Pathways

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

Verapamil is a cardioselective non-dihydropyridine calcium channel blocker that is typically administered orally or intravenously in a clinical setting to reduce angina (chest pain), lower hypertension (high blood pressure), and treat certain types of arrhythmias (also known as dysrhythmias: abnormal heartbeats). As a Class IV antiarrhythmic agent, it elongates the phase 3 (plateau) period of a cardiac action potential. Humans have at least five different types of calcium channels: L-, N-, P/Q-, R-, and T-type; verapamil targets the Cav1.2 portion of the alpha-1 subunit of L-type voltage-dependent calcium channels. As a phenylalkylamine, verapamil is thought to enter the pore subunit of the channel from the cytoplasmic side to block the channel intracellularly. Verapamil binds to these channels in a voltage- and frequency-dependent manner. These channels are highly expressed in vascular smooth muscle and myocardial tissue. Blocking L-type calcium channels decreases conduction and increases the refractory period, slowing conduction through the AV node to alter electrical activity mediating the heart rate such that there is an increase in the PR interval duration. Verapamil’s effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Thus, there is a reduction in inotropy, chronotropy, and heart rate, making verapamil effective for supraventricular dysrhythmia (e.g. atrial fibrillation). Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure as inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation, which lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like verapamil dilate blood vessels, which increases the supply of blood and oxygen to the heart, reducing angina. Due to potential interactions of verapamil with other calcium channels, potassium channels, and adrenergic receptors, it is used off-label for cluster headaches.

Verapamil, known as the brand names Calan, Isoptin, Tarka, and Verelan, is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. It is used for the treament of vasopastic angina, unstable angina, chronic stable angina, treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia,and atrial fibrillation or atrial flutter in combination with digoxin. It is normally given intravenously, so it has a rapid release with a short duration of action. Verapamil acts on smooth muscles and cardiac muscles. Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. The inhibition of L-type calcium channels prevents the influx of calcium in vascular smooth muscle myocytes and the heart's cardiomyocytes, which prevents contraction of vascular smooth muscles and heart muscles. Preventing the contraction of vascular smooth muscles causes relaxation or dilation of peripheral blood vessels. This reduction in vascular resistance also reduces the force on the heart, decreasing myocardial energy consumption and oxygen requirements. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to be involved with its effect on calcium channels.

Verapamil, known as the brand names Calan, Isoptin, Tarka, and Verelan, is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. It is used for the treament of vasopastic angina, unstable angina, chronic stable angina, treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia,and atrial fibrillation or atrial flutter in combination with digoxin. It is normally given intravenously, so it has a rapid release with a short duration of action. Verapamil acts on smooth muscles and cardiac muscles. Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. This is essential for the propogation of action potentials in the myocytes necessary for the contraction of the muscle tissue and the heart's electrical pacemaker activity. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Electrical activity through the AV node is responsible for determining heart rate. This activity is dependent on calcium influx through L-type calcium channels. Therefore, the inhibition of L-type calcium channels, by verapamil, decreases the influx of calcium, which prolongs the refractory period of the AV node and slows conduction. This slows and controls the heart rate. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to be involved with its effect on calcium channels.

Verapamil is a phenylalkylamine calcium channel blocker (CCB) or antagonist. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Verapamil, an organic cation, is thought to primarily block L-type calcium channels in their open state by interfering with the binding of calcium ions to the extracellular opening of the channel. It is one of only two clinically used CCBs that are cardioselective. Verapamil and diltiazem and, the other cardioselective CCB, shows greater activity against cardiac calcium channels than those of the peripheral vasculature. Other CCBs, such as nifedipine and amlodipine, have little to no effect on cardiac cells (cardiac myocytes and cells of the SA and AV nodes). Due to its cardioselective properties, verapamil may be used to treat arrhythmias (e.g. atrial fibrillation) as well as hypertension. The first part of this pathway depicts the pharmacological action of verapamil on cardiac myocytes and peripheral arterioles and coronary arteries. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure. The second part of this pathway illustrates the effect of calcium channel antagonism on the cardiac action potentials. 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 of the cell is negatively charged relative to the cellsŠ—È 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). Blocking L-type calcium channels decreases conduction and increases the refractory period. VerapamilŠ—Ès effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.

Venlafaxine (also named as Effexor or Elafax) is an antidepressant medication, which belongs to the class of serotonin-norepinephrine reuptake inhibitor (SNRI). Venlafaxine is well absorbed into the circulation system. Venlafaxine is also metabolized to N-desmethylvenlafaxine. The N-demethylation is catalyzed by CYP3A4 and CYP2C19. N-desmethylvenlafaxine is a weaker serotonin and norepinephrine reuptake inhibitor. Both O-desmethylvenlafaxine (as potent a serotonin-norepinephrine reuptake inhibitor) and N-desmethylvenlafaxine are further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to a minor metabolite N,O-didesmethylvenlafaxine that is further metabolized into N,N,O-tridesmethylvenlafaxine or excreted as N,O-didesmethylvenlafaxine gucuronide. Later on, O-desmethylvenlafaxine is exported without any change in chemical structure. Venlafaxine is exported via two transporters: Multidrug resistance protein 1 and ATP-binding cassette sub-family G member 2.