Heart Failure 266

What is Heart failure?

• Complex clinical syndrome of symptoms and signs that pumping of heart is inefficient

• Less blood being pumped = Left ventricular hypertrophy

• Definition = Inability of heart to meet circulatory demands of the body

What are 5 causes of HF?

1. IHD

   • Blockage of arteries results in ischaemia and damage downstream

   • Results in myocardial fibrosis and scarring of heart muscle tissue

   • NSTEMI common cause of HF

2. HTN

   • 1/3 causes of HF

   • Heart wall thickens and loses elasticity meaning it cannot pump properly

3. Valve disease

   • Aortic stenosis - Narrowing of aorta meaning less blood flows out (Calcification)

   • Mitral regurgitation - Valves don’t shut properly so blood flows back into left atria when left ventricle contracts

4. Cardiomyopathies

   • Increased thickening and stiffness of the heart muscle which affects its ability to pump

   • Hypertrophic obstructive cardiomyopathy

   • Dilated cardiomyopathy

   • Arrhythmogenic right ventricular cardiomyopathy

   • Restrictive cardiomyopathy

5. Alcohol, drugs and pregnancy

   • Drug example is herceptin

What is EF?

Ejection fraction is amount of blood pumped out ventricles each beat compared to the total amount in the ventricle each time the heart contracts

How to calculate EF

EF = (SV/EDV) x 100

3 types of EF

• normal EF = >50 - 60%

1. HFrEF - reduced less than 40%

2. HFmrEF - mildy reduced 40-49%

3. HFpEF - preserved ≥50

What 6 things precipitate HF?

1. Arrythmias

2. Myocardial infarction

3. Infection

4. Excess alcohol/fluid

5. Anaemia

6. Non-compliance

What are 6 signs of HF?

1. Hypotension

2. Cold peripheries

3. Raised JVP

4. 3rd heart sound

5. Lung crackles

6. Fluid retention

What are 8 symptoms of HF?

1. SoB

2. Oedema

3. Fatigue

4. Paroxysmal nocturnal dyspnoea

5. Swollen or tender abdomen with loss of appetite

6. Cough with frothy sputum

7. Polyuria

8. Confusion

What is the prognosis of HF?

• Poor survival rates

• Over 20% of patients diagnosed with HF die within a year

• Treatment can improve QOL or improve prognosis

What 3 risk factors for HFrEF?

• Volume overload - too much blood entering ventricles

• Myocarditis - damage to muscle cells

• MI - Can cause scarring which results in reduced contraction ability

What 3 risk factors for HFpEF?

• Inflammation

• COPD

• Age

What 4 risk factors for HF?

• Obesity

• Hypertension

• Diabetes

• Kidney disease

What is acute HF and how is it caused?

When fluid is being administered too quickly causing volume overload

What does the Frank-Starling law suggest?

• Increased volume returning to heart = Increased force required to pump back out

• This causes actin and myosin filaments to stretch but if they stretch too much there is not enough overlap to cause contraction

Describe what is happening in this graph

• In heart failure, these patients cannot get their cardiac output high enough when conducting activities like walking, therefore they start to feel SoB

• They need more blood to return to the heart, even at rest

• This can cause the triggering of the RAAS system

• Their myocardial contractility is also much less then a normal heart

How can changes in afterload affect functioning of a failing heart?

• When afterload increases (The amount of resistance the heart must overcome to pump the blood into the periphery), the heart cannot generate enough force to pump blood to periphery from heart

• Stroke volume decreases

Why is untreated hypertension in HF problematic?

• Due to the blood pressure issues caused by HTN, HF hearts cannot reach the higher levels of cardiac output needed to overcome total peripheral resistance so there is insufficient pumping

• This is caused by further cardiac hypertrophy which puts even more stress on the heart

What happens in left-sided HF?

