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12. Year 2: Urinary System COPY > Clinical Pharmacology in Renal Disease *DIFFERENT* > Flashcards

Clinical Pharmacology in Renal Disease *DIFFERENT* Flashcards

1
Q

If renal function is impaired there is a rapid build up of what?

A
  • Active drug
  • Toxic or active metabolites
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2
Q

There is a buid up of drugs when renal function is impaired, when is this a problem?

A

When the drug has a low therapeutic index and high toxicity

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3
Q

What are examples of drugs with a low therapeutic index?

A
  • Gentamicin may cause renal or ototoxicity
  • Digoxin may cause arrhythmia, nausea or death
  • Lithium renal toxicity and death
  • Tacrolimus renal and CNS toxicity
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4
Q

What makes hospital patients particularly vulnerable to toxic effects of drugs when renal function is impaired?

A

This is a worry because patients in hospital are:

  • Sick
  • Volume depleted
  • Hypotensive
  • Prescribed a large number of potentially reno-toxic agents
  • The above factors interact to generate de novo renal impairment or worsen pre existing renal impairment
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5
Q

Who is drug induced nephrotoxicity common in?

A
  • Infants, young children and elderly
  • Patients with underlying renal dysfunction or cardiovascular disease
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6
Q

What diseases related to the kidneys can drugs cause?

A
  • Acute renal injury
  • Intra-renal obstruction
  • Interstitial nephritis
  • Nephrotic syndrome
  • Acid-base and fluid electrolytes disorders
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7
Q

What are the mechanisms of renal excretion of drugs?

A
  • Glomerular filtration
  • Passive tubular reabsorption
  • Active tubular secretion
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8
Q

Where are all drugs and metabolites filtered?

A

All drugs and metabolites are filtered at glomerulus

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9
Q

How does renal impairment impact the half life of drugs?

A

Renal impairment will prolong half-life of all drugs and their metabolites cleared by this route

Prolonged half-life means:

  • Care when using drugs with a low therapeutic index in the presence of renal impairment
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10
Q

What impact does renal impairment have on pharmacokinetics?

A
  • Reduction in GFR reduces clearance of drugs by kidney resulting in accumulation
  • Protein binding also reduced
    • More unbound drug
  • Net result is you must
    • Reduce dosage
    • Increase dose interval
    • TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin and vancomycin
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11
Q

What must you do to counter the effects of drugs on pharmcokinetics in renal impairment?

A
  • Reduce dosage
  • Increase dose interval
  • TDM monitor blood levels for toxic drugs like gentamicin, lithium, digoxin and vancomycin
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12
Q

What effect does renal impairment have on pharmacodynamics?

A
  • Renal disease alters action of drugs on tissues
    • BBB becomes permeable
    • Brain becomes more sensitive to tranquillisers, sedatives and opiates
    • Circulatory volume may be reduced making the patient sensitive to antihypertensive agents like ACEIs or a-blockers
    • May be increased tendency to bleed so beware of warfarin or NSAIDs
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13
Q

In patients with renal disease are direct nephrotoxic actions of drugs synergistic or antagonitic?

A

In patients with renal disease direct nephrotoxic actions of drugs are synergistic:

  • Gentamicin toxicity may be unmasked when used in conjunction with furosemide or lithium
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14
Q

What can renal impairment lead to in relation to drugs?

A
  • Dramatic alterations in pharmacokinetics
    • Increased half life
    • 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
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15
Q

What alterations occur in pharmacokinetics due to renal impairment?

A
  • Increased half life
  • Build up of drug or metabolites
  • Decrease in protein binding, so more free drug available
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16
Q

What alterations occur in pharmacodynamics due to renal impairment?

A
  • Increased sensitivity to pharmacological action
  • Increased sensitivity to toxicity and ADRs
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17
Q

What can we do to support people with renal impairment to safely use drugs?

