Clinical Pharmacology Flashcards
What are the functions of the kidneys?
- 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
What will there be a rapid build up of if renal function is impaired?
- Active drug
- Toxic or active metabolites
What type of drugs do not present a problem in renal impairment?
Drug or metabolites which have a high therapeutic index or low toxicity such as benzylpenicillin
What can drugs/metabolites which have a narrow therapeutic index cause in renal impairment?
Toxicity or death
What can gentamicin cause?
Renal or ototoxicity
What can digoxin cause?
Arrhythmia, nausea or death
What can lithium cause?
Renal toxicity and death
What can tacrolimus cause?
Renal and CNS toxicity
What may dramatically influence the pharmacokinetics or pharmacodynamics of the drugs?
Renal function
Why do we worry about renal impairment in people in hospital?
- 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
What are the 3 mechanisms of renal excretion?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
What will changes in mechanisms of renal excretion due to disease, age or drug therapy change?
Will automatically change drug pharmacokinetics and pharmacodynamics
Why does renal impairment prolong the half life of certain drugs?
- All drugs and their metabolites are filtered at the glomerulus
- Renal impairment will therefore prolong the half life of all drugs or their metabolites cleared by this route
What care needs to be taken due to the prolonged half life of drugs in renal impairment?
Prolongation of half-life means that extra care must be taken when using drugs with a low therapeutic index in the presence of renal impairment
Give examples of high half-life differs for certain drugs in renal impairment
- Benzylpen 0.5h>8h
- Gentamicins 2.5h>50h
- Atenolol 6h>100h
- Digoxin 36h>120h
- Glibenclamide 10h>100h
- Chlopropramide 36h>200h
What does a reduction in GFR result in?
- Reduced clearance of drugs by the kidney resulting in accumulation
- Protein binding is reduced
What must be carried out during drug administration in someone with reduced GFR clearance?
- Reduce dosage
- Increased dose interval
- TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin and vancomycin
In what ways does renal disease alter 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
How can the direct nephrotoxic actions of drugs be described in patients with renal disease?
Synergistic
When will gentamicin toxicity be unmasked?
When used in conjunction with furosemide or lithium
How can renal impairment alter pharmacokinetics?
- Increase t1/2
- Build up of drugs or metabolites
- Decreases in protein binding. So more free drug available
How can renal impairment alter pharmacodynamics?
- Increased sensitivity to pharmacological action
- Increased sensitivity to toxicity and ADRs
How can renal impairment affect combined therapies?
Can increase the sensitivity to the toxic effects of combined therapy
What do we need to know about drugs before administering them to patients with renal impairment?
- Drugs which can be safely used with decreased eGFR
- Drugs which have a narrow therapeutic index may present problems
What considerations need to be made when prescribing in impaired renal function?
- Risk/benefit ratio
- Severity of possible side effects
- Severity of toxicity
- The availability of TDM
Ideally if a patient suffers from renal impairment we should use drugs which:
- Have a high therapeutic index
- Are metabolised by the liver with production of non-toxic metabolites
Why is hypertension common in renal disease?
- Hypertension causes renal damage
- Renal damage causes hypertension
What types of drugs would usually be used for hypertension?
- Thiazide type diuretics
- CCBs
- ACEIs
Why are conventional anti-hypertensives a problem in renal disease?
- They have a low GFR, hyperuricaemia
- They are more sensitive to the hypotensive actions of Antihypertensives
What is the solution to hypertension in renal disease?
We can tackle the problem in two ways.
- Use drugs which are totally metabolised by the liver or else where in the body (ACEI are potentially nephrotoxic)
- Use reduced dose of the drug with longer dosing periods. i.e. atenolol 25mg/day or on alternate days.
What can ACEI cause?
Severe acute renal dysfunction
What can direct vasodilators cause?
Profound hypotension and salt and water retention
What can thiazide type diuretics cause?
Precipitate gout
What is a common cause of morbidity and mortality in hospitalised patients when it comes to the kidneys?
Adverse drug reaction that affect the kidneys as toxic renal effects often remain silent until too late
How do kidneys get damaged by drugs?
- The kidney is particularly vulnerable to drugs and other agents that 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 types of renal damage can occur?
- AKI
- Acute tubular necrosis
- Chronic kidney disease
- Inflammatory disorders
What forms does renal involvement commonly take?
