Cardiac Pharmacology

Heather Melrose, Jonas de Jong

Cardiovascular disease including heart disease, arrhythmias and hypertension, is the leading cause of morbidity and mortality in the Western world. There are numerous devastating conditions affecting the heart and/or the vasculature, leading to high demand for cardiovascular drugs. This chapter focuses on some key therapeutic targets within the cardiovascular system and the drugs used to combat cardiovascular disease.

Renin-Angiotensin-Aldosterone System

RAAS schematic

The renin-angiotensin-aldosterone system (RAAS) is an important hormone-based pathway within the body that regulates fluid balance and thus systemic blood pressure. The system is activated by decreases in blood volume or pressure detected in two ways: a drop in blood pressure detected by baroreceptors (pressure sensors) located in the carotid sinus or a drop in flow rate through the kidneys, detected by the juxtaglomerular apparatus. The body responds to these stimuli to effect a restoration in blood pressure via the actions of three hormones; renin, angiotensin and aldosterone. Following the detected drop in blood pressure, the enzyme renin is released from specialised cells within the kidney. The substrate of renin is the inactive precursor of angiotensin I, angiotensinogen. Angiotensin I is then enzymatically converted by angiotensin converting enzyme (ACE) into angiotensin II, a hormone with various actions throughout the body that ultimately increase blood pressure, restoring fluid balance within the body.

Angiotensin II causes increases in blood pressure by actions at various sites:

• Adrenal Glands: Angiotensin II augments release of the steroid hormone aldosterone, which acts locally to augment sodium retention and potassium secretion from the kidney. The net effect of this is water retention, thus restoring fluid balance.

• Kidneys: Angiotensin II also increases sodium retention via direct actions on renal proximal tubules, as well as affecting glomerular filtration rate and renal blood flow.

• Cardiovascular System: Angiotensin II is a potent endogenous vasoconstrictor, causing resistance arteries and veins to constrict, raising blood pressure. Furthermore in both the blood vessels and the heart, prolonged increases in Angiotensin II encourage cell growth and resultant hypertrophy.

• Central Nervous System: In the brain, Angiotensin II acts on the posterior pituitary gland, stimulating release of antidiuretic hormone (ADH, also known as Arginine Vasopressin (AVP)). ADH increases water reabsorption in the renal collecting ducts. Angiotensin II also acts on the subfornical organ within the brain to cause increased thirst, encouraging water intake.

Chronic activation of the RAAS system can lead to deleterious remodelling and increased inflammation in the heart, vasculature and kidneys, as well as hypertension and chronic kidney disease.

Neural Control of the Cardiovascular System

Interaction between the sympathic and parasympathic nervous system and the heart

Sympathetic (Adrenergic) Nervous System

The adrenergic nervous system is a vital component of many processes throughout the body, including the cardiovascular system. Circulating catecholamines (e.g. adrenaline and noradrenaline) bind to and activate adrenergic receptors on cell membranes. Adrenergic receptors are a class of G-protein coupled receptors that elicit a variety of tissue-specific effects and exist in several subtypes.

Vasculature

The predominant receptor subtype present in blood vessels is the a1-adrenergic receptor, activation of which by catecholamine binding causes activation of the phospholipase-C (PLC), inositol triphosphate (IP3), diacylglycerol (DAG) intracellular signalling pathway. This ultimately results in myocyte contraction, vasoconstriction and consequent increases in systemic blood pressure.

Heart

Although the heart is myogenic, that is the impetus for contraction is self-initiated, the output of the heart is influenced by the central nervous system. The net effect of the sympathetic system on the heart is to increase cardiac output. The adrenergic receptors found in the heart belong to the ß-receptor subfamily and include ß1 and ß3 receptors. Catecholamine binding to ß1-receptors in the heart causes increases in cardiac output via a number of mechanisms: positive chronotropic effects, positive inotropic effects increased automaticity and conduction in both ventricular myocytes and the atrioventricular (AV) node. However ß3-receptor activation antagonises these actions, producing a negative inotropic effect and providing an inbuilt control system within the heart.

Prolonged increase catecholamine levels in the circulation (e.g. when secreted from adrenal tumours or times of stress) can lead to chronic cardiovascular problems such as hypertension and arrhythmias.

Parasympathetic Nervous System

The parasympathetic system relies on the binding of the neurotransmitter acetylcholine (Ach) to muscarinic receptors, and has various roles throughout the body.

Vasculature

Although blood vessels do express muscarinic receptors, they do not receive cholinergic innervation; however application of exogenous Ach results in a swift and profound vasodilation.

Heart

Activation of muscarinic receptors (M2-subtype) in the heart by Ach released from the vagus nerve causes a reduction in cardiac output via opposite effects to adrenergic stimulation: negative chronotropic effects and decreases in AV node conduction as well as decreasing the force of atrial contractions.

Platelet/Clotting System

Platelet activation and inhibition operates through surface receptors on platelets. Feedback loops enhance platelet activation (e.g. ADP released by platelets increases platelet activation, through the ADP receptor)

Platelets (also known as thrombocytes) are small cells lacking nuclei that are responsible for haemostasis, or blood clotting. Damage or injury leading to blood loss and exposure of extracellular collagen fibres is detected, activating platelets. Once activated, platelets become adhesive, sticking to both the damaged vessel wall and each other, forming a clump of cells, or ‘clot’, helping to dam the vessel leak. They then begin to secrete cytokines that encourage invasion of fibroblasts present in the surrounding tissue which form a more permanent patch, either by creating healthy tissue, or depositing extracellular matrix to form a scar.

