Diuretics, Aquaretics

Front 1

.Carbonic Anhydrase Inhibitors
Mechanism of Action:

Back 1

.Inhibit C.A., resulting in bicarbonate loss in the urine.

Front 2

.Net Effect: Carbonic anhydrase inhibitors

Back 2

.• Alkaline urine, due to Na+-bicarbonate loss in the urine.
• Enhanced chloride reabsorption resulting in acidosis.

Front 3

.Carbonic anhydrase inhibitors, Clinical Uses:

Back 3

.• Diuretics: limited use.
• Alkalinize urine (Cysteinurea).
• Reduce intra ocular pressure.
• Management of seizures (unknown).
• Given prophylactically for mountain sickness.

Front 4

.Carbonic anhydrase inhibitors drug

Back 4

Acetazolamide, C.A. inhibitors not used much
-inhibit CA inhibitors of proximal tubule

Front 5

.Carbonic anhydrase inhibitors side effects

Back 5

• Metabolic acidosis.
• Markedly increases K+ loss in the urine (acute effect).

Front 6

Osmotic Diuretics
Characteristics:

Back 6

Small molecules that are filtered, but not reabsorbed by the kidney.

Front 7

osmotic diuretics M.O.A.

Back 7

Effect on the Loop of Henle: (major)
• Given in large doses, they increase the osmolarity of plasma.
• Extract water from peripheral tissues and decrease blood viscosity.
• Increase medullary renal blood flow and reduce its tonicity.
• Impair water reabsorption by thin descending limb of Henle’s loop.
• Impair NaCL & urea extraction by thin ascending limb of Henle’s loop.
• Interfere with transport processes in the TALH.

Proximal conv. tubule: (minor)
• Osmotically inhibit Na+ & H2O reabsorption.

Front 8

Osmotic Diuretics
Net effect:

Back 8

• Significantly increase urine with small increments of NaCl and other
ions.
-immediate effect

Front 9

Osmotic Diuretics
Clinical Uses

Back 9

• Treatment of dialysis disequilibrium syndrome.
• Reduce intra cranial pressure.
• Reduce intraocular pressure.

Front 10

osmotic diuretics examples

Back 10

Mannitol, IV infusion: Injection [50 mL of a 25% solution], usual dose 1-5 g.

Front 11

side effects osmotic diuretics

Back 11

-volume overload
-contraindicicated in cardiac failure

Front 12

Loop Diuretics
Mechanism of action and pharmacological effects

Back 12

• Inhibit Na-K-2Cl symporter in TALH.
• Inhibit the ability of the macula densa to “sense” NaCl.
• Stimulate biosynthesis of prostaglandins.
• Increase total renal blood flow.
• Maintain GFR.
• Potently increase renin release by:
inhibiting the macula densa.
reflexely activating the sympathetic NS.
stimulating intrarenal baroreceptor mechanisms

Front 13

Loop Diuretics (High-ceiling
diuretics)
• Net Effect:

Back 13

• Most potent class of diuretics in mobilizing NaCl.
• Copious diuresis and significant NaCl loss.
• Increase urinary excretion of K+/H+ .
• Increase excretion of Ca2+ and Mg2+.
• Impair the ability of the kidney to concentrate urine.

Front 14

Loop Diuretics (III)
Therapeutic Uses:

Back 14

• Edema of cardiac, hepatic or renal origin (oral) [GFR<30
mL/min].
• Pulmonary edema (IV):
Decrease pulmonary wedge pressure.
Increase compliance (so can hold more blood)of pulmonary vessels.
Increase peripheral venous capacitance.
Reduce left ventricular filling pressure.
Cause brisk diuresis.
• Hypercalcemia to mobilize Ca2+ (Given in normal saline).
• Protect against renal failure [related to prostaglandin and
GFR].
• Washout of toxins by increasing urine flow.
• Antihypertensive diuretics used with other drugs.

