22-02-23 – Drugs and the Kidney

Question 1

learning outcomes

Answer 1

• Understand use and mechanism of action of common drugs acting on the kidney
• Describe the syndrome of inappropriate ADH secretion and its management
• Understand how erythropoietin analogues can help anaemia of renal disease
• List common nephrotoxic drugs
• Describe principles of prescribing in renal impairment

Question 2

What are 4 different parts of the kidney tubule?

Answer 2

• 4 different parts of the kidney tubule:
  1) PCT = Proximal convoluted tubule
  2) TAL = Thick ascending loop
  3) DT = Distal tubule
  4) CT = Collecting tubule

Question 3

What are 2 examples of loop diuretics?

What are 4 steps in the the mechanism of action of loop diuretics?

Answer 3

• 2 examples of loop diuretics:
  1) Furosemide
  2) Bumetanide
• 4 steps in the MOA of loop diuretics:

1) Inhibits the Na+/K+/2Cl- co-transporter in the luminal membrane of the Thick Ascending Loop (TAL) of the loop of Henlé

2) This inhibits transport of NaCl out of the tubule into interstitial tissue

3) This reduces osmotic gradient in the medulla of the kidney, meaning less water recovered

4) Causes profound diuresis

Question 4

What are 3 indications of loop diuretics?

What are 5 side-effects of Loop diuretics?

Answer 4

• 3 indications of loop diuretics:
  1) Oedema (heart failure, pulmonary, ascites, nephrotic syndrome, renal failure)
  2) Resistant Oedema
  3) Resistant hypertension
• 5 side-effects of Loop diuretics:

1) Hypovolaemia, hypotension - dizziness

2) Electrolyte disturbances – low Na, K, Mg, Ca

3) May produce a metabolic alkalosis due to loss of hydrogen ions

4) Hyperuricaemia – exacerbates Gout

5) Renal impairment

Question 5

What are 2 examples of thiazide diuretics?

What are the 2 MOAs of thiazide diuretics?

Answer 5

• 2 examples of thiazide diuretics:
  1) Bendroflumethiazide
  2) Indapamide
• 2 MOAs of thiazide diuretics:

1) Inhibits the NaCl co-transporter in the Distal Tubule (DT), which results in Na/Cl reabsorbed and causes moderate diuresis, reducing oedema & BP

2) Direct relaxant effect on vascular smooth muscle (reduces BP)

Question 6

What are 4 indications of thiazide diuretics?

What are 9 side-effects of thiazide diuretics?

Answer 6

• 4 indications of thiazide diuretics:
  1) Hypertension
  2) Mild heart failure
  3) Severe resistant oedema (plus loop)
  4) Nephrogenic diabetes insipidus
• 9 side-effects of thiazide diuretics:
  1) Hypotension
  2) Hypovolaemia!
  3) Low K, Na, Mg
  4) Promotion of calcium retention / hypocalciuria
  5) Metabolic alkalosis
  6) Gout
  7) Erectile dysfunction
  8) Hyperglycaemia
  9) Hyperlipidaemia

Question 7

What are 2 examples of aldosterone antagonists (K+ sparing diuretics)?

What are 2 MOAs of aldosterone antagonists (K+ sparing diuretics)?

Answer 7

• 2 examples of aldosterone antagonists (K+ sparing diuretics):
  1) Spironolactone
  2) Eplerenone
• 2 MOAs of aldosterone antagonists (K+ sparing diuretics):

1) In Collecting Tubule (CT), antagonise aldosterone receptor

2) Mineralocorticoid receptor antagonists (MRAs)

Question 8

What are 3 indications of Aldosterone Antagonists?

What are 6 side-effects of aldosterone antagonists?

Answer 8

• 3 indications of Aldosterone Antagonists:
  1) Oedema (heart, liver, nephrotic syndrome)
  2) Hypertension
  3) Conn’s syndrome (primary hyperaldosteronism)
• 6 side-effects of aldosterone antagonists:
  1) Renal impairment
  2) Hyperkalaemia
  3) Hyponatraemia
  4) GI upset
  5) Metabolic acidosis
  6) Gynaecomastia with Spironolactone

Question 9

Why type of diuretics are triamterene and amiloride?

What is their MOA?

What are they usually combined with?

What are 2 indications of Triamterene and amiloride?

What are 4 side-effects of Triamterene and amiloride?

Answer 9

• Triamterene and amiloride are Potassium-sparing weak diuretics
• They act by directly blocking epithelial sodium channels in the Collecting Tubule (CT) so less sodium reabsorbed, causing diuresis
• They are usually synergistically combined with thiazide or loop diuretic
• 2 indications of Triamterene and amiloride:
  1) Oedema inc. ascites
  2) Hypertension
• 4 side-effects of Triamterene and amiloride:
  1) High potassium (careful if renal impairment)
  2) GI upset
  3) Metabolic acidosis
  4) Renal impairment

Question 10

What are 2 other types of diuretics used?

