B. RENAL PKs Flashcards
what is renal excretion of drugs based on
- drug filtration
- secretion/re-uptake
- renal clearance
- pH effects on drug excretion
- kidney disease on drug PKs (may need to modify drug dosage)
what happens when there is impaired renal function for drugs which are removed predominantly by renal excretion
toxicity
what is cleared quicker from the blood, drug metabolites or the parent drug
drug metabolites
- drug metabolites are usually more polar than the drug itself. There’s often the addition of hydroxyl groups, and as they’re more polar they are usually more quickly cleared. So if a drug is metabolised it allows for easy renal clearance
*Metabolites may have pharmacological properties that differ from the parent compound
phase I of hepatic metabolism
addition of reactive centres
- cytochrome P450 (and other broad spectrum enzymes)
- oxidation, reduction, hydrolysis
phase II of hepatic metabolism
conjugation
- UDP-glucuronyl transferases
- glucuronidation
what does metabolism do to drugs
makes them more bulky, charged and water soluble promoting excretion
drugs that are excreted largely unchanged in the urine
- 100-75%:
Furosemide, gentamicin, methotrexate, atenolol, digoxin - 75-50%:
Benzylpenicillin, cimetidine, oxytetracycline, neostigmine - 50%:
Propantheline, tubocurarine
*not inactivated in metabolism ie - excreted unchanged (>50%)
*renal elimination is main factor which determines duration of action
*special care where renal function may be impaired
filtration in renal excretion
- eGFR
*eGFR and CL allow excretion to be predicted
secretion in renal excretion
- active export of drug from blood to tubular fluid in proximal tubule
reabsorption in renal excretion
- active uptake of drug from tubular fluid to blood in distal tubule
what drugs can be excreted through glomerular capillaries into filtrate
- MW <60,000 Da (most drugs)
- drugs and metabolites not bound to proteins (‘free’ or unbound drug/metabolite)
*plasma albumin (MW 68,000) and many protein drugs not removed (charge also involved)
*warfarin is 98% protein bound so only 2% can be filtered
equation for drug filtration rate
GFR x fu x [drug]
(fu= free or unbound fraction)
tubular secretion
- many drugs and metabolites actively secreted into the renal tubule and excreted via active carrier systems and more rapidly excreted
- drugs bound to proteins are excreted ie - penicillin
- major route of renal drug elimination from blood (transcellular movement blood → urine)
- lipid-soluble drugs are passively reabsorbed by diffusion across the tubule so are not efficiently excreted in the urine
*Penicillin is 80% protein bound but almost completely removed by tubular secretion due to transporters
types of transporters in PCT (non-specific) involved in tubular secretion of drugs - uniporters
OAT (organic anion transporters)
- transports a broad range of monovalent anions
- anionic drugs, toxins, metabolites
- anion exchange with dicarboxylic acids
- acid drugs secreted (including β‐lactam antibiotics)
OCT (organic cation transporters)
- transports a broad range of monovalent cations
- cationic drugs, toxins, metabolites
- uses membrane potential as driving force: down EC gradient
- basic drugs secreted
*based only on charge so there may be competition. Can decrease excretion of a drug if another drug is overloading a transporter
reabsorption in DCT
- passive diffusion process
- water (approx. 99%) is reabsorbed back into the blood
- lipophilic drugs have high tubule permeability
(so are reabsorbed) - polar drugs and drug metabolites are not
- pH partition effects result in weak acids being
more rapidly excreted in alkaline urine (reverse
applies to weak bases)
*Diazepam 98.5% protein bound, secreted but entirely reabsorbed as lipophilic (opposite to penicillin)
what effect does urine pH have on drug secretion
- due to pH partition:
high pH, weak acid charged and hence rapidly excreted
low pH, weak acid uncharged and slowly excreted
high pH, weak base uncharged and hence slowly excreted
low pH, weak base charged and rapidly excreted
what is normal pH of urine
4.6-8.0
equation for renal clearance
CLr = Cu x Vu / Cp
Cu = urinary drug conc
Vu = rate of flow of urine
Cp = plasma drug concentration
*CLr varies between <1mL/min to approx 700 mL/min (max)
equation for total plasma clearance
CLp = CLr +CLnr
examples of drugs secreted by OAT transporters
- furosemide
- methotrexate
- penicillin
examples of drugs secreted by OCT transporters
- dopamine
- histamine
- morphine
what are the 3 mechanisms for drug interactions
- competition for binding sites
- common binding to plasma proteins or target sites leads to displacement of one drug by another - modulation of cytochrome P450
- induction or inhibition of CYP isoforms will alter metabolism of all substrate drugs - competition for secretion/reabsorption in kidney tubule
- competition for active transport mechanisms can increase or decrease renal clearance of drugs
effects of renal disease due to affecting drug PKs
- glomerular blood flow and filtration (albumin passed?)
