Lec 21- Diuretics Flashcards
Definition or diuretic
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
Physiological compensations
- 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)
What physiological functions balance diuresis
- 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)
Different types of diuretics
- 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
diuretics- things to watch out for
- 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)
Where in the kidneys is the absorption taking place and how much Where are certain diuretics working
- 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

Osmotic diuretics NB normal osmotic pressure is 300 mOsm
- 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
Carbonic anhydrase inhibitors- Acetazolamide
- 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

How carbonic anhydrase inhibitors work
- 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)

Thiazide like diuretics
- 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
Cells of early DCT (diluting segment)
- 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

Thiazide like diuretics and there duration of action
- Pharmacologically similar to thiazides but
- Many with longer durations of action
- Indapamide- 24hour
- Metolazone- 24hour
- Chlortalidone- 48-72 hour
- Xipamide- 12 hours
Problems with thiazide type diuretics- electrolytes
- 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
Problems with thiazide type diuretics- non-electrolyte imbalance
- 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
-Drug interactions with thiazides
- 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
Loop diuretics
- 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
High ceiling effect of loop diuretics
- Huge drop in sodium (increase in urine)
- Means huge drop in volume (water follow Na)

Loop diuretics- mechanism GO BACK OVER THIS
- 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)

Loop diuretics- mechanism of action (direct vasodilator)
- 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)
Loop diuretics- unwanted effects
- 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
Potassium sparring: aldosterone Antagonists e.g. spironolactone and eplerenone
- 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

Potassium sparring: aldosterone Antagonists - mechanism
- 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
Potassium sparring diuretics: aldosterone antagonist- spironolactone and eplerenone
- 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)
Potassium sparing: Na channel blockers- amiloride; triamterene
- 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
K sparring diuretics-Cautions
- 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
Fixed combinations with K sparring diuretics
- 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
Clinical uses of diuretics agents
- 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
Hypokalaemia
- 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
Thiazides- actions and uses
- 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
How thiazides cause hypokalaemia
- 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