Renal pharmacology

Renal Pharmacology

Physiology Review

Background:

Body fluid and electrolyte composition are regulated by the kidney-- drugs that interfere

with renal transport may be useful in management of clinical disorders.

Diuretics are drugs which block renal ionic transport, causing diuresis {an increase in

urine volume}, often associated with natriuresis {increase in sodium excretion}

Diuretics often act at different sites of the tubule transport system, at specific membrane

transport proteins

Diuretics that act on specific membrane transport proteins include:

o loop diuretics

o thiazides

o amiloride (Midamor)

o triamterene (Dyrenium)

Diuretics may act through:

o osmotic effects (preventing water reabsorption)-- mannitol

o enzyme inhibition (carbonic anhydrase inhibitor)-- acetazolamide

o interaction with hormonal receptors: spironolactone

Renal physiology and sites of diuretic action:

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic

Institute, used with permission

"The glomerular capillaries are very leaky about 400 times as high as most

other capillaries and produce a filtrate that is similar to blood plasma

except the it is devoid of proteins and cellular elements.

The glomerular filtration rate (GFR) is effected by the same forces as

other capillaries:

o GFR = Kf X (Pc -Pb - PiG +PiB)

o where Kf = Filtration coefficient

o Pc = Glomerular hydrostatic pressure

o Pb = Bowman's capsule hydrostatic pressure

o PiG = Glomerular capillary colloidal osmotic pressure

o PiB = Bowman's capsule colloidal osmotic pressure "

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute,

used with permission

Proximal tubule:

o Many solutes are reabsorbed in the early portions of the proximal tubule:

85% of filtered sodium bicarbonate

40% of sodium chloride

60% of water

nearly all of filtered organic solutes, including glucose and amino acids

glucose, amino acids, and other organic solutes are reabsorbed by

specific transport systems

Sodium Bicarbonate and the Proximal Tubule

Mechanism of Action: In the proximal tubule, sodium bicarbonate reabsorption can be

influenced by carbonic anhydrase inhibitors.

o Sodium bicarbonate reabsorbed in the proximal tubule depends on the action of

sodium/hydrogen exchanger which is found in the luminal membrane of the

proximal tubule epithelial cell.

1. proton secreted into lumen (urine) combine with bicarbonate to form

carbonic acid (H2CO3)

2. Carbonic acid is dehydrated by an enzyme carbonic anhydrase which is

localized (among other places) on the brush border membrane.

3. The dehydration products carbon dioxide and water easily move across

membranes. Carbon dioxide enters the proximal tubule by diffusion where

it is rehydrated back to carbonic acid.

4. Carbonic acid dissociates back to bicarbonate and the proton (step one)

5. This cycle depends on carbonic anhydrase

o Mechanism of Action: Inhibition of carbonic anhydrase decreases bicarbonate

reabsorption in proximal tubule, which in turn decreases water reabsorption

o Carbonic anhydrase inhibitor: acetazolamide (Diamox)

In the proximal tubule, water is reabsorbed in direct proportion to salt.

With a large concentration of impermeant solute, such as glucose or the diuretic

mannitol, water reabsorption would decrease for osmotic reasons. (Mechanism for

osmotic diuresis)

Organic Acid Secretory System

Located in the middle third proximal tubule

o Organic acid secretory system secretes for example:

uric acid

antibiotics

p-aminohippuric acid

Organic Base Secretory System

Localized in both early and middle segments of the proximal tubule

o Organic base secretory system secretes, for example:

creatinine

procainamide {antiarrhythmic drug}

choline

Organic acid and base transport systems are important in delivery of diuretics to their site

of action: luminal side

Drug interaction: diuretics and probenecid (secretory system inhibitor)

Loop of Henle

o Thin limb

water reabsorption

driving force: osmotic -- due to hypertonic medullary fluid

no active salt reabsorption, but impermeant solutes (mannitol, glucose)

will inhibit water reabsorption {a site of action for osmotic diuretics}

o Thick ascending limb of the loop of Henle: active sodium chloride reabsorption

{about 35% of filtered load}--

impermeable to water

since reabsorption of sodium chloride at this site dilutes the fluid in the

tubule, this segment may be referred to as "diluting segment."

Reabsorption of sodium chloride in the thick ascending limb is dependent

upon the Na/K/2Cl co-transporter.

1. Loop diuretics block this transporter.

furosemide (Lasix)

bumetanide (Bumex)

ethacrynic acid (Edecrin)

torsemide (Demadex)

2. Normal activity of this transporter and Na/K ATPase results in an

increase in intracellular potassium, potassium efflux, and a lumen-

positive electrical potential:

3. This lumen-positive membrane potential provides the driving force

for reabsorption of magnesium and calcium cations.

4. Therefore loop diuretics which inhibit the action of the sodium

potassium chloride co-transporter, leading to increase sodium

excretion also leads to increased magnesium and calcium loss.

Distal Convoluted Tubule

o Properties:

impermeable to water

sodium reabsorption (about 10% of filtered load) by sodium and chloride

co-transporter

further dilution of tubular fluids

o Pharmacological blockade of sodium and chloride co-transporter:

thiazide diuretics

no potassium recycling; no lumen-positive membrane potential; -- no

calcium or magnesium loss by electrical forces

o Calcium is actively reabsorbed by:

an apical calcium channel and

Na/Ca exchanger

regulated by parathyroid hormone

Collecting Tubule

o Properties:

About 2% to 5% of sodium chloride reabsorption

Final site for sodium chloride reabsorption -- responsible for final sodium

concentration in the urine

This site and late distal tubule -- where mineralocorticoids exert their

effect

Major site of potassium secretion

Major sites for sodium, potassium, and water transport

principal cells

Major site for proton secretion -- intercalated cells

Separate sodium and potassium channels:

Significant driving force for sodium entry

Na after entering the principal cell is transported to the blood

{Na/K ATPase} with potassium translocated to the lumen urine

(lumen-negative electrical potential drives chloride back to the

blood)

Accordingly, delivery of increased sodium to the collecting

tubule drives increased potassium efflux

Diuretics (acting upstream) that increased delivery of

sodium to the collecting tubule will cause potassium loss

Delivery of bicarbonate {not readily reabsorbed compared

chloride, increasing lumen-negative potentials}, will

increase further potassium loss.