• Blood is coming from lungs to heart so lots of pulmonary effects

Symptoms:

• Restlessness

• Confusion because not enough blood goes to brain

• Reflex Tachycardia (baro receptors send signals to SNS to try and increase HR)

• Pulmonary congestion

• Paroxysmal nocturnal dyspnoea / exertional dyspnoea

• Orthopnea

• Fatigue

• Cyanosis

What happens in right-sided HF?

• Blood comes back from body to heart

Symptoms:

• Fatigue

• Increase in peripheral venous pressure

• Enlarged spleen and liver

• Ascites

• Anorexia and GI distress

• Weight gain

• Dependent oedema

• Nocturia

Why does oedema occur in HF patients?

1. CO is impaired which is detected by baroreceptors

2. Systems increase CO by increasing blood returning to heart

3. The more blood comes back, the more pumped into circulation

4. In HF, pumping is not efficient so blood hangs around in ventricle

5. This causes ventricle to get bigger and pressure in ventricles increase

6. This causes atrial pressure increase so arterial pressure increases

7. Hydrostatic pressure in arterials increase so fluid leaks out capillaries into interstitial space

How does paroxsymal nocturnal dyspnoea / orthopnoea occur?

1. As you lay down you remove gravity effect, venous return goes up

2. Fluid in the peripheries will start to be reabsorbed in the CV system and return to the heart which increases pressure in ventricles

3. Increase in pressure in the ventricle = increase in atrial pressure = increase in pressure in capillaries = fluid leaks out of capillaries in the lungs making it harder to breathe

4. Need to prop up with pillows at night to introduce gravity and reduce amount of blood coming back

How to diagnose HF?

• Signs and symptoms

• Brain natriuretic peptide (BNP) levels = >400pg/ml

  • 400-2000 = urgently seen within 6 weeks

  • 2000 = urgently seen within 2 weeks

• BNP and ANP released from heart as walls start to stretch

  • They cause reduction in blood volume by increasing salt and water diuresis

• 2D doppler echocardiography (EF <35%)

• Raised JVP

Why is BNP not always a good marker?

• Can be raised:

  • AF

  • PE

  • Renal impairment (GFR <60mL/min

  • COPD

  • LVH

  • Age >70

• Can be reduced if

  • Obese

  • Afro-Caribbean

  • Patients already on treatment with other diuretics, ACE inhibs, beta blockers, ARB's, MRA, SGLT-2i

What is an index event?

• Something causing pumping capacity of heart to be impaired

What does reduced pumping capacity activate?

1. SNS

2. RAAS due to adrenaline release by SNS which binds B1 on kidneys

• compensatory mechanism: work together to restore cardiovascular homeostasis - short term

Why does sustained neurohormonal activation drive HFrEF?

• Acute increases in both are fine as they return back to baseline

• Sustained activation leads to progression of HFrEF

  • this is due to SNS and RAAS being further stimulated which creates a positive feedback loop of damage and at some point you will maximally stimulate all the systems

Long term effects on the heart from sustained neurohormonal activation include:

• Decreased beta receptor responsiveness

• Myocyte hypertrophy

• Myocyte necrosis and fibrosis

• Reduced norepinephrine stores and reduced sympathetic innervation

• Increased risk of arrythmias

Long term effects on the kidney from sustained neurohormonal activation include:

• Decreased renal blood flow

• Increased renin release and RAAS activation

• Increased renal vascular resistance

• Desensitisation and downregulation of NPRA and NPRB

What is the SNS response to ↓CO?

1. Reduced cardiac output is sensed by baroreceptors in the aortic arch

2. This triggers SNS to be activated due to decreased aortic blood flow which releases NA

3. NA can activate 4 pathways to increase CO

   • binds B1 on heart to increase frequency and force of contraction

   • binds a1 on arterioles to cause constriction = ↑afterload

   • binds a1 on venules to cause constriction = ↑preload

   • binds B1 on kidneys to activate RAAS

4. = INCREASED cardiac WORKLOAD

What is the RAAS response to ↓CO?

