The Kidneys and medicine Flashcards
Which of the following pharmacokinetic parameters is most affected by reduced renal function?
- metabolism
- elimination
- distribution
- absorption
- volume of distribution
Elimination
Which is true in regards to acute tubular necrosis?
- extrinsic causes are usually associated with ischaemic or nephrotoxic mechanisms
- it is never drug induced
- it is associated with high doses of drugs
- it is also known as acute interstitial nephritis
- it is usually associated with volume depletion
Extrinsic
Which of the following renal clearance mechanisms can clear protien bound drugs?
- Glomerular filtration
- active secretion
- passive reabsorption
- phase 1 hepatic metabolism
- phase 2 hepatic metabolism
Active secretion
can actively pump protein bound meds
Describe renal clearance
Renal clearance varies significantly
- From <1mL/minute to 700mL/minute (theoretical maximum renal plasma flow)
- “measured” in ml/min/1.73m2
- usually estimated using blood creatinine
- Not particularly accurate, but what we use in practice
- GFR is best overall measure of kidney function
Describe glomerular filtration
- Small drug molecules of molecular weight (MW) below 20 kDa pass into the glomerular filtrate.
- Most drugs – with the exception of macromolecules such asheparinor biopharmaceuticalscross the barrier freely.
- If a drug binds to plasma albumin, only free drug is filtered.
- eg warfarinis approximately 98% bound to albumin, the concentration in the filtrate is only 2% of that in plasma, and clearance by filtration is correspondingly reduced
Describe tubular secretion
- Up to 20% of renal plasma flow is filtered through the glomerulus, leaving at least 80% of delivered drug to pass on to the peritubular capillaries of the proximal tubule.
- Drug molecules are transferred to the tubular lumen by two independent and relatively non-selective carrier systems
- OAT (transports acidic drugs in their negatively charged anionic form) and cantransport drug molecules against an electrochemical gradient, can therefore reduce the plasma concentration nearly to zero,
- OCT(transports organic bases in their protonated cationic form)and facilitates transport down an electrochemical gradient.
- At least 80% of the drug delivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective mechanism of renal drug elimination.
- Unlike glomerular filtration, carrier-mediated transport can achieve maximal drug clearance even when most of the drug is bound to plasma protein.
- Drugs can compete for the same carrier leading to drug interactions
Describe passive reabsorption
- Diffusion from the concentrated tubular fluid back across the tubular epithelium
- Water is reabsorbed as fluid traverses the tubule, the volume of urine emerging being only about 1% of that of the glomerular filtrate.
- Consequently, if the tubule is freely permeable to drug molecules,99% of the filtered drug will be reabsorbed passively down the resulting concentration gradient. (excreted largely unchanged in the urine)
- Lipid-soluble drugs are therefore excreted poorly, whereas polar drugs of low tubular permeability remain in the lumen and become progressively concentrated as water is reabsorbed.
- Polar drugs handled in this way includedigoxinand aminoglycoside antibiotics.
- These drugs are not inactivated by metabolism, the rate of renal elimination being the main factor that determines their duration of action. These drugs have to be used with special care in individuals whose renal function may be impaired, including the elderly and patients with renal disease or any severe acute illness
Describe medication in renal disease
What to do with medications in renal impairment?
- Renal disease alters the effects of many drugs, sometimes decreasing their effects but more often increasing their effects and thus potential toxicity.
- Most of these changes are predictable and can be avoided by changing doses.
- Renal disease and drug interaction
- Patients with renal disease may be more vulnerable to a given drug effect (patient susceptibility).
- Drug effect may be exaggerated or attenuated in patients with renal disease (pharmacodynamic change).
- Some drugs have higher steady-state concentrations when given at usual doses to patients with renal disease (pharmacokinetic changes).
- Some patients may require dialysis (either acutely or chronically) and this changes medication dosing
Describe a stepwise approach to AKI and CKD dosage
- obtain Hx and relevant demo/clin info. - assess demographics, past medical Hx, including Hx of renal disease, and current clinical and laboratory information
- Estimate GFR using most appropriate tool to assess eGFR or CL for the patient, based on age, body size, ethnicity, and concomitant disease states
- Review current medications - identify drugs for which individualisation of the treatment regimen will be necessary
- Calculate individualised treatment regimen - calculate dosage regimen based on pharmacokinetic characteristics of the drug and eGFR/CL
- Monitor drug response and toxicity, monitor drug levels if available or applicable
- Revise regimen and adjust based on drug response or change in patient status including renal function as unwarranted
What drugs might you withhold in patients with renal impairment?