Diuretic-induced potassium loss, which is clinically

important, results from the above mechanisms coupled with

enhanced aldosterone secretion due to volume depletion.

Major pharmacokinetic, pharmacodynamic and mechanism of action of Diuretic Classes:

o Carbonic Anhydrase Inhibitors

o Potassium Sparing

o Loop Diuretics

o Thiazides

o Osmotic Agents

Carbonic Anhydrase Inhibitors

The enzyme, carbonic anhydrase exhibits the following characteristics:

o Its major location is the luminal proximal tubule membrane.

o Carbonic anhydrase catalyzes dehydration of carbonic acid, H2CO3 , required for

bicarbonate reabsorption

o Blockade of carbonic anhydrase activity induces a sodium bicarbonate diuresis,

which reduces body bicarbonate levels

Carbonic anhydrase inhibitors are unsubstituted sulfonamides which are bacteriostatic.

These agents promote alkaline diuresis and a hyperchloremic metabolic acidosis.

o Prototype drug: acetazolamide (Diamox)

Acetazolamide: (Diamox) is well absorbed orally and is excreted by tubular secretion, at

the proximal tubule.

o In renal insufficiency a dose reduction is appropriate.

o At maximal carbonic anhydrase inhibition, a 45% inhibition of bicarbonate

reabsorption is observed.

This level of inhibition results in significant bicarbonate loss and a

hyperchloremic metabolic acidosis.

Acetazolamide (Diamox) administration causes a reduction in aqueous

humor and cerebrospinal fluid production

o Clinical Application:

Glaucoma:

Because acetazolamide decreases the rate of aqueous humor

production, a decline in intraocular pressure occurs.

Management of glaucoma is the most common indication for use

of carbonic anhydrase inhibitors.

Dorzolamide (Trusopf), another carbonic anhydrase inhibitor

exhibits no diuretic or systemic metabolic effect; however,

administration of this agent causes a reduction in intraocular

pressure.

Urinary Alkalinization:

increased uric acid and cystine solubility by alkalinizing the urine

(by increasing bicarbonate excretion)

for prophylaxis of uric acid renal stones, bicarbonate

administration (baking soda) may be required

Metabolic Alkalosis:

Results from:

o decreased total potassium with reduced vascular volume

o high mineralocorticoid levels

o These conditions are usually managed by treating the

underlying causes; however, in certain clinical settings

acetazolamide may assist in correcting alkalosis {e.g.

alkalosis due to excessive diuresis in CHF patients}

Acute Mountain Sickness:

Symptoms: weakness, insomnia, headache, nausea, dizziness

{rapid ascension of all of 3000 meters}; symptoms -- usually mild

In serious cases: life-threatening cerebral or pulmonary edema

Acetazolamide reduces the rate of CSF formation and decreases

cerebral spinal fluid pH.

Prophylaxis against acute mountain sickness may be appropriate

Other Uses:

some role in management of epilepsy

hypokalemia periodic paralysis

increase urinary phosphate excretion during severe

hyperphosphatemia.

o Toxicity:

hyperchloremic metabolic acidosis

due to reduction of body bicarbonate stores

renal stones:

bicarbonate loss is associated with:

o phosphaturia

o hypercalciuria (calcium salts, relatively insoluble at

alkaline pH)

renal potassium loss:

increased sodium bicarbonate in the collecting tubule increases the

lumen-negative electrical potential -- enhances potassium excretion

o counteracted by potassium chloride administration

Others:

drowsiness, parathesias

accumulation in renal failure (CNS toxicity)

hypersensitivity reactions

Contraindications:

hepatic cirrhosis

o urinary alkalinization will decrease ammonium ion

trapping, increasing the likelihood of hepatic

encephalopathy.

Loop Diuretic Drugs

Introduction

o Agents include:

furosemide (Lasix)

bumetanide (Bumex)

torsemide (Demadex)

ethycrinic acid --no longer in use because of toxicity.

Mechanism of action:

o inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle

inhibit the Na/K/2Cl transport system in the luminal membrane

1. reduction in sodium chloride reabsorption

2. decreases normal lumen-positive potential (secondary to potassium

recycling)

3. Positive lumen potential: drives divalent cationic reabsorption

(calcium magnesium)

4. Therefore, loop diuretics increase magnesium and calcium

excretion.

hypomagnesemia may occur in some patients.

hypocalcemia does not usually develop because calcium is

reabsorbed in the distal convoluted tubule.

{in circumstances that result in hypercalcemia,

calcium excretion can be enhanced by

administration of loop diuretics with saline

infusion}

o Since a significant percentage of filtered NaCl is absorbed by the thick ascending

limb of loop of Henle, diuretics acting at this site are highly effective

Loop diuretics--Properties: rapidly absorbed following oral administration (may be

administered by IV)

o acts rapidly

o eliminated by a renal secretion and glomerular filtration (half-life -- depend on

renal function)

o co-administration of drugs that inhibit weak acid secretion (e.g. probenecid or

indomethacin) may alter loop diuretic clearance.

o Other effects:

Furosemide: increases renal blood flow; blood flow redistribution within

the renal cortex

Furosemide decreases pulmonary congestion and the left ventricular filling

pressure in congestive heart failure (CHF) -- prior to an increase in urine

output.