Salt and water abnormalities
- Dehydration
- Oedema
AKI
- Acute tubular necrosis
- Acute interstitial nephritis
Chronic renal failure
What may happen to patients subjected to unnecessary and radical surgery?
May die
What are the 4 major syndrome that drug induced renal toxicity can cause?
- Acute renal failure
- Nephrotic syndrome
- Renal tubular dysfunction with potassium wasting
- Chronic renal failure
Define ARF
- A sudden detioration in renal function which results in a rapid rise in creatinine
- Urine volume falls to < 400ml/day in 40% of patients.
Who is usually affected by ARF?
Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively.
How can ARF be classified?
- Prerenal
- Renal or intrinsic
- Post renal or obstructive
What are pre-renal causes of ARF?
Water and electrolyte abnormalities
-Diuretics, laxatives, lithium, NSAIDs
Increased catabolism
-Steroids, tetracycline’s
Vascular occlusion
-Oestrogens/OCP
What are the 3 types of renal or intrinsic ARF?
- Acute tubular necrosis
- Acute interstitial nephritis
- Thrombotic micro angiography
What drugs can cause 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
When does the onset of 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.
How can the latency period vary in acute interstitial nephritis?
Latency period may be as short as 1 day with rifampicin, or as long as 18 months with an NSAID.
What drugs are implicated in acute interstitial nephritis?
- Penicillin’s
- Cephalosporin’s
- Cocaine
- Sulphonamides
- NSAIDs
- Diuretics
- Lithium
- Ranitidine
- Omeprazole
- Captopril
- Phenytoin
- Valproic acid
- Amphotericin B
- Streptokinase
- 5-aminosalicylates
- Allopurinol
- Rifampicin
- Chinese herbs
What can thrombotic microangiography cause?
Severe acute renal failure
What is the pathological hallmark of thrombotic microangiography?
Thrombi in the microvasculature of many organs
What changes occur in the kidney with thrombotic microangiography?
Afferent arteriolar and glomerular thrombosis
What drugs can cause thrombotic microangiography?
- Cyclosporin, tacrolimus
- Chemotherapeutic agents mitomycin C bleomycin, cisplatin
- Ticlopidine, clopidogrel
- 19 estrogen-containing oral contraceptives
- Quinine
- Cocaine
What sites can drug associated obstruction of urine outflow occur?
- 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 are 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 and marked by?
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria.
What drugs are implicated in nephrotic syndrome?
- Gold,
- NSAIDs,
- Penicillamine,
- Interferon,
- Captopril
What are the recognised adverse renal effects of nonselective NSAIDs include:
- Acute renal failure,
- Nephrotic syndrome,
- Hypertension,
- Hyperkalemia,
- Papillary necrosis
What is the epidemiology of AKI?
- 20% of hospital admissions due to AKI are drug related
- Most are community acquired
- AKI affects 7% of hospitalized patients, and 20-30% of critically ill patients,
What drugs are responsible for hospital acquired renal insufficiency?
- Aminoglycosides 18%
- NSAIDs 13%
- Piperacillin/tazobactam 7%
- Amphotericin B 6%
- Trimethoprim’s/sulfs 65
- Cyclosporine 3%
- ACEI 2%
- Multiple nephrotoxins (>3) 2%
- Ciprofloxacin, cis-platinum, acyclovir, ceftazidime 1%
What does the most common type of NSAID induced acute renal failure result from?
- 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 blood flow is already reduced
What type of reaction occurs in NSAID- induced acute allergic interstitial nephritis?
Idiosyncratic reaction
What drugs are particularly prone to NSAID induced acute allergic interstitial nephritis?
Propionic acid derivatives (ibuprofen, naproxen and fenoprofen)
What is NSAID-induced acute allergic interstitial nephritis associated with in 90% of cases?
Nephrotic syndrome
What is the mechanism of aminoglycoside induced renal injury?
Proximal tubular injury leading to cell necrosis
How can sepsis treatment lead to nephrotoxicity?
Aminoglycoside antibiotics, used in severe gram-negative sepsis, cause nephrotoxicity in 10% to 20% of therapeutic courses.
What is the most common renal damage due to drugs?
Acute renal failure due to ATN is the most common and is due to aminoglycosides