1. Decreased renal blood flow is detected by baroreceptors by the kidneys which activates RAAS

2. Angiotensin II is released which:

   1. Binds AT-1R on arterioles causing constriction to increase afterload which will increase cardiac workload

      • This results in remodelling as the structure of the heart is damaged reduced CO

   2. Binds AT-1R on venules causing constriction to increase preload which will increase cardiac workload

   3. Also releases Aldosterone which increases Na+ and H2O retention which will increase fluid volume increasing preload

What is the natriuretic peptide response to ↓CO?

• BNP has opposite effect to RAAS

• Veins are dilated decreasing venous return decreasing CO

• Same with arteries which prevents remodelling

• Also drives Na and H2O secretion

• Receptors for peptides become desensitised from chronic over-activation of RAAS

• Therefore things get worse and more BNP released but that has no effect as this point and more keeps getting released

What happens in remodelling?

1. Cardiomyocyte loss

   • Necrosis

   • Apoptosis

2. Cardiomyocyte hypertrophy

3. Fibrosis

   • RAAS activation, inflammation

   • Additional connective tissue results in heart getting bigger however contraction is less efficient

   • Build up of non-conductive tissue provide pathway for alternative electrical conduction

4. Insulin resistance

5. Electrophysical changes

   • Structural alterations

What are the problems with prolonged compensation?

• Desensitisation of b1 receptors due to overproduction of noradrenaline

• Abnormal NA levels can result in arrythmias

• Frank starling - heart is overstretched and this leads to loss of function

• Increased angiotensin = increased afterload = remodelling

• Myocardial hypertrophy

Treatment for HFrEF drugs

• Diuretics

  • Furosemide

• SGLT2i

  • Dapagliflozin

  • Empagliflozin

• ACE/ARNI/ARB

  • Ramipril

  • Sacubitril/Valsartan

  • Candesartan

• MRA

  • Spironolactone

• Beta-blockers

  • Bisoprolol

  • Carvedilol

  • Nebivolol

Treatment of HFpEF

• Diuretics

• SGLT2i

• Treatment for Co-morbidities

What are the role of diuretics?

• Loop diuretics are most effective in HF

• symptomatic relief

• Decrease sodium retention and increase diuresis for pulmonary and peripheral oedema

• Decrease pre load and afterload by:

  • Blocks NKCC2 in ascending LoH to prevent fluid retention

  • Decreasing blood volume which decreases blood returning to heart

  • Works on potassium channels on arterial side and dilates them which makes it easier for ventricles to pump blood forwards

What are the side effects of diuretics

• Dehydration

• Hypotension

• Hypokalaemia

• Gout and hyperuricaemia

If normal Loop diuretics don’t work, what do we add in and why?

Metazolone (thiazide diuretic) can be used in combo to overcome resistance

What are ACEi role?

• Improves mortality

• Decreases pre load and afterload

  • Important to decrease both because if you just decreased preload, you would decrease cardiac output = bad

  • By decreasing both, less blood returns to the heart but it will become easier to pump blood forward into the systemic circulation (ejection fraction is likely to improve)

• Decreases remodelling as its driven by aldosterone and Ang 2

• E.g. captopril, lisinopril, enalapril, quinapril, ramipril

What are the side effects of ACEI?

• Dizziness

• Cough

• Hypotension

• Hyperkalaemia

MOA of ACEi

• Prevents conversion of Ang 1 to Ang 2 by blocking ACE

• With no Ang 2, vasodilation occurs and the blood pressure decreases

• This decreases cardiac workload

Why are ARBs better than ACEi in some patients?

• Less SE - increasing ace inhibitor conc will increase side effects too

• ACEi dont completely block production of AngII in all patients (e.g. Afro-caribbean patients may have chymase enzyme which can convert Angi to AngII) therefore you can get competition of ACE inhibitors

  • Due to no negative feedback, renin can still be produced and will produce AngI which will compete with ACEi for ACE = some AngII production

• by giving an ARB in these patients, the AngII receptor is completely blocked, and therefore this is more beneficial/ favourable in these patients

What are the role of BBs?