There are several conditions in which abnormal clotting can be damaging to the body; excess clotting can lead to vascular blockage and ischaemia or stroke; less commonly, deficient clotting can lead to excess blood loss, for example in haemophilia. To combat these diseases, there are drugs that modulate the clotting process.

Anti-coagulants

Drugs that prevent clotting (anti-coagulants) are important in those with an increased risk of clotting-mediated damage such as a stroke or ischaemia.

As well being an analgesic and anti-pyretic, Aspirin is an anti-thrombotic agent given in low doses to those at risk of damage from clotting (e.g. following a heart attack). Aspirin’s anti-coagulant actions come from its suppression of key pro-clotting factors such as prostaglandins and thromboxanes via irreversible inactivation of the PTGS cyclooxygenase enzyme. This suppression of factors such as thromboxane A₂ reduces platelet aggregation and thus prevents clot formation.

P2Y₁₂ inhibitors such as clopidogrel exert their anti-coagulant effect via inhibition of the P2Y₁₂ subtype of the platelet ADP receptor. By blocking P2Y₁₂, these drugs prevent activation of platelets and the formation of the fibrin network needed for clotting.

Drugs such as abciximab and tirofiban prevent clotting via inhibition of the glycoprotein IIb/IIIa receptor preventing both platelet activation and aggregation.

Newer oral anticoagulants (NOACs), also referred to as direct oral anticoagulants (DOACs), include two classes based on their mechanism of action:

• **Direct thrombin inhibitors** (e.g. dabigatran) bind directly to thrombin (factor IIa), inhibiting its ability to convert fibrinogen into fibrin, thereby preventing the formation of fibrin clots.
• **Factor Xa inhibitors** (e.g. rivaroxaban, apixaban, edoxaban) selectively and reversibly inhibit factor Xa, a key enzyme in the coagulation cascade responsible for the conversion of prothrombin (factor II) to thrombin (factor IIa). By reducing thrombin generation, they effectively prevent thrombus formation.

NOACs are recommended by the European Society of Cardiology (ESC) as first-line therapy for stroke prevention in patients with atrial fibrillation, unless contraindicated. They have a predictable anticoagulant effect, rapid onset of action, and fewer drug-food interactions compared to vitamin K antagonists (e.g. warfarin).

Understanding the Cholesterol/LDL System in Cardiovascular Health

Lipid mechanisms of action of common drugs

The cholesterol/LDL (low-density lipoprotein) system plays a pivotal role in cardiovascular health, acting as a key component in the development of atherosclerosis, a primary cause of cardiovascular diseases (CVD). This system's importance lies in its contribution to the transport of cholesterol, a vital lipid molecule, throughout the body. Cholesterol is essential for various biological functions, including the synthesis of cell membranes, hormones, and vitamin D. However, its management within the circulatory system is crucial to preventing adverse cardiovascular outcomes.

Cholesterol Transport and LDL's Role

Cholesterol travels through the bloodstream encapsulated within lipoproteins, which are particles made up of lipids and proteins. These lipoproteins are classified based on their density; low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are among the most significant in terms of cardiovascular risk. LDL is often referred to as "bad" cholesterol because it contributes to the formation of plaque, a thick, hard deposit that can clog arteries and make them less flexible, a condition known as atherosclerosis. HDL, on the other hand, is known as "good" cholesterol because it helps remove cholesterol from the arteries, transporting it back to the liver for excretion or reuse.

LDL and Atherosclerosis

When LDL cholesterol levels are high, LDL particles can penetrate the endothelial lining of the arteries, becoming oxidized by free radicals. This oxidized LDL is recognized by the immune system as a foreign invader, attracting macrophages that ingest the LDL, transforming into foam cells. These foam cells accumulate to form fatty streaks, the earliest signs of atherosclerosis. Over time, these fatty streaks can develop into larger plaques, which can narrow the arteries and restrict blood flow. If a plaque ruptures, it can lead to the formation of a blood clot, which can cause a heart attack or stroke.

Regulation of Cholesterol/LDL Levels

The body's cholesterol levels are regulated by a complex interplay of synthesis, absorption, and excretion. The liver synthesizes cholesterol and secretes it into the bloodstream as part of very low-density lipoproteins (VLDL). As VLDL particles deliver their triglyceride content to cells, they become LDL particles. The liver also plays a key role in removing excess cholesterol from the blood, using receptors that bind to LDL particles and remove them from circulation.

Dietary intake of cholesterol and saturated fats can influence LDL levels, as can genetic factors, such as mutations in the LDL receptor gene, which can lead to familial hypercholesterolemia, a condition characterized by very high levels of LDL cholesterol and an increased risk of heart disease. Lifestyle factors, including diet, exercise, and smoking cessation, are primary interventions for managing LDL levels, alongside pharmacological treatments such as statins, which lower cholesterol levels by inhibiting its synthesis in the liver.

The Integral Role of LDL in Cardiovascular Health

Understanding the cholesterol/LDL system is essential for the prevention and management of cardiovascular diseases. By maintaining healthy levels of LDL cholesterol through lifestyle modifications and, when necessary, medication, individuals can significantly reduce their risk of developing atherosclerosis and its associated complications. This system's management is a cornerstone of cardiovascular health, underscoring the importance of regular monitoring and proactive interventions to maintain heart health and prevent disease.

To manage cardiovascular risk factors like serum lipids, various medication groups are essential:

• Statins (e.g., Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin) lower cholesterol by inhibiting HMG-CoA reductase.
• Fibrates (e.g., Fenofibrate, Gemfibrozil) target triglycerides and increase HDL.
• PCSK9 inhibitors (e.g., Evolocumab, Alirocumab) significantly reduce LDL cholesterol by blocking PCSK9 protein.
• Bempedoic acid lowers LDL-C by inhibiting ATP citrate lyase.

These medications, alongside lifestyle modifications, form the cornerstone of cardiovascular disease prevention and management.

Pharmacokinetics

When administering drugs to a patient, it is crucial to know several facts about the drug in order to maximise efficacy and minimise side-effects/toxicity. These include information about what dose is effective, how long the drug remains active in the body, how quickly it is broken down/removed from the body, and how easily the body can absorb/use that drug. The following table details these pharmacokinetic properties and how they are calculated:

Property	Description	Standard units (Abbreviation)	Formula
Dose	Amount of active drug given to patient	mg (D)	Drug Specific (From clinical studies)
Concentration	Amount of drug in a given plasma volume	µg/ml (C)	= D / Vd
EC50	The concentration of drug needed to elicit a response halfway between zero and maximal responses.	µg/ml (EC50)	y = bottom + (Top-Bottom)/(1+ [x/EC50] Hill Coefficient)
Volume of Distribution	The theoretical volume the drug would occupy if distributed uniformly throughout the tissues to elicit the current plasma concentration.	L (Vd)	D / C
Elimination Constant (Rate)	The rate at which the drug is removed from the body.	h-1 (Ke)	ln(2) / t1/2 or CL / Vd
Bioavailability	How much of the administered dose is available for actual use by the body.	no units as expressing a fraction (f)	100 × (AUC (po)×D (iv))/(AUC (iv)×D (po)) AUC = Area under curve po = oral administration iv = intravenous administration
Cmax or Cmin	The maximum (Cmax) / minimum (Cmin) plasma drug concentration reached following drug administration	µg/ml (Cmax or Cmin)	Identified via direct measurement of plasma C
tmax	The time it takes for a drug to reach Cmax following administration	h (tmax)	Identified via direct measurement of plasma C over time
Half-life	The time it takes for a drug to reach half its original concentration	h (t1/2)	ln(2) / Ke
Drug Clearance	The volume of plasma cleared of the drug over a set time	l/h (CL)	Vd x Ke or D / Area under curve

Common Drug-Drug Interactions

It is important to be aware of the interactions that can occur between concomitantly administered drugs, as they may effect efficacy and/or toxicity, or produce adverse side effects. Such interactions could for example affect drug absorption, drug bioavailability or efficacy, or combine to produce unwanted metabolites, as well as possibly having effects on clinical analyses. If a combination of two drugs decreases the effect of one or both of them, the interaction is termed an antagonistic effect; however if, conversely, a combination of two drugs enhances the effect of one or both of them, the interaction is termed a synergistic effect. Drugs that act on the cardiovascular system are high in interactivity, which is an issue as cardiovascular patients normally receive more than one drug. Some common drug—drug interactions related to cardiovascular drugs are listed below:

Drug	Drugs that ↑ drug action	Drugs that ↓ drug action
Digoxin	Diuretics Antiarrhythmics Macrolide antibiotics Cholestyramine Neomycin Keto- and intraconazole Calcium antagonists Cyclosporine, indomethacin HMG CoA reductase inhibitors Benzodiazepines Amiodarone Verapamil	Rifampicin Antacids (liquid)
Warfarin	Furosemide Amiodarone Sulfa Macrolide and quinolone antibiotics NSAIDs	Azathioprine Phenobarbitone Carbamazepine Dexamethasone Prednisolone Rifampicin Vitamin K Raloxifene
Clopidogrel	Rifampicin Caffeine Methylxanthines Phosphodiesterase inhibitors	Statins Calcium channel blockers Warfarin Proton pump inhibitors
Furosemide		NSAIDs Phenytoin Colesevelam
ACE Inhibitors	NSAIDs Probenecid Calcium channel blockers	Indomethacin Antacids
ß-blockers	Amiodarone Calcium channel blockers Diltiazem Phenoxybenzamine	Phenobarbital Rifampicin Cimetidine Antacids (liquid) NSAIDs
Statins	Amiodarone Verapamil Fibrates Amprenavir Diltiazem	Nevirapine Rifampicin

There are several mechanisms by which drugs are broken down by the body, usually via degradation by enzymes. One common family of enzymes involved in drug metabolismis the cytochrome P450 (CYP) family; a large, diverse group of enzymes that encourage oxidation of a variety of substrates, both endogenous (e.g. steroid hormones) and exogenous (e.g. toxins and drugs). CYP enzymes account for up to 75% of drug metabolism, aiding some drugs to form their active compounds but mostly deactivating drugs into inactive metabolites to be excreted. CYP enzymes can influence drug actions in several ways; they can increase drug metabolism (either increasing action via formation of the active by-product or decreasing action by metabolism of the active drug) or their action can be inhibited by drugs that compete for access to the CYP enzymes active site, preventing the normal interaction between drug and enzyme. Many drugs exert their interactions with other drugs viainterference with the CYP system. For example, if Drug A is metabolised by CYP and Drug B inhibits CYP activity, co-administration will result in a decreased bioavailability of Drug A. In humans there are 18 families and 43 subfamilies of the CYP group of enzymes, which target different substrates. Some CYP enzymes important in cardiovascular medicine, their cardiovascular-drug substrates and some of their interactions are shown in the table below:

