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Diuretics

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They mostly act from the luminal site of the tubules to block the ion transporting molecules ... Allergic reactions sulfonamide moiety ... – PowerPoint PPT presentation

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Title: Diuretics


1
Diuretics
  • Martin Sterba, PharmD. PhD.
  • Department of Pharmacology
  • LFHK UK

2
Diuretics
  • Drugs increasing excretion (volume) of urine
    (diuresis)
  • Most of them have very significant natriuretic
    properties i.e, they increase urinary Na
    excretion
  • They mostly act from the luminal site of the
    tubules to block the ion transporting molecules
  • Some of them have also significant extrarenal
    effects
  • Therapeutically useful - vasodilating effects
    (direct/indirect)
  • Adverse effects e.g., metabolic

3
Functional description of the nephron
50-65
4-8
2-5
15-25
Acetazolamide
Osmotic diuretics
Loop diuretics - furosemide
Thiazides
Aldosterone antagonists
ADH antagonists
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
4
Diuretics
  • Carbonic anhydrase inhibitors
  • Thiazides
  • Loop diuretics
  • Potassium-sparing diuretics
  • Osmotic diuretics
  • Aquaretics (ADH-antagonists)

5
Proximal tubule
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
6
Acetazolamide
  • Inhibitor of the carbonic acid anhydrase
  • Causes the inhibition of the bicarbonate
    reabsorption in the proximal tubule ?
    bicarbonate loosing via urine - ? pH urine within
    0,5-2h and persists 12h (after a single dose)
  • Result hyperchloremic metabolic acidosis
  • Diuretic (natriuretic) effects is limited
    (compensated within the distal parts of the
    nephron) and decreased within few days of the
    treatment
  • Indication
  • Glaukoma treatment (shorter treatment, before
    surgery)
  • carbonic acid anhydrase is also present in the
    cilliary body (it enables there a secretion of
    the bicarbonate and Na in the aqueous humour)
    acetolazamide ? decreases the intraocular
    humour production ? decreases intraocular
    pressure
  • Local glaucoma treatment - dorzalamid
  • Alkalization of the urine e.g., in cysteinuria
    (excretion facilitation)
  • metabolic alkalosis in patients suffering from HF
    and oedema when standard treatment employing
    volume correction is not applicable

7
Acetazolamide adverse reactions
  • Hyperchloremic metabolic acidosis
  • Predictable loses of the HCO3- stores is also a
    limitation for both long term safety and efficacy
    of the treatment
  • Phosphaturia a hypercalciuria - nephrolithiasis
    (higher concentration of the salts and their
    lower solubility in the alkaline environment)
  • Potassium vasting resulting into the hypokalemia
  • Contraindications hepatic encephalopathy
  • alkalization of the urine ? lower NH4
    excretion which may further contribute to the
    hyperammoneamia and hepatic encephalopathy in
    patients with cirrhosis

8
Loop diuretics
  • Furosemide
  • Torasemide
  • Etoziline, ethacrynic acid

9
Loop of Henle
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
10
Loop diuretics
  • 1. Renal effects (within 10 min after i.v.
    administration, but quite short-term effect
    furosemide 2-3 h)
  • Inhibition of Na/K/2Cl- re-uptake
  • Decrease the lumen-positive potential that comes
    from K recycling
  • ? decreased reabsorption divalent cationts,
    resulting into the hypocalcaemia a
    hypomagnesaemia
  • Increased prostaglandine synthesis improved
    renal perfusion
  • 2. Extrarenal effects
  • Vasodilation (venous system) important in i.v.
    treatment of acute pulmonary oedema, where it can
    overtake the urinary effects - incompletely
    understand mechanisms
  • Decreased preload and filling pressures in RV and
    later also in LV important in HF
  • Decreased pulmonary congestion/oedema

11
Loop diureticsPharmacokinetics
  • Oral administration (quite good absorption,
    torasemide is absorbed faster than furosemide)
  • I.V. in urgent cases
  • High plasma protein binding
  • Renal elimination GF (limited) tubular
    secretion
  • Effect duration quite short (2-3 h furosemide),
    torasemide is longer (4-6h) and it has an active
    metabolite
  • Tubular secretion can be decreased by the
    competition due to the competition with other
    drugs (e.g., NSAD)

