Pathways

Quinethazone, also known under the brand-name Hydromox, is a pharmacologically-active small molecule that belongs to a class of drugs called thiazides. Thiazides and thiazide-like drugs are diuretics commonly employed to control hypertension. The short term mechanism of action is relatively well-understood: thiazides inhibit sodium-chloride co-transport into the renal distal convoluted tubule of the nephron and therefore increase fluid loss which decreases extracellular fluid (ECF), plasma volume, and ultimately blood pressure. In the case of quinethazone, it inhibits the sodium-chloride symporter, solute carrier family 12 member 3. Thiazides also inhibit sodium ion transport. However, the long-term mechanism of action isn’t as well-characterized and it is thought that other processes beyond regulating plasma and ECF volumes are involved as these two volumes return to baseline within 4-6 weeks of first use of thiazides.

This pathway illustrates the quinidine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Quinidine, a diastereomer of quinine, is a Class 1A antiarrhythmic drug that is isolated from the bark of the Cinchona plant or other related species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. At low concentrations, it blocks the voltage-gated sodium (I-Na) and rapid delayed rectifying potassium (I-Kr) channels. I-Na is responsible for the rapid upstroke in cell membrane potential observed on the cardiac myocyte action potential. I-Kr is partially responsible for the final repolarization phase of the action potential. By blocking I-Na, quinidine increases the threshold of excitability and decreases automaticity. I-Kr block results in action potential prolongation. At higher concentrations, quinidine also blocks voltage-gated delayed rectifying potassium channel (I-Ks), inward rectifier potassium channel (I-K1), voltage-gated transient outward delayed rectifying potassium channel (I-Kto), and L-type calcium channels (I-CaL). Quinidine also exerts antimuscarinic effects, which increase AV nodal conduction and antagonize alpha-adrenergic effects. Quinidine may be used to maintain sinus rhythm in atrial fibrillation or flutter and prevent recurrence of ventricular fibrillation or tachycardia. The side effects of quinidine include diarrhea and on rare occasions (2-8%) Torsades de Pointes.

Quinidine is a medication used to restore normal sinus rhythm, treat atrial fibrillation and flutter, and treat ventricular arrhythmias. It can be found under the brand name Nuedexta. Quinidine is a D-isomer of quinine present in the bark of the Cinchona tree and similar plant species. This alkaloid was first described in 1848 and has a long history as an antiarrhythmic medication. Quinidine is considered the first antiarrhythmic drug (class Ia) and is moderately efficacious in the acute conversion of atrial fibrillation to normal sinus rhythm. It prolongs cellular action potential by blocking sodium and potassium currents. A phenomenon known as “quinidine syncope” was first described in the 1950s, characterized by syncopal attacks and ventricular fibrillation in patients treated with this drug. Quinidine has a complex electrophysiological profile that has not been fully elucidated. The antiarrhythmic actions of this drug are mediated through effects on sodium channels in Purkinje fibers. Quinidine blocks the rapid sodium channel (INa), decreasing the phase zero of rapid depolarization of the action potential. Quinidine also reduces repolarizing K+ currents (IKr, IKs), the inward rectifier potassium current (IK1), and the transient outward potassium current Ito, as well as the L-type calcium current ICa and the late INa inward current. The type 5 subunit alpha channel is targeted. The reduction of these currents leads to the prolongation of the action potential duration. By shortening the plateau but prolonging late depolarization, quinidine facilitates the formation of early afterdepolarisation (EAD). Some side effects of using quinidine may include nausea, heartburn, fever, and dizziness. Quinidine is administered as an oral tablet.

The administration of quinidine derivatives is utilized to monitor various skin and mucosal reactions. In certain cases, a papulopurpuric eruption can arise in patients (without thrombocytopenia) who are intermittently taking quinidine phenylethyl barbiturate and upon its reintroduction. Barbiturates exert their effects by binding to the GABAA receptor, targeting either the alpha or beta subunit. These binding sites are distinct from both GABA itself and the benzodiazepine binding site. Similar to benzodiazepines, barbiturates enhance the impact of GABA at this receptor. This interaction with the GABAA receptor results in decreased input resistance, suppression of burst and tonic firing, particularly in ventrobasal and intralaminar neurons. Concurrently, it increases burst duration and the average conductance at individual chloride channels. Consequently, this enhances the amplitude and duration of inhibitory postsynaptic currents. Beyond their GABAergic action, barbiturates also inhibit the AMPA receptor, a subtype of glutamate receptor. Notably, glutamate serves as the primary excitatory neurotransmitter in the mammalian central nervous system.

Quinidine barbiturate is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Quinidine barbiturate passes through the liver and is then excreted from the body mainly through the kidney.

Quinine is an alkaloid used to treat uncomplicated Plasmodium falciparum malaria. It is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. The plasmodium falciparum invades the erythrocytes in blood. Quinine accumulates in the parasite’s food vacuole and inhibits the enzyme heme ligase. Heme ligase is involved in hemoglobin breakdown. Hemoglobin from the erythrocyte is broken down in the digestive vacuole of the parasite. Hemoglobin is first broken down into heme and globin. Globin is further broken down to amino acids which are used by the parasite for nutrition and protein synthesis. Therefore, hemoglobin breakdown is essential for the parasite survival. The heme from hemoglobin is toxic to the parasite and is further broken down by heme ligase to detoxify heme. By quinine inhibiting heme ligase, there is a build up of heme in the parasite vacuole which becomes toxic to the parasite, thereby killing it. Quinine has a bitter taste, and oral compliance is often poor. It is irritant to the gastric mucosa and can cause nausea and vomiting. Cinchonism can occur with exceeded plasma concentration in which symptoms like nausea, dizziness, tinnitus, headache and blurring of vision are experienced. Excessive plasma levels may also cause hypotension, cardiac dysrhythmias and severe central nervous system (CNS) disturbances such as delirium and coma.