1: Drugs acting on the kidney 1 & 2 Flashcards
What is a diuretic?
Prevents reabsorption of electrolytes (usually sodium) causing diuresis (because water follows sodium)
What is ADH?
What is its other name?
Anti-diuretic hormone
Acts on V2 receptors (G-protein coupled) to increase water reabsorption
Vasopressin
How do SGLT2 inhibitors work?
What symptom do they cause?
Inhibit combined glucose-sodium transporter
Glycosuria
What are uricosuric drugs?
Stimulate excretion of uric acid into tubules
Diuretics (increase / decrease) urine flow.
increase urine flow
What is
a) hydrostatic
b) osmotic/oncotic pressure?
hydrostatic pressure - pressure of the fluid in a tube pushing outwards
oncotic pressure - negatively charged plasma proteins in the blood pulls fluid from the interstitium
so oncotic pressure opposes hydrostatic pressure
What change in forces causes oedema?
Increase in capillary hydrostatic pressure
and/or
Decrease in capillary oncotic pressure
How does nephrotic syndrome cause oedema in the short and long-term?
Proteinuria
Less protein in the blood
So less oncotic pressure pulling fluid back into the capillaries
So more fluid in the interstitium
(Also: blood volume & pressure drop, RAAS increases BP and BV (aldosterone), capillary hydrostatic pressure increases and oncotic pressure decreases because there’s even less protein in blood = even more fluid in the interstitium)
OEDEMA
How does CCF cause oedema?
Reduced cardiac output
Renal hypoperfusion
RAAS
BV, BP increases
So hydrostatic pressure increases and oncotic pressure decreases (dilution)
OEDEMA
How does cirrhosis cause oedema?
What is abdominal oedema called?
Portal hypertension increases hydrostatic pressure
Liver can’t produce albumin, so oncotic pressure decreases
Plus RAAS activates because blood volume decreases…
OEDEMA
(Ascites)
Where in the nephron is sodium reabsorbed?
Proximal tubules (passively, along with Cl-)
Ascending limb (triple transporter)
Distal tubules (Na+/Cl- co-transporter)
Collecting tubules (Na+/K+ exchange)
How is sodium reabsorbed in the
a) proximal tubules
b) ascending limb
c) distal tubules
d) collecting ducts?
a) Passively
b) Triple transporter
c) Na/Cl co-transport
d) Na/K exchange
Which drugs block sodium reabsorption in the
a) proximal tubules
b) ascending limb
c) distal tubules
d) collecting ducts?
a) Carbonic anhydrase inhibitors (minor)
b) Loop diuretics (block triple transporter)
c) Thiazide & thiazide-like diuretics (block Na/Cl co-transporter)
d) Potassium-sparing diuretics (e.g spironolactone)
As sodium reabsorption is paired to potassium secretion in the collecting ducts, what happens to [K+] if you give a patient
a) thiazide diuretics
b) loop diuretics
c) spironolactone
a) Decreases
b) Decreases
c) Spared, actually increases as a result
What percentage of sodium is reabsorbed by the glomeruli?
99%
diuretics still cause massive changes in sodium conc. in the urine
By which two routes could diuretics enter the urine?
Why is one far more common than the other?
1. Filtration at glomerulus
2. Secretion from peritubular capillaries into proximal tubules
Drug is usually bound to protein so it can’t be filtered
What are
a) positive
b) negative ions called?
a) Cations
b) Anions
What transporters carry
a) acidic diuretics like thiazides and loop drugs
b) basic diuretics?
a) Organic ANION transporters
b) Organ CATION transporters
because acids are negatively charged and bases are positively charged
What two types of transporter cause secretion of diuretics into the proximal tubules?
OATs
OCTs
depending on if they’re acidic or basic
Why aren’t diuretics toxic?
Transporters make sure [diuretic]urine > [diuretic]blood
Which membranes do transporters have to get diuretics through to secrete them into the proximal tubules?
Capillary membrane
Basolateral membrane
Apical membrane
Which transporter moves acidic diuretics across membranes towards the proximal tubule?
OAT
Which transporter moves alkaline diuretics across membranes towards the proximal tubule?
OCTs
Which other transporter may move acidic diuretics across the apical membrane of tubular cells?
MRP2
multi-drug-resistance protein
What effect do loop diuretics have?
How?
Torrential diuresis
Block Na/K/2Cl triple transporter
Medulla’s osmolarity doesn’t increase because it’s not getting Na, K and Cl
So corticomedullary conc. gradient is abolished
So water isn’t reabsorbed in Loop of Henle
By which route is magnesium and calcium absorbed into the interstitium around the ascending limb?
Why?
Paracellular
Electrochemical gradient - Na+, K+ (but leaks back) and 2 Cl- move into interstitium via triple transporter, so medulla is NEGATIVE
So Mg2+ and Ca2+ are attracted to it
The reabsorption of which ions is directly blocked by loop diuretics?
