Pharmacological control of cardiac output

How can drugs affect heart function directly and indirectly?

Directly:

• Force of contraction

• Rate/rhythm

Indirectly:

• Vasculature

• Blood volume/composition - diuretics

What is cardiac output and how is it calculated?

Volume of blood ejected for each ventricular contraction

CO = HR x SV

HR = heart rate

SV = stroke volume

What is stroke volume determined by?

• Pre-load - also known as the left ventricular end-diastolic pressure

• After-load - is the pressure in the wall of the left ventricle during ejection

• Inotropy - contractility

What determines contractility?

The contractile machinery of myocardial striated muscle is the same as that of voluntary striated muscle - it involves Ca²⁺

What are inotropic and chronotropic drugs?

Medicines that alter the force of contraction of the heart muscle

There are 2 main types of inotropic and chronotropic drugs:

• Positive inotropes: increase the force of myocardial contraction, increase Ca²⁺

• Negative inotropes: decrease the force of myocardial contraction, decrease Ca²⁺

• Positive chronotropes increase heart rate

• Negative chronotropes decrease heart rate

Inotropic drugs

• Cardiac glycosides

• Sympathomimetics

• Phosphodiesterase inhibitors

What are positive inotropic drugs?

Increase myocardial contractility, allowing the heart to pump blood more forcefully

They may be used when the heart is unable to generate sufficient force to maintain adequate circulation, such as in certain cases of acute heart failure or cardiogenic shock

Examples:

• Dobutamine

• Digoxin

• Milrinone

What are negative inotropic drugs?

Decrease the force of myocardial contraction

They can reduce the workload and oxygen demand of the heart and are useful in conditions such as hypertension, angina and certain cardiac arrhythmias, although their use depends on the patient's clinical condition

Examples:

• Beta-blockers, such as bisoprolol and carvedilol

• Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem

Digoxin mechanism

• Inhibits cell membrane Na⁺/K⁺ ATPase which leads to reversal of the usual Na⁺/Ca²⁺ exchange

• An increased intracellular calcium level results which in myocardial muscle has the effect of enhancing the strength of contraction (positive inotropism)

• Affects the electrical physiology of the heart → blocks AV conduction and reduces heart rate by enhancing vagal nerve activity

Uses of digoxin

• The principal indication is permanent/persistent atrial fibrillation (AF) with a fast ventricular rate - although it is not the preferred first-line medication

• NICE guidance suggests that digoxin should be used as first-line in patients with AF who also have co- existing heart failure

• Where heart failure is due to left ventricular dysfunction it should be reserved for patients in whom the condition has worsened despite the use of first line treatment (no impact on mortality)

Digoxin toxicity

• Has a low therapeutic effect

• Patients should be reviewed for clinical signs

Signs and symptoms of toxicity:

• Bradycardia

• Arrhythmia

• Nausea, vomiting

• Confusion

• Visual disturbances, blurred or yellow vision

• Toxicity- more pronounced with metabolic or electrolyte disturbance (Potassium levels?)

Treatment might require in emergency - Digoxin-specific-antibody fragments

Digoxin monitoring

Monitoring is important, both to ensure that the correct dosage is being given and also that factors which might provoke toxicity - e.g. renal dysfunction and hypokalaemia - are not developing

Inotropic drugs - receptors position and action

• Alpha receptors: expressed in the vasculature; agonists cause vasoconstriction

• Beta1 receptors: expressed in the heart, agonists are positively chronotropic

• Beta2 receptors: expressed predominantly in the vasculature; agonists cause vasodilation

Sympathomimetics - dobutamine

• IV use, use is mainly limited to hospital

• Acts predominately on beta 1 (some beta 2 action)

• Used in cardiogenic shock on cardiac care units because beta 2 action offloads the heart and beta 1 action increases the force of contraction

Adrenaline and noradrenaline

Adrenaline

• Actions on alpha, beta 1 & 2 receptors

• Used in cardiac arrest and turns patient into heart-brain preparation, attempting to spare the brain and myocardium from ischaemia by causing massive peripheral vasoconstriction (α effects) and strong positive chronotropia (β1 effects)

Noradrenaline (norepinephrine)

• Is an α-adrenoreceptor agonist has vasoconstrictor action

Phosphodiesterase inhibitors

• Now rarely used in clinical practice trials, have shown an increase risk of mortality

• Used only in severe heart failure as an adjunctive therapy. Associated with arrhythmias and increased mortality with chronic use

Examples: enoximone, milrinone

Phosphodiesterase inhibitors mechanism

• Increased cAMP, through its coupling with other intracellular messengers, increases contractility (inotropy), heart rate (chronotropy)

• Cyclic-AMP is broken down by an enzyme called cAMP-dependent phosphodiesterase (PDE)

• The phosphodiesterase inhibitors act by inhibiting the degradation of intracellular concentration of cyclic AMP

What is heart failure?

