Cardiac Pharmacology - Textbook of Cardiology https://www.textbookofcardiology.

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Cardiac Pharmacology
Heather Melrose, Jonas de Jong

Contents
Renin-Angiotensin-Aldosterone System
Neural Control of the Cardiovascular System
Sympathetic (Adrenergic) Nervous System
Vasculature
Heart
Parasympathetic Nervous System
Vasculature
Heart
Platelet/Clotting System
Anti-coagulants
Understanding the Cholesterol/LDL System in Cardiovascular Health
Cholesterol Transport and LDL's Role
LDL and Atherosclerosis
Regulation of Cholesterol/LDL Levels
The Integral Role of LDL in Cardiovascular Health
Pharmacokinetics
Common Drug-Drug Interactions
References

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
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 RAAS schematic
from specialised cells within the kidney. The
substrate of renin is the inactive precursor of

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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

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 Interaction between the sympathic and parasympathic nervous
and consequent increases in systemic blood pressure. system and the heart

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)

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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
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.
Platelet activation and inhibition operates through surface
There are several conditions in which abnormal clotting receptors on platelets. Feedback loops enhance platelet activation
can be damaging to the body; excess clotting can lead to (e.g. ADP released by platelets increases platelet activation,
vascular blockage and ischaemia or stroke; less commonly, through the ADP receptor)
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 prostaglanding 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.

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Understanding the Cholesterol/LDL System in Cardiovascular

Health
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

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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:

Standard units
Property Description Formula
(Abbreviation)

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

The concentration of drug needed to elicit a

y = bottom + (Top-Bottom)/(1+ [x/EC50] Hill
EC50 response halfway between zero and maximal µg/ml (EC50)
Coefficient)
responses.

The theoretical volume the drug would occupy

Volume of
if distributed uniformly throughout the tissues L (Vd) D/C
Distribution
to elicit the current plasma concentration.

Elimination The rate at which the drug is removed from

h-1 (Ke) ln(2) / t1/2 or CL / Vd
Constant (Rate) the body.

100 × (AUC (po)×D (iv))/(AUC (iv)×D (po))

no units as AUC = Area under curve po = oral

How much of the administered dose is
Bioavailability expressing a
available for actual use by the body.
fraction (f)
administration iv = intravenous
administration

The maximum (Cmax) / minimum (Cmin)

µg/ml (Cmax or Identified via direct measurement of plasma
Cmax or Cmin plasma drug concentration reached following
Cmin) C
drug administration

The time it takes for a drug to reach Cmax Identified via direct measurement of plasma
tmax h (tmax)
following administration C over time

The time it takes for a drug to reach half its

Half-life h (t1/2) ln(2) / Ke
original concentration

The volume of plasma cleared of the drug

Drug Clearance l/h (CL) Vd x Ke or D / Area under curve
over a set time

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:

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Drug Drugs that ↑ drug action Drugs that ↓ drug action

Diuretics Rifampicin
Antiarrhythmics Antacids (liquid)
Macrolide antibiotics
Cholestyramine
Neomycin
Digoxin Keto- and intraconazole
Calcium antagonists
Cyclosporine, indomethacin
HMG CoA reductase inhibitors
Benzodiazepines
Amiodarone
Verapamil

Furosemide Azathioprine
Amiodarone Phenobarbitone
Sulfa Carbamazepine
Warfarin Macrolide and quinolone antibiotics Dexamethasone
NSAIDs Prednisolone
Rifampicin
Vitamin K
Raloxifene

Rifampicin Statins
Clopidogrel Caffeine Calcium channel blockers
Methylxanthines Warfarin
Phosphodiesterase inhibitors Proton pump inhibitors

NSAIDs
Furosemide Phenytoin
Colesevelam

NSAIDs Indomethacin
ACE Inhibitors Probenecid Antacids
Calcium channel blockers

Amiodarone Phenobarbital
Calcium channel blockers Rifampicin
ß-blockers Diltiazem Cimetidine
Phenoxybenzamine Antacids (liquid)
NSAIDs

Amiodarone Nevirapine
Verapamil Rifampicin
Statins Fibrates
Amprenavir
Diltiazem

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

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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.)