12
Loop diureticsindications
  • Acute pulmonary oedema i.v. treatment
  • Active tubular secretion makes it useful even in
    shock-like
  • CHF (esp. with signs of blood congestion)
  • Decreased Na retention, intravascular volume and
    preload and reduction of oedema, improve
    symptoms!
  • Other diseases with fluid/sodium retention and
    oedema
  • E.g. In the liver disease associated with
    ascites etc
  • Acute renal failure useful even when Clcr is
    below 30 ml/min.
  • For prevention of Na/fluid retention with
    oligouria/anuria
  • Esp. When oedema and/or hypokalemia occur
  • They can be useful for flush-out of intratubular
    casts arising from haemolysis or rhabdomyolysis
  • Acute hyperkalcemia (accompanying small cell lung
    cancer)
  • Hyperkalemia
  • Hypertension only when associated with
    renal/heart failure (see further)!

13
Loop diureticsadverse reactions
  • Hypokalemia hypokalemic metabolic alkalosis
  • ? Na reabsorption in LoH ? ? Na concentrations in
    collecting tubule ? ? Na reabsorption, but in
    exchange for K !!!!? potassium wasting (H)
  • Increased risk of potentially fatal ventricular
    arrhythmias
  • Prevention low NaCl diet, K compensation (KCl)
    and most importanty combination with K sparring
    diuretics (see below)
  • Hypomagnesemia predictable, most frequent in
    patients with dietary deficit
  • Hypocalcemia
  • Hypovolemia (diuresis up to 4 L/24 h),
    dehydratation and hypotension
  • Ototoxicity
  • Hyperuricemia and gout precipitation can also
    be attributable to hypovolemia
  • Allergic reactions sulfonamide moiety
  • - skin rashes, eosinophilia, exceptionally
    interstitial nephritis

14
Loop diuretics contraindications
  • Electrolyte imbalance (hyponatremia, hypokalemia,
    hypochloremic alkalosis, hypotension)
  • Liver failure with impaired consciousness (the
    risk of profound hypokalemia)
  • Hypersensitivity to furosemide
    cross-hypersensitivity with sulphonamides

15
Distal tubule
Accrding to Katzung's Pharmacology Examination
and Board Review. McGraw-Hill/Appleton Lange
6th edition (August 6, 2001)
16
Thiazides
  • Hydrochlorothiazide
  • Chlorthalidone
  • Indapamide and metipamide
  • All the drugs are actively secreted into the
    tubule and act in the distal tubule

17
Thiazide diureticsstructure and pharmacokinetics
  • Thiazides sulphonamide structure
  • - indapamide a metipamide have different
    structure
  • All of them can be given orally (daily
    treatment, long treatment)
  • Different T1/2, hydrochlorothiazide (12h) others
    (gt24h)
  • All of them are secreted actively by tubular
    secretion
  • Indapamide a metipamide are mainly excreted by
    the liver, but sufficient sufficient amount can
    get into the kidney

18
Thiazides pharmacodynamics
  • 1. Renal effects
  • Inhibition of Na reabsorption in the distal
    tubule decreased Na retention and intravascular
    volume
  • natriuretic and diuretic effects are less
    pronounced than those of loop diuretics!!!
  • increased Ca2 reabsorption
  • 2. Extrarenal effects
  • Decreased preload and consequently also afterload
  • After few weeks (2-3) the PVR gradually decreases
  • Indapamide a metipamide have also direct
    vasodilating effects

19
Thiazide diureticsIndications
  • Arterial hypertension
  • Chronic heart failure (rather milder forms)
  • Recurrent nephrolithiasis arising from idiopathic
    hypercalciuria
  • Might be useful in patient with osteoporosis
  • Nephrogenic diabetes insipidus