A condition caused by the heart failing to pump enough blood around the body at the right pressure

Types of heart failure

1. Heart failure caused by left ventricular systolic dysfunction (LVSD)

• The part of the heart that pumps blood around the body (left ventricle) becomes weak

2. Heart failure with preserved ejection fraction (HFPEF)

• Result of the left ventricle becoming stiff, making it difficult for the heart chamber to fill with blood

3. Heart failure caused by diseased or damaged heart valves

Symptoms of heart failure

General principles for treatment of heart failrure

1. Medicines adherence

• Keep dosing regimens as simple as possible and ensure that patients and carers are kept fully informed

2. Multidisciplinary approach to care

• Heart failure care should be delivered by a multidisciplinary team with an integrated approach across the healthcare community

3. Comorbidities

• Manage comorbidities according to the NICE pathways on hypertension, myocardial infarction: secondary prevention and diabetes

The NYHA classification is the most widely-used stratification tool for assigning patients with HF to functional classes

First line treatment of heart failure

Treatment combinations

• Offer an angiotensin-converting enzyme (ACE) inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA) and a sodium-glucose cotransporter-2 (SGLT2) inhibitor to people with heart failure with reduced ejection fraction [2025]

• For people on the maximum tolerated dose of each of the 4 medicines who continue to have symptoms of heart failure, consider switching the ACE inhibitor to an angiotensin receptor-neprilysin inhibitor (ARNI)

Alternative treatment combinations if certain medicines aren’t tolerated for heart failure

• For people with heart failure with reduced ejection fraction who have symptoms of intolerance to ACE inhibitors (other than angioedema), offer an ARNI, beta-blocker, MRA and SGLT2 inhibitor [2025]

For people with angioedema after taking an ACE inhibitor, or who have symptoms of intolerance to ARNIs:

• Offer a beta-blocker, MRA and SGLT2 inhibitor and consider an ARB [2025]

Specialist treatment for heart failure - ivabradine

Recommended as an option in NICE technology appraisal guidance for treating HF with reduced ejection fraction

What does ivabradine do?

• Inhibits the If channel in the sinus node

• Its only known pharmacological effect is to slow the heart rate in patients in sinus rhythm

• It has been shown to reduce cardiovascular death or hospitalisation for heart failure by 18%

• It also improved left ventricular function and quality of life

• Ivabradine should be initiated by a heart failure specialist

Ivabradine counselling

• Avoid grapefruit juice

• May cause temporary luminous visual phenomena (a temporary brightness in the field of vision). If this happens, be careful when driving or using machines at times when there could be sudden changes in light intensity, especially when driving at night

• You may feel side effects such as breathlessness, fatigue and irregular heartbeat

Hydralazine in combination with nitrate

• If ACE inhibitors, ARNIs and ARBs are not tolerated, seek specialist advice and consider hydralazine in combination with nitrate. [2010, amended 2025]

• Seek specialist advice about whether to offer hydralazine in combination with nitrate (especially if the person is of African or Caribbean ethnicity and has moderate to severe heart failure [New York Heart Association class III/IV] with reduced ejection fraction)

When to offer digoxin

Offer digoxin to people with worsening or severe heart failure with reduced ejection fraction despite optimised treatment combinations. Seek specialist advice before starting treatment

Calcium-channel blockers

Avoid verapamil, diltiazem and short-acting DHP agents in people with heart failure with reduced ejection fraction

Starting and monitoring medication use - tailoring treatment

Use the person's medical history and findings from their clinical assessment, their frailty status, prognosis and preferences when deciding: which specific medicines and medicine combinations to use

• The order and timing for introducing each medicine

• The initial dose of each medicine and any subsequent dose increments

• When and how to optimise the dose of each medicine

• Shared decision making

• Primary care prescribers should consider seeking advice from a heart failure specialist before starting someone on an angiotensin receptor- neprilysin inhibitor (ARNI)

ACE inhibitors, ARNIs, ARBs and MRAs

• Before prescribing an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor-neprilysin inhibitor (ARNI), angiotensin II receptor blocker (ARB) or mineralocorticoid receptor antagonist (MRA), measure the person's renal function and electrolyte levels [2025]

• 1 to 2 weeks after starting treatment

• 1 to 2 weeks after each dose increment

• Every 3 to 6 months once the maximum tolerated dose has been established

• Any time renal function may be compromised

Beta-blockers

• Do not withhold treatment with a beta-blocker solely because of age or the presence of peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease [2010]

• Assess for heart rhythm, heart rate and conduction abnormalities using a 12-lead ECG before deciding whether to prescribe a beta-blocker [2025]

• Do not offer a beta-blocker to people with second-degree or third-degree heart block who do not have a pacemaker or to people with bradycardia (that is, a heart rate of less than 50 beats per minute)

• Assess heart rate and clinical status after each dose increment [2010]

• For people with symptoms and bradycardia, consider repeating a 12-lead ECG after each dose increment [2025]

Beta-blockers counselling

• Don’t stop taking unless doctor advises

• May experience side effects such as fatigue, cold hands & feet, dizziness

• Don’t abruptly stop beta-blockers, as this risks an MI or arrhythmia

Dapagliflozin and empagliflozin

• Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

• Dapagliflozin and empagliflozin are now recommended by NICE for treating symptomatic chronic heart failure, on the advice of a heart failure specialist. Dapagliflozin and empagliflozin can be used in symptomatic chronic heart failure with reduced ejection fraction