Clinical Uses:

o Major uses:

acute pulmonary edema

acute hypercalcemia

management of edema

o Other uses:

hyperkalemia:

loop diuretics increase potassium excretion

effect increased by concurrent administration of NaCl and water.

acute renal failure:

may increase rate of urine flow and increase potassium excretion.

may convert oligouric to non-oligouric failure {easier clinical

management}

renal failure duration -- not affected

anion overload:

bromide, chloride, iodide: all reabsorbed by the thick ascending

loop:

systemic toxicity may be reduced by decreasing reabsorption

concurrent administration of sodium chloride and fluid is

required to prevent volume depletion

Toxicity:

o Hypokalemia metabolic alkalosis:

increased delivery of NaCl and water to the collecting duct increases

potassium and proton secretion-- causing a hypokalemic metabolic

alkalosis

in managed by potassium replacement and by ensuring adequate fluid

intake

o Ototoxicity:

dose-related hearing loss (in usually reversible)

ototoxicity more common:

with decreased renal function

with concurrent administration of other ototoxic drugs such as

aminoglycosides

o Hyperuricemia:

may cause gout

loop diuretics cause increased uric acid reabsorption in the proximal

tubule, secondary to hypovolemic states.

o Hypomagnesemia: loop diuretics cause:



recycling)

3. Positive lumen potential: drives divalent cationic reabsorption (calcium

magnesium)

4. Therefore, loop diuretics increase magnesium and calcium excretion.


reversed by oral magnesium administration

o Allergic reactions:

furosemide: skin rash, eosinophilia, interstitial nephritis(less often)

o Other toxicities:

Dehydration (may be severe)

hyponatremia (less common than with thiazides thought may occur in

patients who increased water intake in response to a hypovolemic thirst)

Hypercalcemia may occur in severe dehydration and if a hypercalcemia

condition {e.g. oat cell long carcinoma} is also present.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-

Lange, 1998, pp 242-259.

Thiazides

Introduction:

o Thiazides inhibit NaCl transport at the distal convoluted tubule

o Prototypical thiazide: hydrochlorothiazide

Thiazides and Related Sulfonamide Diuretics

bendroflumethazide benzthiazide chlorothiazide chlorthalidone

hydrochlorothiazide hydroflumethiazide indapamide methyclothiazide

metolazone polythiazide quinethazone trichlomethiazide

Properties:

o Oral administration

o Secreted by the organic acid secretory system

compete with uric acid for secretion {uric acid secretory rates may

decline}

o Differences between thiazides:

chlorothiazide (Diuril): less lipid soluble (requires relatively large doses)

chlorthalidone (Hygroton): slowly absorbed -- longer duration of action

indapamide (Lozol): mainly biliary secretion

o Mechanism of action:

Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted

tubule (luminal side)

enhance calcium reabsorption in the distal convoluted tubule (unknown

mechanism)

thiazides infrequently cause hypercalcemia but can unmask

hypercalcemia due to other causes such as carcinoma, sarcoidosis,

or hyperparathyroidism.

Clinical Uses:

o Hypertension

o Congestive heart failure

o Nephrolithiasis (due to idiopathic hypercalciuria

o Nephrogenic diabetes insipidus

Toxicity:

o Hypokalemic metabolic alkalosis and hyperuricemia

o Impaired carbohydrate tolerance

may induce hyperglycemia

impaired pancreatic insulin release

decreased tissue glucose utilization

hyperglycemia may be partially reversed by correcting a

hypokalemic state

o Hyperlipidemia

5% to 15% increase in serum cholesterol and an increase in low-density

lipoproteins.

o Hyponatremia:

Significant adverse effect, occasionally life-threatening

Mechanism:

hypovolemia-induced increase in ADH

reduced renal diluting capacity

increased thirst

Prevention: decreasing the drug dose or limiting fluid intake

o Allergic reactions:

Thiazides are sulfonamides: cross-reactivity within the group

photosensitivity {rare}

dermatitis {rare}

Extremely rare reactions:

hemolytic anemia

thrombocytopenia

acute necrotizing pancreatitis

o Other reactions:

weakness

fatigue

paresthesias

Potassium-Sparing Diuretic Agents

Introduction:

o These diuretics inhibit the effects of aldosterone at the cortical collecting tubule

and late distal tubule.

o Mechanisms of action:

In the collecting tubule and duct, sodium reabsorption and potassium

excretion is regulated by aldosterone.

Aldosterone increases potassium secretion by increasing Na/K

ATPase activity and sodium and potassium channel activity.

Normally, sodium absorption in the collecting tubule results in a

lumen-negative electrical force that drives potassium excretion.

Aldosterone antagonists interfere with this effect

Aldosterone antagonists act similarly with respect to proton

movement, accounting for metabolic acidosis associated with

aldosterone antagonists.

pharmacologic antagonism at mineralocorticoid receptors { spironolactone

(Aldactone)}

inhibition of sodium transport through the luminal membrane {triamterene

(Dyrenium), amiloride (Midamor)}

Some Potassium-Sparing effects occur with nonsteroidal anti-

inflammatory drugs, beta-blockers, converting enzyme-inhibitors, and

angiotensin receptor blockers.

