Vilasinee Hirunpanich B.Pharm(Hon), M.Sc In Pharm (Pharmacology)
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Transcript of Vilasinee Hirunpanich B.Pharm(Hon), M.Sc In Pharm (Pharmacology)
Vilasinee HirunpanichB.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 DiureticsCarbonic 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 absorbedEliminate by renal secretionTorsemide (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. Ototoxicityethacrynic most often
Adverse effects (cont)
4. Hyperuricemia5. Hyperglycemia6. Hypersensitivity to sulfonamide
skin rash7. Others: dehydration
Ototoxic drugs; aminoglycoside
digitalis glycosideNSAIDsprobenecidLitiumanticoagulant
Drug interaction
Clinical indications
1. Hypertension and CHF2. 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 imbalanceHypokalemia Hyponatremia
Hypercalcemia2. hyperglycemia due toimpaired pancreatic release of
insulin3.hyperlipidemia
4.allergic reaction
5. Other: weakness, fatigability
Drug interactionDecrease the effect of
anticoagulanturicosuric
agentsulfonylureainsulin
Increase the effect of
digitalis glycoside
lithium
Decrease the effect of thiazideNSAIDsbile acid sequesteringprobencid
Clinical indications
Hypertension, CHF
hepatic cirrhosis
nephrolithiasis due to idiopathic hypercalcinuria
nephrogenic diabetes insipidus
Br- intoxicity
3. K+-sparing 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)
spironolactonespecific 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
SpironolactoneOnset 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 threateningEndocrine effects
-gynecomastia-hirsutism-deepening voice- decrease libido
Pts using salicylate because inhibiting canrenone
K+
administration
coadministration with thiazide or loop diuretic for edema (additive effect)
hyperaldosteronism
contraindication
Clinical use
2. Inhibitor of renal epithelium Na+ channel
Triamtereneamiloride
late distal tubules and collecting ducts
block Na+ channel in the luminal membrane
increase NaCl excretion and decrease K+ excretion
Mechanism of action of K+-sparing diuretic
Adverse effectanemia: triamterene, folic
antagonistkidney stone (triamterene is
poorly soluble)ARF (acute renal failure)(combination of triamterene and
indomethacin has been reported )
life-threatening:
hyperkalemia
contraindication
Renal failureother K+ sparing diureticACEIK+ supplementNSIADs
Co administration with other diuretic (additive effect)
prevent depletion of intracellular K+ store
Clinical Use
Osmotic diuretics
Properties 1. Freely filtered at the glomerulus2. No reabsorption at the renal tubule3. No pharmacological effectsGlycerine, 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 pressureextract water from the eye and brainGlycerine: control intraocular
pressure, pre/post operative ocular surgery
Mannitol, urea: reduce cerebral edema before/after neuro-surgery
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+, secretion2. Metabolic acidosis3. eye; decrease formation of
aqueous humor4. Paresthesia, Drowsiness,
Somnolence
Pharmacokinetic
Well absorbed after oral administration
The effect of increased of HCO3-
is apparent within 30 min.Maximal effect within 2 hPersist for 12 h after single doseExcrete by tubular secretion
Adverse effects
1. Hypersensitivitysulfonamide derivative (fever, rashes,
bone marrow suppression)2. Renal stoneCa2+ salt are relatively insoluble at
alkaline pH.3. Metabolic acidosis and urine
alkalinization4. Renal potassium wasting 5. Others: drowsiness, paresthesia
Clinical indications1. Glaucoma (decrease intraocular
pressure)Dorzolamide, brinzolamide
(topically use)2. Urinary alkalinizationincrease the secretion of uric
acid, weak acid drugs(aspirin)3. Metabolic acidosis4. Acute mountain sickness (24 h
before ascent)
Loop diuretic& thiazide (different position)
K+sparing diuretic& loop diuretic or thiazide (decrease ADR)
Moduretic (amiloride + HCTZ)Dyazide (triamterene+HCTZ)
Diuretic combination