Lorcainide (Lorcainide hydrochloride) is a Class 1c
antiarrhythmic agent
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular ta ...
that is used to help restore normal heart rhythm and conduction in patients with
premature ventricular contractions,
ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
c
and
Wolff–Parkinson–White syndrome
Wolff–Parkinson–White syndrome (WPWS) is a disorder due to a specific type of problem with the electrical system of the heart. About 60% of people with the electrical problem developed symptoms, which may include an abnormally fast heartbeat, ...
.
Lorcainide was developed by
Janssen Pharmaceutica
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American c ...
(Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001.
It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.
Arrhythmia
Cardiac dysrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
is a heart rate disorder that manifests as an altered cardiac rhythm. It results from either abnormal
pacemaker
An artificial cardiac pacemaker (or artificial pacemaker, so as not to be confused with the natural cardiac pacemaker) or pacemaker is a medical device that generates electrical impulses delivered by electrodes to the chambers of the heart eith ...
activity or a disturbance in impulse propagation, or both.
Arrhythmias can be caused by various conditions including
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
,
hypoxia
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
, pH disruptions, B adrenergic activation, drug interactions or the presence of diseased tissue.
These events can trigger the development of
ectopic pacemaker
An ectopic pacemaker, also known as ectopic focus or ectopic foci, is an excitable group of cells that causes a premature heart beat outside the normally functioning SA node of the heart. It is thus a cardiac pacemaker that is ectopic, producing ...
in the heart, which emit abnormal impulses at random times during the
cardiac cycle
The cardiac cycle is the performance of the human heart from the beginning of one heartbeat to the beginning of the next. It consists of two periods: one during which the heart muscle relaxes and refills with blood, called diastole, following ...
. An arrhythmia can present itself as either
bradycardia
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
or
tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
.
Untreated arrhythmias may progress to
atrial fibrillation or
ventricular fibrillation
Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no p ...
.
Treatment is aimed at normalizing cardiac rhythm by altering ion flow across the membrane.
Antiarrhythmic agents
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tac ...
can reduce arrhythmia related symptoms such as
palpitations
Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart.
Symptoms include a rapi ...
or
syncope; however, they often have a narrow
therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
and can also be
proarrhythmic
A Pro-arrhythmic agent is a chemical, drug, or food that promotes cardiac arrhythmias.
Substances
Supplements
Omega 3 fatty acids.
Foods
Chocolate, Coffee, Tea
Drugs
Caffeine, cocaine, beta-adrenergic agonists
Encainide, Lorcainide
S ...
.
Wolff–Parkinson–White syndrome
Wolff–Parkinson–White syndrome
Wolff–Parkinson–White syndrome (WPWS) is a disorder due to a specific type of problem with the electrical system of the heart. About 60% of people with the electrical problem developed symptoms, which may include an abnormally fast heartbeat, ...
(WPW) is a
pre-excitation syndrome
Pre-excitation syndrome is a heart condition in which part of the cardiac ventricles are activated too early. Pre-excitation is caused by an abnormal electrical connection or accessory pathway between or within the cardiac chambers. Pre-excitatio ...
in which individuals are predisposed to supraventricular tachyarrhythmias (rapid and irregular heart beats).
People with this condition have an extra or accessory
atrioventricular conduction pathway that causes re-entry tachycardia.
WPW is characterized by a short
PR interval
In electrocardiography, the PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization) ...
(<0.12 second) and a prolonged, slurred
QRS complex
The QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG or EKG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the ri ...
(>0.12 seconds).
Class 1c activity
Fast-acting voltage-gated sodium channels (
Nav1.5
Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of N ...
) found in high concentrations in the ventricular myocytes, open at a membrane potential of −80 mv in typical cardiac rhythm. This will result in a rapid upstroke of an
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
that leads to contraction of the ventricles.
Class 1c drugs have local
anesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...
properties and have a high affinity for open Nav1.5 (but not closed or inactive Nav1.5), thus irreversibly binding and reducing the fast Na+ influx. Interactions of Lorcainide with Nav1.5 are time and voltage dependent. Class 1c drugs have a characteristically slow dissociation rate, which will slow the upstroke duration and amplitude of ventricular myocytes’ action potential and prolong the PR, QRS and QT intervals of an
ECG
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
.
Lorcainide also increases the ventricular fibrillation threshold in a dose-dependent fashion.
Overall, Lorcainide causes a decrease in tachycardiac events, but also reduced ventricular contractility
ejection fraction
An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...
.
The effect on
sinus node
The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...
function is controversial, as some researchers have noted a decreased sinus cycle length and increase in sinus node recovery, whereas others have observed no change.
Other activities
Lorcainide inhibits adenosine 5’-triphosphate (ATP)-hydrolytic action of myocardial Na+K+ATPase in-vitro in a concentration dependent manner. The mode of action and the implications of this finding are not well known.
Benefits and risks
Lorcainide exhibits a prolonged duration of action (approximately 8-10 hrs), is well absorbed when taken orally and has a good safety profile as well as a good drug
efficacy
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...
.
Hematologic, biochemical and urinary analysis of Lorcainide revealed no significant abnormalities.
However, an increased prevalence of central nervous system effects, including headache, dizziness and sleep disturbances have been associated with oral dosages of Lorcainide when compared to intravenous administration. This could be due to a greater accumulation of plasma Noriorcainide when exposed to oral Lorcainide. Noriorcainide, an N-dealkylated derivative, is an active metabolite of Lorcainide. It is as potent as its parent compound with similar antiarrhythmic efficacy, wherein it suppresses chronic premature ventricular complexes.
It has a half life of 26.5 +-7.2 hrs.
Synthesis
![Lorcainide synthesis](https://upload.wikimedia.org/wikipedia/commons/0/02/Lorcainide_synthesis.svg)
Synthesis starts by reducing the
anil formed from the condensation of
''p''-chloroaniline with ''N''-carbethoxy-4-piperidone, with
sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds appli ...
(NaBH
4). This is then acylated with
phenacetyl chloride to produce amide 2. Selective hydrolysis with
hydrobromic acid
Hydrobromic acid is a strong acid formed by dissolving the diatomic molecule hydrogen bromide (HBr) in water. "Constant boiling" hydrobromic acid is an aqueous solution that distills at and contains 47.6% HBr by mass, which is 8.77 mol/L. H ...
(HBr) followed by alkylation with
isopropyl bromide
2-Bromopropane, also known as isopropyl bromide and 2-propyl bromide, is the halogenated hydrocarbon with the formula CH3CHBrCH3. It is a colorless liquid. It is used for introducing the isopropyl functional group in organic synthesis. 2-Bromopropa ...
completes the synthesis of lorcainide (3).
References
{{Antiarrhythmic agents
Antiarrhythmic agents
Piperidines
Sodium channel blockers
Chloroarenes
Acetanilides
Janssen Pharmaceutica
Belgian inventions
Isopropyl compounds