Spironolactone (Aldactone):

o Synthetic steroid: competitive aldosterone antagonist

binds to cytoplasmic mineralocorticoid receptors -- preventing receptor

complex translocation to the nucleus

also inhibits formation of active metabolite of aldosterone {by inhibiting

5-alpha reductase activity}

o hepatic inactivation

o slow onset of action

Triamterene (Dyrenium):

o Renal excretion; hepatic metabolism-- extensive metabolism (short half life)

o Directly blocks Na entry through sodium-specific channels (apical collecting

tubule membrane) -- note that since potassium secretion is coupled to sodium

entry, potassium secretion {potassium-sparing} is reduced.

Amiloride (Midamor):

o Excreted unchanged (urine)

o Directly blocks Na entry through sodium-specific channels (apical collecting

tubule membrane) -- note that since potassium secretion is coupled to sodium

entry, potassium secretion {potassium-sparing} is reduced.

Clinical Uses:

o Mineralocorticoid excess:

Conn's syndrome (primary hypersecretion)

ectopic ACTH production (primary hypersecretion)

secondary aldosteronism caused by:

congestive heart failure

hepatic cirrhosis

nephrotic syndrome

conditions that cause renal salt retention with reduced intravascular

volume

o other diuretics may further reduce intravascular volume

thus worsening secondary aldosteronism

Toxicity:

o Hyperkalemia:

Potassium-sparing diuretics can cause significant hyperkalemia

Factors that increase the likelihood of hyperkalemia:

renal disease

presence of agents that reduce renin:

o beta-blockers

o nonsteroidal anti-inflammatory drugs (NSAIDs)

o ACE inhibitors

o angiotensin receptor blockers

hyperkalemia more likely when potassium-sparing diuretics are used as

the only diuretic drug or in the presence of renal insufficiency.

given in combination with thiazides, hypokalemia and metabolic

alkalosis associated with thiazide use may be balanced by

aldosterone antagonists

Since thiazide adverse effects may predominate {hyponatremia,

metabolic alkalosis}, due to variations in bioavailability, individual

dose adjustment of the two drugs may be better.

o Hyperchloremic Metabolic Acidosis:

Acidosis cause by inhibition of proton secretion along with potassium

secretion {similar to type IV renal tubular acidosis

o Gynecomastia:

Endocrine abnormalities associated with synthetic steroids --

Spironolactone (Aldactone)

gynecomastia (breast enlargement)

impotence

benign prostatic hyperplasia

o Acute Renal Failure:

Triamterene (Dyrenium) plus indomethacin

o Kidney Stones:

Triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing

renal stones:

Contraindications:

o may cause severe (potentially fatal) hyperkalemia

o potassium supplements should be discontinued prior to administration of


o patients with chronic renal insufficiency are at particular risk

o hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors

are concurrently administered

o impairment of hepatic metabolism of triamterene spironolactone may require dose

adjustment

Osmotic Diuretics

Introduction:

o Osmotic diuretics cause water to be retained within the proximal tubule and

descending limb of loop of Henle (freely permeable to water)

o Mannitol (Osmitrol) is an example of osmotic diuretic.

o Clinical Use: mainly used to reduce increased intracranial pressure;

Osmotic diuretics: properties

o mannitol (Osmitrol) : not metabolized, freely filtered at the glomerular

o usually administered by IV; oral administration results in an osmotic diarrhea--

perhaps useful to promote elimination of toxic substances from the GI tract (in

conjunction with activated charcoal)

o urine volume increases with mannitol excretion due to direct osmotic effects

sodium reabsorption is reduced because of increased urine flow rates

{decreased contact time between urine and tubular epithelial cells}

Clinical Uses:

o To increase urine volume:

may be used to prevent anuria if the kidney due to hemolysis or

rhabdomyolysis is presented with a large pigmented load.

when renal hemodynamics are compromised

o To decrease intracranial or intraocular pressure:

Mannitol (Osmitrol) extract water from intracellular compartments,

reducing total body water

Following IV administration, intracranial pressure falls within 60-90

minutes.

Toxicity:

o Volume expansion effects -- increased extra cellular fluid volume and

hyponatremia may cause pulmonary edema, complicating congestive heart failure

o Headache, nausea, vomiting -- commonly observed

o Dehydration and hypernatremia:

fluid loss leads to significant dehydration and in the absence of adequate

fluid replacement leads to hypernatremia.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-

Lange, 1998, pp 242-259.

Diuretics: antihypertensive properties

Two main classes of diuretics are used in mangement

of hypertension: thiazides and potassium sparing

drugs.

Objective: pharmacological alteration of sodium load

A reduction in sodium leads to reduced intravascular

volume and a blood pressure reduction.

Thiazide diuretics cause an inhibition of NaCl

transport in the Distal Convoluted Tubule (DCT)

Anatomy of the Nephron: From:

Guyton's Textbook of

Physiology, Ninth Edition

Orally active thiazide drugs have historically been a mainstay of

antihypertensive treatment, although present therapy often involves other drugs.

Note the progression

of antihypertensive

medication;

beginning

with a low

dosage of

either an

ACE

inhibitor,

calcium

channel

blocker or

beta blocker

and

proceeding,

if needed to

add a diuretic

and

ultimately

additional

more

powerful

drugs, such

as centrally

acting

sympatholyti

cs, peripheral

vasodilators

or

combination.

At each step dosages

are reviewed and if

the patient's

hypertension is

controlled then

therapy may be

continued with

review for possible

removal of

medication.

Figure adapted from

Harrison's

"Principles of

Internal Medicine,

Thirteenth Edition,

p. 1128

Reduction in blood pressure is initially due to a reduction in extracellular

volume and cardiac output.

Long-term antihypertensive effects of thiazides appear due to reduced vascular

resistance. The exact mechanism responsible for the reduction in vascular

resistance is not known.

