Diuretics (part 2)

DR SOURYA
SR,PHARMACOLOGY
K+ sparing diuretics

❖The CT system - 2–5% of NaCl reabsorption by the kidney.

❖CT system – main site for mineralocorticoid ALDOSTERONE ‘S significant action.

❖The most important site of K + secretion by the kidney and the site
at which virtually all diuretic-induced changes in K + balance
occur.

❖ 2 group of drugs include: ENac inhibitors and aldosterone antagonists.

Cont..
CONT..

ALDOSTERONE

ALDOSTERO • Reabsorption of Na + via the

NE epithelial Na channel
(ENaC) and increased
secretion of K + into lumen.

b/l Na + /K + -ATPase
activity
Aldosterone antagonist

• Drugs such as SPIRONOLACTONE & EPLERENONE

competitively inhibit the binding of aldosterone to the MR.
• Since spironolactone and eplerenone block biological effects of
aldosterone, these agents also are referred to as aldosterone
antagonists.
• Weak diuretics.
SPIRONOLACTONE
❖steroid, chemically related to the mineralocorticoid Aldosterone.

❖It has no effect on Na+ and K+ transport in the absence of aldosterone, while under
normal circumstances, it increases Na+ and decreases K+ excretion. it
❖antagonises K+ loss induced by other diuretics and slightly adds to their natriuretic
effect.
❖The K+ retaining action develops over 3–4 days.

ADME:
❖ORAL ABSORPTION: GOOD

❖MET: LIVER----ACTIVE MET----CANRENONE.

❖The t½ of spironolactone ---1–2 hours, while that canrenone is ~18 hours.

 USES
• WEAK DIURETIC----USE IN COMBINATION WITH OTHERS.
1.To counteract K+ loss due to thiazide and loop diuretics.
2.Edema: Mainly cirrhotic and nephrotic edema(more of refractory edema ) as aldosterone
levels are high.
Spironolactone is frequently added to a thiazide/loop diuretic in the treatment of ascitis
due to cirrhosis of liver.
3.Hypertension: Used as adjuvant to thiazide to prevent hypokalaemia.
4. CHF: As additional drug to conventional therapy in moderate to severe CHF; can retard
disease progression and lower mortality
SPIRONOLACTONE
EPLERENONE

▪ MORE POTENT THAN SPIRO

▪ LESS SIDE EFFECTS RELATED TO OTHER STEROIDAL RECEPTORS
▪ The t½ is 4–6 hours.
USES
▪ moderate to severe CHF,
▪ post-infarction left ventricular dysfunction
▪ hypertension.
▪ It can also be used as alternative to spironolactone.
ENaC inhibitors (Triamterene and
amiloride)
• similar to spironolactone, but their action is independent of aldosterone.

MOA
• Amiloride and triamterene block the luminal Na+ channels and indirectly
inhibit K+ excretion, while the net excess loss of Na+ is minor, because this is
only a small fraction of the total amount of Na+ excreted in urine.
Cont…
• USES: In conjunction with a thiazide type or a high ceiling diuretic to prevent hypokalaemia
and slightly augment the natriuretic response.

• ADR: not be given with K+ supplements; dangerous hyperkalaemia may develop

• DRUG INTERACTIONS:
• Hyperkalaemia WITH-----ACE inhibitors/ARBs, B blockers, NSAIDs and in those with renal
impairment.

• T1/2: triamterene: t½ is 4 hours, effect of a single dose lasts 6–8 hours.

Amiloride: t½ (20 hours)
ANTI DIURETICS
• Antidiuretics (more precisely ‘anti-aquaretics’, because they inhibit water excretion
without
• affecting salt excretion) are drugs that reduce urine volume.
• MC USE: DIABETES INSPIDUS

CLASSIFICATION:
• 1. Antidiuretic hormone (ADH, Vasopressin), Desmopressin, Lypressin, Terlipressin
• 2. Thiazide diuretic: Amiloride.
• 3. Miscellaneous: Indomethacin, Chlorpropamide, Carbamazepine.
ROLE OF ADH
V 2 ROLE IN DI
ADME

• Lypressin:it acts on both V1 and V2 receptors and has longer duration of action (4–6
hours).

• Terlipressin : synthetic prodrug of vasopressin is specifically used for bleeding esophageal

Varices.

• Desmopressin (dDAVP) Desmopressin is the preparation of choice for all V2 receptor

related indications. selective V2 agonist; 12 times more potent antidiuretic than AVP. t½
1–2 hours; duration of action 8–12 hours. Intranasal route is preferred,
Adverse effects of vasopressin analogs
❖Because of V2 selectivity, desmopressin ---- fewer adverse effects than vasopressin, lypressin or
terlipressin.
❖transient headache and flushing are frequent.
❖Nasal irritation, congestion, rhinitis, ulceration and epistaxis can occur on local application.
❖Systemic side effects : belching, nausea, abdominal cramps, pallor, urge to defecate,backache in females
❖Fluid retention and hyponatraemia may develop.

C/I:
❖ischaemic heart disease(AVP can cause bradycardia, increase cardiac
afterload and precipitate angina by constricting coronary vessels),hypertension, chronic nephritis and
psychogenic polydipsia
THIAZIDES AS ANTI DIURETICS
❖ paradoxically exert an antidiuretic effect in DI.
❖Thiazides reduce urine volume in both pituitary origin as well as Renal DI.

MOA: unknown
❖Thiazides induce a state of sustained electrolyte depletion so that glomerular filtrate is more
completely reabsorbed iso-osmotically in PT.
❖Further, because of reduced salt reabsorption in the cortical diluting segment, a smaller
volume of less dilute urine is presented to the CDs and the same is passed out.
❖ thiazides reduce g.f.r. and thus the fluid load on tubules.

❖ Hydrochlorothiazide 25–50 mg TDS or equivalent dose of a longer acting agent is commonly

used.

❖Amiloride is the drug of choice for lithium induced nephrogenic DI

VASOPRESSIN ANTAGONISTS
• Tolvaptan :
❖orally activenonpeptide selective V2 receptor antagonist ----recently introduced for the
treatment of hyponatraemia due to CHF, cirrhosis of liver or syndrome of inappropriate
ADH secretion (SIADH).

❖Mozavaptan (V2 selective antagonist) and Conivaptan (V1a+V2 antagonist) are

the other vasopressin antagonists that are in clinical use.