Renal and Genitourinary Systems

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Chapter 25 Renal and Genitourinary Systems

Thiazide Diuretics

Description

Diuretics result in increased urine production and also lower blood pressure.

Prototype and Common Drugs

Prototype: hydrochlorothiazide

Others: chlorothiazide, chlorthalidone

MOA (Mechanism of Action)

Generally speaking, diuretics manipulate a solute (usually Na⁺), and water passively follows.

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Specifically, thiazide diuretics inhibit the Na⁺/Cl⁻ co-transporter channel in the distal tubule of the nephron (Figure 25-1).

Therefore Na⁺, Cl⁻ (and water) remain in the lumen of the tubule: natriuresis and diuresis. In addition, the actions of the thiazides impact other ions.

A passive Na⁺/H⁺ exchange occurs at a distal site in the tubule. Na⁺ gradients drive this exchange. When the Na⁺/Cl⁻ cotransporter is blocked, the Na⁺ concentration in the lumen of the tubule is high, which facilitates Na⁺ reabsorption in exchange for excretion of H⁺ ions at this distal site. Therefore thiazides create alkalosis by H⁺ ion loss through a secondary, passive exchange.

Similarly, Na⁺ is exchanged for K⁺ at a distal site in the tubule. By enhancing delivery of Na⁺ to distal sites of the nephron, Na⁺ is exchanged for K⁺, leading to enhanced K⁺ excretion, in a similar manner to the K⁺ depletion that occurs with loop diuretics.

Thiazides also promote Ca⁺² reabsorption through a poorly understood mechanism.

Owing to the fact they act so distally in the nephron, after much of the Na⁺ reabsorption has already occurred, thiazides are relatively weak diuretics when compared with loop diuretics.

Thiazides are also vasodilators, an effect independent of their diuretic actions. Their antihypertensive effect is probably related mainly to this mechanism and not the diuretic mechanism.

Effect on plasma ion concentrations:

Decreased Na⁺, Cl⁻, K⁺, Mg⁺²

Increased Ca⁺²

Increased HCO₃⁻. (This creates a metabolic alkalosis.) This is a result of H⁺ ion loss. Remember that the equation will shift left with a loss of H⁺:

Figure 25-1

Pharmacokinetics

Thiazide diuretics exert their pharmacologic actions from the luminal side; therefore they must be in the lumen of the tubule to achieve their effect.

Thiazides primarily enter the renal tubule through secretion in the proximal tubule (PT) via the organic acid co-transporter. In patients with renal impairment, higher doses of thiazides may be required to overcome impaired tubular secretion and maintain sufficient tubular concentrations to achieve a pharmacologic effect.

Most thiazides become ineffective once creatinine clearance gets too low (typically <30 to 50 mL/min).

Indications

First-line treatment for hypertension

Nephrogenic diabetes insipidus (DI) (rare)

Contraindication

Sulfa allergy: Thiazide diuretics should be used with extreme caution (or not at all) in patients reporting hypersensitivity reactions to sulfa-containing drugs.

Side Effects

Dehydration and decreased Na⁺ occur.

Hypokalemia or hypokalemic metabolic alkalosis: Thiazide diuretics enhance excretion of both K⁺ and H⁺ because of increased distal tubule delivery of Na⁺, and hence Na⁺ reabsorption, in the distal nephron.

Impaired glucose tolerance is caused by impaired insulin release and diminished use of glucose.

Hyperlipidemia: Thiazide diuretics increase cholesterol and low-density lipoprotein (LDL); the mechanism has not been established.

Hyperuricemia: Thiazides compete with uric acid for secretion into the PT, reducing the excretion of uric acid. This can lead to attacks of gout.

Impotency (rare) is likely a result of reduced volume.

Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and reduced blood pressure. This is typically only seen in patients with already reduced GFR.

Important Notes

Diuretics that act on the renal tubules require functioning kidneys to exert their effects. Patients with advanced renal dysfunction will not respond to these diuretics.

As noted, thiazides are weaker diuretics than loop diuretics (such as furosemide). This is because they act at a site distal to where loop diuretics act. The loop of Henle is positioned before the distal convoluted tubule, and 90% of Na⁺ will have already been reabsorbed before the ultrafiltrate reaches the distal tubule.

Thiazides have what would appear to be a paradoxical role in the treatment of nephrogenic DI. Although the mechanism has not been confirmed, their efficacy likely stems from their ability to reduce intravascular volume, in turn stimulating Na⁺ reabsorption and reducing the amount of fluid presented to the distal segments of the nephron.

By enhancing reabsorption of calcium and subsequent reduction in urinary calcium concentration, thiazides can be used to reduce formation of calcium-containing renal stones.

Hydrochlorothiazide has a relatively flat dose-response curve, and the effective dose range is 12.5 mg to 50 mg. Doses above 50 mg will only increase the incidence of side effects, without contributing to efficacy.

Advanced

Concomitant administration of thiazides with antiarrhythmic agents that prolong the QT interval (e.g., quinidine, sotalol) may predispose to torsades de pointes. The mechanism is unknown but may be related to hypokalemia induced by the thiazide.

Evidence

As First-Line Agents in Hypertension

A 2009 Cochrane review (24 trials, N = 58,040 participants) compared benefits and harms of first-line antihypertensives with those of placebo or no treatment over a minimum of 1 year. Thiazides (19 trials) reduced mortality (relative risk [RR] 0.89), stroke (RR 0.63), and coronary heart disease (RR 0.84) versus placebo.

