Quinidine is a
class IA antiarrhythmic agent used to treat heart rhythm disturbances.
It is the
enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of
antimalarial agent quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...
, originally derived from the bark of the
cinchona
''Cinchona'' (pronounced or ) is a genus of flowering plants in the family Rubiaceae containing at least 23 species of trees and shrubs. All are native to the Tropical Andes, tropical Andean forests of western South America. A few species are ...
tree. The drug causes increased
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, ...
duration, as well as a prolonged
QT interval
The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...
. As of 2019, its IV formulation is no longer being manufactured for use in the United States.
Medical uses
Quinidine is occasionally used as a
class I antiarrhythmic agent to prevent
ventricular arrhythmia
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 ...
s, particularly in
Brugada Syndrome
Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope ...
, although its safety in this indication is uncertain.
It reduces the recurrence of
atrial fibrillation after patients undergo
cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a sinus rhythm, normal rhythm using electricity or pharmaceutical drug, drugs. Synchronized electrical cardiover ...
, but it has
proarrhythmic effects and trials suggest that it may lead to an overall increased mortality in these patients.
Quinidine is also used to treat
short QT syndrome
Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature s ...
.
Eli Lilly has discontinued manufacture of parenteral quinidine gluconate in the US, and its future availability in many countries is uncertain.
Other uses
There is one study supporting the use of a novel combination of
dextromethorphan
Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...
and low dose quinidine in alleviating symptoms of easy laughing and crying (
pseudobulbar affect
Pseudobulbar affect (PBA), or emotional incontinence, is a type of emotional disturbance characterized by uncontrollable episodes of crying, laughing, anger or other emotional displays. PBA occurs secondary to a neurologic disorder or brain inj ...
); these are a type rather severe uncontrollable behaviors which can be present in various neurological pathologies such as
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
and
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
. The dose of quinidine (10mg two times daily) is about 1/40th of a relatively low antiarrhythmic dose (400mg, twice or 3 times daily, as an example; antiarrhythmic doses can sometimes exceed 1500mg/day). The authors did not observe significant safety risks using the low quinidine dose, but urged caution and also pointed out that quinidine interacts with a large number of other medications in dangerous or unpredictable ways. Interestingly, a meta analysis was published referencing only that one study.
Although intravenous quinidine is sometimes used to treat ''
Plasmodium falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
''
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
, the future availability of this agent is uncertain.
Side effects
Quinidine is also an inhibitor of the
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme 2D6, and can lead to increased blood levels of
lidocaine
Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...
,
beta blockers
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...
,
opioids
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
, and some
antidepressants
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, heada ...
. Quinidine also inhibits the transport protein
P-glycoprotein
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
and so can cause some peripherally acting drugs such as
loperamide
Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed September 4, 2015 is a medication used to decrease the frequency of diarrhea. It is often used for this purpose in inflammatory bowel disease and short bowel syn ...
to have central nervous system side effects, such as respiratory depression, if the two drugs are coadministered.
Quinidine can cause thrombocytopenia, granulomatous hepatitis,
myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...
, and ''
torsades de pointes
''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
'' (dangerous heart rhythm), so is not used much today. ''Torsades'' can occur after the first dose. Quinidine-induced
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
(low platelet count) is mediated by the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, and may lead to thrombocytic
purpura
Purpura () is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, ...
.
Quinidine intoxication can lead to a collection of symptoms collectively known as
cinchonism, with
tinnitus
Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...
(ringing in the ears) being among the most characteristic and common symptoms of this toxicity syndrome.
Pharmacology
Pharmacodynamics
Quinidine acts as a
blocker of
voltage-gated sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
s.
Inhibition of the
Nav1.5 channel is specifically involved in its antiarrhythmic effects as a class I antiarrhythmic agent.
Quinidine also blocks certain
voltage-gated potassium channel
Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...
s (e.g.,
Kv1.4,
Kv4.2,
hERG
hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...
, among others),
acts as an
antimuscarinic
A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the ...
and
alpha-1 blocker
Alpha-1 blockers (also called alpha-adrenergic blocking agents or alpha-1 antagonists) constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperpla ...
,
and is an
antimalarial
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
.