Enzyme	Substrates (e.g.)	Inhibitors (e.g.)	Inducers (e.g.)
CYP2C19	Clopidogrel Propranolol Warfarin	Moclobemide Chloramphenicol Many anti-convulsants (Valproate) Proton pump inhibitors (Omeprazole)	Rifampicin Carbamazepine Prednisone
CYP3A4	Donepezil Statins (Atorvastatin) Ca-channel blockers (Nifedipine) Amiodarone Dronedarone Quinidine PDE5 Inhibitors (Sildenafil) Kinins Caffeine Eplerenone Propranolol Salmeterol Warfarin Clopidogrel	Protease inhibitors (Ritonavir) Macrolides (Clarithromycin) Chloramphenicol Nefazodone Some Ca-channel blockers (Verapamil) Cimetidine Some azole anti-fungals (Ketaconazole) Grapefruit juice	Some anti-convulsants (Carbamazepine) Baribiturates (Phenobarbital) St. John’s Wort Some reverse transcriptase inhibitors (Efavirenz) Some Hypoglycaemics (Pioglitazone) Glucocorticoids Modafinil
CYP2C9	Fluvastatin Angiotensin receptor II agonists (losartan) Warfarin Torasemide	Some azole anti-fungals (Fluconazole) Amiodarone Antihistamines (Cyclizine) Chloramphenicol Fluvastatin Fluvoxamine Probenecid Sertraline	Rifampicin Secobarbital
CYP2D6	ß-blockers (Propranolol) Class I anti-arrythmics (Flecainide) Donepezil	SSRIs (Fluoxetine) Quinidine Sertraline Terbinafine Amiodarone Cinacalcet Ritonavir Antipsychotics (Haloperidol) Antihistamines (Promethazine) Metoclopramide Ranitidine Mibefradil	Rifampicin Dexamethasone Glutethimide

In addition to drug-drug interactions, the actions of many drugs are also affected by food or drink. For example, care should be taken with alcohol consumption with many kinds of drugs, as it can put stress on the liver which is already working hard to metabolise drugs in the body. Grapefruit juice too can cause issues, as it is known to inhibit CYP3a. For more information of interactions between drugs and food/drinks see this guide: General Use of Medicine