Front 15

Loop Diuretics (IV)
Specific Examples:

Back 15

Furosemide [Lasix)
• Sulfonamide type drug that inhibits NaCl reabsorption in
TALH.
• Furosemide is administered orally and IV/IM.
• Secreted by organic acid transporter to inhibit the luminal
symporter.
17
• Has a wide margin of safety.
• Dose-response curve
influenced by renal disease
(impaired secretion)

Front 16

furosemide

Back 16

most popular
-has to be secreted into tubule by proximal convoluted tubule, travels and inhibits importer from inside
-in renal disease patients, impaired secretion, so have to give lots more

Front 17

furosemide

Back 17

have to monitor them for NaCl when first use it
-pt has to be hydrated so kidney stones not formed from Ca
-very good venodilator

Front 18

Loop Diuretics (V)
Pharmacological Effects of Furosemide:

Back 18

• copious diuresis with significant NaCl losses.
• increased urinary excretion of K+/H+
• increased urinary excretion of Ca2+ and Mg2+
• increased renal prostaglandins.
•increased venous capacitance.

Front 19

Dosage and Pharmacokinetics of furosemide:

Back 19

• Administered orally at 20-40 mg OD or BID.
• Diuretic response in 30 min, lasting ~8hr.
• Short half-life (1.5 hr), but extensively protein bound.
• Excreted in the urine 65%.

Front 20

Loop Diuretics (VI)
Side effects of furosemide:

Back 20

Abnormalities of fluid and electrolytes:
—hypokalemia and disorders in pH (mostly alkalosis).
—requires initial monitoring.
Elevated BUN, hyperglycemia, hyperuricemia.
Ototoxicity, sialadentitis (inflammation of salivary glands).

Front 21

Drug interactions of furosemide:

Back 21

• interactions with Li+
• indomethacin, is a prostaglandin inhibitor
• probenecid
• warfarin, 99% highly protein boud so is furosemide, can displace water

Front 22

Bumetanide

Back 22

loop diuretic
-Forty times more potent than furosemide.
• Dose is 1 mg once or twice daily.
• Substituted for furosemide in patients receiving warfarin

Front 23

torsemide

Back 23

• Loop diuretic that also lowers blood pressure.
• Has a longer half-life than other loop diuretics, given
once daily.
-antihypertensive

Front 24

3 segments in Collectin Duct

Back 24

1)Na+-K+ aldosterone-
Independent segment
(Na+-Cl—-symporter)
2)Aldosterone Sensitive
ENaC channel
3)Sodium load segment (proportional to how much sodium makes it to that segment)
-ENaC channel

Front 25

Inner Medullary Collecting
Duct
• Up to 5% of filtered Na+ can
be reabsorbed here.
Two types of Na+ channels
are expressed in IMCD:
1. Amiloride-sensitive,
cyclic nucleotide gated
cation (CNG) channel.
2. low-conductance
highly-selective Na+ ENaC
channel.

Back 25

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Front 26

benzothiadiazides (thiadiazide diuretics) M.O.A.

Back 26

inhibit NaCl reabsorption in the Na+-K+ aldosteroneindependent
segment of the distal tubule.

Front 27

benzothiadiazides (thiadiazide diuretics) pharmacological effects

Back 27

• moderate loss of Na+, K+ and Cl-, cause 3X increase in
urine flow.
• sodium loss results in reduced GFR (chronic).
• elevation of excreted urinary potassium (Hypokalemia).
• Increase excretion of titratable acid, due to increased
delivery of Na+ to the distal tubule.
• Decrease the urinary excretion of Ca2+.
• Increase the urinary excretion of Mg2+.

Front 28

benzothiadiazides (thiadiazide diuretics)

Back 28

works on 1st segment of distal tubule
-prescribed lots, and reduce GFR bc used over long period
-reduce Ca, interfere w PTH, major diff bt loop diuretics

Front 29

(Thiazide Diuretics)
Therapeutic uses:

Back 29

• Diuretic to reduce edema associated with:
CHF, cirrhosis and nephrotic syndrome
• Hypercalciurea and renal calcium stones.
• To reduce blood pressure in essential hypertension
(alone).
• To augment the action of other antihypertensives.
• Osteoporosis
• Nephrogenic Diabetes insipidus.
Note: like loop diuretics, thiazides require secretion into the
tubular fluid to exert their effect.
• With possible exceptions of metolazone and indapamide,
most thiazides are ineffective when GFR <30-40 mL/min.

Front 30

Thiazide Diuretics Class I

Back 30

Preferably used when GFR > 50 mL/min.
• Hydrochlorothiazide: (T1/2 = 2.5 h). Oral, 25-50 mg BID.
• Chlorthalidone: [Hygroton] (T1/2 = 47h). Oral, 50 mg once daily.
• Quinethazone: [Hydromox] Dose 25-50 mg BID.

