Pathways

Terbinafine can be taken orally as a pill. This pill is digested then transported from the intestine into the intestinal epithelial cell possibly via solute carrier family 15 member 1, one of 3 drug transporters into epithelial cells. It is then transported into blood vessels via ATP-binding cassette sub-family C member 3. Once in the blood it travels to the liver where it inhibits squalene monoxygenase, despite having a higher affinity for fungal squalene monoxygenase. In homo sapiens squalene monooxygenase is essential in the biosynthesis of Cholesterol. Like in fungal cells it catalyzes the synthesis of (S)-2,3-epoxysqualene from squalene. (S)-2,3-Epoxysqualene is then catalyzed by lanosterol synthase into lanosterol which then continues into cholesterol biosynthesis. Cholesterol, like ergosterol is essential in membrane integrity by synthesizing fatty acids. It also produces steroid hormones, bile acids, and vitamin D. A lack of cholesterol can cause cholesterol jaundice. The inhibition of squalene monooxygenese causes a increased concentration of squalene which in high concentrations is toxic to the liver. This can cause liver damage or liver death. Terbinafine also inhibits Cytochrome P450 2D6 which is an enzyme present in pregnancy. It is used in the metabolism of fatty acids, steroids and retinoids. For this reason Terbinafine isn't recommended for pregnant people. Terbinafine is metabolized into many different metabolites. Terbinafine is metabolized by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19 to make hydroxyterbinafine which is metabolized into N-Desmethylhydroxyterbinafine by CYP450 3A4, 2B6, 1A2, 2C9, 2C8, and 2C19; and it is metabolized into Carboxyterbinafine by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19. Terbinafine is then also metabolized into N-Desmethylterbinafine by CYP450 2C9, 2C8, 1A2, 2B6, 2C19, and 3A4 which is dihydroxylated into 2 different dihydrodial derivatives as well as being metabolized into N-Desmethylhydroxyterbinafine by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19. Terbinafine is also metabolized into 1-Naphthaldehyde with the same enzymes as N-Desmethylterbinafine. This is predicted by biotransformer to be metabolized into 1-Nahthalenemethanol by CYP450 3A4 and 1-Naphthoic acid by CYP450 1A2. Finally Terbinafine can be dihydroxylated to two different dihydrodiols which are N-demethylated into desmethyldihydrodiol. These metabolites are transported back into the blood where they travel to the kidneys and are excreted through the urine. 80% is excreted in the urine. The remaining 20% of metabolites are transported from the liver into the bile ducts which travels through the ducts into the intestine where they are excreted through the feces. Terbinafine is not present in the urine.

Terbutaline is a beta-2 adrenergic receptor agonist that is used primarily as a bronchodilator. It can be found under the brand name Bricanyl and is an inhaled drug with a short duration. It is used for the prevention and reversal of bronchospasm and for treatment of asthma and bronchitis. Terbutaline relaxes the smooth muscles in the bronchioles by binding to the beta-2 adrenergic receptor and starting a G protein signalling cascade that activates adenylyl cyclase. Once terbutaline 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 from use of terbutaline may include nervousness, drowsiness, weakness, nausea, and headache. Terbutaline may be administered via respiratory inhalation, oral tablets, or subcutaneous injections.

Metabolites of Terbutaline are predicted with biotransformer.

Terconazole is an triazole anti-fungal drug that is mainly used to treat vaginal yeast infections (vaginal candidiasis). The drug comes in a cream or suppository form with high levels of safety, efficacy, and tolerability for both. Terconazole is applied topically to the vagina where it is absorbed into the infected cells, and then diffuses into the candida cell. Terconazole inhibits lanosterol 14-alpha demethylase in the endoplasmic reticulum of fungal cells. Lanosterol 14-alpha demethylase is the enzyme that catalyzes the synthesis of 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol from lanosterol. With this enzyme inhibited ergosterol synthesis cannot occur which causes a significant low concentration of ergosterol in the fungal cell. Ergosterol is essential in maintaining membrane integrity in fungi. Without ergosterol, the fungus cell cannot synthesize membranes thereby increasing fluidity and preventing growth of new cells. This leads to cell lysis which causes it to collapse and die.

Terfenadine is an antihistamine for the treatment of allergy symptoms. 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. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. 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. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Terfenadine also inhibits the H1 histamine receptor on bronchiole smooth muscle myocytes. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin.Calcium bound calmodulin is required for the activation of myosin light chain kinase. This prevents the phosphorylation of myosin light chain 3, causing an accumulation of myosin light chain 3. This causes muscle relaxation, opening up the bronchioles in the lungs, making breathing easier.

Terfenadine is a second-generation piperidine 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.