Diuretics pharmacology Flashcards
How much blood goes into the kidney?
(in 24 hours)
How much is reabsorbed?
How much urine?
120L
99% reabsorbed
1.5L urine
Describe reabsorption in the proximal convulted tubule
and drugs
- ‘leaky’ tight junctions between epithelial cells
- responsible for 60-70% Na+ reabsorption (Na+/ H+ exchanger) with it K+ and Cl- and glucose (these 3 driven by sodium movement)
- active secretion of many organic acids + bases (via OAT)
Sodium ions diffuse down their electrical and concentration gradients into the epithelial cells – this transport is coupled with uptake of glucose, phosphate, amino acids, lactate, chloride and potassium, along with extrusion of protons.
Name some things that are actively secreted from the proximal convulted tubule
. Many organic acids and bases, such as ammonia (diffuses), creatinine and several drugs such as NSAIDs, penicillin and diuretics are actively secreted (e.g. via the organic anion transporter).
Descending loop of henle
Interstitial fluid of medulla hypertonic to filtrate (counter current multiplier)
Cells permeable to water out of the lumen
i.e. water diffuses out of lumen down conc. gradient
concentration of interstitial fluid
Counter-current multiplier is a way of concentrating the interstitual fluid
concentrated as fluid loss from vasa recta
as get more concentrated, close proximity of ascending and descending loops of henle
Thick ascending loop of henle
Cells have low permeability to water
20-30% Na+ actively reabsorbed
down to Na+/K+ exchange pump (basolateral membrance)
Na+→interstitial fluid
K+→enters cells
Therefore important to keep intracellular concentration of Na+ low so it can travel via its concentration gradient
This creates the gradient for sodium to cross the apical membrane via the Na/K/Cl transporter. Most of the potassium diffuses back out (goes into urine) through apical potassium channels but some is reabsorbed.
Also Na+ entering cells via Na+/H+ exchanger
Distal convulted tubule
Impermeable to water
Na+ (~ 7%) reabsorbed down conc gradient (lesser amount)
Na+ entry coupled with Cl- entry
What causes ultrafiltration in kidney to occur?
Higher blood pressure from afferent arteriole
hydrostatic pressure
Collecting tubule
Water reabsorbed via aquaporin channels (ADH-mediated) – up to 15%
Na+ reabsorption mediated by aldosterone
i.e. AQP (aquaporin) channels stored in vesicles – ADH binding to the vasopressin receptors causes their insertion into the apical membrane. Can remove as much as 15% of filtered water, making the urine considerably hypertonic to plasma.
important for concentrating urine
AQP normally in vesicles
Adolesterone causes ↑expression of the Na+/K+ pump and insertion of more Na+ channels to ↑Na+
Diuretics
↑ excretion of Na+ and water (natriuresis)
Achieved through direct action on nephron cells or changing composition of filtrate
N.B. small decrease in reabsorption → large ↑ Na+ excretion
Most diuretics secreted by cells of PCT into lumen (NOT spironolactone)
i.e. excretion of NaCl causes water to follow.
Uses of diuretics
Oedema
- cardiac failure
- hyperadolesteronism (adolesterone reabsorbs Na+ and therefore water)
- liver failure (liver cirrohisis→can cause fluid draining into the peritoneal cavity→produces more aldosterone and hence plasma volume)
- acute renal failure - diuretics to kick start urine production and increase filtration
- hypertension - reduces BP as reducing plasma volume
Loop diuretics
-mide
Powerful diuretics (15-25% filtered Na+ excreted)
Inhibit Na+/K+/2Cl- carrier in thick ascending limb of the loop of henle
Also cause vasodilation (often at sub-diuretic doses) before onset of diuresis!
E.g. furosemide, bumetanide, torasemide
Act on loop of Henle (this is why they are powerful)
indicated for
-severe hypertension
Mechanism for loop diuretics
Act on the Cl- binding site of the Na/K/Cl carrier. i.e. bicarbonate ions continuously reabsorbed from filtrate – if plasma volume reduced then concentration increased (+ loss of H+). Because Na reabsorption is blocked, there is more Na+ delivered to the distal part of the nephron, so reabsorption of water is reduced even more.
where in the kidney produces urine?
Renal pelvis
Collecting tubule and loop of henle are where?
medulla
what parts of the nephron are in the cortex?
Everything apart from loop of henle and collecting tubule
Where are diuretics excreted from?
The proximal convulted tubule (apart from potassium sparing diuretics and spironolactone)
Diuretic means
↑urine output→↑reduction in plasma volume
Loop diuretic indications
Acute pulmonary oedema Chronic heart failure (reduce afterload) Liver cirrhosis (+ ascites) Nephrotic syndrome Renal failure Hypertension (+ ↓ renal function) Hypercalcaemia - increase excretion of calcium
Loop diuretics on CHF
i.e. conditions of salt/ water overload. APO arises due to congestion in the pulmonary circulation and therefore inc blood pressure there. In CHF, the heart struggles to eject blood, so reducing the overall blood volume will reduce the workload. In liver cirrhosis, congestion occurs in the hepatic portal vein – this results in fluid loss into the peritoneal cavity – this leads to fluid retention by the kidneys, stimulated by aldosterone. Nephrotic syndrome is a condition in which damage to renal glomeruli causes loss of plasma albumin. As a result, the osmotic pressure of the plasma is reduced, resulting in peripheral oedema – diuretics therefore increase the osmotic pressure in the blood, reversing the oedema. RF can result in production of small volumes of urine. In hypertension with reduced renal function, the kidneys can be kickstarted to increase urine output + reduce blood volume. As loop diuretics increase calcium excretion, they can be used to treat hypercalcaemia.