What is an example of each?

What is their MOA?

What are indications for each?

Answer 10

• 2 other types of diuretics used:

1) Osmotic diuretics
* e.g., mannitol intravenously
* MOA - Modify filtrate content increasing amount of water excreted
* Indications: cerebral oedema + raised intra-ocular pressure

2) Carbonic anhydrase inhibitors
* e.g. acetazolamide (very weak diuretic)
* MOA - Increase excretion of bicarbonate with accompanying Na +, K + and water, resulting in an increased flow of an alkaline urine and metabolic acidosis.
* Indications: glaucoma, altitude sickness

Question 11

Practise question 1

Answer 11

Question 12

Practise question 2

Answer 12

Question 13

Practise question 3

Answer 13

Question 14

What are 4 other types of drugs that act on the renal system?

What are they each used for?

Answer 14

• 4 other types of drugs that act on the renal system:

1) Vasopressin receptor agonists
* For diabetes insipidus (Desmopressin), oesophageal varices (Terlipressin)

2) Sodium-Glucose Co-Transporter- 2 (SGLT-2) Inhibitors
* for type 2 diabetes mellitus.
* E.g. Canagliflozin

3) Uricosuric drugs
* For gout
* e.g. sulphinpyrazone, rarely used these days

4) Drugs affecting pH of urine
* e.g. ascorbic acid (acidify), potassium citrate (alkalinise) for urine infection symptoms or kidney stone formation.
* Rarely done

Question 15

What is SIADH?

What are 4 signs of SIADH?

Answer 15

• SIADH is Syndrome of inappropriate ADH secretion
• It is excess Anti-Diuretic Hormone (ADH) secreted by posterior pituitary gland
• 4 signs of SIADH:
  1) Hyponatraemia (plasma osmolality)
  2) Low plasma osmolality
  3) Inappropriately elevated urine osmolality (>plasma osmolality)
  4) Euvolemia (normal amount of bodily fluids)

Question 16

What are 4 symptoms of mild SIADH?

What are 4 symptoms of moderate SIADH?

What are 3 symptoms of severe SIADH?

Answer 16

• 4 symptoms of mild SIADH:
  1) Nausea
  2) Vomiting
  3) Headaches
  4) Anorexia
• 4 symptoms of moderate SIADH:
  1) Muscle cramps
  2) Weakness
  3) Tremor
  4) Mental health disorders
• 3 symptoms of severe SIADH:
  1) Drowsiness
  2) Seizures
  3) Coma

Question 17

What are 5 different types of causes of SIADH?

Answer 17

• 5 different types of causes of SIADH:

1) Neurological causes
* e.g. tumour, trauma, meningitis, SAH

2) Pulmonary causes
* E.g lung small cell carcinoma, pneumonia

3) Malignancy

4) Hypothyroidism

5) Drugs
* e.g. thiazide and loop diuretics, ACEIs, SSRIs and PPIs

Question 18

What are 4 steps in the treatment of SIADH?

What are 3 medications that can be used for SIADH?

Answer 18

• 4 steps in the treatment of SIADH:
  1) Correct underlying cause
  2) Monitor plasma osmolality
  3) Monitor serum sodium and bodyweight
  4) Fluid restrict (500-1000ml daily)
• 3 medications that can be used for SIADH:

1) Demeclocycline – antibiotic, also inhibits action of ADH on kidney

2) Tolvaptan – vasopressin (ADH) V2 antagonist in renal collecting ducts

3) Hypertonic sodium chloride in severe cases only

Question 19

What is Erythropoietin (EPO)?

What is the role of EPO?

Which condition will result in less EPO being produced?

Answer 19

• Erythropoietin (EPO) is a hormone produced by the kidney (peritubular interstitial cells)
• EPO promotes RBC formation in bone marrow
• Moderate-severe renal impairment kidneys produce less EPO, resulting in anaemia (when renal function gets down to 30%)

Question 20

What are ESAs?

What are 2 examples of ESAs?

How are they administered?

What are 5 advantages of using ESAs om renal disease?

What are symptoms of ESAs?

What must we avoid when using ESAs?

Answer 20

• ESAs are Erythropoietin Stimulating Agents
• 2 examples of ESAs:
  1) Epoetin Alfa
  2) Darbopoetin
• They are administered using the IV/SC route
• 5 advantages of using ESAs om renal disease:
  1) Reduce the need for blood transfusions
  2) Boost production of red blood cells
  3) Improve survival
  4) Reduce cardiovascular morbidity
  5) Enhance quality of life
• ESAs can produce flu-like symptoms
• When using ESAs, we must Avoid overcorrection/too rapid correction of haemoglobin – increases risk of hypertension and CV effects

Question 21

What are 10 common nephrotoxic drugs/drug types?

