Download Therapeutic uses of Loop Diuretics

Dr. Kaukab Azim
Drug List
Carbonic Anhydrase
Inhibitors
Acetazolamide
Dorzolamide
Potassium Sparing Diuretics
Triamterene
Amiloride
Spironolactone
Thiazide Diuretics and
Congeners
Hydrochlorthiazide
Indapamide
Osmotic Diuretics
Mannitol
Loop Diuretics
Furosemide
Ethcrynic Acid
ADH Antagonists
Conivaptan
Tolvaptan
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 glomerulus
b) hydrostatic pressure in the proximal tubule
c) mean oncotic pressure in the glomerulus
d) 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 Tubule
About 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 Tubule
The early distal tubule
• This tubule also actively reabsorbs NaCl through a Na+/Clsymport (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. ADH
2. 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+/2Clsymporter
15
Thiazide Diuretics
Early distal tubule
Block the Na+/Clsymporter
5
Potassium Sparing
Diuretics
Late distal tubule and Block Na+ channels
cortical collecting
duct
1
Osmotic Diuretics
Thin descending limb Increase osmolarity
of the loop of Henle of tubular fluid
and proximal tubule
6
Carbonic Anhydrase Inhibitors
Chemistry
• - 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).
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
Therapeutic Uses
Edema
Glaucoma (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 sickness
Metabolic 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
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 Diuretics
Chemistry
• Furosemide, bumetanide, and torsemide are sulfonamides. Ethacrynic
acid is not a sulfonamide
Mechanism 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 Diuretics
Renal 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 )
Adverse Effects
 Ototoxicity
 Hyperuricemia
 Hypotension
 Hypokalemia
 Hypomagnesemia
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).
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.
Therapeutic Uses
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 Precautions
Absolute
Anuria
Sulfonamide hypersensitivity, thiazide diuretic hypersensitivity
Precautions
Hyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure
Adverse Effects
 Hypokalemia
 Hyperuricemia
 Hypercalcemia
 Hyperlipidemia
 Hyperglycemia
Potassium Sparing Diuretics
Chemistry
• 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.
Therapeutic uses
Absolute contraindications
Most commonly used in
combination with other
diuretics
Hyperkalemia
Renal failure
There are other uses that we
will discuss in 3rd semester
Precautions
Gout
Pregnancy
Acid base imbalance
PHARMACOLOGY OF ANTIDIURETIC
HORMONE ANTAGONISTS
Drugs
• - Conivaptan, tolvaptan
Mechanism 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 effects
Other effects
• Conivaptan is a strong inhibitor of CYP3A4
Pharmacokinetics
• 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
Mannitol
(An IV osmotic diuretic)
Therapeutic Uses
Cerebral edema (To reduce raised intracranial pressure)
Oliguria in renal failure
Acute attack of Glaucoma
Contraindications and Precautions
Absolute
Heart Failure, dehydration, intracranial bleeding
Precautions
Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation