Clinical Pharmacology in Renal Disease Flashcards
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
If the drug or metabolites have a high therapeutic index or low toxicity then no problem -Benzylpenicillin
In renal disease, if the drug or its metabolites have a narrow therapeutic index, what happens?
then 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
Renal function may have a dramatic influence on the ______________ or ________________ of the drugs we use
pharmacokinetics
pharmacodynamics
why do we worry about renal disease?
Patients in hospital are:
- Sick
- Volume depleted
- Hypotensive
- Prescribed a large number of potentially reno-toxic agents
All factors interact to generate de novo renal impairment or worsen pre existing renal impairment / toxicity
Drug-induced nephrotoxicity is common in who?
Infants, young children and the elderly
Patients with underlying renal dysfunction or cardiovascular disease
What things can drugs cause to the kidneys?
Drugs can cause acute renal injury, intra-renal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders
what is the mechanisms of renal excresion?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
Changes in any of these parameters due to disease, age or drug therapy will automatically change what?
drug pharmaokinetics and pharmacodynamics
glomerular filtration - All drugs and their metabolites are _______ at the _________
Renal impairment will prolong the _______ of all drugs or their metabolites cleared by this route
filtered
glomerulus
half-life
Prolongation of half-life means what?
care when using drugs with a low therapeutic index in the presence of renal impairment
Half-life with Impaired Renal Function
what are the pharmacokinetic effects of impaired renal function?
- A reduction in GFR reduces clearance of drugs by the kidney resulting in accumulation
- Protein binding is also reduced - More unbound drug
- The net result is you must:
- REDUCE DOSAGE
- Increase dose interval
- TDM Monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin
what are the Pharmacodynamic Effects of impaired renal function?
• Renal disease alters the actions of drugs on the tissues:
- The blood brain barrier becomes permeable
- 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 ar ethe toxic effect of drugs in someone with impaired renal function?
In patients with renal disease the direct nephrotoxic actions of drugs are synergistic
- gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
Renal Impairment may lead to what?
• 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 Should We Do?
•We need to know:
– drugs which may be used safely when eGFR ↓
–and which drugs have a narrow therapeutic index
•Realise the importance of:
–reducing loading dose and maintenance dose
–and increasing the dosing interval
•The importance of TDM, and monitoring renal function and blood pressure during the course of treatment
Impaired Renal Function and Prescribing?
What should you consider?
Risk/benefit ratio
Severity of possible side effects
Severity of toxicity
the availability of TDM
Impaired Renal Function and Prescribing?
what should you do?
reduce the dose of drug
change the dosing frequency
change the drugs
Ideally if a patient 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
can drugs caused induced renal disease?
- Adverse drug reactions affecting the kidneys are a common cause of morbidity and mortality especially in hospitalised patients
- Toxic renal effects often remain silent until too late
The _____ is particularly vulnerable to drugs and other agents that cause renal damage
Any drug in the blood will eventually reach _____
May potentially cause _________ renal failure
If the drug is primarily cleared by the kidney, it will be increasingly _________ as it is moves from the glomerulus and along the renal tubules
The concentrated drug exposes the kidney tissue to far greater drug ___________ per surface area
kidney
kidneys
drug-induced
concentrated
concentration
Renal damage causes significant morbidity and mortality such as what?
Acute Kidney Injury
Acute Tubular Necrosis
Chronic Kidney Disease
Inflammatory Disorders
does renal damage cause more expense?
Increasing healthcare expense - Both to individual and nation
Drug induced renal damage is usually __________
preventable
Renal involvement commonly takes what following forms?
• Salt and water abnormalities:
- Dehydration
- Oedema
• Acute renal failure:
- Acute tubular necrosis
- Acute interstitial nephritis
• Chronic renal failure
DO many drugs cause renal disease?
- Many of the drugs we routinely use can cause renal disease
- Patients may die of be subjected to unnecessary and radical surgery
what part of the urinary system can drugs effect?