Answer 21

• 10 common nephrotoxic drugs/drug types:
  1) ACE inhibitors, Angiotensin II blockers
  2) NSAIDs e.g. ibuprofen
  3) Diuretics
  4) Lithium (for bipolar disorders)
  5) Digoxin
  6) Aminoglycosides e.g. Gentamicin
  7) Vancomycin
  8) Metformin (for T2DM)
  9) Iodinated contrast media
  10) Opioids e.g. Morphine

Question 22

What is Drug-induced AKI?

What are 2 pre-renal causes of Drug-induce AKI?

What indicates a potential AKI?

What are 2 pre-renal causes of drug-induce AKIs?

What is a intra-renal cause of drug-induced AKIs?

What is a post-renal cause of drug-induced AKIs?

What are examples of drugs that cause each type?

Answer 22

• Drug-induced AKI is drug-induced acute kidney injury
• It is a short-term, hopefully reversible, reduction in kidney function from the patient’s normal baseline
• A potential AKI can be detected when we measure the patients Us and Es and the creatinine level is rising
• 2 pre-renal causes of drug-induce AKIs:

1) Blood flow to kidney restricted = renal underperfusion e.g. NSAIDs

2) Excessive water and electrolyte loss e.g. diuretics

 Intra-renal cause of drug-induced AKIs:
* Tubular necrosis or interstitial nephritis or rhabdomyolysis
* e.g. Gentamicin, ciclosporin

• Post-renal cause of drug-induced AKIs?
• Obstruction of renal tract, or urine retention
• e.g. Anticholinergics (amitriptyline), opioids, chemotherapy

Question 23

What are 7 steps in the management of an AKI?

Answer 23

• 7 steps in the management of an AKI:

1) Treat any sepsis or uro obstruction

2) Aim for good fluid / electrolyte balance

3) Optimise B.P

4) With-hold/stop toxins

5) Review drug doses and side effect profile

6) Monitor U&E’s

7) Refer nephrology / urology if worsening

Question 24

What are 5 different causes of AKIs?

What are examples of causes of each?

Answer 24

• 5 different causes of AKIs:

1) Low BP
* E.g sepsis, D&V, poor oral intake

2) Low cardiac output
* E.g MI, heart Failure, arrythmia

3) Reduced blood volume
* E.g GI bleed, burns, intra-op losses

4) Post-renal obstruction
* E.g prostate, constipation, blocked catheter, blood clot

5) Intra-renal
* E.g. rhabdomyolysis, myeloma, vasculitis

Question 25

What are 5 effects of drugs in the presence of renal impairment?

Answer 25

• 5 effects of drugs in the presence of renal impairment:

1) Reduced renal excretion of a drug and its metabolites may cause toxicity

2) Sensitivity to some drugs is increased even if elimination is unimpaired

3) Increased risk of ADRs

4) Some drugs are not effective when renal function is reduced

5) Chronic Kidney Disease (CKD) increases risk of drug-induced kidney disorders

Question 26

What are 6 considerations when prescribing medications?

Answer 26

• 6 considerations when prescribing medications:

1) Degree of renal impairment?

2) Whether acute or chronic kidney disease

3) Proportion of drug renally excreted

4) Does drug have a narrow or wide therapeutic window?

5) Is drug potentially nephrotoxic?

6) Is this patient established on renal replacement therapy?

Question 27

How is chronic kidney disease (CKD) classified?

What is CKD an important risk factor for?

What are 3 aims of prescribing in CKD?

Answer 27

• Chronic kidney disease (CKD) is classified chronic kidney disease (CKD) classified?
• CKD is an Important risk factor for cardiovascular disease
• 3 aims of prescribing in CKD:

1) Prevent or reverse worsening

2) Review all meds, check doses appropriate

3) Manage concurrent conditions e.g. hypertension, sepsis, diabetes, heart failure, renal anaemia, bone disease, electrolyte and acid-base disturbances

Question 28

How can dialysis affect prescriptions of drugs?

What are 3 considerations when prescribing to patients on renal replacement therapy?

Answer 28

• Some drugs actively removed during dialysis – will affect dose and timing of drug
• 3 considerations when prescribing to patients on renal replacement therapy (RRT), such as dialysis:

1) Many variables – what kind of dialysis?

2) Is drug removed from circulation during dialysis?

3) What is dialyser membrane, blood and dialysate flow rate?

Question 29

What are 2 ways we can estimate renal function?

