Pathways

Ritodrine is a adrenergic beta agonist used for the treatment and prophylaxis of premature labour. Beta-2 adrenergic receptors are located at sympathetic neuroeffector junctions of many organs, including uterus. Ritodrine is beta-2 adrenergic agonist. It stimulates beta-2 adrenergic receptor, increases cAMP level and decreases intracellular calcium concentration. The decrease of calcium concentration leads to a relaxation of uterine smooth muscle and, therefore, a decrease in premature uterine contractions. Ritodrine binds to receptors on outer membrane of myometrial cells. Once ritodrine 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. There are two mechanisms by which KCa++ channels can be activated in these cells, the first being when PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization, and the second being directly by the G proteins by direct gating. Phosphorylation of ATP-sensitive potassium channels occurs as well. 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 uterus causes the uterine muscles to relax which causes a decrease in premature contractions, effectively treating premature labour. In summary, ritodrine is able to complete this through its activation of beta-2 adrenergic receptors, activation of ATP-sensitive potassium channels, and activation of calcium activated potassium channels. Ritodrine is typically administered via intravenous injection, or as an oral tablet. Some side effects of using ritodrine may include chest pain or tightness, dizziness or lightheadedness, flushed and dry skin, and increased urination.

Herpes simplex virus 1 (HSV-1) is a neurotropic virus with DNA, it causes orofacial diseases in humans. Herpes simplex virus 2 (HSV-2) primarily affects the anogenital region. Docosanol is an antiviral used as a topical cream to treat recurrent herpes simplex labialis episodes (episodes of cold sores or fever blisters). This saturated aliphatic alcohol molecule exhibits antiviral activity against some lipid-enveloped viruses. It speeds the healing of cold sores or/and fever blisters on the face and lips. The mechanism of action is to inhibit the fusion between the host cell plasma membrane and the HSV envelope. This drug prevents viral entry and subsequent viral replication. In this way, docosanol does not act directly on the virus; as such, it is unlikely it will produce drug-resistant mutants of the virus Docosanol enters the cell and is oxidized as n-docosanoic acid. This last molecule can incorporate itself in ether lipids. When the n-docosanoic acid gets incorporated in the formation of the envelope glycoprotein GP350, the upcoming viruses will not attach to the host B-lymphocyte cell, then it will not enter the cell.

Amantadine is an antiviral used in the symptomatic treatment of various strains of influenza A virus. It can also be used to treat parkinsonism and drug-induced extrapyramidal reactions. The mechanism of action in the Parkinson's treatment is not known. As an antiviral, Amantadine interacts with the M2 (matrix protein 2) viral protein. This viral protein is an ion channel needed for the viral particule to become uncoated once it is in the host cells. This drug is available as an oral capsule and as a syrup,

Bamlanivimab, also known as LY-CoV555 or LY3819253, is a human IgG1K monoclonal antibody (mAb) against the SARS-CoV2 spike protein, called S. This drug was synthesized from the first blood samples of a patient who recovered from COVID-19 in the USA. This molecule is not approved by the FDA, but it is authorized under an Emergency Use Authorization (EUA) for the treatment of COVID-19 patients. X-ray crystallography and cryo-EM structural determination suggest that this molecule binds the receptor-binding domain (RBD) of the spike protein of CoV-19. This binding overlaps the ACE2 binding site. Bamlanivimab is available as an intravenous injection.

Micafungin, also known as Mycamine, is an echinocandin antifungal agent used for the treatment of candidemia, acute disseminated candidiasis, and certain other fungal infections..More commonly, Micafungin is used against Aspergillus infections, and only used against some Candida infections. It is also used to treat the prophylaxis of Candida infections during stem cell transplantation. It is a glucan synthesis inhibitor which is essential for cell wall synthesis. Micafungin inhibits glucan synthase, an enzyme present in fungal, but not mammalian cells. This prevents the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, which ultimately leads to osmotic instability and cell death.

Peramivir, also known as Rapivab, is an antiviral agent used to treat acute uncomplicated influenza A and B. Being a specific influenza virus neuraminidase inhibitor, peramivir works by preventing new viruses from emerging out of infected host cells. Viral Neuraminidase helps viruses to be released from the plasma membrane of the host cell after budding by cleaving terminal sialic acid residues from glycan structures on the surface of the infected cell. The active site of the neuraminidase enzyme is highly conserved, making it a good structure to inhibit. By inhibiting the NA catalytic site, peramivir causes viruses to aggregate and fail to be released from the cell surface. This drug has a low bioavailability when taken orally, so the only available formulation is the injectable intravenous.

