Pharmacology of Propranolol

Introduction/Overview

Propranolol hydrochloride represents a foundational agent in the pharmacotherapeutic arsenal, being the first clinically successful beta-adrenoceptor antagonist. Its introduction in the 1960s marked a paradigm shift in the management of cardiovascular diseases and established a new drug class with diverse therapeutic applications. As a prototypical non-selective beta blocker, propranolol’s pharmacology provides a critical framework for understanding the entire class of beta-adrenergic blocking agents. The drug’s clinical relevance extends from its primary cardiovascular indications to a wide array of neurological, psychiatric, and endocrine conditions, underscoring its importance as a versatile therapeutic tool. Mastery of propranolol’s pharmacology is essential for medical and pharmacy students, as it illuminates fundamental principles of autonomic nervous system modulation, receptor pharmacology, and the translation of molecular action to clinical effect.

Learning Objectives

• Describe the chemical classification of propranolol and its position within the broader category of beta-adrenergic antagonists.
• Explain the detailed molecular mechanism of action, including competitive antagonism at beta-1 and beta-2 adrenoceptors and the relevance of membrane-stabilizing activity.
• Analyze the pharmacokinetic profile of propranolol, including its absorption, extensive first-pass metabolism, distribution, and elimination pathways.
• Identify the approved therapeutic indications for propranolol and evaluate the evidence supporting its common off-label uses.
• Recognize the spectrum of adverse effects, contraindications, and significant drug interactions associated with propranolol therapy, and apply this knowledge to special patient populations.

Classification

Propranolol is definitively classified within the therapeutic category of beta-adrenergic blocking agents, commonly referred to as beta blockers. Its classification can be further refined based on pharmacological properties that dictate its clinical behavior and application.

Therapeutic and Pharmacological Classification

The primary classification is as a non-selective beta-adrenoceptor antagonist. This denotes its ability to bind with relatively equal affinity to both beta-1 and beta-2 adrenergic receptor subtypes. This non-selectivity is a defining characteristic that differentiates it from cardioselective agents like atenolol or metoprolol, which preferentially block beta-1 receptors. Furthermore, propranolol is characterized as a competitive antagonist, meaning it competes with endogenous catecholamines (epinephrine and norepinephrine) for binding sites on the beta-adrenoceptor, thereby reversibly inhibiting receptor activation. It lacks intrinsic sympathomimetic activity (ISA), meaning it does not partially activate the receptor while blocking it. However, propranolol does possess significant membrane-stabilizing activity (MSA), also known as a quinidine-like or local anesthetic effect. This property, relevant at high concentrations, involves the inhibition of sodium channels in cardiac and neuronal membranes.

Chemical Classification

Chemically, propranolol is an aryloxypropanolamine. Its systematic name is 1-(Isopropylamino)-3-(1-naphthyloxy)propan-2-ol hydrochloride. The molecular structure consists of a naphthalene ring system linked via an ether oxygen to a propanolamine side chain, which contains a secondary isopropylamine group. This structure is integral to its affinity for the beta-adrenoceptor. The presence of the naphthyl ring, rather than a substituted phenyl ring found in some other beta blockers, contributes to its high lipophilicity. This lipophilic nature profoundly influences its pharmacokinetic behavior, including good gastrointestinal absorption, high protein binding, extensive hepatic metabolism, and significant penetration across the blood-brain barrier.

Mechanism of Action

The therapeutic and adverse effects of propranolol are primarily mediated through its antagonism of beta-adrenergic receptors, though ancillary properties may contribute under specific conditions.

Receptor Interactions and Pharmacodynamics

Propranolol exerts its principal effects as a competitive, reversible antagonist at beta-adrenoceptors. These receptors are G-protein coupled receptors (GPCRs) whose activation by catecholamines typically stimulates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. By occupying the receptor’s ligand-binding site, propranolol prevents agonist binding and subsequent G-protein activation.