Answer 29

• We can estimate renal function using Creatinine clearance or eGFR depending on drug

Question 30

Creatinine Clearance (CrCl) using Cockroft and Gault (C&G)

Answer 30

• Creatinine Clearance (CrCl) using Cockroft and Gault (C&G)
• Need to know age, weight and serum creatinine
• CrCl= (140 – age) x weight (kg) x F serum creatinine (micromol/L)
• F= 1.04 for females, 1.23 for males
• In obese patients use ideal body weight (IBW)
• Don’t need to specifically remember this

Question 31

What are 2 pros of estimating CrCl from C&G?

What are 3 cons of estimating CrCl from C&G?

Answer 31

• 2 pros of estimating CrCl from C&G:
  1) Good validated formulae
  2) Advised for narrow therapeutic index drugs
• 3 cons of estimating CrCl from C&G:
  1) Inaccurate for rapidly changing creatinine levels and in severe renal disease
  2) Need to use IBW at extremes of body weight
  3) Adults only

Question 32

What are 4 factors that affect Estimated Glomerular Filtration Rate (eGFR)?

What races has eGFR been validated in?

Answer 32

• 4 factors that affect Estimated Glomerular Filtration Rate (eGFR):
  1) Creatinine
  2) Age
  3) Sex
  4) Ethnicity
• eGFR has only been validated in adults of Caucasian and African Caribbean origin

Question 33

What are 4 pros of Using eGFR to guide dosing?

What are 2 cons of Using eGFR to guide dosing?

Answer 33

• 4 pros of Using eGFR to guide dosing:

1) Easy reporting allows early detection of CKD

2) BNF offers a broad range for guidance on dosage based on eGFR

3) eGFR increasingly being used to alter drug dosing and evidence growly regarding accuracy

4) Good for majority of patients and drugs

• 2 cons of Using eGFR to guide dosing:

1) Not validated in some patient groups e.g. acute renal failure, pregnancy, oedematous states and malnourished, extremes of weight.

2) Not validated for drug dose calculations – risk of drug toxicity or therapeutic failure

Question 34

How does impaired renal function affect the half-life of gentamicin and digoxin?

How can renal impairment cause drug toxicity?

How can we prescribe to patients with renal impairment?

Answer 34

• Drug half-life (t1/2) normal renal function and t1/2 impaired renal function
• Gentamicin 2.5 hours and 50 hours
• Digoxin 36 hours and 120 hours
• In renal impairment, some renally excreted drugs stay in the body for longer and can accumulate, which can be toxic
• In prescribing to patients with renal impairment, use normal loading dose as per normal renal function to reach target therapeutic serum drug concentrations then reduce maintenance dose

Question 35

Drug dosing in renal impairment resources.

What BNF monographs results indicate rivaroxaban should not be prescribed to those with renal impairment?

Answer 35

• Drug dosing in renal impairment resources:
• BNF https://www.new.medicinescomplete.com
• SmPC http://www.medicines.org.uk/emc/
• Renal Drug Handbook (Specialist use only)

Question 36

What BNF monographs results indicate rivaroxaban should/should not be prescribed to those with renal impairment?

What are implications if anticoagulant dosing is too high/too low?

Answer 36

• BNF monographs results that indicate rivaroxaban should not be prescribed to those with renal impairment:
• Manufacturer advises use with caution if creatinine clearance 15– 29 mL/minute; avoid if creatinine clearance less than 15 mL/minute
• Implications if anticoagulant dosing is too high/too low:
• Too high a dose may have worse outcomes with respect to bleeding risk. * Too low a dose may result in an increase in embolic events and result in potentially preventable strokes.

Question 37

What are renal impairment dose adjustments for Ramipril based on BNF monograph results?

Answer 37

• Renal impairment dose adjustments for Ramipril based on BNF monograph results:
• Max daily dose 5 mg if eGFR 30–60 mL/minute/1.73 m2
• Max initial dose 1.25 mg once daily (do not exceed 5 mg daily) if eGFR less than 30 mL/minute/1.73 m2.

Question 38

What are 8 principles of prescribing in renal impairment?

Answer 38

• 8 principles of prescribing in renal impairment:

1) Check U’s and E’s, including eGFR and creatinine

2) Look at baseline and trends in renal function

3) Consider stopping or with-holding nephrotoxic drugs

4) Check resources

5) Choose non-nephrotoxic drug if possible

6) Reduce size of dose or increase dosing interval or stop or with-hold

7) Use therapeutic drug monitoring to guide dose / frequency if appropriate

8) Continue to monitor U&E’s, BP, and clinical response

Question 39

Practise question 1

Answer 39

Question 40

Practise question 2

Answer 40