Review of Pharmacology - 9E (2015)

Review of Pharmacology
impermeable to water and absorbs only solutes. By increasing excretion of solutes, thiazides
make the urine concentrated (i.e. decrease positive free water clearance without affecting negative
free water clearance). These drugs reach the lumen of nephron by secretion through organic acid
transporter system. Additional CA inhibitory action is also exhibited by thiazides. Decreased
absorption of Na + results in its greater delivery to late DT and CD that is responsible for
hypokalemia (more than loop diuretics). Chlorthiazide has minimum potency and efficacy
whereas other drugs differ only in potency (efficacy is similar). Thiazides are moderate efficacy
diuretics with low ceiling effect (flat DRC, natriuretic effect does not increase appreciably
with increase in dose). These drugs tend to reduce GFR, therefore are not indicated in renal
failure patients.
• Polythiazide and trichloromethiazide are most potent thiazides.
• Chlorthalidone is the longest acting thiazide.
• Metolazone is useful even in severe renal failure.
• Indapamide has no CA inhibitory action. It has vasodilatory property because
of which, its antihypertensive effect precedes the natriuretic effect.
Thiazides are used for the treatment
of patients with recurrent
Ca ++ stones in the kidney.
Uses
Thiazides are used as first line antihypertensive drugs. These are also used to mobilize the
edema fluid in mild to moderate heart failure. Paradoxically, these drugs decrease urine output
in diabetes insipidus. Thiazides reduce the excretion of Ca ++ in the kidney, so can be used for
the treatment of patients with hypercalciurea and recurrent Ca ++ stones in the kidney.
Kidney
Adverse effects
These are similar to loop diuretics except the effect on Ca ++ excretion. Incidence of erectile
dysfunction is greater with thiazides than with other antihypertensive drugs (like β blockers,
CCBs, ACE inhibitors and α blockers).
Interactions of thiazides and loop diuretics
• Thiazides and loop diuretics enhance digitalis toxicity by causing hypokalemia and
hypomagnesemia.
• Loop diuretics can enhance nephrotoxicity and ototoxicity of aminoglycosides.
• NSAIDs attenuate the actions of loop diuretics.
• Lithium toxicity can occur if used with diuretics (due to increased absorption of lithium
in the PT).
• Resistance to loop diuretics can be reversed by addition of thiazides and resistance to
latter can be decreased by adding potassium sparing diuretics.
218
Amiloride is drug of choice for
lithium-induced diabetes insipidus.
Potassium Sparing Diuretics
These diuretics act in the late DT and CD cells to preserve K + . Luminal membrane of these
portions of renal tubule contains epithelial Na + channels responsible for reabsorption of Na + .
Due to decreased positive charge in the lumen, a transepithelial potential difference is
generated (lumen negative). Under this potential gradient, K + and H + are secreted. These
actions are promoted by aldosterone. Drugs that inhibit the epithelial Na + channels or the
actions of aldosterone can decrease the reabsorption of Na + (diuretic effect) and excretion of
K + (potassium sparing effect) and H + .
(a) Epithelial Na + channel inhibitors
These drugs are basic in nature and reach the lumen of PT by secretion through organic base
secretory system. By travelling through the lumen, these drugs reach its site of action i.e. late
DT and CD. Important members of this group are amiloride and triamterene. Pentamidine
and high dose trimethoprim (used for pneumocystis) are also weak inhibitors of this channel.
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