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    Diuretic Agents: Dept. of Pharmacology & Therapeutic

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    angelica glory
    This document discusses diuretic agents, including their mechanisms of action, pharmacokinetics, clinical uses, and side effects. It covers several classes of diuretics such as carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. The key mechanisms and sites of action that produce diuresis and natriuresis are explained for each class. Common adverse effects like hypokalemia are also summarized.

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    Diuretic Agents: Dept. of Pharmacology & Therapeutic

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    angelica glory
    21 views44 pages
    This document discusses diuretic agents, including their mechanisms of action, pharmacokinetics, clinical uses, and side effects. It covers several classes of diuretics such as carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. The key mechanisms and sites of action that produce diuresis and natriuresis are explained for each class. Common adverse effects like hypokalemia are also summarized.

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    This document discusses diuretic agents, including their mechanisms of action, pharmacokinetics, clinical uses, and side effects. It covers several classes of diuretics such as carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. The key mechanisms and sites of action that produce diuresis and natriuresis are explained for each class. Common adverse effects like hypokalemia are also summarized.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    21 views44 pages

    Diuretic Agents: Dept. of Pharmacology & Therapeutic

    Uploaded by

    angelica glory
    This document discusses diuretic agents, including their mechanisms of action, pharmacokinetics, clinical uses, and side effects. It covers several classes of diuretics such as carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. The key mechanisms and sites of action that produce diuresis and natriuresis are explained for each class. Common adverse effects like hypokalemia are also summarized.

    Copyright:

    © All Rights Reserved
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    of 44

    Diuretic agents

    Dept. of Pharmacology & Therapeutic,


    Faculty of Medicine
    Universitas Sumatera Utara
    INTRODUCTION
    •Abnormalities in fluid volume and
    electrolyte composition are common and
    important clinical problems.

    •Diuresis : Increase in urine volume.

    •Natriuresis : Increase in renal sodium


    excretion.
    2
    Physiology of Urine Formation
    • Urine formation starts from glomerular
    filtration in a prodigal way
    • Normally, about 180 L of fluid is filtered
    everyday
    • More than 99% of the glomerular filtrate is
    reabsorbed in the tubules
    • About 1.5 L urine is produced in 24 hours
    5
    Carbonic Anhydrase Inhibitors

    CA

    H+ + HCO3- H2 CO3
    CA - I
    CA IV

    H2O + CO2

    Carbonic anhydrase terdapat terutama


    diproximal tubule dari ginjal.
    6
    8
    CA i:Acetazolamide
    • Sulfonamide derivative
    • Noncompetitively but reversibly inhibits Case in
    PT cells → slowing hydration of CO2→ ↓
    availability of H+ to exchange with luminal Na+
    through the Na+H+ antiporter
    • Pkinetic:
    - well absorbed orally
    - excreted unchanged in urine
    - action 8-12 hours
    Acetazolamide: Uses
    • Glaucoma: topical dorzolamide, brinzolamide)
    • To alkalinise urine
    • Epilepsy
    • Acute mountain sickness
    • Periodic paralysis
    Acetazolamide: adverse effects
    • Acidosis, hypokalemia,drowsiness,
    paresthesia, fatique, abdominal discomfort
    • Hypersensitivity reactions: fever, rashes
    • Bone marrow depression is rare but serious
    Acetazolamide: Contraindicate
    • Liver disease: may precipitate hepatic coma by
    interfering with urinary elimination of NH3
    /NH4 +
    High ceiling (Loop) Diuretics:
    Furosemide
    High ceiling (Loop) Diuretics:
    Furosemide
    • Prototype: furosemide
    • Highly efficacious diuretic
    • Natriuretic effect is much greater than that of
    other class
    • OA (iv 2-5 min, im 10-20 min, oral 20-40 min)
    • DA: short: 3-6 hours
    • Excreted unchanged by glomerular filtration as
    well as tubular secretion
    High ceiling diuretics: indication
    • Edema
    • Acute pulmonary edema
    • Cerebral edema
    • Hypertension
    • Along with blood transfusion in severe anemia, to
    prevent vascular overload
    • Hypercalcemia and renal calcium stones:
    furosemide and its congeners increase calcium
    excretion and urine flow
    Thiazide
    Thiazide and Related Diuretics
    • Site of action: cortical diluting segment or the early
    distal tubule
    • MoA: inhibit Na+-Cl- symport at the luminal
    membrane
    • Pharmacokinetic:
    - well absorbed orally (are administered only by this
    route)
    - protein binding : variable
    - excreted: glomerular. Tubular reabsorption depends
    on lipid solubility: the more soluble one are highly
    reabsorbed-prolonging duration of action)
    PHARMACODYNAMIC

