Clinical Pharmacology in Renal Disease Flashcards
If renal function is impaired then in terms of clinical pharmacology what will there be a buildup of?
- Active drug
- Toxic or active metabolites
What 2 features would a drug have for there to be no problem between impaired renal function and pharmacology?
High therapeutic index
Low toxicity
(e.g. benzylpenicillin)
Certain drugs have a narrow therapeutic index which can lead to toxicity and death; what are the specific possible effects of these drugs: gentamicin, digoxin, lithium, tacrolimus
Gentamicin = may cause renal or ototoxicity
Digoxin = may cause arrythmia, nausea or death
Lithium = renal toxicity and death
Tacrolimus = renal and CNS toxicity
What factors found in hospital patients will interact to generate de novo renal impairment or worsen pre-existing renal impairment/toxicity?
Patients are:
- Sick*
- Volume depleted*
- Hypotensive*
- Prescribed a large number of potentially reno-toxic agents*
Mechanism of renal excretion; changes in what parameters of kidney physiology (due to disease, age or drug therapy) will automatically change drug pharmacokinetics and pharmacodynamics?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
All drugs and their metabolites are filtered at the glomerulus, renal impairment will do what to drugs cleared by this route?
Prolong their half-life
(reduction in GFR reduces clearance of drugs by the kidney resulting in accumulation; protein binding is also reduced)
What 3 things must be done with drugs when they have effects with renal impairment?
- REDUCE DOSAGE
- Increase dose interval
- TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
How does renal disease alter the actions of drugs on tissues in terms of: blood brain barrier, circulatory volume, tendency to bleed
- BBB becomes more permeable + brain becomes more sensitive to tranquilisers, sedative and opiates
- Circulatory vol may be reduced making the patient sensitive to antihypertensive agents ACEIs or alpha-blockers
- Increased tendency to bleed (beware warfarin or NSAIDs)
In patients with renal disease how do the direct nephrotoxic actions of drugs work?
Synergistically (e.g. gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium)
Renal impairment may lead to: dramatic alterations in pharmacokinetics; alteration in pharmacodynamics; increased sensitivity to the toxic effects of combined therapy - here is a more detailed summary:
When prescribing in patients with impaired renal function, what 4 things should be considered? What should be done?
Consider:
- risk/benefit ratio
- severity of possible side effects
- severity of toxicity
- availability of TDM
Do: reduce dose, change dose freq, change the drugs
Ideally if a patient suffers from renal impairment, we should should use drugs which have which 2 features?
- Have a high therapeutic index
- Are metabolised by the liver with the production of non-toxic metabolites
What is the relationship between hypertension and 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.
What are the 2 ways we can tackle to problem of treating hypertension in renally impaired patients?
- Use drugs which are totally metabolised by the liver or elsewhere in the body (e.g. ACEI (but can be nephrotoxic))
- Use reduced dose of the drugs with longer dosing periods i.e. atenolol 25mg/day or on alternate days
What is the problem with using direct vasodilators for hypertension?
Can produce profound hypotension and salt + water retention
What is a possible problem with using thiazide/thiazide-type diuretics to treat hypertension?
May precipitate gout
If a drug is primarily cleared by the kidney, what will happen to it as it moves from the glomerulus along the renal tubules?
It will become increasingly concentrated
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
- Inflammatory disorders
- Salt and water abnormalities - dehydration, oedema
- Acute renal failure - acute tubular necrosis, acute interstitial nephritis
- Chronic renal failure
What are the 4 major syndromes which drug-induced toxicity can cause?
Acute renal failure
Nephrotic syndrome
Renal tubular dysfunction with potassium wasting
Chronic renal failure
What is 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
What patients does acute renal failure usually occur in?
Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively
Give 3 pre-renal causes of drug induced renal disease
- Water and electrolyte abnormalities (diuretics, laxatives, lithium, NSAIDs)
- Increased catabolism (steroids, tetracyclines)
- Vascular occlusion (oestrogens/OCP)
What are the 3 types of intrinsic acute renal failure?
- Acute tubular necrosis (ATN)*
- Acute interstitial nephritis*
- Thrombotic microangiopathy*
What 4 drugs can cause acute tubular necrosis (intrinsic acute renal failure)?
Aminoglycoside abx
Amphotericin B
Cisplatin (up to 25% patients), radiocontrast agents
Statin drugs in combo with immunosuppressive agents e.g. cyclosporin (i.e. transplant patients - highly susceptible to atherosclerosis)
In acute interstitial nephritis (intrinsic acute renal failure), give 2 drugs which cause it and the difference in their latency period
Rifampicin - can be as short as 1 day
NSAID - can be as long as 18 months
Give more examples of drugs possible implicated in 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 (intrinsic acute renal failure) cause?
- Severe acute renal failure
- Thrombi in the microvasculature of many organs - pathological hallmark !
- Changes in kidney - inc afferent arteriolar and glomerular thrombosis
What drugs can cause thrombotic microangiopathy?
Cyclosporin, tacrolimus
Chemotherapeutic agents mitocyin C, bleomycin, cisplatin
Ticipidine, clopidogrel
19 eostrogen-containing oral contraceptives
Quinine (used in malaria, leg cramps, restless leg syndrome)
Cocaine
Drug associated obstruction of urine outflow (post-renal/obstructive uropathy causes of intinsice acute renal failure) - how does it occur in the tubules or ureters?
Due to crystal formation
How does drug associated obsruction of urine outflow occur outside the ureters?
Due to retroperitoneal fibrosis by agents such as methysergide (prophylaxis for migraine/cluster headaches)
Name some drugs implicated in crystal formation
- Acyclovir, indinavir
- Sulfonamides
- Triamterene
- Methotrexate
- Vit C in large doses (due to oxalate crystals)
- Guaifenesin and ephidrine can also cause stones to form in kidneys (found in weight loss preparations)
What is nephrotic syndrome due to (pathophysiologically)?
What is it marked by?
Glimerular dysfunction
Marked by heavy proteinuria
Name some dugs implicated in nephrotic syndrome
Gold
NSAIDs
Penicillamine
Interferon
Captopril
Give some recognisde adverse renal effects of non-selective NSAIDs
Acute renal failure
Nephrotic syndrome
Hypertension
Hyperkalaemia
Papillary necrosis (females>males)
(NSAIDs = one of biggest causes of ADRs and mortality)
Mechanisms of nephrotoxicity
What drugs are most commonly responsible for HOSPITAL ACQUIRED renal insufficiency (not inc primary care)
Aminoglycosides
NSAIDs
Piperacillin/tazobactam
Amphotericin B
Trimethoprin/sulfa
(also cyclosporin, ACEI, multiple nephrotoxins, ciprofloxacin, cis-platinum, acyclovir, ceftazidine - to a lesser extent)
What does the most common type of NSAID-induced acute enal failure result from?
Decreases synthesis of renal vasodilator prostaglandins, which can lead to reduced BF and reduced GFR
Which patients become more susceptible to acute renal failure?
Patients who’s renal blood flow is already reduced
What type of reaction is NSAID-induced acute allergic intestitial nephritis? What drugs is it particularly a reaction to?
Idiosyncratic reaction (rare and unpredictable)
Propionic acid derivatives - ibruprofen, naproxen, fenoprofen
What is NSAID-induced acute allergic interstitial nephritis associated with in about 90% of cases?
Nephrotic syndrome
What are aminoglycosde abx used in?
Severe gram-negative sepsis
In how many therapeutic courses does aminoglycoside abx cause nephrotoxicity?
10-20%
What is the mechanism of aminoglycoside-induced renal injury? (basic)
Proximal tubular injury leading to cell necrosis
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