Drugs affecting renal system

Prof. Genny Dominguez

Pharmacology Department
 Summary
• The kidneys and the nephron.
• Drugs affecting renal system.
• Diuretics:
– Loop diuretics.
– Thiazide diuretics and related drugs.
– K+-sparing diuretics.
– Osmotic diuretics.
– Carbonic anhydrase inhibitors.
 The kidneys
• Their main function is to maintain the constancy of
the 'interior environment' by eliminating waste
products and by regulating the volume, electrolyte
content and pH of the extracellular fluid in the face of
varying dietary intake and varying environmental
demands.
• They are the main organs by which drugs and their
metabolites are eliminated from the body, and so
when they fail, dosing regimens of many drugs must
be adapted.
• Furthermore, they are a target for various kinds of
drug toxicity.
Physiologic anatomy of the kidneys
 Nephron
• Functional unit of the kidney.
• Its function is to form a filtrate of protein-free
plasma (Ultrafiltration).
• Tubular structure that contains:
– Renal corpuscle (glomerulus, Bowman capsule).
– Proximal convoluted tubule.
– Loop of Henle.
– Distal convoluted tubule.
– Collecting duct.
Tubular segments of the nephron
Tubular segments & blood vessels
Process of urine formation depend on:
 Drugs affecting renal system
• Diuretics- Crucial for the management of
cardiovascular disease.
• Antihypertensive drugs- Commonly indicated
in Kidney disease.
• Immunosuppressant- Effective in several of
the diseases that can cause renal failure, &
crucial for maintaining the health of patients
who have received a kidney transplant.
• Some antibacterial- To treat renal and urinary
tract infections.
 Diuretics
• Are drugs which block renal ionic transport
(blockade of Na+ and Cl- reabsorption),
causing diuresis (an increase in urine volume),
often associated with natriuresis (increase in
Na+ excretion).
• Increase in urine flow that a diuretic produces
is directly related to the amount of Na+/Cl-
reabsorption that it blocks.
• 1% of solute rearbsorption that is blocked,
urine output will increase 1.8 L.
 CVS effects of diuretics
• Through their effects on Na+ and water balance, they
decrease blood volume and venous pressure.
• This decreases cardiac filling (preload), ventricular
stroke volume and cardiac output, which leads to a
fall in arterial pressure.
• The decrease in venous pressure reduces capillary
hydrostatic pressure, which decreases capillary fluid
filtration and promotes capillary fluid reabsorption,
thereby reducing edema if present.
• Long-term use of diuretics results in a fall in systemic
vascular resistance (by unknown mechanisms) that
helps to sustain the reduction in arterial pressure.
 Diuretics may act through
• Blocking effects on specific membrane
transport proteins at different sites of the
tubule transport system:
– High-ceiling (Loop) diuretics,
– Thiazides diuretics,
– Potassium sparing diuretics.
• Interaction with hormonal receptors (Potassium
sparing diuretics).
• Osmotic effects (preventing water
reabsorption) (Osmotic diuretics).
• Enzyme inhibition (Carbonic anhydrase inhibitors).
Specific transport mechanism inhibited
by Diuretics
LOOP DIURETICS
or
HIGH-CEILING
DIURETICS
 Loop Diuretics
• The most effective diuretics available
producing more loss of fluids/electrolytes than
any other diuretics.
• They act on the thick segment of the
ascending limb of Henle´s loop blocking the
reabsorption of Na+ and Cl- (normally 25% of
filtered NaCl is reabsorbed).
• Prototype: Furosemide (Lasix)
• Others: Bumetamide, torsemide, ethacrynic
acid
 Loop diuretics
They block the Na+/K+/2Cl- co-transporter.
 Loop diuretics (Furosemide)-
Pharmacokinetics
– Administered orally, IV and IM.
• Oral: Diuresis begins in 60 min and
persists for 8 hours.
• IV: Diuresis begins in 2 min and
persists for 2 hours.
