The Heart and

Circulatory System
and The Kidney 2
Asst. Prof. Dr. Izzuddin Ahmad Nadzirin
Dept. of Biomedical Sciences
Kulliyyah of Allied Health Sciences
KIDNEY
● Functions
○ Excretion of wastes
○ Acid-base
homeostasis
○ Osmolality
regulation
○ Blood pressure
regulation
○ Hormone secretion
○ Functional Unit
Urine formation
• Filtration
• At glomerulus (GFR)
• Reabsorption
• Water, electrolytes
• Active tubular secretion
• Organic acids and bases
Excretion = Filtration – Reabsorption + Secretion
= GLOMERULAR HYDROSTATIC
PRESSURE (60 mmHg)

= BLOOD COLLOID OSMOTIC

PRESSURE (32 mmHg)

CAPSULAR HYDROSTATIC
PRESSURE (18 mmHg)

NET OUTWARD = 60-18-32

PRESSURE = +10 mmHg
 FLOW OF GLOMERULAR FILTRATE
GLOMERULUS

ASCENDING
PROXIMAL LIMB OF
CONVOLUTED HENLE'S COLLECTING
TUBULE (PCT)  LOOP (AscLH) DUCT

BOWMAN'S DISCENDING DISTAL

SPACE IN LIMB OF CONVOLUTED
BOWMAN'S LOOP OF TUBULE
CAPSULE  HENLE (DCT) 
RENAL PELVIS
Goals of Diuretics
• Increase the excretion of Na+ and water.
• Decrease the reabsorption of Na+ and an accompanying anion (usually
Cl−) from the filtrate, increased water loss being secondary to the
increased excretion of NaCl (natriuresis).
• This can be achieved:
• by a direct action on the cells of the nephron
• indirectly, by modifying the content of the filtrate
• Because a very large proportion of salt (NaCl) and water that passes
into the tubule via the glomerulus is reabsorbed, even a small decrease
in reabsorption can cause a marked increase in Na+ excretion.
Diuretics - Classification of Diuretics

1. Acts directly on cells of nephron

a) Loop diuretics
b) Distal tubule diuretics
i. Thiazide
ii. Potassium-sparing diuretics
• Aldosterone antagonists
• Inhibition of Na+ influx in the luminal membrane
iii. Carbonic anhydrase Inhibitors
2. Acts indirectly by modifying filtrate content
a) Osmotic diuretics
1. DRUGS THAT
ACT DIRECTLY
ON CELLS OF
NEPHRON
 a) LOOP DIURETICS
• Most powerful diuretics
• Capable of causing the excretion of 15%-25% of filtered Na+.
• Acts on thick ascending limb
• E.g.: Furosemide, bumetanide, torasemide
• Indication: HT, acute pulmonary oedema, chronic heart failure,
cirrhosis of the liver complicated by ascites, nephrotic syndrome,
hypercalcaemia.
• Adverse effects:
• Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia,
hyponatremia
• Dehydration and postural hypotension
• Hypocalcemia (in contrast to thiazides)
• Hypersensitivity
• Ototoxicity (especially if given by rapid IV bolus)
• Pharmacokinetics
• Oral, but may also be given as IV for urgency
• If oral - absorbed from the GIT, action within 1h.
• If IV, peak action within 30 min.
• Pharmacodynamic
• Inhibit the Na+/K+/2Cl− co-transporter in the luminal membrane by combining with its Cl− binding site.
 b) Distal tubule diuretics
i) Thiazides
• Less powerful than loop diuretics, but better tolerated. (reduced risk of stroke and
heart attack associated with HT)
• Acts on distal tubule
• E.g.: Hydrochlorthiazide, bendroflumethiazide,
• Indication: HT, mild heart failure, oedema, prevent recurrent stone formation in
idiopathic hypercalciuria, nephrogenic diabetes insipidus.
• Adverse effects:
• Hyperlipidemia: mechanism unknown but; cholesterol increases usually 1% increase
• Impotence
• Hyponatremia due to thirst, sodium loss, inappropriate ADH secretion (can cause confusion in
the elderly)
• Hypersensitivity
• Pharmacokinetic
• Oral
• Rapid GI absorption
• All excreted in urine unchanged, mainly by tubular secretion
• Variable elimination kinetics and therefore variable half-lives of elimination ranging
from hours to days.
• Pharmacodynamic
• Binds the Cl- site of the distal tubular Na+/Cl− co-transport system and inhibits its action
• Results in natriuresis with loss of sodium, chloride and water in urine.
• However, homeostatic mechanism kicks in: ↓ Blood volume  renin secretion 
angiotensin formation  aldosterone secretion  increases Na+ and water
reabsorption.
 b) Distal tubule diuretics
ii) Potassium-sparing
Direct antagonist of
mineralocorticoid receptors
01 (Aldosterone Antagonists
e.g spironolactone,
eplerenone
CLASSIFICATION
Indirect via inhibition of
Na+ influx in the
luminal membrane 02
(e.g. Amiloride,
triametrene)

