Renal PCO

RENAL PHARMACOLOGY
The main functions of the kidney include;

• The secretion of waste products (such as urea, uric acid and creatinine),
• Fluid and electrolyte balance. Approximately 99% of water is reabsorbed from the kidney, and
therefore a slight interference with water reabsorption will cause a large increase in the volume of
urine.
• Acid-base balance
• Renal processes
• Filtration – glomerulus
• Reabsorption
• Tubular secretion
• The functional unit of the kidney is the nephron, and there are about one million nephrons in
each kidney.
• Each nephron consists of

• a glomerulus (which consists of glomerular capillaries and the bowman’s capsule)
• the renal tubular network, which is comprised of (in order of flow) the proximal convoluted
tubule, the loop of henle, the distal convoluted tubule and the collecting tubule and duct (figure
1).
• Fluid from the glomerular capillaries is filtered into the bowman’s capsule by hydrostatic
pressure, removing all proteins and protein-bound substances.
• Diuretics
• diuretics are agents that promote the excretion of water from the body.
• When the water loss is associated with sodium loss the process is known as natriuresis.
• The two main therapeutic uses of diuretics are in the treatment of high blood pressure (hypertension) and in
the treatment of excessive water retention (edema).
• In hypertension, diuretics promote the loss of water from the body, and this leads to a decrease in blood
volume, and then to a decrease in blood pressure.
• Edema is secondary to cardiac, hepatic or renal disorders.
• The cardiac disorder most commonly associated with edema is heart failure.
• The hepatic disorder most commonly associated with accumulation of fluids is cirrhosis, which
(in turn) is most commonly caused by alcoholism.
• The diuretics most commonly used in the treatment of hypertension are the thiazide diuretics,
whereas the loop (high ceiling) diuretics are most commonly used in the treatment of edema
• Basic mechanism:
• block reabsorption of sodium and chloride => water will also stay in the nephron
• diuretics that work on the earlier nephron have greatest effect, since they are able to block more
sodium and chloride reabsorption

Classification of diuretics and their site of action
• The osmotic diuretics act at the proximal convoluted tubule and the loop of henle.
•
• The carbonic anhydrase inhibitors act on the proximal convoluted tubule, whereas
• the thiazide diuretics act on the distal convoluted tubule.
• The loop diuretics are so named because they act on the loop of henle.
• The K+ -sparing diuretics act on the collecting tubule and duct.

•
Figure 1. Nephron structure and site of diuretic action
• Osmotic diuretics:
• To act as an osmotic diuretic, an agent has to be freely filterable at the glomerulus, undergo
limited reabsorption and be pharmacologically inert.
• – Small, non-reabsorbable molecules that inhibit passive reabsorption of water
• – predominantly increase water excretion without significantly increasing na+ excretion =>
limited use
• – Used to prevent renal failure, reduction of intracranial pressure (does not cross blood-brain
barrier => water is pulled out of the brain into the blood)
• • Mannitol
• The diuretic effect of mannitol is short-lived, making mannitol unsuitable for use in chronic
conditions such as hypertension and heart failure
• – Only given IV – can crystallize (=> given with filter needle or in-line filter)
• Carbonic anhydrase inhibitors:
• • Azetazolamide
• – can trigger metabolic acidosis
• – not in use as diuretic anymore –
• Inhibits carbonic anhydrase in renal proximal tubule cells
• Primary indications is glaucoma (prevents production of aequous humor)
• • Dorzolamide: topically acting, anti-glaucoma agent
• Ca-inhibitors are sulfonamides => cross-allergenic with antibiotics etc
• Loop diuretics (= high ceiling diuretics):
• – strong, but brief diuresis (within 1 hr, lasts ~ 4hrs)
• – used for moderate to severe fluid retention and hypertension
• – most potent diuretics available
• – Act by inhibiting the Na+/K+/2cl- symporter in the ascending limb in the loop of henle
• – major side effects: loss of K+ (and ca++ and mg++)
• loss of K+ and mg++ may precipitate cardiac arrhythmias
• Furosemide • bumetanide • torasemide
• Furosemide can inhibit uric acid secretion and excretion resulting in gout
• Ototoxicity
• Thiazide diuretics: –
• used for mild to moderate hypertension, mild heart failure,
• – medium potency diuretics
• – Act by inhibiting the na+/cl- symporter in the distal convoluted tube
• – major side effects: loss of K+ (and mg++, but not ca++)
• • Hydrochlorothiazide • benzthiazide • chlorthalidone, cyclothiazide …