FYI

It is believed that thiazides also exert weak diuretic effects at the PT. Some thiazides inhibit carbonic anhydrase (CA) at this site, perhaps accounting for their diuretic effect at the PT.

Thiazides were derived from the CA inhibitor acetazolamide. It is therefore not surprising that some thiazides inhibit Na⁺ reabsorption at the PT.

Diuretics result in increased urine production and also lower blood pressure.

Prototype and Common Drugs

Prototype: furosemide

Others: ethacrynic acid, torsemide, bumetanide

MOA (Mechanism of Action)

Generally speaking, diuretics manipulate a solute (usually Na⁺), and water passively follows:

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Loop diuretics inhibit the Na⁺/K⁺/2Cl⁻ co-transporter channel in the thick ascending limb (Henle’s loop) of the renal tubule. This results in less Na⁺ being reabsorbed back into the body. Cl⁻ and K⁺ also move in the same direction through this ion channel, as does Na⁺ (Figure 25-2).

Therefore Na⁺, Cl⁻, and K⁺ are lost in the urine: Natriuresis and diuresis. Blockade of the Na⁺/K⁺/2Cl⁻ cotransporter has effects on other ions as well.

Normally, the K⁺ channel on the luminal membrane (cell membrane adjacent to the tubular lumen) and the Cl⁻ channel on the basolateral membrane (cell membrane opposite the tubular lumen) creates a potential difference between the tubular lumen (positive) and the interstitium (negative). Blockade of the Na⁺/K⁺/2Cl⁻ cotransporter interferes with the ability of these channels to create this positive to negative gradient.

Disruption of this electrochemical gradient facilitates excretion of Ca⁺² and Mg⁺². Normally these divalent cations undergo paracellular reabsorption, repelled by the positively charged tubular lumen and attracted to the negatively charged interstitium. Attenuation of the positive to negative gradient reduces paracellular reabsorption of Ca⁺² and Mg⁺², and they are excreted.

A passive Na⁺/H⁺ exchanger is present at a distal site in the tubule. Na⁺ gradients drive this exchange. When the Na⁺/K⁺/2Cl⁻ channel is blocked, the Na⁺ concentration in the lumen of the tubule is high, which facilitates the reabsorption of Na⁺ and excretion of H⁺ at this distal site. Therefore furosemide creates alkalosis by H⁺ ion loss through a secondary, passive exchange.

Similarly, by enhancing delivery of Na⁺ to distal sites of the nephron, Na⁺ is exchanged for K⁺, leading to enhanced K⁺ excretion, and this further depletes K⁺.

Like the thiazides, the loop diuretics are also believed to act as vasodilators, an effect independent of their diuretic actions. This may contribute to the anti-hypertensive effects of the loop diuretics.

Figure 25-2

Effect on Ions

Decreased Na⁺, K⁺, Cl⁻, Ca⁺², Mg⁺². Note the large number of cations excreted.

Increased HCO₃⁻. (This creates a metabolic alkalosis.) This is a result of H⁺ ion loss. Remember that the equation will shift left with a loss of H⁺:

Pharmacokinetics

Loop diuretics act on the apical (lumen) side of the tubule and therefore must be in the tubule in order to exert their effects.

Most loop diuretics are bound extensively to plasma proteins, limiting delivery of these agents to the tubules by filtration. Therefore they rely on secretion by the organic acid transport system in the PT.

The secretion of loop diuretics into the PT may be inhibited by agents that compete for weak acid secretion, such as nonsteroidal antiinflammatory drugs (NSAIDs) or probenecid.

Nephrotic syndrome

Acute hypercalcemia

Contraindications

Hypovolemia is a contraindication.

Severe K⁺ abnormalities are contraindications.

Sulfa allergy: Furosemide, bumetanide, and torsemide may be cross-reactive in those who have an allergy to sulfonamides.

Dehydration may occur.

Hypokalemia is caused by Na⁺ reabsorption in exchange for K⁺ excretion at the distal tubule.

Metabolic alkalosis (increased HCO₃⁻)

Increased exchange of Na⁺ in the lumen for H⁺ in the cell, resulting in H⁺ loss.

and that decreased H⁺ will drive the equation to the right and cause increased HCO₃⁻.

Other electrolytes disturbances: Given the large number of ions (Na⁺, Cl⁻, and so on) that are affected by these agents, electrolytes should be monitored.

Ototoxicity: Reversible hearing loss occurs most often in those with reduced renal function or who are receiving other ototoxic agents such as aminoglycoside antibiotics. The mechanism has not been established, although the Na⁺/K⁺/2Cl⁻ transporter is also found in the inner ear. High-dose furosemide can cause permanent deafness.

Hyperuricemia: The reduction in volume induced by the potent actions of loops elicits a compensatory increase in uric acid reabsorption in the PT. Loop diuretics also compete with uric acid for secretion into the PT. Increased levels of uric acid may precipitate attacks of gout.

Renal dysfunction (increased serum creatinine) may occur secondary to hypovolemia and reduced blood pressure. This is typically only seen when high doses are used in patients with already reduced GFR.