Clopidogrel Moclobemide Rifampicin

Propranolol Chloramphenicol Carbamazepine
CYP2C19
Warfarin Many anti-convulsants (Valproate) Prednisone
Proton pump inhibitors
(Omeprazole)

Donepezil Protease inhibitors (Ritonavir) Some anti-convulsants (Carbamazepine)

Statins (Atorvastatin) Macrolides (Clarithromycin) Baribiturates (Phenobarbital)
Ca-channel blockers (Nifedipine) Chloramphenicol St. John’s Wort
Amiodarone Nefazodone Some reverse transcriptase inhibitors
Dronedarone Some Ca-channel blockers (Efavirenz)
Quinidine (Verapamil) Some Hypoglycaemics (Pioglitazone)
PDE5 Inhibitors (Sildenafil) Cimetidine Glucocorticoids
CYP3A4
Kinins Some azole anti-fungals Modafinil
(Ketaconazole)
Caffeine
Grapefruit juice
Eplerenone
Propranolol
Salmeterol
Warfarin
Clopidogrel

Fluvastatin Some azole anti-fungals Rifampicin

Angiotensin receptor II agonists (Fluconazole) Secobarbital
(losartan) Amiodarone
Warfarin Antihistamines (Cyclizine)
CYP2C9 Torasemide Chloramphenicol
Fluvastatin
Fluvoxamine
Probenecid
Sertraline

ß-blockers (Propranolol) SSRIs (Fluoxetine) Rifampicin

Class I anti-arrythmics (Flecainide) Quinidine Dexamethasone
Donepezil Sertraline Glutethimide
Terbinafine
Amiodarone
CYP2D6 Cinacalcet
Ritonavir
Antipsychotics (Haloperidol)
Antihistamines (Promethazine)
Metoclopramide
Ranitidine
Mibefradil

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 (http://www.f
da.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/Ge
neralUseofMedicine/UCM229033.pdf)

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Cardiovascular Drugs

Examples
Guidelines / Class of Side Effects
Drug Type (generic Indications Typical Dosage
Indication (Prevalence %)
name)

:Anti-hypertensives

Mild gastro-intestinal
disturbances,
pancreatitis, hepatic
Furosemide: 20-40mg encephalopathy,
Oedema
once daily postural hypotension,
temporary increase in
serum-cholesterol and
triglyceride
concentration,
hyperglycaemia, acute
urinary retention,
Diuretics Furosemide
electrolyte
disturbances,
Hypertension in metabolic alkalosis,
Resistant Furosemide: 40-80mg symptomatic (NYHA class blood disorders,
Hypertension once daily II-IV) HF and LVD: Class hyperuricaemia, visual
IC [1] disturbances, tinnitus
and deafness, and
hypersensitivity
reactions (including
rash, photosensitivity,
and pruritus).

Hypotension (2.4%),
Hypertension: Class IA [2] renal impairment,
persistent dry cough,
Hypertension in angioedema, rash
pancreatitis, upper
symptomatic (NYHA respiratory-tract
Captopril: 12.5mg twice class II-IV) HF and symptoms (2-10%),
Hypertension
daily LVD: Class IA [1] gastro-intestinal
symptoms (1-2%),
Hypertension in altered liver function
tests, cholestatic
diabetics: Class IA [3] jaundice, hepatitis,
fulminant hepatic
necrosis and failure,
hyperkalaemia (2%),
hypoglycaemia, blood
Post STEMI: Class IA [4] disorders including
ACE Captopril,
thrombocytopenia,
Inhibitors Monopril
Diabetic patients: leucopenia,
Class IC [2] neutropenia, headache
(3%), dizziness
Captopril: 12.5mg 3 times
Heart Failure (2-12%), fatigue,
daily Symptomatic (NYHA malaise, taste
class II-IV) HF: Class disturbance,
IA; Acute heart failure paraesthesia,
with ACS: Class IA [1] bronchospasm, fever,
serositis, vasculitis,
myalgia (3%),
arthralgia, positive
antinuclear antibody,
Prophylaxis Following Captopril: 6.25mg once
raised erythrocyte
MI daily
sedimentation rate,
eosinophilia,
Captopril: 75-100mg once leucocytosis, and
Diabetic nephropathy
daily photosensitivity.

