Drugs on the Kidney Flashcards
Central Role of Kidney in Action of Drugs
WHat happens when we take a drug?ADME
What is pharmacokinetics?
WHat is pharmodynamics?
What is the most important drug for eliminating drugs?
what must the drugs be to be reabsorbed and what must they be to be excreted?
where are most drugs metabolised? and what are they metabolised into?
We take a drug, maybe IV, intramuscularly etc. to get it into our system, it must be absorbed (A).
It is absorbed into a central compartment e.g. intravascular - in our blood plasma.
This drug is then taken around the body and distributed (D) to sites of action and hopefully produce effects on the body.
The drug will be metabolised (M) and excreted (E) at the same time, the excretion part is very much
The effect of giving a dosage of a drug and how much drug gets to do what it needs to, is called pharmacokinetics (kinetics means time). It takes time to be absorbed, time to be distributed and time to be metabolised and excreted.
Pharmacokinetics is what the body is doing to the drug, is it metabolising it very fast or excreting it very quickly Pharmacokinetics = ADME
Pharmacodynamics is what the drug does to the body, is it blocking or stimulating a receptor for example.
- How much we excrete by the kidney, will determine how much drug we take.
The kidney is the most important organ for eliminating drugs from the body (note though that some will be lost in stool).
Some drugs are excreted unchanged (e.g. aspirin).
To be eliminated by the kidney, drugs need to be hydrophilic (polar, charged), if they are lipophilic (non-polar) then these drugs will be reabsorbed by the kidney.
You need the drug in a form that is polar and doesn’t like to cross the membrane of tubule cells, so once filtered stays in the filtrate.
Most drugs are metabolised by the liver to a polar compound (often inactive) that can be excreted by the kidney, sometimes this increases/decreases the drugs effect.
So, the kidney is very important in excreting polar molecules and as said if not they tend to be reabsorbed into the blood stream.
Excretion of Drugs by the Kidney
what are the 3 things going on?
When we excrete a drug, we have three things going on:
1. Glomerular filtration (filter drugs through GFR)
- Passive tubular reabsorption (due to movement of drug down their conc. gradient, if non-polar)
- Tubular secretion
Together, these lead to excretion of drug in the urine
Glomerular Filtration of Drugs
How much % of renal blood flow is filtered through glomerulus?
What will affect whether or not if a drug is filtered or not?
What MW can the GF handle?
What is warfarin? why is it a difficult drug to use?
Why is it difficult to dose? How do physicians work around this?
Approximately 20% of renal plasma flow is filtered through the glomerulus. In the blood plasma we have lots of plasma proteins, drugs can either be on their own or bound to a plasma protein (usually albumin).
This therefore makes a significant difference in whether the drug will be filtered or not, because the filtration through the glomerulus will allow small things through but not plasma proteins.
Hence if a drug is bound to a plasma protein a lot, it will not be freely filtered through the glomerulus, if it is not bound to a plasma protein and free it will be freely filtered and then subsequently reabsorbed/secreted and excreted.
The MW of a drug and whether it is increased by a plasma protein will effect whether it is filtered freely or not.
Glomerular capillaries allow drugs of a MW < 20kDa to be filtered freely, but not when bound to albumin (albumin MW around 68kDa, so far greater than 20kDa)
One such drug that binds to albumin is warfarin, an important anticoagulant. Warfarin is a difficult drug to use on many accounts, but one important reason is that it binds to albumin very readily. In fact, 98% is bound to albumin so only about 2% gets into the filtrate.
This results in warfarin having a very long half-life, it stays in the body for a long time.
- Because it stays in the body for a long time, it makes warfarin difficult to dose, as you’re not sure how much is in the circulation, due to the fact it binds albumin, and little is excreted.
- For this reason, people on warfarin are checked regularly, because there are issues of toxicity with continued dosing e.g. excess bleeding.
Tubular Secretion of Drugs
Where does this mainly occur?
How does this occur? (transporters)
examples of transport
what is the clinical importance of saturation and competition for these transporters?
Example of this
Tubular secretion of drugs (from blood, through interstitium, into tubule) mainly occurs in the PCT.
This excretion occurs via specialised transporters, these transporters will either carry cations (e.g. Morphine, a weak base, so will be positively charged) or anions (e.g. Penicillin, a weak acid, a proton donor so more likely to be –ve charged).
These transporters are non-specific, i.e. they will bind any cation/anion. It is just a way of getting charged molecules into the tubular fluid to be excreted.
Clinically important
The fact that these transporters can get saturated, where they are working at their maximum capacity and cannot work anymore. Competition can occur between drugs at these transporters (as remember they are non-specific, there are no selective binding sites).
This could mean if you take one drug, it saturates the transporter so another drug you take cannot be secreted/excreted.
