Lecture 20 - Clinical Pharmacology of Renal Disease Flashcards
How does renal disease affect clinical pharmacology?
Renal dysfunction –> rapid build up of active drug/toxic/active metabolites
What features of drugs make them okay to use in renal disease?
If the drug has a high therapeutic index or a low toxicity
Give egs of 4 drugs with narrow therapeutic indexes that should be avoided in renal disease and what may happen if the level of the drug goes above the therapeutic index
Gentamicin - renal/ototoxicity
Digoxin - arrhythmias, naussea, death
Lithium - renal toxicity, death
Tacrolimus - renal and CNS toxicity
What are the 3 methods of renal excretion?
Glomerular filtration
Passive tubular resorption
Active tubular secretion
Are all drugs/their metabolites filtered at the glomerulus? Which drugs aren’t if not?
Yes
Renal impairment prolongs what of every drug cleared by the kidneys?
Half life (so be careful using drugs with a low therapeutic index in renal impairment)
A reduction in GFR in kidney disease leads to what?
Reduced clearance of drugs –> accumulation
What must things must you consider when prescribing for someone with renal dsiease?
Reduce dose
Increase dose interval
TDM - monitor level, e.g. for gentamicin, lithium, digoxin etc.
Consider changing drug
Renal disease alters the actions of drugs on different tissues. Describe the effect on: - Blood brain barrier - Circulatory volume - Bleeding in those with renal disease
Blood brain barrier becomes more permeable so pts more sensitive to tranquilisers/sedatives/opiates
Circulatory volume may be reduced, pt more sensitive to anti-HTNs
May be increased tendency to bleed, be aware of NSAIDs/warfarin
How is protein binding affected in kidney disease?
Can be reduced so more free drug is available
Ideally if a patient suffers from renal impairment we should use drugs that -
Have a high therapeutic index and are metabolised by the liver to non-toxic metabolites
What is the link between HTN and renal disease?
HTN causes renal disease and vice cersa
What is the issue with treating HTN in renal disease?
They are more sensitive to hypotensive actions of antihypertensive agents
What is the problem with using ACEi in renal disease?
They may produce severe acute gout
What is the issue with using direct vasodilators in renal disease?
May cause profound hypotension and salt and water retention
What is the issue with using thiazides/thiazide type diuretics in renal disease?
May precipitate gout
Drug induced renal toxicity can causes what 4 major syndromes?
Acute renal failure
Nephrotic syndrome
Renal tubular dysfunction with potassium wasting
Chronic renal failure
What is acute renal failure?
Sudden deterioriation in renal function leading to a rapid rise in creatinine
Who often gets acute renal failure?
Elderly pts who are sick, have poor fluid intake, on multiple meds + are not being monitored aggressively
How is acute renal failure categorised?
Prerenal
Renal/intrinsic
Postrenal or obstructive
What are causes of pre-renal drug induced renal failure?
Due to water and electrolyte abnormalities - diuretics, laxatives, NSAIDs, lithium
Due to increased catabolism - steroids, tetracyclines
Due to vascular occlusion - oestrogen/OCP
What are the three types of intrinsic acute renal failure?
Acute tubular necrosis
Acute interstitial nephritis
Thrombotic microangiopathy
What is the most common cause of AKI?
Acute tubular necrosis
What is ATN?
Necrosis of the renal tubular epithelial cells leading to kidney dysfunction
Is ATN reversible?
If treated in the early stages it can be
What are the two main causes of ATN?
Ischaemia and nephrotoxins
What things causing ischaemia may lead to ATN?
Shock
Sepsis
What nephrotoxins may lead to ATN?
Aminoglycosides Myoglobin secondary to rhabdomyolysis Radiocontrast agents Lead Cisplatin Amphotericin B
What are features of ATN?
Raised urea, cr, K
Muddy brown casts in the urine
What are the histopathological features of ATN?
Tubular epithelial necrosis - loss of nuclei and detachment of tubular cells from the basement membrane
Dilatation of tubules may occur
Necrotic cells obstruct the tubule lumen
What are the three phases of ATN?
Oliguric
Polyuric
Recovery
What are causes of acute interstitial nephritis?
Drugs (most common, esp antibiotics) - penicillin, rifampicin, NSAIDs, allopurinol, furosemide, omeprazole, cocaine
Systemic disease - SLE, sarcoidosis, Sjogren’s
Infection - Hanta virus, staphylococci
What is the histopathology of acute interstitial nephritis?
Marked interstitial oedema and interstitial infiltrate in the connective tissue between renal tubules
What are the clinical features of acute interstitial nephritis?
Fever, rash, arthalgia
Eosinophilia
Mild renal impairment
Hypertension
What do you see when you investigate the urine of someone with acute interstitial nephritis?
Sterile pyuria
White cell casts
What is the pathological hallmark of thrombotic microangiopathy?
Thrombi in the microvasculature of many organs
What changes in the kidney occur in thrombotic microangiopathy?
Afferent arteriolar and glomerular thrombosis
What drugs can precipitate thrombotic microangiopathy?
Cyclosporin, tacrolimus Chemotherapeutic agents, e.g. cisplatin, bleomycin Clopidogrel Quinine Oestrogen containing contraceptives Cocaine
What drugs are implicated in crystal formation in the urinary tract?
Aciclovir, indinavir Sulfonamides Triamterene Methotrexate Vit C
What drugs can cause a nephrotic syndrome?
Gold
NSAIDs
Penicillamine
Interferon
What are the most recognised adverse renal effects of NSAIDs?
Acute renal failure Nephrotic syndrome HTN Hyperkalaemia Papillary necrosis
What is the most common type of NSAID induced acute renal failure resulting from?
Decreased synthesis of renal vasodilator prostaglandins –> reduced renal blood flow + reduced glomerular filtration
What is the mechanism by which aminoglycosides are nephrotoxic?
Proximal tubular injury –> necrosis
Define contrast media nephrotoxicity
25% increase in creatinine occurring within 3 days of the intravascular administration of contrast media
What are risk factors for contrast media nephrotoxicity?
Known renal impairment (esp. diabetic nephropathy) Age >70 years Dehydration Cardiac failure Use of nephrotoxic drugs, e.g. NSAIDs
How long does contrast induced nephropathy tend to occur after administration?
2-5 days
How can contrast media nephrotoxicity be prevented?
IV 0.9% NaCl at a rate of 1ml/kg/h for 12h pre and post procedure
