Session 9: Diuretics and Drugs in Kidney Failure, Treatments in Hypertension and Heart Failure Flashcards Preview

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Flashcards in Session 9: Diuretics and Drugs in Kidney Failure, Treatments in Hypertension and Heart Failure Deck (52):
1

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

2

What are the 4 main kidney drugs used in clinical practice?

Loop Diuretics

Thiazides

Aldosterone antagonists

K+ Sparing

3

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. 

4

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.

5

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).

6

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. 

7

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. 

8

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

9

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. 

10

What are common specific ADRs of diuretics?

    Thiazide:

  • Gout
  • Erectile dysfunction

     Spironolactone

  • Hyperkalaemia
  • Painful gynaecomastia

    Furosemide (but generally well tolerated)

  • Ototoxicity

   Bumetanide

  • Myalgia

11

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

12

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.

13

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

14

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.

15

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. 

16

What are the two key issues when prescribing in renal disease? General advice?

  1. Drugs may reduce kidney function by direct or indirect toxicity
  2. 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. 

17

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 

18

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

19

Describe the physiological control of BP

    Autonomic Nervous System

    Renin-Angiotensin System

   Others

  • Bradykinin
  • Endothelin
  • Nitric Oxide
  • Atrial Natriuretic Peptide

20

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)

21

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. 

22

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.

    Secondary hypertension

  • High BP with a discrete, identifiable underlying cause
  • 10% hypertensive population

    Hypertension in pregnancy is a specialised topic – not covered here. 

23

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)

24

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.

25

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

26

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

    Diuretics

27

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)

  • Hypokalaemia
  • 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)

28

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

29

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

Adverse effects

  • Lethargy, impaired concentration
  • Reduced exercise tolerance (fairly common)
  • Bradycardia
  • 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

30

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. 

31

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

32

What are the indications, cautions and contraindications for ACE inhibitors and ARBs?

    ACE Inhibitors:

  • Indications: heart failure, LV dysfunction, MI, diabetes (type 1), nephropathy
  • Caution: renal impairment, peripheral vascular disease
  • Contraindication: pregnancy, renovascular, hypertension

   ARBS

  • Indications: ACE inhibitor intolerance, hypertension with left ventricular hypertrophy, Type 2 diabetes mellitus
  • Caution: renal impairment, peripheral vascular disease
  • Contraindication: pregnancy, renovascular, hypertension

33

What are the 3 main classes of Calcium Channel Blockers? What are their general effects?

Bind to specific alpha subunit of L-type calcium channel, reducing cellular calcium entry.

Calcium-channel blocking drugs are of 3 pharmacological classes.

  • Dihydropyridines (Nifedipine, Amlodipine) – most commonly used
  • Benzothiazepines (Diltiazem) – not often used in hypertension
  • Phenylalkylamines (Verapamil)

All are effective in lowering blood pressure but some (the dihydropyridines e.g. amlodipine) are predominantly vasodilators while others (e.g. diltiazem and verapamil) appear to act mainly or partially via an effect on myocardial contractility.

Calcium Channel Blockers vasodilate peripheral, coronary and pulmonary arteries

No significant effect on veins

Short acting dihydropyridines => baroreflex mediated tachycardia

Verapamil depresses SA Node and slows A-V conduction

34

What are the properties and adverse effects of dihydropyridines?

Properties

  • Good oral absorption
  • Protein bound > 90%
  • Metabolised by the liver
  • Few have active metabolite
  • Positively indicated with concurrent angina, elderly systolic hypertension

Adverse effects: (mostly vasodilator related)

  • Sympathetic nervous system activation – tachycardia and palpitations
  • Flushing, sweating, throbbing headache
  • Oedema (ankle swelling)
  • Gingival hyperplasia (rare)
  • Gynaecomastia (uncommon)
  • Generally well-tolerated 

35

What are the properties and adverse effects of phenylakylamines

Properties

  • Impedes calcium transport across the myocardial and vascular smooth muscle cell membrane
  • Class IV anti-arrhythmic agent - prolongs the action potential / effective refractory period
  • Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility

Adverse effects:

  • Constipation particularly in elderly people
  • Risk of bradycardia - Verapamil should not be given with a beta-blocker – severe bradycardia and/or hypotension can occur.
  • Reduce myocardial contractility (negative inotrope) – can worsen heart failure

36

What are the properties and adverse effects of benzothiazepines?

Properties

  • Impedes calcium transport across the myocardial and vascular smooth muscle cell membrane
  • Prolongs the action potential / effective refractory period
  • Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility

Adverse effects

- Risk of bradycardia

- Less negative inotropic effect than verapamil – can worsen heart failure (but safer than veramipril)

37

What are the indications and contradindications for rate-limiting calcium channel blockers?

