5) Prescribing renal impairment

Question 1

What is glomerular filtration rate (GFR) and how is it measured?

Answer 1

GFR is the volume of filtrate produced by the glomeruli each minute. It is best measured using a 24-hour urine collection with inulin as the filtration marker. Normal GFR is approximately 90-120 mL/min.

Question 2

What are the main methods used to estimate renal function?

Answer 2

1. eGFR (estimated Glomerular Filtration Rate): Uses MDRD or CKD-EPI equations, normalized to 1.73m² body surface area.
2. Creatinine Clearance (CrCl): Uses Cockcroft-Gault equation to estimate renal clearance.
3. Serum Creatinine (Cr): A simple blood test that can be influenced by muscle mass and diet.
4. Albumin:Creatinine Ratio (ACR): Used to detect proteinuria, an important marker of kidney disease.

Question 3

What are the limitations of eGFR in renal function estimation?

Answer 3

eGFR is less accurate in extremes of body weight, elderly patients, and certain ethnic groups. It should not be used for dosing drugs with a narrow therapeutic index.

Question 4

When should CrCl be used instead of eGFR for drug dosing?

Answer 4

CrCl is preferred for dosing direct-acting oral anticoagulants (DOACs) and drugs with a narrow therapeutic index like aminoglycosides and digoxin. It is also recommended in chemotherapy dosing and for patients with fluctuating renal function.

Question 5

How does renal impairment affect creatinine levels?

Answer 5

Serum creatinine increases as kidney function declines. However, in elderly, frail, or low muscle mass patients, creatinine levels may underestimate kidney impairment, leading to an overestimation of renal function.

Question 6

What is Acute Kidney Injury (AKI) and its causes?

Answer 6

AKI is a sudden decline in renal function over hours or days, leading to fluid, electrolyte, and acid-base imbalances.
Causes include:
- Pre-renal: Hypovolemia, dehydration, hypotension.
- Intra-renal: Nephrotoxic drugs, acute tubular necrosis, glomerulonephritis.
- Post-renal: Obstruction due to kidney stones, enlarged prostate, or tumors.

Question 7

What is Chronic Kidney Disease (CKD)?

Answer 7

CKD is defined as persistent kidney damage for over 3 months with health consequences. It can progress to end-stage renal disease (ESRD). Common causes include hypertension, diabetes, and glomerulonephritis.

Question 8

What are the consequences of renal impairment? (6)

Answer 8

Renal impairment can cause:
- Hypertension (due to fluid overload and renin-angiotensin system activation)
- Anaemia (due to reduced erythropoietin production)
- Metabolic acidosis (impaired acid excretion)
- Hyperkalaemia (reduced potassium excretion)
- Fluid retention (leading to oedema and heart failure)
- Drug toxicity (due to reduced renal clearance).

Question 9

How does renal impairment affect drug pharmacokinetics?

Answer 9

1. Absorption:
2. Distribution:
3. Metabolism:
4. Excretion:

Question 10

Which drugs require dose adjustment or caution in renal impairment?

Answer 10

1. Drugs accumulating due to reduced clearance: Aminoglycosides, Digoxin, Lithium, Vancomycin.
2. Drugs with increased sensitivity despite normal elimination: Morphine, Insulin, Warfarin.
3. Drugs poorly tolerated in renal impairment: NSAIDs, ACE inhibitors, ARBs, Diuretics.
4. Drugs losing efficacy in renal impairment: Thiazide diuretics, Nitrofurantoin, SGLT2 inhibitors (dapagliflozin).

Question 11

What are the general prescribing principles in renal impairment?

Answer 11

1. Assess renal function (eGFR, CrCl) before prescribing.
2. Adjust drug doses based on renal clearance.
3. Avoid nephrotoxic drugs where possible.
4. Monitor drug levels for toxicity (e.g., aminoglycosides, digoxin).
5. Consider pharmacokinetic changes (altered metabolism and clearance).
6. Monitor for adverse effects (e.g., hyperkalaemia, fluid overload).
7. Use alternative medications when possible (e.g., acetaminophen instead of NSAIDs).

Question 12

What are Medication Sick Day Guidelines for renal impairment?

Answer 12

Certain medications should be temporarily stopped during acute illness to prevent worsening renal function:
- NSAIDs: Can precipitate acute kidney injury (AKI).
- Diuretics: May cause dehydration and hypotension.
- ACE inhibitors & ARBs: Can worsen kidney function in dehydration.
- Metformin: Risk of lactic acidosis in renal dysfunction.
- SGLT2 inhibitors: Can increase dehydration risk.

Question 13

How should drugs be adjusted in dialysis patients?

Answer 13

1. Drugs significantly removed by dialysis may require post-dialysis dosing (e.g., aminoglycosides, vancomycin).
2. Drugs poorly removed by dialysis may require lower doses to prevent toxicity (e.g., digoxin, lithium).
3. Dialysis can alter protein binding and drug metabolism, requiring careful monitoring and dose adjustments.

Question 14

What role do pharmacists play in prescribing for renal impairment?

Answer 14

Pharmacists play a key role in:
- Identifying nephrotoxic drugs and recommending alternatives.
- Adjusting doses based on renal function.
- Monitoring drug accumulation and toxicity.
- Providing education to healthcare providers and patients on safe prescribing.

Question 15

What considerations should be made when prescribing anticoagulants in renal impairment?

Answer 15

1. Warfarin: Generally preferred as it is not renally excreted.
2. DOACs (e.g., apixaban, rivaroxaban): Require dose adjustment based on CrCl.
3. Heparins: Unfractionated heparin is preferred over low-molecular-weight heparin in severe renal impairment.
4. Monitoring is crucial to prevent bleeding complications.

Question 16

Why is dose adjustment necessary for renally excreted antibiotics?

Answer 16

Many antibiotics are cleared by the kidneys, requiring dose reductions to prevent toxicity. Examples include:
- Aminoglycosides: Require therapeutic drug monitoring.
- Beta-lactams: Require extended dosing intervals in renal impairment.
- Vancomycin: Requires close monitoring to avoid nephrotoxicity.

Question 17

What are the key challenges in managing drug therapy in renal impairment?

Answer 17

1. Drug accumulation and toxicity.
2. Variability in renal function estimates (eGFR vs CrCl).
3. Altered drug metabolism and protein binding.
4. Limited data on drug use in severe renal disease.
5. Need for individualized dose adjustments and monitoring.

Question 18

What is the primary function of the kidneys?

Answer 18

The kidneys maintain homeostasis by regulating fluid balance, electrolyte levels, acid-base balance, and removing waste products through urine production.

Question 19

How does kidney disease affect drug elimination?

Answer 19

In kidney disease, drug clearance is reduced due to impaired filtration, secretion, or reabsorption, leading to drug accumulation and increased toxicity risks.

Question 20

Why is renal function assessment important in drug dosing?

Answer 20

Renal function determines the ability to clear drugs. Dosing adjustments are required for renally excreted drugs to avoid toxicity and ensure therapeutic efficacy.

Question 21

What are common nephrotoxic drugs that should be avoided or used with caution?

Answer 21

1. NSAIDs: Can cause acute kidney injury by reducing renal perfusion.
2. Aminoglycosides: Can cause nephrotoxicity and require therapeutic drug monitoring.
3. Contrast media: Used in imaging, can induce contrast-induced nephropathy.
4. ACE inhibitors & ARBs: May worsen renal function in some patients.

Question 22

What is the Cockcroft-Gault equation and how is it used?

Answer 22

The Cockcroft-Gault equation estimates creatinine clearance (CrCl) to assess renal function:
CrCl = (140 - Age) × Weight × Constant / Serum Creatinine
Constant = 1.23 for men, 1.04 for women.
It is commonly used for drug dosing adjustments in renal impairment.

Question 23

Why is creatinine clearance (CrCl) preferred over eGFR for certain drugs?

Answer 23

CrCl provides a better estimation of actual renal drug clearance, especially for drugs with a narrow therapeutic index like digoxin, aminoglycosides, and DOACs.

Question 24

What are the stages of chronic kidney disease (CKD)?

Answer 24

CKD is classified into five stages based on eGFR:
- Stage 1: eGFR ≥90 (normal but with kidney damage)
- Stage 2: eGFR 60-89 (mild reduction)
- Stage 3a: eGFR 45-59 (moderate)
- Stage 3b: eGFR 30-44 (moderate-severe)
- Stage 4: eGFR 15-29 (severe)
- Stage 5: eGFR <15 (end-stage renal disease, requiring dialysis or transplant).

Question 25

How does renal impairment affect drug half-life?

Answer 25

In renal impairment, drug elimination is slower, prolonging drug half-life and increasing drug accumulation, necessitating dose adjustments.

Question 26

Why should metformin be used cautiously in renal impairment?

Answer 26

Metformin carries a risk of **lactic acidosis** in renal impairment, especially when eGFR falls below 30 mL/min. It should be used with caution and monitored closely.

Question 27

What is the impact of reduced albumin levels in renal impairment?

Answer 27

Low albumin levels reduce protein binding of drugs, increasing the free (active) drug concentration and enhancing drug effects, leading to potential toxicity.

Question 28

Which diuretics are preferred in renal impairment?

Answer 28

- **Loop diuretics (e.g., furosemide, bumetanide)** are effective in CKD as they work at the loop of Henle. - **Thiazide diuretics (e.g., hydrochlorothiazide, bendroflumethiazide)** lose effectiveness in severe renal impairment (eGFR <30 mL/min).

Question 29

Why are SGLT2 inhibitors (e.g., dapagliflozin) ineffective in advanced CKD?

Answer 29

SGLT2 inhibitors work by blocking glucose reabsorption in the proximal tubule, but in CKD, their efficacy declines as less glucose is filtered through the glomeruli.

Question 30

Why should nitrofurantoin be avoided in renal impairment?

Answer 30

Nitrofurantoin requires adequate renal function (eGFR >45 mL/min) to reach therapeutic urinary concentrations. It is ineffective and may accumulate in renal failure.

Question 31

What are the indications for renal replacement therapy (RRT)?

Answer 31

Dialysis is indicated in: - Severe fluid overload unresponsive to diuretics. - Life-threatening hyperkalaemia. - Severe metabolic acidosis. - Uraemic complications (encephalopathy, pericarditis).

Question 32

How does dialysis affect drug clearance?

Answer 32

- **Highly water-soluble, low-protein-bound drugs** (e.g., aminoglycosides, lithium) are efficiently removed by dialysis. - **Lipid-soluble, highly protein-bound drugs** (e.g., digoxin, warfarin) are poorly removed and may require dose adjustments.

Question 33

How does hypoalbuminemia affect drug dosing?

Answer 33

Low albumin levels in CKD reduce protein binding of highly protein-bound drugs (e.g., phenytoin, warfarin), increasing free drug levels and toxicity risk.

Question 34

Why do patients with CKD have an increased risk of bleeding?

Answer 34

CKD leads to platelet dysfunction, increasing the risk of bleeding, which can complicate anticoagulation therapy.

Question 35

What monitoring parameters should be considered when prescribing in renal impairment?

Answer 35

Key monitoring includes: - Renal function tests (eGFR, CrCl, serum creatinine). - Electrolytes (potassium, sodium, calcium, phosphate). - Drug levels for narrow therapeutic index drugs (e.g., digoxin, vancomycin). - Fluid status and blood pressure.

Question 36

Why are elderly patients at higher risk of drug toxicity in renal impairment?

Answer 36

Elderly patients have **reduced renal clearance**, lower muscle mass (affecting creatinine-based renal function estimates), and increased drug sensitivity, leading to higher toxicity risks.

Question 37

What are common signs of drug toxicity in renal impairment?

Answer 37

- **Digoxin toxicity**: Nausea, confusion, arrhythmias. - **Aminoglycoside toxicity**: Ototoxicity, nephrotoxicity. - **Lithium toxicity**: Tremors, ataxia, nephrogenic diabetes insipidus. - **NSAID toxicity**: Acute kidney injury, gastrointestinal bleeding.

Question 38

How does fluid overload impact drug therapy in CKD?

Answer 38

Fluid overload can **increase the volume of distribution (Vd) of hydrophilic drugs**, diluting plasma drug concentrations and reducing drug efficacy.

Question 39

What is the difference between haemodialysis and peritoneal dialysis in terms of drug clearance?

Answer 39

- **Haemodialysis**: More effective at removing small, water-soluble drugs (e.g., aminoglycosides). - **Peritoneal dialysis**: Less efficient at drug removal, requiring different dosing strategies.

Question 40

What factors influence drug dialyzability?

Answer 40

Drug removal by dialysis depends on: - **Molecular weight**: Small molecules (e.g., aminoglycosides) are more readily removed. - **Protein binding**: Highly protein-bound drugs (e.g., warfarin) are poorly removed. - **Water solubility**: Hydrophilic drugs (e.g., lithium) are more easily cleared.

Question 41

What are the key roles of the kidneys in drug handling?

Answer 41

The kidneys regulate fluid and electrolyte balance, eliminate metabolic waste and drugs, produce hormones (e.g. erythropoietin, vitamin D activation), maintain acid-base balance, and regulate blood pressure.

Question 42

When is true GFR used and what is the gold standard method?

Answer 42

True GFR is rarely used in clinical practice due to complexity. The gold standard is inulin clearance.

Question 43

Why is serum creatinine not always a reliable marker of renal function?

Answer 43

SCr can be misleading: low in elderly or those with muscle wasting (overestimation), and high in muscular individuals (underestimation).

Question 44

What are the diagnostic criteria for acute kidney injury (AKI)?

Answer 44

AKI is diagnosed by a rise in SCr ≥26 µmol/L in 48h, or ≥50% over 7 days, or urine output <0.5 mL/kg/h for >6h.

Question 45

Which pharmacokinetic processes are altered in renal impairment?

Answer 45

Distribution (↑ Vd in fluid overload), metabolism (↓ metabolism of prodrugs), and excretion (↓ renal clearance, ↑ drug half-life).

Question 46

What principles guide safe prescribing in renal impairment?

Answer 46

Assess renal function, adjust doses using references, avoid nephrotoxins, monitor levels, apply sick day rules, and review therapy post-AKI.

Question 47

Why should aminoglycosides be avoided in dialysis patients if alternatives exist?

Answer 47

They are nephrotoxic, accumulate in renal impairment, and require TDM. Safer alternatives like cefalexin are preferred.

Question 48

What is the general approach to dose adjustment in acute kidney injury (AKI)?

Answer 48

In AKI, avoid premature dose reductions in the first 48 hours unless the drug is nephrotoxic or has a narrow therapeutic window. Monitor renal function closely.

Question 49

What is the approach to loading and maintenance doses in chronic kidney disease (CKD)?

Answer 49

Use a normal loading dose if required to achieve therapeutic levels, then reduce the maintenance dose or increase the dosing interval to prevent accumulation.

Question 50

How are dosing decisions made for patients on dialysis?

Answer 50

Adjust doses based on drug dialysability, protein binding, volume of distribution, and timing of dialysis sessions. Use resources like the UK Renal Drug Database.

Question 51

What types of drugs commonly require therapeutic drug monitoring (TDM) in renal impairment?

Answer 51

Drugs with a narrow therapeutic index such as vancomycin, aminoglycosides (e.g. gentamicin), and digoxin require TDM to avoid toxicity.

Question 52

What are 'medication sick day rules' and how do they help in renal impairment?

Answer 52

Patients should stop ACE inhibitors, ARBs, NSAIDs, and diuretics during acute illness (vomiting, diarrhoea, fever) to reduce the risk of AKI.

Question 53

How is Absorption affected in renal impairment and what is the significance?

Answer 53

Often unchanged, though delayed in some cases due to delayed gastric emptying. Usually not clinically significant

Question 54

How is distribution affected in renal impairment and what is the significance?

Answer 54

Changes in plasma protein binding may occur Fluid retention could increased Vd for hydrophilic drugs. Potentially significant e.g. phenytoin

Question 55

How is metabolism affected in renal impairment and what is the significance?

Answer 55

Change the activity of drug-metabolising enzymes in the liver. Potentially significant e.g. morphine is metabolised to morphine-6-glucuronide which can accumulate in renal impairment

Question 56

How is excretion affected in renal impairment and what is the significance?

Answer 56

Decreased renal clearance (primary effect).- A reduced glomerular filtration rate (GFR) leads to prolonged half-life of renally excreted drugs. Highly significant e.g. vancomycin and digoxin