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
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)
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)
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
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)
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
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
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
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)
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
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
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
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
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
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
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)
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