Front 31

Thiazide Diuretics Class 2

Back 31

More potent, might be effective in some patients with GFR <50 but >30
mL/min.
• Metolazone [Zaroxolyn]: 10X more potent than HCTZ.
• Indapamide [Lozol]: 20X more potent than HCTZ.

Front 32

Thiazide Adverse Rxns
1)Depletion phenomena
-Hypokalemia Dilutional, hyponatremia,
Hypochloremic alkalosis, Hypomagnesemia
2)Retention phenomena: Hyperuricemia Hypercalcemia
3)Metabolic changes
Hyperglycemia, Hyperlipidemia,
Hypersecretion of renin & aldosterone
4)Hypersensitivity &
Other
-Fever, Rash, purpurea -Pancreatitis
-Sialadentitis -Withdrawal edema

Back 32

safe class of drug

Front 33

loop diuretics excrete more NaCl for the most part compared to thiazides, def at high doses

Back 33

f

Front 34

Late DCT and CD
• Principal and intercalated cells.

Back 34

• Principal cells:
• Type A (hormonally responsive)
and Type B (load responsive).
• Type A, involved in Na+
reabsorption and K+ SECRETION.
• Hormonally regulated by
ALDOSTERONE.
• Type B, involved in Na+
reabsorption and K+ secretion.
• LOAD DEPENDENT; The more
Na+ is delivered, the more is
absorbed in exchange for K+
secretion.

Front 35

Aldosterone Antagonists
Physiological actions of Aldosterone:

Back 35

• Aldosterone binds to a mineralocorticoid receptor in DCT.
• Traslocate to nucleus and binds to hormone-sensitive elements.
• Regulate the expression Aldosterone-induced EnaC Na+ channels.
• Consequently transepithelial NaCl transport is enhanced.
• Lumen-negative transepithelial voltage in increased.
• The latter effect increases the secretion of K+ and H+.

Front 36

Mechanism of action of Aldosterone antagonists:

Back 36

• Bind to aldosterone receptor in the cytoplasm and prevent its
translocation to the nucleus.
• Reduce Enac channels that are involved in Na+ reabsorption.
• Net effect:
—Increase Urinary excretion of Na+ (Natriuretic effect)
—inhibit the secretion of K+ and H+ (K-sparring)

Front 37

Aldosterone Antagonists drugs

Back 37

spironolactone and eplenerone

Front 38

Aldosterone Antagonists pharmacokinetics

Back 38

• Spironolactone is a pro-drug that is extensively metabolized.
• Canrenone is an active metabolite with a longer T1/2.

Front 39

Aldosterone Antagonists pharmacokinetics side effects

Back 39

Spironolactone side effects
• Hyperkalemia (combine with a thiazide)
• Gynecomastia, hirsutism, uterine bleeding.
B. Eplenerone: [Inspra]
• Expected to have less side effects because it has very low affinity
for androgen receptors compared to spironolactone.

Front 40

clinical uses eplenerone, more used bc of side effects w hydrochlorothyezide

Back 40

• Diuretic, usually in combination with HCTZ ( hydrochlorothyezide)
• Treatment of CHF and cirrhosis.

Front 41

K-sparing diuretics drugs

Back 41

Triametrene, Amiloride
-Are organic bases and are not structurally related to aldosterone
-very popular

Front 42

K sparing diuretics Mechanism of action

Back 42

Inhibit Na reabsorption in late distal tubule, (sodium load segment).

Front 43

K sparing diuretics pharmacologc effects

Back 43

• Increase Urinary excretion of Na+ (weak effect).
• inhibit the secretion of K+ and H+ (K-sparring)

Front 44

K sparing diuretics clinical uses

Back 44

Diuretics. Combined with HCTZ [Dyazide] to increase their
effectiveness and decrease K+ excretion.

