Diuretics
By. Dr. Smita Singh
• Natriuretics:- increases Na excretion in urine
• Diuretics :- increases urine volume
Classification of diuretics
1. High efficacy diuretics:
– Furosemide, Bumetanide, Torasemide
2. Medium efficacy diuretics:
(a) Thiazides:
• Hydrochlorothiazides, benzthiazide, hydroflumethiazide,
clopamide
(b) Thiazide like:
• Chlorthalidone, metolazone, Xipamide, Indapamide
3. weak or adjunctive diuretics
(a) Carbonic anhydrase inhibitors:
- Acetazolamide
(b) Potassium sparing diuretics:
(i) Aldosterone antagonist: Spironolactone,Eplerenone
(ii) Inhibitor of renal epithelial Na+ channel: Triamterene,
Amiloride
(c) Osmotic diuretics:
• Mannitol, Isosorbide, Glycerol
1. Proximal tubule
• Approx. 65% of filtered Na+, K+ , water, and
virtually almost all glucose, AA are reabsorbed
in the proximal tubule
• Proportionately, water also gets reabsorbed so
tubular fluid is isotonic
Four mechanisms of Na transport +
1) Direct entry of Na+ along a favorable electrochemical
gradient.
2) Transport of Na + coupled to active reabsorption of
glucose, amino acids, other organic
anions and phosphate through specific symporters.
3) Exchange with H + : The PT cells secrete H + with the
help of a Na + /H + antiporter located at the lumjnal
membrane.
4)The disproportionately large HCO3, acetate,
PO43-, amino acid and other anion reabsorption
create passive driving forces for Cl- to diffuse
through the paracellular pathway
. This takes Na+ and water along to maintain
isotonicity
Secretory system
1. Organic acid secretory system:- secrete organic
acid i.e Uric acid, Penicillin, Thiazide and Loop
diuretics (into lumen from where they act) etc.
2. Organic base secretory system:- secrete bases
like creatinine, choline etc
1. CA inhibitors
MOA
- Inhibit CA no NaHCO3
reabsorption in PCT alkaline diuresis
- Secretion of H+ in late DCT and CD is interfered.
- Though H+ is secreted by H+ATPase it is generated
in cell by CAase which is blocked by CAase
inhibitor.
• Carbonic anhydrase:
– present in a number of extrarenal tissues: eye, gastric mucosa,
pancreas, central nervous system, and RBC
• Reduces IOP
• Decrease gastric HCl and pancreatic HCO3secretion at very
high dose
• Raised level of CO2 in brain & lower pH sedation &
elevation of seizure threshold
Therapeutic Uses of CAI
1. Glaucoma
2. As adjuvant in absence seizure
3. Symptomatic and prophylactic relief in acute
mountain/altitude sickness
4. To alkalinize urine
• Side effects:
– drowsiness and paresthesias
– bone marrow depression, skin toxicity(sulfonamide
derivative)
– Metabolic Acidosis
– Renal Stones (because of alkaline urine),
– Hypokalemia (maxm)
• Contraindicaton:
– hepatic cirrhosis(decreases formn NH4 by decreasing H
formn precipitation of HE), metabolic acidosis or severe
chronic obstructive pulmonary disease
2. Loop of Henle
• Descending limb of loop of Henle :-
- Impermeable to Na but highly permeable
to water so fluid in LOH is hypertonic
• Thick ascending limb of loop of Henle:-
- Impermeable to water but highly permeable to Na, K and Cl
mediated by Na+ -K+- 2Cl- cotransporter
- Ca and Mg also reabsorbed via paracellular pathway due to
positive potential created by back diffusion of K
- Fluid in loop is hypotonic
Loop diuretics
Eg. Furosemide, bumetanide, ethacrynic acid, and
torsemide
- Highly efficacious
• Effective at low glomerular filtration rates (as
occur in chronic renal failure), where thiazides
are ineffective
Inhibits Ca, Mg
absorption
Bumetanide
Rarely causes myopathy
Therapeutic Uses
– Edema:
• acute pulmonary, nephrotic syndrome, liver cirrhosis
– Hypertensive ER
– Acute Renal Failure
– Hypercalcemia
– Hyperkalemia
• Along with blood transfusion in severe anaemia, to prevent
volume overload.
