Dr. Kaukab Azim

Carbonic Anhydrase Inhibitors

Thiazide Diuretics and Congeners Loop Diuretics

AcetazolamideDorzolamide

HydrochlorthiazideIndapamide

FurosemideEthcrynic Acid

Potassium Sparing Diuretics Osmotic Diuretics ADH Antagonists

TriamtereneAmilorideSpironolactone

Mannitol ConivaptanTolvaptan

Drug List

In the next few slides we will revisit some useful physiological concepts

For each nephron unit, the glomerular filtration rate (GFR) is a function of the:a) hydrostatic pressure in the glomerulusb) hydrostatic pressure in the proximal tubulec) mean oncotic pressure in the glomerulusd) mean oncotic pressure in the proximal tubule (this is negligible as no proteins are filtered into nephron under normal physiological conditions)e) ultrafiltration coefficient (Kf)

The proximal TubuleAbout 65% of the solutes are reabsorbed by the proximal tubule(since this tubule is highly permeable to water the reabsorption is isotonic)Na+ is transported across the proximal tubule by:1) Symports that reabsorb Na+ with other organic nutrients

like amino acids and glucose.2) Antiports that reabsorb Na+ while secreting H+ into the

tubular lumen.The energy for these secondary active transport systems is furnished by the Na+/K+ pump in the basolateral membrane.

The loop of Henle• The thin descending limb is permeable to water, yet its

permeability to NaCl and other solutes is low.• The thin and thick ascending limbs are impermeable to

water and urea.• The thick ascending limb (TAL) actively reabsorbs NaCl

through a Na+/K+/2Cl symport (about 25% of the Na+ filtered load is reabsorbed) so diluting the tubular fluid.

• This symport is capable of establishing about 200 milliosmole concentration gradient between the tubular lumen and the interstitial fluid and so is the most important cause of the high renal medullary osmolarity.

The Macula Densa• TAL makes contact with the afferent and efferent arterioles via

macula densa which senses the concentration of Na+ in the tubule.• If the amount of sodium is increased macula densa stimulates the

formation and release of ATP (and/or adenosine) which causes contraction of mesangial cells and afferent arterioles through purinergic receptor activation, so decreasing GFR (tubuloglomerular feedback)

• If the amount of sodium is decreased macula densa stimulates renin release which increases the synthesis of angiotensin II. Angiotensin II constricts the efferent arterioles more than the afferent, so increasing GFR.

[these mechanisms are specifically directed toward stabilizing GFR]

The Distal TubuleThe early distal tubule• This tubule also actively reabsorbs NaCl through a Na+/Cl-

symport (about 5-10% of the Na+ filtered load is reabsorbed) but is impermeable to water.

• The TAL and the early distal tubule are parts of the ‘diluting segment’ of the nephron which regulates the diluting ability of the kidney.

The late distal tubule and the cortical collecting tubule• Water permeability here depends on ADH. With high levels of ADH

these tubules are highly permeable to water thus causing large amount of water to be reabsorbed into the hypertonic interstitium.

Principal and Intercalated Cells

• Luminal membranes of principal cells of these nephron segments have Na+ channels that allow Na+ entry down the electrochemical gradient created by the Na+/K+ pump (normally 2-3% of filtered Na+ load is reabsorbed through these channels). The permeability of these channels is modulated by aldosterone.

• The intercalated cells of these nephron segments avidly secrete H+ by an active H+-ATPase pump. This pump plays a key role in the acid-base regulation of body fluids.

The Medullary Collecting Duct

• Water reabsorption here depends on:1. ADH2. The osmolarity of the medullary

interstitium established by the countercurrent mechanism.

• This high osmolarity contributes to the high concentrating ability of the kidney.

Name the hormones secreted by the kidneys?

3 of them

So what will you treat in chronic renal failure?

Are there any waste products that are going to accumulate in the body? Name 2 that you will clinically measure?

Clinical Condition in which Diuretics are used

Edematous States

• Heart Failure

• Hepatic Ascites

• Increased portal pressure

• hypoalbuminemia

• Secondary Aldosteronism

• Nephrotic Syndrome

• Premenstrual edema

Non-edematous States

• Hypertension

• Hypercalcemia

• Diabetes insipidus

Site and Mechanism of Action of Diuretics

Name Site of Action Mechanism of Action

Relative efficacy

Carbonic Anhydrase Inhibitor

Proximal tubule Inhibit NaHCO3 reabsorption

2

Loop Diuretics Thick ascending limb of the loop of Henle

Block the Na+K+/2Cl- symporter

15

Thiazide Diuretics Early distal tubule Block the Na+/Cl- symporter

5

Potassium Sparing Diuretics

Late distal tubule and cortical collecting duct

Block Na+ channels 1

Osmotic Diuretics Thin descending limb of the loop of Henle and proximal tubule

Increase osmolarity of tubular fluid

6

Carbonic Anhydrase InhibitorsChemistry• - Acetazolamide, dorzolamide (All compounds are sulfonamides).Mechanism of action• Inhibition of membrane-bound carbonic anhydrase (CA) in the

cells of proximal tubule which leads to blockade of the reaction H2CO3 = H2O + CO2 that normally occurs in the proximal tubule lumen

