Lec 21- Diuretics Flashcards

1
Q

Definition or diuretic

A

Diuretic: an agent that causes increased urine flow

  • Altered water output without solute output decreases plasma osmolarity and so produces a rapid and marked compensation i.e. changes in extracellular fluid volumes (ECFV) are short lasting Natriuretic: an agent that produces an increase in sodium excretion
  • All useful diuretics agents are natriuretics
  • By producing a balance loss of water and solute, a long-lasting effect on ECFV (extra cellular fluid volume) is achieved
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2
Q

Physiological compensations

A
  • Natriuresis (eexcretion of sodium in urine) is a limited phenomena- continued imbalance between Na+ input and output is incompatible with life
  • Continued administration of a diuretic agent leads to a point of dynamic compensation when physiological mechanisms balance diuresis (levels out)
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3
Q

What physiological functions balance diuresis

A
  • Activation of sympathetic nervous system due to decreased BP
  • Activation of RAAS axis
  • Decreased renal BP and of renal fluid output
  • Changes in natriuretic factors (kinins, atrial natriuretic factors)
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4
Q

Different types of diuretics

A
  • Loop e.g. furosemide Primary function to remove water in HF Loses K+
  • Thiazide e.g. indapamide Used for HTN and add on in HF to increase fluid loss Loses K+ and Na+
  • Potassium sparring-amiloride Used for K+ sparring effects Loses Na+
  • Aldosterone antagonist- spironolactone Used in HF to reduce mortality; minor use in HTN; Loses Na
  • Osmotic (mannitol)- used to reduced IOP (Intra-occulat pressure) or cerebral oedema
  • Carbonic anhydrase inhibitor (acetazolamide)- reduce IOP
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5
Q

diuretics- things to watch out for

A
  • Diet- increase K+ intake e.g. spinach and fruit
  • Input/output- careful of salt in food; fluid intake; record weight
  • Unbalance in fluid and electrolytes e.g.K/Na
  • Rate of heart beat/K+ level/ arrhythmias; but BP will decrease
  • Evening dose is a no-no (not removing water at night)
  • Take diuretic in the morning because of increased urination
  • Increased risk of orthostatic hypotension (drop in BP when you stand= dizziness)
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6
Q

Where in the kidneys is the absorption taking place and how much Where are certain diuretics working

A
  • PCT- reabsorption= 65% Osmotic diuretics; carbonic anhydrase inhibitors
  • Loop of Henle-reabsorption25% Loop; osmotic diuretics
  • DCT- reabsorption= 10% Thiazide diuretics
  • Collecting duct-reabsorption 5% K+ Sparring diuretics
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7
Q

Osmotic diuretics NB normal osmotic pressure is 300 mOsm

A
  • Pharmacologically inert -Freely filterable at glomerulus and enter tubule
  • Limited or no tubular reabsorption
  • Generally are non-electrolytes e.g. mannitol IV Main effects -Increased solutes (e.g.Na:K)
  • Decrease osmotic gradient between blood and tubular fluid and so impair water reabsorption
  • Expand ECFV + BV so inc GFR Uses - mainly reduction in cerebral oedema and IOP
  • Problems- volume expansion
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8
Q

Carbonic anhydrase inhibitors- Acetazolamide

A
  • Competitive inhibitor of carbonic anhydrase
  • Casuses rapid natriuresis
  • Increased renal loss of HCO3- (max dose about 50% overall inhibition)
  • Developing metabolic acidosis- renal response is to increase H+ secretion
  • Marked tachyphylaxis in use
  • Main use for treatment of acute glaucoma to reduce IOP
  • Supplement dietary K whilst on course of treatment
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9
Q

How carbonic anhydrase inhibitors work

A
  • Early PCT Na reabsorption is coupled to H+ secretion via sodium proton exchanger (NHE)
  • Na is reabsorbed into the blood via the sodium bicarbonate co-transporter (NBC) and the sodium potassium pump (Na;K;ATPase)
  • Carbonic anhydrase inhibitor inhibits the CA
  • By inhibiting CA, this means that no proton is created therefore NHE doesn’t work and Na can’t be reabsorbed
  • Inhibiting CA also inhibits NBC- therefore sodium can’t be absorbed via the carbonate NB- water follows sodium
  • Na would normally be transported from PCT to blood by stopping this the osmolarity of the blood stays low meaning water will not enter and will pass straight through
  • With no sodium being exchanged into the blood it also means pottasium remains in the blood (Na;K;ATPase)
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10
Q