• Beta-1 Adrenoceptor Antagonism: Blockade of cardiac beta-1 receptors is responsible for most of its cardiovascular effects. This results in decreased sinoatrial (SA) node automaticity (negative chronotropy), reduced atrioventricular (AV) node conduction velocity (negative dromotropy), and diminished myocardial contractility (negative inotropy). The net hemodynamic consequences include a reduction in heart rate, cardiac output, and myocardial oxygen demand. Renin release from the juxtaglomerular cells of the kidney is also inhibited via beta-1 blockade, contributing to its antihypertensive effect.
• Beta-2 Adrenoceptor Antagonism: Antagonism at beta-2 receptors mediates several extrapulmonary effects and contributes to certain adverse reactions. This includes unopposed alpha-adrenergic mediated vasoconstriction in peripheral vessels (potentially causing cold extremities), inhibition of glycogenolysis and gluconeogenesis in the liver and skeletal muscle, and blockade of bronchodilation in the airways. The latter effect is clinically significant, as it can precipitate bronchospasm in susceptible individuals.

Molecular and Cellular Mechanisms

At the molecular level, propranolol’s binding alters the conformation of the beta-adrenoceptor, preventing its coupling to the stimulatory G-protein (G_s). Consequently, the activation cascade involving adenylyl cyclase and the conversion of ATP to cAMP is inhibited. Reduced intracellular cAMP levels lead to decreased activation of protein kinase A (PKA). In cardiac myocytes, this results in reduced phosphorylation of L-type calcium channels, ryanodine receptors, and phospholamban, ultimately leading to decreased calcium influx and sequestration, which underlies the negative inotropic and chronotropic effects. In the juxtaglomerular cells, reduced cAMP diminishes renin secretion, lowering activity of the renin-angiotensin-aldosterone system (RAAS).

Ancillary Properties: Membrane-Stabilizing Activity

At concentrations significantly higher than those required for beta-blockade (typically > 100 ng/mL), propranolol exhibits membrane-stabilizing activity. This effect is independent of beta-adrenoceptor blockade and involves inhibition of voltage-gated fast sodium channels, similar to class I antiarrhythmic drugs. It decreases the rate of depolarization (phase 0) of the cardiac action potential. While this property may contribute to its efficacy in certain arrhythmias like digitalis-induced tachyarrhythmias, it is generally not relevant at standard therapeutic doses used for hypertension or angina. The MSA is, however, implicated in the direct cardiotoxic effects seen in acute overdose.

Central Nervous System Effects

Due to its high lipophilicity, propranolol readily crosses the blood-brain barrier. The mechanism for its CNS effects, such as in essential tremor, anxiety, and migraine prophylaxis, is not fully elucidated but may involve several pathways. These include blockade of central beta-adrenoceptors, reduction of noradrenergic outflow from the locus coeruleus, and possibly a peripheral component for conditions like tremor. Its efficacy in migraine prophylaxis is thought to relate to inhibition of cortical spreading depression and blockade of beta receptors on cerebral vasculature, preventing vasodilation.

Pharmacokinetics

The pharmacokinetic profile of propranolol is complex and characterized by high interindividual variability, largely influenced by its lipophilicity and extensive metabolism.

Absorption

Propranolol is almost completely absorbed from the gastrointestinal tract following oral administration. However, its oral bioavailability is relatively low and variable, typically ranging from 25% to 35% for immediate-release formulations. This significant reduction is due to a pronounced first-pass effect in the liver. Nearly all of the absorbed drug passes through the portal circulation and undergoes extensive pre-systemic metabolism before reaching the systemic circulation. Bioavailability increases proportionally with dose, suggesting that hepatic extraction may become saturated at higher doses. The presence of food can enhance bioavailability by increasing splanchnic blood flow and potentially slowing gastric emptying, allowing more gradual presentation of the drug to metabolic enzymes. Absorption is generally rapid, with peak plasma concentrations (C_max) achieved within 1 to 3 hours post-ingestion.