THEY ARE VERY IMPORTANT TO BALANCE K+ IN THE BODY.

• Limited diuretic action when used singly.
• Acts on distal nephron (CT and CD) – only accounts for 2% Na + reabsorption.
• Aldosterone antagonists: Synthetic steroid acts as a competitive antagonist of
aldosterone with a slow onset of action.
• Indications:
• heart failure
• primary hyperaldosteronism (Conn’s syndrome)
• resistant essential hypertension (especially low-renin hypertension)
• secondary hyperaldosteronism caused by hepatic cirrhosis complicated by ascites
• To overcome the hypokalemic action of diuretics (loop or thiazide).
• Hirsutism (the condensation and elongation of female facial hair) because it is an
antiandrogenic drug (aldosterone antagonists)
• Side effects:
• Hyperkalemia (some times it's useful other wise it's a side effect).
• Hyperchloremic metabolic acidosis
• Antiandrogenic effects (e.g. gynecomastia: breast enlargement in males, impotence) by
spironolactone.
• Triametrene causes kidney stones.
• Pharmacokinetic (spironolactone):
• Well absorbed from the gut.
• Plasma half-life 10 min.
• Slow onset of action
• Pharmacodynamic (spironolactone and eplerenone):
• Aldosterone cause ↑ K+ and H+ secretion and ↑ Na+ reabsorption.
• Antagonists compete with aldosterone  less aldosterone binding.
• Results in inhibition of distal Na+ retention and K+ secretion.
• Pharmacokinetic (triamterene):
• Well absorbed in the GIT.
• Onset of action within 2 h.
• Duration of action 12-16 h.
• Pharmacodynamic (triamterene, amiloride):
• Inhibits luminal sodium channel  Na+ reabsorption ↓.
• Indirectly decreases K+ excretion.
 b) Distal tubule diuretics
iii) Carbonic anhydrase inhibitors
• A classic diuretics – not now used as diuretics.
• But still used for glaucoma (reduce formation of aqueous humour), infantile
epilepsy, accelerate acclimatization to high altitude.
• CA – present in many nephron sites but predominantly in epithelial cells of PCT
• Catalyses H2CO3  CO2 + H2O and vice versa
• E.g.: Acetazolamide
• Clinical indications
• Glaucoma
• Urinary alkalization – uric acid and cystinuria
• Metabolic alkalosis
• Side effects:
• Sedation and drowsiness
• Hypersensitivity reaction (because it contains sulfur)
• Acidosis (because of decreased absorption of HCO )
• Renal stone (because of alkaline urine)
• Hyperchloremia, hyponatremia and hypokalaemia
• Weak diuretic effect
• Pharmacokinetics
• Well absorbed after oral administration
• Pharmacodynamics
• Inhibition of CA reduces HCO reabsorption in the PCT (excretion of HCO increases)  alkaline urine.
• But reabsorption still occurs at other sites (CA-independent mechanisms).
• Hence CAI action is max at 45% inhibition.
 2) Drugs that
act indirectly
by modifying
filtrate content
 a) Osmotic Diuretics
• Inert, hydrophilic and low molecular weight substances
• Main effect is in nephron parts that are freely permeable to water – PCT, descending
limb of LOH, CT.
• E.g.: Mannitol
• Adverse Reactions:
• Extracellular water expansion may complicate heart failure & produce pulmonary edema.
• Dehydration
• Hypernatremia due to loss more water than sodium
• Pharmacokinetic:
• Given parentally. If given orally it will cause osmotic diarrhea.
• Pharmacodynamic:
• Easily filtered through the glomerulus with little reabsorption.
• Urine becomes more concentrated.
• Thus, increase urinary output via osmosis.
 Thanks!

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