• Improve mortality

• Frontline with ACEI

• Start on low dose and increase until optimal level is achieved

What is MOA of BBs?

1. BB bind to B1 receptors on the heart to block action of NA to slow heart rate

2. This increases diastolic filling time of ventricles = Increase EDV = Increase preload

3. Ventricles can contract and push out more blood, even if their ejection fraction is still the same (e.g. reduced ejection fraction 35%)

4. CO remains constant as increased filling time compensates for decreased force of contraction

What are SE of BBs?

• DO NOT START IN COMMUNITY, ONLY IN HOSPITAL

• Hypotension

• Bradycardia

• Peripheral vasoconstriction

• Impotence

• Bronchospasm

Why are all BBs not equivalent?

• Bisoprolol - Inverse agonist of B1

• Carvedilol - Inverse agonist of B1 and a1 antagonist (dilates arteries)

• Nebivolol - Inverse agonist of B1 and increases NO = dilates veins and arteries

What do inverse agonists do and how do BB use this mechanism?

• Work to reduce response of tissue through a particular receptor in the absence of any agonist molecules

  • absence of agonist molecules, receptor shifts into the resting state. if you give an inverse agonist when its in this state, you are preventing it from moving back into its active state, therefore agonist molecule cant bind and you get no response.

  • Inverse agonists like Bisoprolol bind to B1 receptor in its inactivated state and prevent conversion back to active state preventing NA binding to B1

Why are inverse BB useful in HF?

• Reduces NA on muscle tissue = reduces force and frequency of contraction

• Stabilises inactive receptors, upregulating the number of receptors on muscle cells and therefore making tissue more sensitive to the agonist so their levels can be reduced again

• Aim is to resensitise B1 receptors again and upregulate them so levels of NA/A return back to baseline

Role of ARNIs

• Sacubitril/Valsartan

• Given in patients

  • With NYHA class 2 to 4

  • Left ventricular EF of <35%

  • Pts. taking stable dose of ACEi or ARB

MOA of ARNIs

• Has dual action by targeting RAAS and Natriuretic peptide system

1. Valsartan (ARB)

   1. Block Ang2 binding to Ang2R

      1. Vasodilation = Decreases BP

      2. Decreases Aldosterone effects on the heart and blood vessels

2. Sacubitril (Neprilising inhibitor)

   1. Inhibits Neprilysin enzyme = Increases levels of BNP and ANP = Vasodilation = inhibits RAAS system

What is used if ACE/ARB/BB are not tolerated?

• Venodilators (nitrates) = Decreases preload

• Arterial dilators (Hydralazine) = Decreases afterload

What is the SE of ACE/ARB/BB?

• Hypotension

• Headache

• Tachycardia

Role of Spironolactone

• Aldosterone antagonist by blocking MR receptor = Decreases remodelling

• Improves mortality

• Only small doses required

MOA of Spironolactone

• Mineralocorticoid receptor is blocked which reduces expression of sodium channels in the distal tubule, therefore less sodium is reabsorbed

• More sodium excreted = more water excreted

• Potassium is not involved and is therefore unchanged

SE of Spironolactone

• Gynaecomastia

• Hyperkalaemia

Alternative option to reduce SE of Spironolactone?

Eplerenone = More selective for MR = no anti-androgen effects (less man boobies)

Role of digoxin

• Increases QoL

• No effect on mortality

• Has narrow therapeutic index

• Renal clearance so use is dependant on age, weight, and renal function

MOA of Digoxin

1. Binds to K binding site of Na/K pump on cardiac myocytes = inhibition

2. Leads to increased Na levels intracellularly

3. Na/Ca pump exchanges the Na for Ca influx

4. Increase in calcium results in enhanced myocardial contractility = increase force of contraction = Increased CO

SE of Digoxin

• Arrhythmias

• Heart block

Why are SGLT-2 inhibitors useful in HF?