Distribution

Propranolol is highly lipophilic, which facilitates its wide distribution throughout body tissues. The volume of distribution is large, approximately 3 to 6 L/kg, indicating extensive tissue binding. It readily crosses the blood-brain barrier and the placenta, and is distributed into breast milk. Plasma protein binding is extensive, primarily to albumin and alpha-1 acid glycoprotein, with a binding percentage of approximately 90%. The binding to alpha-1 acid glycoprotein, an acute-phase reactant, can increase during stress, inflammation, or myocardial infarction, potentially altering the free fraction of the drug.

Metabolism

Hepatic metabolism is the principal route of propranolol elimination. The process is predominantly mediated by the cytochrome P450 enzyme system, specifically the CYP2D6 and CYP1A2 isoenzymes. The primary metabolic pathways include:

1. Ring Oxidation: Hydroxylation at the 4-position of the naphthalene ring, catalyzed mainly by CYP2D6, to form 4-hydroxypropranolol. This metabolite possesses some beta-blocking activity but is usually present in low concentrations.
2. Side-Chain Oxidation: N-dealkylation to form naphthoxylactic acid, an inactive metabolite.
3. Glucuronidation and Sulfation: Conjugation reactions of the parent drug and its oxidative metabolites.

The metabolism via CYP2D6 exhibits genetic polymorphism. Approximately 5-10% of Caucasian populations are poor metabolizers (PMs), lacking functional CYP2D6 activity. These individuals may achieve plasma propranolol concentrations 3 to 5 times higher than extensive metabolizers (EMs) following the same oral dose, potentially leading to enhanced beta-blockade and a greater risk of adverse effects. The formation of 4-hydroxypropranolol is markedly reduced in PMs.

Excretion

Propranolol is eliminated almost exclusively by hepatic metabolism, with less than 1% of an administered dose excreted unchanged in the urine. The metabolites are primarily excreted in the urine, with a small fraction appearing in the feces via biliary elimination. The elimination half-life (t_1/2) of immediate-release propranolol is relatively short, ranging from 3 to 6 hours in most individuals. However, the duration of pharmacological effect often exceeds the plasma half-life, particularly for beta-1 blockade, which may persist for up to 12 hours. This disconnect is attributed to the slow dissociation of the drug from the beta-adrenoceptor. Sustained-release formulations are designed to prolong absorption, allowing for once- or twice-daily dosing.

Pharmacokinetic Parameters and Dosing Considerations

The relationship between plasma concentration and therapeutic effect is not linear for all indications, and wide interpatient variability necessitates individualized dosing. For antiarrhythmic and antianginal effects, a correlation with plasma levels is more apparent. The typical therapeutic plasma concentration range is broad, often cited as 50 to 100 ng/mL. Because of its short half-life and the duration of effect, dosing schedules for immediate-release formulations typically begin at 10-40 mg two to four times daily, with titration based on clinical response and tolerability. The extensive first-pass metabolism means that oral doses are much higher than potential intravenous doses, which are used in acute settings like thyrotoxicosis or certain arrhythmias.

Therapeutic Uses/Clinical Applications

Propranolol has a broad spectrum of clinical applications, both approved and off-label, reflecting its fundamental role in modulating sympathetic nervous system activity.