– Undergoes hepatic metabolism and renal
excretion.
 Loop diuretics- Uses
• Utilized by patients requiring rapid or massive
mobilization of fluids.
– Acute pulmonary edema (major use).
– CHF (when diminution of ECF volume is desirable
to minimize venous and pulmonary congestion).
– Cirrhosis of the liver complicated by ascites.
– The edema of nephrotic syndrome.
– Edema of renal failure.
– Hypertension uncontrolled with other diuretics.
(their short elimination half-lives render them less
useful than thiazides)
– Hypercalcemia.
 Loop diuretics- ADR
• Hyponatremia, Hypochloremia, Hypocalcemia,
Hypomagnesemia.
• Hypokalemia caused by increased delivery of Na+ to
the distal tubule, particularly when combined with
activation of the renin-angiotensin system, leads to
increased urinary excretion of K+ and H+ (they are
frequently given together with K+-sparing diuretics-
amiloride).
• Hyperuricemia (due to a decrease excretion of uric
acid leading to Gout in susceptible patients).
• Hyperglycemia (due to the hypokalaemia which
decrease the insulin secretion and the sensitivity to
insulin in diabetic patients)- See next slides.
 Mechanism of insulin release
• When glucose levels increase there is an entry of
glucose to the pancreatic β cells, glucose is oxidise to
G6P with a release of intracellular ATP.
• The K+-ATP dependant channels located at the cell
membrane of the pancreas get close when the ATP
attach them and the exflux of K+ through these channels
stop.
• This provoke a change in the RMP (relative
depolarization) and the specific voltage value needed for
opening the voltage gated Ca2+ channels at the
pancretatic membranes is reached.
• When these channels open, the Ca2+ flow into the cell
and these is the stimulus for the insulin release from the
vesicles.
 Hypokalaemia and membrane potential
• Hypokalaemia: Decrease K+ concentrat. in the ECF.
• As consequence there is an increase in the K+-gradient
across the cell membrane for the K+ diffusion out of the
cells.
• This cause (in all cells) an extra deficit in positives
charges in the inner site of the cell membranes, and
the RMP becomes more negative than normal.
• As a result the gap between the RMP and the voltage
at which the Ca2+ channels will open has become
greater because is necessary to move more voltage
due to the excessive negativity inside the cells.
• Being more difficult to open the Ca2+ channels the influx
of Ca2+ will be reduced as well as the release of insulin
by the pancretaic cells.
 Loop diuretics- ADR cont.
• Dehydration (hypovolemia) leading to
hypotension.
• The increased hydrogen ion loss can lead to
metabolic alkalosis.
• Hypercholesterolemia; hypertriglyceridemia,
Increased low-density lipoproteins.
• Dose-related ototoxicity (tinnitus, hearing
impairment, deafness, vertigo, and a sense of
fullness in the ears).
• Rashes, photosensitivity, paresthesias, bone
marrow depression, and GI disturbances.
 Loop diuretics- Interactions
• Hypokalemia potentiates digitalis toxicity.
• NSAIDs: reduced diuretic efficacy.
• Aminoglycosides: enhance ototoxicity &
nephrotoxicity (diuretics reduce plasma volume
leading to reduced renal blood flow).
• Lithium (increased plasma levels of Li+ due to
decreased renal elimination).
• Cisplatin (increased risk of diuretic-induced
ototoxicity).
• They may diminish the effects of sulfonylureas
and insulin.
 Loop diuretics- Interactions cont.
• A potentially lethal drug interaction is with
antiarrhythmic drugs that prolong QT interval
(ventricular repolarization) such as quinidine.
• Prolongation of the QT interval can lead to the
development of polymorphic ventricular
tachycardia (torsades de pointes) owing to
triggered activity originating from early after-
depolarizations.
• Hypokalemia increases the risk of quinidine-
induced torsades de pointes.
Loop diuretics- Interactions cont.
