Clinical Pharmacology of Renal Disease Flashcards
with regards to functions of the kidney, what is the most important in relation to clinical pharmacology
the excerpt of active drugs or their metabolites
also important are regulations extracellular volume and regulation of ionic concentration
what happens to levels of drugs if renal function is impaired
rapid build up of active drug, or toxic or active metabolites
what type of drugs are less likely to cause renal impairment
drugs that have a high therapeutic index or low toxicity e.g. benzylpenicillin
what type of drugs are more likely to cause renal impairment
drugs that have a narrow therapeutic index or high toxicity
give examples of 4 drugs that can cause toxicity and name the resulting complications
gentamicin - may cause renal or ototoxicity
digoxin -may cause arrhythmia, nausea or death
lithium - renal toxicity and death
tacrolimus - renal and CNS toxicity
name some factors that can interact to generate de novo renal impairment or worsen pre existing renal impairment/toxicity
sickness level (i.e. the more unwell a patient is the more likely they are to have complications)
volume depletion
hypotension
polypharmacy of potentially reno-toxic agents
what mechanism of renal excretion is most affected in renal impairment and what is the result
GLOMERULAR FILTRATION
- passive tubular reabsorption
- active tubular secretion
**changes in parameters due to disease, age or drug therapy will automatically change pharmacokinetics and pharmacodynamics
define pharmacokinetics
the bodies affect on the drug
define pharmacodynamics
the drugs affect on the body
how does renal impairment affect the half life of drugs
prolongs the half life of all drugs or their metabolites cleared by the glomerulus
**need to be extra careful when using drugs with a low therapeutic index
give some examples of normal drug half lives vs impaired half lives
benzylpen - 0.5hr - 8hr
gentamicin - 2.5 - 50
atenolol - 6 - 100
digoxin - 36 - 120
glibenclamide - 10 - 100
chlopropramide - 36 - 200
name two pharmacokinetic effects of renal impairment
- reduced GFR - leads to reduced clearance of drugs from the kidneys = ACCUMULATION
- reduced protein bindign - more active drug present in blood
what can be done to reduce the pharmacokinetic effects of renal impairment
- REDUCE DOSE
- increase dose interval
- therapeutic drug monitoring (TDM) of blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
name three pharmacodynamic effects of renal impairment
- the blood brain barrier (and barrier to the testis and ovaries) becomes more permeable - e.g. brain becomes more sensitive to tranquillisers, sedatives and opiates
- circulatory volume may be reduced - patient more sensitive to antihypertensives, ACEIs or a-blockers
- increased tendency to bleed - beware warfarin or NSAIDs (ibuprofen, paracetamol, etc)
what can be said about the direct nephrotoxic actions drugs
SYNERGISTIC
- gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
i. e. leads to increased sensitivity to the toxic effects of combined therapy
what are important things to know when prescribing drugs to a patient with renal impairment
- which drugs can be used safely when eGFR decreased
- which drugs have a low therapeutic index
- risk/benefit ratio
- severity of possible side effects
- severity of toxicity
- availability of TDM
what are important things that can reduce the possibility of renal impairment
- reduce loading dose
- reduce maintenance dose
- increase down interval
- importance of monitoring throughout course of treatment (TDM, renal function, blood pressure)
Ideally if a patient suffers from renal impairment what types of drug should be used
- drugs with a high therapeutic index
- drugs that are metabolised by the liver to produce non-toxic metabolites
what is a common medical problem that can arise from renal damage
hypertension (HBP causes renal damage and vice versa)
normally what drugs would be used for a patient with hypertension
thiazide-type diuretics, CCBs, ACEIs
why can’t hypertensive patients with renal damage have the usual HBP treatments
they have a low GFR - can lead to hyperuricaemia
they are also more sensitive to the hypotensive actions of antihypertensives
eg ACEIs commonly recommend but can produce severe acute renal dysfunction
eg direct vasodilators can produce profound hypotension and salt and water retention
eg thiazide diuretics may precipitate gout
how can hypertensive really impaired patients be managed
use drugs which are totally metabolised by the liver or elsewhere in the body
- ACEIs (BUT monitor!)