Ca2+, Mg2+
because loop diuretics abolish electrochemical gradient between tubules and medullary interstitium
and these ions aren’t reabsorbed anywhere else
Apart from Ca2+ and Mg2+, what other ion will patients on loop diuretics be deficient in?
K+
more Na+ reabsorption in collecting ducts, so more K+ secretion
look over this
Why can loop diuretics be used to treat pulmonary oedema?
Drains fluid pretty much
How do loop diuretics enter the proximal tubules?
Transport by OATs
because they’re acidic
Which diseases are loop diuretics used to treat?
Pulmonary oedema (IV)
CCF
Cirrhosis with ascites
Kidney failure and nephrotic syndrome
Resistant hypertension
Hypercalcaemia
Loop diuretics are sometimes used to treat ___ but may cause ___.
(hyper/hypokalaemia, hyper/hypocalcaemia)
used to treat hypercalcaemia
may cause hypokalaemia
How is hypokalaemia caused by loop diuretics treated?
Potassium-sparing diuretic
K+ supplements
Which cardio drugs may loop diuretics interact with?
Digoxin
Class III arrythmia drugs
What acid-base imbalance can loop diuretics cause?
Why?
Metabolic alkalosis
More Na+ gets to collecting ducts, so more K+ is secreted (paired)
And K+ / H+ secretion is also paired
may be seen with hypokalaemia
To summarise, what are fluid, electrolyte and acid-base imbalances caused by loop diuretics?
Hypovolaemia
Hypokaelamia, hypocalcaemia, hypomagnesaemia, hyperuricaemia (causing GOUT)
Metabolic alkalosis
Why do thiazide and loop diuretics become less effective over time?
Transporters they act on are UPREGULATED with prolonged use
What channel do thiazide diuretics block?
Where are they found in the nephron?
Na+/Cl- co-transporter
Distal tubules
Where in particular do loop diuretics and thiazide diuretics bind on their respective targets?
Cl- site
What effect do thiazide diuretics have on
a) K+
b) Ca2+?
a) Decrease in K+ - more Na+ makes it to collecting ducts to be reabsorbed, so more K+ is secreted
b) Increase in Ca2+ - opposite of loop diuretics, reason isn’t important
What effects do loop diuretics and thiazide diuretics have on calcium concentration?
Loop diuretics cause a DECREASE
Thiazide diuretics cause an INCREASE
How big a diuresis do thiazide diuretics cause compared to loop diuretics?
Mild diuresis
What cardio diseases are treated with thiazide diuretics?
Mild heart failure (revise)
Hypertension
Which disease, causing renal colic, are thiazide diuretics used to treat?
Why?
Renal stones
Reduce Ca2+ excretion (increased reabsorption), reducing stone formation
What is the effect of thiazide diuretics on
a) calcium
b) magnesium?
a) Increases blood conc.
b) Decreases blood conc. as in loop diuretics
To summarise, what are fluid, electrolyte and acid-base imbalances caused by thiazide diuretics?
Hypovolaemia
Hypokalaemia, Hypercalcaemia, hypomagnesiaemia, hyperuricaemia
Metabolic alkalosis
Which hormones increase
a) sodium
b) water
reabsorption in the distal tubules and collecting ducts?
How do they do this?
a) Aldosterone - increase no. of Na/K/ATPase channels (more sodium reabsorbed, more potassium secreted)
b) ADH - increase no. of aquaporins (more water in)
In the distal tubules and collecting ducts, Na+ ___ is paired to K+ ___.
Na+ reabsorption
K+ secretion
The more ___ which arrives at the distal tubules and collecting ducts, the more ___ which is secreted.
More Na+ (as in diuretics, which block reabsorption in ascending limb and distal tubules), more Na+ reabsorption, more K+ secretion
Why does more Na+ reabsorption cause more K+ secretion?
More Na+ reabsorption means tubular fluid is more negative
So more K+ passes through K+ channels into tubules (positive ion)
What are some examples of potassium-sparing diuretics?
Amiloride and Triamterene
Spironolactone and Eplerenone
How do
a) amiloride and triamterene
b) spironolactone and eplerenone work?
a) Block Na+ reabsorption in distal tubule and collecting ducts
b) Block Na+ channels (apical) AND Na/K/ATPase (less Na+ in, less K+ out as well)
Spironolactone and eplerenone compete with which hormone?
Aldosterone
What electrolyte imbalance does an aldosterone antagonist cause if used alone?
Hyperkalaemia
Where do aldosterone antagonists bind to block K+ secretion?
Cytoplasmic receptors
What must aldosterone antagonists be given with?
Thiazide or loop diuretics
to prevent hyperkalaemia
What cardio diseases are aldosterone antagonists used to treat?
Heart failure
Resistant hypertension
Which endocrine disease are aldosterone antagonists used to treat?
Hyperaldosteronism