Diuretics versus Placebo or Other Interventions for Treatment of Heart Failure

A 2006 Cochrane review (14 trials, N = 525 participants) compared diuretics with placebo (seven trials) and other interventions (seven trials) for treatment of heart failure. The diuretics included were a mixture of loop diuretics, potassium-sparing diuretics, and thiazides. Based on three trials (N = 202 participants), diuretic treatment reduced the odds of death versus placebo (OR 0.24), and in two trials (N = 169 participants) it reduced the odds of admission because of worsening heart failure (OR 0.07). Diuretics improved exercise capacity in four trials (N = 91 participants) versus active controls.

Blood-Pressure–Lowering Effect versus Placebo or No Treatment

A 2009 Cochrane review (nine trials, N = 460 participants) compared the blood-pressure–lowering efficacy, tolerability, and biochemical effects of a variety of loop diuretics versus placebo or no treatment. The authors found a mean reduction (systolic/diastolic blood pressure) of −7.9/−4.4 mmHg and no differences between drugs in this class with respect to blood-pressure–lowering efficacy. This is considered to be a modest antihypertensive effect. Withdrawals because of adverse effects and biochemical changes were not significantly different from control.

Important Notes

Diuretics that exert their effects by acting on the renal tubules require functioning kidneys to induce diuresis. Patients with advanced renal dysfunction will not respond to these diuretics.

Loop diuretics are much stronger diuretics than thiazides. This is because they work in the loop of Henle, which is positioned before (proximal to) the distal convoluted tubule where the thiazides work.

Potassium-Sparing Diuretics

Potassium-sparing diuretics are diuretics that result in increased urine production and also lower blood pressure while increasing serum levels of potassium.

Prototypes and Common Drugs

Aldosterone Antagonist

Prototypes: spironolactone

Others: eplerenone

Epithelial Na Channel (ENaC) Blockers

Prototypes: Triamterene, amiloride

MOA (Mechanism of Action)

Diuretics manipulate a solute (usually Na⁺), and water passively follows:

↓ Na⁺ reabsorbed in kidney → ↑ Na⁺ lost in urine → ↑ water lost in urine

Thus most diuretics lead to enhanced Na⁺ in the lumen of the tubule (i.e., the urine). High Na⁺ concentrations in the tubule lead to a compensatory reabsorption of Na⁺ in exchange for K⁺ excretion in the distal nephron, leading to the hypokalemia associated with many diuretics.

The goal of potassium-sparing diuretics is to prevent this reabsorption of Na⁺ and subsequent loss of K⁺ in the late distal tubule or collecting duct of the nephron.

The exchange of Na⁺ for K⁺ in the distal nephron is mediated by the actions of the epithelial Na⁺ channel (ENaC) on the luminal side of the membrane and the Na⁺/K⁺-ATPase pump on the basolateral membrane (side opposite the lumen of the tubule).

The basolateral Na⁺/K⁺-ATPase pump creates a gradient for the entry of Na⁺ into the cell from the ENaC on the luminal side of the membrane.

The Na⁺/K⁺-ATPase pump actively pumps Na⁺ out of the cell into the interstitium, in exchange for a K⁺ ion.

The Na⁺ that is lost from the cell is replaced by another Na⁺ ion, which enters passively through ENaC.

The K⁺ that entered the cell exits into the lumen of the tubule through a K⁺ channel.

The potassium-sparing diuretics inhibit this exchange of Na⁺ for K⁺ by inhibiting ENaC alone or both ENaC and the Na⁺/K⁺-ATPase pump.

Triamterene and Amiloride

Amiloride and triamterene inhibit ENaC on the luminal membrane, preventing Na⁺ from moving from the tubular lumen into the cell. This keeps Na⁺ in the lumen of the tubule, therefore facilitating natriuresis.

Reduced entry of Na⁺ into the cell also reduces the amount of Na⁺ that can be exchanged for K⁺ at the ATPase pump. With the Na⁺/ K⁺-ATPase pump unable to exchange Na⁺ for K⁺, the K⁺ stays in the bloodstream.

Spironolactone and Eplerenone (Figure 25-3)

Spironolactone and eplerenone directly antagonize aldosterone:

Normally, aldosterone binds to the mineralocorticoid receptor (MR).

The MR-aldosterone complex translocates to the nucleus, where it binds to specific DNA sequences to increase the number of ENaC channels and Na⁺/K⁺-ATPase pump.

Therefore, by blocking the MR, aldosterone antagonists inhibit the activity of ENaC and the Na⁺/K⁺-ATPase pump, reducing Na⁺ reabsorption and producing mild natriuresis and diuresis.

Inhibiting the basolateral Na⁺/K⁺-ATPase pump reduces the excretion of K⁺, increasing the amount of K⁺ in blood.

Figure 25-3

Other Effects

Spironolactone also binds to androgen and progesterone receptors. This is not by design but reflects the similarities in chemical structure between androgens (e.g., testosterone) progesterone, and aldosterone. Because these receptors are also similar in structure, spironolactone, which was designed before these receptors were mapped, binds to all three.

Antagonism at these receptors leads to some of the side effects but has also led to some unique indications for spironolactone. Eplerenone was designed after the structure of the aldosterone receptor had been mapped and is therefore more specific for this receptor.

Pharmacokinetics

Spironolactone has an active metabolite, canrenone, which is also marketed in some jurisdictions. Canrenone has a much longer elimination half-life (16 hours) than spironolactone (2 hours).

Important Notes

K⁺-sparing diuretics all produce a fairly modest diuresis and are typically given as adjunctive (add-on) therapy with more potent diuretics, with the intention of mitigating the hypokalemia associated with those agents.

