Kidneys require 25% of the cardiac output. What is meant by REEM?
Renal Physiology: REEM (require 25% of cardiac output)
- Fluid balance
- Acid-base balance
- Electrolyte balance
- Waste products
- Drug elimination
- Glomerular filtration
- Tubular secretion e.g. penicillin (proximal tubule)
- Renin-Angiotensin-Aldosterone System
- Erythropoietin (deficiency could lead to anaemia)
- Prostaglandins (too much vasoconstriction could lead to reduced renal perfusion)
- Vitamin D
What are the 4 main kidney drugs used in clinical practice?
Describe the actions of Carbonic Anhydrase Inhibitors and Osmotic Diuretics. GIve examples
Carbonic anhydrase inhibitors e.g. Acetazolamide: act mainly on the PCT to prevent action of carbonic anhydrase in the tubule, which in turn affects the reabsorption rate of Na+ ions => Na, K and PO3 excretion (increases osmotic gradient leading to excessive water loss). It is rarely used as a diuretic due to risk of metabolic acidosis and hypokalaemia, yet is given as a topic treatment for glaucoma.
Osmotic diuretics such as mannitol, act to increase the osmotic gradient systemically (including in the renal tubules). Like the carbonic anhydrase inhibitors, they are rarely used as diuretics now due to excessive water loss and causing hypernatraemia. They are currently used in in severe or pulmonary oedema.
Describe loop diuretics. Give examples
E.g. furosemide, act on the NKCC2 transporters on the TAL of the Loop of Henle, so act directly to prevent reabsorption of Na+ and Cl- ions (as well as concurrent excretion of Ca2+ and Mg2+ ions). They have a risk of causing hypokalaemia (with furosemide having a specific risk of causing reversible ototoxicity).
Main indications for use are heart failure (due to slight venodilatory effect) and in liver failure (effective at dealing with fluid overload). Very efficacious when given IV for fluid overloading.
Furosemide: Half-life can range from 90 mins to 2 hours – suitable for once daily dosing otherwise can pee too much.
Bumetanide works within the same time frame but has better bioavailability (better absorbed) and duration of action is longer (up to 6 hours)
They should not be used with aminoglycosides due to risk of ototoxicity and nephrotoxicity and arely used with digoxin or steroids due to the risk of hypokalaemia.
Describe thiazide and thiazide-like diuretics
Thiazide and thiazide-like diuretics act on the Na+-Cl symporter to have a diuretic effect whilst also promoting Ca2+ reabsorption (so can be helpful in limiting calcium loss and preventing kidney stone formation).
They have the risk of causing hypokalaemia, hypercalcaemia and hyperuricaemia (to predispose to causing gout) as well as risk of erectile dysfunction.
Their main indications for use are heart failure and hypertension. They should not be prescribed alongside digoxin or steroids due to risk of hypokalaemia, or Beta-blockers due risk of hyperglycaemia, hyperlipidaemia and hyperuriacemia.
Effect on diuresis is less compared to loop diuretics but greater effect on BP.
They are used to treat hypertension and also can be used for kidney stones (causing calcium reabsorption from the urine).
Describe potassium sparing diuretics
Potassium sparing diuretics
E.g. amiloride, act solely on the ENaC channel in the late DCT and collecting duct, and so can be classed as potassium sparing as they have no effect on potassium reabsorption.
They should not be used alongside ACE inhibitors due to the risk of hyperkalaemia.
Often used in combination with furosemide.
Describe aldosterone antagonists
E.g. Spironolactone or Eplerenone act to inhibit the action of aldosterone on the mineralocorticoid receptors, thus affecting Na+-K+-ATPase and ENaC protein synthesis.
Spironolactone’s active metabolite is canrenone, which has a half life of 18-24 hours thus allowing longer term use but takes a few days to work.
Its main ADRs are causing hyperkalaemia and also some androgenic cross-reactivity, thus may cause gynaecomastia and breast tenderness
Eplerenone has no androgenic cross-reactivity
main indications for use are in heart failure (add-on), hypertension (commonly used), liver failure or hyperaldosteronism (such as Conn’s syndrome). There are no real DDIs concerned with aldosterone antagonists.