Front 45

K sparing diuretics side effects

Back 45

Hyperkalemia, megaloblastic anemia in patients with cirrhosis

Front 46

Atrial Natriuretic Peptides
Inhibitors of the Nonspecific Na+ Channel

Back 46

f

Front 47

Peptides related to ANP:

Back 47

-Atrial natriuretic peptide (ANP) and Brain Natriuretic peptide (BNP)- are produced by the heart in response to wall stretch
-C-Type Natriuretic peptide (CNP)- endothelial and renal origin
-Urodilantin- found in urine, paracrine regulator of Na+ transport

Front 48

ANP M.O.A

Back 48

• ANP: an atrial peptide produced in response to stretch.
• It binds to NP receptor-A (NPR), activates GC and
increases cGMP.
• BNP is produced by the ventricle.
• BNP also binds to NPR-A and acts like ANP.
• CNP binds to NPR-B in vascular smooth muscle cells and
mediates relaxation.

Front 49

ANP and related peptides

Back 49

• Urodilatin arises from the same precursor of ANP.
• Binds with low affinity to ANP-B in the glomeruli and IMCD.

Front 50

ANP related peptide drug

Back 50

-Nesiritide, recombinant B type natriuretic peptide (IV)
Clinical effects:
• Increases Na+ excretion by inhibiting:
—The CNG_nonspecific cation channel in IMCD.
—The renin angiotensin system and endothelin production.
• Useful in congestive heart failure because:
—Decreases systemic vascular resistance.
—Decreases left ventricular filling pressure.
—Increases cardiac output.
Side effects: Numerous, related to its narrow therapeutic index.
No data that it reduces mortality in patients with CHF.

Front 51

Clinical uses Diuretics (review)

Back 51

• Can be used as monotherapy or as adjuncts.
• Diuretics, alone or in combination with beta-blockers have
been demonstrated through large-scale trials to decrease
mortality in patients with hypertension.
• Diuretics (particularly in low doses) and ACEIs are the best
tolerated drugs for the monotherapy of hypertension.
• Patients with edematous conditions, such as heart failure
and renal insufficiency, frequently require the use of a
diuretic for optimal control of BP.
• Responses to diuretics (thiazides in particular) are seen at
lower doses, which produce a small but optimal natriuretic
effect; higher doses should be avoided because of increase
risk of side effects.
• Cheap.

Front 52

thiazides diuretics review

Back 52

• Widely used to treat mild or moderate hypertension.
• HCTZ is the most popular drug for therapy of high BP.
• Metolazone and indapamide may be effective in patients
with impaired renal function when thiazides are not.
However, most of these compounds are usually
ineffective when GFR lower than 30 mL/min and/or
serum creatinine above 2.5 mg/dL.
• Patients with “volume dependent” hypertension (with
low renin levels) show better responses. A poor
response to thiazides may reflect either an overwhelming
load of dietary sodium or an impaired renal capacity to
excrete the sodium
• A single morning dose of HCTZ will provide sustained
effect, while reducing K+ wastage during the nighttime.

Front 53

loop diuretics review

Back 53

• More efficient diuretics than the thiazides. used in patients
with severe hypertension unresponsive to thiazides,
especially with renal insufficiency, cardiac failure or cirrhosis.
• The resulting natriuresis with these agents can be excessive
and lead to more side effects than those caused with
thiazides. Therefore, they require more frequent monitoring.
• Due to their high efficacy, these diuretics (furosemide in
particular) is administered I.V. in hypertensive crisis or in
acute pulmonary edema.
• Co-administration of NSAID with loop diuretics is a common
preventable cause of diuretic resistance. Prostaglandins
reduce Na+ reabsorption in the distal nephron, antagonize
ADH, and distribute renal blood from the cortex to the
juxtaglomerulus.

Front 54

K+ sparing diuretics review

Back 54

• Useful in patients at risk of K+ depletion (due to treatment
with thiazides or loop diuretics, patients with primary
aldosteronism, etc.). Useful in patients with hyperuricemia.
• Spironolactone is the diuretic of choice in cirrhosis and is
titrated to 400 mg/day. If GFR is <50 mL/min add a loop diuretic.
• Equipotent to Thiazides as antihypertensives, useful to
enhance the natriuretic effects of other diuretics.
• Available combination formulations include: Spironolactone
+Hydrochlorothiazide; Amiloride +Hydrochlorothiazide =
[Dyazide] a very popular antihypertensive diuretic.
• They are contraindicated in significant renal insufficiency
GFR <75 mL/min or other K+-retaining conditions.