• Inhibition of cytoplasmic CA in the cells of proximal tubule which leads to blockade of the reaction: H2 O + CO2 = H2 CO3 that normally occurs in the cytoplasm

• The final effect is a nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (but NaHCO3 reabsorption by mechanisms independent from carbonic anhydrase still occur in other parts of the nephron).

Na+

HCO3-

K+

Volume of Urine

IncreasedUrinary

secretion

DecreasedUrinary

secretion

Acetazolamide

Please see notes below

Pharmacokinetics

• Oral bioavailability: .100%.• Urinary excretion: .90% by tubular secretion.• Administration: acetazolamide PO,

dorzolamide topical (eye drops)

Adverse effects• Paresthesias (frequent), drowsiness• Nephrolithiasis (due to precipitation of calcium phosphate

salts inalkaline urine)• Hyperchloremic metabolic acidosis• Hyperuricemia• Hypokalemia (the main mechanism is the same as that of

thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion).

• Sulfa-type allergic reactions

EdemaGlaucoma (50-60% reduction in aqueous humor production)Epilepsy (direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission) High altitude sicknessMetabolic alkalosis

Contraindications and Precautions

• Hepatic cirrhosis (alkalinization of urine decreases urinary trapping of NH 4+)• Chronic obstructive pulmonary disease (the risk of metabolic acidosis is

increased)• Hypersensitivity to sulfa drugs.• Hypokalemic states

Therapeutic Uses

Please see notes below

Adverse effects• Paresthesias (frequent), drowsiness• Nephrolithiasis (due to precipitation of calcium phosphate

salts in alkaline urine)• Hyperchloremic metabolic acidosis• Hyperuricemia• Hypokalemia (the main mechanism is the same as that of

thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion).

• Sulfa-type allergic reactions

Loop DiureticsChemistry• Furosemide, bumetanide, and torsemide are sulfonamides. Ethacrynic acid is

not a sulfonamideMechanism of action• Inhibition of electroneutral Na+/K+/2Cl- cotransport located on the luminal

surface of the thick ascending limb of Henle's loop, which leads to:• a decreased lumen-positive potential which normally drives divalent cation

reabsorption.• a decreased hypertonicity of the medulla and therefore a decreased ability of the

kidney to concentrate the urine.• an inhibition of macula densa sensitivity (by inhibiting Na+ and Cl- transport into

macula densa, the macula densa is no longer able to sense salt concentration in the tubular fluid. Therefore it initiates two responses that can increase GFR:• It inhibits the tubuloglomerular feed back• It stimulates renin release from the adjacent juxtaglomerular cells.

• Loop diuretics that are sulfonamide compounds also cause a slight inhibition of carbonic anhydrase.

Pharmacology of Loop DiureticsRenal effects• Increased renal excretion of: Na+,Cl-, K+, H+, Ca++, (sulfonamides also increase the

excretion of HCO3).• Acid-base balance: metabolic alkalosis.• The diluting and concentrating capacity of the kidney are decreased.• Efficacy of diuretic effect: high (the maximum increase in Na+ excretion is 20-25% of the

filtered Na+ load. Moreover the diuretic effect remains even when the GFR is less than 30 mL/min).

• Duration of diuretic effect: 2-6 hours.Vascular effects• Vasodilation, mainly in the venous bed.• Redistribution of blood flow within the renal cortex. (these effects are due, at least in part,

to drug induced induction of prostaglandin synthesis and stimulation of prostaglandin release)

Pharmacokinetics• Absorption, and biotransformation are drug-related.• Kidney excretion occurs by active secretion by the proximal tubule.• Administration: PO, IM, IV.