• there are multiple mechanisms of action however most prominent two include:

1. increased urinary sodium and glucose excretion will result in diuresis which will decrease blood volume = reduction in ventricular preload and therefore how hard the heart is having to work

2. increased sodium and glucose excretion will increase the glucagon vs.insulin ratio

   1. as the blood glucose concentration decreases, these will work to increase blood glucose again

   2. however if you are taking this drug, it will continue to remove the glucose and decrease glucose stores

   = lipolysis and improved glycaemic control which is beneficial and protective for the heart (diabetes is a risk factor, and this will decrease arterial risk factors)

Why is the bioavailability of an oral solution likely less than an oral tablet?

• Less stable in the GIT - in solution the drug is already available as molecules to automatically available for attack via hydrolysis etc.

• May be ionised/unionised in the wrong part of the GIT for absorption to occur (tablet may get farther into the GIT where drug can be adequately released)

• Dissolution of a tablet gives it more protection through the GIT to get to the correct place for absorption

Why might bioavailability of a tablet be less than that of a solution?

• Inability to fully dissolve out of the formulation

• Incomplete disintegration

• Drug itself does not have correct physiochemical properties or particle size to be able to dissolve rapidly enough

How to calculate absolute bioavailability?

• Absolute bioavailability = F

F = AUC absorbed ÷ AUC IV bolus

• To correct for different doses

F = (AUC absorbed/Dose absorbed) ÷ AUC IV bolus/Dose IV)

What are the 4 factors affecting oral bioavailability measurement/assessment?

1. Release of drug from dosage form

2. Stability in biological fluids

3. Permeability

4. Pre-systemic metabolism

• We often measure invitro (in glass) and then extrapolate to invivo (in living forms - animal or humans)

  • Therefore for measurement to be effective, there needs to be a good correlation between in vitro results and observations made in vivo

What is the biopharmaceutical classification system?

What are 3 class boundaries?

1. Solubility: drug substance considered highly soluble when the highest dose strength is soluble in 250mL or less of water over a pH range of 1-7.5 at 37ºC

2. Permeability: A drug substance is considered highly permeable when the extent of absorption in humans is greater than 90% of an administered dose, based on mass-balance or compared with an intravenous reference dose

3. Dissolution: A drug product is considered rapidly dissolving when 85% or more of the labelled amount of drug substance dissolves within 30 min using USP Apparatus 1 or 2 in a volume of 900 mL or less of buffer solutions.

What is dissolution testing used for?

1. Formulation development

2. Product characterisation (How product behaves)

3. QC

• In basic dissolution testing, the focus is on in vitro and not compared with in vivo

Release of drug from its dosage form and how it affects oral bioavailability measurement/assessment

In-vitro to in-vivo correlation is essential because here we are trying to mimic GIT conditions (but only if dissolution is the rate limiting step - if permeability is the slowest step, we probably wont see good correlation)

What can we alter to improve in vitro - in vivo correlation for drug release?

Need to use biorelevant media:

• dissolution medium which:

  • Simulates GI fluids in fed and fasted states

    • Gastric= dilute HCl pH 1.2

    • Intestinal=Phosphate buffered solution pH 6.8

• Consider pH, ion composition, surface tension, buffer capacity, bile, lecithin

• Homogenise the meal to be used in clinical study to see how drug interacts with food

  • Long-life milk - its pH and its fats and surfactants

How can food influence dissolution of a drug?

• In the fed state, presence of food raises pH

• This increases dissolution of the drug in the stomach

• In SI, pH is higher so fed and fasted states dont influence dissolution

What else can be altered to mimic the dissolution of the drug?

• Agitation to simulate mixing and stomach churning

• Change volume of fluid drug is dissolving in to mimic fed or fasted state

• Change how long the test is run for

  • Drug may be absorbed further along upper intestine

  • Even further for colon

• Note that a short test would run for 15-30 in medium to mimic the gastric fluid in a fasted state

How do we ensure drug is well absorbed in GI (In-vitro)?