Common Cardiovascular Drugs

Cardiovascular Drugs

Drug Type	Examples (generic name)	Indications	Typical Dosage	Guidelines / Class of Indication	Side Effects (Prevalence %)
Anti-hypertensives
Diuretics	Furosemide	Oedema	Furosemide: 20-40mg once daily		Mild gastro-intestinal disturbances, pancreatitis, hepatic encephalopathy, postural hypotension, temporary increase in serum-cholesterol and triglyceride concentration, hyperglycaemia, acute urinary retention, electrolyte disturbances, metabolic alkalosis, blood disorders, hyperuricaemia, visual disturbances, tinnitus and deafness, and hypersensitivity reactions (including rash, photosensitivity, and pruritus).
		Resistant Hypertension	Furosemide: 40-80mg once daily	Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IC Esc1
ACE Inhibitors	Lisinopril, Captopril	Hypertension	Lisinopril: 10mg once daily initially, maintenance 20mg once daily	Hypertension: Class IA Esc2 Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IA Esc1 Hypertension in diabetics: Class IA Esc3	Hypotension (2.4%), renal impairment, persistent dry cough, angioedema, rash pancreatitis, upper respiratory-tract symptoms (2-10%), gastro-intestinal symptoms (1-2%), altered liver function tests, cholestatic jaundice, hepatitis, fulminant hepatic necrosis and failure, hyperkalaemia (2%), hypoglycaemia, blood disorders including thrombocytopenia, leucopenia, neutropenia, headache (3%), dizziness (2-12%), fatigue, malaise, taste disturbance, paraesthesia, bronchospasm, fever, serositis, vasculitis, myalgia (3%), arthralgia, positive antinuclear antibody, raised erythrocyte sedimentation rate, eosinophilia, leucocytosis, and photosensitivity.
		Heart Failure	Lisinopril: 2.5-5mg once daily initially, maintenance 20-35mg once daily	Post STEMI: Class IA Esc4 Diabetic patients: Class IC Esc2 Symptomatic (NYHA class II-IV) HF: Class IA; Acute heart failure with ACS: Class IA Esc1
		Prophylaxis Following MI	Lisinopril: 5mg within 24 hours of onset, 5mg after 24 hours, then 10mg after 48 hours
		Diabetic nephropathy	Lisinopril: 10-20mg once daily
Angiotensin Receptor Blockers	Losartan, Candesartan	Hypertension	Losartan: 50mg once daily	Hypertension: Class IA Esc2 Hypertension in diabetics: Class IA Esc3	Gastro-intestinal disturbances (<3%), dizziness (14%), angina, palpitation, oedema, dyspnoea, headache (14%), malaise, urticaria, pruritus, rash;
		Left ventricular hypertrophy	Losartan: 12.5-150mg daily	LVH: Class IB Esc4
		Diabetic nephropathy	Losartan: 50mg daily
Angiotensin Receptor Neprilysin Inhibitors	Sacubitril/Valsartan (Entresto)	Heart Failure with reduced ejection fraction (HFrEF)	49/51mg twice daily initially; target dose 97/103mg twice daily	Symptomatic (NYHA class II-IV) HF: Class IA Esc1	Hypotension (18%), renal dysfunction (3%), hyperkalemia (16%), cough, dizziness, angioedema (<1%), fatigue. Should not be used with ACE inhibitors (36-hour washout period required) or in pregnancy.
		Heart Failure with mildly reduced or preserved ejection fraction	49/51mg twice daily initially; target dose 97/103mg twice daily	HFmrEF and HFpEF: Class IA Esc1
Alpha Blockers	Doxazosin, Prazosin	Hypertension	Doxazosin: 1mg once daily initially, increased to 4-8mg once daily		Drowsiness, hypotension (notably postural hypotension) (10-70% initially), syncope (1%), asthenia, dizziness, depression, headache (8-18%), dry mouth, gastro-intestinal disturbances, oedema, blurred vision (<5%), intra-operative floppy iris syndrome, rhinitis (<4%), erectile disorders (including priapism), tachycardia and palpitations (7-14%), gastrointestinal side-symptoms (4-5%), hypersensitivity reactions including rash, pruritus and angioedema.
		Congestive Heart Failure	Doxazosin: 4-16mg daily
		Raynaud's Syndrome	Doxazosin: 1-4mg daily
Beta Blockers	Atenolol, Metoprolol, Propranolol	Hypertension	Atenolol: 25-50mg daily Metoprolol: 100-200mg daily		Gastro-intestinal disturbances (2-4%); bradycardia, heart failure, hypotension, conduction disorders, peripheral vasoconstriction, bronchospasm, dyspnoea; headache, fatigue, sleep disturbances (2-5%), paraesthesia, dizziness (2-5%), vertigo, psychoses; sexual dysfunction; purpura, thrombocytopenia; visual disturbances; exacerbation of psoriasis, alopecia; rarely rashes and dry eyes.
		Angina	Atenolol: 100mg once/twice daily Metoprolol: 50-100mg twice daily	ACS: Class IIaB Esc2 Angina in symptomatic (NYHA class II-IV) HF and LVD: Class IA Esc1
		Arrhythmias	Atenolol: 50-100mg daily Metoprolol: 100-200mg daily	Atrial fibrillation: Class IA; Polymorphic VT: Class IB Esc4 Symptomatic (NYHA class II-IV) HF, LVD and AF: Class IA; Management of VA in HF: Class IA Esc1 SVT: Class IIbC; Wide QRS-complex tachycardia of unknown origin: Class IIIC; Sinus tachycardia: Class IC; Poorly tolerated AVNRT with haemodynamic intolerance: Class IIaC; Recurrent symptomatic AVNRT: Class IC; Documented PSVT with only dual AV-nodal pathways or single echo beats demonstrated during electrophysiological study and no other identified cause of arrhythmia: Class IC; Infrequent, well tolerated AVNRT: Class IB; Focal junction tachycardia: Class IIaC; Nonparoxysmal junctional tachycardia: Class IIaC; WPW Syndrome: Class IIaC; AVRT, poorly tolerated: Class IIbC; Since or infrequent AVRT episode(s): Class IIaB; Acute treatment of Focal Atrial Tachycardia: Class IIaC; Prophylactic therapy for AT: Class IC; AF (Poorly tolerated): Class IIaC; AF (Stable flutter): Class IC; Prophylaxis of SVT during pregnancy: Class IIaB Acc5
