Pathways

Ketobemidone is an opioid analgesic and is used to treat severe pain such as postoperative, cancer, fractures and kidney stones. It has some NMDA antagonist properties. It is administered intravenously, orally and rectal, and is mainly only used in Scandinavian countries. Compared to morphine it is more effective for analgesia and has a reduced risk of addiction under supervision. Ketobemidone is metabolized by conjugation of phenolic hydroxyl group and by N-methylation, with only roughly 24% excreted unchanged after intravenous administration.

Ketobemidone (also known as Ketogan) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of ketobemidone acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

Ketobemidone is mainly metabolized by conjugation of the phenolic hydroxyl group, and by N-desmethylation. Only about 13-24% is excreted unchanged after iv. administration. Ketobemidone (Cliradon, Ketogan, Ketodur, Cymidon, Ketorax, &c.) is a powerful opioid analgesic. It also has some NMDA-antagonist properties. This makes it useful for some types of pain that don't respond well to other opioids. The most commonly cited equalisation ratio for analgesic doses is 25 mg of ketobemidone hydrobromide to 60 mg of morphine hydrochloride or sulfate and circa 8 mg of ketobemidone by injection. (DrugBank)

Ketobemidone is a powerful opioid analgesic with some NMDA-antagonist properties. Ketobemidone is an agonist of mu, kappa, and delta opioid receptors. Mu-binding sites are discretely distributed in the brain, spinal cord, and other tissues. It exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Ketobemidone also depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Ketobemidone binds very strongly to mu opioid receptors and acts as a competitive agonist. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as GABA is inhibited. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability. Carfentanil acts at A delta and C pain fibres in the dorsal horn of the spinal cord. By decreasing neurotransmitter action there is less pain transmittance into the spinal cord. This leads to less pain perception.

Ketoconazole is an antifungal imidazole, known as the brand name Extina, Ketodan, Ketoderm, Nizoral, Xolegel. It is typically applied as a topical cream since there are now better oral anti-fungal drugs with less side-effects. Ketoconazole is used for treatment or prevention of fungal infections including blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. It is most commonly used for athlete's foot, jock itch, ringworm, and certain kinds of dandruff. It is recommended that oral Ketoconazole be used only when other anti-fungal drugs are not an option. It is also used to treat Cushing's syndrome. It does this by targetting Steroid 17-alpha-hydroxylase/17,20 lyase which is essential in cortisol synthesis. This is only approved for in Europe. Ketoconazole works like other antifungal azoles by inhibiting lanosterol 14-alpha demethylase which is an enzyme that catalyzes the synthesis of 4,4-Dimethylcholesta-8,14,24-trienol from Lanosterol. This is one of the first steps in Ergosterol synthesis. The inhibition of lanosterol 14-alpha demethylase prevents the synthesis of ergosterol which is essential in the maintenance and synthesis of fungal cell membranes. The lack of ergosterol increases cell permeability which allows intracellular components to leak out and eventually the fungal cell collapses and dies. Fungal cells also require ergosterol to synthesize new cell membranes for buds and new cells, and so they cannot do so when the synthesis of ergosterol is inhibited. Ketoconazole also causes an accumulation of 14α-methyl-3,6-diol which is toxic to the cell and will also kill the fungal cell and the cell membrane. The exact method of 14α-methyl-3,6-diol synthesis is not known, but it has been found in a study that lanosterol is catalyzed by Methylsterol monooxygenase and 3-keto-steroid reductase along with ERG26 to synthesize 14α-methyl-fecosterol. This only occurs when lanosterol 14-alpha demethylase is inhibited. 14α-methyl-fecosterol is catalyzed by Delta(7)-sterol 5(6)-desaturase to synthesize 14α-methyl-3,6-diol.

Metabolites of Ketoconazole are predicted with biotransformer.