• Start in acid for 20 minutes (mimic stomach)

• Mimic pH and enzyme changes from stomach to intestine

Stability in physiological fluids and how it affects oral bioavailability measurement/assessment

• The chemical stability across pH range of gut (1-8)

  • Done with buffers

• Enzymatic stability:

  • GI fluids

    • Incubate with real or stimulated GI fluid

    • Loss of 5% = Potential instability

  • Bacterial enzymes in colon

    • SR formulations

• Permeability methods can be used to identify wether stability of drug is a problem

• For drugs that are still in GIT in colon, stability in bacteria presence considered

• If absorption here still required, bioavailability can be reduced by bacterial enzymes

Permeability and how it affects oral bioavailability measurement/assessment

• A drug is considered highly permeable when extent of absorption in humans is greater than 90% of administered dose, based on mass-balance or compared with IV dose reference

• Most difficult criteria to establish due to requiring absolute bioavailability studies

What models are used to predict or measure permeability?

• Computational

  • c Log P

• Physiochemical

  • Partition coefficient

  • Immobilised artificial membrane

• Biological

  • In vitro

    • Cell culture models like Caco-2

    • Excised tissues - cells and membrane vesicles

  • In situ - vascularly perfused intestine

  • In vivo

    • Animal - intestinal loop

    • Human - Loc-I gut

What physiochemical approaches are used to predict permeability?

• Partition coefficient

  • Shake flask method (LogP or LogD)

• Computational - aka In Silico (cLogP or mLogP)

  • Looks at structure of different fragments of the molecule and how they contribute different amounts to lipophilicity, cLogP and mLogP

• HPLC (coat column with octanol)

• Immobilised artificial membranes (IAM) - well correlated with in vitro method of predicting transcellular absorption

• Log P between an oil (octanol to model biological membranes) and a water phase can predict how well it will cross a membrane

• Log D measured if aqueous phase is at particular pH - ionisation of molecule

What is the in vitro method for permeability?

• Cell culture techniques: Caco-2 model small intestine

  • Immortalised cells that come from colonic cancer cells

  • Have tight junctions, act as model for drugs absorbed in gut

Limitations to the in vitro method for permeability

• Tight junctions in these cancer colonic cells are tighter than colonic cells

• No secretion of mucus and digestive enzymes

What are transport experiments?

• Transport experiments are carried out by replacing culture medium with a buffer and measuring TER.

• Then replace the buffer with fresh buffer containing the drug in the apical chamber

• Sample at regular intervals from the basolateral chamber and determine concentration of drug in the basolateral chamber

• Sample basolaterally measures rate at which drug crosses membrane

• Mannitol used as marker to check membrane integrity

Other than permeability what do transport experiments help figure out?

• Helps us work out absorption mechanism:

  • Passive

  • Active

  • Involvement of pGP

  • Paracellular

  • Transcellular

How does this model show absorption mechanisms too

• As we increase the concentration in donor chamber, we see linear increase in green line = passive diffusion

• Red line = active process with saturation of a transporter

  • Start to see a plateau because the transporter or protein has been saturated.

  • Then do more experiments to work out the transporter

Explain the graph showing Furosemide permeability

• Graph shows that furosemide has better permeability going from the basolateral membrane to apical rather than the other way round. This could be due to action of pGP

• Going from A to B is more difficult than going from B to A, therefore our values going from B to A are much higher than going from A to B

• These are typical results for efflux pumps – the efflux pumps go from B to A, therefore if the drug goes from B to A it gets actively pumped into chamber A

• If our drug goes from A to B, we have efflux pumps that pump the drug back into A, therefore we get a much lower concentration

• If we had passive diffusion taking place both these lines would be the same

What is EGTA and what does it help us see in this model

• Chelating agent for free ions

• Ca ions responsible for tight junctions in between cells because they are divalent

• EGTA helps open tight junctions

• This helps us see if the drug can move paracellularly if the drug concentration goes up

What are the advantages of the Caco-2 model

• Can give mechanisms of drug absorption

• Non-animal - Human colon cancer cells

• Can use small amounts of drug (Less than in vivo)

• Rapid screening of many potential new drugs

• Potential toxicity can be seen

What are the limitations of the Caco-2 model

• The paracellular route is too tight in comparison to the intestinal cells and has no mucus

• If the drug is going through the paracellular route, this model may underestimate it

• This model does not take into account drugs that bind intestinal mucus

Name another permeability model?