Describe ADH antagonists. Does digoxin have a diuretic effect?
ADH antagonists reduce the concentrating ability of urine in the collecting ducts and include both lithium (used in bipolar disorder treatment) and demeclocycline (helps with severe hypernatraemia)
Other drugs with diuretic activity
Inhibits tubular Na/K-ATPase => slight diuretic effect
What are general adverse drug reactions of diuretics?
Hypovolaemia and hypotension leading to acute renal failure
Metabolic abnormalities (particularly thiazide diuretics – hyperuricaemia, impaired glucose tolerance)
When prescribing diuretics, it is important to constantly monitor the U&Es to prevent any adverse effects from developing.
What are common specific ADRs of diuretics?
- Erectile dysfunction
- Painful gynaecomastia
Furosemide (but generally well tolerated)
What are potential drug-drug interactions with diuretics?
interacting drugs; potential interactions
- ACE Inhibitors / K+-Sparing Diuretics; increased hyperkalaemia => cardiac problems
- Aminoglycosides/Loop Diuretic; ototoxicity and nephrotoxicity
- Digoxin/Thiazide and Loop Diuretics; Hypokalaemia => increased digoxin binding and toxicity
- Beta-Blockers/Thiazide Diuretics; Hyperglycaemia, hyperlipidaemia, hyperuricaemia
- Steroids/Thiazide and Loop Diuretics; increased risk of hypokalaemia
- Carbamazepine / Thiazide Diuretics; increased risk of hyponatraemia
What can lead to diuretic resistance?
Incomplete treatment of the primary disorder
Continuation of high Na+ intake
Poor absorption e.g. due to oedematous gut wall
Volume depletion decreases filtration of diuretics
Volume depletion increases serum aldosterone which enhances Na+ reabsorption
NSAIDs – can reduce renal blood flow
NB: local production of dopamine vasodilates renal arterioles.
What the major indications for use of diuretics?
- Loop diuretics
- Thiazide diuretics
- (Spironolactone – non-diuretic benefits – effects of potassium sparing etc)
- ACE inhibitors / Ang II anatagonists
- Thiazide/Thiazide-like diuretics
- (Loop diuretics) (particularly in chronic kidney disease)
- ACE inhibitors / Ang II antagonists
- Beta-blockers (no longer recommended as first line therapy) – Calcium Channel Blockers instead
Decompensated Liver Disease (liver failure leading to activated RAAS due to fluid retention)
- Spironolactone (high doses used, monitor treatment)
- Loop diuretics
- *role of secondary hyperaldosteronism
- NB: need to consider renal impairment
Diuretics also used in the trearment of
Liver failure: aldosterone antagonists (due to RAAS activation from fluid retention) and loop diuretic (role of secondary hyperaldosteronism)
Conn’s Syndrome: aldosterone antagonist
How can these drugs cause renal complications?
Drugs and kidney function
- Drugs may reduce kidney function by direct or indirect toxicity
- Drugs may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired
- Potentially Nephrotoxic Drugs
ACE inhibitors (decreased GFR => a 10% change in creatinine levels is allowable in normal people, if higher creatinine levels then get worried)
Aminoglycosides e.g. gentamicin
Metformin (risk of lactic acidosis especially in diabetic nephropathy)
Even more clinically significant if renal function is impaired.
Describe how ACE inhibitors/ARBs can precipitate acute kidney failure
Decreased glomerular filtration pressure leads to activation of Renin-Ang-Aldo System
This leads to vasoconstriction which leads to increased blood pressure and decreased renal perfusion
ACE inhibitor /ARB preferentially dilate efferent arterioles leading to further decreased glomerular filtration pressure => acute renal failure – ACE inhibitors/ARBs can precipitate acute kidney injury particularly in patients with undiagnosed renovascular disease.
What are the two key issues when prescribing in renal disease? General advice?
- Drugs may reduce kidney function by direct or indirect toxicity
- Drugs at normal doses may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired.
General advice about prescribing drugs to patients with renal failure:
- Avoid nephrotoxins if possible
- Reduce dosage in line with Glomerular Filtration Rate if metabolism or eliminated via the kidneys (general rule of thumb: consider creatinine levels – if 300, give 300 mg furosemide)
- Monitor renal function and drug levels if narrow therapeutic range
- Hyperkalaemia is more likely
- Uraemic patients have greater tendency to bleed.
