Transcript Diuretic - e

Vilasinee Hirunpanich
B.Pharm(Hon), M.Sc In Pharm (Pharmacology)
Outline of diuretic drugs
Basic knowledge in anatomy and
physiology
Classification of diuretics
Classification of Diuretics
Loop Diuretics
Thiazides Diuretics
K+-sparing diuretics
Osmotic Diuretics
Carbonic anhydrase inhibitors
1. Loop diuretics
(high ceiling diuretics)
 block Na+-K+-2Cl- cotransport in the thick ascending
limb of the loop of Henle
high efficacy: 25% of filtrated solute is reabsorbed
Structure of loop diuretics
Mechanism of action of Loop of Henle
pharmacokinetic
Rapidly absorbed
Eliminate by renal secretion
Torsemide (1h) is more rapidly than
furosemide (Lasix) (2-3 h)
Duration 2-3 h (furosemide), 3-4 h(torsemide)
Adverse effects
1. Fluid and electrolytes imbalance
Hyponatremia, Hypokalemia and hypomagnesia
2. H+ loss
metabolic alkalosis
3. Ototoxicity
ethacrynic most often
Adverse effects (cont)
4. Hyperuricemia
5. Hyperglycemia
6. Hypersensitivity to sulfonamide
skin rash
7. Others: dehydration
Drug interaction
Ototoxic drugs; aminoglycoside
digitalis glycoside
NSAIDs
probenecid
Litium
anticoagulant
Clinical indications
1. Hypertension and CHF
2. Acute pulmonary edema
3. Other edematous conditions
3. Mild hyperkalemia (simultaneous NaCl and water)
4. I-, Br- intoxication
2.Thiazide Diuretics
Thiazide diuretics
Sulfonamide and benzothiadiazide (thiazide)
derivatives
– Hydrochlorothiazide (HCTZ), indapamide,
chlorthalidone, metolazone
Mechanism of action of thiazide diuretics
Mechanism of actions
Increase Na+, Cl-, K+, Mg2+ in urine….water
retention
Some drug has vasodilator effect such as
indapamide (Natrilix )
Pharmacokinetic
Chlorothiazide is less lipid soluble and
must given in large dose
Indapamide is excreted primarily by the
billiary system
Adverse effects
1.Fluid and electrolytes imbalance
Hypokalemia Hyponatremia Hypercalcemia
2. hyperglycemia due to
impaired pancreatic release of insulin
3.hyperlipidemia
4.allergic reaction
5. Other: weakness, fatigability
Drug interaction
Decrease the effect of
Increase
the
effect
of
anticoagulant
digitalis glycoside
uricosuric agent
lithium
sulfonylurea
insulin
Decrease the effect of thiazide
NSAIDs
bile acid sequestering
probencid
Clinical indications
Hypertension, CHF
hepatic cirrhosis
nephrolithiasis due to idiopathic hypercalcinuria
nephrogenic diabetes insipidus
Br- intoxicity
+
K -sparing
3.
diuretics
+
K
sparing diuretics
1. Aldosterone antagonists
2. Inhibitor of renal epithelium Na+
channel
Aldosterone antagonist
Structure similar to aldosterone hormone
Ex.
spironolactone (synthesis steriod),
 eplerenone (spironolactone analog)
spironolactone
specific antagonist
prevent protein synthesis that required for Na+ and K+
transport
increase Na+ excretion and preserve of K+
Potentcy is low and depend on aldosterone level
pharmacokinetic
Spironolactone
Onset and duration of action are determined by the
kinetic of aldosterone response in target tissue.
Slow onset (48 hr)
Canrenone is the active metabolized which has very
long t12.than parent drug.
Adverse effects
hyperkalemia…..life threatening
Endocrine effects
-gynecomastia
-hirsutism
-deepening voice
- decrease libido
contraindication
Pts using salicylate
because inhibiting
canrenone
K+ administration
Clinical use
coadministration with thiazide or
loop diuretic for edema (additive
effect)
hyperaldosteronism
2. Inhibitor of renal epithelium Na+ channel
Triamterene
amiloride
Mechanism of action of K+-sparing diuretic
late distal tubules and
collecting ducts
block Na+ channel in the
luminal membrane
increase NaCl excretion
and decrease K+
excretion
Adverse effect
anemia: triamterene, folic antagonist
kidney stone (triamterene is poorly soluble)
ARF (acute renal failure)
(combination of triamterene and indomethacin has
been reported )
hyperkalemia
life-threatening:
contraindication
Renal failure
other K+ sparing diuretic
ACEI
K+ supplement
NSIADs
Clinical Use
Co administration with other diuretic
(additive effect)
+
prevent depletion of intracellular K
store
Osmotic diuretics
 Properties
1. Freely filtered at the glomerulus
2. No reabsorption at the renal tubule
3. No pharmacological effects
Glycerine, Isosorbide, Mannitol, Urea
site of action: Proximal tubule and descending
limb of Henle’s loop
Structure of osmotic diuretics
Mechanism of action
Limit water reabsorption
 act as increase urine volume.
increase renal blood flow
Pharmacokinetic
Poorly absorbed so they must be given
parenterally
Mannitol is excreted by glomerular filtration
within 30-60 min
Adverse effects
1. Extracellular volume expansion
Rapidly distributed in the extracellular
compartment and extract water from the
intracellular compartment
2. Dehydration
3. Nausea, vomiting, headache
Clinical Indications
1. To increase urine volume
2. Reduction of intracranial and intraocular pressure
extract water from the eye and brain
Glycerine: control intraocular pressure, pre/post operative
ocular surgery
Mannitol, urea: reduce cerebral edema before/after neurosurgery
5. Carbonic anhydrase inhibitors
Inhibit carbonic anhydrase enzyme at proximal
tubule
SO2NH2 (sulfonamide) group is essential for
activity.
Acetazolamide (Diamox), dichlorophenamide,
ethoxalamide, methazolamide
Structure of carbonic anhydrase inhibitors
Mechanism of action of carbonic
anhydrase inhibitors
1. increase the excretion of HCO3(Urine alkalinization, pH 8)
Increase Na+, K+, secretion
2. Metabolic acidosis
3. eye; decrease formation of aqueous humor
4. Paresthesia, Drowsiness, Somnolence
Pharmacokinetic
Well absorbed after oral administration
The effect of increased of HCO3- is apparent
within 30 min.
Maximal effect within 2 h
Persist for 12 h after single dose
Excrete by tubular secretion
Adverse effects
1. Hypersensitivity
sulfonamide derivative (fever, rashes, bone marrow
suppression)
2. Renal stone
Ca2+ salt are relatively insoluble at alkaline pH.
3. Metabolic acidosis and urine alkalinization
4. Renal potassium wasting
5. Others: drowsiness, paresthesia
Clinical indications
1. Glaucoma (decrease intraocular pressure)
Dorzolamide, brinzolamide (topically use)
2. Urinary alkalinization
increase the secretion of uric acid, weak acid
drugs(aspirin)
3. Metabolic acidosis
4. Acute mountain sickness (24 h before ascent)
Diuretic combination
Loop diuretic& thiazide (different position)
K+sparing diuretic& loop diuretic or thiazide
(decrease ADR)
Moduretic (amiloride + HCTZ)
Dyazide (triamterene+HCTZ)