Drugs and The Kidney Flashcards
Describe the central role of the kidney in the excretion of drugs.
The kidney is the most important organ for eliminating drugs from the body.
Most of them are metabolised by the liver to an inactive compound that can be excreted by the kidney. The kidney excretes polar (charged) drugs more readily than non-polar (uncharged) drugs. Non-polar drugs can be reabsorbed by the kidney.
Describe the glomerular filtration of drugs.
Approximately 20% of the renal plasma flow is filtered through the glomerulus.
The glomerular capillaries allow drugs with a molecular weight of < 20kDa to be filtered freely, but not when bound to albumin (as albumin’s molecular weight is ~68kDa).
OF CLINICAL IMPORTANCE:
There is an anti-coagulant drug named warfarin. 98% of it is bound to albumin, while 2% is passed freely through the filtrate. This results in a long half-life - it stays in the body for a long time. This causes issues of toxicity with continued dosing as it may (for eg.) cause excessive bleeding, etc.
Describe the tubular secretion of drugs.
It occurs mainly in the proximal tubule.
There are non-specific cation and anion transporters for charged drugs or metabolites, for example:
- morphine (a weak base) needs a cation transporter
- penicillin (a weak acid) needs an anion transporter
Most drugs are weak acids or bases - the degree of ionization depends on the drug pKa and the pH of the environment.
Describe diuretics and their effect on the kidneys.
Diuretics can an increase in urine output (diuresis). Many diuretics also produce increased Na+ (natriuretics)/ and K+ excretion (hypokalaemia). They’re very important drugs as they can help with hypertension, acute pulmonary oedema, heart failure, etc.
There are two major groups of diuretics:
- MAINLY EFFECT H2O EXCRETION:
such as water, ethanol (decreases ADH release), osmotic diuretics
- INCREASE IN ELECTROLYTE EXCRETION:
such as carbonic anhydrase inhibitors, loop diuretics, thiazides, K+-sparing diuretics
Generally, describe the mechanism of action of diuretics.
Diuretic agents act at specific sites (Sites 1 to 6) on the nephron and collecting ducts.
- sites 5 and 6 require aldosterone
- the thick ascending Loop of Henle is impermeable to water
- the late parts of the distal convoluted tubule and duct are permeable to water in the presence of ADH
Describe what happens at Site 1 and 2.
Sites 1 and 2 are at the proximal convoluted tubule (PCT).
SITE 1:
The reabsorption of Na with the passive movement of organic molecules (glucose, amino acids) and H2O.
SITE 2:
The reabsorption of Na in exchange for H - the role of carbonic anhydrase.
Describe what happens at Site 3.
Site 3 is in the Loop of Henle.
SITE 3:
The transport of NaCl by a co-transporter for Na, K and 2 Cl. The thick ascending Loop of Henle is not permeable to H2O, so the interstitial fluid in this region becomes hypertonic. The reabsorption of H2O happens from the collecting duct (and is controlled by ADH).
Describe what happens at Site 4, 5 and 6.
Sites 4, 5 and 6 are on the distal convoluted tubule (DCT).
SITE 4:
The reabsorption of Na/Cl (via a cotransporter), followed by H2O.
SITE 5:
Na is reabsorbed (through the ENaC channels) in exchange for K efflux (through the K channels) - this is stimulated by aldosterone.
SITE 6:
another Na-H exchanger - this is also stimulated by aldosterone.
NOTE: Sites 5 and 6 can produce K loss (in response to Na reabsorption) and alkalosis (due to increased proton excretion).
Describe osmotic agents and their uses.
They are agents that mainly affect H2O excretion; they are inert substances that are freely filtered but not reabsorbed (examples include Mannitol, usually administered via I.V.)
In high concentrations, they increase the osmolarity in tubules, so decreasing the reabsorption of water.
It acts on the PCT, DCT and collecting duct. It has little effect on electrolyte excretion.
USES:
- reduce intracranial and intraocular pressure (mannitol doesn’t enter the CNS, thus creates an osmotic gradient, so H2O leaves the CNS (into the plasma) )
- prevent acute renal failure (mannitol cannot prevent anuria, the distal nephron can dry up when filtration is very low)
- excretion of some types of poisoning
Describe agents that affect electrolyte excretion (carbonic anhydrase inhibitors).