• Thiazide diuretics (synergism of diuretic
activity of both drugs leading to profound
diuresis).
• Amphotericin B (increased potential for
nephrotoxicity and intensification of
electrolyte imbalance).
• Corticosteroids: enhance hypokalemia
because their mineralocorticoid effect.
 THIAZIDES
DIURETICS AND
RELATED DRUGS
 Thiazide diuretics
• The most commonly used diuretic.
• Increase renal excretion of Na+, Cl-, K+, & water.
• Less powerful than loop diuretics (causing less
diuresis, loop diuretics are effective in renal
impairment, thiazides not), their action depend
on adequate kidney function (are ineffective
when GFR is low).
• Weak diuretics but also weak vasodilators.
• Better tolerated than loop diuretics, and in
clinical trials have been shown to reduce risk of
stroke and heart attack associated with
hypertension.
 Thiazide diuretics
They block the Na+/Cl- co-transporter

Urine Blood
 Thiazide diuretics
• A blockade of the Na+/Cl- co-transporter, leads
to a reduction of Na+ and Cl- ions reabsorption.
• There is a consequent reduction in intracellular
Na+, and an increase in the Na+-gradient
across the cell membrane.
• As the Na+-gradient increase, the activity of
the Na+/Ca2+ exchanger increase, and
intracellular Ca2+ tends to fall.
• The fall in intracellular Ca2+ promotes re-
uptake of Ca2+ from the nephron (Thiazides
thus elevate serum Ca2+).
 Thiazide diuretics and related
drugs
• Prototype: Hydrochlorotiazide
• Others: Bendroflumethiazide, chlorothiazide
• Related drugs (Chemically distinct drugs
with similar actions): Metolazone,
chlortalidone, indipamide.
• Pharmacokinetics:
- They are taken orally once a day.
- Onset: 2 h after oral administration.
- Peaks: 4-6 h and persist up to 12 h.
 Thiazide diuretics- Uses
• Hypertension (preferred in uncomplicated
hypertension).
• Edema (mild/moderate CHF) (Loop diuretics
are preferred).
• Severe resistant edema (Metolazone
especially is used with loop diuretics).
• To prevent recurrent stone formation in
idiopathic hypercalciuria.
• Nephrogenic diabetes insipidus (reducing
urine volume by up to 50%- The mechanism
of this paradoxical effect remains unknown).
 Thiazide diuretics- ADR
• Hypokalaemia, Hyponatremia, Hypocholoremia,
Hypomagnesemia, Hypercalcemia, Hyperuricemia.
• Metabolic alkalosis.
• Dehydration (hypovolemia), leading to hypotension.
• Hyperglycemia in diabetics.
• Hypercholesterolemia, hypertriglyceridemia,
Increased low-density lipoproteins.
• Azotemia (in renal disease patients).
• Male impotence (the reduced blood volume and
arterial pressure cause activation of the RAAS
which lead to vasoconstriction).
• Idiosyncratic reactions (e.g. rashes, blood
dyscrasias (Thrombocytopenia)).
 Thiazide diuretics- Interactions
• Hypokalemia potentiates digitalis toxicity.
• NSAIDs: reduced diuretic efficacy.
• Bile acid sequestrants: reduction of absorption of
thiazides.
• Corticosteroids: enhance hypokalemia
(mineralocorticoid effect).
• They may diminish the effects of sulfonylureas
and insulin.
• They may induce lithium toxicity due to decreased
renal elimination of lithium.
• Synergistic diuretic effect with loop diuretics.
• The hypokalemia increases the risk of quinidine-
induced torsades de pointes.
 POTASSIUM
SPARING DIURETICS
 K+-sparing diuretics
• They have two useful responses:
– Produce a modest increase in urine production.
– Produce a substantial decrease in K+ excretion.
• They are weak diuretics.
• Used in conjunction with loop and thiazide
diuretics.