An example of this is between penicillin (antibiotic) and probenecid (removes uric acid). If probenecid is administered with penicillin the half-life of penicillin is increased because both act at the anion transporter.
The two drugs are competing for the same anion transporter, so penicillin stays around for longer as it is not being secreted due to being saturated by the other drug.
Passive Tubular Reabsorption of Drugs
How will re-absroption of water affect the drug?
What crtieria need to be fufilled for the drug to be reabsorbed?
Where does this occur?
What can change the polarity of drugs?
Example - aspirin taken with bicarb will mean it is excreted more, why?
What affects the degree of ionisation?
Re-absorption of H2O increases [Drug] in the tubular filtrate, this therefore increases the drug concentration gradient for reabsorption (between tubule and interstitial space) back into blood from the filtrate.
To do this though the drug needs to be non-polar, be able to cross the membrane easily, these drugs will rapidly be reabsorbed.
This occurs mainly in the proximal and distal convoluted tubules.
What can change the polarity of drugs is the pH they are in, because they are often bases/acids. So depending on pH they will either donate/accept protons and this will influence whether they are charged or not.
E.g. Aspirin can be excreted much more if you take a bicarb solution, as it makes the urine more alkaline. This makes aspirin more ionised because it donates protons, because it is a weak acid in an alkaline solution it will donate protons.
This making aspirin polar will lead to more of it being excreted.
- As said above, uncharged or unionised drugs are lipophilic and will cross the lipid membrane and be reabsorbed.
- Charged or ionised drugs are lipophobic and need transporters to cross the membrane.
Most drugs are weak acids or bases and so the degree of ionisation depends on the drug pKa and pH of the environment.
Drugs on the Kidney – Diuretics
What is diuresis?
How is this done?
what can they be used to treat?
what are the 2 groups ofr diuretics? and examples of how they bring about their affect?
Diuretics cause an increase in urine output (increased peeing), this is diuresis.
Many diuretics produce increased excretion of Na+ (natriuresis), and K+ excretion (may lead to hypokalemia).
By getting rid of more Na+, you get rid of more water.
For this reason, they are very important drugs, they can be used to treat hypertension, when other drugs don’t work, when there is excess fluid such as in heart failure or pulmonary oedema.
There are two major groups of diuretics:
- Mainly affect H2O secretion/excretion
- Water (drink a lot of water, you will pee more)
- Ethanol (decreased ADH release)
- Osmotic diuresis (use more concentrated solutions e.g. mannitol to change osmotic pressure and move more water from blood/interstitial area into tubule) - Increase electrolyte excretion
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazides
- K+ sparing diuretics
Mechanism of Action of Diuretics
What are the 2 transporters on PCT that drugs can act on?
Main site of action for loop of henle? why and what transporter?
DCT - 3 important transporters
name 4th
why is 5 and 6 important?
Diuretics agents act at specific areas of the nephron and collecting ducts
In PCT we have most of our reabsorption of Na+, we have two main types of transporters here, illustrated on diagram as site 1 (Na+ and aa/glucose) and site 2 (Na+-proton exchanger).
These can be sites of action of drugs.
- In the LoH the main sites of action are in the ascending limb, which is impermeable to water. Here we have our Na+/K+/2Cl- symporter, which is an important site of drug action.
- In DCT we have site 4, with N+ and Cl- being kicked out.
- Sites 5 and 6 are important because they are modulated by aldosterone, the ENaC channels, Na+/K+ pump and Na+/H+ antiport (important in acid-base balance).
Proximal Convoluted Tubule
What happens at site 1?
What happens at site 2?
why is carbonic anhydrase an important enzyme?
the cycle of H+ with respect to carbonic anhydrase?
Site 1:
At site 1 we have reabsorption of Na+ with passive movement of Cl- and H2O, here there is a net reabsorption of NaCl and H2O.
Site 2:
At site 2 we have exchanging of Na+ and protons, this where the role of carbonic anhydrase is.
Carbonic anhydrase is an important enzyme that catalyses its reaction in both directions. It makes protons inside the cell by making carbonic acid, which then breaks up into protons and bicarbonate.
The protons are kicked out of the cell in exchange for Na+, the bicarbonate gets reabsorbed with Na+.
The protons react with bicarbonate in lumen to form carbonic acid which dissociate into water and CO2.The CO2 diffuses into the cell, in this way, bicarb is reabsorbed.
Loop of Henle
site - 3
what is the transporter?
Site 3:
This is transport of NaCl by a co-transporter for Na+, K+, 2Cl- (this way it is neutral). The thick ascending limb is not permeable to H2O, so the interstitial region here (in medulla) becomes hypertonic.
This is important because as a result allows re-absorption of H2O from the collecting duct as it passes down through the medulla.
