical, pharmacy, and nursing students in the U.S. preparing for exams such as USMLE Step 1, NCLEX-RN, NAPLEX, and PharmD coursework.

Stepwise Mechanism of Action of Furosemide

  1. Site of Action – Thick Ascending Limb (TAL):
    Furosemide acts primarily on the thick ascending limb of the loop of Henle in the nephron.
  2. Inhibition of Na⁺/K⁺/2Cl⁻ Cotransporter (NKCC2):
    It selectively inhibits the NKCC2 symporter, blocking the reabsorption of sodium (Na⁺), potassium (K⁺), and chloride (Cl⁻) ions from the tubular lumen into the renal interstitium.
  3. Disruption of Medullary Osmotic Gradient:
    This decreases the concentration gradient necessary for water reabsorption in the collecting duct, resulting in increased urinary excretion of water (diuresis).
  4. Increased Excretion of Other Ions:
    Furosemide also promotes the loss of calcium (Ca²⁺), magnesium (Mg²⁺), potassium (K⁺), and hydrogen ions (H⁺), which can lead to electrolyte disturbances.
  5. Rapid and Potent Diuresis:
    Due to its high efficacy and rapid onset, it is especially useful in acute settings involving fluid overload or edema.

Pharmacokinetic Parameters of Furosemide

ParameterValue
Bioavailability~50% (oral); varies between individuals
Onset of ActionOral: 30–60 minutes; IV: within 5 minutes
Half-life~1.5–2 hours
Protein Binding~95%
MetabolismPartial hepatic metabolism
ExcretionPrimarily renal (as unchanged drug)

Clinical Uses of Furosemide

  • Acute pulmonary edema
  • Congestive heart failure (CHF)
  • Nephrotic syndrome
  • Chronic kidney disease (CKD) with fluid retention
  • Liver cirrhosis with ascites
  • Severe hypertension with fluid overload
  • Hypercalcemia (off-label)
  • Hyperkalemia (with saline and glucose)

Adverse Effects of Furosemide

  • Hypokalemia
  • Hyponatremia
  • Hypocalcemia and hypomagnesemia
  • Ototoxicity (dose-dependent, especially with IV use)
  • Hyperuricemia (may trigger gout)
  • Volume depletion and hypotension
  • Allergic reactions (especially in sulfa-sensitive patients)

Comparative Analysis: Furosemide vs Hydrochlorothiazide

FeatureFurosemide (Loop Diuretic)Hydrochlorothiazide (Thiazide)
Site of ActionThick ascending limb (NKCC2)Distal convoluted tubule (NCC)
EfficacyHigh (strong natriuresis)Moderate
Onset of ActionFast (IV: 5 mins, oral: 30–60 mins)Slower (2–4 hours)
Use in CKDPreferredLess effective at low GFR
Calcium ExcretionIncreases (hypocalcemia)Decreases (hypercalcemia)
Electrolyte LossMore pronouncedModerate

Practice MCQs

Q1. Furosemide acts on which part of the nephron?
A. Proximal tubule
B. Distal tubule
C. Thick ascending limb ✅
D. Collecting duct

Q2. The primary transporter inhibited by furosemide is:
A. Na⁺/Cl⁻ symporter
B. ENaC
C. Na⁺/K⁺/2Cl⁻ cotransporter ✅
D. H⁺/K⁺ ATPase

Q3. Which electrolyte disturbance is most associated with furosemide use?
A. Hyperkalemia
B. Hypokalemia ✅
C. Hypernatremia
D. Hypercalcemia

Q4. What is the onset of action for intravenous furosemide?
A. 30 minutes
B. 1 hour
C. 5 minutes ✅
D. 2 hours

Q5. Furosemide is used in all of the following EXCEPT:
A. Pulmonary edema
B. Liver cirrhosis
C. Diabetes insipidus ✅
D. Heart failure

Q6. A rare but serious side effect of furosemide is:
A. Retinopathy
B. Ototoxicity ✅
C. Hepatitis
D. Asthma

Q7. Which drug should be used cautiously with furosemide to avoid excessive ototoxicity?
A. Digoxin
B. Metformin
C. Aminoglycosides ✅
D. Statins

Q8. Furosemide may increase the risk of:
A. Hypouricemia
B. Hyperuricemia ✅
C. Hyperglycemia
D. Hypophosphatemia

Q9. In patients with sulfonamide allergy, furosemide may cause:
A. Cardiac arrhythmias
B. Hemolytic anemia
C. Hypersensitivity reaction ✅
D. Stevens-Johnson syndrome

Q10. Which of the following is TRUE regarding furosemide?
A. It decreases calcium excretion
B. It has a long half-life
C. It is effective at low GFR ✅
D. It reduces LDL cholesterol

FAQs

Q1: Can furosemide be used in patients with kidney failure?
Yes, it is effective in patients with low GFR and is preferred over thiazides in CKD.

Q2: Does furosemide cause ototoxicity?
Yes, especially at high doses or when given rapidly IV. Risk increases when combined with aminoglycosides.

Q3: Should potassium supplements be used with furosemide?
Yes, they are often co-prescribed to prevent hypokalemia.

Q4: Is furosemide safe in pregnancy?
It should only be used if clearly needed; monitor fluid and electrolyte balance carefully.

References

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