Clinical Pharmacology in Renal Disease Flashcards
If renal function is impaired there is a rapid build up of what?
- Active drug
- Toxic or active metabolites
There is a buid up of drugs when renal function is impaired, when is this a problem?
When the drug has a low therapeutic index and high toxicity
What are examples of drugs with a low therapeutic index?
- Gentamicin may cause renal or ototoxicity
- Digoxin may cause arrhythmia, nausea or death
- Lithium renal toxicity and death
- Tacrolimus renal and CNS toxicity
What makes hospital patients particularly vulnerable to toxic effects of drugs when renal function is impaired?
This is a worry because patients in hospital are:
- Sick
- Volume depleted
- Hypotensive
- Prescribed a large number of potentially reno-toxic agents
- The above factors interact to generate de novo renal impairment or worsen pre existing renal impairment
Who is drug induced nephrotoxicity common in?
- Infants, young children and elderly
- Patients with underlying renal dysfunction or cardiovascular disease
What diseases related to the kidneys can drugs cause?
- Acute renal injury
- Intra-renal obstruction
- Interstitial nephritis
- Nephrotic syndrome
- Acid-base and fluid electrolytes disorders
What are the mechanisms of renal excretion of drugs?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
Where are all drugs and metabolites filtered?
All drugs and metabolites are filtered at glomerulus
How does renal impairment impact the half life of drugs?
Renal impairment will prolong half-life of all drugs and their metabolites cleared by this route
Prolonged half-life means:
- Care when using drugs with a low therapeutic index in the presence of renal impairment
What impact does renal impairment have on pharmacokinetics?
- Reduction in GFR reduces clearance of drugs by kidney resulting in accumulation
- Protein binding also reduced
- More unbound drug
- Net result is you must
- Reduce dosage
- Increase dose interval
- TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin and vancomycin
What must you do to counter the effects of drugs on pharmcokinetics in renal impairment?
- Reduce dosage
- Increase dose interval
- TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin and vancomycin
What effect does renal impairment have on pharmacodynamics?
- Renal disease alters action of drugs on tissues
- BBB becomes permeable
- Brain becomes more sensitive to tranquillisers, sedatives and opiates
- Circulatory volume may be reduced making the patient sensitive to antihypertensive agents like ACEIs or a-blockers
- May be increased tendency to bleed so beware of warfarin or NSAIDs
In patients with renal disease are direct nephrotoxic actions of drugs synergistic or antagonitic?
In patients with renal disease direct nephrotoxic actions of drugs are synergistic:
- Gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
What can renal impairment lead to in relation to drugs?
- Dramatic alterations in pharmacokinetics
- Increased half life
- Build up of drug or metabolites
- Decrease in protein binding, so more free drug available
- Alteration in pharmacodynamics
- Increased sensitivity to pharmacological action
- Increased sensitivity to toxicity and ADRs
- Increased sensitivity to the toxic effects of combined therapy
What alterations occur in pharmacokinetics due to renal impairment?
- Increased half life
- Build up of drug or metabolites
- Decrease in protein binding, so more free drug available
What alterations occur in pharmacodynamics due to renal impairment?
- Increased sensitivity to pharmacological action
- Increased sensitivity to toxicity and ADRs
What can we do to support people with renal impairment to safely use drugs?
Need to know drugs:
- Drugs which may be used safely with lowered GFR
- And which drugs have a narrow therapeutic index
Realise importance of:
- Reducing loading dose and maintenance dose
- And increasing the dosing interval
- TDM and monitoring renal function and blood pressure during course of treatment
Impaired renal function and prescribing:
- Consider
- Risk/benefit ratio
- Severity of possible side effects
- Severity of toxicity
- Availability of TDM
- Do
- Reduce the dose of drug
- Change the dosing frequency
- Change the drugs
- If a patients suffers from renal impairment we should use drugs which
- Have a high therapeutic index and
- Are metabolised by the liver with the production of non-toxic metabolites
- If a patients suffers from renal impairment we should use drugs which
What should we consider when prescibing drugs to people with renal impairment?
- Risk/benefit ratio
- Severity of possible side effects
- Severity of toxicity
- Availability of TDM
What should we do when prescribing drugs to people when renal impairment?
- Reduce the dose of drug
- Change the dosing frequency
- Change the drugs
- If a patients suffers from renal impairment we should use drugs which
- Have a high therapeutic index and
- Are metabolised by the liver with the production of non-toxic metabolites
- If a patients suffers from renal impairment we should use drugs which
Why are the kidneys particularly vulnerable to drugs that cause renal damage?
- Kidney is particularly vulnerable to drugs that cause renal damage
- Any drug in the blood will eventually reach kidneys
- May potentially cause drug-induced renal failure
- If drug is primarily cleared by kidney, will become increasingly concentrated as it moves from the glomerulus and along the renal tubules
- Concentrated drug exposes the kidney tissue to far greater drug concentration per surface area
Renal damage causes significant morbidity and mortality, what are examples?
- Acute kidney injury
- Acute tubular necrosis
- Chronic kidney disease
- Inflammatory disorders
What are common conditions caused by drugs on the renal system?
- Salt and water abnormalities
- Dehydration
- Oedema
- Acute renal failure
- Acute tubular necrosis
- Acute interstitial nephritis
- Chronic renal failure
What part of the urinary system can drugs affect?