A

Need to know drugs:

  • Drugs which may be used safely with lowered GFR
  • And which drugs have a narrow therapeutic index

Realise importance of:

  • Reducing loading dose and maintenance dose
  • And increasing the dosing interval
  • TDM and monitoring renal function and blood pressure during course of treatment

Impaired renal function and prescribing:

  • Consider
    • Risk/benefit ratio
    • Severity of possible side effects
    • Severity of toxicity
    • Availability of TDM
  • Do
    • Reduce the dose of drug
    • Change the dosing frequency
    • Change the drugs
      • If a patients 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
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18
Q

What should we consider when prescibing drugs to people with renal impairment?

A
  • Risk/benefit ratio
  • Severity of possible side effects
  • Severity of toxicity
  • Availability of TDM
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19
Q

What should we do when prescribing drugs to people when renal impairment?

A
  • Reduce the dose of drug
  • Change the dosing frequency
  • Change the drugs
    • If a patients 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
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20
Q

Why are the kidneys particularly vulnerable to drugs that cause renal damage?

A
  • Kidney is particularly vulnerable to drugs that cause renal damage
  • Any drug in the blood will eventually reach kidneys
  • May potentially cause drug-induced renal failure
  • If drug is primarily cleared by kidney, will become increasingly concentrated as it moves from the glomerulus and along the renal tubules
  • Concentrated drug exposes the kidney tissue to far greater drug concentration per surface area
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21
Q

Renal damage causes significant morbidity and mortality, what are examples?

A
  • Acute kidney injury
  • Acute tubular necrosis
  • Chronic kidney disease
  • Inflammatory disorders
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22
Q

What are common conditions caused by drugs on the renal system?

A
  • Salt and water abnormalities
    • Dehydration
    • Oedema
  • Acute renal failure
    • Acute tubular necrosis
    • Acute interstitial nephritis
  • Chronic renal failure
23
Q

What part of the urinary system can drugs affect?

A

Drugs can affect any part of the urinary system from the kidney to the bladder and genitalia

24
Q

Drug induced renal toxicity can cause 4 major syndromes, what are these?

A
  • Acute renal failure
  • Nephrotic syndrome
  • Renal tubular dysfunction with potassium wasting
  • Chronic renal failure
25
Q

What is acute renal failure?

A

Is a sudden deterioration in renal function which results in a rapid rise in creatinine:

  • Urine volume falls to <400ml/day in 40% of patients
26
Q

What are the different kinds of acute renal failure?

A
  • Prerenal
  • Renal or intrinsic
  • Post renal or obstructive
27
Q

What are examples of pre-renal drug induced disease?

A
  • Water and electrolyte abnormalities
    • Diuretics, laxatives, lithium, NSAIDs
  • Increased catabolism
    • Steroids, tertracyclines
  • Vascular occlusion
    • Oestrogens/OCP
28
Q

There are 3 types of intrinsic acute renal failure, what are these?

A

Acute tubular necrosis (ATN)

Acute interstitial nephritis

Thrombotic microangiopathy

29
Q

What does ATN stand for?

A

Acute tubular necrosis

30
Q

What is acute tubular necrosis caused by?

A
  • Aminoglycoside antibiotics
  • Amphotericin B
  • Cisplatin, radiocontrast agents
  • Statins given in combination with immunosuppressive agents such as cyclosprin
31
Q

What drugs are implicated with acute interstitial nephritis?

A
  • Penicillins, cephalosporins, cocaine, sulfonamides, NSAIDs diuretics, lithium, ranitidine, omeprazole, captopril, lithium, phenytoin, valproic acid, amphotericin B, streptokinase, 5-aminosalicylates, allopurinol, rifampin,
  • Chinese herbs
32
Q

What can thrombotic microangiopathy cause?

A
  • Severe acute renal failure
  • Pathologic hallmark is thombi in the microvascular of many organs
  • Changes in the kidney include afferent arteriolar and glomerular thrombosis
33
Q

What is thrombotic microangiopathy caused by?