    - Thiazide inhibit NaCl reabsorbtion by blocking the Na+/Cl-


    transporter.
    - Enhance Ca2+ reabsorbtion. 18
    Thiazide and Related Diuretics:
    Indication
    • Hypertention
    • Edema
    • Diabetes insipidus
    • Hypercalciuria: thiazide act by reducing Ca2+
    excretion
    Adverse effects: high ceiling and
    thiazide
    • Hypokalemia
    It can be prevented and treated by:
    a. high dietary K+ intake, or
    b. Supplements of KCl (24-72 mEq/day), or
    c. Concurrent use of K+ sparing diuretics
    • Acute saline depletion
    • Dilutional hyponatremia
    • GIT and CNS disturbances
    • Hearing loss (loop)
    • Allergic manifestations
    • Hyperuricemia (loop)
    • Hyperglycaemia (thiazide)
    • Hypercalcemia (thiazide)
    • Magnesium depletion (loop)
    Interactions: high ceiling and thiazide
    • Potentiate all other antihypertensive
    • Hypokalemia induced by this diuretics:
    - ↑ digitalis toxicity
    - ↑ the incidence of polymorphic ventricular
    tachycardia due to quinidine and other
    antiarhhythmics
    - potentiates competitive neuromuscular
    blockers and reduces sulfonylurea action
    Interactions: high ceiling and thiazide
    • Aminoglycoside: additive toxicity (ototoxic and
    nephrotoxic)
    • Cotrimoxazole:higher incidence trombocytopenia
    • Indomethacin and other NSAIDs diminish the
    action of high ceiling diuretics
    • Diuretic diminish uricosuric action of probenecid
    • Serum lithium level rises when diuretic therapy is
    institued due to enhanced reabsorption of Li+
    (and Na+) in proximal tubule
    Resistance to high ceiling diuretics
    Cause Mechanism
    Renal ↓ access of diuretic to its site of action due
    to low gfr and low PT secretion
    insufficiency
    Nephrotic Binding of diuretic to urinary protein
    syndrome
    Cirrhosis of Abnorm phdynamics, hyperaldosteronism,
    mechanism not clear
    liver
    CHF Impaired oral absorption due to intestinal
    congestion, ↓ renal blood flow and gfr ,↑
    salt reabsorption in PT
    Potassium Sparing Diuretics
    • Aldosterone antagonist (spironolactone), or
    • Directly inhibit Na+ channels in DT and CD
    cells to directly converse K+ (Triameterene)
    Pharmacokinetics
    - orally active, duration of action 12-72
    jam.

    Spironolactone : slow onset of action, several


    days.

    Triamterene : metabolized extensively 🡪


    shorter half-life 🡪 given more frequent.

    26
    Pharmacodynamic
    = reduce Na+ absorbtion in the collecting
    tubule and ducts (regulated by aldosterone).
    🡪 Spironolactone Block the cytoplasmic
    eplerenone aldosterone receptors.
    = amiloride
    = triamterene Block sodium channels

    K+ secretion is coupled with Na+ entry in that


    segment 🡪 K+ sparing
    = actions of spironolactone and triamterene
    depend on renal prostaglandin synthesis 🡪
    NSAIDs will inhibit the action of the diuretics.
    27
    Clinical Indications
    - Mineralocorticoid excess
    - Secondary aldosteronium / from
    - heart failure
    - hepatic cirrhosis
    - nephrotic syndrome

    28
    Adverse Drug Reactions
    - hyperkalemia: - mild
    - moderate
    - life-threatening
    🡪 Cautious : drug interaction :
    - β-blocker
    - NSAIDs
    - ACE-I
    - ARB
    - hyperchloremic metabolic acidosis
    - gynaecomastia
    - acute renal failure (with indomethacin)
    - triamterene is poorly soluble 🡪renal 29
    Contra Indication
    - Chronic renal insufficiency
    - Concomitant use of drugs that blunt the
    R.A.S; - β-blocker
    - ACE-I
    - Livers disease (triamteren &
    spironolactone)