- tubular secretion and reabsorption
- renal bioactivation and metabolism
- drug absorption, bioavailability, protein binding and volume of distribution (as a result of altered renal clearance)
- non-renal clearance (hepatic metabolism overloaded if a drug is exposed in body for a longer period of time)
- dose adjustment may be required in patients with renal impairment (age, disease)
what is suboptimal renal function defined as
GFR <60mL/minute/1.73m2 for ≥ 3 months
what is kidney damage defined as
pathologic abnormalities or marker of damage including abnormalities in blood or urine tests or imaging studies
what drugs require dose adjustment in kidney disease
- antihypertensives
ACE inhibitors
Beta-blockers
Diuretics - hypoglycaemic agents
Metformin - antimicrobials
Penicillins
Cephalosporins
Macrolides
Antifungals
Aminoglycosides - analgesics
Meperidine
Dextropropoxyphene
Morphine
Tramadol
Codeine - NSAIDs (all)
aminoglycoside nephrotoxicity
- ototoxic and nephrotoxic at high concentrations
- vancomycin, gentamicin, tobramycin, amikan - high risk
(streptomycin less toxic) - responsible for 10-15% of all renal failure cases
- really cleared drugs are at risk of overdose
how do aminoglycosides cause toxicity
- accumulation in proximal tubular cells
- filtration and secretion are reduced
- accumulation of antibiotic in tissue depots means toxicity worsens even though serum levels are
stable
risk factors for aminoglycoside nephrotoxicity
- prolonged duration of therapy
- increased age
- pre-existing renal insufficiency
- recent aminoglycoside therapy
- concurrent use of other nephrotoxins
- volume depletion, liver disease
how is aminoglycoside nephrotoxicity reversible
proximal tubular cells can
regenerate
digoxin toxicity caused by age-related decline in renal function
- 1 of 10 drugs most commonly associated with preventable drug-related admissions to hospital
- Digoxin half-life is normally 36 hours
- in patients with low urine production (anuric): >100 hours (low renal function and hence more exposure to drug)
- digoxin has linear pharmacokinetics so halving the dose of digoxin would half the digoxin level
- in elderly patients the same daily dose of digoxin often given over many years and does not account for renal function declining with age (longer t1/2, increase Css, longer elimination time)
pharmacist and kidney disease
- dose alteration of renally-cleared drugs can be achieved by reduction in dose, extension of dosing interval, or use of an alternative drug not extensively cleared by kidney
- dosages should be adjusted based on the patient’s renal function (calculated as CrCl or GFR)
- patients may be more sensitive to pharmacological effects or side-effects of certain drugs when renally impaired
- be aware of drugs with active metabolites that can exaggerate pharmacologic effects in patients with renal impairment (we rely on renal excretion to decrease exposure of drug)
- some drugs are less effective when renal function is reduced, e.g. thiazide-like diuretics, which require renal excretion for their actions so need to increase dose