Hypertension: Class IA [2] Gastro-intestinal

disturbances (<3%),
Hypertension Losartan: 50mg once daily Hypertension in dizziness (14%),
Angiotensin angina, palpitation,
Losartan, diabetics: Class IA [3]
Receptor oedema, dyspnoea,
Candesartan
Blockers headache (14%),
Left ventricular Losartan: 12.5-150mg malaise, urticaria,
LVH: Class IB [4] pruritus, rash;
hypertrophy daily

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Diabetic nephropathy Losartan: 50mg daily

Drowsiness,
hypotension (notably
postural hypotension)
Prazosin: 1-10mg 2-3 (10-70% initially),
Hypertension syncope (1%),
times daily
asthenia, dizziness,
depression, headache
(8-18%), dry mouth,
gastro-intestinal
disturbances, oedema,
blurred vision (<5%),
Alpha Prazosin, intra-operative floppy
Blockers Doxazosin iris syndrome, rhinitis
Congestive Heart (<4%), erectile
Prazosin: 4-20mg daily
Failure disorders (including
priapism), tachycardia
and palpitations
(7-14%),
gastrointestinal side-
symptoms (4-5%),
hypersensitivity
Raynaud’s Syndrome Prazosin: 1-2mg daily reactions including
rash, pruritus and
angioedema.

Hypertension Atenolol: 25-50mg daily Gastro-intestinal

disturbances (2-4%);
ACS: Class IIaB [2] bradycardia, heart
failure, hypotension,
Angina in conduction disorders,
Atenolol: 100mg once/ peripheral
Angina symptomatic (NYHA
twice daily vasoconstriction,
class II-IV) HF and bronchospasm,
LVD: Class IA [1] dyspnoea; headache,
fatigue, sleep
disturbances (2-5%),
Atrial fibrillation: Class IA; paraesthesia,
Polymorphic VT: Class IB dizziness (2-5%),
[4] vertigo, psychoses;
sexual dysfunction;
Symptomatic (NYHA purpura,
class II-IV) HF, LVD thrombocytopenia;
and AF: Class IA; visual disturbances;
exacerbation of
Management of VA in psoriasis, alopecia;
HF: Class IA [1] rarely rashes and dry
eyes.
SVT: Class IIbC; Wide
Beta Atenolol, QRS-complex
Blockers Propranolol
tachycardia of
unknown origin: Class
IIIC; Sinus
tachycardia: Class IC;
Arrhythmias Atenolol: 50-100mg daily
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

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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 [5]

Migraine Atenolol: 50-200mg daily

Gastro-intestinal
disturbance (2-11%);
hypotension (1-5%),
oedema (7-29%),
vasodilatation,
palpitation; headache
(7-35%), dizziness
Hypertension in (3-27%), lethargy
Nifedipine: 20-30mg once symptomatic (NYHA class (4-6%), asthenia
Hypertension
daily II-IV) HF and LVD: Class (10-12%); less
IA [1] commonly tachycardia
(<1-7%), syncope
(<1%), chills, nasal
congestion, dyspnoea
(<3%), anxiety, sleep
disturbance (<2%),
vertigo (<3%),
migraine,
Calcium Nifedipine, paraesthesia, tremor
Channel Verapamil, (1-8%), polyuria,
Blockers Diltiazem dysuria, nocturia,
erectile dysfunction
Nifedipine: 5-20mg 3 times (<2%), epistaxis,
Raynaud’s Syndrome myalgia, joint swelling,
daily
visual disturbance
(<2%), sweating
(<2%), hypersensitivity
reactions (<1%); rarely
anorexia, gum
Angina in symptomatic hyperplasia, mood
Nifedipine: 5-20mg 3 times disturbances,
Angina (prophylaxis) (NYHA class II-IV) HF and
daily hyperglycaemia, male
LVD: Class IIaA [1]
infertility, purpura
(<1%), and
photosensitivity
reactions (<1%); also
reported dysphagia,
intestinal obstruction,
intestinal ulcer, bezoar

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formation,
gynaecomastia,
agranulocytosis, and
anaphylaxis;
Anti-Arrhythmics

Sustained VT and VF:

Class IIbC [4]
Oedema, pro-
Pre-excited SVT/AF: arrhythmic effects
Class IB; Wide QRS- (1-13%); dyspnoea;
complex tachycardia nervous-system side-
effects including
of unknown origin: dizziness, asthenia,
Lidocaine (Class IIbB) fatigue, fever; visual
/ Procainamide (Class disturbances (13-28%);
IB); Wide QRS- rarely pneumonitis,
hallucinations,
complex tachycardia depression, confusion,
of unknown origin with amnesia, dyskinesia,
LVD: Class IB; Focal convulsions, peripheral
junction tachycardia: neuropathy; also
reported gastro-
Class I
Flecainide,
Class IIaC; WPW intestinal disturbances
(sodium Ventricular Flecainide: 50-100mg Syndrome: IIaC;
Lidocaine, (1-4%), anorexia,
channel Arrhythmias twice daily
blockers)
Procainamide AVRT, poorly hepatic dysfunction,
tolerated: IIaC; Single flushing, syncope,
drowsiness, tremor,
or infrequent AVRT vertigo, headache,
episode(s): Class anxiety, insomnia,
IIbC; Acute treatment ataxia, paraesthesia,
of Focal Atrial anaemia, leucopenia,
thrombocytopenia,
Tachycardia: Class corneal deposits,
IIaC; Prophylactic tinnitus, increased
therapy for AT: Class antinuclear antibodies,
IIaC; AF (Stable hypersensitivity
reactions (including
flutter): Class IIbA; rash, urticaria, and
Prophylaxis of SVT photosensitivity),
during pregnancy: increased sweating.
Class IIbB [5]

Class II
(Beta (See above) (See above) (See above) (See above)
blockers)

Sustained VT and VF: Gastro-intestinal

Class IIaC; Polymorphic disturbances (2-20%)),
VT: Class IC [4] taste disturbances,
hepatic disturbances
Management of VA in (up to 50%);
bradycardia;
HF: Class IA; pulmonary toxicity
Prevention of VA in (1-17%); tremor
HF: Class IIbB [1] (9-59%), sleep
disorders;
SVT: Class IIBC; Wide hypothyroidism
Class III (5-10%),
QRS-complex hyperthyroidism
(Potassium Amiodarone, Ventricular, Amiodarone: 200mg 2-3
channel Sotalol Arrhythmias times daily tachycardia of (5-10%); reversible
blockers) unknown origin: Class corneal microdeposits
IB; Wide QRS- (up to 98%);
phototoxicity,
complex tachycardia persistent slate-grey
of unknown origin with skin discoloration
LVD: Class IB; (1-7%), injection-site
Recurrent AVNRT reactions; less
commonly onset or
unresponsive to beta worsening of
blocker or calcium- arrhythmia, conduction
channel blocker and disturbances,
patient not desiring peripheral neuropathy

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RF ablation: Class
IIbC; Focal junction
tachycardia: Class (1-105) and myopathy;
IIaC; WPW Syndrome: very rarely sinus arrest,
IIaC; AVRT, poorly bronchospasm, ataxia
tolerated: Class IIaC; (2-37%), benign
intracranial
Since or infrequent hypertension,
AVRT episode(s): headache, vertigo,
Class IIbB; Acute epididymo-orchitis,
treatment of Focal impotence, haemolytic
or aplastic anaemia,
Atrial Tachycardia: thrombocytopenia,
Class IIaC; rash, hypersensitivity
Prophylactic therapy including
for AT: Class IIaC; AF photosensitivity
(2-20%), anaphylaxis
(Poorly tolerated): on rapid injection,
Class IIbC; AF (Stable hypotension (10-30%),
flutter): Class IIbC; respiratory distress
Prophylaxis of SVT syndrome, sweating,
and hot flushes
during pregnancy:
Class IIIC [5]

Class IV
(Calcium
(See above) (See above) (See above) (See above)
channel
blockers)

SVT: Class IIbC; WPW Gastro-intestinal

Syndrome: Class IIIC; disturbances (vomiting,
AVRT, poorly tolerated: diarrhoea, anorexia,
Acute: 0.75-1.5mg over 24 abdominal pain) (25%);
Supra-ventricular Class IIIC; Since or
hours; Maintenance: arrhythmias (up to
Arrhythmias infrequent AVRT
125-150µg daily 50%), AV conduction
episode(s): Class IIIC;
Prophylaxis of SVT during disturbances (50%);
pregnancy: Class IC [5] nervous system
disturbances
(dizziness, apathy,
Digoxin Symptomatic (NYHA class
confusion, headache,
II-IV) HF: Class IIbB
fatigue, weakness)
(25%); blurred or
Symptomatic (NYHA yellow vision; rash,
Heart Failure 62.5-125 µg daily class II-IV) HF, LVD eosinophilia,
and AF: Class IB; depression, anorexia,
intestinal ischaemia
Acute HF with AF and and necrosis,
VT: Class IC [1] psychosis,
gynaecomastia on
long-term use, and
Anti-platelet Drugs thrombocytopenia.

