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year 2 renal > Clinical Pharmacology in Renal Disease > Flashcards

Clinical Pharmacology in Renal Disease Flashcards

1
Q

How does renal disease affect clinical pharmacology?

A

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

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2
Q

In renal disease, if the drug or its metabolites have a narrow therapeutic index, what happens?

A

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
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3
Q

Renal function may have a dramatic influence on the ______________ or ________________ of the drugs we use

A

pharmacokinetics

pharmacodynamics

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4
Q

why do we worry about renal disease?

A

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

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5
Q

Drug-induced nephrotoxicity is common in who?

A

Infants, young children and the elderly

Patients with underlying renal dysfunction or cardiovascular disease

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6
Q

What things can drugs cause to the kidneys?

A

Drugs can cause acute renal injury, intra-renal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders

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7
Q

what is the mechanisms of renal excresion?

A

Glomerular filtration

Passive tubular reabsorption

Active tubular secretion

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8
Q
  • 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?

A

drug pharmaokinetics and pharmacodynamics

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9
Q

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

A

filtered

glomerulus

half-life

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10
Q

Prolongation of half-life means what?

A

care when using drugs with a low therapeutic index in the presence of renal impairment

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11
Q

Half-life with Impaired Renal Function

A
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12
Q

what are the pharmacokinetic effects of impaired renal function?

A
  • 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
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13
Q

what are the Pharmacodynamic Effects of impaired renal function?

A

• 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
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14
Q

what ar ethe toxic effect of drugs in someone with impaired renal function?

A

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
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15
Q

Renal Impairment may lead to what?

A

• 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

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16
Q

What Should We Do?

A

•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

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17
Q

Impaired Renal Function and Prescribing?

What should you consider?

A

Risk/benefit ratio

Severity of possible side effects

Severity of toxicity

the availability of TDM

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18
Q

Impaired Renal Function and Prescribing?

what should you do?

A

reduce the dose of drug

change the dosing frequency

change the drugs

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19
Q

Ideally if a patient suffers from renal impairment we should use drugs which……

A

have a high therapeutic index and

are metabolised by the liver with the production of non-toxic metabolites

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20
Q

can drugs caused induced renal disease?

A
  • 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
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21
Q

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

A

kidney

kidneys

drug-induced

concentrated

concentration

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22
Q

Renal damage causes significant morbidity and mortality such as what?

A

Acute Kidney Injury

Acute Tubular Necrosis

Chronic Kidney Disease

Inflammatory Disorders

23
Q

does renal damage cause more expense?

A

Increasing healthcare expense - Both to individual and nation

24
Q

Drug induced renal damage is usually __________

A

preventable

25
Q

Renal involvement commonly takes what following forms?

A

• Salt and water abnormalities:

  • Dehydration
  • Oedema

• Acute renal failure:

  • Acute tubular necrosis
  • Acute interstitial nephritis

• Chronic renal failure

26
Q

DO many drugs cause renal disease?

A
  • Many of the drugs we routinely use can cause renal disease
  • Patients may die of be subjected to unnecessary and radical surgery
27
Q

what part of the urinary system can drugs effect?

A

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

28
Q

Drug induced renal toxicity can cause four major syndromes, what are they?

A

Acute renal failure

Nephrotic syndrome

Renal tubular dysfunction with potassium wasting

Chronic renal failure

29
Q

what is actue renal failure?

A

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

30
Q

Acute Renal Failure can occur in what locations?

A
  • Prerenal
  • Renal or Intrinsic
  • Post renal or Obstructive
31
Q

what are examples of pre-renal Drug Induced Renal Disease?

A

Water and electrolyte abnormalities - diuretics, laxatives, lithium, NSAIDs

Increased catabolism - Steroids, tertracyclines

Vascular occlusion - Oestrogens/ OCP

32
Q

What are three types of intrinsic acute renal failure?

A
  • Acute tubular necrosis (ATN)
  • Acute interstitial nephritis
  • Thrombotic microangiopathy
33
Q

what causes Acute Tubular Necrosis?

A
  • 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
34
Q

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)

A

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

35
Q

Drugs implicated for Acute Interstitial Nephritis include

A

• 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

36
Q

Thrombotic microangiopathy can cause what?

(a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury)

A
  • 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

37
Q

Thrombotic Microangiopathy may be caused by what?

A
  • cyclosporin, tacrolimus
  • chemotherapeutic agents mitomycin C bleomycin, cisplatin
  • ticlopidine, clopidogrel
  • 19 estrogen-containing oral contraceptives
  • quinine
  • cocaine
38
Q

Post Renal or Obstructive Uropathy can occur in what places?

A
  • 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
39
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
40
Q

what is nephrotic syndrome?

A

The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria

41
Q

Drugs implicated in nephrotic syndrome include what?

A

gold

NSAIDs

penicillamine

interferon

captopril

42
Q

what are some NSAID-induced renal syndromes?

A
  • The recognized adverse renal effects of nonselective NSAIDs include
  • acute renal failure,
  • nephrotic syndrome,
  • hypertension,
  • hyperkalemia,
  • papillary necrosis
43
Q

Mechanisms of Nephrotoxicity

A
44
Q

What is the epidemiology?

A
  • 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,
45
Q

Table showing Drugs Responsible for Hospital Acquired Renal Insufficiency

A
46
Q

The most common type of NSAID-induced acute renal failure results from what?

A

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

47
Q

Associated with _________ syndrome in about 90% of cases

A

nephrotic

48
Q

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.
A

nephrotoxicity

proximal

49
Q

summary:

Drugs frequently induce renal disease cauisng what effects?

A

Assymptomatic increase in urea and creatinine

Fluid and electrolyte abnormalities

Acute tubular necrosis

Acute and chronic interstitial nephritis

50
Q

Acute renal failure due to ___ is the most common and is due to aminoglycosides

A

ATN

51
Q

Avoid nephrotoxic drugs in what patients?

A

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
52
Q

how does hypertension relate to renal disease?

A

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.

53
Q

how can we tackle the problem of drugs causing renal disease?

A

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.

54
Q
  • ACEIs are commonly recommended however they can produce severe ____ _____ __________.
  • Direct _________ can produce profound hypotension and salt and water retention
  • _________________ diuretics may precipitate gout
A

acute renal dysfunction

vasodilators

Thiazides/thiazide-type

year 2 renal (26 decks)

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