Antagonism of the aldosterone receptor might have beneficial effects beyond diuresis. The Randomized Aldactone Evaluation Study (RALES) found that treatment with spironolactone significantly reduced mortality in a moderate-sized (approximately 800 subjects in each group) population, reducing the risk of death by about 30%. Risk of hospitalization was reduced by about 35%.

The results of RALES suggested that in heart failure patients, spironolactone was not simply acting as a diuretic. There are many theories as to what this additional beneficial effect might be, but most focus around the link between elevated aldosterone and heart failure. A large trial, EPHESUS (N = 6000 patients), had similar results for eplerenone in patients who had developed heart failure after a myocardial infarction. However, in EPHESUS the magnitude of benefit was not as great as in RALES; therefore it is not clear whether aldosterone antagonism alone is contributing to benefit or whether there is some other factor involved.

Drospirenone is a new progestogen that also antagonizes aldosterone receptors. It is used as a component in oral contraceptive regimens with estrogen, in the hope that the aldosterone antagonism will counteract the Na⁺ and water retention from the estrogen.

All three prototypical K⁺-sparing diuretics (spironolactone, triamterene, and amiloride) are available in fixed-dose combinations (i.e., in the same pill) with hydrochlorothiazide.

Carbonic Anhydrase Inhibitors (CAIs)

Carbonic Anhydrase (CA) is classified as a diuretic, but its important clinical effects are related to its effect on acid-base balance and on intraocular fluid formation.

Prototype and Common Drugs

Prototype: Acetazolamide

Others: Dorzolamide, brinzolamide, methazolamide

MOA (Mechanism of Action)

CA catalyzes the following reaction:

CAIs inhibit this enzyme, which results in this reaction occurring at a much slower rate compared with the catalyzed rate, effectively stopping the reaction. The difference in reaction speed is over 1000-fold (Figure 25-4).

CA is present at various sites throughout the nephron, but is mainly found on the luminal membrane of proximal tubule cells.

CO₂ is highly lipophilic and easily crosses from the lumen into the tubule cell.

As seen in the diagram, this allows for the recycling of H⁺ from the lumen into the cell and back to the lumen again.

The Na⁺ is transported across the basolateral membrane (the side opposite the tubular lumen) into the blood along with the HCO₃⁻. The net effect of these movements is Na⁺ and HCO₃⁻ reabsorption. Note that “H₂O” is embedded in HCO₃⁻.

The movement of these ions is largely driven by electrical and concentration gradients. Therefore inhibiting CA will effectively stop this entire cycle.

Thus the effect of CAIs is to reduce the reabsorption of both Na⁺ and HCO₃⁻. The net effect is loss of Na⁺ and HCO₃⁻ in the urine.

The effect of CAIs on the acid-base status is that loss of HCO₃⁻ lowers the pH.

Figure 25-4

Pharmacokinetics

Acetazolamide is cleared by the kidneys, whereas methazolamide is cleared primarily by the kidneys but also partially by the liver.

Dorzolamide and brinzolamide are administered topically, as eye drops in the management of glaucoma.

Metabolic alkalosis

Acute mountain sickness (altitude sickness)

Contraindications

No major contraindications

Hyperchloremic metabolic acidosis occurs because of reduction in bicarbonate stores.

Renal stones: Renal output of phosphates and calcium increases with CAI use. Chronic use of CAIs may also reduce excretion of solubilizing factors and, coupled with the alkalinization of the urine (Ca⁺² salts are relatively insoluble at alkaline pH), creates an ideal environment for stone development.

Hypokalemia: Additional NaHCO₃ in the collecting tubule stimulates the secretion of K⁺ because of maintenance of the ion gradient.

Important Notes

Acting early in the nephron, the diuretic actions of CAIs are countered by a number of sites for Na⁺ reabsorption that appear distally in the tubule. That, coupled with the complication of metabolic acidosis, has limited the therapeutic usefulness of CAIs in the management of edema, and certainly in hypertension. In fact, CAIs are not even used for the treatment of edema or hypertension currently.

The main use for CAIs at present is in the treatment of glaucoma (increased intraocular pressure [IOP]). The most popular agents are topical (dorzolamide, brinzolamide) drops administered to the eye. Locally administered agents are very low dose and therefore avoid the diuretic and systemic metabolic effects.

The tendency toward metabolic acidosis helps to stimulate breathing, which, through a mechanism not entirely understood, helps a climber acclimatize more quickly to high altitude.

One systematic review found that acetazolamide was more efficacious than placebo in preventing acute mountain sickness (number needed to treat [NNT], two to three). A lower dose was not found to be more effective than placebo.

How do CAIs work in the treatment of glaucoma? Glaucoma is a condition of the eye characterized by increased intraocular pressure (IOP). CA located in the ciliary processes of the eye results in the formation of HCO₃⁻ in aqueous humor. By decreasing the rate of formation of aqueous humor, CAIs reduce IOP.

Osmotic Diuretics

Osmotic diuretics increase the oncotic pressure of fluids and carry water with them.

MOA (Mechanism of Action)

Osmotic agents increase the oncotic pressure of the blood; this pulls water from tissues and increases the volume of the blood acutely. The increased blood volume will inhibit renin release, thus increasing renal blood flow.

Osmotic agents freely enter the glomerulus and Bowman’s space and enter the nephron in the ultrafiltrate.