Thiazides, due to their inhibition of the Na+-Cl

- symport system, increase

sodium and chloride excretion.(renal synport diagram)

Distal Convoluted Tubule:From: Goodman and Gilman's "The Pharmacological Basis

of Therapeutics, Ninth Edition

Thiazide diuretics, when used in the management of hypertension, is

administered in combination with a potassium-sparing drug. Reduction in the

amount of potassium loss can be achieved by:

using potassium sparing drugs block Na+ channels in the late distal

tubule and collecting duct (amiloride (Midamor) &triamterene

(Dyrenium))

Note that

amiloride

(Midamor) and

probably

triamterene

(Dyrenium) blocks

sodium channels

in the luminal

membrane in the

late distal tubule

and collecting

duct.

Such action

inhibits the normal

movement of Na+

into the cell.

Normally, Na+

entry create the net

negative luminal

charge that results

in K+ efflux.

By reducing the

net negative

luminal charge,

amiloride

(Midamor)/triamte

rene (Dyrenium)

administration

help conserve

potassium.

Therefore, they are

called "potassium

sparing".

Figure adapted from

"Goodman and Gillman's

The Pharmacological

Basis of Therapeutics"

Ninth Edition, p. 705

Inhibition of aldosterone action (spironolactone (Aldactone))

Spironolactone is

an antagonist of

mineralocorticoid

receptors

(aldosterone-

antagonist) .

Normally,

aldosterone

interactions with

mineralocoricoid

receptors result in

synthesis of

aldosterone-

induced proteins

(AIPs).

These proteins

appear to increase

the number or

activity of Na+

channels and

cause an increase

in Na+

conductance.

Increased Na+

conductance (with

inward movement

of Na+)

results in a

net negative

luminal charge

favoring K+ loss.

Antagonism of the

interaction

between

aldosterone and its

receptor by

spironolactone

conserves K+

(potassium

sparing).

Figure from Goodman

and Gilman's "The

Pharmacological Basis of

Therapeutics" Ninth

Edition, p. 708

inhibition of aldosterone release by ACE inhibitors or angiotensin-receptor

blockers

Clinical uses of diuretics

Carbonic Anhydrase Inhibitor

Acetazolamide (Diamox)

Glaucoma:

o decreases rate of aqueous humor production -- leads to a declining in intraocular

pressure

o most common indication for use of carbonic anhydrase inhibitors

o Dorzolamide (Trusopf): topical carbonic anhydrase inhibitor.

no diuretic or systemic metabolic effects

reduction in intraocular pressure comparable to oral agents

Urinary Alkalinization:

o increased uric acid and cystine solubility by alkalinizing the urine (by increasing

bicarbonate excretion)

o for prophylaxis of uric acid renal stones, bicarbonate administration (baking soda)

may be required

Metabolic Alkalosis:

o Results from:

decreased total potassium with reduced vascular volume

high mineralocorticoid levels

These conditions are usually managed by treating the underlying causes;

however, in certain clinical settings acetazolamide may assist in correcting

alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}

Acute Mountain Sickness:

o Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of

all of 3000 meters}; symptoms -- usually mild

o In serious cases: life-threatening cerebral or pulmonary edema

o Acetazolamide (Diamox) reduces the rate of CSF formation and decreases

cerebral spinal fluid pH.

o Prophylaxis against acute mountain sickness may be appropriate

Other Uses:

o some role in management of epilepsy

o hypokalemia periodic paralysis

o increase urinary phosphate excretion during severe hyperphosphatemia.

Loop Diuretics

Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), ethacrynic acid

(Edecrin)

Major Clinical uses:

o acute pulmonary edema

o acute hypercalcemia

o management of edema

Other uses:

o hyperkalemia:

loop diuretics increase potassium excretion

effect increased by concurrent administration of NaCl and water.

o acute renal failure:

may increase rate of urine flow and increase potassium excretion.

may convert oligouric to non-oligouric failure {easier clinical

management}

renal failure duration -- not affected

o anion overload:

bromide, chloride, iodide: all reabsorbed by the thick ascending loop:

systemic toxicity may be reduced by decreasing reabsorption

concurrent administration of sodium chloride and fluid is required

to prevent volume depletion

Thiazides

bendroflumethazide benzthiazide chlorothiazide

(Diuril)

chlorthalidone

(Hygroton)

hydrochlorothiazide

(HCTZ, Esidrix,

HydroDIURIL)

hydroflumethiazide indapamide

(Lozol) methyclothiazide

metolazone

(Zaroxolyn,

Mykrox)

polythiazide quinethazone trichlomethiazide

Hypertension

Congestive heart failure

Nephrolithiasis (due to idiopathic hypercalciuria

Nephrogenic diabetes insipidus

Osmotic Diuretics

Mannitol (Osmitrol)

To increase urine volume:

o may be used to prevent anuria if the kidney due to hemolysis or rhabdomyolysis is

presented with a large pigmented load.

o when renal hemodynamics are compromised

To decrease intracranial or intraocular pressure:

o Mannitol extract water from intracellular compartments, reducing total body

water

o Following IV administration, intracranial pressure falls within 60-90 minutes.