• Two subcategories:
– Aldosterone antagonists.
– Nonaldosterone antagonists.
 Aldosterone
• It is released from adrenal cortex- stimulated
by Angiotensin II.
• It induces expression of the apical Na+
channel, and probably also promotes its
activity (via a protein activator).
• Aldosterone stimulates:
• Increased Na+ reabsorption
• Increased K+ secretion
• Increased H+ secretion
Aldosterone antagonist
• Spironolactone
(Aldactone), Eplerenone.
• Spironolactone is an
steroid hormone.
• It is a weak diuretic that
blocks the action of
aldosterone in the distal
nephron.
• Opposite effect: retention
of K+ and excretion of
Na+.
 Aldosterone antagonist
• Pharmacokinetic:
– Spironolactone is well absorbed from the gut.
– Its onset of action is slow, taking 48 h to develop.
– Its plasma half-life is only 10 min, but its active
metabolite, canrenone, has a plasma half-life of
16 h.
– The action of spironolactone is largely attributable
to canrenone.
– Eplerenone has a shorter elimination half-life than
canrenone and has no active metabolites.
– They are administered orally once daily.
 Aldosterone antagonist- Uses
• With K+-losing diuretics (i.e. loop or thiazide)
to prevent K+ loss, where hypokalaemia is
especially hazardous (e.g. patients requiring
digoxin or amiodarone).
• Spironolactone is considered the diuretic of
choice in patients with hepatic cirrhosis.
• Heart failure (added to standard therapy).
• Primary hyperaldosteronism (Conn's
syndrome).
• Secondary hyperaldosteronism caused by
hepatic cirrhosis complicated by ascites.
 Aldosterone antagonist- ADR
• Hyperkalemia (which is potentially fatal).
• Tumors.
• Endocrine effects (Actions of
spironolactone/canrenone on progesterone
and androgen receptors in tissues other than
the kidney can result in gynaecomastia,
menstrual disorders and testicular atrophy).
• GI upset.
 Nonaldosterone antagonists
(Inhibitors of renal epithelial Na+ channels)
• Triamterene & Amiloride.
• MOA: Bind to the apical
Na+ channel of the distal
part of the distal tubule
and collecting duct and
block the Na+/K+
exchange inhibiting K+
loss.
• They produce modest
diuresis.
 Nonaldosterone antagonists
(Inhibitors of renal epithelial Na+ channels)

• Adverse effects: Hyperkalemia.

• Contraindications:
- Patients with hyperkalemia,
- Patients at increased risk of developing
hyperkalemia (e.g., renal failure, receiving
other K+-sparing diuretics, taking ACEI, or
taking K+ supplements).
OSMOTIC DIURETICS
 Osmotic diuretics
• Mannitol (most common, administered IV), Urea (IV),
Glycerin (o), Isosorbide (o).
• Mannitol (Osmitrol). It is a sugar
– Free filtered in the glomerulus.
– Undergoes minimal reabsorption.
– Not metabolized to a significant degree.
– It is pharmacologically inert.
• MOA: Creates osmotic force within the lumen of the
nephron, inhibiting passive reabsorption of water,
increasing urine flow.
• No significant effect on the excretion of K+ and other
electrolytes.
 Osmotic diuretics- Mannitol
• In the brain its presence causes water to be
drawn to it.
• Works the same way in the eye: The excess
intraocular fluid is drawn to the mannitol in the
hyperosmotic plasma.
• Pharmacokinetics:
– Poorly absorbed by the GI tract, and when
administered orally it causes osmotic diarrhea. For
systemic effect, must be given parenterally (IV).
– Distributes into extracellular water.
– Diuresis begins 30-60 min, persists for 6 hours.
 Osmotic diuretics- Mannitol
• Therapeutic uses:
– Prophylaxis of renal failure to maintain urine
flow.
– Reduction of intracranial pressure (ICP).
– Reduction of intraocular pressure (IOP).