Osmotic diuretics are not reabsorbed from the lumen of the nephron and create an osmotic force, pulling more fluid into the lumen. This is then carried out as urine.

As a second primary mechanism for a diuretic, the increased renal blood flow effectively washes away solutes from the renal medulla, reducing tonicity in this region of the kidney. The hypertonicity of the medulla is a major driving force for reabsorption of fluid from the renal tubule. Reducing this tonicity mitigates the forces that concentrate the urine in the ascending limb of Henle.

Lowering the concentration of Na⁺ in the ascending limb of Henle reduces the driving force for Na⁺ reabsorption in this region, leading to diuresis.

Pharmacokinetics

Osmotic diuretics are poorly absorbed, so they are given parenterally (intravenously).

Raised intracranial pressure (ICP) and cerebral edema. The concept behind using osmotic manipulation for treating raised ICP is that water will get sucked out of the brain and into the blood (which has high osmotic pressure from the mannitol); this will reduce brain swelling and ICP.

Glaucoma is an indication for use of these agents.

Disequilibrium syndrome in dialysis (rare): Osmotic diuretics restore fluid to the extracellular compartment in patients who have been dialyzed and develop problems with the rapid shift in fluid and electrolytes that can sometimes accompany dialysis.

Contraindications

Active cranial bleeding: If bleeding is occurring into the brain, then the mannitol will be directly added to the brain and will raise the osmotic pressure in the brain and lead to water being added to the brain, which is the opposite of what the mannitol is being given for.

Continuous administration of mannitol should not occur, because the drug will accumulate in the tissues and result in osmotic-induced tissue edema, including in the brain.

Extracellular volume expansion: Osmotic diuretics rapidly distribute to the extracellular compartment, extracting water from cells. Before onset of the diuresis, this can lead to expansion of the extracellular space. Frank pulmonary edema can arise in patients with heart failure or pulmonary congestion.

Dehydration and hypernatremia: Excess use without fluid replacement can lead to dehydration. Composition of serum ions and fluid balance should be monitored.

Important Notes

Osmotic diuretics increase the excretion of nearly all electrolytes (Na⁺, K⁺, Ca⁺², Mg⁺², Cl⁻, HCO₃⁻, and phosphate).

Patients with uncontrolled diabetes mellitus will have an osmotic diuresis from elevated blood glucose. This is what causes polyuria (excessive urination), leading to thirst and excessive drinking of fluids (polydipsia).

Acute Traumatic Brain Injury

A 2007 Cochrane review (four trials, N = 197 participants) compared different mannitol regimens with other interventions, including placebo and no treatment, in patients with acute traumatic brain injury. There was no difference in the incidence of death between mannitol and “standard care,” pentobarbital, hypertonic saline, or placebo.

Mannitol is a six-carbon sugar alcohol. It was first discovered in the sap of a plant and was thought to resemble biblical food; therefore the plant was called manna ash, after manna (biblical reference to food).

Antidiuretic Hormone (Vasopressin) Analogues

Vasopressin analogues are analogues of the hormone vasopressin (also called VP, antidiuretic hormone [ADH] or arginine vasopressin [AVP]).

Prototype and Common Drugs

Prototype: vasopressin (identical to what the body produces)

Others: desmopressin (DDAVP), terlipressin

MOA (Mechanism of Action)

Vasopressin is produced in the hypothalamus and stored in the posterior pituitary gland. Factors that stimulate its physiologic release include increased serum osmolarity and hypotension. Its primary actions are therefore to increase body water to control osmolality and to increase blood pressure. A third action that it exerts is to help stop bleeding through platelet stimulation.

Vasopressin binds two types of receptors: V₁ and V₂. V₁ is subtyped into V_1a and V_1b. V₁ receptors are found in many locations of the body, including endothelium and many other sites. V₂ receptors are located in the collecting ducts of the nephron.

At very low concentrations vasopressin acts on V₂ receptors. Only at higher doses are the V₁ receptors activated.

Vasoconstriction

V₁ receptors are located on vascular smooth muscle and produce a potent vasoconstrictor effect when stimulated. This occurs only at higher serum levels of vasopressin.

Activation of V₁ receptors results in increased intracellular calcium.

The hemodynamic effects of vasopressin are similar to norepinephrine; the difference is that norepinephrine also possesses some β-agonist activity and therefore will increase heart rate and contractility, whereas vasopressin will not.

Filtrate that reaches the collecting duct in the kidney has been diluted by previous tubules. Therefore filtrate that is reabsorbed in the collecting duct is quite dilute and low in sodium.

V₂ receptors are located in the collecting duct of the nephron. When stimulated, they activate pores called aquaporins (e.g., aquaporin 2). These pores usually are stored in intracellular vesicles and when stimulated by vasopressin will fuse with the luminal membrane and facilitate the reabsorption of water from the nephron lumen back into the body. In the absence of the vasopressin and the aquaporins, the collecting duct is impermeable to water and will not absorb any water.

Desmopressin is a synthetic compound; it is more specific for V₂ receptors and has a longer half-life than vasopressin. Compared with vasopressin, desmopressin (DDAVP) is 3000 times more selective for V₂ receptors. Therefore desmopressin minimizes the potent vasoconstrictor effects associated with vasopressin.

Platelet Function

Factor VIII and von Willebrand’s factor (vWF) bind together and then bind platelets, which causes platelet activation. A deficiency in either of these two factors will result in decreased platelet function and bleeding disorders (hemophilia A and von Willebrand’s disease).