Front 55

clinical use of diuretics table

Back 55

38 slide

Front 56

aquadiuretics (antidiuretics)

Back 56

-8 arginine-vasopressin also known as ADH
affects water handleing in kidney
-occurs by arginine vasopressin
-acts on 2 classes of receptors

Front 57

Aquaretics (Anti-diuretics)

Back 57

Structure and biosynthesis:
• 9 AA peptide derived from AVP preprohormone.
• Synthesized in paraventricular and supraoptic nuclei of
hypothalamus.
Release:
• Elevation in plasma osmolarity > 280 mOsm/Kg.
• Depletion of extracellular volume
• Other: pain, nausea hypoxia

Front 58

aquaretics; Vasopressin receptors and their activation:
VI Receptor:

Back 58

Found in vascular smooth muscle.
• Binding of vasopressin to V1R activates Gq-PLC-IP3 pathway,
mobilizes Ca2+ causing vasoconstriction

Front 59

Aquaretics: vasopression - continued
• V2 receptor:

Back 59

in principal cells in renal collecting ducts (CD).
• Binding of vasopressin to V2R activates Gs-cAMP, PKA.
• PKA increase rate of insertion of water channel containing
vesicles (WCV’s) into the apical membrane of CD.
• PKA phosphorylates the water forming channel
aquaporin-2, which are then inserted as tetramers into the
apical membrane.
• Aquaporin channels increase the permeability of CD to water.
• PKA also phosphorylates the urea transporter (termed
VRUT or UT1), and increase the permeability of CD to urea.
• This in concert with the TALH and the multiplier
concentrates urine, up to 4 times the osmolarity of plasma.

Front 60

actions of AVP on its receptors
-look @ chart slide 42 as well

Back 60

-Activation of V1 causes vasoconstriction thru calcium
-V2 found in collecting duct, a GS activator 1st step, PKA phosphorylates aquaporin 2, insertion into channel
-perserve water

Front 61

aquaretics II. Synthetic peptides that are V1 receptor agonists:

Back 61

-causes vasoconstriction
-most common used for bleeding ulcers

Front 62

aquaretics

Back 62

Rationale: Activation of V1R cause GI and vascular smooth
muscle contraction.
Clinical uses: V1R agonists are given IV to treat post
oprative ileus, reduce bleeding in esophageal varices, to
reduce bleeding during acute hemorrhagic gastritis

Front 63

aquaretics example

Back 63

—8-arginine vasopressin [Pitressin]
Administered IV; use discontinued because of numerous side
effects: facial pallor, nausea (increased GI motility) and
effects on the coronary circulation.
—terlipressin [Glypressin] has fewer side effects.

Front 64

Diseases affecting the
Vasopressin system
Diabetes insipidus (DI)

Back 64

-drinks lots of water and produces lots of urine
-if taste urine it is tasteless

Front 65

diabetes insipidus (DI) characteristics

Back 65

Etiology: Impaired water conservation caused by:
• Inadequate AVP secretion (Central DI)
• insufficient kidney AVP response (nephrogenic DI).
Symptoms:
• Excrete large volumes or dilute urine.
• Drink a lot of water (polydipsia)
Diagnosis:
• Central DI is distinguished from nephrogenic DI by the
administration of a V2R agonist (such as desmopressin),
which will increase urine osmolarity in patients with central
DI but not nephrogenic DI.

Front 66

when treat don't want to touch the V1 receptor bc cause hypertension, thats why they created desmopressin, V2R agonist

Back 66

f

Front 67

Diseases affecting vasopressin

Back 67

Causes and Treatment of central Diabetes insipidus:
• Head injury, surgery or trauma in the pituitary or
hypothalamus, tumors, CNS ischemia etc.
• Autosomal dominant (chrom 20)- in gradual loss of AVP.
Treatment of Central DI:
Synthetic vasopressin peptides: selective V2 R agonists.
Desmopressin: [DDAVP]:
• Synthetic AVP derivative: highly selective V2R agonist with
minimal V1R effects.
• Administered nasally (10 μg/whiff), IV, or oral tablet.
• Also used in bleeding disorders, given IV. or nasally to
increase circulating levels of factor VIII and von Willebrand
factor via extrarenal V2 receptors
• Used also in nocturnal enurisis (bed wetting in children).