Approved Indications

• Hypertension: As an antihypertensive, propranolol is used alone or in combination with other agents. Its mechanism involves reducing cardiac output, inhibiting renin release, and possibly reducing central sympathetic outflow. It is generally not considered a first-line agent for uncomplicated hypertension in current guidelines but remains a valuable option, particularly in patients with concomitant conditions like angina, migraine, or essential tremor.
• Angina Pectoris: By reducing heart rate, contractility, and blood pressure, propranolol decreases myocardial oxygen demand, making it effective for the prophylaxis of chronic stable angina. It can increase exercise tolerance and reduce the frequency of anginal episodes.
• Cardiac Arrhythmias: It is indicated for the management of supraventricular tachyarrhythmias (e.g., atrial fibrillation, atrial flutter) by slowing AV nodal conduction, and for ventricular arrhythmias, particularly those associated with catecholamine excess (e.g., during anesthesia, pheochromocytoma, or thyrotoxicosis). It is also used for prophylaxis in mitral valve prolapse and for suppressing arrhythmias in the long QT syndrome (LQT1 subtype).
• Migraine Prophylaxis: Propranolol is effective in reducing the frequency and severity of migraine headaches. The therapeutic effect is prophylactic and not for aborting an acute migraine attack.
• Essential Tremor: It is considered a first-line pharmacologic treatment for essential tremor, often providing significant symptomatic improvement in postural and kinetic tremor.
• Hypertrophic Obstructive Cardiomyopathy (HOCM): By reducing myocardial contractility and heart rate, it alleviates outflow tract obstruction and improves symptoms such as angina, dyspnea, and syncope.
• Pheochromocytoma: Used only after adequate alpha-adrenergic blockade has been established (to prevent unopposed alpha-mediated vasoconstriction and hypertensive crisis), propranolol controls tachycardia and other beta-mediated symptoms.
• Myocardial Infarction (Secondary Prophylaxis): Long-term use post-myocardial infarction reduces the risk of reinfarction and mortality, though cardioselective agents are often preferred in modern practice.

Common Off-Label Uses

• Anxiety Disorders: Particularly useful for performance anxiety or situational anxiety (e.g., stage fright) due to its ability to blunt peripheral autonomic symptoms like tachycardia and tremor. Its use in generalized anxiety disorder is less common.
• Thyrotoxicosis (Thyroid Storm): Rapidly controls tachycardia, tremor, and anxiety associated with hyperthyroidism. It may also inhibit the peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).
• Portal Hypertension and Variceal Bleeding Prophylaxis: Non-selective beta blockers like propranolol reduce portal pressure by decreasing cardiac output (beta-1 effect) and inducing splanchnic vasoconstriction via unopposed alpha activity (beta-2 effect), making them first-line for primary and secondary prophylaxis of variceal hemorrhage in cirrhosis.
• Akathisia: Induced by antipsychotic medications, akathisia often responds to low-dose propranolol.
• Post-Traumatic Stress Disorder (PTSD): May be used to attenuate autonomic hyperarousal and potentially interfere with memory reconsolidation, though evidence is evolving.

Adverse Effects

The adverse effect profile of propranolol is largely predictable from its pharmacological actions, with most being extensions of its therapeutic beta-blockade.

Common Side Effects

These effects are often dose-dependent and may diminish with time or dose reduction.

• Cardiovascular: Bradycardia, heart block, hypotension, cold extremities (due to reduced peripheral perfusion), and Raynaud’s phenomenon.
• Central Nervous System: Fatigue, lethargy, dizziness, insomnia, vivid dreams or nightmares, depression, and impaired memory. These are more common with lipophilic agents like propranolol.
• Respiratory: Bronchoconstriction, which can be severe in patients with asthma or chronic obstructive pulmonary disease (COPD), manifesting as wheezing and dyspnea.
• Metabolic/Endocrine: May mask the tachycardia associated with hypoglycemia in diabetic patients, potentially delaying its recognition. It can also exacerbate hyperkalemia in susceptible patients.
• Gastrointestinal: Nausea, vomiting, diarrhea, or constipation.

Serious or Rare Adverse Reactions

• Exacerbation of Heart Failure: In patients with compensated heart failure dependent on sympathetic drive, beta blockade can precipitate acute decompensation. However, when initiated cautiously at very low doses, certain beta blockers are cornerstone therapies for heart failure with reduced ejection fraction (HFrEF); propranolol is generally not used for this indication.
• Severe Bronchospasm: Can be life-threatening in patients with reactive airway disease.
• Cardiogenic Shock: Particularly with overdose or in susceptible individuals.
• Worsening of Prinzmetal (Variant) Angina: Unopposed alpha-adrenergic activity after beta-2 blockade may lead to coronary vasoconstriction.
• Peripheral Ischemia and Gangrene: Rare but serious, related to reduced peripheral circulation.
• Hypersensitivity Reactions: Rare occurrences of rash, fever, agranulocytosis, or thrombocytopenia.