- Those that may cause Acute Tubular Necrosis (eg aminoglycosides, contrast, cisplatin), not an exhaustive list!
- Risk of accumulation with negative consequences
- Drugs that alter renal physiology (ACEI, diuretics, NSAIDs)
- Drugs associated with Acute Interstitial Nephritis - allergic reaction - lots of drugs may be implicated
Discuss the effects of chronic renal impairment on medication management
Sodium imbalance with retention (and water retention)
- Impaired ability to concentrate urine
- Loop diuretics may still work (may require higher doses), distal nephron diuretics probably inactive
Hypertension
- Need to consider overall CVD risk
- Often multiple antihypertensives are required to control hypertension
Potassium retention or hyperkalaemia
- High risk for cardiac adverse effects eg bradycardia, conduction delays, cardiac arrest
- skeletal muscle weakness
- Be careful prescribing drugs that cause potassium retention
- ACEI and ARB
- Spironolactone (and other potassium sparing diuretics)
- beta blocker
- trimethoprim
acute management of severe hyperkalaemia
- Insulin (increase K uptake into cells) + Glucose (to control for hypoglycaemia)
- salbutamol (shift K intracellularly)
- calcium gluconate: counteracts the cardiac effects of hyperkalaemia (when ECG changes are present)
Non-acute management
- diuretics (such as loop diuretics) - with careful consideration of renal function
- polystyrene sulfonate resins (eg resonium) slightly enhance GIT potassium excretion
- Risk of bowel impaction leading to necrosis or perforation
- Causes GIT upset as well as electrolyte disturbances
- Onset of action is several hours and therefore should not be used acutely
Phosphate retention
- Phosphate binders
- calcium containing
- aluminium containing
- lanthanum
- sevalamer
- iron
- Vitamin D minimisation
- Correct hyperparathyroidism
Inability to excrete acid
- reduce animal protein
- calcium carbonate
- sodium bicarbonate
Anaemia
- erythropoetin (or analogues such as darbepoetin)
What to do with medications in renal impairment?
-Renal disease alters the effects of many drugs, sometimes decreasing their effects but more often increasing their effects and thus potential toxicity.
-Most of these changes are predictable and can be avoided by changing doses.
- Renal disease and drug interaction
>Patients with renal disease may be more vulnerable to a given drug effect (patient susceptibility).
> Drug effect may be exaggerated or attenuated in patients with renal disease (pharmacodynamic change).
>Some drugs have higher steady-state concentrations when given at usual doses to patients with renal disease (pharmacokinetic changes).
-Some patients may require dialysis (either acutely or chronically) and this changes medication dosing
Describe how to manage phosphate retention, inability to excrete acid and anaemia
Phosphate binders
calcium containing
aluminium containing
lanthanum
sevalamer
iron
Vitamin D minimisation
Correct hyperparathyroidism
-
- reduce animal protein
- calcium carbonate
- sodium bicarbonate
-
erythropoetin (or analogues such as darbepoetin)
Describe howto manage hyperkalaemia in CKD
High risk for cardiac adverse effects eg bradycardia, conduction delays, cardiac arrest
skeletal muscle weakness
Be careful prescribing drugs that cause potassium retention
ACEI and ARB
Spironolactone (and other potassium sparing diuretics)
beta blocker
trimethoprim
acute management of severe hyperkalaemia
Insulin (increase K uptake into cells) + Glucose (to control for hypoglycaemia) salbutamol (shift K intracellularly) calcium gluconate: counteracts the cardiac effects of hyperkalaemia (when ECG changes are present)
Non-acute management
diuretics (such as loop diuretics) - with careful consideration of renal function polystyrene sulfonate resins (eg resonium) slightly enhance GIT potassium excretion Risk of bowel impaction leading to necrosis or perforation Causes GIT upset as well as electrolyte disturbances Onset of action is several hours and therefore should not be used acutely
How to manage hypertension in CKD
-Need to consider overall CVD risk
-Often multiple antihypertensives are required to control hypertension