Pathways

Phenylpropanoid biosynthesis is responsible for creating large amounts of secondary metabolites from many different intermediates from other pathways such as the shikimate pathway. The biosynthesis has many different reductases, oxygenases and transferases which help create the specific secondary metabolites necessary for characteristic plant development. From L-phenylalanine, cinnamic acid and cinnamoyl-CoA are products which can further create coumaroyl-CoA, an important metabolite with feeds into all downstream reactions for other metabolites. Downstream metabolites caffeic acid, ferulic acid, 5-hydroxyferulic acid, and sinapic acid can all be reduced into their CoA, aldehyde and aldehyde form through similar enzymes and can be converted between each other as well. All the alcohols at the end can feed into lignin biosynthesis, which is important for plant structure. The metabolites cinnamoyl-CoA and p-coumaroyl-CoA can feed into flavonoid, stillnenoid, diarylhe paranoid and gingerol biosynthesis.

Phenyltoloxamine is a first-generation ethanolamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

This pathway illustrates the phenytoin 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). Phenytoin is an antiepileptic drug that exhibits Class 1B antiarrhythmic activity. Although phenytoin is used to treat epileptic seizures, beneficial antiarrhythmic effects have also been observed. Phenytoin preferentially binds to sodium channels (I-Na) in their inactive state. This causes a slight delay in the rapid depolarization phase of cardiac myocyte action potentials. In contrast to Class 1A antiarrhythmic drugs (e.g. quinidine) which prolong action potential duration, phenytoin and other Class 1B antiarrhythmics reduce the refractory period or action potential duration due to their membrane stabilizing effects. Phenytoin has been found to be beneficial in the treatment of atrial and ventricular arrhythmias.

Phenytoin is an anticonvulsant drug used in the prophylaxis and control of various types of seizures. It can be found under the brand names Dilantin and Phenytek. Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels. Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. This blocks sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady-state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state. Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissassociate from the inactive channel, there is a time-dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials. Phenytoin is typically administered as an oral capsule, but can also be delivered via intravenous or intramuscular injection. Some side effects of using phenytoin may include headaches, drowsiness, nervousness, and constipation.

Phenytoin is a class 1B antidysrythmIc as well as an anticonvulsant that is used to treat partial seizures, tonic-clonic seizures, bipolar disorder and ventricular dysrhythmias. It has a very narrow therapeutic index despite having a very high protein binding affinity which makes dosing difficult in patients. Phenytoin mainly inhibits sodium channels protein type 5 subunit alpha but also inhibits the potassium voltage gated channel subfamily H member 2 and L type calcium channels. 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. In seizures, blockages of sodium and potassium channels to prolong the inactivation of the cells making repetitive firing more difficult. It can be used to help treat partial and tonic-clonic seizures. It also inhibits calcium influx which important in the treatment of partial and tonic-clonic seizures when they are secondary to other types of seizures. Phenytoin 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 phenytoin can bind to the channel and block it. Phenytoin can be administered through either oral or intravenous routes with the oral route having varying half-life of anywhere from 7 to 42 hours while intravenous is from 10-15 hours.

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