Thiazide like diuretics

A
  • Discovered in a search for powerful carbonic anhydrase inhibitor
  • All are weak acids; substrates for PCT secretion
  • Inhibit Na and Cl transporter in DCT
  • Term originally used to describe agents with a thiazide ring system. Now also used to describe agents with similar properties
  • Examples: bendroflumethazide; chlorothiazide; hydrochlorothiazide
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11
Q

Cells of early DCT (diluting segment)

A
  • Na and Cl reabsorption occur via the sodium chloride symporter (NCC)
  • Ca2+ is reabsorbed via TRPV5 calcium channels activated via the parathyroid (PTH) pathways
  • The Ca2+ transporter and Na+ exchanger (NCX)
  • Thiazides inhibit NCC
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12
Q

Thiazide like diuretics and there duration of action

A
  • Pharmacologically similar to thiazides but
  • Many with longer durations of action
  • Indapamide- 24hour
  • Metolazone- 24hour
  • Chlortalidone- 48-72 hour
  • Xipamide- 12 hours
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13
Q

Problems with thiazide type diuretics- electrolytes

A
  • Hypokalaemia- increased the exchange of Na and K in late DCT due to: Increased Na load in late DCT Activation of RAAS
  • Hyponatraemia- can be very marked in some cases
  • Hypercalcaemia- Ca2+ absorption in DCT
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14
Q

Problems with thiazide type diuretics- non-electrolyte imbalance

A
  • Uricosuric action- reduced PCT secretion of uric acid (competition with diuretics for organic anion transporter)= gout or arthritis
  • Glucose intolerance- 2ndary hypokalaemia (reduced insulin release via hypokalaemia, with less K+ entering B iselt cell means we don’t get depolarisation of cell meaning no influx of Ca2+= no exocytosis of insulin containing vesicle= no insulin release)
  • Hyperlipoproteinaemia- 5-15% rise in serum ChE and increased LDL
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15
Q

-Drug interactions with thiazides

A
  • Sulphonylureas: may be reduced efficacy due to hyperglycaemic action of thiazides
  • Uricosuric agents: may be reduced efficacy -NSAID: reduced efficacy of thiazides
  • Hypokalaemia: increases risk of tornadoes de pointes: polymorphic ventricular tachycardia. (quinidine;astemizole) Torsades de pointes may deteriorate into arrhythmias
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16
Q

Loop diuretics

A
  • Chemically related agents containing sulphonamide Furosemide; bumetanide; torasemide
  • Powerful diuretics with rapid onset of action (1 hour) short duration (6 hour)
  • Dose related diuresis and may be used to high doses in renal failure
17
Q

High ceiling effect of loop diuretics

A
  • Huge drop in sodium (increase in urine)
  • Means huge drop in volume (water follow Na)
18
Q

Loop diuretics- mechanism GO BACK OVER THIS

A
  • Bind to and closes Na/K/2Cl co-transporter in ascending thick limb of loop of Henle, thus prevents reabsorption from lumen- this is inhibited by loop diuretics
  • Cl- in cell leaves into the blood through CLC-K receptor -K enters the cell through Na;K;ATPase pump. K leaves into the lumen through the ROMK channel this is inhibited by loop diuretic (no Na)
  • Under drug free conditions K back diffusion creates + lumenial membrane that drives divalent cation (Mg2+ but mainly Ca2+) reabsorption
  • Cells hyper polarise, no net ion movement across cell causing Ca2+ loss -There is a Na/H+ ion exchanger which brings H+ into lumen and Na+ into cell this causes Metabolic alkalosis (we pair that with the hypokalaemia that it causes meaning we say hypokalaemia metabolic alkalosis)
19
Q

Loop diuretics- mechanism of action (direct vasodilator)

A
  • Direct vasodilator action
  • Contributes to action in congestive cardiac failure (RAP falls before any reduction in blood volume)
  • Increases RBF and medullary/cortical blood flow
  • High concentrations inhibit carbonic anhydrase (CA) (loop diuretics also inhibit CA)- this is due to the proton loss
  • Marked effects on K+ excretion (direct on macula dense; via RAAS and DCT Na load)
20
Q

Loop diuretics- unwanted effects

A
  • Hyperuricaemia- as thiazides
  • Electrolyte disturbances: hypokalaemia; hypocalcaemia; hypomagnesaemia
  • Metabolic alkalosis
  • Range of very rare blood disorders including thrombocytopenia; leucopenia; aplastic anaemia
  • Hyperglycaemia- less than thiazides
  • Skin rashes and photosensitivity reactions
21
Q

