Diuretics

Diuretic does and DON'Ts

1. Diuretics (except osmotics) do not "pull fluid from tissues."



2. Diuretics are not appropriate for edema caused by inflammation or any other condition where normal blood-tissue barriers have broken down. (and no, I don't understand udder edema well enough to explain thiazide + steroid for therapy).



3. Diuretics are not appropriate for edema associated with hypoproteinemia. You CANNOT replace the osmotic contribution of albumin with elevated electrolyte concentrations.



4. Diuretics do not increase GFR. (Osmotics a subtle exception IF they expand blood volume and enhance renal flow AND it was already below normal).
   • The elimination of a VERY few drugs and toxins CAN be hastened by diuretics if tubular reabsorption is a normal part of their clearance.
   • Diuretics CAN reduce DISTAL tubular concentrations of things toxic to the kidney. Aminoglycosides (among others) poison the PROXIMAL tubule.


5. Thiazide diuretics produce a gentle and sustained diuresis. They are used widely in human hypertension and heart failure. Loop diuretics produce aggressive and short-lived diuresis. Veterinarians rarely use thiazides and tend to rely on Lasix.

   Veterinarians rarely use thiazides and tend to rely on Lasix. Why?

   • Because "more potent is more better"
   • Because blood pressure determinations in our patients have been virtually impossible for years and are very difficult now.

Osmotic diuretics

Glucose (metabolizable)
Mannitol, Urea, Glycerin (non-metabolizable)
Iodine Radiocontrast Agents (incidental)

Mechanism(s) of Action

1. Reduce tissue fluid (edema) by creating osmotic draw from tissue to blood stream
2. Reflex cardiovascular effect by osmotic retention of fluid within vascular space which increases blood volume (contraindicated with Congestive heart failure)
3. Diuretic effect
   
   • Makes H₂O reabsorption far more difficult for tubular segments insufficient Na & H₂O capacity in distal segments
     
   • Increased intramedullary blood flow (washout)
     
   • Incomplete sodium recapture (asc. loop). this is indirect inhibition of Na reabsorption (Na stays in tubule because water stays)
   • Net diuretic effect:
     • Tubular concentration of sodium decreases
     • Total amount of sodium lost amount increases
     • GFR unchanged or slightly increased

Toxicity

1. Fluid and electrolyte imbalance
   • produces over-expansion of extracellular fluid and circulatory overload.
   • Circulatory overload may be accompanied by dilutional hyponatremia.
   • Hyperkalemia is possible

2. Extravasation
   • may cause edema and skin necrosis. (Be careful with mannitol).
   • Extravasation may also occur into central nervous system Be careful with cranial trauma cases (hemorrhage leads to extravasation)

Pharmacokinetics

Aquaretics

lithium
demeclocycline

Mechanism of Action

1. Block ADH action on distal tubule and collecting duct. Blocking ADH decreases H₂O permeability. H₂O is not recovered (distal tubule) using osmotic draw of counter-current multiplier so aquaretics reduce water reabsorption (tubule to blood stream).
2. Net effect is an increase in free water clearance

Carbonic anhydrase inhibitors

Acetazolamide
Dichlorphenamide
Methazolamide
Ethoxzolamide

Mechanism of Action

1. Carbonic anhydrase (CA) facilitates excretion of H⁺ and recovery of bicarbonate by the proximal renal tubule and ciliary epithelium of the eye. Sodium is recovered in exchange for H⁺.
2. Inhibitors block CA block sodium recovery. A very mild diuresis is produced (this is really a side effect of their use in glaucoma) because relatively unimportant mechanism for Na recovery and because proximal tubule site means that other sodium recovery mechansims continue to process their normal fraction of the sodium load.

Thiazide diuretics

Chlorothiazide
Hydrochlorothiazide

Mechanism(s) of Action

1. Block facilitated Na/Cl co-transport in the early distal tubule. This is a relatively minor Na absorption mechanism and the result is modest diuresis
2. Potassium wasting effect
   1. Blood volume reduction leads to increased production of aldosterone
   2. Increased distal Na load secondary to diuretic effect
   3. a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting
3. Increase distal Ca re-absorption (direct effect)
   • causes an increase in plasma calcium.
   • This is unimportant NORMALLY but makes thiazides VERY inappropriate choice for hypercalcemic patients.
4. Anti-diuretic effect in nephrogenic diabetes insipidus patients secondary to depletion of Na and Water.

Toxicity

• Electrolyte imbalance (particularly hypokalemia)
• Agranulocytosis
• Allergic reactions
• Hyperuricemia
• Thrombocytopenia

Pharmacokinetics

• Onset in 2 hours
• Peak in 4 hours
• Duration 6 - 12 hours
• Eliminated unchanged in the urine

Loop (High Ceiling) Diuretics

Furosemide

Mechanism(s) of Action

1. Diuretic effect is produced by inhibit of active 1 Na⁺, 1 K⁺, 2 Cl^- co-transport (ascending limb - Loop of Henle).
   • This produces potent diuresis as this is a relatively important Na re-absorption site.
2. Potassium wasting effect
   1. Blood volume reduction leads to increased production of aldosterone
   2. Increased distal Na load secondary to diuretic effect
   3. a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting (same as thiazides but more likely)
3. Increased calcium clearance/decreased plasma calcium
   • secondary to passive decreases in loop Ca⁺⁺ reabsorption.
   • This is linked to inhibition of Cl^- reabsorption.
   • This is an important clinical effect in patients with ABNORMAL High Ca⁺⁺

Pharmacokinetics (Furosemide)

• Absorption - oral bioavailability = 60 - 70 %.
  • Bioavailability is reduced with renal failure and chronic severe congestive heart failure (bowel edema?)
• Protein binding = 90% or more

• Elimination - half-life 1 - 2 hours. Half-life is prolonged with hepatic and renal failure (especially the combination).

