Mechanism of Action
Toxicities/Side Effects
Other
Carbonic Anhydrase Inhibitors
(Site 1 – primarily in proximal
tubule, secondarily in collecting
ducts)
Category/Class
Acetazolamide

Absorption – oral
Enters renal tubules by active
secretion and is eliminated entirely
unchanged
Noncompetitive inhibition of renal
carbonic anhydrase – near complete
prevention of NaHCO3
reabsorption
Inhibition indirectly inhibit Na-H
exchange by limiting the formation
of intracellular protons → increases
both Na and HCO3 levels within
the nephron
↑ loss of HCO3 – alkalization of the
urine, can result in metabolic
acidosis
hypokalemia, ↑ Ca excretion in
alkaline urine – renal calculi,
hypersensitivity rxns, prolongs
action of quinidine
Contraindicated in hepatic cirrhosis
Very moderate effect b/c almost all
of the NaCl is reabsorbed in loop of
Henle
CA catalyzes the conversion of
H2O and CO2 to H2CO3 and the
reverse in the cell (facilitates HCO3
reabsorption and H+ excretion)
↑ K excretion
↑ Phosphate excretion
No effect on Mg2 or Ca2
Tx: chronic metabolic alkalosis, ↑
excretion of weak acidic drugs,
acute mountain sickness, edema
due to CHF
Main use – glaucoma
Loop (high-ceiling) Diuretics –
very potent
(Site II)
Furosemide

Abs – oral or IV, organic anions,
highly bound, rapid onset
Secretion by the proximal tubule cells or
organic anions

Metab – small amt by liver

Elim – 2/3 kidney, 1/3 bile

T ½ - short
Inhibits luminal membrane
Na/K/2Cl Symporter at thick
ascending segment of the loop of
Henle, maximally inhibits 25%
reabsorption, distal tubule cannot
compensate
Hypovolemia (dizziness, HA,
orthostatic hypotension)
Increased loss of K and H –
hypokalemic metabolic alkalosis,
hypomagnesemia, hypocalcemia,
hyperuricemia, glucose intolerance,
N, V, diarrhea, rare – ototoxicity
Loop Diuretics – Net loss of:
Na, K, Ca, Cl
Induce venodilation
As long as volume depletion is
compensated for - ↑ RBF
So, can induce a diuretic response
even when renal function is
impaired
Can ↓left ventricular filling
pressure
Tx: Edematous states (CHF)
Hydrochlorothiazide

Abs – oral
Enter proximal tubule by active secretion

T1/2 – varies, 1.5hr – 44hr depending
on drug

Metab – hepatic

Elim – renal
Inhibit Na/Cl symporter in the early
distal convoluted tubule on the
luminal membrane side – ↑NaCl
excretion and ↓ability to dilute the
urine
↓ plasma volume - ↑ aldosterone
production
Normally Na/K/2Cl results in
transepitelium positive potential
which drives paracellular flux of
Ca, Na and Mg
Thiazide
(Site III)
Moderate in nature
Prototype/Pharmacodynamics
Thiazide effectiveness ↓ as renal
function ↓
Thiazide-like
Metolazone
Differ chemically from thiazides in the
heterocyclic ring structures
Longer acting, once a day dosing
See thiazides
Drug interactions: digitalis,
glucocorticoids, NSAIDs,
aminoglycoside antibiotics, weak
acidic drugs, highly plasma protein
bound drugs
Reduce renal blood flow and GFR
Generally well-tolerated
Side effects – dose related:
volume depletion, hypotension,
hypokalemia, hypomagnesemia,
hyponatremia, metabolic alkalosis,
weakness, fatigue
metabolic side effects hyperlipidemia (↑ TG and total
chol.), hyperglycemia, glucose
intolerance, ↑ plasma uric acid –
may precipitate an attack of gout
Drug interactions – similar to loop
diuretics except thiazides and
quinidine – prolong QT interval, Vtac, torsades de pointes (esp.
w/hypokalemia)
Reduces RBF and GFR to a lesser
extent than thiazides, retain
effectiveness in the presence of
advanced renal insufficiency
Promote reabsorption of Na distally
and loss of H and K
Net effect - ↑ excretion of Na, K, Cl
and small amt of HCO3
Decrease Ca excretion
Primarily used of tx of HTN
Other tx: edematous states, CHF,
cirrhosis, renal dysfunction,
premenstrual state, steroid hormone
therapy, reducing hypercalciuria
and renal stones, nephrogenic
diabetes insipidus
See thiazides
Category/Class
Potassium sparing
(Site IV and V)
Act primarily at the late distal
tubules and the early collecting
ducts
Potassium sparing
(Site IV and V)
Act primarily at the late distal
tubules and the early collecting
ducts
Potassium sparing
(Site IV and V)
Act primarily at the late distal
tubules and the early collecting
ducts
Prototype/Pharmacodynamics
Mechanism of Action
Triamterene

Abs – oral, party bound
Actively secreted into proximal tubules,
via the organic base mechanism