Desmopressin binds to V₂ receptors, which are instrumental in endothelial release of factor VIII.

Pharmacokinetics

Both agents are poorly absorbed through the oral route.

Vasopressin is administered by intravenous infusion. It has a short half-life and therefore is given by infusion.

Desmopressin can be administered by the intravenous, subcutaneous injection, or intranasal routes. Intranasal is the preferred route of administration for desmopressin for patients not in the hospital.

To decrease urine production:

Central DI (deficiency of ADH secretion)

Nocturnal enuresis (bedwetting)

To help reduce bleeding:

von Willebrand’s disease (vWF deficiency)

Hemophilia A (factor VIII deficiency)

Vasopressin, Terlipressin

To provide vasoconstriction:

Pathologic states of vasodilation:

• Sepsis (vasopressin only)

• Liver failure

Contraindications

Desmopressin only: patients at risk for unregulated water consumption (psychogenic polydipsia), because they can develop hyponatremia

Excessive vasoconstriction. The use of vasopressin should be restricted to physicians trained in critical care.

Water intoxication (hyponatremia): This is caused by the antidiuretic action and results in water retention leading to dilution of electrolytes, specifically Na⁺.

Hypotension (paradoxical to other analogues): If administered by the intravenous route, desmopressin must be given slowly.

Important Notes

DI can be classified as central (neurogenic) or nephrogenic.

Central DI is a condition of ADH deficiency caused by low or no production.

Nephrogenic DI is a condition of nonresponsiveness of the kidney to normal circulating levels of ADH.

In DI there is too much water relative to Na⁺ in the blood. Therefore, hyponatremia exists. Furthermore, there is very little water in the urine and so the urine osmolality is very high.

Varices are abnormal blood veins: dilated, elongated, and tortuous. They are caused by abnormally high venous pressures. They are most commonly seen in the gastrointestinal (GI) tract (esophagus, anus) in patients with liver failure and portal hypertension and also in the legs when one-way valves in the upper leg fail to prevent backflow and pressure. Administration of vasopressin or other vasoconstricting analogues results in mesenteric vasoconstriction and reduced blood flow and thus reduced portal blood pressure. This is beneficial to patients with portal hypertension secondary to liver disease who have bleeding variceal vessels in the esophagus.

There are many subtypes of von Willebrand’s disease, depending on the levels of vWF in the body. Desmopressin is really effective in only the mild forms of the disease.

V₂ antagonists are the newest class of diuretics. These agents are referred to as aquaretics, because by blocking V₂ receptors in the collecting duct they produce a water diuresis, with minimal loss of electrolytes. The first aquaretic, tolvaptan, has been approved in most jurisdictions for patients with volume overload and electrolyte problems that would be exacerbated by conventional diuretics.

Desmopressin and Bedwetting (Enuresis) in Children

A Cochrane review in 2002 (47 studies, 3448 children) demonstrated that desmopressin is effective at reducing bedwetting but that the effects do not persist when the drug is stopped. Using a wake-up alarm (the alarm goes off when the child gets wet) was just as effective as desmopressin but had better long-lasting effects.

Desmopressin and Surgical Blood Loss in Patients without Bleeding Disorders

A Cochrane review in 2004 (19 studies, 1387 patients) demonstrated that bleeding with desmopressin was statistically less compared with placebo (mean difference = 241 mL less). However, there was no difference in blood transfusions, and the volume of blood loss reduction is not a clinically significant amount.

Diabetes: to go through entirely (referring to water in the body)

Insipid means lack of flavor or taste. Mellis means honey.

The urine is bland in DI. The urine is sweet in diabetes mellitus.

Varix means twisted. Varicose veins are twisted.

DDAVP stand for 1-desamino-8-d-arginine vasopressin.

Aquaporin 1 is present in the proximal tubule and is responsible for water reabsorption in this part of the nephron. It is not responsive to AVP.

Syndrome of inappropriate ADH (SIADH) is a condition of too much ADH. It is essentially the opposite of DI.

Oxytocin and vasopressin are structurally very similar. Therefore oxytocin and vasopressin agonists or antagonists can interact with either receptor.

Anticholinergics: Bladder

Bladder anticholinergics are agents that antagonize muscarinic receptors and are used to treat overactive bladder (OAB), a form of incontinence.

Prototype and Common Drugs

Prototype: darifenacin

Others: solifenacin

Prototype: oxybutynin

Others: tolterodine, trospium

MOA (Mechanism of Action)

The human bladder contains all five subtypes (M1 to M5) of muscarinic (M) receptors. Although M2 receptors are more abundant in this region, M3 receptors mediate contraction of the detrusor muscle in the bladder.

Detrusor muscle contraction facilitates emptying of the bladder (micturition). Abnormal contractions of the detrusor, also known as hyperreflexia, can lead to incontinence, specifically urge incontinence. Urge incontinence is defined as the inability to reach the toilet in time following the urge to urinate (Figure 25-5).

Anticholinergics that antagonize the M3 receptor inhibit these detrusor contractions, easing the symptoms of urge incontinence.

Muscarinic receptors, both M3 and other subtypes, are also found throughout the human body.

M1 receptors are found in the central nervous system (CNS), on glands (enteric and salivary), and on enteric nerves.