Calcium Channel Blockers	Nifedipine, Verapamil, Diltiazem	Hypertension	Nifedipine: 30-60mg once daily (slow-release)	Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IA Esc1	Gastro-intestinal disturbance (2-11%); hypotension (1-5%), oedema (7-29%), vasodilatation, palpitation; headache (7-35%), dizziness (3-27%), lethargy (4-6%), asthenia (10-12%); less commonly tachycardia (<1-7%), syncope (<1%), chills, nasal congestion, dyspnoea (<3%), anxiety, sleep disturbance (<2%), vertigo (<3%), migraine, paraesthesia, tremor (1-8%), polyuria, dysuria, nocturia, erectile dysfunction (<2%), epistaxis, myalgia, joint swelling, visual disturbance (<2%), sweating (<2%), hypersensitivity reactions (<1%); rarely anorexia, gum hyperplasia, mood disturbances, hyperglycaemia, male infertility, purpura (<1%), and photosensitivity reactions (<1%); also reported dysphagia, intestinal obstruction, intestinal ulcer, bezoar formation, gynaecomastia, agranulocytosis, and anaphylaxis;
		Raynaud's Syndrome	Nifedipine: 20-40mg once daily (slow-release)
		Angina (prophylaxis)	Nifedipine: 30-60mg once daily (slow-release)	Angina in symptomatic (NYHA class II-IV) HF and LVD: Class IIaA Esc1
Heart Failure Medications
Angiotensin Receptor Neprilysin Inhibitors	Sacubitril/Valsartan (Entresto)	Heart Failure with reduced ejection fraction (HFrEF)	49/51mg twice daily initially; target dose 97/103mg twice daily	Symptomatic (NYHA class II-IV) HF: Class IA Esc1	Hypotension (18%), renal dysfunction (3%), hyperkalemia (16%), cough, dizziness, angioedema (<1%), fatigue. Should not be used with ACE inhibitors (36-hour washout period required) or in pregnancy.
		Heart Failure with mildly reduced or preserved ejection fraction	49/51mg twice daily initially; target dose 97/103mg twice daily	HFmrEF and HFpEF: Class IA Esc1
SGLT2 Inhibitors	Empagliflozin, Dapagliflozin, Canagliflozin, Sotagliflozin	Heart Failure with reduced ejection fraction	Empagliflozin: 10mg once daily Dapagliflozin: 10mg once daily	Symptomatic (NYHA class II-IV) HF with reduced EF: Class IA Esc1	Genital mycotic infections (10%), urinary tract infections (4-8%), volume depletion (1-3%), hypotension, euglycemic diabetic ketoacidosis (<0.1%), acute kidney injury (2%), hypoglycemia (when used with insulin or insulin secretagogues), increased urination, thirst, and cholesterol levels. Rare serious adverse effects include Fournier's gangrene and lower limb amputations (particularly with canagliflozin).
		Heart Failure with preserved ejection fraction	Empagliflozin: 10mg once daily Dapagliflozin: 10mg once daily	HFmrEF and HFpEF: Class I Esc1
		Type 2 Diabetes with high CV risk or CKD	Empagliflozin: 10-25mg once daily Dapagliflozin: 10mg once daily Canagliflozin: 100-300mg once daily	Type 2 diabetes with CV disease: Class IA Esc2 Type 2 diabetes with CKD: Class I Esc1
Anti-Arrhythmics
Class I (sodium channel blockers)	Flecainide, Lidocaine, Procainamide	Ventricular Arrhythmias	Flecainide: 50-100mg twice daily	Sustained VT and VF: Class IIbC Esc4 Pre-excited SVT/AF: Class IB; Wide QRS-complex tachycardia of unknown origin: Lidocaine (Class IIbB) / Procainamide (Class IB); Wide QRS-complex tachycardia of unknown origin with LVD: Class IB; Focal junction tachycardia: Class IIaC; WPW Syndrome: IIaC; AVRT, poorly tolerated: IIaC; Single or infrequent AVRT episode(s): Class IIbC; Acute treatment of Focal Atrial Tachycardia: Class IIaC; Prophylactic therapy for AT: Class IIaC; AF (Stable flutter): Class IIbA; Prophylaxis of SST during pregnancy: Class IIbB Acc5	Oedema, pro-arrhythmic effects (1-13%); dyspnoea; nervous-system side-effects including dizziness, asthenia, fatigue, fever; visual disturbances (13-28%); rarely pneumonitis, hallucinations, depression, confusion, amnesia, dyskinesia, convulsions, peripheral neuropathy; also reported gastro-intestinal disturbances (1-4%), anorexia, hepatic dysfunction, flushing, syncope, drowsiness, tremor, vertigo, headache, anxiety, insomnia, ataxia, paraesthesia, anaemia, leucopenia, thrombocytopenia, corneal deposits, tinnitus, increased antinuclear antibodies, hypersensitivity reactions (including rash, urticaria, and photosensitivity), increased sweating.
Class II (Beta blockers)	(See above)	(See above)	(See above)		(See above)
Class III (Potassium channel blockers)	Amiodarone, Sotalol	Ventricular, Arrhythmias	Amiodarone: 200mg 2-3 times daily	Sustained VT and VF: Class IIaC; Polymorphic VT: Class IC Esc4 Management of VA in HF: Class IA; Prevention of VA in HF: Class IIbB Esc1 SVT: Class IIBC; Wide QRS-complex tachycardia of unknown origin: Class IB; Wide QRS-complex tachycardia of unknown origin with LVD: Class IB; Recurrent AVNRT unresponsive to beta blocker or calcium-channel blocker and patient not desiring RF ablation: Class IIbC; Focal junction tachycardia: Class IIaC; WPW Syndrome: IIaC; AVRT, poorly tolerated: Class IIaC; Since or infrequent AVRT episode(s): Class IIbB; Acute treatment of Focal Atrial Tachycardia: Class IIaC; Prophylactic therapy for AT: Class IIaC; AF (Poorly tolerated): Class IIbC; AF (Stable flutter): Class IIbC; Prophylaxis of SVT during pregnancy: Class IIIC Acc5	Gastro-intestinal disturbances (2-20%)), taste disturbances, hepatic disturbances (up to 50%); bradycardia; pulmonary toxicity (1-17%); tremor (9-59%), sleep disorders; hypothyroidism (5-10%), hyperthyroidism (5-10%); reversible corneal microdeposits (up to 98%); phototoxicity, persistent slate-grey skin discoloration (1-7%), injection-site reactions; less commonly onset or worsening of arrhythmia, conduction disturbances, peripheral neuropathy (1-105) and myopathy; very rarely sinus arrest, bronchospasm, ataxia (2-37%), benign intracranial hypertension, headache, vertigo, epididymo-orchitis, impotence, haemolytic or aplastic anaemia, thrombocytopenia, rash, hypersensitivity including photosensitivity (2-20%), anaphylaxis on rapid injection, hypotension (10-30%), respiratory distress syndrome, sweating, and hot flushes
