drugs and kidney

Question 1

what happens to most drugs?

Answer 1

most are metabolised by the liver to an inactive compound that can be excreted by kidney

Question 2

does the kidney excrete non-polar or polar drugs more readily?

Answer 2

polar (charged)

Question 3

what can happen to non-polar drugs?

Answer 3

non-polar/uncharged drugs) can be reabsorbed by kidney

Question 4

what protein might drugs bind to?

Answer 4

albumin

Question 5

sources of excretion in the nephron

Answer 5

glomerular filtration and tubular secretion

Question 6

what drugs will be filtered freely through the glomerulus?

Answer 6

drugs that are freely soluble in plasma and have a small molecular weight

Question 7

when will drugs not be freely filtered through the glomerulus?

Answer 7

glomerular capillaries allow drugs of MW < 20kDa to be filtered freely, but not when bound on albumin

Question 8

give an example of the clinical importance of drugs being bound to albumin?

Answer 8

when the anti-coagulant drug warfarin is in the body, 98% is bound to albumin and 2% goes into the filtrate

this results in a long half-life so the drug stays in the body a long time - this results in issues of toxicity with continued dosing (e.g. excess bleeding)

Question 9

drugs being bound to albumin causes what?

Answer 9

causes them to have a long half-life

Question 10

where does tubular secretion of drugs mostly occur?

Answer 10

proximal convoluted tubule

Question 11

how do charged drugs/metabolites leave the proximal convoluted tubule? give examples

Answer 11

through non-specific cation and anion transporters

Morphine (weak base), cation transporter
Penicillin (weak acid), anion transporter

Question 12

what is the relevance of the transporters being non-specific? give an example of how this works?

Answer 12

no selective binding sites, meaning competition can occur between drugs at these transporters

e.g. Penicillin (antibiotic) and Probenecid (removes uric acid, treat gout). If Probenecid is administered with Penicillin the half-life of penicillin is increased as they both act at the anion transporter

Question 13

most drugs are…

Answer 13

weak acids or bases - the degree of ionization depends on drug pKa and pH of environment

Question 14

effects that diuretics cause:

Answer 14

an increase in urine output (diuresis)

ALSO SOMETIMES CAUSE:
increased Na (natriuresis) / and K excretion (hypokalaemia)

Question 15

what can diuretics be used to treat?

Answer 15

act to lower the overall extracellular volume

hypertension
acute pulmonary oedema
heart failure

Question 16

what are the 2 major groups diuretics can be split into (function)?

Answer 16

-affect H2O excretion
(Ethanol- ADH release,
Osmotic diuretics)

-increase electrolyte excretion 
(Carbonic anhydrase inhibitors
Loop diuretics
Thiazides
K- sparing diuretics)

Question 17

carbonic anhydrase

Answer 17

the enzyme that converts water and carbon dioxide into bicarbonate and hydrogen ions (in the tubular cell)

flow of H ions out of the tubular cell into the lumen via the Na/H antiporter - so Na+ enters the tubular cell

net result = reabsorption of sodium bicarbonate in the PCT (na and hco3 combine in the tubular cell)

Question 18

name the 6 sites diuretics can act at:

Answer 18

1. PCT Re-absorption of Na
   with passive movement of
   organic molecules
2. PCT Re-absorption of Na+ in exchange for H+ (carbonic anhydrase)
3. LoH Transport of NaCl by a co- transporter for Na, K, 2Cl
4. DCT Re-absorption of Na/Cl (co-transporter) followed by H2O
5. DCT Na is reabsorbed through ENaC channels in exchange for K efflux (through K channels. stimulated by aldosterone
6. DCT Another Na-H exchanger - also stimulated by aldosterone

Question 19

sites 5 and 6

Answer 19

stimulated by aldosterone which means they can produce:

1. K loss in response to Na reabsorption
2. alkalosis due to increased proton excretion

Question 20

osmotic agents

Answer 20

agents that mainly affect H2O excretion

Question 21

example of an osmotic agent and how it works

Answer 21

mannitol - usually administered via i.v.