Mechanism of action
Like all other class I
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 ...
s, quinidine primarily works by blocking the fast inward
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
current (I
Na). Quinidine's effect on I
Na is known as a 'use dependent block'. This means at higher heart rates, the block increases, while at lower heart rates, the block decreases. The effect of blocking the fast inward sodium current causes the phase 0 depolarization of the
cardiac action potential
The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...
to decrease (decreased V
max).
It seems still efficacious as an IV antimalarial against Plasmodium falciparum. This electrolyte dependent agent also increases action potentials and prolongs the QT interval.
Quinidine also blocks the slowly inactivating,
tetrodotoxin
Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered ...
-sensitive
Na current, the slow inward
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
current (I
Ca), the rapid (I
Kr) and slow (I
Ks) components of the
delayed potassium rectifier current, the
inward potassium rectifier current (I
KI), the
ATP-sensitive potassium channel
An ATP-sensitive potassium channel (or KATP channel) is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) ...
(I
KATP) and I
to.
At micromolar concentrations, quinidine inhibits
Na+/K+-ATPase by binding to the same receptor sites as the digitalis glycosides such as
ouabain
Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. ...
.
The effect of quinidine on the ion channels is to prolong the cardiac action potential, thereby prolonging the QT interval on the surface ECG.
Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. These are the results of both slowed depolarization and repolarization.
Pharmacokinetics
Elimination
The
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
of oral quinidine is 6 to 8 hours, and it is eliminated by the
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
system in the liver. About 20% is excreted unchanged via the kidneys.
History
The effects of
cinchona
''Cinchona'' (pronounced or ) is a genus of flowering plants in the family Rubiaceae containing at least 23 species of trees and shrubs. All are native to the Tropical Andes, tropical Andean forests of western South America. A few species are ...
bark (the botanical source from which quinidine is extracted) had been commented on long before the understanding of cardiac physiology arose.
Jean-Baptiste de Sénac
Jean-Baptiste de Sénac (1693–1770) was a French physician was born in the district of Lombez in Gascony, France.
Early life and education
Details of his early life are sketchy, however, it is generally thought that he studied medicine at the ...
, in his 1749 work on the anatomy, function, and diseases of the heart, had this to say:
"Long and rebellious palpitations have ceded to this febrifuge
An antipyretic (, from ''anti-'' 'against' and ' 'feverish') is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which ...
".
"Of all the stomachic remedies, the one whose effects have appeared to me the most constant and the most prompt in many cases is quinquina eruvian barkmixed with a little rhubarb."
Sénac subsequently became physician to Louis XV of France, a counselor of the state, and superintendent of the mineral waters and medicinals in France. As a result of his influence, throughout the 19th century, quinine was used to augment digitalis therapy. It was described as ''das Opium des Herzens'' (the opium of the heart).
However, the use of quinidine to treat arrhythmia really only came into its own because a physician listened to the astute observation of one of his patients. In 1912,
Karel Frederik Wenckebach
Karel Frederik Wenckebach (; March 24, 1864 – November 11, 1940) was a Dutch anatomist who was a native of the Hague.
He studied medicine in Utrecht, and in 1901 become a professor of medicine at the University of Groningen. Later he was a profe ...
saw a man with
atrial fibrillation. He was a Dutch merchant, used to good order in his affairs. He would like to have good order in his heart business, also, and asked, "why there were heart specialists if they could not abolish this very disagreeable phenomenon ... he knew himself how to get rid of his attacks. As I did not believe him, he promised to come back next morning with a regular pulse, and he did."
The man had found by chance that when he took one gram of quinine during an attack, it reliably halted it in 25 minutes; otherwise it would last for two to 14 days. Wenckebach often tried quinine again, but he succeeded in only one other patient.
He made passing mention of it in his book on cardiac arrhythmias published in 1914. Four years later, Walter von Frey of Berlin reported in a leading Viennese medical journal that quinidine was the most effective of the four principal cinchona alkaloids in controlling atrial arrhythmias.
Chemistry
Quinidine-based ligands are used in AD-mix-β for
Sharpless asymmetric dihydroxylation
Sharpless asymmetric dihydroxylation (also called the Sharpless bishydroxylation) is the chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol. The reaction has been applied to al ...
.
Veterinary use
Quinidine sulfate is used in the treatment of atrial fibrillation in horses.
References
External links
MedlinePlus
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Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...
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