Pharmacology: Diuretics Overview

Diuretics Overview

• Diuretics increase urine excretion.
• Most diuretics are inhibitors of ion transporters, reducing sodium ion reabsorption.
• Diuretic effects vary, with weak potassium-sparing diuretics having a 2% effect, and potent loop diuretics having a 20% effect.
• Other types of diuretics include osmotic diuretics, aldosterone antagonists, and carbonic anhydrase inhibitors.
• Common indications for diuretics include edema, hypertension, and heart failure.

Strategy

• The strategy includes using scientific terms, storytelling, prioritizing fine details, and assessing risk-benefit ratios (including absolute or relative contraindications).
• Compensatory mechanisms are considered.
• Reference is made to Lippincott's Illustrated Reviews: Pharmacology 6th Edition 2015.

Risk Benefit Ratio

• Risk benefit ratio considers treatment, lifestyle changes, medication, short-term and long-term health status, and diseases/injuries (acute or chronic, life-threatening).

The Circulation

• Cardiac output (CO) is calculated by heart frequency (HF) multiplied by stroke volume (SV).
• Total peripheral resistance (TPR) is a crucial factor impacting blood pressure, which is calculated by CO multiplied by TPR.
• Different parts of the circulatory system contribute differently to blood pressure.

Compensatory Mechanisms for Blood Pressure Regulation

• First line treatment strategies are outlined as A, B, C, and D.
• Blood pressure is tightly regulated through sympathetic and renin-angiotensin-aldosterone systems.

Diuretics: Kidney and Nephron

• Diuretics' effects are understood by analyzing the kidney and nephron components: vas afferens, vas efferens, glomerulus, Bowman capsule, proximal tubule, loop of Henle, distal tubule, juxtaglomerular cells, and collecting duct.

Five Functional Zones of the Nephron

• The five functional zones of the nephron are detailed, including roles of carbonic anhydrase, bicarbonate, the organic acid, and base secretory systems within the proximal convoluted tubule
• Ascending and descending loops of Henle are described, focusing on salt reabsorption (potassium and water)
• Distal convoluted tubule is noted for calcium excretion regulation linked to parathyroid hormone.
• Collecting tubule and duct functions are discussed.

Diuretic Types: Details and Considerations

• Different types of diuretics (e.g., weak potassium-sparing diuretics, potent loop diuretics, osmotic diuretics, aldosterone antagonists, carbonic anhydrase inhibitors) and their mechanisms are detailed.
• Specific examples (e.g., Acetazolamide, Thiazides, Loop diuretics, Potassium-sparing diuretics) are highlighted with their specific actions on the nephron.

Thiazide and Thiazide-like Diuretics

• Thiazides are frequently used for hypertension.
• Thiazides target the distal convoluted tubule for sodium and chloride reabsorption inhibition.
• These diuretics must be excreted into the tubular lumen to be effective; decreased renal function negatively impacts their effectiveness.
• Interactions with NSAIDs (e.g., Indomethacin) decrease renal prostaglandin and blood flow.
• Therapeutic applications, including hypertension, heart failure, hypercalciuria, and diabetes insipidus are discussed.
• Adverse effects are detailed, including potassium depletion, hyponatremia, hyperuricemia, volume depletion, and hypercalcemia. One specific example, Hydrochlorothiazide is associated with non-melanocytic skin cancer

Loop or High Ceiling Diuretics

• Furosemide is a primary loop diuretic, with bumetanide and torsemide being more potent options.
• Ethacrynic acid is less frequently used due to adverse side effects.
• Loop diuretics impact sodium reabsorption in the ascending loop of Henle and lead to increased excretion.
• Interactions with NSAIDs can reduce renal prostaglandin and blood flow.
• Loop diuretics are first-line choices for treating lung edema and heart failure.
• They are commonly administered orally or parenterally, with effects evident within 2-4 hours.
• Adverse effects include ototoxicity, hyperuricemia, acute hypovolemia, potassium depletion, and hypomagnesemia.

Potassium-Sparing Diuretics

• These diuretics act on the collecting tubule to inhibit sodium reabsorption and promote potassium excretion.
• Aldosterone antagonists (like spironolactone, eplerenone, and finerenone), which are derived from synthetic steroids, alter hormone function related to the kidneys, but are often associated with potential side effects (such as gynecomastia and menstrual irregularities).
• Polycystic ovary syndrome treatment is another application for these diuretics.
• These drugs have varied specificities in relation to mineralocorticoid receptors affecting their efficiency.

Carbonic Anhydrase Inhibitors

• Carbonic anhydrase inhibitors decrease bicarbonate reabsorption leading to increased urine production.
• They are used for conditions like glaucoma to decrease aqueous humor production, and for mountain sickness.
• Adverse effects can include metabolic acidosis (mild) and potassium depletion, and they are also shown to be useful in treating metabolic acidosis
• Topical carbonic anhydrase inhibitors (e.g., dorzolamide and brinzolamide) are particularly effective due to their lack of systemic effects.
• The target-organ of these diuretics is the proximal tubule.

Osmotic Diuretics

• These diuretics, like mannitol, are hydrophilic substances not reabsorbed by the kidney.
• They are used to maintain urine flow after acute ingestion of toxins.
• Mannitol is administered intravenously as oral absorption is absent.
• Extracellular water expansion, dehydration, and electrolyte imbalances (hypo-or hypernatremia) are potential side effects.

Case Studies

• Case studies of patients with diuretic prescriptions and the potential problems that can develop when diuretics are misused are presented. In these cases, additional consultation with a physician is required.