Potassium Sparing Agents

Amiloride (Midamor), triamterene (Dyrenium), spironolactone (Aldactone)

Reduction of potassium loss associated with thiazide or loop diuretic administration

Mineralocorticoid excess:

o Conn's syndrome (primary hypersecretion)

o ectopic ACTH production (primary hypersecretion)

o secondary aldosteronism caused by:

congestive heart failure

hepatic cirrhosis

nephrotic syndrome

conditions that cause renal salt retention with reduced intravascular

volume

other diuretics may further reduce intravascular volume thus

worsening secondary aldosteronism

Diuretic-Other Drug Interactions

cardiac

glycosides

oral

hypoglycemics

aminoglycoside

antibiotics

oral

anticoagulants

uricosuric

drugs

non-steroidal

anti-

inflammatory

drugs

Adverse Diuretic effects and contraindications

Adverse Effects: Carbonic Anhydrase Inhibitors (Acetazolamide)

Toxicity:

o hyperchloremic metabolic acidosis

due to reduction in body bicarbonate stores

o renal stones:

bicarbonate loss is associated with:

phosphaturia

hypercalciuria (calcium salts, relatively insoluble at alkaline pH)

o renal potassium loss:

increased sodium bicarbonate in the collecting tubule increases the lumen-

negative and in inelectrical potential -- enhances potassium excretion

counteracted by potassium chloride administration

o Others:

drowsiness, parathesias

accumulation in renal failure (CNS toxicity)

hypersensitivity reactions

o Contraindications:

hepatic cirrhosis

urinary alkalinization will decrease ammonium ion trapping,

increasing the likelihood of hepatic encephalopathy.

Adverse Effects: Loop Diuretics

Toxicity:

Hypokalemia metabolic alkalosis:

o increased delivery of NaCl and water to the collecting duct increases potassium

and proton secretion-- causing a hypokalemic metabolic alkalosis

o in managed by potassium replacement and by ensuring adequate fluid intake

Ototoxicity:

o dose-related hearing loss (in usually reversible)

o more common:

with decreased renal function

with concurrent administration of other ototoxic drugs such as

aminoglycosides

Hyperuricemia:

o may cause gout

o loop diuretics cause increased uric acid reabsorption in the proximal tubule,

secondary to hypovolemic states.

Hypomagnesemia: loop diuretics cause:


2. decreases normal lumen-positive potential (secondary to potassium recycling)

3. Positive lumen potential: drives divalent cationic reabsorption (calcium

magnesium)

4. Therefore, loop diuretics increase magnesium and calcium excretion.


reversed by oral magnesium administration

Allergic reactions:

o furosemide: skin rash, eosinophilia, interstitial nephritis(less often)

Other toxicities:

o Dehydration (may be severe)

o hyponatremia (less common than with thiazides thought may occur in patients

who increased water intake in response to a hypovolemic thirst)

o Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition

{e.g. oat cell long carcinoma} is also present.

Adverse Effects: Thiazides

Toxicity:

Hypokalemic metabolic alkalosis and hyperuricemia

Impaired carbohydrate tolerance

o may induce hyperglycemia

impaired pancreatic insulin release

decreased tissue glucose utilization

hyperglycemia may be partially reversed by correcting a hypokalemic

state

Hyperlipidemia

o 5% to 15% increase in serum cholesterol and an increase in low-density

lipoproteins.

Hyponatremia:

o Significant adverse effect, occasionally life-threatening

o Mechanism:

hypovolemia-induced increase in ADH

reduced renal diluting capacity

increased thirst

Prevention: decreasing the drug dose or limiting fluid intake

Allergic reactions:

o Thiazides are sulfonamides: cross-reactivity within the group

o photosensitivity {rare}

o dermatitis {rare}

o Extremely rare reactions:

hemolytic anemia

thrombocytopenia

acute necrotizing pancreatitis

Other reactions:

o weakness

o fatigue

o paresthesias

Adverse Effects: Osmotic Diuretics

Toxicity:

Volume expansion effects -- increased extra cellular fluid volume and hyponatremia may

cause:

o pulmonary edema, complicating congestive heart failure

Headache, nausea, vomiting -- commonly observed

Dehydration and hypernatremia:

o flow gloss leads to significant dehydration and in the absence of adequate fluid

replacement leads to hypernatremia.

Adverse Effects: Potassium-Sparing Diuretics

Toxicity:

o Hyperkalemia:

Potassium-sparing diuretics can cause significant hyperkalemia

Factors that increase the likelihood of hyperkalemia:

renal disease

presence of agents that reduce renin:

beta-blockers

nonsteroidal anti-inflammatory drugs (NSAIDs)

ACE inhibitors

angiotensin receptor blockers

hyperkalemia more likely when potassium-sparing diuretics are used as

the only diuretic drug or in the presence of renal insufficiency.

Given in combination with thiazides, hypokalemia and metabolic

alkalosis associated with thiazide use may be balanced by


Since thiazide adverse effects may predominate {hyponatremia,

metabolic alkalosis}, due to variations in bioavailability, individual

dose adjustment of the two drugs may be better.

o Hyperchloremic Metabolic Acidosis:

Acidosis cause by inhibition of proton secretion along with potassium

secretion {similar to type IV renal tubular acidosis

o Gynecomastia:

Endocrine abnormalities associated with synthetic steroids --

spironolactone:

gynecomastia (breast enlargement)

impotence

benign prostatic hyperplasia

o Acute Renal Failure:

triamterene (Dyrenium) plus indomethacin

o Kidney Stones:

triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing

renal stones:

Contraindications:

o may cause severe (potentially fatal) hyperkalemia

o potassium supplements should be discontinued prior to administration of


o patients with chronic renal insufficiency are at particular risk

o hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors

are concurrently administered

o impairment of hepatic metabolism of triamterene spironolactone may require dose

adjustment

Mechanisms whereby furosemide and thiazides are useful in calcium metabolism

disorders management

Role of Diuretics in Calcium Metabolism

Loop Diuretics & Calcium Metabolism

o Furosemide (Lasix)

o Torsemide (Demadex)

o Bumetanide (Bumex)


o Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle

inhibit the Na/K/2Cl transport system in the luminal membrane



recycling)

3. Positive lumen potential: drives divalent cationic reabsorption

(calcium magnesium)

4. Therefore, loop diuretics increase magnesium and calcium

excretion.


hypocalcemia does not usually develop because calcium is

reabsorbed in the distal convoluted tubule.