Class IV (Calcium channel blockers)	(See above)	(See above)	(See above)		(See above)
	Digoxin	Supra-ventricular Arrhythmias	Acute: 0.75-1.5mg over 24 hours; Maintenance: 125-150µg daily	SVT: Class IIbC; WPW Syndrome: Class IIIC; AVRT, poorly tolerated: Class IIIC; Since or infrequent AVRT episode(s): Class IIIC; Prophylaxis of SVT during pregnancy: Class IC Acc5	Gastro-intestinal disturbances (vomiting, diarrhoea, anorexia, abdominal pain) (25%); arrhythmias (up to 50%), AV conduction disturbances (50%); nervous system disturbances (dizziness, apathy, confusion, headache, fatigue, weakness) (25%); blurred or yellow vision; rash, eosinophilia, depression, anorexia, intestinal ischaemia and necrosis, psychosis, gynaecomastia on long-term use, and thrombocytopenia.
		Heart Failure	62.5-125 µg daily	Symptomatic (NYHA class II-IV) HF: Class IIbB Symptomatic (NYHA class II-IV) HF, LVD and AF: Class IB; Acute HF with AF and VT: Class IC Esc1
Anti-platelet Drugs
	Aspirin	Prevention of thrombotic cerebro- or cardio-vascular disease	75mg once/day	Prevention in AF: Class IC; Prevention in diabetic patients: IIaB Esc2 Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA Esc1 Prevention in hypertensive patients with CV events: Class IA; Prevention in hypertensive patients without CV history but with reduced renal function/high risk: Class IIbA Esc3 Post-MI: Class Ia Esc3	Bronchospasm (10-30% in asthmatics); gastro-intestinal irritation (up to 83%), gastro-intestinal haemorrhage (occasionally major), also other haemorrhage (e.g. intracranial (0.5%), subconjunctival), chest pain (8.3%), oedema (4.5%), hypertension (4.3%).
		Pain / pyrexia	300-600mg every 4-6 hours as necessary
	Clopidogrel	Prevention of thrombotic events (esp. when warfarin not tolerated)	75mg once/day	Prevention in diabetic patients: IIaB; Primary and secondary prevention of stroke: Class IB Esc2 Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA Esc1 Acute phase of coronary artery syndrome: Class IB; Non-cardioembolic cerebral ischaemic events: Class IA Esc3	Dyspepsia (5.2%), abdominal pain (5.6%), diarrhoea (4.5%); bleeding disorders including gastro-intestinal (2.0%) and intracranial (0.4%), nausea (3.4%), vomiting, gastritis, flatulence, constipation, gastric and duodenal ulcers, headache (7.6%), epistaxis (2.9%), dizziness (6.2%), paraesthesia, leucopenia, decreased platelets (very rarely severe thrombocytopenia), eosinophilia, rash (4.2%), pruritus (3.3%), vertigo, colitis, pancreatitis, hepatitis (<1%), acute liver failure, hypertension (4.3%), chest pain (8.3%), oedema (4.1%), vasculitis, confusion, hallucinations, taste disturbance, cough (3.9%), fatigue (4.8%) stomatitis, bronchospasm, interstitial pneumonitis, pyrexia (2.2%), blood disorders including thrombocytopenic purpura (5.3%), agranulocytosis, neutropenia (0.04%) and pancytopenia and hypersensitivity-like reactions (<0.1%)including fever, glomerulonephritis, arthralgia, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus.
		Acute myocardial infarction	300mg daily initially then 75mg once/day	Post STEMI: Class IA Esc4
		Acute coronary syndrome	300mg daily initially then 75mg once/day	ACS: Class IIaC Esc2
	Prasugrel	Prevention of thrombotic events.	60mg bolus then 5-10mg once daily	Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA Esc1 Acute phase of coronary artery syndrome: Class IB Esc3	Haemorrhage (11.3%) (including gastro-intestinal (1.5%) and intracranial), haematoma, haematuria, hypertension (7.5%), hypotension (3.9%), headache (5.5%), back pain (5.0%), dyspnoea (4.9%), nausea (4.6%), dizziness (4.1%), cough (3.9%), fatigue (3.7%), chest pain (3.1%), arrhythmias including atrial fibrillation (2.9%) and bradycardia (2.9%), rash (2.8%), pyrexia (2.7%), oedema (2.7%), diarrhoea (2.3%), hypercholesterolaemia/hyperlipidaemia (7.5%), anaemia, rash,hypersensitivity reactions including angioedema (0.06%), thrombocytopenia (0.06%), thrombotic thrombocytopenic purpura.
	Ticragelor	Prevention of thrombotic events.	180mg bolus then 90mg twice daily	Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA Esc1 Acute phase of coronary artery syndrome: Class IB Esc3	Dyspnoea (13.8%), haemorrhage, bruising; nausea (4.3%), vomiting, diarrhoea (3.7%), hypertension (3.8%), hypotension (3.2%), back pain (3.6%), abdominal pain, dyspepsia, gastritis, dizziness (4.5%), chest pain (3.7%), headache (6.5%), cough (4.9%), rash, pruritus, fatigue (3.2%), constipation, arrhythmias including atrial fibrillation (4.2%), paraesthesia, confusion, hyperuricaemia, raised serum creatinine (7.4%), vertigo.
Vitamin K Antagonists
	Warfarin	Prevention of thrombotic/ embolic events (esp. after prosthetic valve insertion)	5-10mg initially then tailored to individual (usually 3-9mg once daily at the same time)		Haemorrhage, nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia, purpura, rash, 'purple toes', skin necrosis (increased risk in patients with protein C or protein S deficiency)
