23B08: Exam Report

Compare and contrast the pharmacology of frusemide and acetazolamide

31% of candidates passed this question.

Pharmacology questions largely have a standardised structure to follow; pharmaceutics, pharmacokinetics and pharmacodynamics.

However compare and contrast questions require answering in a way that highlights important similarities and differences between the drugs chosen and the impact of these differences when administered.

Whilst these are both diuretics they have very different renal and non-renal effects and thus very different metabolic and electrolyte disturbances.

It was expected that these points be highlighted as well as the provision of other pharmacological information in order to pass this question.

H3i / 23B08: Compare and contrast the pharmacology of frusemide and acetazolamide

Pharmaceutics

  • Both sulfonamide derivatives (and contraindicated in patients with true sulfur allergies) 
  • Both come in oral and IV formulations.

Frusemide

  • Anthranilic acid (sulfonamide derivative),
  • High-ceiling, loop diuretic
  • PO – 20/40/500 mg tablets
  • Syrup – 20/40/500 mg in 5 ml available
  • Fixed dose combinations with amiloride, triamterene, spironolactone and KCl also available
  • IV – clear solution that must be protected from light, 10 mg/ml

Acetazolamide

  • Sulfonamide
  • Carbonic anhydrase inhibitor
  • PO – 250 mg tablets
  • Vials – 500 mg of acetazolamide for reconstitution with water prior to injection

Indications

  • Can be used in diuresis but wide otherwise, widely different indications

Frusemide

  • Fluid overload of all aetiologies
  • Acute pulmonary oedema
  • Electrolytes – Hyperkalemia, Hypercalcaemia
  • Chronic renal insufficiency
  • Hypertension
  • Raised ICP

Acetazolamide

  • Glaucoma
  • Petit Mal epilepsy
  • Meniere disease
  • Familial periodic paralysis
  • Prophylaxis and treatment of altitude sickness
  • Diuresis and decrease in intraocular pressure

Mechanism of Action

  • Different mechanisms of action and target sites

Frusemide

  • PO – 20-2000 mg/day

  • IV – 10-1000 mg recommended

  • Infusion not to exceed 4 mg/min due to risk of ototoxicity

Acetazolamide

  • PO/IV – 250-1000 mg/day

Dosages

Frusemide

  • Inhibits Na/K/2Cl transporter on Thick Asc. LoH
  • Most potent diuretic
  • 25% filtered Na+ not reabsorbed, thus increased presentation of solute to distal tubule
  • Potent diuresis
  • Late in tubule ∴ minimal compensation
  • Loss of counter-current multiplier of medulla nephrons
  • Loss of K+ recycling generating +ve luminal voltage
  • ∴loss of Mg2+ & Ca2+

Acetazolamide

  • Non-competitive inhibition of CA
  • CA present in PCT (heaps), Thick Asc. LoH
  • Intercalated cells of Collecting Duct
    • ↓H+ supply in cell of tubule
    • H/Na antiporter can’t work
    • Na not reabsorbed
    • Na+, HCO3–, H2O lost in urine

Pharmacodynamics

  • Both cause diuresis and loss of electrolytes
  • Main difference being furosemide causing metabolic alkalosis and acetazolamide inducing metabolic acidosis.
  • IV furosemide also has a limit on speed of administration.

CVS

Frusemide

  • Systemic vasodilatation
  • Hypotension

Acetazolamide

Resp

Frusemide

  • Pulmonary vasodilation

  • Symptomatic relief of breathlessness prior to diuresis

Acetazolamide

  • Compensatory increase in ventilation in response to metabolic acidosis and increased tissue CO2

CNS

Frusemide

  • Reduces ICP

Acetazolamide

  • Anticonvulsant properties, possibly related to an elevated CO2 tension within CNS
  • Decreases pressure of CSF and intraocular compartment by decreasing rate of formation of the CSF and aqueous humour (by 50-60%)

GIT

Frusemide

Acetazolamide

  • Inhibits gastric and pancreatic secretion

Renal

Frusemide

  • Free water clearance is increased
  • Renal blood flow is increased and redistributed in favour of inner corticomedullary flow
  • Oxygen consumption in loop of Henle is reduced to basal levels and may protect the kidney from ischemia.

Acetazolamide

  • Increases loss of bicarbonate, inducing a hyperchloremic metabolic acidosis

Metabolic

Frusemide

  • Metabolic alkalosis
  • Serum urate concentrations increased

Acetazolamide

  • Interferes with iodide uptake by the thyroid

Toxicity

Frusemide

  • Hypokalemia, hypocalcaemia, hypomagnesaemia
  • Interstitial nephritis
  • Ototoxicity when administered at a rate > 4 mg/min (hearing impairment, deafness, reversible tinnitus)

Acetazolamide

  • Metabolic acidosis
  • GIT and haemopoietic disturbances, rashes, renal stones and hypokalemia

Pharmacodynamics

  • Both well absorbed and are highly protein bound.
  • Frusemide is metabolised in the kidney while acetazolamide is not metabolised at all.
  • Both excreted mostly by kidneys.

A

Frusemide

  • 60-70% absorbed after PO administration.
  • Oral bioavailability 43-71%

Acetazolamide

  • Rapidly and well absorbed when administered orally (virtually 100%)

D

Frusemide

  • 96% protein binding, exclusively to albumin
  • Vd – 0.11-0.13L/kg

Acetazolamide

  • 70-90% protein bound in the plasma

M

Frusemide

  • Metabolised in the kidney to a glucuronide

Acetazolamide

  • Not metabolised in man

E

Frusemide

  • 80% excreted as unchanged / glucuronidated furosemide, rest in faeces

Acetazolamide

  • Excreted unchanged in urine

Special points

Frusemide

  • Effects of NDMB may be enhanced by furosemide (likely due to hypokalemia and hypomagnesemia).
  • Response of vasopressors may be diminished and vasodilators enhanced as manifestations of contracted circulating blood volume.

Acetazolamide

  • Contraindicated in presence of hepatic ore renal failure as it worsens metabolic acidosis and may cause urolithiasis
  • Removed by haemodialysis

Author: Michael Wu