reduce dose of the drug with longer dosing periods - i.e. atenolol 25mg/day or on alternate days
how does drug induced renal disease come about
any drug in the blood will eventually reach the kidney
if the drug is primarily cleared by the kidney, will be increasingly concentrated as it moves from glomerulus along tubules
concentrated drug exposes kidney tissue to far greater drug concentration per surface area
give an example how drug induced renal failure can go undetected
cardiac arrest
- from acute hyperkalaemia
- from acute renal dysfucntion
- from drug toxicity
why can bloods show “normal” renal function even though a patient may be really impaired
if looking at urea and creatinine levels - only show up as increased in blood when GFR <60% of normal
therefore patient have have some degree of renal impairment and reduced GFR but it not show up if not looking at correct things
what are 4 types of disease that can occur from renal damage
- acute kidney injury
- acute tubular necrosis
- chronic kidney disease
- inflammatory disorders*
*eg cystitis - can be a drug induced inflammatory disorder o the bladder
how can renal involvement in disease be identified
salt and water abnormalities - dehydration, oedema
acute renal failure
- from e.g. acute tubular necrosis, acute interstitial nephritis
chronic renal failure
why is monitoring important when treating a patient with diuretics
to ensure renal function does not e impaired
what are the four major syndromes associated with drug induced renal disease e
- acute renal failure
- nephrotic syndrome
- renal tubular dysfucntion with potassium wasting
- chronic renal failure
define acute renal failure
A sudden deterioration in renal function which results in a rapid rise in creatinine
Urine volume falls to < 400ml/day in 40% of patients.
**Often elderly patients who are sick, have a poor fluid intake*, who are on multiple medications and who are not being monitored aggressively.
*also don’t have a thirst drive so don’t drink fluids
what are the three types of acute renal failure
pre-renal
renal (intrinsic)
post-renal (obstructive)
give examples of drugs that can induce pre-renal AKI (and how)
Water and electrolyte abnormalities:
diuretics, laxatives, lithium, NSAIDs
Increased catabolism:
Steroids, tertracyclines
Vascular occlusion:
Oestrogens/ OCP
what are the three types of intrinsic acute renal failure
- Acute tubular necrosis (ATN)
- Acute interstitial nephritis
- Thrombotic microangiopathy.
what drugs can cause acute tubular necrosis
- aminoglycoside, antibiotics
- amphotericin B
- cisplatin**, radiocontrast agents
- statins + immunosuppressives (eg cyclosporin
**always over hydrate patients before giving cisplatin
when does acute interstitial nephritis present
Onset after drug exposure is 3-5 days with a second exposure, to as long as several weeks with a first exposure.
Latency period may be as short as 1 day with rifampicin, or as long as 18 months with an NSAID
give some examples of drugs that can lead to acute interstitial nephritis
penicillins, cephalospirins, cocaine, NSAIDS*, omeprazole
chinese herbs
*could even be from e.g. ibuprofen used on a daily basis
what is thrombotic microangiopathy
thrombi in the microvasculature of many organs - can use acute renal failure
include afferent arteriolar and glomerular thrombosis
give some examples of drugs that can cause thrombotic microangipathy
cyclosporin, tacrolimus, OCP, cocain, quinine, clopidogrel
how can drugs cause post renal/obstructive uropathy
drug associated obstruction of urine outflow:
- within tubules or ureters (CRYSTAL FORMATION)
- outside ureters due to retroperitoneal fibrosis (caused by e.g. methysergide)
give some examples go drugs that can cause post renal damage
acyclovir, sulfonamides, methotrexate, vit C in alrge doses
what drugs can lead to nephrotic syndrome
gold, NSAIDs, penicillamine, interferon
due to glomerular dysfunction and marked by heavy proteinuria
give examples of some NSAID-induced renal syndromes
acute renal fiercer, hypertension, hyperkalemia, papillary necrosis*
*esp in women
**can be caused from even paracetamol
what is the most common type of NSAID-induced acute renal failure
deceased synthesis of renal vasodilators prostaglandins - leads to reduced renal blood flow and reduced glomerular filtration
which NSAIDs are related to NSAID-induced acute allergic interstitial nephritis
propionic acid derivatives - ibuprofen, naproxen, and fenoprofen
idiosyncratic reaction
associated with nephritic syndrome in 90% of cases
what is amino glycoside-induced renal injury
proximal tubular injury leading to cell necrosis from nephrotoxicity of amino glycoside antibiotics used to treat severe gram eve sepsis
SUMMARY: what should you be on the look out for in patients with renal damage
asymptomatic increase in urea and creatinine
fluid and electrolyte abnormalities
acute tubular necrosis
acute and chronic interstitial nephritis
SUMMARY: what is the most common cause of acute renal failure
acute tubular necrosis due to aminoglycosides
SUMMARY: what patients should you avoid nephrotoxic drugs in
volume deplete patients or
hypotensive patients with pre-existing renal disease
patents receives other nephrotoxic agents
**be aware of elderly, sick, polypharmacy patients too