- BNF gives advice about dosage for drugs.
What do you need to consider when prescribing in the elderly?
Renal function is over-estimated as creatinine is dependent on body mass – renal function will be reduced
Polypharmacy more likely to be present
Describe the management of hyperkalaemia
ECG (tall tented t-waves, p wave diminuition, prolonged QRS interval with bizarre QRS morphology – prolonged PR segment, sine wave)
Describe the physiological control of BP
Autonomic Nervous System
- Nitric Oxide
- Atrial Natriuretic Peptide
Describe the pathophysiology of higher BP and recap RAAS
Higher blood pressure => increased arterial thickening => smooth muscle cell hypertrophy + accumulation of vascular matrix -> loss of arterial compliance => target organ damage => Heart – Kidney – Brain – Eyes [CV Morbidity and Mortality)
What is the threshold for hypertension classification? Describe the epidemiology
Defined as 140/90 mmHg, 40% of the adult population of England are hypertensive although the proportion increases with age.
Lowering diastolic BP by 10 mmHg is associated with reductions in stroke of 58% and coronary heart disease of 37%.
High blood pressure very seldom causes symptoms so it is therefore not a ‘disease’ but a risk factor for future vascular disease.
The organs affected by sustained hypertension are the brain, the heart, the arterial system, the kidney and the eye.
Epidemiologically, blood pressure is a strong predictor of risk of ischaemic heart disease and stroke.
There is now good evidence from clinical trials that lowering blood pressure with drugs reduces these risks.
Differentiate between primary and secondary hypertension
Hypertension is rarely (<5%) secondary to a definable cause such as renal (interstitial or renovascular) or endocrine (phaeochromocytoma, Conn’s, Cushing’s) disease or coarctation of the aorta.
Primary (essential) hypertension:
- High BP without any single evidence cause
- 90% hypertensive population
- Drug history should be taken, to identify potential causative agents such as oral contraceptive pill, corticosteroids or high alcohol intake.
- High BP with a discrete, identifiable underlying cause
- 10% hypertensive population
Hypertension in pregnancy is a specialised topic – not covered here.
Give an overview of the treatment for hypertension
It is important to address the full range of modifiable risk factors such as smoking, cholesterol level, obesity and physical inactivity. For patients with diabetes, high blood pressure is particularly adverse and should be stringently controlled.
- Identify and treat underlying cause if present
- Identify and treat other cardiovascular risk factors or co-morbidities.
- Lifestyle advice / non-pharmacological therapy: Optimum body weight, regular physical activity and moderation of alcohol and salt intake should be encouraged. At the borderline, these measures may avoid the need for drug treatment. Smoking cessation should be strongly advised and supported as necessary e.g. with nicotine replacement therapy.
Current UK guidelines
British Hypertension Society (‘ACD)
National Institute for Health and Clinical Excellence (NICE0
SIGN No.49 (Scotland)
What is meant by lifestyle therapy?
Lifestyle therapy: important non-pharmacological interventions to encourage any hypertensive patient to take up.
- Patient education
- Maintain normal body weight (BMI 20-25 kg/m2)
- Reduce salt intake <6g/day
- Limit alcohol consumption to <3 units/day for men, <2 units/day for women
- Engage in regular aerobic physical exercise for >30 minutes/day
- Consume >5 portions of fresh fruit/vegetables daily
- Reduce intake of total and saturated fat
- (Smoking cessation) (despite no effect on BP, reduces overall CV risk)
- (Relaxation therapies)
- These should be used alone at borderline blood pressure levels and concurrently with any pharmacological therapies when levels are higher.
What influences the decision to treat with drug therapy? What are the thresholds for drug treatment
The decision to offer drug therapy is influenced by:
- The sustained level of blood pressure
- The overall cardiovascular risk profile
Thresholds for drug treatment
- Sustained pressure equal to or greater than 150 mm systolic and 100 mm diastolic justify drug treatment.