Side effects of loop diuretics
Hypotension (through hypovolaemia) Hypokalaemia* Metabolic alkalosis Gout Hearing loss (CN VIII damage?)
Loop diuretics possible interactions
hyperkalaemia- Increases effects/ toxicity of several drugs, such as digoxin + Type III antidysrhythmic drugs
. must be careful when prescribing loop diuretics in patients treated for heart problems (because digoxin blocks Na/K pump, a low blood potassium will exacerbate this, causing cardiac toxicity). Effects can be reduced by giving potassium supplements or jointly prescribing K+ sparing diuretics.
Why do loop diuretics cause hypokalaemia?
Increased Na+ in collecting duct influences Na+/K+ ‘exchange’
i.e. large conc of Na+ remaining in filtrate (as ↓reabsorption in LoH) → drives Na+/K+ pump
Pharmacokinetics of loop diuretics
Absorbed through GI tract - stomach and small intestine
Given orally/ i.v. (in emergencies)
Peak effect < 1 hr (30 min i.v.)
Bind strongly to albumin (reach site of action via PCT excretion)
i.e. excreted in urine
T½ = 90 mins
Furosemide absorbed in stomach/ upper small intestine.
Thiazide-like and thiazide diuretics
Act on distal tubule
Inhibit Na+/ Cl- cotransporter
Smaller effect than loop diuretics – act in different place, further down nephron
Also has vasodilator effect (later phase)
E.g. chlortalidone, indapamide*, metolazone, (bendroflumethiazide)
Indapamide lowers blood pressure at subdiuretic doses (and with less metabolic disturbance than other diuretics).
Indications of thiazides
Hypertension (may be combined with loop diuretics)
Mild – moderate heart failure
Oedema
Nephrogenic diabetes insipidus
N.B. Thiazide-like diuretics better tolerated than loop diuretics + reduce the risk of stroke and MI associated with hypertension.
Side effects of thiazides
Increased urinary frequency – is this a big problem?
Erectile dysfunction
Hypokalaemia
Impaired glucose tolerance (inhibits insulin secretion)
Increased freq usually not a great problem because doses used are low. ED – due to red blood pressure? This effect is reversible on stopping taking the drug. i.e. inhibition of insulin sec thought to result from activation of KATP channels in pancreatic islet cells. Could be exacerbated by activation of RAS which promotes insulin insensitivity.
Strategies to reduce K+ depeltion
Increase intake in diet fruit juice instant coffee bananas Give K+ supplements Alone combined with diuretic Use K+ sparing diuretics
Thiazides pharmacokinetics
Only effective orally
Excreted in urine
Bendroflumethiazide (2.5mg daily) – peak effect 4-6 hrs (duration 8-12 hrs)
Chlortalidone (25mg daily) – longer-acting
*hypertension
Potassium-sparing diuretics
Aldosterone antagonists – block Na+ reabsorption and Na+/ K+ exchange in collecting tubule (limited diuretic action)
Have marked anti-hypertensive effects without hypokalaemia
May be used in combination with thiazide/ loop diuretics
E.g. spironolactone, eplerenone
Indications of potassium-sparing diuretics
Spironolactone
Ascites caused by liver cirrhosis
Oedema
Severe heart failure
Eplerenone
Adjunct in patients with left ventricular failure following MI
Side effects of potassium sparing diuretics
Hyperkalaemia
GI upset
Gynaecomastia*
Menstrual disorders/ testicular atrophy
- more pronounced with Spironolactone
i. e. Fewer Na/ K pumps so less K+ taken up from blood, leads to increased plasma potassium. Blocks reabsorption of Na+ from colon, hence water remains in the faeces. Gynaecomastia may be caused by spironolactone displacing androgen from the androgen receptor and sexual-hormone-binding globulin, and by causing increased metabolic clearance of testosterone and higher estradiol production. This imbalance between oestrogen and testosterone can result in menstrual disorders and testicular atrophy.
Pharmacokinetics of potassium-sparing diuretics
Spironolactone
Well absorbed from gut
Metabolised to canrenone t½ = 16 hrs
Slow onset of action
Eplerenone
Shorter elimination t½
Limited effect of Triamterene and amiloride as diuretics
i.e. very little sodium reabsorption in c.t. Used as an adjunct to thiazide or loop diuretics for hypertension, congestive heart failure, or hepatic cirrhosis with ascites.
Side effects triamterene and amiloride
Hyperkalaemia
Not safe to use in patients with renal impairment or on drugs which ↑ K+
Pharmacokinetics of triamterene and amiloride
Triamterene
Well absorbed orally
Partially metabolised in liver
Amiloride
Less well-absorbed
Slower onset
Excreted unchanged in urine
Combined tablets
Co-amilofruse – amiloride and furosemide combined
Used to treat oedema
Co-amilozide – amiloride and hydrochlorothiazide
Used to treat hypertension/ congestive HF/ oedema
Osmotic diuretics
E.g. mannitol
Filtered in glomerulus but not reabsorbed
Increase osmolarity of filtrate
i.e. main effects on PCT, ascending LoH and CD (freely permeable to water)
Increase excretion of water and also Na+*
Osmotic diuretics indications
Cerebral oedema
Raised intra-ocular pressure
Acute renal failure
Given with loop/ thiazide diuretics to maintain K+ balance
i.e. reduces plasma volume, therefore increases osmolality. Causes water to be drawn in from interstitial fluid.
In acute renal failure, patients are unable to remove waste products or concentrate urine without losing electrolytes. As reabsorption of Na+ is reduced, there is less drive for Na/K pump so K+ retention occurs. This is limited by use of diuretics which reduce K+.
Side effects osmotic diuretics
e.g. mannitol
Hyponatraemia
Headache
Nausea + vomiting
Headache – changes in plasma volume, hence blood flow to brain. N+V due to effect on gut?
