Browsing Pathways

Tocainide is an orally active class 1b antiarrhythmic agent that interferes with cardiac sodium channels and typically used to treat ventricular arrhythmias. It is used to treat conditions including sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. Tocainide acts in neurons where it inhibits voltage gated sodium channels in the pre synaptic neurons. In neurons, voltage gated sodium channels allow sodium to come into the neuron triggering the depolarization phase. the potassium channels are responsible for the repolarization phase to bring the neuron back to resting potential. The action potentials created travel down the axon of the neuron and at the nerve terminal, calcium channels open, allowing calcium to enter the cell. Calcium entry causes synaptic vesicles containing neurotransmitters like glutamate to fuse with the membrane and expel the neurotransmitter into the synapse. Glutamate binds to AMPA and NMDA receptor on the post synaptic neurons where they cause excitation of the neuron. By blocking the voltage gated sodium channels, carbamazepine prevents the depolarization phase, inhibiting action potential generation and the release of excitatory neurotransmitter like glutamate. Pre and post synaptic neuronal firing are therefore reduced. Tocainide works as a “use-dependent” block. This means that it preferentially binds to channels that are being opened. In neurons that are repetitively firing, their sodium channels are being opened more often, and as a result, tocainide is able to produce a greater block in these neurons. It also possesses some anticholinergic and local anesthetic properties. Side effects of tocainide include nausea, vomiting, headaches, feeling dizzy, or feeling hot and flushed.

Ethotoin is a hydantoin antiepileptic used to control tonic-clonic and complex partial seizures that can be found under the brand name Peganone. Ethotoin is a hydantoin derivative and anticonvulsant. Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges. Ethotoin inhibits nerve impulses in the motor cortex by lowering sodium ion influx, limiting tetanic stimulation. Some side effects of using ethotoin may include agitation, irritability, chest pain, and fever.

Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension. Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. It is structurally related to felodipine, nifedipine, and nimodipine and is the most potent calcium-channel blocking agent of the DHP class. Isradipine binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and arterial smooth muscle cells. Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. 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. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. Some side effects of using isradipine may include headache, dizziness, flushing, and tiredness.

Maribavir, known as the brand name Livtencity, is a benzimidazole riboside that inhibits cytomegalovirus (CMV) pUL97 kinase used to treat refractory post-transplant CMV infections. Human cytomegalovirus is a herpesvirus that is a common infection following stem cell or organ transplants. Like other herpesviruses, it tends to presist in the host and become reactivated under immunosuppressive conditions, such as during a transplant. Maribavir competitively inhibits human CMV pUL97 viral protein kinase which plays a role in viral egress, and viral replication or regulation of hot cell cycle progression. It has been found to participate in the acquisition of tegument during virion morphogenesis. It has also been found to phosphorylate the nuclear egress complex, which allows to viral release from the host cell. It also plays a role in the phosphorylation of Lamins-A/C and DNA polymerase. Lamin-A/C contributes to viral release with the nuclear egress complex, while DNA polymerase is essential in DNA replication. The inhibition of pUL97 viral protein kinase results in a viable, but severely defective virus upon replication. The exact reasons for this remain poorly defined.

Parnaparin is a low-weight molecular heparin (LWMH), an anticoagulant that acts on antithrombin III in order to inhibit coagulation. Inhibition of antithrombin III leads to no conversion of prothrombin to thrombin in addition to halting the conversion of fibrinogen to fibrin due to little concentrations of thrombin. It is usually administered subcutaneously and like other heparins has the risk of adverse effects such as deep vein thrombosis. It offers more toleration than heparin, as well as greater bioavailability and a longer half-life although more studies are being conducted to gain more insight into the therapeutic advantages of the drug. It can have interactions with food, it best to avoid herbs and supplements with anticoagulant and antiplatelet activity such as garlic, ginger, bilberry, danshen, piracetam and ginkgo biloba.

Reviparin is a low molecular weight heparin derived from a pig's intestinal mucus and used to prevent thromboembolism.

Gentamicin is an aminoglycoside derived from Micromonospora purpurea. This antibiotic is mainly used to treat severe gram-negative infections caused by Pseudomonas aeruginosa. It has some severe adverse effects like nephrotoxicity and ototoxicity which can limit its use. Gentamicin goes through 3 phases to infiltrate the bacterial cell: the first phase is the binding of polycationic antibiotics to the negatively charged bacterial cell membrane, which increases the membrane permeability. The second phase is the entry of the drug through oxygen-dependent active transport into the bacteria where it binds the 30S ribosomal subunit. The final phase is the inhibition of protein synthesis and the accumulation of Gentamicin in the cell which further exacerbates its inhibition of protein synthesis and mistranslation. Much like other aminoglycosides, gentamicin is linked with nephrotoxicity and ototoxicity. While nephrotoxicity is reversible by stopping the usage of gentamicin, ototoxicity can have permanent effects. Gentamicin is administered by intravenous or intramuscular injection. It is also possible to use it as an ophthalmic drop or topical cream.

Fish oil is made of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). It is an essential source of fatty acid (omega-3) indicated primarily as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (FDA). Also, this molecule is indicated by the EMA as an adjuvant treatment in secondary prevention after myocardial infarction, in addition to other standard therapy (ie. statins, antiplatelet medicinal products, beta-blockers, ACE inhibitors). EPA and DHA do competition with arachidonic acids for both COX-1 and COX-2 enzymes. These are responsible for the conversion of arachidonic acid (an omega-6 fatty acid) into prostaglandins and thromboxanes, which are important mediators of inflammation and pain. Like DHA, EPA also interacts with the cyclooxygenase (COX) enzymes. EPA, as an omega-3 fatty acid, can competitively inhibit the activity of both COX-1 and COX-2 enzymes. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. EPA and DHA inhibit the action of COX-1 and COX-2 on the endoplasmic reticulum membrane by doing competition with the normal substrate (arachidonic acid). This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fish oil is administered as an oral capsule or tablet, it can also be found as a parenteral emulsion when oral or enteral nutrition is not possible, insufficient, or contraindicated for different reasons.

Cocaine is a local anesthesia and vasoconstrictor that is clinically used during diagnostic proceedures or during surgery in or through the nasal cavity. It comes in drugs called Goprelto and Numbrino which comes as a nasal spray. In these clinical drugs it takes the form of cocaine hydrochloride. The illicit drug has the same effects. It primarily acts on sensory neurons in the nasal cavity, but also inhibits dopamine, serotonin, and norepinephrine re-uptake channels. Cocaine inhibits the sodium-dependent noradrenaline channel which causes norepinephrine to accumulate in the synapse. The high concentration of norepinephrine readily activates both alpha adrenergic receptors in the smooth muscles of blood vessels. This, through the Gq signalling cascade, leads to vasoconstriction of blood vessels especially in the nose. This also causes higher heart rate and higher blood pressure, due to vasoconstriction, in the rest of the body as seen in the norepinephrine subpathway.

Tolfenamic acid is a nonsteroidal anti-inflammatory agent (NSAID) used to treat pain associated with the acute attack of migraine in adults. This drug binds as an antagonist to both prostaglandin G/H synthase 1 and prostaglandin G/H synthase 2 in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. The inhibition of both COX-1 and COX-2 by tolfenamic acid reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. This drug is administered as an oral tablet.