    30
    POSOLOGI

    Spironolactone 25 mg 1-4 times/day


    Triamterene 25 mg 1-4 times/day
    Eplerenone 25 or 50 mg 1-2 /day
    Amiloride 5 mg once

    31
    AGENTS THAT ALTER WATER EXCRETION

    I. OSMOTIC DIURETIC
    Prototype : Mannitol
    Pharmacokinetic
    - Poorly absorbed 🡪 given parenterally
    - Given orally 🡪 diarrhea
    - Not metabolized
    - Excreted by glomerular filtration

    32
    Pharmacodynamics
    - Mannitol is a nonreabsorbable solute
    🡪 prevents the normal absorbtion of water
    in proximal tubule and descending limb of
    Henle’s loop 🡪 Na+ reabsorbtion increase 🡪
    hypernatremia.

    33
    Clinical Indications
    1. To increase urine volume / to maintain urine
    volume) in case of:
    - hemolysis.
    - rhabdomyolysis
    2. Reduction of intracranial or intraocular
    pressure.

    34
    Adverse Drug Reactions
    - Extracellular volume expansion (prior to
    the diuresis).
    - Dehydration.
    - Hypernatremia

    35
    Urinary electrolyte pattern and natriuretic efficacy of some diuretics

    Diuretic Urinary electrolyte excretion Max % of Efficacy


    filtered

    Na+ K+ Cl- HCO3- Na


    excreted
    Furose ↑↑↑ ↑ ↑↑ ↑,- 25 High
    mide
    Thiazide ↑↑ ↑ ↑ ↑ 8 Intermedi
    ate
    Acetazola ↑ ↑↑ ↑,- ↑↑ 5 Mild
    mide
    Spironolac ↑ ↑ -, ↑ 3 Low
    tone
    Amiloride ↑ ↑ -, ↑ 3 Low

    Mannitol ↑↑ ↑ ↑ ↑ 20 High
    Diuretics : Classification
    1. High efficacy diuretics (inhibitor of Na+-K+-2Cl- cotransport)
    → sulphamoyl derivatives: furosemide, bumetanide,
    torasemide
    2. Medium efficacy diuretics (inhibitors of Na+-Cl- symport)
    a, benzothiadiazines (thiazides): hydrochlorothiazide, benzthiazide,
    hydroflumethiazide, clopamide
    b. thiazide like: chlorthalidone, metolazone, xipamide, indapamide
    3. Weak or adjunctive diuretics
    a. carbonic anhydrase inhibitors: acetazolamide
    b. potassium sparing diuretics:
    - aldosterone antagonist: spironolactone
    - inhibitor of renal epithelial Na+ channel:
    triamterene , amiloride
    c. osmotic diuretics: mannitol, isosorbide, glycerol
    Anti diuretik
    1. ADH
    - vasopresin (alamiah)
    - desmopresin (sintesis)
    * Absorpsi peroral : tidak efektif karena segera mengalami
    inaktifasi oleh tripsin.
    * Mekanisme kerja pengaturan sekresi ADH diatur oleh
    konsep :
    1. Osmoreseptor
    dehidrasi 🡪 osmolalitas plasma >> 🡪
    sekresi ADH >>
    2. Reseptor volume
    volume darah yang beredar ↓
    🡪 perangsangan sekresi ADH ↑ .
    3. Stres emosional atau fisik
    4. Obat : - nikotin
    - klofibrat
    - siklofodfamid
    - antidepresan trisiklik
    - karbamezepin
    - diuretik
    2.Benzotiadiazid

    untuk yang resisten terhadap ADH (diabetes insipidus nefrogen)


    Mekanisme kerja Natriuretik🡪 Na deplesi
    🡪 reabsorbsi Na >> di tubulus proksimal.
    3. Indometasin ( penghambat sintesa
    prostaglandin)
    Indikasi: diabetes insipidus
    Antagonis
    ADH
    Absorpsi melalui oral
    Metabolisme: hati
    Eliminasi: melalui sekresi tubulus ginjal
    Mekanisme kerja :
    menghambat efek ADH pd tub.kolektivus /koligens
    melalui reseptor V1a & V2
    -Conivaptan

    Indikasi
    * SIADH (sindrome of Inappropriate ADH secretion)
    * Penyebab lain yang menyebabkan pe↑ ADH
    Thank you for
    the attention

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