Potassium-sparing diuretics:
• • Often used in combination with high-ceiling diuretics or thiazides due to potassium-sparing

effects
• • Produce little diuresis on their own
• – act on the distal portion of the distal tube (where Na+ is exchanged for K+)
• – aldosterone promotes reabsorption of Na+ in exchange for K+ (transcriptionally upregulates

the Na+/K+ pump and sodium channels)
•
• Potassium-sparing diuretics contd
• • Spironolactone
• – aldosterone receptor antagonist
• – onset of action requires several days
• • amiloride; trimterene – block sodium channels – quick onset

• Major side effects of these diuretics:
• hypokalemia, hyponatremia, hypochloremia
• hypotension and dehydration
• interaction with cardiac glycosides => potassium can be given orally or IV or potassium-sparing
diuretics may be used.
Urine pH altering agents (pH modifiers)
• Urinary pH modifiers are agents that increase the pH of urine. They make the urine more alkaline and prevent
the formation of kidney stones.
• Making the urine more alkaline also helps the kidneys to remove toxic substances.
• Urinary alkalinizing agents are medications used to make the urine less acidic and prevent the formation
of calcium oxalate, cystine, and uric acid stones.
• Urinary alkalinizing agents are used to prevent kidney stone (nephrolithiasis) formation in people

with kidney disorders such as
• Renal tubular acidosis or
• Low citrate excretion in the urine (hypocitraturia).

• Mechanism of action
• Renal tubular acidosis is a condition in which the kidneys do not remove the acid wastes from
the blood as they normally do, which can lead to the formation of calcium oxalate stones in the kidneys.
• Inadequate citrate excretion in the urine is another risk factor for kidney stones.
• Urinary alkalinizing agents prevent kidney stone formation by raising urinary pH value and increasing
urine citrate levels.
• Citrate binds to urinary calcium and inhibits the formation of calcium oxalate and
calcium phosphate crystals.
Side effects of urinary alkalinizing agents
• Hyperkalemia (high potassium levels in the blood)
• Alkalosis (excess base/alkali in body fluids)
• Nausea
• Vomiting
• Abdominal discomfort
• Diarrhea
• Gastrointestinal lesions and bleeding

• Examples;
• Sodium citrate
• Sodium bicarbonate
• Potassium citrate
• Potassium citrate/citric acid
Potassium acid phosphate

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RENAL PHARMACOLOGY

The main functions of the kidney include;

• Each nephron consists of

• Edema is secondary to cardiac, hepatic or renal disorders.

• the thiazide diuretics act on the distal convoluted tubule.

• The K+ -sparing diuretics act on the collecting tubule and duct.

• used for mild to moderate hypertension, mild heart failure,

• – medium potency diuretics

• – Act by inhibiting the na+/cl- symporter in the distal convoluted tube

• – major side effects: loss of K+ (and mg++, but not ca++)

• • Hydrochlorothiazide • benzthiazide • chlorthalidone, cyclothiazide …

• • Often used in combination with high-ceiling diuretics or thiazides due to potassium-sparing

• • Produce little diuresis on their own

• – aldosterone promotes reabsorption of Na+ in exchange for K+ (transcriptionally upregulates

• – aldosterone receptor antagonist

• – onset of action requires several days

• • amiloride; trimterene – block sodium channels – quick onset

• hypokalemia, hyponatremia, hypochloremia

• hypotension and dehydration

• Urinary alkalinizing agents are used to prevent kidney stone (nephrolithiasis) formation in people

• Low citrate excretion in the urine (hypocitraturia).

• Inadequate citrate excretion in the urine is another risk factor for kidney stones.

• Alkalosis (excess base/alkali in body fluids)

• Gastrointestinal lesions and bleeding

• Potassium citrate/citric acid

Potassium acid phosphate

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