Diuretics

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Diuretics

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

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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

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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)
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Diuretics

• Carbonic anhydrase inhibitors
• Thiazides
• Loop diuretics
• Potassium-sparing diuretics
• Osmotic diuretics
• Aquaretics (ADH-antagonists)

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Proximal tubule
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
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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

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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

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Loop diuretics

• Furosemide
• Torasemide
• Etoziline, ethacrynic acid

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Loop of Henle
upraveno podle Katzung's Pharmacology
Examination and Board Review. McGraw-Hill/Appleto
n Lange 6th edition (August 6, 2001)
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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

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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)

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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)!

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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

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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

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Distal tubule
Accrding to Katzung's Pharmacology Examination
and Board Review. McGraw-Hill/Appleton Lange
6th edition (August 6, 2001)
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Thiazides

• Hydrochlorothiazide
• Chlorthalidone
• Indapamide and metipamide
• All the drugs are actively secreted into the
  tubule and act in the distal tubule

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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

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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

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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

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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

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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)
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Potassium-sparing diuretics

• Spironolactone
• Eplerenone
• Amiloride
• Trimaterene

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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

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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

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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)

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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

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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)