Black Box Warnings and Major Risks

Propranolol carries specific, serious warnings. Abrupt discontinuation of therapy, particularly in patients with coronary artery disease, can precipitate a rebound phenomenon characterized by worsening angina, ventricular arrhythmias, acute myocardial infarction, or even sudden death. This is attributed to upregulation of beta-adrenoceptors during chronic blockade. Withdrawal should be gradual over 1-2 weeks. Furthermore, its use is contraindicated in patients with bronchial asthma due to the risk of fatal bronchospasm. It is also contraindicated in sinus bradycardia, greater than first-degree heart block, and cardiogenic shock.

Drug Interactions

Propranolol is involved in numerous pharmacokinetic and pharmacodynamic drug interactions, necessitating careful review of concomitant medications.

Major Pharmacodynamic Interactions

• Other Negative Chronotropes/Inotropes: Concomitant use with calcium channel blockers (especially verapamil or diltiazem), digoxin, or other antiarrhythmics can lead to additive bradycardia, heart block, or heart failure.
• Antihypertensives: Additive hypotensive effects with other antihypertensive agents, including diuretics, ACE inhibitors, and alpha-blockers.
• Insulin and Oral Hypoglycemics: Increased risk of hypoglycemia, with masking of the warning signs (tachycardia, tremor).
• Sympathomimetics: Drugs like epinephrine, contained in some local anesthetics, can lead to severe hypertension and bradycardia due to unopposed alpha-adrenergic effects after beta-2 blockade.
• Non-Dihydropyridine Calcium Channel Blockers (Verapamil, Diltiazem): Potentiate negative inotropic and chronotropic effects; combination is generally avoided.

Major Pharmacokinetic Interactions

• Enzyme Inducers: Drugs like phenobarbital, phenytoin, rifampin, and cigarette smoking can induce CYP1A2 and potentially CYP2D6, increasing the metabolism of propranolol and reducing its plasma concentration and efficacy.
• Enzyme Inhibitors: Cimetidine (a non-specific CYP inhibitor), fluoxetine, paroxetine (CYP2D6 inhibitors), and ciprofloxacin (CYP1A2 inhibitor) can decrease propranolol clearance, leading to increased plasma levels and potential toxicity.
• Aluminum Hydroxide Gel: This antacid may reduce the gastrointestinal absorption of propranolol if administered concurrently.
• Lidocaine: Propranolol may reduce the clearance of lidocaine, increasing the risk of lidocaine toxicity, likely by reducing hepatic blood flow.

Contraindications

Absolute contraindications include bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree heart block (without a pacemaker), cardiogenic shock, decompensated heart failure, and severe hypersensitivity to the drug. It is also contraindicated in patients with pheochromocytoma unless alpha-blockade has been initiated first.

Special Considerations

The use of propranolol requires careful adjustment and monitoring in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or risk-benefit ratios.

Pregnancy and Lactation

Propranolol is classified as Pregnancy Category C (US FDA) under the old classification system, indicating that risk cannot be ruled out. Animal studies have shown adverse effects, and human data suggest a possible association with intrauterine growth restriction, neonatal bradycardia, hypoglycemia, and respiratory depression at birth. Its use during pregnancy should be reserved for situations where the benefit clearly outweighs the potential risk, such as in maternal thyrotoxicosis or severe hypertension. It crosses the placenta and is excreted in breast milk. While the amount in milk is considered low, nursing infants may be exposed, and monitoring for symptoms of beta blockade (e.g., bradycardia, lethargy) is advised if the mother is treated.

Pediatric Considerations

Propranolol is used in pediatric populations for conditions such as infantile hemangioma (a significant off-label use), hypertension, arrhythmias, and hyperthyroidism. Pharmacokinetics in children can differ; they may metabolize the drug more rapidly than adults, sometimes requiring higher mg/kg doses or more frequent dosing. Close monitoring of heart rate, blood pressure, and blood glucose is essential. Its use in infants for hemangioma requires specialist supervision due to risks of bradycardia, hypotension, hypoglycemia, and bronchospasm.

