vilasinee hirunpanich b.pharm(hon), m.sc in pharm (pharmacology)
TRANSCRIPT
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Vilasinee HirunpanichB.Pharm(Hon), M.Sc In Pharm (Pharmacology)
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Outline of diuretic drugs
Basic knowledge in anatomy and physiology
Classification of diuretics
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Classification of Diuretics
Loop Diuretics Thiazides Diuretics K+-sparing diuretics Osmotic DiureticsCarbonic anhydrase
inhibitors
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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
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Structure of loop diuretics
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Mechanism of action of Loop of Henle
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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)
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Adverse effects
1. Fluid and electrolytes imbalance
Hyponatremia, Hypokalemia and hypomagnesia
2. H+ loss metabolic alkalosis
3. Ototoxicityethacrynic most often
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Adverse effects (cont)
4. Hyperuricemia5. Hyperglycemia6. Hypersensitivity to sulfonamide
skin rash7. Others: dehydration
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Ototoxic drugs; aminoglycoside
digitalis glycosideNSAIDsprobenecidLitiumanticoagulant
Drug interaction
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Clinical indications
1. Hypertension and CHF2. Acute pulmonary edema 3. Other edematous conditions
3. Mild hyperkalemia (simultaneous NaCl and water)
4. I-, Br- intoxication
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2.Thiazide Diuretics
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Thiazide diuretics
Sulfonamide and benzothiadiazide (thiazide) derivatives–Hydrochlorothiazide (HCTZ), indapamide, chlorthalidone, metolazone
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Mechanism of action of thiazide diuretics
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Mechanism of actions
Increase Na+, Cl-, K+, Mg2+ in urine….water retention
Some drug has vasodilator effect such as indapamide (Natrilix )
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Pharmacokinetic
Chlorothiazide is less lipid soluble and must given in large dose
Indapamide is excreted primarily by the billiary system
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Adverse effects
1.Fluid and electrolytes imbalanceHypokalemia Hyponatremia
Hypercalcemia2. hyperglycemia due toimpaired pancreatic release of
insulin3.hyperlipidemia
4.allergic reaction
5. Other: weakness, fatigability
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Drug interactionDecrease the effect of
anticoagulanturicosuric
agentsulfonylureainsulin
Increase the effect of
digitalis glycoside
lithium
Decrease the effect of thiazideNSAIDsbile acid sequesteringprobencid
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Clinical indications
Hypertension, CHF
hepatic cirrhosis
nephrolithiasis due to idiopathic hypercalcinuria
nephrogenic diabetes insipidus
Br- intoxicity
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3. K+-sparing diuretics
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K+ sparing diuretics
1. Aldosterone antagonists
2. Inhibitor of renal epithelium Na+ channel
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Aldosterone antagonist
Structure similar to aldosterone hormone
Ex.spironolactone (synthesis
steriod), eplerenone (spironolactone
analog)
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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
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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.
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Adverse effects
hyperkalemia…..life threateningEndocrine effects
-gynecomastia-hirsutism-deepening voice- decrease libido
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Pts using salicylate because inhibiting canrenone
K+
administration
coadministration with thiazide or loop diuretic for edema (additive effect)
hyperaldosteronism
contraindication
Clinical use
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2. Inhibitor of renal epithelium Na+ channel
Triamtereneamiloride
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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
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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
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contraindication
Renal failureother K+ sparing diureticACEIK+ supplementNSIADs
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Co administration with other diuretic (additive effect)
prevent depletion of intracellular K+ store
Clinical Use
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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
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Structure of osmotic diuretics
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Mechanism of action
Limit water reabsorption
act as increase urine volume.
increase renal blood flow
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Pharmacokinetic
Poorly absorbed so they must be given parenterally
Mannitol is excreted by glomerular filtration within 30-60 min
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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
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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
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5. Carbonic anhydrase inhibitors
Inhibit carbonic anhydrase enzyme at proximal tubule
SO2NH2 (sulfonamide) group is essential for activity.
Acetazolamide (Diamox), dichlorophenamide, ethoxalamide, methazolamide
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Structure of carbonic anhydrase inhibitors
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Mechanism of action of carbonic anhydrase inhibitors
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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
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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
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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
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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)
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Loop diuretic& thiazide (different position)
K+sparing diuretic& loop diuretic or thiazide (decrease ADR)
Moduretic (amiloride + HCTZ)Dyazide (triamterene+HCTZ)
Diuretic combination