Prevention in AF: Class Bronchospasm

IC; Prevention in diabetic (10-30% in
patients: IIaB [2] asthmatics); gastro-
intestinal irritation (up
Prevention in to 83%), gastro-
intestinal haemorrhage
Symptomatic (NYHA (occasionally major),
class II-IV) HF and also other
Prevention of
AF: Class IIA [1] haemorrhage (e.g.
intracranial (0.5%),
thrombotic cerebro-
Aspirin 75mg once/day Prevention in subconjunctival), chest
or cardio-vascular
pain (8.3%), oedema
disease hypertensive patients (4.5%), hypertension
with CV events: Class (4.3%).
IA; Prevention in
hypertensive patients
without CV history but
with reduced renal
function/high risk:

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Class IIbA [3]

Post-MI: Class Ia [3]

300-600mg every 4-6

Pain / pyrexia
hours as necessary

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
Prevention in diabetic
and duodenal ulcers,
patients: IIaB; Primary and
headache (7.6%),
secondary prevention of
epistaxis (2.9%),
stroke: Class IB [2]
dizziness (6.2%),
paraesthesia,
Prevention in leucopenia, decreased
Symptomatic (NYHA platelets (very rarely
Prevention of class II-IV) HF and severe
thrombotic events thrombocytopenia),
75mg once/day AF: Class IIA [1] eosinophilia, rash
(esp. when warfarin
not tolerated) (4.2%), pruritus (3.3%),
Acute phase of vertigo, colitis,
coronary artery pancreatitis, hepatitis
syndrome: Class IB; (<1%), acute liver
failure, hypertension
Clopidogrel Non-cardioembolic (4.3%), chest pain
cerebral ischaemic (8.3%), oedema
events: Class IA [3] (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
Acute myocardial 300mg daily initially then hypersensitivity-like
Post STEMI: Class IA [4]
infarction 75mg once/day reactions
(<0.1%)including fever,
glomerulonephritis,
arthralgia, Stevens-
Johnson syndrome,
Acute coronary 300mg daily initially then
ACS: Class IIaC [2] toxic epidermal
syndrome 75mg once/day
necrolysis, lichen
planus.

Haemorrhage (11.3%)
(including gastro-
Prevention in Symptomatic intestinal (1.5%) and
(NYHA class II-IV) HF and intracranial),
AF: Class IIA [1] haematoma,
haematuria,
Prevention of 60mg bolus then 5-10mg Acute phase of hypertension (7.5%),
Prasugrel hypotension (3.9%),
thrombotic events. once daily
coronary artery headache (5.5%), back
syndrome: Class IB pain (5.0%), dyspnoea
[3] (4.9%), nausea (4.6%),
dizziness (4.1%),
cough (3.9%), fatigue
(3.7%), chest pain

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(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.
Dyspnoea (13.8%),
haemorrhage, bruising;
nausea (4.3%),
vomiting, diarrhoea
(3.7%), hypertension
(3.8%), hypotension
Prevention in Symptomatic (3.2%), back pain
(NYHA class II-IV) HF and (3.6%), abdominal
AF: Class IIA [1] pain, dyspepsia,
gastritis, dizziness
Prevention of 180mg bolus then 90mg Acute phase of (4.5%), chest pain
Ticragelor
thrombotic events. twice daily coronary artery (3.7%), headache
(6.5%), cough (4.9%),
syndrome: Class IB rash, pruritus, fatigue
[3] (3.2%), constipation,
arrhythmias including
atrial fibrillation (4.2%),
paraesthesia,
confusion,
hyperuricaemia, raised
serum creatinine
(7.4%), vertigo.