Potassium sparring: aldosterone Antagonists e.g. spironolactone and eplerenone

A
  • You can get ENaC blockers (Na channel blocker)
  • Aldosterone receptor agonist, Aldosterone increases the amount of ENac channels as well as Na;K;ATPase, this drug binds to aldosterone channels preventing these channels being produced therefore this takes along time (Eplerenone)

NB- they cause loss of Na and water; hyperkalaemia and some risk of acidosis

22
Q

Potassium sparring: aldosterone Antagonists - mechanism

A
  • Binds to mineralocorticoid receptor in the intercalated cells
  • thus blocking binding of aldosterone to its receptor, -thus inhibiting expression of Na/K pump
  • Thus inhibits Na reabsorption and prevents K secretion. slow onset because of mechanism requires inhibition of expression
23
Q

Potassium sparring diuretics: aldosterone antagonist- spironolactone and eplerenone

A
  • Spironolactone: oral absorption 60-70%; extensive 1st pass metabolism; T1/2 1.4hrs; HF.HTN step 3 and ascites treatment
  • Eplerenone- licensed only as adjunct in LVSD with evidence of HF post MI
  • Action depends on the extent to which Na reabsorption is determined by aldosterone
  • Steriods with anti-adrogenic action; gynaecomastia in men; may induce menstrual cycle irregularities in women
  • Side effect: low Na; High K gynaecomastia and vaginal bleeding (spironolactone more)
24
Q

Potassium sparing: Na channel blockers- amiloride; triamterene

A
  • Main site of action is luminal Na channel- a protein dimer with MW- 100,000
  • Reduced Na movement maintains Hugh luminal membrane pd gradient (-85mV) which opposes K+ secretion
  • Agents have some weak inhibitory action on ablumminal Na/K/ATPase
  • At very high concentrations, agents inhibit Na/K/Cl co-transporter
  • Use: in combination with more potent diuretics to reduce overall K loss
25
Q

K sparring diuretics-Cautions

A
  • Pottasium supplements -Potassium sparing diuretics with ACEI/ARB increase monitoring of K as both will increase levels
  • Lots of patient successfully on ACEI and aldosterone antagonist together. If necessary reduce dose of diuretic or increase dosing interval days
  • Important to keep aldosterone antagonists in HF patients as well reduce mortality
  • Aldosterone is made from Angiotensin II binding to AT-1 receptors so if we inhibit this we inhibit aldosterone release, so therefore this is bit pointless
26
Q

Fixed combinations with K sparring diuretics

A
  • Co-amilozide: 2.5/25 and 5/50. amiloride with HCT
  • Co-amilofruse: 2.5/25 and 5/40 amiloride with furosemide
  • Co-triamterzide 50/25 and 50/50. tiamterine and HCT
  • Triamtere and loop diuretic- 50/40 with furosemide
  • Co-flumactone- 25/25 and 50/50- hydroflumethazide and spironolactone
27
Q

Clinical uses of diuretics agents

A
  • HTN- chronic reduction of BP by 16/8 -Congestive HF: act to reduce load (oedema). Loops first line ; to reduce mortality. aldosterone antagonists
  • Ascites: spironolactone (removal of fluid and stopping accumulation by blocking aldosterone) -

May help in acute and chronic renal failure. Loops may be used in oliguria

-Increased intra-cranial pressure and IOP- mannitol, acetazolamide

28
Q

Hypokalaemia

A
  • Definition: plasma K+ <30mmol/L
  • Plasma K normally controlled by kidney
  • Normal dietary intake 50 mol daily
  • Thiazide, moderate dosage may increase excretion by 20mmol day but loop may increase by >50mmol day at higher doses
  • K+ supplements may be used to correct for loss due to diuretics: effervescent preps or slow release forms
  • Alternatively may add a K sparring diuretics
29
Q

Thiazides- actions and uses

A
  • Dont cause metabolic acidosis
  • Cause moderate natriuresis with marked loss of K+
  • Act within 1 or 2 hours with a duration of action of 12 to 24 hours, administer early in day
  • Site of action is early DCT- tubular surface
  • Uses: widely used agents

+Long term control of hypertension =chronic therapy in congestive failure as add on to loop

30
Q

How thiazides cause hypokalaemia

A
  • PTH causes CA2+ influx
  • Ca2+ is then transported out of the cell via the Na/Ca2+ exchanger so Na+ enters DCT
  • Na is then transported out of the cell via the Na;K;ATPase pump which takes K out of the cell and into the DCT hence hypokalaemia