Toxicity

Relatively frequent

• electrolyte imbalances

Relatively rare

• allergic reactions
• leukopenia or agranulocytosis
• ototoxicity
• pancreatitis
• thrombocytopenia

Drug Interactions

• Effect of loop diuretic reduced by non-steroidal anti-inflammatory drugs
• Potentiate hypotensive effects of "ACE" inhibitors
• Potentiated ototoxicity or nephrotoxicity of amphotericin B, aminoglycosides, many others
• Potentiate hypokalemia associated with amphotericin B, mineralocorticoids, some synthetic penicillins, many others (that induce hypokalemia)
• Decreased activity of oral anticoagulants, heparin, enzymes, insulin
• Potentiate neuromuscular junction blockers (hypokalemia)

Distal (Potassium Sparing) Diuretics

spironolactone
triamterene

Mechanism of action

Inhibition of Na/K exchange at aldosterone dependent distal tubular site
Spironolactone - competes with aldosterone for regulatory site
Triamterene - decreases activity of pump directly

• Either mechanism decreases potassium wasting
  
• Either mechanism produces poor diuresis (when used alone)
  
  • relatively unimportant Na recovery site

• sodium load (body) is high
• aldosterone concentrations are high
• sodium load (tubule) is high - secondary to diuresis

Drug interactions

see other references - interact with any other drugs affecting:
sodium balance
potassium balance
renin-angiotensin-aldosterone see other references - interact with any other drugs affected by:
electrolyte balance

Toxicity

• spironolactone may produce adrenal and sex hormone effects with LONG-TERM use
• Both drugs may produce electrolyte imbalance

Renal Physiology

Overview

• 1/5 of plasma water passes into tubule through glomerulus
• 99% of water and 90+% of electrolytes recovered
• metabolically useful compounds are recovered

Sites of diuretic action

1. Proximal tubule high metabolic activity (secretion/resorption)
   Recovery of:
   • 65% to 80% of sodium and water (Na/Cl co-transport, water follows)
     
   • 99% of glucose, protein, amino acids recovered
2. Descending limb - Loop of Henle
   • passive diffusion of urea, H₂O, Na (thin wall)
   • source of counter-current multiplier
3. Ascending limb - Loop of Henle
   
   • strong active transport - Na
   • not permeable to H₂O, urea
4. Distal tubule - diluting segment
   • as for ascending limb - loop
5. Distal tubule / Collecting tubule
   • not permeable to urea
   • active sodium resorption
   • sodium / potassium exchange
   • water permeability under ADH influence

Net Effects: Interaction between physiology and pharmacology

Pre-existing physiologic parameters

• Whole-body electrolyte values
• Whole-body water content
• ADH concentrations
• Renal status
• Blood flow
• Medullary tonicity
• ADH responsiveness

Disease states

• Hypercalcemia
• Hyperaldosteronism

Previous diuretic therapy

• Type (how has electrolyte status been altered?)
• Duration (single dose vs. several days)

Topic Summary (Diuretics)

1. The potency of diuretics depends on the importance (relative to Na and H₂0 recovery) of the site of action and the opportunity that the kidney has to process the tubular fluid after the diuretic has acted.
   
   
2. Net effect of a diuretic also depends on the pre-existing state of the cardiovascular system relative to fluid and electrolyte composition.
   
   
3. Potassium wasting associated with diuretics is directly dependent on the amount of additional sodium retained in the tubule and the plasma concentration of aldosterone.
   
   
4. Osmotic diuretics are used primarily to reduce tissue (usually CNS or renal tubule) edema and to expand circulatory volume. This ability is HIGHLY dependent on intact blood vessels (contraindicated with CNS trauma).
   
   
5. Aquaretics are only used clinically for "inappropriate" secretion of ADH (rare).
   
   
6. Carbonic anhydrase inhibitors are never used as diuretics but do reduce production of aqueous humor (eye).
   
   
7. Thiazide diuretics produce a mild but sustained diuresis that tends to be limited by dehydration. They are useful for chronic diuretic therapy in congestive heart failure and primary hypertension.
   
   
8. Loop diuretics produce a potent but short-lived diuresis that is not limited by dehydration. They are most useful for emergency reduction of fluid volumes in congestive heart failure. Because of advertising and potency (over-rated) they are the primary class of diuretics used in veterinary medicine.
   
   
9. Loop diuretics also appear to have a primary effect on prostaglandin production. Associated with modest vasodilation, bronchodilation, and autoregulation of renal blood flow.