Ribavirin is a synthetic guanosine nucleoside used to treat Influenza A and, recently, Hepatitis C. This an antiviral agent that interferes with the synthesis of viral mRNA. Ribavirin is a prodrug that is metabolized into nucleoside analogs that blocks viral RNA synthesis and viral mRNA capping. According to 2017 American Association for the Study of Liver Diseases (AASLD) and 2015 consensus guidelines from the Canadian Association for the Study of the Liver (CASL), ribavirin is typically used as an adjunct therapy to various first-line and second-line combination therapies recommended for each genotypes. Ribavirin is added to decrease relapse rates by accelerating viral clearance early in the treatment course. When used to treat Hepatitis C virus (HCV) infections, it is always used as a part of combination therapies as ribavirin monotherapy is not efficacious in the treatment of chronic hepatitis C infection. Ribavirin has several mechanism of actions that lead to inhibition of viral RNA and protein synthesis. Firstly, this drug is activated by its phosphorylation by adenosine kinase and result in ribavirin mono-, di-, and triphosphate metabolites. Ribavirin triphosphate (RTP) is the predominant metabolite which directly inhibits viral mRNA polymerase by binding to the nucleotide binding site of the enzyme. This prevents the binding of the correct nucleotides, leading to a reduction in viral replication or to the production of defective virions. Ribavirin is reported to have several mechanism of actions that lead to inhibition of viral RNA and protein synthesis. After activation by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites. Ribavirin triphosphate (RTP) is the predominant metabolite which directly inhibits viral mRNA polymerase by binding to the nucleotide binding site of the enzyme. This prevents the binding of the correct nucleotides, leading to a reduction in viral replication or to the production of defective virions. Inhibition of host inosine monophosphate dehydrogenase (IMPDH) and subsequent depletion of GTP pool is proposed to be another mechanism of action of ribavirin. This drug acts as a mutagen in the target virus to cause an 'error catastrophe' due to increased viral mutations. RTP pairs with cytidine triphosphate or uridine triphosphate with equal efficiency and to block HCV RNA elongation. It causes premature termination of nascent HCV RNA and increases mutagenesis by producing defective virions. This pathway shows the mechanism of action of this drug on influenza A virus only. This drug can also treat Hepatitis C, in hepatocyte cells instead of in the trachea's epithelial cells.

Zofenopril is a specific angiotensin-converting enzyme (ACE) inhibitor. It is used in the treatment of acute myocardial infaction (AMI), hypertension and mild to mmoderate hypertension. Zafenopril has the ability to improve endothelial function and protect against ischemia. Zofenopril is a prodrug, once absorbed, the cell metabolizes it in zofenoprilat. Zefonoprilat is the molecule that does the inhibition of the ACEs. This interaction blocks the conversion of angiotensin I to angiotensin II. This production of angiotensin II modulates blood pressure. Angiotensin II causes vasoconstriction and this leads to an increase of blood pressure. This system starts with the renin being released from prorenin due to kallikrein. After that, renin will cleave angiotensinogen to release angiotensin I. Angiotensin II binds to AT1 and AT2, these receptors will activate many signaling cascades that will lead to the retaining of sodium and water in the renal tubules. At the same time, these receptors will activate signaling cascades that lead to the stimulation of aldosterone release from the adrenal gland (an important role in the renin-angiotensin-aldosterone system (RAAS)).

Necitumumab is an intravenously administered recombinant monoclonal IgG1 antibody used to treat metastatic squamous non-small cell lung cancer. It is approved for use in combination with cisplatin and gemcitabine. It blocks other ligands of the EGFR from binding and activating numerous signalling cascades to promote cell growth, proliferation, and differentiation. The main cascades that are affected are the MAPK signalling cascade, which affects the synthesis of DNA for proliferation and differentiation and the PI3K/AKT1 signalling cascade which also affects proliferation but also controls apoptosis. MAPK is activated through the epidermal growth factor receptor on the cell membrane and goes on to phosphorylate and regulate the activities of several transcription factors affecting cellular growth and proliferation. The PI3K/AKT1 signalling cascade is apart of the PI3K/AKT1/mTOR pathway which is an intracellular signalling pathway that also helps regulate the cell cycle. This signalling cascade can affect the regulation and activity of transcription factors as well. In cancer, the PI3K/AKT1/mTOR is overactive reducing apoptosis and allowing excessive cellular proliferation.

Droxidopa is a medication used to treat symptomatic neurogenic orthostatic hypotension (nOH) caused by dopamine beta-hydroxylase deficiency, non-diabetic autonomic neuropathy and primary autonomic failure caused by conditions such as Parkinson's disease. Droxidopa is a precursor of noradrenaline that is used in the treatment of Parkinsonism. Droxidopa is an orally active synthetic precursor of norepinephrine that increases the deficient supply of norepinephrine in patients with NOH, thereby improving orthostatic blood pressure and alleviating associated symptoms of lightheadedness, dizziness, blurred vision, and syncope through the induction of tachycardia (increased heart rate) and hypertension. Through the beta-1 adrenergic receptor, the heart is stimulated by norepinephrine. Droxidopa crosses the blood-brain barrier where it is converted to norepinephrine via decarboxylation by L-aromatic-amino-acid decarboxylase. Norepinephrine is stored in synaptic storage sites where norepinephrine was already being stored. When the neuron is depolarized, this accumulation of norepinephrine is released into the synapse. The norepinephrine activates Beta-1 adrenergic receptor which is coupled to the G-protein signalling cascade. Activation of the receptor activates the cascade which leads to activated protein kinase through activation of adenylate cyclase. Protein kinase activates calcium channels in the membrane, causing the channels to open and allow Ca2+ into the cell. This causes a high concentration of Ca2+ to be present in the cardiomyocyte which activates activates the ryanodine receptor on the sarcoplasmic reticulum. This transports more Ca2+ into the cytosol. The high concentration of Ca2+ binds to troponin to cause cardiac muscle contractions and therefore, an increased heart rate. Some side effects of using droxidopa may include headache, dizziness, nausea, high blood pressure, and fainting.