Pathways

Menthyl salicylate, also known as Max-freeze, is an ester of menthol and salicylic acid, therefore it is a member of the salicylates drug class (NSAIDs). It is used to relieve mild to moderate pain associated with rheumatism, arthritis, neuralgia, sprains, and strains of joints and muscles. The menthol part of the molecule dilates blood vessels while the salicylate portion provides a topical anesthetic and analgesic action on the applied area of the skin/muscle. The salicylate drugs target the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-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. Menthyl salicylate inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. 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. Menthyl salicylate is administered as a topical cream, ointment, patch, gel or liquid.

The DOXP/MEP pathway, also known as the non-mevalonate pathway, plays an essential role in creating the chemicals needed for many plants to function. This pathway, combined with the MEP/DOXP pathway give many plants their scents, such as cinnamon and ginger, and are responsible for the red colour in tomatoes. Terpenoids, also called isoprenoids, are a substantial yet varied class of organic chemicals that occur naturally. Plant terpenoids have aromatic qualities and are used for this and their role in traditional herbal remedies. The pathway begins with D-glyceraldehyde 3-phosphate, which is produced through glycolysis. Together with pyruvic acid and the enzyme 1-deoxy-D-xylulose 5-phosphate synthase 1, these are catalyzed into 1-deoxy-xylulose 5-phosphate. From there, 1-deoxy-xylulose 5-phosphate teams up with 1-deoxy-D-xylulose 5-phosphate reductoisomerase to create 2-c-methyl-D-erythritol 4-phosphate. Moving along in the chloroplast, after being produced through 2-c-methyl-D-erythritol 4-phosphate and the enzyme 2-c-methyl-D-erythritol 4-phosphate cytidyltransferase,4-cytidine 5'-diphospho)-2-C-methyl-D-erythritol is catalyzed by 4-diphosphocytidyl-2-c-methyl-D-erythritol kinase to create 2-phospho-4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol. After that, 2-c-methyl-D-erythritol 2,4-cyclodiphosphate synthase uses the newly produced 2-phospho-4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol to create 2-c-methyl-D-erythritol-2,4-cyclodiphosphate. This compound is then joined with 4-hydroxy-3-methylbut-2-en-1-yl diphosphate synthase to become 1-hydroxy-2-methyl-2-butenyl 4-diphosphate. This compound gets busy soon after its inception, branching off into two separate reactions: first reacting with 4-hydroxy-3-methylbut-2-enyl diphosphate reductase to create isopentenyl pyrophosphate, then reacting with the same enzyme to create dimethylallylpyrophosphate. Dimethylallylpyrophosphate is then looped into another reaction with isopentenyl-diphosphate delta-isomerase II, recreating isopentenyl pyrophosphate. It also reacts with geranylgeranyl pyrophosphate synthase 6, bringing the pathway into the mitochondrion to create geranyl pyrophosphate. This is later followed by a monoterpenoid biosynthesis pathway.

Meperidine is a narcotic analgesic opioid that is used for moderate to severe pain. It is less effetive than Morphine, but also has shorter side-effects. Mepereidine is effective locally or in the central nervous system in the brain and spinal cord. It can ross the blood-brain barrier to access the brain. It is regularly injected, but sometimes can be taken orally which has a 50-60% bioavailability because of first pass metabolism in the liver. In the nervous system meperidine binds to the kappa-type opioid receptor. The Kappa-opioid receptor is coupled with G-protein receptors. Binding of meperidine stimulates the exchange of GTP for GDP on the G-protein complex. The G-protein system inhibits adenylate cyclase which prevents ATP from being synthesized into cAMP which causes a decrease in intracellular cAMP. The activated G-proteins also close N-type voltage-operated calcium channels which prevents calcium from entering the neuron, and it opens calcium-dependent inwardly rectifying potassium channels which causes sodium to leave the neuron. This results in hyperpolarization and reduced neuronal excitability. Subsequently, this leads to the release of nociceptive neurotransmitters such as GABA, substance P, dopamine, acetylcholine, and noradrenaline. Less GABA leads to disinhibition of dopamine cell firing in the spinal cord and brain pain transmission neurons as well as the pleasure center of the brain. Less substance P, acetylcholine, and noradrenaline directly prevents firing of nociceptors as they bind and activate receptors that cause firing in nociceptors. Both these neurotransmitters and GABA lead to analgesia. Dopamine while normally not present in the pain pathway to cause pain, but has been shown to be involvedin chronic pain, and meperidine can stop that pain as well. Meperidine also has side-effects caused by the activation of opioid receptors in muscle signalling. Opioid receptors prevent the release of acetylcholine which is the neurotransmitter used on smooth muscles. This therefore prevents contraction of those smooth muscles which can lead to constipation and depression of the cough reflex.

Metabolites of sildenafil are predicted with biotransformer.