How does renal disease affect clinical pharmacology?
•If renal function is impaired then there will be a rapid build up of:
– active drug
– toxic or active metabolites
Reduced GFR means reduced clearance of drugs
Protein binding is also reduced
Renal impairment will prolong the half life of all drugs or their metabolites cleared by the glomerulus
What drugs are still okay to use in renal impairment?
If the drug or metabolites have a high therapeutic index or low toxicity
Which classifications of drugs are particularly dangerous when there is renal impairment?
When the drugs or metabolites have a narrow therapeutic index - causes toxicity or death
What is the effect of toxicity of the following drugs?
Gentamicin - may cause renal or otoxicity
Digoxin - may cause arrhythmia, nausea or death
Lithium - renal toxicity and death
Tacrolimus - renal and CNS toxicity
What factors interact to generate new renal impairment / worsen pre-existing renal impairment / toxicity?
Prescribed a large number or potentially reno-toxic agents
Changes in what parts of kidney function will alter the pharmacokinetics and pharmacodynamics?
Passive tubular reabsorption
Active tubular reabsorption
How must you respond the the new pharmacokinetic effects of drugs when there is renal impairment?
You must reduce the dosage (loading dose and maintenance dose)
Increase the dose interval
TDM (therapeutic drug monitoring) - monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
Monitor renal function and blood pressure during the course of the treatment
How does renal disease alter the actions of drugs on the tissues?
–The blood brain barrier becomes more permeable and the brain becomes more sensitive to tranquillisers, sedatives and opiates
–Circulatory volume may be reduced making the patient sensitive to antihypertensive agents ACEIs or a-blockers
–There may be an increased tendency to bleed beware warfarin or NSAIDs
Describe the toxic effects of drugs when used in conjunction with one another - (when there is renal failure)
The direct nephrotoxic actions of drugs are synergistic
–gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium.
Here is a summary of the effects of pharmacokinetics and pharmacodynamics
What type of drugs are best for patients with renal impairment?
–have a high therapeutic index and
–are metabolised by the liver with the production of non-toxic metabolites
What is the relationship between hypertension and renal disease?
–A common problem in patients with renal disease
–Hypertension causes renal damage,
–Renal damage causes hypertension.
What is the dilema associated with treating hypertension in patients with renal disease?
–Normally use thiazide-type diuretics, CCBs, ACEIs
–However patients with renal impairment have a low GFR, hyperuricaemia,
–More sensitive to the hypotensive actions of antihypertensive agents.
How do we treat hypertension in kidney disease?
Use drugs which are totally metabolised by the liver or elsewhere in the body
(ACEi - these are commonly recommended however they produce severe acute renal dysfunction)
Use reduced dose of the drug with longer dosing periods
or use on alternative days
What is the issue with vasodilators?
Can produce profound hypotension and salt and water retention
What is the issue associated with thiazide - type diuretics in the treatment of high blood pressure?
Thiazides/thiazide - type diuretics may precipitate gout
•Adverse drug reactions affecting the kidneys are a common cause of morbidity and mortality especially in hospitalised patients
How does the drug concentration change as it is processed by the kidney?
If the drug is primarily cleared by the kidney, it will be increasingly concentrated as it is moves from the glomerulus and along the renal tubules
The concentrated drug exposes the kidney tissue to far greater drug concentration per surface area
What are the outcomes of renal damage?
Acute kidney injury
Acute tubular necrosis
Chronic kidney disease
Salt and water abnormalities - dehydration, oedema
Acute renal failure - acute tubular necrosis, acute interstitial nephritis
Chronic renal failure
What part of the urinary system does drug induced renal disease damage?
Can affect any part of the urinary system from the kidney to the bladder and genitalia
What are the 4 major syndromes caused by drug induced renal disease?
–Acute renal failure
–Renal tubular dysfunction with potassium wasting
–Chronic renal failure
What is the definition of acture 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.
What are the pre-renal causes of drug induced renal disease?
Water and electrolyte abnormalities
(diuretics, laxitives, lithium and NSAIDs)
What are the three types of intrinsic acute renal failure?
Acute tubular necrosis (ATN)
• Acute interstitial nephritis
• Thrombotic microangiopathy.
What drugs cause acute tubular necrosis?
•cisplatin (causes renal failure in up to 25% of patients after a single dose), radiocontrast agents
•statin drugs given in combination with immunosuppressive agents such as cyclosporin
When is the onset of acute interstitial nephritis?
Usually delayed - may come on faster with a second dose of the medication
•Latency period may be as short as 1 day with rifampicin, or as long as 18 months with an NSAID.
What drugs are implicated in acute interstitial nephritis?
What is the pathological hallamark of thrombotic angiopathy?
Thrombi in the microvasculature of many organs
Changes in the kidney include afferent arteriolar and glomerular thrombosis
What drugs are responsible for thrombotic microangiopathy?
Chemotherapeutic agents mitomycin C, Bleomycin, cisplastin
19 oestrogen containing oral contraceptives
Where does post renal obstructive uropathy occur as a result of drugs?
Within the tubules or the ureters (due to crystal formation)
Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
What drugs are implicated in crystal formation?
•vitamin C in large doses (due to oxalate crystals).
• Guaifenesin and ephedrine can also cause stones to form in kidneys
What causes nephrotic syndrome?
Glomerular dysfunction - marked by heavy proteinuria
What drugs are implicated in glomerular dysfunction?
What are the recognised adverse renal effects of non-selective NSAIDs?
•acute renal failure,
What percentage of hospital admissions due to AKI are drug related?
AKI affects 7% of hospitalized patients
20-30% of critically ill patients
What percentage of patients prescribed ibuproprofen experience renal failure?
•In the elderly population (mean age 87 years), acute renal failure occurred in 13% of patients prescribed NSAIDs.
What are the most common drugs responsible for hospital acquired renal insufficiency?
When are nephrotoxic drugs best avoided?
In volume depleted or hypotensive patients with pre existing disease
Avoid nephrotoxic drugs in patients receiving other nephrotoxic agents
Most Common in elderly, sick and multiple medications
Here is a small summary table