Drugs can affect any part of the urinary system from the kidney to the bladder and genitalia
Drug induced renal toxicity can cause 4 major syndromes, what are these?
- Acute renal failure
- Nephrotic syndrome
- Renal tubular dysfunction with potassium wasting
- Chronic renal failure
What is acute renal failure?
Is 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 different kinds of acute renal failure?
- Prerenal
- Renal or intrinsic
- Post renal or obstructive
What are examples of pre-renal drug induced disease?
- Water and electrolyte abnormalities
- Diuretics, laxatives, lithium, NSAIDs
- Increased catabolism
- Steroids, tertracyclines
- Vascular occlusion
- Oestrogens/OCP
There are 3 types of intrinsic acute renal failure, what are these?
Acute tubular necrosis (ATN)
Acute interstitial nephritis
Thrombotic microangiopathy
What does ATN stand for?
Acute tubular necrosis
What is acute tubular necrosis caused by?
- Aminoglycoside antibiotics
- Amphotericin B
- Cisplatin, radiocontrast agents
- Statins given in combination with immunosuppressive agents such as cyclosprin
What drugs are implicated with acute interstitial nephritis?
- Penicillins, cephalosporins, cocaine, sulfonamides, NSAIDs diuretics, lithium, ranitidine, omeprazole, captopril, lithium, phenytoin, valproic acid, amphotericin B, streptokinase, 5-aminosalicylates, allopurinol, rifampin,
- Chinese herbs
What can thrombotic microangiopathy cause?
- Severe acute renal failure
- Pathologic hallmark is thombi in the microvascular of many organs
- Changes in the kidney include afferent arteriolar and glomerular thrombosis
What is thrombotic microangiopathy caused by?
- cyclosporin, tacrolimus
- chemotherapeutic agents mitomycin C bleomycin, cisplatin
- ticlopidine, clopidogrel
- 19 estrogen-containing oral contraceptives
- quinine
- cocaine
What is the pathological hallmark of thrombotic microangiopathy?
- Pathologic hallmark is thombi in the microvascular of many organs
What is an example of post-renal or obstructive uropathy?
- Drug associated obstruction of urine outflow can occur at several sites
- Within the tubules or ureters (due to crystal formation)
- Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
What does obstruction within the tubules or ureters occur due to?
Cystal formation
What does obstruction outside the ureters occur due to (in regards to drugs)?
- Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
What are some drugs implicated in crystal formation?
- acyclovir, indinavir
- sulfonamides,
- triamterene
- methotrexate,
- vitamin C in large doses (due to oxalate crystals).
- Guaifenesin and ephedrine can also cause stones to form in kidneys
What is nephrotic syndrome due to?
Due to glomerular dysfunction
What is nephrotic syndrome marked by?
Heavy proteinuria
What are some drugs implicated in nephrotic syndrome?
- Gold
- NSAIDs
- Penicillamine
- Interferon
- Captopril
What are some recognised adverse renal effects of nonselective NSAIDs?
- Acute renal failure
- Nephrotic syndrome
- Hypertension
- Hyperkalaemia
- Papillary necrosis
What are some mechanisms of nephrotoxicity?
Nephrotic syndrome
Vasculitis
Acute pre-renal failure
Acute intersittial nephritis
Chronic intersttiial nephritis
Obstruction
Tubular necrosis
What percentage of hospital appointments due to AKI are drug related?
20%
What are some common drugs responsible for hospital acquired renal insufficiency?
1) Aminoglycosides
2) NSAIDs
3) Piperacillin
What does the most common type of NSAID induced acute renal failure result from?
Decreased synthesis of renal vasodilator prostaglandins which can lead to reduced renal blood flow and reduced glomerular filtration
What does NSAID induced acute allergic intersitial nephritis often occur due to?
Idiosyncratic reaction
Particular to the propionic acid derivatives (ibuprofen, naproxen, fenoprofen)
Associated with nephrotic syndrome in about 90% of cases
What are aminoglycoside antibiotics used for?
Aminoglycoside antibiotics are used in severe gram negative sepsis, cause nephrotoxicity in 10-20% of therapeutic course
Mechanism is proximal tubular injury leading to cell necrosis
What is the mechanism of aminoglycosides causing renal injury?
Mechanism is proximal tubular injury leading to cell necrosis
What renal failure is most common due to drugs?
Acute tubular necorosis
What is acute tubular necrosis usually due to?
Aminoglycosides
Who should nephrotoxic drugs be avoided in?
- Volume depleted or hypotensive patients with pre-existing renal disease
- Patients receiving other nephrotoxic agents
Why is it a problem patients being hypertensive and also having renal disease in terms of drugs?
- Hypertension causes renal damage
- Renal damage causes hypertension
- Normally used thiazide type diuretics, CCBs, ACEIs
- However patients with renal impairment have a low GFR, hyperuricaemia
- More sensitive to the hypotensive actions of antihypertensive agents
- Tackle this problem in two ways
- Use drugs which are totally metabolised by the liver or elsewhere in the body
- ACEIs
- Use reduced dose of drug with longer dosing periods
- Use drugs which are totally metabolised by the liver or elsewhere in the body
How do you tackle the problem of patients being hypertensive and also having renal damage?
- Use drugs which are totally metabolised by the liver or elsewhere in the body
- ACEIs
- Use reduced dose of drug with longer dosing periods
