Drugs and the Kidney Flashcards
Identify the main classes of diuretics.
1) Loop Diuretics
2) Thiazide like Diuretics
3) Potassium sparing Diuretics
4) Aldosterone antagonists
5) Osmotic diuretics
6) Carbonic Anhydrase Inhibitors
LOOP DIURETICS
- Examples
- Mechanism of action
LOOP DIURETICS
- Examples: furosemide, bumetanide
- Mechanism of action: Inhibits the Na+/K+/2Cl- co-transporter in the luminal membrane of the TAL of Henle’s loop, so inhibits transport of NaCl out of the tubule into interstitial tissue, so reduces osmotic gradient in the medulla of the kidney, less water recovered, so causes profound diuresis
LOOP DIURETICS
- Indications
- Side effects
LOOP DIURETICS
- Indications: Oedema (heart failure, pulmonary, ascites, nephrotic syndrome, renal failure) + resistant hypertension + hypercalcaemia
- Side effects: hypoV, hypoT, electrolyte disturbance (may produce a metabolic alkalosis due to loss of hydrogen ions), hyperuricaemia (gout), renal impairment
THIAZIDE LIKE DIURETICS
- Examples
- Mechanism of action
THIAZIDE LIKE DIURETICS
- Examples: bendroflumethiazide, indapamide
- Mechanism of action:
1) Inhibits the NaCl co-transporter in the distal tubule, so less Na/Cl reabsorbed, so causes moderate diuresis, reducing oedema and BP
2) Direct relaxant effect on vascular smooth muscle (reduces BP)
THIAZIDE LIKE DIURETICS
- Indications
- Side effects
THIAZIDE LIKE DIURETICS
- Indications: Hypertension + mild hear failure + severe resistant oedema (plus loop) + nephrogenic diabetes insipidus
- Side effects: hypoV, hypoT, electrolyte disturbance (may produce a metabolic alkalosis), hyperuricaemia (gout), promotion of calcium retention/hypocalciuria, erectile dysfunction, hyperglycaemia, hyperlipidaemia
POTASSIUM SPARING DIURETICS
-Examples
POTASSIUM SPARING DIURETICS (weak diuretic)
-Examples: Amiloride, Aldosterone antagonists
AMILORIDE
- Indications
- Side effects
AMILORIDE
- Indications: Usually synergistically combined with thiazide or loop diuretic. Used in oedema (including ascites), hypertension
- Side effects: high potassium (care if renal impairment), GI upset, metabolic acidosis, renal impairment
ALODOSTERONE ANTAGONISTS
- Examples
- Mechanism of action
ALODOSTERONE ANTAGONISTS
- Examples: Spironolactone, eplerenone
- Mechanism of action: In CT, antagonise aldosterone receptor (Mineralocorticoid receptor antagonists (MRAs))
AMILORIDE
-Mechanism of action
AMILORIDE
-Mechanism of action: Acts by directly blocking epithelial sodium channels in the collecting tubule so less sodium reabsorbed, causing diuresis.
ALODOSTERONE ANTAGONISTS
- Indications
- Side effects
ALODOSTERONE ANTAGONISTS -Indications: Oedema (heart, liver, nephrotic syndrome) + hypertension + Conn’s syndrome (primary hyperaldosteronism) -Side effects: • Hypotension! • Renal impairment • high potassium (care if renal impairment!) • Hyponatraemia • GI upset • Metabolic acidosis • Gynaecomastia with Spiro
OSMOTIC DIURETICS
- Examples
- Mechanism of Action
- Indications
OSMOTIC DIURETICS
- Examples: mannitol intravenously
- Mechanism of Action: Modify filtrate content increasing amount of water excreted
- Indications: cerebral oedema + raised intra-ocular pressure
CARBONIC ANHYDRASE INHIBITORs
- Examples
- Mechanism of Action
- Indications
CARBONIC ANHYDRASE INHIBITORs
- Examples: acetazolamide (very weak diuretic)
- Indications: glaucoma, altitude sickness
Identify which part of the nephron each kind of diuretic affects.
Osmotic diuretics: Modify filtrate content (act mainly in PCT)
Loop diuretics: Thick Ascending loop (Na+/K+/2Cl- co-transporter)
Thiazide like diuretics: DT (NaCl co-transporter)
Amiloride: CT (Na+ channels)
Spironolactone: CT (Mineralocorticoid/aldosterone receptor)
An 80 year old female patient in hospital post total knee replacement develops shortness of breath, 4 pillow orthopnoea and paroxysmal nocturnal dyspnoea.
Which diuretic would you prescribe?
Furosemide, get fluid off (patient is in cardiac failure). Bendroflumethazide and Spironoloactone not strong enough.