• In situ rat perfusion model - tissue stay in the animal and still has nerve, lymphatic and blood system

• Tissue should remain viable with transport mechanism functional

What do we do after pumping drug solution into intestine of animal?

• We measure absorption and excretion of drug

• We can then assume that any drug that is lost is absorbed in the intestine of the rat

What is the experimental value of both models?

• Measures drug absorption from lumen

• Need to check there was no degradation of drug in lumen or intestinal wall

Assessment of permeability with Loc-I-Gut

Drug absorption calculated from rate of disappearance of drug from perfused section

Pre-systemic metabolism and how it affects oral bioavailability measurement/assessment

• Gut wall

  • brush border membranes

    • Remove vesicles from within them and incubate with drug to see if it gets taken up or destroyed

  • gut wall homogenate

    • Mash up and liquidise whole gut, put drug into contact and then look at the breakdown of the drug

    • Only really beneficial if you know the drug is going transcellularly

• Liver

  • Cut up liver and incubate with drug

PBPK modelling - in silico

• Describe concentration profile of drug in various over time on basis of:

  • Physiochemical properties of the drug

  • Site and means of admin

  • Physiological processes to which drug is subjected

• We use this as computer model incorporating blood flow and tissue composition to define PK of drugs

What effect does chronic HF have on bioavailability?

• Lower Cmax

• Longer Tmax

• CHF leads to decreased ability to transport drug into urine

Likely causes of this

• Delayed gastric emptying

• Decreased GI motility

• Decreased renal function

• Bowel wall oedema

What is the aim of HF treatment?

• Relieves signs and symptoms

• Prevent hospital admission

• Improves survival

• Improves QOL

• Prevents disease progression

What 4 things do you give guidance for based on EBM?

1. Drugs

2. Devices

3. Exercise

4. Lifestyle

• HF clinical trials based on EF <35%

How do we achieve these aims?

• Early and accurate diagnosis

• Prescribe in line with evidence based drugs, exercise and devices

• Encourage self assessment

• Good access to professional help - reduces hospital admission

• Good end of life care

What do we take from patient upon hospital admission?

• Detailed history

• Patient examination

  • Signs and symptoms

  • ECG

  • Chest X-ray

• Blood tests

  • Renal function

  • FBC

  • Thyroid

  • HbA1C

  • LFTs

• NT-pro BNP

• ECG

What diuretics are used for HF control?

• Loop

  • IV then step down to oral after ensuring stability

  • Smallest dose to control congestion

  • Bumetanide for ascites pts. as better absorbed

• Thiazide

  • Used alone in mild HF

  • Ineffective in poor renal function <30mL/min

  • Monitor potassium, sodium, magnesium and calcium

  • May exacerbate diabetes and gout

• Loop and thiazide combination

  • Only when fluid retention is very resistant

  • Can happen when new drug started but previous isn’t held - CHECK KIDNEY FUNCTION

Name the 4 pillars of HF treatment

• ACEI/ARB or ARNI

• BB

• MRA

• SGLT2i

What are some SE of ACEI?

• Hypotension

  • Dizziness

  • Start small dose then increase and take at bedtime

• Persistent dry cough

  • Non-productive and worse and night

  • May need alt. drug

• Affects kidneys and electrolytes

  • Routine blood tests and kidney function and potassium levels check

• Angioedema - Swelling of lips, tongue, airways

Why are ARNI’s not combined with ACEi instead?

• Sacubitril and ACEi = high risk of angioedema

• NEPRILYSIN + ACEi = HIGHLY CONTRAINDICATED