•Drugs can affect the any part of the urinary system from the kidney to the bladder and genitalia
Drug induced renal toxicity can cause four major syndromes, what are they?
Acute renal failure
Nephrotic syndrome
Renal tubular dysfunction with potassium wasting
Chronic renal failure
what is actue 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.
Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively
Acute Renal Failure can occur in what locations?
- Prerenal
- Renal or Intrinsic
- Post renal or Obstructive
what are examples of pre-renal Drug Induced Renal Disease?
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 causes Acute Tubular Necrosis?
- aminoglycoside antibiotics
- amphotericin B
- 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
what is the onset of Acute Interstitial Nephritis?
(a renal lesion that causes a decline in renal function and is characterized by an inflammatory infiltrate in the kidney interstitium
the spaces between tubules (small tubes) inside the kidney become inflamed)
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
Drugs implicated for Acute Interstitial Nephritis include
• Drugs implicated include:
penicillins, cephalosporins, cocaine, sulfonamides, NSAIDs diuretics, lithium, ranitidine, omeprazole, captopril, lithium, phenytoin, valproic acid, amphotericin B, streptokinase, 5-aminosalicylates, allopurinol, rifampin,
• Chinese herbs
Thrombotic microangiopathy can cause what?
(a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury)
- Severe acute renal failure
- Pathologic hallmark is thrombi in the microvasculature of many organs
- Changes in the kidney include afferent arteriolar and glomerular thrombosis
a renal lesion that causes a decline in renal function and is characterized by an inflammatory infiltrate in the kidney interstitium
Thrombotic Microangiopathy may be caused by what?
- cyclosporin, tacrolimus
- chemotherapeutic agents mitomycin C bleomycin, cisplatin
- ticlopidine, clopidogrel
- 19 estrogen-containing oral contraceptives
- quinine
- cocaine
Post Renal or Obstructive Uropathy can occur in what places?
- 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 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?
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria
Drugs implicated in nephrotic syndrome include what?
gold
NSAIDs
penicillamine
interferon
captopril
what are some NSAID-induced renal syndromes?
- The recognized adverse renal effects of nonselective NSAIDs include
- acute renal failure,
- nephrotic syndrome,
- hypertension,
- hyperkalemia,
- papillary necrosis
Mechanisms of Nephrotoxicity
What is the epidemiology?
- 20% of hospital admissions due to AKI are drug related
- Most are community acquired
- AKI affects
- 7% of hospitalized patients,
- 20-30% of critically ill patients,
Table showing Drugs Responsible for Hospital Acquired Renal Insufficiency
The most common type of NSAID-induced acute renal failure results from what?
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
Associated with _________ syndrome in about 90% of cases
nephrotic
AMINOGLYCOSIDE-INDUCED RENAL INJURY:
- Aminoglycoside antibiotics, used in severe gram-negative sepsis, cause ___________ in 10% to 20% of therapeutic courses.
- Mechanism is ________ tubular injury leading to cell necrosis.
nephrotoxicity
proximal
summary:
Drugs frequently induce renal disease cauisng what effects?
Assymptomatic increase in urea and creatinine
Fluid and electrolyte abnormalities
Acute tubular necrosis
Acute and chronic interstitial nephritis
Acute renal failure due to ___ is the most common and is due to aminoglycosides
ATN
Avoid nephrotoxic drugs in what patients?
volume deplete or hypotensive patients with pre-existing renal disease
Avoid nephrotoxic drugs in patients receiving other nephrotoxic agents
Most common in:
- Elderly
- Sick
- Multiple medications
how does hypertension relate to renal disease?
A common problem in patients with renal disease
Hypertension causes renal damage,
Renal damage causes 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 can we tackle the problem of drugs causing 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. i.e. atenolol 25mg/day or on alternate days.
- ACEIs are commonly recommended however they can produce severe ____ _____ __________.
- Direct _________ can produce profound hypotension and salt and water retention
- _________________ diuretics may precipitate gout
acute renal dysfunction
vasodilators
Thiazides/thiazide-type
