FRCA Notes

Drugs and the kidneys

Renal drug handling occurs at three main stages:

Glomerular filtration
Active, proximal convoluted tubular secretion
Passive, distal convoluted tubular reabsorption

Drugs 7kDa - 70kDa in molecular weight are freely filtered e.g. fluconazole, ofloxacin
Drugs that are of low MW but highly protein bound are less readily filtered e.g. propofol (98% protein bound)
Drugs that carry a permanent charge may have a large fraction excreted unchanged in the urine e.g. pancuronium, vecuronium
Large molecules are not filtered e.g. heparin

Tubular secretion is an active process that occurs via carrier proteins

The rate of tubular secretion is governed by renal blood flow

It can secrete drugs against their concentration gradient
It is efficient even for highly protein-bound drugs
Overall it is a more important route of handling for acidic drugs

Carrier proteins

Carrier proteins exist for both acidic and basic drugs
Acidic molecules with carrier proteins include:

Furosemide
NSAIDs
Penicillin
Glucuronyl or sulphate conjugates
Para-aminohippuric acid (PAH)

Basic molecules include:

Histamine
Dopamine
Creatine
Thiamine
Guanidine
Choline

Mechanisms

Active secretion from the renal blood vessels into the proximal tubules

This is because 80% of renal blood flow escapes filtration at the glomerulus (filtration fraction 0.2)
Examples include ACE-I and penicillin

Competition for carriers occurs as more than one drug can be transported by the same carriers

E.g. probenecid administered with penicillin
E.g. sulphonamide administered with indomethacin

As water is absorbed in the descending loop of Henle, there will be an increased concentration of drug in the DCT
This can cause passive reabsorption of the drug into the bloodstream

Lipid solubility

Highly lipid soluble drugs are more readily reabsorbed into the circulation e.g. fentanyl
Some are too lipid insoluble to undergo reabsorption e.g. digoxin, aminoglycosides, glucuronide/sulphate conjugates

Urinary pH

Changes in urinary pH can alter the ionised/unionised fraction of drugs and therefore their lipid solubility
This will affect their ability to be reabsorbed
Weak acids become more ionised at alkaline pH, which is why sodium bicarbonate is used to alkalinise the urine to enhance aspirin, phenobarbital and TCA excretion
Weak bases become more ionised at acidic pH

Increasing age is associated with a progressive loss in kidney structure, reduced nephron number and function
If required to give a drug that is renally excreted, a reduced dose ± increased dosing interval should be used

Reduced dose = usual dose x (impaired CrCl / normal CrCl)

There is a reduction in GFR

Decreases 8ml/min/1.73m² per decade after 40
Serum creatinine tends to stay normal due to reduced production (lower muscle mass, less physical activity)

There is a reduction in renal blood flow (decreases 10% per decade after 40)

The net effect of these changes is:

A reduction in renal drug elimination
An increased risk of AKI in the perioperative period in elderly patients

Mechanisms of these changes

Haemodynamic changes

Generally altered haemodynamics e.g. lower CO, increased SBP, increased vasopressor response but impaired vasodilator responses
Reduced glomerular plasma flow rate
Reduced ultrafiltration coefficient
Reduced afferent arteriolar resistance leads to progressive proteinuria and glomerular sclerosis

Structural changes

Reduced renal cortical mass
Glomeruli: fewer in number, decreased function and sclerosis
Afferent arteriole hyalinisation, forming aglomerular connections with efferent arterioles

Specific drugs affected

Drug class	Examples
Opioids/analgesics	Morphine, oxycodone, remifentanil, gabapentin
NMBA	Aminosteroids
Reversal agents	Neostigmine, sugammadex
CVS drugs	ACE-I, digoxin
Diuretics	Furosemide, thiazides, amiloride
Antibiotics	Aminoglycosides, quinolones