- At levels of 140-159 systolic and 90-99 diastolic (mild hypertension), the decision depends on the overall cardiovascular risk profile (is there >15% risk of cardiovascular event in the next 10 years) and the presence or absence of end organ damage in the heart (Left Ventricular Hypertrophy), eye or kidney. Normally only non-pharmacological therapies are required.
- Isolated Systolic Hypertension is a low diastolic BP with a high systolic BP (>140 mmHg); it is common with increasing age, occurring from the loss of compliance of elastic arteries.
- In the presence of diabetes, the treatment threshold is 140 mm systolic or 90 mm diastolic, with a target level of
What are the main drugs used in first line therapy?
1st Line Pharmacological Therapy: ACD
Angiotensin Converting Enzyme (ACE) inhibitors / Angiotensin Receptor Blockers (ARB)
Calcium Channel Blockers
Describe the mechanisms and adverse effects of thiazides
Thiazide diuretics e.g. Bendroflumethiazide
- Reduce distal tubular sodium reabsorption (natriuresis)
- Sustained action
- Blood pressure reduction – complex
- Several mechanisms
- Initial blood volume decrease
- Later – total peripheral resistance falls
- Dose-blood pressure response curve flat (any uptitrating of levels of thiazides will not cause any increase in response, will only cause an increase in the risk of adverse effects)
- Direct vasodilating properties
Adverse effects (rare)
- Increased urea and uric acid levels => gout
- Mild impairment of glucose tolerance (especially with beta-blockers) – but give with Amiloride => no effect on glucose (synergistic BP reduction)
- Cholesterol and triglyceride levels increased.
- Activates RAAS (so give with ACE inhibitor => synergistic blood pressure reduction)
What are the indications and contraindications for thiazides?
Indications: elderly, isolated systolic hypertension, heart failure
NB: ALLHAT study showed whatever regimen you gave, outcome is pretty much the same (all participants had the same BP) so focus on the medication that lowers BP best in the individual you’re treating
Describe the mechanisms and adverse reactions of beta-blockers. Why aren't they used for BP very commonly these days? Give positive indications and contraindications
Beta-blockers (e.g. atenolol, bisoprolol, nebivolol) have their main action on the heart by reducing myocardial contractility => reduce heart rate and cardiac output
Developed for angina but found to lower blood pressure. However they actually appear to have little significant effect on blood pressure (not much effect on the aortic pressure – which influences stroke risk) so are rarely used as a hypertensive.
- Inhibit renin release
- Initially total peripheral resistance increases, later falls to normal
- Lethargy, impaired concentration
- Reduced exercise tolerance (fairly common)
- Cold hands/ extremities – Raynaud’s
- Impaired glucose tolerance
- Bronchospasm (important to avoid in asthmatic patients)
- Precipitation of acute heart failure
Positively indicated with concurrent angina, chronic heart failure or past myocardial infarction.
Caution with heart failure*, peripheral vascular disease, diabetes (except with coronary heart disease)
Contraindication: asthma, COPD, heart block
Describe the actions and adverse reactions of ACE inhibitors. What is a positive indication?
ACE inhibitors (e.g. lisinopril) are competitive inhibitors of Angiotensin Converting Enzyme lower angiotensin-II (A-II) levels (by ~70%) and thereby cause vasodilatation and natriuresis.
- Mainly arteriolar vasodilators
- Some venodilation
- Circulating aldosterone is reduced
Examples of ACE inhibitors include lisinopril and ramipril. They also potentiate the action of bradykinin by preventing its breakdown.
Dry cough is a common (main) (10-15%) side effect. A-II receptor antagonists (e.g. losartan) do not cause cough but act otherwise similarly to ACE inhibitors – a suitable substitute.
Important side effects: (need to check U&Es)
- Angio-oedema (rare, but more common in black population)
- Renal failure (especially those with bilateral renal artery stenosis)
First-dose hypotension can occur, especially in patients who are volume-depleted and/or on diuretics. Rarely, a sharp and potentially irreversible decline in renal function may occur in patients with (probably unsuspected) renal artery stenosis; renal function should be monitored when starting or increasing ACE inhibitor dose.
ACE inhibitors are generally well-tolerated and positively indicated with concurrent heart failure.