    Calcium Channel Blockers (rate-limiting) such as Diltiazem and Verapamil 

Indication: angina

Caution: combination with beta-blockade

Contraindication: heart block, heart failure

Also used in arrhythmias

38

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)

39

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

40

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

41

Describe Direct Acting Vasodilators

Relax vascular smooth muscle (arteries > veins(

Selective action on heart, peripheral vasculature, cerebral circulation

Used in resistant/severe hypertension

Minoxidil: open ATP-modulated potassium channels thus inhibits influx of Ca2+

  • Usually needs to be accompanied by a diuretic and a Beta-blocker to reduce effects of tachycardia and fluid retention
  • Other main side effect is hirsuitism

Hydralazine: mechanism unclear (? Similar to minoxidil)

  • Oral or IV
  • Main ADRs: flushing, tachycardia and mild fluid retention
  • A lupus-like syndrome may occur

42

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. 

43

Appreciate how drug choices are made with the use of combination therapy. 

The selection is made on the basis of simplicity of dosing, any concurrent disease (e.g. angina, heart failure), tolerability and cost.

  •     Beta-blockers should be avoided in asthmatics.
  •     Response to treatment, and possible adverse effects, should be closely monitored in the early months of treatment.
  •     Combination therapy is commonly needed to achieve optimum blood pressure control.
  •     Although all the above classes can be combined, some combinations are particularly suitable (e.g. diuretic and ACE inhibitor, diuretic and beta-blocker). 

44

Describe the aetiology of HF and prognosis 

Aetiology of heart failure:

  •     Ischaemic heart disease
  •     Hypertension
  •     Cardiomyopathies e.g. alcohol/idiopathic/chemotherapy/iron overload etc
  •     Valve disease
  •     Others

Prognosis after MI (or any cardiac injury) is inversely related to amount of LV damage (LV dysfunction). Prognosis can be influenced by pharmacological therapy

45

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

46

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

47

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

48

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)

49

What are possible causes of secondary hypertension?

    Endocrine causes:

  • Conn’s Syndrome
  • Bilateral adrenal hyperplasia
  • Glucocorticoid-remediable aldosteronism
  • Congenital adrenal hyperplasia
  • Cushing’s syndrome
  • Phaeochromocytoma
  • Thyroid disease
  • Acromegaly
  • Hyperparathyroidism/Hypercalcaemia
  • Carcinoid
  •     Monogenic Renal Tubular Defects
  • Liddle’s Syndrome
  • Gordon’s Syndrome
  • (Bartters Syndrome)
  • (Gitelman’s Syndrome)

    Renal Causes

  • Renovascular hypertension
  • Chronic pyelonephritis
  • Diabetic renal disease
  • Renal parenchymal disease

   Miscellaneous

  • Coarctation of the aorta
  • Neurological disorder
  • Psychogenic
  • Sleep apnoea
  • Drug-indcued
  • Glycyrrhetinic aicd (licorice)
  • Oral contraceptive and oestrogen replacement
  • Pregnancy

50

Describe Phaeochromocytoma

    Adrenal catecholamine-secreting tumour

    Producing large amounts off Adrenaline/Noradrenaline/(dopamine)

    Paroxysmal symptoms (tachycardia, palpitations, sweting, headaches) v sustained high BP

    Diagnosed: urinary catecholamines/imaging

    10% rule

  • 10% are malignant, bilateral, extra-adrenal (found within nervous tissue outside of the adrenal glands), children, familial, recur, associated with MEN syndromes (associated with rare syndromes of endocrine tumours)
  • 10% of tumours are found after stroke.
  •     Treat with non-selective alpha-blockers: direct effect on alpha-1 and alpha-2 adrenoceptors preventing the action of released noradrenaline.

Phenoxybenzamine: oral non-competitive

Phentolamine – IV competitive for use in hypertensive crisis

Beta-blockers are given after alpha-blockade

51

What is meant by Primary Hyperaldosteronism?

    Causes hypertension due to significant fluid reabsorption

Includes   

  • Conn’s Syndrome (aldosterone secreting adenoma)
  • Bilateral adrenal hyperplasia

    Excess secretion of aldosterone

    Plasma renin suppressed

    Treat with aldosterone antagonists

  • Spironolactone
  • Eplerenone

    Alternative: high dose amiloride

52

What is meant by Hypertensive Emergencies?

    Very high BP (often over 220/120 mmHg)

    Associated with acute complications – pulmonary oedema, renal failure, aortic dissection etc

    Need to reduce BP by ~20% or to 100mHg diastolic within 1-2 hours otherwise acute complications may very rapidly develop

    Sodium Nitroprusside: mimics the action of endogenous nitric oxide on vascular smooth muscle, acting as a potent vasodilator

  • Intravenous use with powerful rapid onset and offset
  • Breakdown to cyanide – caution in liver disease, but renal excretion. Avoid prolonged use (>72 hours)