Distal Convoluted Tubule (DCT)
site 4 transporter?
site 5 transporter?
site 6 transporter?
how can site 5 and 6 lead to hypokalemia and alkalosis
Site 4:
There is reabsorption of Na+ followed by Cl- and H2O
Site 5:
Here Na+ is reabsorbed in exchange for K+, this is stimulated by aldosterone, aldosterone increases ENaC channels on luminal membrane and also the Na+/K+ pump on the basolateral membrane (due to electrical gradient K+ leaves into luminal membrane)
Site 6:
Here there is another Na+/H+ exchanger that is also stimulated by aldosterone
Note that sites 5 and 6 have a very high capacity, if they are stimulated a lot you will kick out a large amount of K+ and H+. This may result in hypokalemia and alkalosis.
Agents that mainly affect H2O excretion – Osmotic Agents
What do osmotic agents affect?
What is mannitol? Why is it given in high conc?
Where does it act?
Does it affect electrolyte excretion?
Why is mannitol useful for head traumas?
How can it be used to prevent acute renal failure and drying up?
Why is it used in poisoning treatment?
Osmotic agents are substances that affect the osmotic gradients
An example is mannitol, which is usually administered intravenously. and is given when you want to get rid of a lot of fluid very quickly.
Mannitol is an inert substance that is freely filtered into the filtrate but not reabsorbed. It is given at high concentrations so that the filtrate has a very high concentration of mannitol, this increases the osmolality within the tubule resulting in less reabsorption of H2O (as decreased gradient between tubule and interstitial space). In this way mannitol is a diuretic because more water is excreted in the urine.
- > Mannitol acts at the PCT and DCT and collecting duct, it is acting at a lot of places as just causing osmotic changes.
- > It also has little effect on electrolyte excretion, it is just changing osmotic gradient to remove more water.
- > In this way it is very good in treating ‘waterlogged’ cells, this may be seen in various instances:
Mannitol can be used to reduce intracranial and intraocular pressure often seen in head injury/trauma.
Mannitol doesn’t enter the CNS (cannot cross BBB) so creates an osmotic gradient between CNS and plasma. Mannitol therefore would drag water out from the intracellular space into interstitial space and into the plasma, which then circulates and is gotten rid of in the kidneys.
Mannitol can also be used to prevent acute renal failure, when the kidneys aren’t working well the filtrate is poor and this can lead to the nephron drying up. So, mannitol can prevent anuria (distal tubule drying up), by bringing in more water from the interstitial space/blood to make the tubules ‘wet’.
Mannitol can be used in poisoning. As if you want to excrete lots of water, this can be a good way of flushing out lots of poisons.
Agents that affect electrolyte excretion
How do these drugs increase urine flow?
What is the effect of these drugs on blood volume?
An important example is Carbonic anhydrase inhibitors - name a drug
What is the strength determined by?
What does this drug decrease the formation of?
What effect does this have?
What happens when there is increased Na+ in lumen?
what is ca inhibitors used more for?
These are drugs that increase urine flow by increasing excretion of Na+ (natriuresis), as where Na+ goes, water will follow (so more water will be excreted into tubule).
- NaCl is the major determinant of ECF volume.
So, if you increase NaCl excretion, ECFV will go down, hence blood volume will go down, we will see a decrease in cardiac output (due to Starling’s law) and decreased oedema.
An important example is Carbonic anhydrase inhibitors e.g. Acetazolamide
- It is a mild diuretic (due to the site it works on, the strength is ultimately determined by the amount of Na+ being excreted at the site)
- So, by inhibiting the formation of carbonic acid, you decrease formation of H+ (and bicarbonate) in the luminal cells of the proximal tubules.
- As a result, there is going to be less protons being kicked out, so there will be less Na+ coming in through the Na+/H+ exchanger. This will mean there will be less Na+ entering our tubular cells and entering the interstitial space.
- Because we have increased Na+ in the lumen, the bicarb ions in our filtrate will combine with Na+ to give NaHCO3 (sodium bicarbonate). So, you will excrete NaHCO3.
- This is a way of increasing excretion of Na+ so water will also move in the direction of the tubule/be retained in it and we will excrete more water.
CA inhibitors are not used that much in renal medicine, but more commonly used for non-renal effects. An important example is in glaucoma, where the aqueous humour formation is dependent on CA activity. CA inhibitors work in a similar way here only it is in the eye.
Another important group of agents that affect electrolyte excretion are Loop diuretics
Loop Diuretics E.g. Furosemide
How strong are these?
Which site will they affect? what is the affect of this?
Why won’t aquaporins have an effect?
what is the problem with loop diuretics?
what are the 3 main uses of the diuretics?
What is an important side effect? How does this tie into sites 4, 5 and 6? WHat can be the consequences of this?
These are powerful diuretics with a rapid effect (given IV.)
- Loop diuretics inhibit the Na+/K+/2Cl- co-transporter at the thick ascending LoH (site 3).
