Pathways

Prion diseases, often called transmissible spongiform encephalopathies (TSEs), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. Prion diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (CWD) in deer and elks. The cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. As demonstrated in the BSE outbreak and its transmission to humans, the onset of disease is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature ofprions has generated huge concerns in public health and attracted serious attention in the scientific communities. To date, the potential transmission ofprions to humans via foodbome infectiorn and iatrogenic routes has not been alleviated. Rather, the possible transmission of human to human or cervids to human aggravates the terrifying situation across the globe.

Metabolites of Probenecid are predicted with biotransformer.

This pathway illustrates the procainamide 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). Procainamide, an analogue of the local anesthetic procaine, is a Class 1A antiarrhythmic drug. It has similar effects to quinidine, but lacks the antimuscarinic and antiadrenergic effects of quinidine. Like other Class 1A drugs, procainamide blocks open sodium channels leading to an increased threshold of excitability. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization seen during cardiac contractile cell action potentials. I-Na block results in delayed excitability of the cells. Procainamide also prolongs action potential duration, likely by slowing the final repolarization phase via potassium channel blocking. This drug may be administered intravenously to treat supraventricular and ventricular arrhythmias. It is better tolerated intravenously than quinidine. Oral administration is poorly tolerated long term.

Procainamide is a class 1A antidysrythmIc as well as an anesthetic that is used to treat ventricular dysrhythmias, tachycardia and atrial fibrillation. Procainamide mainly inhibits sodium channels protein type 5 subunit alpha but also inhibits the potassium voltage gated channel subfamily H member 2. The main antidysrythmIc effect is mediated through the sodium channel blockage though. Phenytoin slows the rate of rise in the pacemaker potential and shortens the plateau phase of atrial and ventricular myocytes as well as purkinje fibre cells as they have 'fast' action potential. This converts a one way block into a two block effectively stopping the circus rhythm irregularity. Procainamide works through use-dependent blockage meaning that it preferentially binds to the inactivate state of the sodium channel. The more active the channel the more chances procainamide can bind to the channel and block it. Procainamide can be administered through either oral or intravenous routes with both having a relatively short half-life of 2.5 to 4.5 hours. Some side effects of using procainamide may include cardiac toxicity, bradycardia, hypotension, drug-induced lupus erythematosus-like syndrome, and blood dyscrasias.

Procainamide is a class 1A antidysrythmIc as well as an anesthetic that is used to treat ventricular dysrhythmias, tachycardia and atrial fibrillation. Procainamide mainly inhibits sodium channels protein type 5 subunit alpha but also inhibits the potassium voltage gated channel subfamily H member 2. The main antidysrythmIc effect is mediated through the sodium channel blockage though. Phenytoin slows the rate of rise in the pacemaker potential and shortens the plateau phase of atrial and ventricular myocytes as well as purkinje fibre cells as they have 'fast' action potential. This converts a one way block into a two block effectively stopping the circus rhythm irregularity. Procainamide works through use-dependent blockage meaning that it preferentially binds to the inactivate state of the sodium channel. The more active the channel the more chances procainamide can bind to the channel and block it. Procainamide can be administered through either oral or intravenous routes with both having a relatively short half-life of 2.5 to 4.5 hours