Pathways

Levosalbutamol is a beta-2 adrenergic receptor agonist that is used to treat COPD and asthma. It is a short acting drug that can be found under the brand name Xopenex. Levosalbutamol is inhaled, and works by relaxing the smooth muscle in bronchial tubes to increase air flow. Levosalbutamol is Gs coupled and relaxes the muscles through activation of adenylyl cyclase. Short-acting inhaled beta-2 agonists are used for acute symptomatic relief of bronchospasm and to prevent exercise-induced asthma (EIA). Once levosalbutamol is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. Inhibits the phosphorylation of myosin. PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the lungs causes the bronchial airways to relax which causes bronchodialation, making it easier to breathe. Some side effects of using levosalbutamol may include headache, dizziness, nausea, fatigue, and stomach pain.

Metabolites of Levosalbutamol are predicted with biotransformer.

This pathway illustrates the lidocaine 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). Lidocaine is a local anaesthetic that is also used to treat ventricular arrhythmias in emergency situations. It is a Class 1B antiarrhythmic drug that binds to sodium channels in their open and closed inactive state. Voltage-gated sodium channels are responsible for the inward sodium current (I-Na) that causes the rapid depolarization phase of cardiac myocyte action potentials. Inhibition of the sodium current increases the threshold of excitability of cells and decreases automaticity. Like other Class 1B antiarrythmics, lidocaine causes a slight decrease in action potential duration due to its membrane stabilizing effects. Lidocaine is not effective for treating atrial arrhythmias. Lidocaine undergoes rapid hepatic metabolism (t1/2 = 15 – 30 minutes) by cytochrome P450 enzymes, CYP2C6 and CYP3A4. As a result, other related drugs with longer half-lives, such as mexiletine and tocainide, were developed.

Lidocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Lidocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore lidocaine preferentially inhibits neurons that are actively firing.

Lidocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Lidocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore lidocaine preferentially inhibits neurons that are actively firing.

Lidocaine is a local anesthetic used in the treatment of ventricular arrhythmias that is administered intravenously. It is a class 1B antiarrhythmic drug, considered moderately effective at blocking sodium ion channels. Its chemical structure consists of an aromatic group which is linked to diethylglycine through an amine bond. Lidocaine works by slowing the rise of the action potential and is therefore effective for treating tachycardia (rapid heart rate) rather than bradycardias (slowed heart rate). The primary mechanism of action occurs in cardiomyocytes, where the unionized form of lidocaine passively diffuses through the cell membrane and into the cytosol. In the cytoplasm, lidocaine becomes ionized by hydrogen ions and is able to bind to sodium ion channels in the membrane. This locks the sodium channels in an “open” state, where they are no longer able to effectively depolarize the cell. The decreased ability to depolarize slows the generation of signals by suppressing the propagation of an action potential. In turn, the decreased action potential slows the rate of heart contractions, treating the ventricular tachycardia.

Lidocaine is a local anesthetic used in a wide variety of superficial and invasive procedures. It can be found under the brand names Agoneaze, Akten, Alivio, Anestacon, Anodyne Lpt, Astero, Band-aid Hurt-free, Cathejell, Curacaine, Depo-medrol With Lidocaine, Dermacinrx Lido V Pak, Dermacinrx Phn Pak, Dermacinrx Prikaan, Diphen, Emla, Fortacin, Glydo, Instillagel, Kenalog, Lido Bdk, Lido-prilo Caine Pack, Lidodan, Lidoderm, Lidopac, Lidopril, Lidopro, Lidothol, Lidotral, Lignospan, Marcaine, Max-freeze, Medi-derm With Lidocaine, Neo-bex, Octocaine, Octocaine With Epinephrine, Oraqix, P-care, P-care X, Pliaglis, Prilolid, Prizotral, Procomycin, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Relador, Synera, Triple Antibiotic, Venipuncture Px1, Viadur, Xylocaine, Xylocaine With Epinephrine, Xylocard, Xylonor, Zingo, and Ztlido. Ever since its discovery and availability for sale and use in the late 1940s, lidocaine has become an exceptionally commonly used medication. In particular, lidocaine's principal mode of action in acting as a local anesthetic that numbs the sensations of tissues means the agent is indicated for facilitating local anesthesia for a large variety of surgical procedures. Nevertheless, lidocaine's local anesthetic action sees its use in many medical situations or circumstances that may benefit from its action, including the treatment of premature ejaculation. Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. Some side effects of using lidocaine may include chest pain, difficulty breathing, and lightheadedness.