This will hence decrease reabsorption of Na+/K+ and 2Cl-
This prevents concentration of the cortico-medullary interstitial fluid and therefore reduces the effect of ADH on the collecting duct
- As there is less osmotic drive for water to move out into the interstitium.
- This will therefore increase fluid loss.
Usually by kicking out so much electrolytes, the medullary interstitium becomes very hyperosmolar, this produces a very big drive for the dilute filtrate when in the collecting duct to move out into the interstitial space and be reabsorbed through the aquaporins.
But if we block these transporters, the interstitium will be less concentrated so the osmotic gradient between collecting duct and interstitial space will be less, so despite aquaporins there will be less drive of fluid out and more lost in the urine).
But with loop diuretics there is a marked loss of electrolytes
There are three main uses of loop diuretics:
1. In chronic heart failure, to decrease ECFV and decrease CVP and decrease CO, reducing the work the heart must do
- Can be used in pulmonary oedema to decrease fluid and it has a role as a venodilator so would reduce Pc
- Can be used in acute renal failure, to increase renal blood flow due to its vasodilator properties
An important side effect of loop diuretics such as furosemide is a significant loss of K+, because although you do excrete a lot of Na+ you excrete a lot of K+.
Although you are excreting large amounts of Na+ in the LoH, you end up with a lot of K+ and Na+ in the tubule going up to the DCT.
So then in the DCT, looking at the diagram below, it can be seen that Na+ can be reabsorbed by all three sites, these transporters will be working more.
- However, we are still and to an increased extent, due to the high Na+ kicking out K+
- We may also see an alkalosis due to kicking out of H+
Thiazide drugs e.g. Bendrofluazide and chlorothiazide
What are these drugs normally used for? are they powerful? what site do they act on? WHat affect will this have?
Side effecst of this drug? (transporter 5 and 6)
How can this drug activate RAAS system and whats the effect of this?
what is this drug used for? (3 things)
other side effects of this drug?
How can it cause hypercalcemia?
Thiazides are important as often used in hypertension. These are moderately powerful diuretics and work by inhibiting the Na/Cl transporter at the DCT (site 4).
So, these are preventing reabsorption of Na+ and Cl-.
This produces the same effect as previously seen, if we block there we get more Na+ in the DCT, so more water will move into the tubule.
But some of the Na+ can move back into blood via the two other transporters, this means K+ gets hit again (hypokalemia) with increased loss and also some H+ loss (metabolic alkalosis), as these transporters will be working harder.
- Kicking out so much Na+ may cause Na+ to get a bit lower, which can stimulate the macula densa, this will result in increased RAAS, more aldosterone which upregulates Na+ re-absorption and further K+/H+ excretion.
We use thiazides for various things:
1. In treatment of hypertension, as diuresis will cause a drop-in blood volume which will decrease cardiac output and hence decrease BP. It is also a major vasodilator which will reduce TPR and so also reduce BP.
- Thiazides can be used in mild heart failure to reduce ECF volume
- Can be used in oedema to get rid of this excess fluid
Side effects of thiazides include the hypokalemia and metabolic alkalosis. It may also cause you to lose so much fluid and vasodilate so much it causes hypotension.
Can also cause hypercalcemia.
If we block the Na+/Cl- symporter, then there will be decreased Na+ in the cell. This will result the Ca2+/Na+ being more active to bring Na+ into the cell.
As a result, more Ca2+ will be taken from the cell out into the interstitial fluid and thus you will start pulling Ca2+ from the tubule into the cell down a gradient (as Ca2+ will start decreasing in the cell). In this way, there is greater Ca2+ reabsorption and less excretion, so you get hypercalcemia.
Another group of agents that affect electrolyte excretion is K+ sparing diuretics, this is a way to get around the hypokalemia caused by the other diuretics.
K+ Sparing Diuretics
strength of these diuretics?
Where do they act?
3 examples and what they do?
These have weak diuretic action that are important as the counter the powerful electrolyte secretions of diuretics such as furosemide.
They act at the end of the DCT and collecting duct (sites 5 and 6)
Examples include:
-> Spironolactone
Is a competitive antagonist of aldosterone at sites 5 and 6, so it prevents the effects of aldosterone. This means at 5+6 it will inhibit ENaC channels, so less Na+ entering into cells and reabsorption and also you will inhibit the Na+/K+ ATPase, so you have less Na+ coming in and less K+ going out.
At the same time you’re still losing water.
CVS diseases are linked to overproduction of aldosterone, leading to volume overload so this drug can be useful
-> Amiloride
Blocks Na+ channels at site 5 (blocks ENaC itself). Therefore reduces Na+ reabsorption and K+ loss
-> Captopril
Is an ACE inhibitor, that inhibits producing of Ang II. A decrease in Ang II will decrease aldosterone levels, thus decreasing aldosterone’s effects.