{in circumstances that result in hypercalcemia,

calcium excretion can be enhanced by

administration of loop diuretics with saline

infusion}

Clinical Uses:

Major uses:

acute pulmonary edema

acute hypercalcemia

management of edema

Thiazides & Calcium Metabolism


o Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted tubule

(luminal side)

o enhanced calcium reabsorption in the distal convoluted tubule (unknown

mechanism)

thiazides infrequently cause hypercalcemia but can unmask hypercalcemia

due to other causes such as carcinoma, sarcoidosis, or

hyperparathyroidism.

Thiazides: nephrogenic diabetes insipidus

Diabetes insipidus: impaired renal water conservation, caused by:

o Inadequate vasopressin secretion (Central or cranial diabetes insipidus)

o Insufficient kidney response to vasopressin (nephrogenic diabetes insipidus)

o Induction of diabetes insipidus:

hypercalcemia

hypokalemia

postobstructive renal failure

lithium (incidence: as high as 33%)

demeclocycline (Declomycin)

o Familial nephrogenic diabetes insipidus: X-linked, typically,recessive)

Thiazides are central in treatment of nephrogenic diabetes insipidus, reducing urine

volume by up to 50%.

Other drugs:

o Amiloride: by blocking lithium uptake by the sodium channel in the collecting

duct, amiloride is the drug of choice for lithium-induced nephrogenic diabetes

insipidus.


o Decrease in volume promotes increased proximal tubule reabsorption.

Decreased extracellular fluid volume results in compensatory mechanisms

that increase NaCl reabsorption in the proximal tubule -- reducing the

volume delivered to the distal tubule.

As a result, less free water is formed and polyuria is decreased

o Since the effectiveness of thiazide diuretics in treating nephrogenic diabetes

insipidus follows the extent of natriuresis, the effectiveness may be enhanced by

decreasing sodium intake.

Jackson, E.K. Diuretics In, Goodman and Gillman's The Pharmacologial Basis of

Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds)

TheMcGraw-Hill Companies, Inc.,1996, pp. 685- 713

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In,

Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird,

L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies,

Inc.,1996, pp.715-732

Chlorpropamide (Diabinese) and clofibrate (Abitrate, Atromid-S) : Central

(Cranial) Diabetes Insipidus

Diabetes insipidus: impaired renal water conservation, caused by:

o inadequate vasopressin secretion (Central or cranial diabetes insipidus)

o inadequate kidney response to vasopressin (nephrogenic diabetes insipidus)

Clinical Presentations:

o Large volumes of dilute (200 mOsm/kg) urine excreted

o With normal thirst, polydipsia is present

o By contrast with diabetes mellitus, the urine in diabetes insipidus is tasteless.

o Central or cranial diabetes insipidus can be discriminated from nephrogenic

diabetes insipidus by administration of desmopressin (DDAVP).

Urine osmolality will

increase following desmopressin administration in patients with

central diabetes insipidus

have limited effect or no effect in patients with nephrogenic

diabetes insipidus.

Causes of central diabetes insipidus:

o Head injury (near the pituitary and/or hypothalamus

o Hypothalamic or pituitary tumor

o Cerebral aneurysms

o CNS ischemia

o CNS infections

o Central diabetes insipidus: idiopathic or familial

familial: autosomal dominant (chromosome 20)

point mutations in the signal peptide and VP-neurophysin--

causing defects in synthesis, processing, and preprohoromone

transport.

Treatment:

o Primary treatment: (antidiuretic peptides): desmopressin (DDAVP)

o Patients intolerant of desmopressin: chlorpropamide (Diabinese) (oral

sulfonylurea)

Mechanism of action -- chlorpropramide

potentiates effects of residual, circulating vasopressin (reduces

urine volume in more than 50% of patients)

Antidiuretic mechanisms of carbamazepine (Tegretol), clofibrate,

chlorpropamide (Diabinese) have not been definitively determined.

o If polyuria is insufficiently reduced by chlorpropramide, a thiazide diuretic may

be added.

o For short-term management, the combination of carbamazepine (Tegretol) and

clofibrate (Abitrate, Atromid-S) will also decreased polyuria in central diabetes

insipidus:

Serious, adverse effects associated with prolonged use of this combination

are limiting




Inc.,1996, pp.715-732.

Management of inappropriate secretion of antidiuretic hormone

Disease of impaired water excretion caused by inappropriate vasopressin secretion,

resulting in:

o hyponatremia

o hypoosmolality

Clinical effects:

o lethargy

o muscle cramps

o anorexia

o coma

o nausea

o convulsions

o vomiting

o death

Clinical effects are seen only if excessive fluid intake (in oral or IV) occurs concurrently

with inappropriate vasopressin secretion.

Causes:

o malignancies

o pulmonary disease

o CNS injury/diseases

trauma

infections

tumors

o surgery

o drugs {cisplatin, Vinca alkaloids, cyclophosphamide (Cytoxan),chlorpropamide

(Diabinese), thiazide diuretics, phenothiazines, carbamazepine (Tegretol),

clofibrate, nicotine, narcotics, tricyclic antidepressants}

Treatment

o water restriction

o IV hypertonic saline

o loop diuretics

o drugs that reduce the ability of vasopressin to increase water permeability in the

renal collecting ducts:demeclocycline (Declomycin)




Inc.,1996, pp.715-732.

