diastereomer
In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have di ...
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 ...
, 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 (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
duration, as well as a prolonged
QT interval
The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...
. As of 2019, its IV formulation is no longer being manufactured for use in the United States.
atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
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 normal rhythm using electricity or drugs.
Synchronized electrical cardioversion uses a therapeutic dose of ...
, 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 genetics, genetic disease of the electrical system of the heart, and is associated with an increased risk of Heart arrhythmia, abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from ...
.
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, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
and low dose quinidine in alleviating symptoms of easy laughing and crying (
pseudobulbar affect
Pseudobulbar affect (PBA), or emotional incontinence, is a type of affect disorder connected to Neurological condition, neurological conditions. It is characterized by brief, intense, uncontrollable episodes of crying or laughter, laughing. The ...
); these are a type of 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—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...
and
multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. The dose of quinidine (10 mg two times daily) is about 1/40th of a relatively low antiarrhythmic dose (400 mg, twice or 3 times daily, as an example; antiarrhythmic doses can sometimes exceed 1500 mg/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. 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 is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''
malaria
Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
, the future availability of this agent is uncertain.
Side effects
Quinidine is an inhibitor of the
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
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 and ventricular fibrillation. When used for local anae ...
,
beta blockers
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack (secondary prevention). ...
,
opioids
Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
, and some
antidepressants
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include dry mouth, weight gain, dizziness, headaches, akathisia, sexu ...
. Quinidine also inhibits the
transport protein
A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...
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 4 September 2015 is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable ...
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, ...
, and ''
torsades de pointes
''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP; also called ''torsades'') (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorph ...
'' (dangerous heart rhythm), and has been largely phased out in favor of other antiarrhythmics. ''Torsades'' can occur after the first dose. Quinidine-induced
thrombocytopenia
In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
(low platelet count) is mediated by the
immune system
The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
, 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 a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
(ringing in the ears) being among the most characteristic and common symptoms of this toxicity syndrome.
voltage-gated sodium channel
Voltage-gated sodium channels (VGSCs), also known as voltage-dependent sodium channels (VDSCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeability t ...
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 potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...
antimuscarinic
A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...
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, alpha-1-adrenergic receptors. They are mainly used to tr ...
, 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 ...
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.
Mechanism of action
Like all other class I
antiarrhythmic agent
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.
M ...
s, quinidine primarily works by blocking the fast inward
sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
current (INa). Quinidine's effect on INa 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
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generati ...
to decrease (decreased Vmax).
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 (biology), order that includes Tetraodontidae, pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Alt ...
calcium
Calcium is a chemical element; it has 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 it ...
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 (S ...
(IKATP) and Ito.
At micromolar concentrations, quinidine inhibits Na+/K+-ATPase by binding to the same receptor sites as the digitalis glycosides such as ouabain.
The effect of quinidine on the ion channels is to prolong the
cardiac action potential
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generati ...
P wave
A P wave (primary wave or pressure wave) is one of the two main types of elastic body waves, called seismic waves in seismology. P waves travel faster than other seismic waves and hence are the first signal from an earthquake to arrive at any ...
, wide
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 ...
repolarization
In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarizat ...
.
Pharmacokinetics
Elimination
The
elimination half-life
Biological half-life (elimination half-life, pharmacological 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 blood plasma. ...
of oral quinidine is 6 to 8 hours, and it is eliminated by the
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
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, 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 r ...
".
"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, quinidine 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 saw a man with
atrial fibrillation
Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
. 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 chirality (chemistry), chiral quinine ligand to form a Vicinal (chemistry), vicinal ...
.
Veterinary use
Quinidine sulfate is used in the treatment of atrial fibrillation in horses.
Pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...