Clinical pharmacology

Question 1

What might build up in the blood as a result of impaired renal function?

Answer 1

Active drug

Toxic or active metabolites

Question 2

Which well known drug has a high therapeutic index and low toxicity?

Answer 2

Benzylpenicillin

Question 3

Which well known drugs have a narrow therapeutic index and have the potential to cause toxicity and/or death?

Answer 3

Gentamicin - may cause renal or ototoxicity (ear)

Digoxin - risk of arrhythmias, nausea or death

Lithium - risk of renal toxicity and death

Tacrolimus - risk of renal and CNS toxicity

Question 4

What factors create worry in regards to patients in hospital?

Answer 4

They are often:
Sick
Volume depleted
Hypotensive
Prescribed a large number of potentially renotoxic agents

All factors interact to bring on renal impairment or worsen pre existing renal impairment / toxicity

Question 5

What damage can drugs cause to the urinary system?

Answer 5

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

Question 6

List some changes in renal excretion that will automatically change drug pharmacokinetics or pharmacodynamics

Answer 6

Changes in passive tubular reabsorption or active tubular secretion (due to disease age or drug therapy)

Question 7

Where are all drugs and their metabolites filtered?

Answer 7

At the glomerulus

Question 8

If renal impairment means prolongation of half life what care must be taken

Answer 8

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

Question 9

In a patient with reduced GFR what must you do? (3)

Answer 9

REDUCE DOSAGE

Increase dose interval

TDM Monitor blood levels for toxic drugs like gentamicin, lithium, digoxin, vancomycin

Question 10

How does renal disease alter the actions of drugs on the brain?

Answer 10

The BBB becomes permeable and the brain becomes more sensitive to tranquillisers, sedatives and opiates

Question 11

If a patient’s circulatory volume is decreased, which agents may they be more sensitive to?

Answer 11

Antihypertensive agents like ACE inhibitors or alpha-blockers

Question 12

What are some dramatic changes in pharmacokinetics that can be caused by renal impairment

Answer 12

Increased t1/2 (half life)

Build up of drug or metabolites

Decrease in protein binding. So more free drug available

Question 13

What are some alterations in pharmacodynamics that can be caused by renal impairment

Answer 13

Increased sensitivity to pharmacological action

Increased sensitivity to toxicity and ADRs

Increased sensitivity to the toxic effects of combined therapy - synergism

Question 14

What is therapeutic index?

Answer 14

The Therapeutic Index is used to compare the therapeutically effective dose to the toxic dose of a drug.

The larger the therapeutic index (TI), the safer the drug is.

Question 15

Look

Answer 15

We need to know:

The drugs which may be used safely when eGFR ↓
and which drugs have a narrow therapeutic index

We need to 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

Question 16

Look

Answer 16

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

Question 17

How can drug induced renal disease come about?

Answer 17

Any drug in the blood will eventually reach the kidneys.

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

But drug induced renal damage is usually preventable

Question 18

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

Answer 18

Acute renal failure

Nephrotic syndrome

Renal tubular dysfunction
with potassium wasting

Chronic renal failure

Question 19

Acute renal failure

Answer 19

A sudden deterioration in renal function which results in a rapid rise in creatinine

Often elderly patients who are sick, have a poor fluid intake, who are on multiple medications and who are not being monitored aggressively.

Question 20

Classification of acute renal failure

Answer 20

Pre-renal - prevents bloodflow to the kidneys - reduced GFR

Renal or intrinsic - affecting kidney itself

Post-renal or obstructive - urinary flow obsturction etc

Question 21

Pre-renal drug induced renal disease

Answer 21

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

Increased catabolism - Steroids, tertracyclines

Vascular occlusion - Oestrogens/ OCP

Question 22

What are the 3 types of intrinsic acute renal failure?

Answer 22

Acute tubular necrosis

Acute interstitial nephritis

Thrombotic microangiopathy

Question 23

Which drugs can cause acute tubular necrosis?

Answer 23

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

Question 24

Which drugs can cause acute interstitial nephritis

Answer 24

Penicillins

Cephalosporins

Cocaine

NSAIDs

Chinese herbs

Question 25

What can thrombotic microangiopathy cause?

Answer 25

Severe acute renal failure

Pathologic hallmark is thrombi in the microvasculature of many organs

Changes in the kidney include afferent arteriolar and glomerular thrombosis

Question 26

Main drugs causing thrombotic microangiopathy?

Answer 26

19 estrogen-containing oral contraceptives

Cocaine

Question 27

Which agent can cause damage due to retroperitoneal fibrosis of the ureters? (ie outside the ureters)

Answer 27

Methysergide

Question 28

Drugs implicated in crystal formation

Answer 28

Acyclovir, indinavir

Sulfonamides

Methotrexate

Question 29

Main drug causing nephrotic syndrome

Answer 29

NSAIDs

Question 30

NSAID-induced renal syndromes

Answer 30

Acute renal failure,

Nephrotic syndrome,

Hypertension,

Hyperkalemia,

Papillary necrosis

Question 31

What is the most common type of NSAID-induced acute renal failure?

Answer 31

Decreased synthesis of renal vasodilator prostaglandins - leads to reduced renal blood flow and reduced glomerular filtration

Question 32

NSAID-induced acute allergic interstitial nephritis

Answer 32

Idiosyncratic reaction

Particularly to the propionic acid derivatives (ibuprofen, naproxen, and fenoprofen),

Associated with nephrotic syndrome in about 90% of cases

Question 33

Aminoglycoside-induced renal injury

Answer 33

Aminoglycoside antibiotics, used in severe gram-negative sepsis, cause nephrotoxicity in 10% to 20% of therapeutic courses.

Mechanism is proximal tubular injury leading to cell necrosis.

Question 34

Summary

Answer 34

Drugs frequently induce renal disease:
Asymptomatic increase in urea and creatinine
Fluid and electrolyte abnormalities
Acute tubular necrosis - death of tubular cells
Acute and chronic interstitial nephritis

Acute renal failure due to Acute tubular necrosis is the most common and is due to aminoglycosides.

Avoid nephrotoxic drugs in 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

Question 35

How do we avoid problems with patients that have hypertension and renal disease

Answer 35

Use drugs which are totally metabolised by the liver or elsewhere in the body e.g ACEIs

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 acute renal dysfunction.

Direct vasodilators can produce profound hypotension and salt and water retention

Thiazides/thiazide-type diuretics may precipitate gout