• Acute pulmonary oedema
- iv furosemide increases PG synthesis which increases RBF
and also causes increase in systemic venous capacitance thus
right ventricular filling pressure decreases before saluretic
action occurs
3. Early Distal tubule
• Impermeable to water
• Na and Cl reabsorbed with help of co-
transporter
• PTH helps in Ca reabsorbtion
Medium efficacy diuretics (Inhibitors of
Na+–Cl– Symport)
1. Thiazides diuretics:
– Bendroflumethiazide, Chlorothiazide, Hydrochlorothiazide,
Hydroflumethiazide
2. Thiazide-like diuretics:
– Chlorthalidone, Indapamide, Metolazone
MOA and Effects
• Secreted into tubular lumen of PCT by competing
with …….. inhibits Na+–Cl– symporter in DCT and
increases excretion
• Hyperuricaemia
• Hypokalemia
• Decrease Ca2+ excretion
Extrarenal action
1. Slowly developing fall in BP in Hypertensive patient
– Flat dose response curve little diuresis occurs when
dose increased beyond 100mg of HCT but maximum
anti- Hypertensive effect is reached at 25mg/day
2. Elevation of blood sugar level due to decreased insulin
release(Hypokalemia)
[Link]
• Used in severe renal failure (gfr less than 15)
• Additive action when combined with furosemide
• Used in oedema occ for HTN
3. Xipamide :- s/e VT
Therapeutic Uses of Thiazide
1. Edema:- furosemide preferred
- Thiazide as maintenance
- Thiazide less effective in case of RF(Metolazone )
2. Hypertension
3. Hypercalciuria
4. Nephrogenic diabetes insipidus
S/E
1. Abnormalities of fluid and electrolyte balance.
• Extracellular volume depletion(hypotension)
• Hypokalemia
• Hyponatremia
• Hypomagnesaemia
• Hyperuricaemia
• Hypo/hypercalcaemia(FUROSEMIDE/THIAZIDE)
2. Hyperglycemia
3. Impotence/erectile dysfunction
– CNS (vertigo, headache, paresthesias, and weakness)
– gastrointestinal ( anorexia, nausea, vomiting, cramping,)
– hematological (blood dyscrasias)
– dermatological (photosensitivity and skin rashes)
– Ototoxicity ( furosemide)
• Contraindication:
– hypersensitive to sulfonamides, Hepatic coma,
preeclampsia
4. Late distal tubule
and Collecting Duct
• CD has two types of cells
1. Principal cells:-
- reabsorb Na through Amiloride/epithelial sensitive Na
channel and secrete K under influence of Aldosterone
2. Intercalated cells :- secrete H in lumen
• Absorption of fluid in CD is in influence of ADH
• Na enters principal cells from luminal side though epithelial Na
channel and is transported to interstitium via Na/ K ATPase.
• This creates negative electrical potential in lumen to compensate
this some Cl moves through paracellular route while K are driven
out of principal cell towards luminal fluid :- loss of K+
• Any diuretic acting proximal to the DCT causes increased delivery
of Na+ leading to more exchange with K+. Thus, K+ is excreted
K -Sparing Diuretics
+
1) Aldosterone antagonist:
Spironolactone, Eplerenone
2) Inhibitors of renal epithelial Na+ channel
- Triamterene, Amiloride
• Converted to active metabolite canrenone (t1/2 – 18 hrs)which is
responsible for ½-2/3 of its action in vivo.
Uses
1. To counteract K+ loss due to thiazide and loop diuretics.
2. Edema:-Cirrhotic and Nephrotic edema in which aldosterone levels are high.
3. HTN:- Used as adjuvant to thiazide to prevent hypokalaemia, it may slightly
add to their antihypertensive action.
4. CHF
• Interactions
- More pronounced hyperkalaemia can occur in patients receiving ACE inhibitors/ARBs.
