Clinical Pharmacology and Renal Disease Flashcards
What is the therapeutic index?
Quantitative measure - relative safety of the drug
Ratio comparison of the does that produces desired effect and which causes toxicity
What does it mean if the drug has a narrow therapeutic index?
Prescribe with care
Ratio is very close (largest non-toxic: minimum effective)
What is the measurement of clearance?
PK measurement
Volume of plasma from which the drug would be totally removed per unit time
What is low clearance equal to?
High systemic exposure
What is renal clearance mainly a function of?
Glomerular filtration
Tubular secretion
Reabsorption
What is filtration dependant on?
Drug must be free in plasma - Vd and protein binding
Kidney perfusion
Health of kidneys - specifically glomerulus
What is total renal clearance?
No secretion/ reabsorption
What is used to measure GFR?
Creatine and insulin
Explain active renal secretion
Mainly occurs in proximal tubule
Can clear drugs too large to filter
Weak acid/base, nucleoside P-glycoprotein transporters
Saturable
What drugs are actively secreted?
B-lactam antibiotics, frusemide, ranitidine, ribavirin and verapamil
What is secretion equal to?
When renal clearance more than GFR
Describe passive tubular reabsorption
Lipid solubility and conc. gradient
Depends on urine flow rate and pH
What can be used to increase clearance of weak acids (aspirin)?
Urinary alkalisation
More alkaline the tubular fluid pH the more likely the drug is ionised so more likely reabsorbed
Explain how volume of drug influences plasma conc.
Drugs with high Vd have longer elimination half life
Drug cleared from plasma redistributes from other tissues. Shift from compartments to plasma - plasma conc. maintained
What is half life equal to?
0.693 x (Vd/clearance)
Describe steady state
Attained approx. after 4-5 half lives
Peaks and throughs
Can take a while to get to steady state
Vd used to calculate loading does
When is nephrotoxicity worse in patients?
Polypharmacy
Renally impaired
Age
Renal disease
Other illnesses - volume depleted, dehydrated and hypotensive
What do we do about avoiding nephrotoxicity?
Measuring GFR
Recognise other risk factors and drugs with narrow TI
Know which drugs can be used safely with low GFR
Importance of reducing loading/ maintenance doses
Importance of TDM
What needs to be considered when prescribing in renal impairment?
Risk/ benefit ratio
Severity of toxicity and possible adverse effects
Availability of TDM
What should be done when prescribing in renal impairment?
Use drugs with wide therapeutic index
Consider changing to drug which isn’t renally excreted
Reduce dose and dose frequency
Describe acute kidney injury
Clinical syndrome with multiple contributory factors - pre-renal (impacted perfusion), intra-renal or post-renal (structural obstruction)
What are common causes of AKI?
Acute tubular necrosis - death of tubular epithelial cells
Glomerulonephritis - collection of conditions causing glomerular damage
Interstitial nephritis - inflammatory
How do drugs exert nephrotoxic effects?
Immune drug effects
Combination of nephrotoxic drugs
Insoluble drug in urine
Increase in drug conc. within cells
Intracellular drug accumulation
Drug-uromodulin interaction
Direct drug nephrotoxicity
What drugs can cause acute tubular necrosis - AKI?
Aminoglycoside antibiotics, amphotericin B, cisplatin, statins, Colistimethate, foscarnet and radiocontrast agents (rare)
What drugs can cause acute interstitial nephritis (latency)?
Penicillin, cephalosporins, cocaine, omeprazole and herbal medicines
What biotherapeutics can cause glomerulonephritis?
Thrombotic microangiopathy - cyclosporine, chemotherapeutic drugs and 19-oestrogen containing oral contraceptives
What drugs can cause drug-associated obstruction of urine outflow?
Acyclovir, sulphonamides, triamterene, methotrexate and Vitamin C in large doses
Describe nephrotic syndrome
Due to glomerular dysfunction and marked by heavy proteinuria
Hypoalbuminemia
What are some drugs impacted by nephrotic syndrome?
DMARDs like gold and penicillinamine
NSAIDs, interferon and captopril
What can NSAIDs cause?
AKI in 35% of drug induced AKI
Tow forms - haemodynamically mediated and immune mediated
When should nephrotoxic drugs be avoided?
Volume depleted with renal disease
And if on other nephrotoxic drugs