Geriatric Considerations

Elderly patients often have reduced hepatic blood flow and possibly impaired hepatic enzyme function, which can decrease propranolol clearance and increase plasma levels. They may also have increased sensitivity to the pharmacodynamic effects, such as bradycardia, hypotension, and CNS effects like sedation or confusion. Age-related declines in renal function have minimal impact on propranolol elimination but may affect metabolite clearance. The principle of “start low and go slow” is paramount, with careful titration from a low initial dose.

Renal Impairment

Since less than 1% of propranolol is excreted unchanged by the kidneys, dosage adjustment is not typically required in renal impairment. However, the accumulation of inactive metabolites is possible in severe renal failure, though their clinical significance is unclear. Hemodialysis does not remove a significant amount of propranolol due to its high protein binding and large volume of distribution.

Hepatic Impairment

Hepatic impairment significantly alters propranolol pharmacokinetics. Reduced hepatic blood flow and impaired metabolic enzyme activity decrease first-pass metabolism and systemic clearance. This leads to markedly increased bioavailability and prolonged elimination half-life. Patients with cirrhosis or severe liver disease are at risk for excessive and prolonged beta blockade, potentially leading to hepatic encephalopathy (due to reduced cardiac output and splanchnic perfusion) or complications like ascites. Dose reduction is necessary, and therapy should be initiated at very low doses with close monitoring. Its use in portal hypertension is a specific therapeutic indication, but requires careful hemodynamic assessment.

Summary/Key Points

• Propranolol is the prototypical non-selective beta-adrenoceptor antagonist with competitive, reversible action at both beta-1 and beta-2 receptors. It possesses membrane-stabilizing activity at high concentrations and is highly lipophilic.
• Its mechanism underlies diverse effects: negative chronotropy, inotropy, and dromotropy in the heart; inhibition of renin release; bronchoconstriction; and reduced peripheral perfusion.
• Pharmacokinetics are defined by nearly complete oral absorption but low (25-35%) and variable bioavailability due to extensive hepatic first-pass metabolism via CYP2D6 and CYP1A2. It has a large volume of distribution, penetrates the CNS, and has a short plasma half-life (3-6 hours) but longer duration of receptor effect.
• Major approved indications include hypertension, angina, cardiac arrhythmias, migraine prophylaxis, essential tremor, hypertrophic obstructive cardiomyopathy, and secondary prevention post-MI.
• Significant off-label uses encompass performance anxiety, thyrotoxicosis, portal hypertension prophylaxis, and antipsychotic-induced akathisia.
• The adverse effect profile is an extension of its pharmacology, including bradycardia, fatigue, bronchospasm, cold extremities, and CNS disturbances. Abrupt withdrawal can cause a rebound hyperadrenergic state.
• Important drug interactions occur with other cardioactive drugs, enzyme inducers/inhibitors, and insulin. It is contraindicated in asthma, significant bradycardia/heart block, and cardiogenic shock.
• Special caution is required in pregnancy, lactation, pediatrics, the elderly, and patients with hepatic impairment, where dosage adjustment and close monitoring are essential.

Clinical Pearls

• When initiating therapy for hypertension or angina, start with a low dose (e.g., 10-20 mg BID-TID) and titrate upward gradually based on heart rate and blood pressure response.
• Always taper the dose over 1-2 weeks when discontinuing chronic therapy, especially in patients with known ischemic heart disease.
• In patients with a history of mild COPD or asthma, a cardioselective beta blocker is strongly preferred over propranolol. If propranolol must be used, extreme caution and pulmonary function monitoring are required.
• Be vigilant for masked hypoglycemia in diabetic patients, educating them to recognize other signs like sweating and confusion.
• Consider the potential for CYP2D6 polymorphism when patients exhibit unexpectedly pronounced effects or toxicity at standard doses.
• For acute intravenous administration (e.g., in thyroid storm), doses are much smaller than oral doses, and administration must be slow with continuous hemodynamic monitoring.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.