A 60 year old female patient presents to the practice for an annual review of her essential hypertension. She is currently on Ramipril plus Felodipine. Her blood pressure is 160/100mmHg. Bloods normal. Concordance with lifestyle advice and medications is good. Which diuretic might you add in to help lower BP to target?
Bendroflumethazide, because Furosemide too profound of a diuresis (and Spironoloactone potentially next if needed).
A 49 year old male patient is has marked ascites due to alcohol- induced hepatic impairment. His K+ is 2.5 but renal function is normal. Which diuretic would you choose?
Sprionolactone (want to raise K+, not lower it)
Define Syndrome of inappropriate ADH secretion (SIADH).
Too much anti-diuretic hormone being secreted by posterior pituitary gland regardless of what serum osmolality is.
What are the main causes of SIADH ?
Caused by range of factors:
- Neurological causes (e.g. tumour, trauma, meningitis, SAH)
- Pulmonary causes (e.g. lung small cell ca, pneumonia, bronchiectasis)
- Malignancy
- Hypothyroidism
- Drugs (e.g. thiazide and loop diuretics, ACE-is, SSRIs and PPIs)
What are the characteristic signs of SIADH ?
- Hyponatraemia (<135) (high Na+)
- Low plasma osmolality
- Inappropriately elevated urine osmolality (>plasma osmolality)
- Euvolaemia
What are the symptoms of mild, moderate, and severe SIADH ?
• Mild – Nausea, Vomiting, Headaches, Anorexia
• Moderate – Muscle cramps, weakness, tremor,
mental health disorders
• Severe – Drowsiness, Seizures, Coma
Describe the treatment of SIADH.
- Correct underlying cause, monitor plasma osmolality, serum sodium and bodyweight
- Fluid restrict (500-1000ml daily)
• Drugs:
-Demeclocycline – inhibits action of vasopressin
on kidney, anti-ADH action
-Tolvaptan – vasopressin V2 antagonist in renal collecting ducts
-Hypertonic sodium chloride in severe cases only
Define EPO.
Erythropoietin, hormone produced by kidney (peritubular interstitial cells) , promotes RBC formation in bone marrow
When may EPO be reduced ?
In moderate-severe renal impairment kidneys produce less EPO resulting in anaemia
What is the appropriate treatment for reduced EPO ?
Artificial versions of EPO called ESAs (erythropoeisis stimulating agents) boost production of red blood cells, improve survival, reduce cardiovascular morbidity, enhance quality of life.
Examples – Epoetin Alfa, Darbapoietin (injectable route for both)
Identify drugs affecting pH of urine. What are the indications for these ?
Ascorbic acid (acidify) Potassium citrate (alkalinise)
For urine infection symptoms or kidney stone formation. Rarely done.
Identify drugs given for gout that act on the kidney.
Uricosuric drugs (e.g. sulphinpyrazone, rarely used these days)
Identify drugs given for type II diabetes mellitus that act on the kidney.
Sodium-Glucose Co-Transporter- 2 (SGLT-2) Inhibitors (e.g. Canagliflozin)
Identify a class of drugs given for Diabetes Insipidus and oesophageal varices that acts on the kidney.
• Vasopressin receptor agonists – for diabetes insipidus (Desmopressin), oesophageal varices (Terlipressin)
Identify key considerations for safe prescribing in renal impairment.
- Degree of renal impairment?
- Whether acute or chronic kidney disease
- proportion of drug renally excreted
- Does drug have a narrow or wide therapeutic window?
- Is drug potentially nephrotoxic?
- Is this patient established on renal replacement therapy?
Identify examples of drugs with high renal clearance and narrow therapeutic window. What is the implication of this clinically ?
Vancomycin/Gentamicin, Digoxin, Lithium
Require dose reductions or extended dosing intervals
Identify examples of drugs with high renal clearance and wide therapeutic window. What is the implication of this clinically ?
Penicillins and cephalosporins.
Unlikely to be problematic
Identify examples of drugs with low renal clearance and narrow therapeutic window. What is the implication of this clinically ?
Theophylline, carbamazepine, phenytoin
Dose and monitor in the same way as patients without renal impairment
Identify some ways to estimate renal function with certain drugs.
Creatinine clearance or eGFR depending on drug
Explain how we may calculate creatinine clearance.
Using Cockroft and Gault (CandG) formula:
- 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)
What are the pros and cons of estimating Creatinine Clearance from CandG ?
PROS
• Good validated formulae
• Advised for narrow therapeutic index drugs
CONS
• Inaccurate for rapidly changing creatinine levels and in severe renal disease
• Need to use IBW at extremes of body weight
• Adults only
How is eGFR calcualted ?