Metab – liver, some metabolites
have biological activity

Biologic activity – 7-9 hrs
Inhibit the Na channel in the
luminal membrane of the principal
cells in the late distal tubule and
collecting duct
↓ Na reabsorption and K and H
secretion
Inhibition of K secretion is
secondary to the inhibition of Na
entry
Not direct aldosterone antagonists
Inhibit the Na channel in the
luminal membrane of the principal
cells in the late distal tubule and
collecting duct
Hyperkalemia – serious and
possibly fatal, metabolic acidosis
(likely to occur in pts w/impaired
renal fxn or excessive K intake)
See above
See above
Exert effects by acting as
aldosterone antagonists (structural
analog of aldosterone)
Competitively bind to aldo.
Receptor
Exerts diuretic effect only in the
presence of endogenous
aldosterone production
Hyperkalemia – serious and
possibly fatal, metabolic acidosis
(likely to occur in pts w/impaired
renal fxn or excessive K intake
Normally, mineralocorticoids bind
receptors and cause the retention of
NaCl and water and increase the
excretion of K and H
Response time slow, 48-72 hrs for
onset
Ca, Mg sparring effect
Net effect: ↑ Na, Cl excretion and ↓
the loss of K, Mg and H
Tx: hyperaldosteronism related
edema, HTN from glucocorticoid
therapy, refractory edema w/
secondary aldosteronism, CHF
↓ renin response and blood
viscosity - ↑ RBF - ↑ removal of
NaCl and urea from renal medulla
Amiloride

Abs – oral, not bound
Actively secreted into proximal tubules,
via the organic base mechanism

Elim – renal

Biologic activity – 24 hrs
Spironolactone

Abs – oral, extensively bound

Metab – hepatic, metabolized to
canrenone (majority of biologic activity)

T1/2 – 8hr
Toxicities/Side Effects
Drug interactions – captopril (ACE
inhibitor) can ↑plasma K levels and
can cause hyperkalemia,
glucocorticoids, NSAIDs
Males - gynecomastia, impotence
Females – menstrual irregularities
Same captopril interactions
Osmotic
Acts primarily at the loop of Henle
and secondarily at the proximal
tubule
Mannitol

Abs – IV
Filtered at glomerulus

Elim – renal
Retard reabsorption of water from
renal tubules b/c of osmotic
properties and low level of tubular
reabsorption - ↑ urine excretion
HA, N, V, chest pain,
hyponatremia, temporary volume
expansion can trigger CHG,
hypersensitivity
Other
K, Ca and Mg sparring effect
Rarely used alone b/c diuretic effect
is very small (2-4%)
Primary use – prevent hypokalemia
and hypomagnesemia by other
diuretics
Excrete 25-30% of filtered water
Net effect - ↑ excretion of Na, Ca,
Cl
Induces mobilization fluid from the
intracellular to the extracellular
compartment
Major use: prevention of acute
renal failure, ↓ ICP and intraocular
pressure
Drugs used to Treat Gout
Anti-inflammatory
Colchicine

Abs – oral or IV, selective
distribution, high levels in kidney,
liver, spleen, intestines, low levels in
heart, skeletal muscle, brain

Metab – partially hepatic

Elim – feces
Suppress IL-8 induced PMN
migration caused by the urate
crystals, Anti-mitotic agent,
prevents normal polymerization,
which is required for motility and
secretory events in neutrophils, by
binding tubulin
Reduces rate of production of
leukotriene B4
Dose-related: N, V, diarrhea,
abdominal pains
Overdoses are a major problem
Less common: renal damage,
muscular weakness, paralysis,
blood dyscrasias, resp. depression
Effective only against gout arthritis
Category/Class
Uricosuric
Uric acid biosynthesis inhibitor
Prototype/Pharmacodynamics
Probenecid

Abs – oral, highly bound
Enters renal tubules by active secretion by
the weak acidic transporter in the proximal
tubules

Metab – partially hepatic
Allopurinol

Abs – oral

Metab –hepatic, active metabolite alloxanthine

T1/2 – 1-3 hrs
Mechanism of Action
↑ urinary excretion of uric acid by
blocking the tubular secretion of
urate in the proximal tubules
Used only in under-excretors
Inhibits urate biosynthesis by
inhibiting xanthinie oxidase, causes
↓ in plasma levels and urinary
excretion of urate
Can use in under-excretors and
over-producers
Toxicities/Side Effects
Other
Well-tolerated, GI irritation
Contraindicated in over-producers,
if large tophi are present, impaired
renal fxn, in pts on antineoplastic
agents
Can reduce the secretion of other
weak acids and prolong their serum
½ life by inhibition of the renal
tubular transport of weak organic
acids ½ life of uric acid not affected
b/c it is filtered thru the glomerulus
Well-tolerated, GI irritation
infrequent
Temporary increase in acute gout
attacks, hypersensitivity reactions,
hepatotoxicity
Can interfere with anti-cancer drug
6-mercaptopuren and other purine
analogs and can ↑ toxicity, can
inhibit hepatic drug metabolism
Note: pts should ↑ water intake to
prevent renal stones
Inhibits de novo synthesis of
purines and the salvage pathways
for purines
Tx: early, uncomplicated gout
Recommended: high risk of uric
acid stone formation, severe renal
failure