The Clinical Pharmacology of Renal Disease Flashcards
What are the different function of the kidney?
- Excretion of metabolic waste products
- Regulation of extracellular volume
- Regulation of ionic concentration
- Regulation of physiological pH
- The metabolism of a small number of drugs such as insulin and vit D
- Excretion of active drugs or their metabolites
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 metabolite
If the drug or metabolites have a high therapeutic index or low toxicity then no problem (benzylpenicillin)
What is the therapeutic index of a drug?
The ratio of the dose of drug needed to produce the desired response to the dose producing toxicity
Why is a narrow therapeutic index dangerous and give examples?
If the drug or its metabolites have a narrow therapeutic index then higher risk of toxicity or death
• Gentamicin may cause renal or ototoxicity
• Digoxin may cause arrhythmia, nausea or death
• Lithium - renal toxicity and death
• Tacrolimus - renal and CNS toxicity
What characteristics of drugs can renal failure effect?
Dramatic influence on the pharmacokinetics or pharmacodynamics of the drugs
What risk factors for patients in hospital to generate renal impairment or worsen pre-existing renal impairment?
- Sick
- Volume depleted
- Hypotensive
- Prescribed a large number of potentially reno-toxic agents
What are three mechanisms of renal excretion for drugs?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
Changes in any of these will change drug pharmacokinetics
What is the importance of glomerular filtration?
All drugs and their metabolites are filtered at the glomerulus
Renal impairment will prolong the half-life of all drugs or their metabolites cleared by this route.
What is the significance of prolongation of a drug’s half life?
Care when using drugs with a low therapeutic index in the presence of renal impairment
What are the pharmacokinetics of a drug?
The way in which drugs move through the body
What are the pharmacokinetic effects of renal failure?
A reduction in GFR reduces clearance of drugs by the kidney resulting in accumulation
What steps need to be taken to adjust drugs to reduced GFR?
- Reduce dosage
- Increase dose interval
- TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
What are the pharmacodynamic effects of renal failure?
Renal disease alters 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
What are toxic effects of renal disease?
Direct nephrotoxic action of drugs are synergistic
i.e. gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
How can renal impairment alter drug action?
Dramatic alterations in pharmacokinetics:
• Increased t1/2
• 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 do doctors need to be aware of before prescribing drugs to a Pt with renal failure?
Drugs which may be used safely when eGFR ↓ and which drugs have a narrow therapeutic index
The importance of TDM, and monitoring renal function and blood pressure during the course of treatment
What needs to be considered before prescribing drugs to a Pt with renal failure?
Consider: • Risk/benefit ratio • Severity of possible side effects • Severity of toxicity the availability of TDM
Do:
• Reduce the dose of drug
• Change the dosing frequency
• Change the drugs
What type of drugs should be used with a Pt who has renal impairment?
- Have a high therapeutic index
* Are metabolised by the liver with the production of non-toxic metabolites
What is the problem in treating hypertension in renal disease?
- Renal damage hypertension
- 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 is hypertension treated in renal disease?
Use drugs which are totally metabolised by the liver or else where in the body
ACEIs (ACEI potentially nephrotoxic)
Use reduced dose of the drug with longer dosing periods.
What are ACEI potential nephrotoxic?
- Can produce severe acute renal dysfunction
* Direct vasodilators can produce profound hypotension and NaCl and H2O
How can drugs cause renal damage?
Any drug in the blood will eventually reach kidneys
May potentially cause drug-induced renal failure
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 conditions can renal damage cause?
- Acute Kidney Injury
- Acute Tubular Necrosis
- Chronic Kidney Disease
- Inflammatory Disorders
What are the forms of renal involvement?
Salt and water abnormalities
• Dehydration
• Oedema
Acute renal failure
• Acute tubular necrosis
• Acute interstitial nephritis
Chronic renal failure
What four syndromes can cause drug induced renal toxicity?
- Acute renal failure
- Nephrotic syndrome
- Renal tubular dysfunction with potassium wasting
- Chronic renal failure
What are the features of acute renal failure?
A sudden deterioration in renal function which results in a rapid rise in creatinine.
Urine volume falls to <400ml/day
Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively.
What are three types of acute renal failure?
Pre-renal, intrinsic and post renal or obstructive
What are the features in pre-renal acute renal failure?
- Water and electrolyte abnormalities: diuretics, laxatives, lithium, NSAIDs
- Increased catabolism - Steroids, tertracyclines
- Vascular occlusion - Oestrogens/ OCP
What are three types of intrinsic acute renal failure?
- Acute tubular necrosis (ATN)
- Acute interstitial nephritis
- Thrombotic microangiopathy.
What Drugs cause Acute Tubular Necrosis?
- Aminoglycoside antibiotics
- Amphotericin B
- Cisplatin, radiocontrast agents
- Statin drugs given in combination with immunosuppressive agents such as cyclosporin
How does Acute interstitial nephritis occur?
Onset after drug exposure 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.
What drugs can cause Acute Interstitial Nephritis?
Penicillins, cephalosporins, cocaine, NSAIDs, omeprazole and Chinese herbs
What is thrombotic microangiopathy?
Thrombosis in capillaries and arterioles, due to an endothelial injury.
What can thrombotic microangiopathy cause?
- Severe acute renal failure.
- Pathologic hallmark is thrombi in the microvasculature of many organs.
- Changes in the kidney include afferent arteriolar and glomerular thrombosis
What drugs can cause thrombotic microangiopathy?
- Cyclosporin, tacrolimus
- 19 estrogen-containing oral contraceptives
- Cocaine
What is post-renal acute renal failure?
Drug-associated obstruction of urine outflow can occur at several sites: 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 cause crystal formation in post-renal acute renal failure?
- 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?
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria.
What drugs are implicated in nephrotic syndrome?
- NSAIDs
- Penicillamine
- Interferon
- Captopril
What pathologies are caused by NSAIDs?
- Acute renal failure
- Nephrotic syndrome
- Hypertension
- Hyperkalemia
- Papillary necrosis
How do NSAIDs cause pre-renal cute renal failure?
The most common type of NSAID-induced acute renal failure results from decreased synthesis of renal vasodilator prostaglandins, which can lead to reduced renal blood flow and reduced glomerular filtration.
Patients become susceptible to acute renal failure if their renal blood flow is already reduced.
How do ahminoglycosides cause renal injury?
Mechanism is proximal tubular injury leading to cell necrosis.