A
  • cyclosporin, tacrolimus
  • chemotherapeutic agents mitomycin C bleomycin, cisplatin
  • ticlopidine, clopidogrel
  • 19 estrogen-containing oral contraceptives
  • quinine
  • cocaine
34
Q

What is the pathological hallmark of thrombotic microangiopathy?

A
  • Pathologic hallmark is thombi in the microvascular of many organs
35
Q

What is an example of post-renal or obstructive uropathy?

A
  • Drug associated obstruction of urine outflow can occur at several sites
    • Within the tubules or ureters (due to crystal formation)
    • Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
36
Q

What does obstruction within the tubules or ureters occur due to?

A

Cystal formation

37
Q

What does obstruction outside the ureters occur due to (in regards to drugs)?

A
  • Outside the ureters due to retroperitoneal fibrosis caused by agents such as methysergide
38
Q

What are some drugs implicated in crystal formation?

A
  • 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
39
Q

What is nephrotic syndrome due to?

A

­­Due to glomerular dysfunction

40
Q

What is nephrotic syndrome marked by?

A

Heavy proteinuria

41
Q

What are some drugs implicated in nephrotic syndrome?

A
  • Gold
  • NSAIDs
  • Penicillamine
  • Interferon
  • Captopril
42
Q

What are some recognised adverse renal effects of nonselective NSAIDs?

A
  • Acute renal failure
  • Nephrotic syndrome
  • Hypertension
  • Hyperkalaemia
  • Papillary necrosis
43
Q

What are some mechanisms of nephrotoxicity?

A

Nephrotic syndrome

Vasculitis

Acute pre-renal failure

Acute intersittial nephritis

Chronic intersttiial nephritis

Obstruction

Tubular necrosis

44
Q

What percentage of hospital appointments due to AKI are drug related?

A

20%

45
Q

What are some common drugs responsible for hospital acquired renal insufficiency?

A

1) Aminoglycosides
2) NSAIDs
3) Piperacillin

46
Q

What does the most common type of NSAID induced acute renal failure result from?

A

Decreased synthesis of renal vasodilator prostaglandins which can lead to reduced renal blood flow and reduced glomerular filtration

47
Q

What does NSAID induced acute allergic intersitial nephritis often occur due to?

A

Idiosyncratic reaction

Particular to the propionic acid derivatives (ibuprofen, naproxen, fenoprofen)

Associated with nephrotic syndrome in about 90% of cases

48
Q

What are aminoglycoside antibiotics used for?

A

Aminoglycoside antibiotics are used in severe gram negative sepsis, cause nephrotoxicity in 10-20% of therapeutic course

Mechanism is proximal tubular injury leading to cell necrosis

49
Q

What is the mechanism of aminoglycosides causing renal injury?

A

Mechanism is proximal tubular injury leading to cell necrosis

50
Q

What renal failure is most common due to drugs?

A

Acute tubular necorosis

51
Q

What is acute tubular necrosis usually due to?

A

Aminoglycosides

52
Q

Who should nephrotoxic drugs be avoided in?

A
  • Volume depleted or hypotensive patients with pre-existing renal disease
  • Patients receiving other nephrotoxic agents
53
Q

Why is it a problem patients being hypertensive and also having renal disease in terms of drugs?

A
  • Hypertension causes renal damage
  • Renal damage causes hypertension
  • Normally used thiazide type diuretics, CCBs, ACEIs
  • However patients with renal impairment have a low GFR, hyperuricaemia
  • More sensitive to the hypotensive actions of antihypertensive agents
  • Tackle this problem in two ways
    • Use drugs which are totally metabolised by the liver or elsewhere in the body
      • ACEIs
    • Use reduced dose of drug with longer dosing periods
54
Q

How do you tackle the problem of patients being hypertensive and also having renal damage?

A
  • Use drugs which are totally metabolised by the liver or elsewhere in the body
    • ACEIs
  • Use reduced dose of drug with longer dosing periods

12. Year 2: Urinary System COPY (30 decks)

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