Based on MDRD Study (Modification of Diet in Renal Disease) data (factors include creatinine, age, sex, ethnicity
What are the pros and cons of using eGFR to estimate renal function ?
PROS
• Easy reporting allows early detection of CKD
• BNF offers a broad range for guidance on dosage
based on eGFR
• eGFR increasingly being used to alter drug dosing and evidence growly regarding accuracy
• Good for majority of patients and drugs
CONS
• Not validated in some patient groups e.g. acute renal failure, pregnancy, oedematous states and malnourished, extremes of weight (also only valid in adults of Caucasian and African Caribbean origin)
• as not validated for drug dose calculations – risk of drug toxicity or therapeutic failure.
Why is it important to be able to estimate renal function when giving drugs ?
- Reduced renal excretion of a drug and its metabolites may cause toxicity
- Sensitivity to some drugs is increased even if elimination is unimpaired
- Increased risk of ADRs
- Some drugs are not effective when renal function is reduced
State the normal half life of Gentamicin, and its half life with renal impairment.
Normal half life = 2.5 h
Half life impaired renal function = 50 h
State the normal half life of Digoxin, and its half life with renal impairment.
Normal half life = 36 h
Half life impaired renal function = 120h
Identify examples of potentially nephrotoxic drugs. Which conditions should we avoid giving these in ?
- ACE inhibitors, Angiotensin II blockers
- NSAIDs e.g. ibuprofen
- Diuretics
- Lithium (for bipolar disorders)
- Digoxin
- Aminoglycosides (Gentamicin)
- Vancomycin
- Metformin (for T2DM)
- Iodinated contrast media
- Opioids (e.g. Morphine)
Use with caution or avoid in renal impairment!
What is the normal course of action when we need to give drugs despite renal impairment, and we are in a hurry to get to therapeutic levels ?
• Initial doses/loading doses often not reduced
• Renal disease = prolongs half-lives of some
drugs, so can take longer to get to steady state
• Usual loading dose as per normal renal function to reach target therapeutic serum drug concentrations then reduce maintenance dose
Give examples of pre-renal drug induced acute renal injuries (along with associated drugs)
- Blood flow to kidney restricted = renal underperfusion
(e. g. NSAIDs) - Excessive water and electrolyte loss
(e. g. diuretics)
Give examples of intra-renal drug induced acute renal injuries (along with associated drugs)
Tubular necrosis or interstitial nephritis or rhabdomyolysis (e.g. Gentamicin, ciclosporin)
Give examples of post-renal drug induced acute renal injuries (along with associated drugs)
Obstruction of renal tract (e.g. Anticholinergics (amitriptyline), cytotoxic chemotherapy)
How do we know what doses to use for certain drugs in renal impairment ?
BNF (may give different doses for cretanine clearance below normal, or for eGFR below normal)
Identify the main principles of prescribing in renal impairment.
- Check U’s and E’s, including eGFR and creatinine
- Look at baseline and trends in renal function
- Consider stopping or with-holding nephrotoxic drugs
- Check resources
- Choose non-nephrotoxic drug if possible
- reduce size of dose or increase dosing interval or stop or with- hold
- Use therapeutic drug monitoring to guide dose / frequency if appropriate
- Continue to monitor U and E’s, BP, AND clinical response
Describe the treatment for acute kidney injury.
- Treat any sepsis or uro obstruction
- Aim for good fluid / electrolyte balance
- Optimise B.P
- With-hold/stop toxins
- Review drug doses and side effect profile
- Monitor U and E’s, refer nephrology / urology if worsening
What are the risk factors for AKI ?
- Drugs
- Aged over 65
- CKD
- Dehydration – hypovolaemia, fever
- Urinary blockage
- Sepsis
- Liver disease
- diabetes
- hypotension
- heart failure
What are the main stages of CKD ?
- CKD Classified stage 1 (mild) through to 5 (severe impairment)
- Important risk factor for cardiovascular disease
What are the aims of treatment for Chronic Kidney Disease ?
Aim to:
• Prevent or reverse worsening
• review all meds, check doses appropriate
• manage concurrent conditions e.g. hypertension, sepsis, diabetes, heart failure, renal anaemia, bone disease, electrolyte and acid-base disturbances
How does a patient being on renal replacement therapy affect other drug prescribing ? What is the course of action in this case ?
- Some drugs actively removed during dialysis – will affect dose and timing of drug.
- Many variables – what kind of dialysis?
- Is drug removed from circulation during dialysis?
- What is dialyser membrane, blood and dialysate flow rate?
• Course of action: Refer to specialist renal team!