Therapeutic uses of Loop Diuretics• Acute pulmonary edema (given IV).• Heart failure.• Edema (associated with chronic renal failure or nephrotic

syndrome).• Ascites (associated with hepatic cirrhosis or right-sided heart

failure).• Hypertension (when associated with renal insufficiency or

heart failure).• Hypercalcemia.• (Addition of a thiazide can cause a dramatic synergistic effect

when a patient become refractory to a loop diuretic alone )

Na+

Ca2+

K+

Volume of Urine

IncreasedUrinary

secretion

DecreasedUrinary

secretion

Furosemide

Ototoxicity

Hyperuricemia

Hypotension

Hypokalemia

Hypomagnesemia

Adverse Effects

Remember the one’s in the red

box

Thiazide Diuretics

The most commonly used

diuretics

Pharmacology of Thiazide(and congeners)

Chemistry• Thiazides are benzothiadiazine derivatives• Other compounds (congeners) are not thiazides but are

pharmacologically similar to thiazides.• All compounds are sulfonamides.Mechanism of action• Inhibition of electroneutral Na+/Cl- cotransport located

on the luminal surface of early distal convolute tubule• Slight inhibition of carbonic anhydrase.

Renal effects• Increased renal excretion of: Na+, K+, H+, Cl-, HCO3-,.• Decreased renal excretion of: Ca++, NH4+, urates.• Urine pH: alkaline (due to inhibition of carbonic anhydrase).• Acid-base balance: metabolic alkalosis.• Kidney diluting capacity: decreased.• Efficacy of diuretic effect: moderate (the maximum increase in

Na+ excretion is 5-10% of the filtered Na+ load. Moreover, with the exception of indapamide and metolazone, the diuretic effect disappears if the glomerular filtration rate is less than 30 mL/min).

• Duration of diuretic effect: variable (6-48 hours).

Na+

Ca2+

K+

Volume of Urine

IncreasedUrinary

secretion

DecreasedUrinary

secretion

Hydrochlorothiazide

Other effects

Vascular effects• Arteriolar vasodilation (after chronic administration)

that occurs at lower dosages than are required for diuresis

Pharmacokinetics• Absorption, distribution and biotransformation are

drug-related.• Kidney excretion occurs by glomerular filtration and

active secretion by the proximal tubule.• Administration: PO, IM, IV.

Hypertension (first choice diuretics).- Edema associated with diseases of:a) the heart (i.e. heart failure)b) the liver (i.e. hepatic cirrhosis)c) the kidney (i.e. nephrotic syndrome).- Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.)- Calcium nephrolithiasis, idiopathic hypercalciuria.- Meniere’s disease (they can prevent the endolymphatic fluid buildup)- Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)

Contraindications and PrecautionsAbsoluteAnuriaSulfonamide hypersensitivity, thiazide diuretic hypersensitivityPrecautionsHyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure

Therapeutic Uses

Hypokalemia

Hyperuricemia

Hypercalcemia

Hyperlipidemia

Hyperglycemia

Adverse Effects

Potassium Sparing DiureticsChemistry• Triamterene and amiloride are organic bases.• Spironolactone is a steroid drug.Mechanism of action• Spironolactone blocks aldosterone receptors in the late distal

tubule and cortical collecting tubule (the synthesis of Na+/K+ ATPase in the basolateral membrane, as well as the synthesis of protein Na+ channels in the luminal membrane are impaired).

• Triamterene and amiloride directly block Na+ channels in the luminal membrane of late distal tubule and cortical collecting tubule.

Na+

K+

Volume of Urine

IncreasedUrinary

secretion

DecreasedUrinary

secretion

Triamterene

Therapeutic uses

Most commonly used in combination with other diuretics

There are other uses that we will discuss in 3rd semester

Absolute contraindications

HyperkalemiaRenal failure

Precautions

GoutPregnancyAcid base imbalance

PHARMACOLOGY OF ANTIDIURETIC HORMONE ANTAGONISTS

Drugs• - Conivaptan, tolvaptanMechanism of action• Competitive antagonists at vasopressin receptors (conivaptan at

V1a and V2, tolvaptan at V2)Renal effects• Increased water diuresis (these drugs are also called aquaretics)• Water diuresis increases more than salt diuresis (in this way

hyponatremia is relieved).• Increased renal excretion of: Na+, K+, Ca++• Urine osmolality: decreased

Other effectsOther effects• Conivaptan is a strong inhibitor of CYP3A4Pharmacokinetics• Half lives: Conivaptan 5-10 hrs, tolvaptan < 12 hrs• Administration: Conivaptan IV. Tolvaptan PO.Adverse effect• Infusion-site reactions (with conivaptan)• Nephrogenic diabetes insipidus• Postural hypotension (if hypovolemia develops)• Hypokalemia (. 9%)Therapeutic uses• Syndrome of inappropriate ADH secretion (when water restriction failed to correct

the disorder)• Chronic euvolemic hyponatremia

Therapeutic UsesCerebral edema (To reduce raised intracranial pressure)

Oliguria in renal failure

Acute attack of Glaucoma

Contraindications and PrecautionsAbsoluteHeart Failure, dehydration, intracranial bleedingPrecautionsElectrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation

Mannitol(An IV osmotic diuretic)