• weak diuretic, so at high concentrations it increases the osmolarity of the tubules, decreasing water reabsorption
• acts at the PCT, DCT and the collecting duct
• has little effect on electrolyte excretion

Question 22

uses of this mannitol (osmotic agent)

Answer 22

Reduce intracranial and intraocular pressure
-mannitol does not enter the CNS, so creates an osmotic gradient for H2O to leave the CNS into plasma

Prevent acute renal failure
-this drug can can prevent ANURIA

Excretion of some types of poisoning

Question 23

agents that affect electrolyte excretion - general mechanism

Answer 23

these are drugs increase urine flow by increasing Na+ excretion (natriuresis), as where Na goes H2O follows (osmosis)

increasing NaCl excretion will therefore decrease ECF volume and blood volume, leading to a decrease in cardiac output and a decrease in oedema

Question 24

example of agents that affect electrolyte excretion

Answer 24

• carbonic anhydrase inhibitors
• loop diuretics
• thiazide drugs
• K- sparing diuretics

Question 25

Carbonic anhydrase inhibitors

Answer 25

e.g. Acetazolamide
mild diuretics that inhibit activity of carbonic anhydrase, decreasing the formation of H+ ions in the tubular cells in PCT (site 2)

used when ECFV expands

loss of Na+, CO3- and Cl- into lumen, meaning loss of H2O

also used in non-renal effects, eg. glaucoma as aqueous humor formation is dependent on CA activity

Question 26

Loop diuretics how they work

Answer 26

powerful diuretics with rapid effect (i.v.)

act at site 3, where it inhibits the Na/K/Cl co transporter in the thick ascending limb of the LoH, leading to decreased reabsorption of these 3 ions

these 3 add to the concentration of the medullary interstitial fluid, so these concentration of this fluid therefore drops when loop diuretics are used

decreases the concentration gradient for water to move, so you have increased water loss

Question 27

Loop diuretics uses

Answer 27

used in chronic heart failure to decrease ECFV, which decreases CVP, venous return to the heart, stretch on the heart, SV and CO

causes vasodilatation by increasing PG’s in blood vessels

used in acute renal failure to increase renal blood flow

used in acute pulmonary oedema to decrease capillary pressure

Question 28

side effects of loop diuretics

Answer 28

Significant loss of K leading to hypokalaemia

Question 29

Thiazide drugs

Answer 29

moderately powerful diuretics that inhibit Na/Cl uptake via co-transporter in DCT (Site 4)

there are compensatory mechanisms which the drugs try and override:

Site 5: Na uptake via ENaC, leading to K excretion and loss

Site 6: Na uptake via Na/H exchanger, leading to H loss

decrease in BV will stimulate the RAAS system, increasing aldosterone levels which increase Na+ reabsorption and increase K+/H+ excretion

Question 30

uses of thiazide

Answer 30

treating hypertension - diuresis causes a decrease in BV and a decrease in CO

major effect is vasodilatation, decreasing TPR

mild heart failure, decreases ECFV

oedema

Question 31

side effects of thiazide

Answer 31

Hypokalaemia (loss of K)
Metabolic alkalosis (loss of H)
Hypercalcemia (Increased Ca/Na exchanger)
Hypotension (too much vasodilatation)

Question 32

why are K+ sparing diuretics used?

Answer 32

Used in combination with other drugs, like the loop and the thiazide

they cause K retention, countering the powerful electrolyte secretions of diuretics such as frusemide

act at end of DCT and collecting duct (Sites 5 + 6)

Question 33

examples of K+ sparing diuretics

Answer 33

Spironolactone
Competitive antagonist of aldosterone which acts at sites 5 and 6

CVS diseases linked to overproduction of aldosterone volume overload, e.g. Heart failure

Amiloride
Blocks ENaC at site 5
Reduces Na reabsorption and K loss

Captopril
Inhibition of angiotensin- converting enzyme - Ang II formation - aldosterone

Question 34

if a drug is nephrotoxic, what does this mean?

Answer 34

it causes damage to the kidney

Question 35

name for a groups of drugs that is nephroxic

Answer 35

NSAIDS

Nonsteroidal anti-inflammatory drugs, eg. lithium, prescribed for bipolar disorder

Question 36

give an example of an NSAID and why it is used and the side effects

Answer 36

lithium, prescribed for bipolar disorder

lithium has a nephrotoxic effect with long use – can develop nephrogenic diabetes insipidus (insensitivity of ADH though it is released from the hypothalamus)

Question 37

why are NSAIDS nephrotoxic?

Answer 37

prevent formation of PGs by inhibiting COX - PGs are important for vasodilatation of afferent renal arterioles, so they are important for renal blood flow and GFR

NSAIDs exacerbate issues of poor GFR (they decrease GFR)