Session 9: Diuretics and Drugs in Kidney Failure, Treatments in Hypertension and Heart Failure Flashcards
Kidneys require 25% of the cardiac output. What is meant by REEM?
Renal Physiology: REEM (require 25% of cardiac output)
Regulatory
- Fluid balance
- Acid-base balance
- Electrolyte balance
Excretory
- Waste products
- Drug elimination
- Glomerular filtration
- Tubular secretion e.g. penicillin (proximal tubule)
Endocrine
- Renin-Angiotensin-Aldosterone System
- Erythropoietin (deficiency could lead to anaemia)
- Prostaglandins (too much vasoconstriction could lead to reduced renal perfusion)
Metabolism
- Vitamin D
- Polypeptides
- Insulin
- PTH
What are the 4 main kidney drugs used in clinical practice?
Loop Diuretics
Thiazides
Aldosterone antagonists
K+ Sparing
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
Digoxin
Inhibits tubular Na/K-ATPase => slight diuretic effect
What are general adverse drug reactions of diuretics?
Anaphylaxis/rash etc
Hypovolaemia and hypotension leading to acute renal failure
Electrolyte disturbances
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?
Thiazide:
- Gout
- Erectile dysfunction
Spironolactone
- Hyperkalaemia
- Painful gynaecomastia
Furosemide (but generally well tolerated)
- Ototoxicity
Bumetanide
- Myalgia
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
Patient non-compliance
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?
Heart Failure:
- Loop diuretics
- Thiazide diuretics
- (Spironolactone – non-diuretic benefits – effects of potassium sparing etc)
- ACE inhibitors / Ang II anatagonists
- Beta-blockers
- *Resistance
Hypertension
- Thiazide/Thiazide-like diuretics
- Spironolactone
- (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
Penicillins
Cylosporin A
Metformin (risk of lactic acidosis especially in diabetic nephropathy)
NSAIDS
++ more
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
Start low
Titrate cautiously
Polypharmacy more likely to be present
Describe the management of hyperkalaemia
Identify cause
ECG (tall tented t-waves, p wave diminuition, prolonged QRS interval with bizarre QRS morphology – prolonged PR segment, sine wave)
Treatment:
Calcium gluconate
Insulin/Dextrose
Calcium resonium
Sodium bicarbonate
Salbutamol
Describe the physiological control of BP
Autonomic Nervous System
Renin-Angiotensin System
Others
- Bradykinin
- Endothelin
- 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.
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 indications and contraindications for thiazides?
Indications: elderly, isolated systolic hypertension, heart failure
Contraindication: gout
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 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)
- Hyperkalaemia.
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.
Describe the actions and adverse reactions of angiotensin receptor blockers
E.g. Losartan, Valsartan
- Bind to angiotensin AT1 receptor
- Inhibit vasoconstriction and aldosterone stimulation caused by angiotensin II
Well tolerated, few side effects
Important side effects:
- Renal failure
- Hyperkalaemia
Other agents for resistant hypertension or patients intolerant of other agents: describe alpha-blockers
Alpha adrenoceptor blockers (alpha blockers) e.g. Doxazosin
- Indication: Benign prostatic hyperplasia
- Caution: Postural hypotension, heart failure
- Contraindication: urinary incontinence
- Properties
Selective antagonism at post-synaptic alpha-1 adrenoceptors and antagonise the contractile effects of noradrenaline on vascular smooth muscle (selective antagonism)
Reduce total peripheral vascular resistance
More effect in upright position
Benign effect on plasma lipids / glucose
Safe in renal disease
Adverse effects
- Postural hypotension (particularly in the elderly)
- Dizziness
- Headache and fatigue
- Oedema (especially if combined with dihydropyridines)
Describe Direct Renin Inhibitors
Direct Renin Inhibitors (new class) – Aliskiren
Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I
Suppression at point of activation
Aliskiren reduces plasma renin activity by 50-80%
Vasodilatory properties leading to BP reduction
Pharmacokinetics
- Bioavailability ~2.6%
- Half life ~40 hours (range 25-45) – supports once-daily dosing
- Steady state takes 5-8 days (takes a long time to work)
- Main elimination route:
- Mainly eliminated as unchanged compound in faeces (78%)
- Less than 1% is renal excreted
- NOT metabolised via cytochrome P450
Caution in patients at risk of hyperkalaemia, sodium and volume-depleted patients, patients with HF, severe renal impairment and renal stensosiss
No initial dosage adjustments required in elderly patients
Diarrhoea side effect
Contra-indicated in pregnancy
Only significant drug interaction: furosemide
Describe Centrally Acting Agents
Less commonly used in hypertension
Methyldopa: converted to alpha-methyl-noradrenaline – a potent alpha2-adrenoceptor agonist
Clonidine: direct pre-synaptic alpha2-adrenoceptor agonist
Moxonide: imidazoline I(1) receptor agonist and some alpha-2 agonist effect
Reduce sympathetic outflowto reduce BP
Side effects restrict use:
- Tiredness/ lethargy
- Depression
Alpha-methyldopa can be used to treat hypertension in pregnancy
Describe BHS and NICE Pharmacological Treatment Guidance
Any anti-hypertension pharmacological therapies will be started when a patient’s BP is above 160/100 mmHg. NICE guidelines suggest starting on one anti-hypertensive drug before progressing along the levels if blood pressure levels do not improve. The drugs show good synergistic action so this method can prove very effective; around 30% of hypertensive patients will not take their anti-hypertensive drugs though.
First line therapy (Step 1)
- Younger than 55 years (thought to have more active RAAS): ACE inhibitor (consider ATII receptor antagonist if ACE intolerant)
- 55 years or older or black (those of African or Caribbean descent, and not mixed-race, Asian or Chinese patients) patients of any age: Calcium Channel Blocker
Step 2: ACE Inhibitor + Calcium Channel Blocker or ACE Inhibitor + Thiazide-type diuretic
Step 3: ACE inhibitor + Calcium Channel Blocker + Thiazide-type diuretic
Step 4: add on further diuretic therapy or alpha-blocker or beta-blocker. Consider seeking specialist advice.
What is meant by the vicious cycle of heart failure?
Impaired LV Function => decreased cardiac output and stroke volume => neurohormonal activation => increased systemic vascular resistance => increased outflow resistance => further impaired LV function
Decreased cardiac output and stroke volume also leads to decreased renal perfusion => neurohormonal activation…(see above)
Reduced renal perfusion also leads to increased sodium/water retention => increased blood volume = increased preload (increased filing pressure) => ventricular dilatation + increased wall stress => further decreases cardiac output and stroke volume
Neurohormonal activation includes Sympathetic, increased Renin-Angiotensin-Aldosterone and Vasopressin
How may prognosis be improved by?
Prognosis may be improved by:
RAS antagonism
- ACE inhibitors / ARBs (studies have shown realbenefit occurs in the first year)
- Aldosterone blockade
Beta-blocker
NB: diuretics: loop +/- thiazide useful for treatment but no evidence to suggest improves prognosis
AIRE: Acute infarction ramipril (ACE inhibitor) efficacy study
ARB as an alternative to ACE inhibitor
- Primary outcome: CV death or CHF (chronic heart failure) hospitalisation
What is meant by aldosterone escaping?
In spite of ACE inhibitor / ARB therapy, aldosterone concentration returns to normal
Aldosterone ‘escapes’
Aldosterone can lead to endothelial dysfunction, myocardia fibrosis and K+/Mg2+ loss
- Endothelial dysfunction => acute coronary events => sudden cardiac death AND/OR endothelial dysfunction => myocardial fibrosis => arrhythmias => sudden cardiac death
- Myocardial fibrosis => arrhythmias => sudden cardiac death
- K+/Mg2+ loss => arrhythmias => sudden cardiac death
Describe the physiological effects of Beta-blockers and and Beta-blockers in heart failure
Beta-Blockers: physiological effects
- Reduce heart rate (cardiac beta receptor)
- Reduce BP (reduced CO)
- 1+2 => reduced myocardial oxygen demand
- Reduce mobilisation of glycogen
- Negate unwanted effects of catecholamines
Beta-Blockers in heart failure
- Care is required! (can make heart failure worse)
- Wait for the pulmonary oedema to clear first
- Failing myocardium dependent on heart rate
- Initiate at low dose
- Titrate slowly
- May have to alter concomitant medication (e.g. diuretic)