• Adverse effects
- Drowsiness, ataxia, mental confusion, epigastric distress, and loose motions.
- Spironolactone enhance testosterone clearance or its peripheral conversion
to estradiol, producing gynaecomastia, erectile dysfunction or loss of libido
in men, and menstrual irregularities in women( PR& androgen).
• Most serious is hyperkalaernia
2. Eplerenone
• More selective aldosterone antagonist which
has lower affinity for steroidal receptors
• Less hormonal disturbances like
gnaecomastia, impotence, menstrual
irregularities, etc.
Inhibitors of renal
epithelial Na+ channel
• Triamterene and amiloride
nonsteroidal drugs.
• Luminal membrane of late DT and CD cells expresses epithelial Na+
channel through which Na+ enters down its electrochemical gradient
generated by Na+K+ ATPase operating at basolateral membrane.
• This Na+ entry partially depolarizes luminal membrane creating -15 m V
transepithelial potential difference which promotes secretion of K+ into
the lumen through K+ channels.
• Decreases H+ ion secretion from intercalated cells and predisposes to
acidosis
Uses
• Same as Spironolactone
• Amiloride blocks entry of Li+ through Na+ channels in the
CD cells and mitigates diabetes insipidus induced by lithium.
• Given as an aerosol it affords symptomatic improvement in
cystic fibrosis by increasing fluidity of respiratory secretions.
S/E
• Triamterene less used becoz of incomplete
absorption photosensitivity, interstitial
nephritis, megaloblastic anaemia
• Amiloride :- N/V, headache, diarrhoea
OSMOTIC DIURETICS
• Inert drugs that act in PCT, Loop of Henle.
• Freely filtered at glomerulus undergoes limited
reabsorption, therefore used as osmotic diuretic.
• Expands extracellular fluid volume (because it does not enter
cells, draws water from intracellular
compartment)increases G. f.r.
• It is minimally metabolized in the body
Mannitol
• Nonelectrolyte of low molecular weight
• Not given orally; has to be given i.v. as 10-20%
solution.
USES
• Never used for treatment of edema or as a natriuretic.
• Its indications are:
1. Increased intracranial or intraocular tension(by osmotic
action encourages movement of water from brain
parenchyma, CSF and aq. Humour)
2. To maintain G.f.r. and urine flow in impending acute renal
failure, e.g. in shock, severe trauma, cardiac surgery,
haemolytic reactions
C/I
• RF, cerebral haemorrhage.
• The most common side effect is headache.
Nausea and vomiting , hypersensitivity
reactions are rare.
• Isosorbide and glycerol:- orally active osmotic
diuretics which may be used to reduce
intraocular or intracranial tension
Relation to diuretic action
• Na+ reabsorption at different sites are:
PT 65-70%; Asc LH 20-25%; DT 8-9%; CD 1-2%.
• It may appear diuretics acting on PT should be the most
efficacious but increased reabsorption down the nephron so
they aren’ t efficacious , also causes distortion of acid-base
balance
• A diuretic acting on Loop of Henle (furosemide) can produce
maximum effect because of limited capacity for salt
absorption in DT and CD.
Free water clearance
• The volume of water in urine excreted per unit
time in excess of that required to excrete the
contained solute isoosmotically with plasma
• The nephron of kidney is arranged in such a
way that some part lies in cortex and some
portion in medulla
Parts of nephron in Parts of nephron in
cortex medulla
1. PCT 1. Descending thin limb
of loop of Henle
2. DCT
2. Ascending thin limb of
3. Thick Asc Loop of Henle loop of Henle
4. Cortical CD 3. Medullary CD
• Cortical portion of nephron are responsible for
diluting urine (i.e positive free water clearance)
• Medullary portion of nephron are responsible for
concentrating urine (i.e negative free water
clearance)
• So, diuretic acting on both cortex and medulla
will affect both positive and negative free
water clearance
• Furosemide acts on both cortical and
medullay part of thick asc LH so blocks both
positive and negative free water clearance
• Thank U
