49) Drugs and the kidneys Flashcards
1
Q
What happens to drugs in the kidney?
A
- The kidney is involved in eliminating drugs from the body
- Most of these drugs are metabolised in the liver into an inactive compound which can be safely excreted
- Polar drugs or metabolites (i.e. those that are water soluble or partially ionized) are excreted through specialized transporters (mainly found in the proximal tubule)
2
Q
How do drugs dissociate?
A
- Most drugs are weak acids or bases and the degree of their ionisation depends on the drugs pKa and the pH of the environment
- For weak acids: HA <=> H+ + A-
- For weak bases: B <=> OH- + BH+
- The A- is removed by anion transporters and BH+ is removed by cation transporters
- These transports belong to a family of non-specific anion and cation transporters which remove the cations and anions to keep the reaction going
3
Q
What are diuretics?
A
- Drugs that increase urine output (diuresis)
- They can also increase electrolyte excretion which leads to the loss of water
- Loss of Na in the urine is called natriuresis and loss of K in the urine is called kaliuresis
- They are used to treat acute pulmonary oedema, heart failure and hypertension
- All of them (except osmotic diuretics) increase natriuresis/ Na excretion
4
Q
What are the different classes of diuretic drugs?
A
- Carbonic anhydrase (CA) inhibitors
- Loop diuretics
- Thiazide
- K (potassium) sparing
- Osmotic
5
Q
How do osmotic diuretics work?
A
- They are inert compounds that are freely filtered but are not reabsorbed
- This causes an increase in osmolarity of solutes within the tubular fluid so the osmotic gradient for the reabsorption of water is reduced
- This means there is less reabsorption of water and hence more diuresis (more excretion of water in the urine)
- E.g. mannitol which is used to treat cerebral oedema as it does not cross the blood brain barrier
. Hence it creates an osmotic gradient with greater osmolarity in the plasma (compared to the cerebrospinal fluid) - Therefore there will be a movement of water out of the CSF into the plasma reducing the oedema occurring
6
Q
How do Carbonic Anhydrase (CA) inhibitors work?
A
- They are mild diuretics which inhibit the CA activity which is present in the lumen and in the cells of the proximal tubule
- The drug is filtered into the tubular fluid as well be present in the plasma to have take full effect
- By inhibiting CA activity we are reducing the supply of H+ which reduces Na+ reabsorption (as it inactivates H+/Na+ antiporter)
- It also inhibits HCO3- formation in the lumen so there is less absorption of CO2 and H2O into the renal cells
- Ultimately there is less absorption of NaHCO3 (Na+ and HCO3-) and hence reduced osmotic reabsorption of the H2O that moves with them
7
Q
How do Loop diuretics work?
A
- They are the most powerful diuretics which inhibit the Na/K/2Cl transporter in the thick ascending limb of the LOH
- This inhibits salt reabsorption in this segment of the LOH which reduces the concentration of the medullary interstitial fluid
- This means the tubular fluid diluted and so the osmotic gradient between the tubular fluid and the medullary interstitial fluid decreases
- Hence there is less ADH-mediated osmotic reabsorption of water
- An example is frusemide
8
Q
What are the uses of Loop diuretics?
A
- Used to treat severe volume overload (e.g. pulmonary oedema due to left ventricular failure)
9
Q
What is a side effect of Loop diuretics?
A
- There may be a significant loss of K leading to hypokalaemia
10
Q
How do thiazide diuretics work?
A
- They are moderately powerful diuretics which inhibit Na+/Cl- cotransporter in the distal tubule (a symporter transporting Na+ and Cl- into the renal cells)
- This decreases the dilution of tubular which decreases the osmotic gradient between the tubular fluid and the medullary interstitial fluid
- As a result this decreases ADH-mediated water reabsorption
11
Q
What are the uses of thiazide diuretics?
A
- Effective at low doses for treating hypertension
- Higher doses may be used for volume overload (e.g. mild to moderate heart failure)
12
Q
What are the side effects of thiazide diuretics?
A
- There can be significant loss of K+ leading to hypokalaemia
- Hypercalcemia as there is increased activity of the Na+/Ca2+ exchanger
13
Q
How do K sparing diuretics work?
A
- They are weak acting diuretics which are important as they cause K retention and so can counter the effects of loop diuretics
- Thiazide diuretics and loop diuretics cause an increase in Na+ in the tubular fluid in the initial part of the collecting duct
- This means there is greater Na+ reabsorption taking place leading to greater K+ excretion
- There are two types of K sparing diuretics. One type blocks ENaCs (e.g. amiloride) and the other are aldosterone antagonists (Spironolactone).
- ENaC blockers inhibit the intake of Na+ which in turn causes the decrease of the excretion K+
- Aldosterone antagonists decreases the expression of ENaCs, Na+/K+ ATPase and also the H+ ATPase. Ultimately it reduces the channels in which K+ can be excreted and hence decreases K+ excretion
14
Q
What are K sparing diuretics used to treat?
A
- Volume overload in heart failure
- They are used in combination with powerful diuretics (such as loop diuretics) to counter the hypokalaemia caused by the powerful diuretics
- Aldosterone antagonists are used to control hyperaldosteronism
15
Q
What are the sodium-glucose cotransporters (SGLTs)?
A
- Glucose from the plasma is filtered out into the tubules that contains the same concentration as the plasma
- All of the glucose within the tubules will be reabsorbed along the proximal tubule through two transporters: SGLT-1 and SGLT-2
- SGLT-1 aaccounts for glucose that is absorbed from the gut
- SGLT-2 accounts for majority of glucose uptake from the tubules and is a Na+/Glucose symporter.
- Na+ moves out of the cell (into the plasma) via Na+ channels which causes Na+ to move into the cell via the symporter from the tubules
- This powers the movement of glucose into the cell which then diffuses into the plasma via GLUT-2 transporters