Front 68

Aquaretics

Back 68

-resistance/mutation in V2 stuff, use these, treat the cause
-thiazide can becoume antidiuretic; in slide, reduce the volume delivered to distal tubule

Front 69

aquaretics

Back 69

Causes & Treatment of Nephrogenic Diabetes insipidus:
• Acquired: obstructive renal disease, Drugs: Li, clozapine
• Genetic: X-linked caused by the gene encoding V2R that
result in frame shift, truncated receptor or single amino
acid mutations.
Treatment of Nephrogenic DI:
• Maintain adequate water intake.
Thiazide diuretics: might reduce polyuria by ~50%.
• Cause mild depletion of extracellular water and sodium.
• Compensatory renal mechanisms increase the
reabsorbtive capacities of the proximal convoluted
tubule, reducing the volume delivered to the distal
tubule.

Front 70

Syndrome of Inappropriate
secretion of ADH (SIADH)

Back 70

Etiology: Excessive production of ADH resulting in impaired
water excretion and plasma Hypoosmolarity (Hyponatremia).
Causes: Three drug classes are associated with SIADH:
• Psychotropics: SSRI, haloperidol & tricyclic anti depressants.
• Sulfonylureas: chloropropamide.
• Vinca Alkaloids: (Vincristine and vinblastine).
Treatment of SIADH:
• Patient is asymptomatic if plasma osmolarity is 125-132 mM
• Water restriction is enough.
• Generally when plasma Na+ falls below 120 mM.
*don't treat this unless sodium a big problem (hyponatremia)

Front 71

Patients with SIADH are treated with:

Back 71

• Water restriction, IV hypertonic saline
• Loop diuretics (interfere with kidney concentrating ability)
• Demeclocycline: antagonizes ADH at V2 receptors.
• Vaptans (discussed in the next slide)

Front 72

Other water retaining conditions:

Back 72

• In CHF, cirrhosis, or nephrotic syndrome, effective blood
volume is reduced; hypovolemia exacerbated by diuretics.
• Hypovolemia stimulates AVP release; patients may become
hyponatremic owing to vasopressin-mediated retention of
water.
• Orally active V2 R antagonists provides a new therapeutic
strategy in patients with SIADH and hyponatremia in
patients with heart failure, liver cirrhosis, and nephrotic
syndrome.

Front 73

treatment of SIADh and hyponatremia drug

Back 73

Selective V2R antagonists (Vaptans):
Tolvaptan

Front 74

treatment of SIADh and hyponatremi

Back 74

Pharmacology: 29X more selective for the V2R than the V1aR.
Indications:
• Significant hypervolemic and euvolemic hyponatremia
[serum sodium <125 mEq/L].
• Symptomatic hyponatremia that has resisted correction with
fluid restriction], including patients with heart failure, cirrhosis
and SIADH).
• Used only in a hospital setting.
• Pharmacokinetics: completely metabolized by CYP3.
Side effects:
Hyperglycemia, GI disturbances and clotting problems.

Front 75

tolvaptan and conivaptan
-both used only in a hospital setting, bc volemics would use them to stay thin, increases urinary excretion of H2O

Back 75

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Front 76

Conivaptan

Back 76

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND
MONITOR SERUM SODIUM
See full prescribing information for complete boxed warning.
• SAMSCA should be initiated and re-initiated in patients only in a
hospital where serum sodium can be monitored closely.
• Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can
cause osmotic demyelination resulting in dysarthria, mutism,
dysphagia, lethargy, affective changes, spastic quadriparesis,
seizures, coma and death. In susceptible patients, including those with
severe malnutrition, alcoholism or advanced liver disease, slower
rates of correction may be advisable.

Front 77

Convivaptan injection

Back 77

-also treats SIADH
• Less selective for the V2R than tolvaptan.
• Given IV for acute treatment of hyponatremia in
hospital setting.
• Metabolized by CYP3A4.
• Numerous side effects: such as infusion site reaction.

Front 78

Carbonic Anhydrase Inhibitors summary

Back 78

Acetazolamide
Mechanism of Action:
• Potent competitive inhibitors of carbonic anhydrase.
• Act in proximal tubule (90%) distal tubule (10%).
• Inhibit C.A. resulting in bicarbonate loss into urine.
• Net effect: alkaline urine, enhanced chloride reabsorption
(hyperchloremic systemic acidosis)
Clinical uses in:
• Glaucoma to reduce intraocular pressure.
• Cystinuria to alkalinize tubular urine.
• Management of seizures and mountain sickness.
• Prophylaxis of mountain sickness.