They are drugs that increase urine flow by increasing excretion of Na (natriuresis), and where the Na goes, water will follow.
NaCl is the major determinant of extracellular fluid (ECF) volume.
Increased NaCl excretion leads to a decreased ECF volume, which decreases the blood volume, which decreases cardiac output, which decreases oedemas.
Examples of such agents would be carbonic anhydrase inhibitors (such as Acetazolamide). They’re mild diuretics, and they inhibit the activity of CA by decreasing the formation of protons in the luminal cells of the PCT (Site 2).
There is a loss of NAHCO3 into the lumen, and thus a loss of H2O.
They can also be used in nonrenal effects - in glaucomas, aqueous humour formation is dependant on carbonic anhydrase activity.
Describe agents that affect electrolyte excretion (loop diuretics, and their uses and side-effects).
Another example of such agents would be loop diuretics (such as Frusemide). They are powerful diuretics with a rapid effect (given via i.v.).
They inhibit the Na/K/Cl co-transporter at the thick ascending Loop of Henle (Site 3). They decrease the reabsorption of Na, K and 2Cl, so there is a marked loss of these electrolytes.
It prevents the concentration of the cortico-medullary interstitial fluid and, therefore, reduces the effect of ADH on the collecting duct (less osmotic drive), so increases H2O loss.
USES:
- chronic heart failure (decreased ECFV, decreased CVP, decreased CO)
- vasodilation by increasing PGs in blood vessels
- acute renal failure by increasing renal flow
- acute pulmonary oedema by decreasing capillary pressure
SIDE-EFFECTS:
- significant loss of K, leading to hypokalaemia
- metabolic alkalosis (compensatory)
Describe agents that affect electrolyte excretion (thiazide drugs, and their uses and side-effects).
Another example of such drugs would be thiazide drugs (such as Bendrofluazide). They are moderately powerful diuretics. They inhibit Na/Cl uptake via the co-transporter at the DCT (Site 4).
They are compensation mechanisms:
- Site 5: Na uptake via ENaC - K excretion, so K loss
- Site 6: Na uptake via the Na/H exchanger - H loss
They decrease blood volume, which stimulates RAAS and aldosterone, so there is increased Na reabsorption at sites 5 and 6, so we increase the K/H loss.
USES:
- treatment of hypertension (the diuresis causes a decreased blood volume, so decreasing the CO)
- treatment of mild heart failure - decreased ECFV
- oedema
SIDE-EFFECTS:
- hypokalaemia
- metabolic alkalosis
- hypercalcaemia
- hypotension
Describe agents that affect electrolyte excretion (K+-sparing diuretics, and some examples).
They have a weak diuretic action. They are, however, important as they cause K retention - to counter the powerful electrolyte secretions of diuretics such as Frusemide. They act at the end of the DCT (Sites 5 and 6).
EXAMPLES:
- Spironolactone:
It’s a competitive antagonist of aldosterone at Sites 5 and 6. It’s used for CVs diseases linked to the overproduction of aldosterone, which could lead to volume overload (eg. heart failure).
- Amiloride:
It blocks ENaC at Site 5, so reduces the Na reabsorption and K loss. - Captopril:
Inhibits the ACE (Angiotensin-Converting Enzyme). This leads to decreased Angiotensin II formation, so decreased aldosterone formation.
Describe drugs that induce kidney damage.
A list of such drugs:
- NSAIDs
- radiocontrast agents
- aminoglycosides (gentamicin)
- lithium (bipolar disorder)
- cyclosporine (anti-rejection)
- chemotherapy drugs
NSAIDs are commonly prescribed drugs. NSAIDs prevent the formation of prostaglandins (PGs) by inhibiting COX.
PGs are important for vasodilation in the afferent renal arterioles. Hence, COX and PG formation is important for renal blood flow and GFR.
Importantly: NSAIDs are contraindicated in renal failure - they exacerbate issues of poor GFR.