Mechanism by which lithium compounds may cause a syndrome like diabetes

insipidus

Introduction

Vasopressin: regulates water conservation

Synonymous terms: vasopressin: arginine vasopressin (AVP): antidiuretic hormone

(ADH)

Similar peptide: oxytocin-- common vasopressin and oxytocin receptor antagonists

o binds to myoepithelial cells in the mammary gland (milk ejection) and on uterine

smooth muscle cells (uterine contraction)

The antidiuretic system consists of:

o CNS component (vasopressin synthesis, transport, storage, release)

supraoptic nucleus (SON)

paraventricular nucleus (PVN)

o Renal collecting duct system

epithelial cells -- increased water permeability in response to vasopressin.

Increased plasma osmolality: increased vasopressin release

Factors affecting/modifying vasopressin release

o hypovolemia

o hypotension

o hypoxia

o drugs

o pain

o nausea

o certain endogenous hormones

Regulation of vasopressin secretion

Osmotic Stimulation of Vasopressin Release

o CNS structures: osmoreceptive complex

1. Osmosensitive: magnocellular neurons (SON, PVN)

2. Subfornical organ (SFO) project to SON/PVN

3. Organum vasculosum of the lamina terminalis (OVLT) project during

clearing directly to SON/PVN

Hypovolemic/hypotension stimulation of Vasopressin Release:

o Baroreceptors:

Blood volume (filling pressures)--baroreceptors in:

left atrium

left ventricle

pulmonary veins

Arterial blood pressure: baroreceptors -- carotid sinus and aorta

Nerve impulses from baroreceptors are carried:

by the vagus and glossopharyngeal nerves to the nucleus of the

solitary tract

to the A1-noradrenergic cells in the caudal ventrolateral medulla

to the SON and PVN

Hormonal Effects

Vasopressin release: stimulation

o acetylcholine (nicotinic)

o glutamine

o histamine (H1)

o dopamine (D1 & D1)

o neuropeptide Y

o prostaglandins

o aspartate

o cholecystokinin

o substance P

o vasoactive intestinal peptide

o angiotensin II

Vasopressin release: inhibition:

o atrial natriuretic peptide

o gamma aminobutyric acid (gaba)

o opioids (dynorphin)

Drug Effects

Vasopressin Release: Stimulation

o vincristine (Oncovin)

o nicotine

o morphine (high doses)

o cyclophosphamide

o tricyclic antidepressants

o epinephrine

o lithium (inhibits renal effects of vasopressin; enhances vasopressin release

Vasopressin Release: Inhibition

o ethanol

o glucocorticoids

o haloperidol (Haldol)

o promethazine (Pherergan)

o phenytoin (Dilantin)

o morphine (low dose)

o fluphenazine (Prolixin)

o oxilorphan

o carbamazepine (Tegretol)(renal effects -- anti-diuresis; inhibits vasopressin

secretion (central effect)

Lithium Effects:

Inhibits antidiuretic effect of vasopressin

o Lithium is used widely for management of bipolar disorder (manic- depressive).

o Lithium uptake by the sodium channel in the collecting duct, causes lithium-

induced nephrogenic diabetes insipidus.

o Lithium polyuria: normally reversible

o Mechanism of action:

reduces V2 receptor-mediated adenyl cyclase stimulation

Often, the antibiotic demeclocycline (Declomycin) reduces the antidiuretic effects of

vasopressin (possibly because of reduced cyclic AMP)




Inc.,1996, pp.715-732.

Diuretics

Thiazides

o Hydrochlorothiazide (HCTZ, Esidrix, HydroDIURIL)

o chlorthalidone (Hygroton)

o Chlorothiazide (Diuril)

The thiazides act in the distal tubule to decrease sodium reabsorption

(inhibits Na/Cl transporter).

As a result of decreased sodium and chloride reabsorption, a

hyperosmolar diuresis ensues.

Delivery of more sodium to the distal tubule results in potassium loss by

an exchange mechanism.

Thiazides also promote calcium reabsorption, in contrast to loop diuretics.

The initial decrease in blood volume followed by a longer-termed

reduction in vascular resistance appears to account for the hypotensive

effects of the thiazides.

Adverse Effects

Potassium depletion is a potentially serious side-effect that

may require potassium supplementation and/or concurrent

use of potassium-sparing diuretics.

Hyperuricemia may occur precipitating gout.

The increase in systemic uric acid is due to a

decrease in the effectiveness of the organic acid

secretory system.

Diabetic patient may have difficulty in maintaining proper

blood sugar levels.

o Indapamide (Lozol)

o Metolazone (Zaroxolyn, Mykrox)

Potassium Sparing

o Amiloride (Midamor)

o Spironolactone (Aldactone)

o Triamterene (Dyrenium)

Loop Diuretics

o Furosemide (Lasix), Bumetaninde (Bumex), Ethacrynic Acid (Edecrin)

Furosemide (Lasix),bumetanide (Bumex), and ethacrynic acid (Edecrin)

are "high-ceiling" loop diuretics acting primarily at the ascending limb of

the loop of Henle.

The effectiveness of these agents is related to their site of action

because reabsorption of about 30 - 40% of the filtered sodium and

chloride load occurs at the ascending loop.

Distal sites are not able to compensate completely for this

magnitude of reduction of NaCl reabsorption.

Loop diuretics increase urinary Ca2+

in contrast to the action of thiazides.

Loop diuretics also increase renal blood flow by decreasing renal vascular

resistance.

These drugs are rarely used in the management of hypertension because of

their short duration of action and the availability of better drugs.

o Adverse Effects

Ototoxicity

Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal excretion of

uric acid by competition with renal secretory and biliary secretory

systems.

Therefore these agents can precipitate gout.

Potassium depletion.

Osmotic Diuretic: Mannitol (Osmitrol)

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