M2 receptors are found in the CNS, heart, and smooth muscle, including the bladder.

M3 receptors are found in the CNS, heart, smooth muscle, and glands, in addition to the bladder.

Because of the wide distribution of M receptors, anticholinergics for OAB have an extensive side effect profile, and considerable research is going into localizing the effects of these agents to the detrusor.

Figure 25-5

Pharmacokinetics

Most of the anticholinergics for OAB are lipophilic, meaning that they readily cross the blood-brain barrier. The exception is trospium, a polar molecule that does not cross into the brain.

The half-lives of these agents vary widely, and agents with short half-lives (oxybutynin, tolterodine) typically have extended-release (ER) preparations available.

Oxybutynin is also marketed as a transdermal patch. The patch is applied twice weekly and delivers 3.9 mg of oxybutynin per day.

OAB with symptoms of urge urinary incontinence, urgency, and frequency

Contraindications

Conditions in which cholinergic blockade would exacerbate an already serious condition, or patients at risk for the following:

Urinary retention

Gastroparesis, gastric obstruction

Narrow-angle glaucoma (uncontrolled)

Typical anticholinergic side effects:

Important Notes

CNS side effects are a concern with the use of anticholinergics, particularly in seniors and the elderly. Attempts have been made to develop compounds that either have limited penetration into the CNS (trospium) or that bind with lower affinity to M1 receptors (darifenacin), receptors that are thought to play an important role in cognition. However, although there is some evidence of reduced CNS side effects in older, otherwise-healthy patients, there is no definitive proof that these approaches are able to reduce the burden of CNS side effects in patients with OAB.

Some of the drugs used for treating irritable bowel syndrome also have anticholinergic properties, including dicyclomine. The antagonism of muscarinic receptors in the gut helps to reduce hypermotility and may also reduce spasms.

All of the anticholinergics for OAB are metabolized by CYP3A4, with the exception of trospium, which is metabolized by non-CYP ester hydrolysis. Many of these agents are also metabolized by CYP2D6.

Anticholinergics for Overactive Bladder

A 2008 systematic review (83 trials) compared various anticholinergics in treating OAB. All the included anticholinergics (oxybutynin, tolterodine, fesoterodine, propiverine, solifenacin, darifenacin, and trospium) demonstrated efficacy in a variety of outcome measures related to incontinence (incontinence episodes, frequency, urgency) versus placebo.

Although there were no definitive conclusions with respect to comparisons among agents, there was some indication that newer agents (solifenacin) may have greater efficacy than slightly older agents (tolterodine) for some outcomes. Oxybutynin was the only agent with a higher risk of withdrawals versus placebo. Tolterodine consistently had the most favorable safety and tolerability data compared with other agents.

Controversy still exists over the relative benefit to risk of anticholinergics for OAB, particularly in seniors and the elderly. Although these agents have demonstrated improved symptoms versus placebo, the clinical significance of these benefits is constantly being weighed against a considerable list of side effects.

Alpha-1 (α₁) Antagonists

Prototype and Common Drugs

Prototype: prazosin

Others: terazosin, doxazosin, tamsulosin

Nonurinary: phenoxybenzamine, phentolamine

MOA (Mechanism of Action)

Antagonism of α₁ receptors on vascular smooth muscle induces vasodilation and decreases systemic vascular resistance (SVR).

Both resistance (arterial) and capacitance (venous) vessels are dilated.

α₁ Receptors are also found in the urinary sphincter (also smooth muscle) of the bladder. The sphincter controls the flow of urine out of the bladder (Figure 25-6).

In patients with an enlarged prostate, pressure exerted by the prostate on the sphincter can interfere with normal urine flow. Therefore patients with an enlarged prostate experience hesitancy (difficulty starting urination) and typically do not urinate much at a time but experience urinary frequency.

An α₁ antagonist can relax the urinary sphincter, which facilitates the flow of urine.

Another rare use for α₁ antagonists is in the management of pheochromocytoma. This is a tumor of the adrenal medulla that secretes catecholamines such as epinephrine and norepinephrine. α₁ Antagonists such as phenoxybenzamine are used preoperatively and postoperatively to manage the symptoms of catecholamine excess.

Figure 25-6

Pharmacokinetics

Prazosin has a short half-life and thus must be given twice daily. Longer-acting agents such as terazosin and doxazosin were developed to provide the advantage of once-daily administration.

Benign prostatic hypertrophy (BPH)

Hypertension (but not as first line)

Phentolamine and Phenoxybenzamine Only

Management of patients with pheochromocytoma

Contraindications

No significant contraindications

Orthostatic hypotension is common and can be quite significant, usually occurring within 90 minutes of the first dose of the drug. It can lead to dizziness and falls.

Headache might be caused by cerebral vasodilation.

Somnolence may occur.

Nasal congestion is caused by dilation of vessels in the nasal passages, causing mild swelling.

Palpitation is a result of reflex tachycardia.

Cardiovascular events: Although these agents are typically well tolerated, results of a recent study suggest that they may be associated with an increased risk, summarized in the Advanced section.

Important Notes

Compensatory sympathetic nervous system responses such as renin release and tachycardia are significant in the short term. However, in many cases these reflex responses subside, leaving a vasodilatory effect that predominates in the long term.

Tamsulosin was developed to selectively target α_1A receptors, which are found in the bladder sphincter and not in vascular smooth muscle. Therefore by antagonizing these α_1A receptors selectively, it is believed that tamsulosin will be less likely to cause orthostatic hypotension and therefore less likely to cause dizziness and falls.