20
Thiazide diureticsadverse effects
  • Hypokalemia and metabolic alkalosis (the same
    mechanism and prevention, dose !)
  • Impaired glucose tolerance mechanism
    inhibition of insulin secretion due to the
    hypokalemia?! Dose!
  • Dyslipidemia increased total cholesterol and
    LDL, potentially triglycerides might be
  • Hyperuricemia competition for secretion
    transporters with uric acid (prevention/correction
    with allopurinol)
  • Hyponatremia, hypovolemia
  • Allergic reaction sulphonamide structure, skin
    rashes, very rarely haemolytic anaemia
  • Currently it is recommended to use quite low
    doses still good therapeutic response along
    with much less complication (e.g., in
    hypertension the doses are 6,25/12,5-25mg/den

21
Potassium-sparring diuretics
Collecting tubule
Lumen
Spironolactone
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
22
Potassium-sparing diuretics
  • Spironolactone
  • Eplerenone
  • Amiloride
  • Trimaterene

23
Potassium-sparing diuretics
  • PD effects
  • Decreased Na reabsorption in the collecting
    tubule with slightly increased natriuresis
  • Decreased K secretion (excretion) into the lumen
    of the collecting tubule
  • Overall diuretic effect quite small
  • PK
  • Amiloride p.o., slower onset of action (peak at
    6th , duration 24h)
  • Spironolacton short plasma T1/2 but it is
    metabolised into its active metabolite canrenone
    (T1/2 16h) responsible for most of the drugs
    effects
  • Eplerenon once daily, p.o., no active
    metabolites

24
Potassium-sparing diuretics indications
  • In combination with other diuretics
  • To effectively prevent K wasting (hypokalemia)
    in patients on low NaCl diet
  • Superior alternative to long term KCl
    supplementation (it is not as practical, poor
    compliance)
  • It should be discourage to combine both
    approaches
  • Spironolactone and eplerenone
  • Primary and secondary hyperaldosteronism (e.g.,
    induced by liver cirrhosis etc.) to prevent
    excessive Na and extravascular fluid retention
  • Chronic heart failure moderate to severe forms
  • in addition to other drugs
  • Improve symptoms and prognosis
  • Prevent and regress pathological remodelling of
    the heart and vessels

25
Potassium-sparing diuretics adverse effects
  • Hyperkalemia
  • dose dependent
  • It is very likely to develop in combination with
    other drugs with antiladosterone effects
    ACE-inhibitors, beta-blockers or K
    supplementation
  • Hyperchloremic metabolic acidosis
  • Spironolacton - gynaecomastia, menstrual
    disorders etc (much less in eplerenon)

26
Osmotic diuretics
  • Mannitol 10-20 solution
  • Osmotically active substances without specific
    pharmacological action
  • They act mostly in proximal tubule, thin
    descendent limb of the loop where the nephron
    is penetrable for water
  • Non-reabsorbable osmotically active agents
    significantly increase diuresis via water
    excretion along with minor Na excretion
  • Indication in the situations where the most
    important is to enhace water excretion without
    loss of Na
  • Indications due to the lack of natriuretic
    action rather limited
  • E.g,. to prevent anuria in acute renal failure
    due to the pigment load (hemolysis,
    rhabdomyolysis), infections or haemorrhage
  • To decrease pathologically elevated intracranial
    or intraocular pressures (they enter neither eye
    nor brain, they just increase plasma osmolarity
    and this result in the extraction of water from
    these compartments

27
Osmotic diureticsadverse reactions
  • Pronounced water extration from the intracellular
    compartment and expansion of the intravascular
    but also interstitial fluid volume
  • Hyponatremia
  • Complications
  • Acute pulmonary oedema
  • HF
  • Common headache, nauzea, vomiting
  • Overdose dehydratation, hypernatremia

ADH antagonists - vaptans
  • conivaptan
  • - small molecule V1 and V2 receptor antagonists
  • decrease water (not Na) reabsorption which
    increase the diuresis
  • Poor bioavailability i.v. formulation only
  • Indications hyponatremia associated with
    Syndrome of Inappropriate ADH (SIADH)
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