	Acenocoumarol	Prevention of thrombotic/ embolic events (esp. after prosthetic valve insertion)	4mg initially, followed by 1-8mg daily		Haemorrhage, nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia, purpura, rash, 'purple toes', skin necrosis (increased risk in patients with protein C or protein S deficiency)
Non-vitamin K Antagonist Oral Anticoagulants (NOACs)
Direct Thrombin Inhibitors	Dabigatran	Prevention of stroke and systemic embolism in non-valvular atrial fibrillation	150mg twice daily (110mg twice daily if >80 years, GFR 30-50 mL/min, or increased bleeding risk)	Prevention of stroke in AF: Class IA Esc3	Dyspepsia (10%), gastritis, esophagitis, gastroesophageal reflux (1-3%), abdominal pain (3%), diarrhea (3%), bleeding (including gastrointestinal 1-2%, intracranial <1%), hypersensitivity reactions (<0.1%), hepatic dysfunction. Highest renal elimination (80%) among NOACs; contraindicated if CrCl <30 mL/min.
		Treatment and prevention of deep vein thrombosis and pulmonary embolism	150mg twice daily after 5-10 days of parenteral anticoagulation	VTE treatment: Class IA Esc3
		Prevention of VTE after knee or hip replacement	110mg 1-4 hours after surgery then 220mg once daily for 10 days (knee) or 28-35 days (hip)	VTE prophylaxis post-surgery: Class IA Esc3
Factor Xa Inhibitors	Rivaroxaban, Apixaban, Edoxaban	Prevention of stroke and systemic embolism in non-valvular atrial fibrillation	Rivaroxaban: 20mg once daily with food (15mg if CrCl 15-49 mL/min) Apixaban: 5mg twice daily (2.5mg twice daily if ≥2 of: age ≥80 years, weight ≤60kg, or serum creatinine ≥133μmol/L) Edoxaban: 60mg once daily (30mg if CrCl 15-50 mL/min or body weight ≤60kg)	Prevention of stroke in AF: Class IA Esc3	Bleeding (major 2-3%, clinically relevant non-major 4-7%), nausea (1-3%), anemia (1-2%), rash (1-2%), abnormal liver function tests (1-2%), thrombocytopenia (<1%). Rivaroxaban and edoxaban must be taken with food. Varying degrees of renal elimination: edoxaban (50%), rivaroxaban (35%), apixaban (27%). Apixaban has lowest bleeding risk among NOACs. All contraindicated with CrCl <15 mL/min.
	Treatment of deep vein thrombosis and pulmonary embolism	Rivaroxaban: 15mg twice daily for 21 days, then 20mg once daily Apixaban: 10mg twice daily for 7 days, then 5mg twice daily Edoxaban: 60mg once daily after 5-10 days of parenteral anticoagulation	VTE treatment: Class IA Esc3
	Prevention of recurrent deep vein thrombosis and pulmonary embolism	Rivaroxaban: 10-20mg once daily Apixaban: 2.5mg twice daily Edoxaban: 60mg once daily (30mg if CrCl 15-50 mL/min or body weight ≤60kg)	VTE recurrence prevention: Class IA Esc3
	Prevention of VTE after knee or hip replacement	Rivaroxaban: 10mg once daily for 2 weeks (knee) or 5 weeks (hip) Apixaban: 2.5mg twice daily for 10-14 days (knee) or 32-38 days (hip)	VTE prophylaxis post-surgery: Class IA Esc3
Lipid-Lowering Drugs
Statins	Simvastatin, Atorvastatin	Primary hyper-cholesterolaemia, combined hyperlipidaemia	Simvastatin: 10-20mg once daily	Dyslipidaemia: Class IA; Low HDL-C: Class IIbB; Elderly patients with CVD: IB; Elderly patients with no CVD but CV risk factors: IIbB; Type I diabetes: IC; Patients with CKD: IIaC; Transplant patients: Class IIaB; PAD: Class IA; HIV patients: IIaC Esc2 Hypertension in diabetics: Class IA; ACS: Class IA Esc3	Oedema (2.7%), abdominal pain (5.9%), nausea (5.4%), atrial fibrillation (5.7%), constipation (2.2%), gastritis (4.9%), diabetes mellitus (4.2%), myalgia (3.7%), headache (2.5%), insomnia (4.0%), vertigo (4.5%), bronchitis (6.6%), sinusitis (2.3%), eczema (4.5%), urinary tract infection (3.2%)
		Homozygous Familial Hypercholesterolemia	Simvastatin: 40mg once daily	Homozygous Familial Hypercholesterolemia: Class I Esc2
		Secondary prevention in very high-risk patients	Atorvastatin: 40-80mg once daily	Very high-risk patients failing to achieve LDL-C goals on maximum tolerated statin: Class I Esc3
PCSK9 Inhibitors	Evolocumab, Alirocumab, Inclisiran	Primary hypercholesterolemia, Mixed Dyslipidemia	Evolocumab: 140mg every 2 weeks or 420mg once monthly Alirocumab: 75mg to 150mg every 2 weeks Inclisiran: 300mg initial dose, then 300mg at 3 months, followed by 300mg every 6 months	Primary hypercholesterolemia and Mixed Dyslipidemia: Class I Esc2	Injection site reactions (5.9%), nasopharyngitis (5.5%), upper respiratory tract infections (2.3%), flu (3.1%), back pain (3.2%), hypersensitivity reactions including rash, pruritus (1.7%), and rare cases of neurocognitive effects such as memory loss or confusion. Inclisiran has less frequent administration (twice yearly) as a small interfering RNA that inhibits PCSK9 production in the liver.
		Homozygous Familial Hypercholesterolemia	Evolocumab: 420mg once monthly (may increase to 420mg every 2 weeks if needed)	Homozygous Familial Hypercholesterolemia: Class I Esc2
		Secondary prevention in very high-risk patients	Evolocumab: 140mg every 2 weeks Alirocumab: 75mg to 150mg every 2 weeks Inclisiran: 300mg initial dose, then 300mg at 3 months, followed by 300mg every 6 months	Very high-risk patients failing to achieve LDL-C goals on maximum tolerated statin: Class I Esc3

References

<biblio>

1. Esc1 pmid=22611136
2. Esc2 pmid=17220161
3. Esc3 pmid=22555213
4. Esc4 pmid=22922416
5. Acc5 pmid=14557344
6. Esc6 pmid=21712404

</biblio>