The use of α antagonists in hypertension was dealt a severe blow after treatment in the doxazosin arm of the landmark ALLHAT study had to be halted prematurely after observations of a significantly increased incidence of congestive heart failure, angina, and stroke in subjects treated with this α antagonist.

Tamsulosin versus Placebo for Treatment of Benign Prostatic Hypertrophy

A 2002 Cochrane review (14 studies, N = 4122 participants) assessed tamsulosin for treatment of BPH. Tamsulosin improved symptoms and peak urine flow relative to placebo and was as effective as nonselective α antagonists. Men receiving a low dose of tamsulosin (0.2 mg) were less likely to discontinue treatment compared with men receiving terazosin. The adverse effects of terazosin increased markedly with increasing dose, compared with placebo. The most common adverse effects associated with tamsulosin were dizziness, rhinitis, and abnormal ejaculation.

Terazosin versus Other α-Blockers for Treatment of Benign Prostatic Obstruction

A 2000 Cochrane review (17 studies, N = 5151 participants) assessed terazosin versus placebo (10 trials), α-blockers (seven trials), or the 5α-reductase inhibitor finasteride (one trial) for benign prostatic obstruction. Terazosin improved symptom scores and urine flow rates more than placebo or finasteride and similarly to other α antagonists. The proportion of men discontinuing treatment was higher than the proportion of men receiving other α antagonists and was comparable to what was seen with placebo and finasteride. Adverse effects occurring more often than with placebo included dizziness, asthenia, headache, and postural hypotension.

Phenoxybenzamine is an irreversible antagonist of α₁ receptors, whereas other α₁ antagonists are reversible.

Phentolamine antagonizes both α₁ and α₂ receptors. Through antagonism of presynaptic α₂ receptors, it increases presynaptic noradrenaline release, which in turn stimulates the heart.

Yohimbine is an α₂ antagonist with limited antagonism of α₁ receptors. It is not widely used, but as with phentolamine, it can promote norepinephrine release and can be used in patients with orthostatic hypotension. It was also once used to treat erectile dysfunction, although it has been effectively replaced by the phosphodiesterase inhibitors (e.g., sildenafil).

5α-Reductase Inhibitors

5α-Reductase inhibitors are a class of drugs that reduce the production of dihydrotestosterone (DHT), the active form of testosterone.

Prototype and Common Drugs

Prototype: finasteride

Others: dutasteride

MOA (Mechanism of Action)

The 5α-reductase enzyme is the last step in the synthesis of DHT, the active form of testosterone (Figure 25-7).

Prostate cells depend on stimulation by DHT for their growth. Reducing levels of DHT will therefore slow growth of the prostate.

The 5α-reductase type II isoform is highly expressed in prostate epithelial cells.

Selective or nonselective blockade of this enzyme results in decreased formation of DHT, inhibiting the growth-stimulating effects of this androgen.

Figure 25-7

Pharmacokinetics

No drug interactions of clinical significance have been detected with finasteride. Dutasteride is metabolized by CYP3A4; thus the potential for drug interactions with inhibitors or inducers of this isozyme does exist.

Male pattern baldness

Contraindication

Pregnancy: Women of childbearing age should not use 5α-reductase inhibitors. They are strictly contraindicated in pregnancy. Testosterone is essential for development of genitalia in males; therefore these agents can lead to abnormal development. Pregnant women are advised not only to avoid taking the medication but also to avoid even handling the pills.

Sexual dysfunction: Decreased libido, ejaculation disorders, and erectile dysfunction are caused by the antiandrogenic effects.

Finasteride versus Placebo for Prevention of Prostate Cancer

A 2008 Cochrane review (nine trials, N = 34,410 males) examined the effectiveness and harms of 5α-reductase inhibitors in preventing prostate cancer. Finasteride reduced the risk of prostate cancer by 2.9% (incidence of 6.3% in finasteride versus 9.2% in placebo). Impaired erectile function or endocrine effects were more common with finasteride than with placebo. However, the risk of high-grade disease may be increased with finasteride therapy. The authors recommended that future studies examine the impact of 5α-reductase inhibitors on mortality and also further examine the risk associated with development of high-grade cancers.

Important Notes

Because of their lowering effects on prostate serum antigen (PSA), there is concern that 5α-reductase inhibitors may mask elevations in PSA associated with a malignancy of the prostate. This could lead to a delay in the diagnosis of prostate cancer because of false-negative screening test results.

The 5α-reductase inhibitors have not performed well in comparative trials with α antagonists for treatment of BPH. This is thought to result from, at least in part, the fact that the beneficial effects of 5α-reductase inhibitors are more gradual, whereas symptomatic improvement with α antagonists occurs rapidly.

As a means of overcoming the delayed effects of 5α-reductase inhibitors, consideration has been given to combining α antagonists with these agents. The Medical Therapy of Prostatic Symptoms (MTOPS) trial found that the combination of doxazosin and finasteride performed better than either agent alone in a variety of key clinical indicators of BPH progression, over the course of 4.5 years.

The effects of finasteride in treating male pattern baldness are also delayed. Patients are typically advised to undergo a 3- to 6-month trial before expecting any noticeable results.

The dose of finasteride used to treat male pattern baldness is lower than that used to treat BPH.

Related

Applied Pharmacology