• Adverse effects:
- Transient expansion of the extracellular fluid
volume (with a risk of causing left ventricular
failure) and hyponatremia.
- Headache, nausea and vomiting can occur
caused by the hyponatremia.
 CARBONIC
ANHYDRASE
INHIBITORS
 Bicarbonate

• Bicarbonate reabsorption in the proximal

tubule depends on the action of Na+/H+
exchanger which is found in the luminal
membrane of the proximal tubule epithelial
cell.
Reabsorption of Bicarbonate

PROXIMAL CELL
 Carbonic anhydrase inhibitors
• In the proximal tubule, bicarbonate reabsorption
can be influenced by carbonic anhydrase
inhibitors.
• Acetazolamide (Diamox, Glaumox),
dichlorphenamide (Daranide), and methazolamide
(Glauctabs).
• Although the proximal tubule is the major site of
action of carbonic anhydrase inhibitors, carbonic
anhydrase also is involved in secretion of titratable
acid in the collecting duct system, which is a
secondary site of action for these drugs.
• Very weak diuretics- Not used as diuretics.
Carbonic anhydrase inhibitors-
Actions
• They increase excretion of bicarbonate with
accompanying Na+, K+ and water, resulting in
an increased flow of an alkaline urine.
• Carbonic anhidrase catalyzes inside the cell
the formation of HCO3– from H2O and CO2.
• Carbonic anhydrase is present in a number of
extrarenal tissues.
• In the ciliary processes of the eye mediates
the formation of large amounts of HCO3– in
aqueous humor.
 Carbonic anhydrase inhibitors-
Actions cont.
• Inhibition of carbonic anhydrase decreases
the rate of formation of aqueous humor and
consequently reduces IOP.
• Acetazolamide frequently causes
paresthesias and somnolence, suggesting a
CNS action.
• The efficacy of acetazolamide in epilepsy is
due in part to the production of metabolic
acidosis; however, direct actions of
acetazolamide in the CNS also contribute to
its anticonvulsant action.
Carbonic anhydrase inhibitors-
Therapeutic uses
• Open-angle glaucoma.
• Secondary glaucoma and preoperatively in acute
angleclosure glaucoma.
• Some unusual types of infantile epilepsy (rapid
development of tolerance limit their usefulness).
• Acute altitude sickness owing to interference with
carbonic anhydrase activity in erythrocytes, they
increase CO2 levels in peripheral tissues and
decrease CO2 levels in the expired gas. (more
effective given prophylactically).
• For correcting metabolic alkalosis, especially that
caused by diuretic-induced increases in H+ excretion.
 Carbonic anhydrase inhibitors- ADR
 They are sulfonamide derivatives and may cause
bone marrow depression, skin toxicity,
sulfonamide-like renal lesions, and allergic
reactions.
 With large doses, drowsiness and paresthesias.
 Most ADR, contraindications, and interactions are
secondary to urinary alkalinization or metabolic
acidosis, including:
 Diversion of ammonia of renal origin from urine
into the systemic circulation, that may induce or
worsen hepatic encephalopathy (the drugs are
contraindicated in patients with hepatic
cirrhosis).
 Carbonic anhydrase inhibitor-
ADR cont.
 Calculus formation and ureteral colic owing
to precipitation of calcium phosphate salts
in an alkaline urine.
 Worsened metabolic or respiratory acidosis
(the drugs are contraindicated in patients
with hyperchloremic acidosis or severe
chronic obstructive pulmonary disease).
 Reduced urinary excretion of weak organic
bases.
 General indications for the
use of Diuretics
• Edema: Urinary output will increase and
excess fluid is flushed out of the body.
• CHF: The sodium loss in the kidney is
associated with water loss.
• Hypertension: Diuretics will decrease the
blood volumen and serum sodium.
• Glaucoma: Diuretics will provide osmotic pull
to remove some of the fluid from the eye to
decrease the IOP.
Thank you