The ketogluconate metabolism starts with the degradation of 2,5-didehydro-D-gluconate either through a NADPH dependent 2,5-diketo-D-gluconate reductase resulting in the release of a NADP and 5-dehydro-D-gluconate or through a NADPH dependent 2,5-diketo-D-gluconate reductase protein complex resulting in the release of a NADP and a 2-keto-L-gulonate. The 2-keto-L-gulonate interacts with a NADPH 2-keto-L-gulonate reductase resulting in a NADP and a L-idonate. The L-idonate interacts with a NADP L-idonate 5-dehydrogenase resulting in the release of hydrogen ion, a NADPH and a 5-dehydro-D-gluconate. The 5-dehydro-D-gluconate interacts with a NADPH driven 5-keto-D-gluconate 5-reductase resulting in the release of a NADP and a D-gluconate. The other way to produce D-gluconate is by having 2,5-Didehydro-D-gluconate interacting with a NADPH and hydrogen ion resulting in the release of a NADP and a 2-keto-D-gluconate which then interact with NADPH a 2-keto-D-gluconate reductase resulting in a NADP and a D-gluconate The D-gluconate is phosphorylated by an ATP driven D-gluconate kinase resulting in a ADP, a hydrogen ion and a D-gluconate 6-phosphate. This compound can either join the Entner-Doudoroff pathway or be metabolized by a NADP dependent 6-phosphogluconate dehydrogenase resulting in a NADPH, a carbon dioxide and a D-ribulose 5-phosphate. The Entner-doudoroff pathway is dehydrated by a phosphogluconate dehydratase resulting in a water molecule and a 2-dehydro-3-deoxy-D-gluconate 6-phosphate. This compound then interacts with a 2-keto-3-deoxygluconate 6-phosphate aldolase resulting in a D-glyceraldehyde 3-phosphate and a pyruvic acid. The d-glyceraldehyde 3-phosphate is incorporated into a glycolysis while the pyruvic acid is decarboxylated into acetyl CoA

The ketogluconate metabolism starts with the degradation of 2,5-didehydro-D-gluconate either through a NADPH dependent 2,5-diketo-D-gluconate reductase resulting in the release of a NADP and 5-dehydro-D-gluconate or through a NADPH dependent 2,5-diketo-D-gluconate reductase protein complex resulting in the release of a NADP and a 2-keto-L-gulonate. The 2-keto-L-gulonate interacts with a NADPH 2-keto-L-gulonate reductase resulting in a NADP and a L-idonate. The L-idonate interacts with a NADP L-idonate 5-dehydrogenase resulting in the release of hydrogen ion, a NADPH and a 5-dehydro-D-gluconate. The 5-dehydro-D-gluconate interacts with a NADPH driven 5-keto-D-gluconate 5-reductase resulting in the release of a NADP and a D-gluconate. The other way to produce D-gluconate is by having 2,5-Didehydro-D-gluconate interacting with a NADPH and hydrogen ion resulting in the release of a NADP and a 2-keto-D-gluconate which then interact with NADPH a 2-keto-D-gluconate reductase resulting in a NADP and a D-gluconate The D-gluconate is phosphorylated by an ATP driven D-gluconate kinase resulting in a ADP, a hydrogen ion and a D-gluconate 6-phosphate. This compound can either join the Entner-Doudoroff pathway or be metabolized by a NADP dependent 6-phosphogluconate dehydrogenase resulting in a NADPH, a carbon dioxide and a D-ribulose 5-phosphate. The Entner-doudoroff pathway is dehydrated by a phosphogluconate dehydratase resulting in a water molecule and a 2-dehydro-3-deoxy-D-gluconate 6-phosphate. This compound then interacts with a 2-keto-3-deoxygluconate 6-phosphate aldolase resulting in a D-glyceraldehyde 3-phosphate and a pyruvic acid. The d-glyceraldehyde 3-phosphate is incorporated into a glycolysis while the pyruvic acid is decarboxylated into acetyl CoA

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation. Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.