Front 79

Osmotic Diuretics
summary

Back 79

Mechanism of action:
• Osmotically inhibit Na+/H2O reabsorption in proximal
convoluted tubule.
• Expand extracellular volume & é renal medullary blood
flow.
• ê medullary tonicity to impair ability of thin segments of
loop of Henle to extract water and absorb NaCl.
Net effect:
• é urine flow with small increments of Na, K+ & Cl-.
• Initially é plasma volume & B.P.
Clinical uses:
• Treatment of dialysis disequilibrium syndrome.
• Reduce intracranial pressure.
• Reduce intraocular pressure.

Front 80

loop diuretics summary

Back 80

Furosemide, Bumetanide and Torsemide
Mechanism of action:
• Inhibit Na+-K+-2Cl— symporter in TALH.
• increase renal blood flow
• increase renal prostaglandins
• Stimulate renin release and maintain GFR.
Net effect:
• Copious diuresis with significant Na loss
• increase K, Ca2+ and Mg2+ excretion
• increase excretion of H+ resulting in mild metabolic alkalosis

Front 81

loop diuretics summary

Back 81

Therapeutic utility:
• Edema of cardiac, hepatic & renal origin (oral)
• Acute pulmonary edema.
• Given I.V. for rapid mobilization of edema fluid
Effects:
• decrease pulmonary wedge pressure
• Venodilation resulting in decrease left ventricular filling pressure
• increase compliance of pulmonary vasculature that facilitates
mobilization of fluid
• Brisk copious diuresis
• Mobilization of calcium; as in hypercalcemia
• Maintenance of renal PGs & renin to prevent renal failure
• Washout of toxins
• Antihypertensive particularly when GFR is very low.

Front 82

Examples of Loop Diuretics summary

Back 82

Furosemide:
• High margin of safety
• Dilates veins, increases venous capacitance (decrease L.V.
filling pressure)
• Side effects:
• Fluid and electrolyte imbalance
• Ototoxicity,
• increase BUN, hyperglycemia, hyperuricemia
Bumetanide:
• Useful with warfarin
Torsemide:
• Vasodilator

Front 83

thiazide diuretics summary

Back 83

Hydrochlorothiazide, Chlorthalidone and Metolazone
Mechanism of action:
• Inhibit Na-CL symporter in early distal tubule
• Net effect: mild loss of sodium and water
• increase K+ excretion.....Hypokalemia
Therapeutic utility:
• Treatment of mild to moderate edema
• Essential hypertension
• Diabetes insipidus
• Hypercalciurea
Side effects:
• Hypokalemia & Hypomagnesemia
• Hyperuricemia, hypercalcemia, hyperglycemia
• Lipid disorders
Potent thiazide diuretics: METOLAZONE, QUINOTHAZONE

Front 84

Aldosterone antagonists summary

Back 84

Spironolactone and Eplenorone
• Competitive inhibitors to aldosterone in late D.T. and
collecting ducts
• Spironolactone extensively metabolized
• active metabolite “Canrenone”
Net Effect:
increase Na+ excretion, reduces K+ secretion
Mild diuretic administered with HCTZ [Aldactazide]
Side effects:
• Spironolactone Gynecomastia (in males)
• Hirsutism and uterine bleeding (in females
•
• Eplenorone, appears to be safer

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K+ Sparing diuretics :summary

Back 85

Triamterene and amiloride
• Inhibits Na+ reabsorption and K+ secretion in late distal
tubule and collecting ducts
• Combined with thiazides [Dyazide]

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Drugs affecting ADH: summary

Back 86

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ADH and ADH-like drugs:
• Synthesis and release
• Increases water permeability in collecting tubule (V2)
• Is a vasopressor (V1)
Clinical uses:
• ADH-sensitive diabetes insipidus (Desmopressin)
• Nephrogenic diabetes insipidus (Thiazides)
Inappropriate Secretion of AD
• Diagnosis: Plasma hypoosmolarity.
• Treatment: Demeclocycline and Vaptans.