Vitamin K Antagonists

Haemorrhage, nausea,
vomiting, diarrhoea,
jaundice, hepatic
Prevention of dysfunction,
5-10mg initially then
thrombotic/ embolic pancreatitis, pyrexia,
tailored to individual
Warfarin events (esp. after alopecia, purpura,
(usually 3-9mg once daily
prosthetic valve rash, ‘purple toes’, skin
at the same time)
insertion) necrosis (increased
risk in patients with
protein C or protein S
deficiency)

Haemorrhage, nausea,
vomiting, diarrhoea,
jaundice, hepatic
Prevention of dysfunction,
thrombotic/ embolic pancreatitis, pyrexia,
4mg initially, followed by
Acenocoumarol events (esp. after alopecia, purpura,
1-8mg daily
prosthetic valve rash, ‘purple toes’, skin
insertion) necrosis (increased
risk in patients with
protein C or protein S
deficiency)

Lipid-Lowering Drugs

Dyslipidaemia: Class IA; Oedema (2.7%),

Primary hyper- Low HDL-C: Class IIbB; abdominal pain (5.9%),
Simvastatin, cholesterolaemia, Simvastatin: 10-20mg Elderly patients with CVD: nausea (5.4%), atrial
Statins IB; Elderly patients with no fibrillation (5.7%),
Atorvastatin combined once daily
hyperlipidaemia CVD but CV risk factors: constipation (2.2%),
IIbB; Type I diabetes: IC; gastritis (4.9%),
Patients with CKD: IIaC; diabetes mellitus

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Transplant patients: Class (4.2%), myalgia

IIaB; PAD: Class IA; HIV
patients: IIaC [2]
Hypertension in
diabetics: Class IA;
ACS: Class IA [3]
(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%)

Familial hyper- Simvastatin: 40mg once

HeFH: Class IC [2]
cholesterolaemia daily

Prevention of
20-40mg once daily Class IA [2]
cardiovascular events

Gastro-intestinal
disturbances including
dyspepsia (19.6%),
nausea (4%),
abdominal pain (9.8%),
diarrhoea (7.2%),
vomiting (1.2%);
headache (1.2%),
fatigue (3.8%), vertigo
(1.5%), eczema, rash
(1.7%), atrial fibrillation
(0.7%), pancreatitis,
appendicitis,
disturbances in liver
Low HDL-C: Class IIbB; function including
Hyperlipidaemias of
Gemfibrozil: 0.9-1.2mg Transplant patients (with hepatitis and
Gemfibrozil types IIa, IIb, III, IV
daily HTG, low HDL-C): Class cholestatic jaundice,
and V
IIbC [6] dizziness,
paraesthesia, sexual
dysfunction,
thrombocytopenia,
anaemia, leucopenia,
eosinophilia, bone-
marrow suppression,
myalgia, myopathy,
myasthenia, myositis
accompanied by
Fibrates increase in creatine
kinase, blurred vision,
exfoliative dermatitis,
alopecia, and
photosensitivity

Gastro-intestinal
disturbance including
diarrhoea (4.1%) and
abdominal pain (3.0%);
headache, fatigue
(2.4%); myalgia,
arthralgia (3.0%),
sinusitis (3.6%),
pharyngitis (2.3%),
viral infection (2.2%),
Primary and familial
Transplant patients (with coughing (2.3%),
Ezetimibe hyper- 10mg once daily
high LDL-C): Class IIbC [6] hypersensitivity
cholesterolaemia
reactions including
rash, angioedema, and
anaphylaxis,
hepatitis,pancreatitis,
cholelithiasis,
cholecystitis,
thrombocytopenia,
raised creatine kinase,
myopathy, and
rhabdomyolysis

Primary Evolocumab: 140mg every Primary Injection site reactions

Evolocumab, hypercholesterolemia, 2 weeks or 420mg once hypercholesterolemia and (5.9%),
PCSK9
Alirocumab, Mixed Dyslipidemia, monthly Mixed Dyslipidemia: Class nasopharyngitis
Inhibitors
Inclisiran Homozygous Familial I; Homozygous Familial (5.5%), upper

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respiratory tract
infections (2.3%), flu
Alirocumab: 75mg to (3.1%), back pain
150mg every 2 weeks (3.2%), hypersensitivity
Hypercholesterolemia
Inclisiran dosages Hypercholesterolemia: reactions including
according to specific Class I [2] [3] rash, pruritus (1.7%),
and rare cases of
treatment regimes neurocognitive effects
such as memory loss
or confusion.

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