Browsing Pathways

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

Metabolites of sildenafil are predicted with biotransformer.

Diltiazem is a benzothiazepine derivative with antihypertensive and vasodilating properties. Approved in 1982 by the FDA, it is a member of the non-dihydropyridine calcium channel blockers drug class. It works through various mechanisms of action, but it primarily works by inhibiting the calcium influx into cardiac and vascular smooth muscle during depolarization. Compared to dihydropyridine drugs, such as nifedipine, that preferentially act on vascular smooth muscle and verapamil that directly acts on the heart muscle, diltiazem displays an intermediate specificity to target both the cardiac and vascular smooth muscle. Being a potent vasodilator, diltiazem is used clinically as an antihypertensive, anti-arrhythmic, and as an anti-anginal agent 8 for the management of cardiovascular conditions such as hypertension, chronic stable angina, atrial fibrillation, atrial flutter. Apart from its main FDA-approved indications, diltiazem has also been used for numerous off-label indications, such as anal fissures (in topical formulations), migraine prophylaxis, pulmonary hypertension, and rest-related cramps in the lower extremities. Typically available in extended-release oral and intravenous formulations, diltiazem is marketed under various brand names with Cardizem and Tiazac being the most common ones. 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 channels3 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. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina. (DrugBank)

Diltiazem is a benzothiazepine calcium channel blocker (CCB) or antagonist, the only drug of this class in clinical use. 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. Diltiazem is thought to primarily block L-type calcium channels in their open state. It is one of only two clinically used CCBs that are cardioselective. Diltiazem and verapamil, 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, diltiazem may be used to treat arrhythmias (e.g. atrial fibrillation, atrial flutter and paroxysmal supraventrucular tachycardia) as well as hypertension. The first part of this pathway depicts the pharmacological action of diltiazem on cardiac myocytes and peripheral arterioles and coronary arteries. Diltiazem 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. Diltiazem 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. DiltiazemŠ—Ès effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.