Download Pharmacology Objectives 7

Pharmacology
Lecture 7 Diuretics
1) Indicate the anatomical sites in the
nephron where each class of
diuretic drug acts.
Osmotic Diuretics (red) – act in the
proximal tubule and loop of Henle.
Carbonic Anhydrase Inhibitors
(blue) – act in the proximal tubule.
Loop Diuretics (orange) – act in the
thick ascending limb of the loop of
Henle.
Thiazide Diuretics (green) – act in
the distal convoluted tubule.
Potassium-Retaining Diuretics
(purple) – act in the late distal tubule
and collecting duct.
2) Describe the mechanism of action for each class of diuretic.
Osmotic Diuretics – Mannitol is filtered by the glomerulus and not reabsorbed thus
exerting an osmotic action. Na+ reabsoption is impaired in the proximal tubule and
thick ascending limb.
Carbonic Anhydrase Inhibitors – Acetazolamide inhibits the membrane-bound and
cytoplasmic pools of carbonic anhydrase in the proximal tubule. Na+/H+ exchange
normally causes Na+ to be pumped into the interstitium and H+ to react with HCO3- in
the lumen to form H2CO3. Carbonic anhydrase converts this to CO2 and H2O. The
CO2 diffuses into the epithelial cells where carbonic anhydrase converts it back to
H2CO3. When this process is inhibited by acetazolamide, HCO3- is lost, resulting in
metabolic acidosis and an increase in Na+ and Cl- delivered to the loop of Henle.
Loop Diuretics – Furosemide (or ethacrynic acid) inhibits the Na+/K+/2Cl- symporter
of the thick ascending loop of Henle. This causes an increase in Na+ and Cl- excretion
with an associated increase in Ca2+ and Mg2+ excretion due to the loss of the
electrochemical gradient that drives their transport. The Na+ that reaches the distal
tubule causes increased K+ and H+ excretion.
Thiazide Diuretics – hydrochlorothiazide (or thiazide-like chlorthalidone) inhibits
Na+/Cl- symport in the distal convoluted tubule thus causing a moderate increase in
Na+ and Cl- excretion, chronic uses decreases Ca2+ excretion.
Potassium-Retaining Diuretics – Triamterene and ameloride inhibit epithelial Na+
channels of the late distal tubule and collecting duct where Na+ is exchanged with K+
and H+ thus causing slight NaCl excretion without K+ loss.
Aldosterone antagonists – Spironolactone is a competitive antagonist of the high
affinity aldosterone receptors found in the cytoplasm of the late distal tubule and
collecting duct, which when activated, cause NaCl reabsorption with K+ and H+
secretion into the tubular lumen. Spironolactone block this action causing NaCl
excretion without K+ loss, much like the potassium sparing diuretics.
3) Describe the use of the various types of diuretics in the management of
edematous and non-edematous disorders.
Diuretic
Uses
Mannitol
Transient management of cerebral edema
Promote renal excretion of toxins
Maintenance of renal blood flow during vascular surgery
Acetazolamide
Glaucoma, Altitude sickness, Anti-seizure medication
Rarely as diuretic
Furosemide
Pulmonary edema, Heart failure, Hypercalcemia
*Loop diuretics are appropriate for edematous disorders in all but
emergent situations
Hydrochlorothiazide Antihypertension treatment, edema states, Ca+ nephrolithaisis,
Osteoporosis, nephrogenic diabetes insipidous
Triamterene &
Not very efficacious, for use in combination with loop diuretics or
Amiloride
thiazides to offset their kaluretic effects
Spironolactone
Coadministration with other diuretics in the treatment of edema
and hypertension, also beneficial in congestive heart failure
4) Describe the interactions of diuretics with digoxin, angiotensin converting
enzyme inhibitors, nonsteroidal anti-inflammatory drugs and sulfonamide drugs
(antimicrobials, certain COX-2 inhibitors and oral hypoglycemics).
Drug
Interaction
Digoxin
Potassium-wasting diuretics (loop diuretics and thiazides) are
contraindicated because they increase the likelihood of digoxin
toxicity
ACE inhibitors
Potassium-retaining diuretics are contraindicated because they may
cause hyperkalemia
NSAIDs
Blocks prostaglandin mediated renal blood flow
Potassium-retaining diuretics are contraindicated
Sulfonamides
Furosemide should not be given to people with hypersensitivity to
sulfonamides
5) Describe the pathogenesis of diuretic-induced to fluid and electrolyte imbalance.
The major adverse effects of diuretics are fluid and electrolyte imbalance. Osmotic
diuretics can cause an increase in intravascular volume thus causing or worsening
heart failure. Carbonic anhydrase inhibitors cause metabolic acidosis. Loop diuretics
can cause dehydration with increase in BUN and creatinine, hypo or hypernatremia,
hypokalemia, and mild metabolic acidosis. Thiazides cause similar fluid and
electrolyte imbalances to loop diuretics. Potassium sparing diuretics can cause
hyperkalemia, which can be life threatening. Aldosterone antagonists can also cause
hyperkalemia.