Pathways

Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. (DrugBank)

Valsartan (also named Diovan) is an antagonist of angiotensin II receptor blockers (ARBs). Valsartan competes with angiotensin II to bind type-1 angiotensin II receptor (AT1) in many tissues (e.g. vascular smooth muscle, the adrenal glands, etc.) to prevent increasing sodium, water reabsorption and peripheral resistance (that will lead to increasing blood pressure) via aldosterone secretion that is caused by angiotensin II. Therefore, action of valsartan binding to AT1 will result in decreasing blood pressure. For more information on the effects of aldosterone on electrolyte and water excretion, refer to the description of the \spironolactone\:http://pathman.smpdb.ca/pathways/SMP00134/pathway or \triamterene\:http://pathman.smpdb.ca/pathways/SMP00132/pathway pathway, which describes the mechanism of direct aldosterone antagonists. Valsartan is an effective agent for reducing blood pressure and may be used to treat essential hypertension and heart failure.

Valsartan is angiotensin receptor blocker (ARB) which block the action of angiotensin II by binding to the type 1 angiotensin II receptor. Angiotensin II is a critical circulating peptide hormone that has powerful vasoconstrictive effects and increases blood pressure. Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. Angiotensin II has many vasoconstrictive effects by binding to angiotensin II type 1 receptors (AT1) in blood vessels, kidneys, hypothalamus, and posterior pituitary. In blood vessels AT1 receptors cause vasoconstriction in the tunica media layer of smooth muscle surrounding blood vessels increasing blood pressure. Blocking this AT1 receptor lowers the constriction of these blood vessels. AT1 receptors in the kidney are responsible for the production of aldosterone which increases salt and water retention which increases blood volume. Blocking AT1 receptors reduces aldosterone production allowing water retention to not increase. AT1 receptors in the hypothalamus are on astrocytes which inhibit the excitatory amino acid transporter 3 from up-taking glutamate back into astrocytes. Glutamate is responsible for the activation of NMDA receptors on paraventricular nucleus neurons (PVN neurons) that lead to thirst sensation. Since AT1 receptors are blocked, the inhibition of the uptake transporter is not limited decreasing the amount of glutamate activating NMDA on PVN neurons that makes the individual crave drinking less. This lowers the blood volume as well. Lastly, the AT1 receptors on posterior pituitary gland are responsible for the release of vasopressin. Vasopressin is an anti-diuretic hormone that cases water reabsorption in the kidney as well as causing smooth muscle contraction in blood vessels increasing blood pressure. Lowering angiotensin II action on activating vasopressin release inhibits blood pressure from increasing. All these effects of valsartan contribute to an overall lowered blood pressure.

Vancomycin is a glycopeptide antibiotic used to treat severe but susceptible bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus) infections. Administered intravenously, vancomycin is indicated in adult and pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections. Administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile-associated diarrhea and for enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains). The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. Vancomycin may also alter bacterial-cell-membrane permeability and RNA synthesis. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

The VanA-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanA operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 7 genes which can be divided into regulatory (vanR and vanS), resistance (vanH, vanA and vanX) and accessory genes (vanY and vanZ). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). A D-Ala-D-Ala dipeptidase, encoded by the vanX gene, hydrolyzes D-Ala-D-Ala dipeptides thus preventing their integration into the peptidoglycan and subsequent peptidoglycan formation in the presence of vancomycin. vanA encodes a D-alanine D-alanine ligase which synthesizes the D-Ala-D-Lac dipeptide that replaces the normal D-Ala-D-Ala in the peptidoglycan precursor, thereby reducing vancomycin's binding affinity. Additionally, the accessory gene vanY, encodes a D,D-carboxypeptidase that, ensures that only D-Ala-D-Lac is used in cell wall synthesis by eliminating the terminal D-alanine residue from peptidoglycan precursors while VanZ confers teicoplanin resistance through an unknown mechanism.

The VanB-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in the VanB operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 7 genes which can be divided into regulatory (vanR and vanS), resistance (vanH, vanB and vanX) and accessory genes (vanY and vanW). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). A D-Ala-D-Ala dipeptidase, encoded by the vanX gene, hydrolyzes D-Ala-D-Ala dipeptides thus preventing their integration into the peptidoglycan and subsequent peptidoglycan formation in the presence of vancomycin. vanB encodes a D-alanine D-alanine ligase which synthesizes the D-Ala-D-Lac dipeptide that replaces the normal D-Ala-D-Ala in the peptidoglycan precursor, thereby reducing vancomycin's binding affinity. Additionally, the accessory gene vanY, encodes a D,D-carboxypeptidase that, ensures that only D-Ala-D-Lac is used in cell wall synthesis by eliminating the terminal D-alanine residue from peptidoglycan precursors while VanW whose function is unknown.

The VanC-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanC operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 5 genes which can be divided into regulatory (vanR and vanS) and resistance (vanC, vanT and vanXY). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. vanC gene encodes a D-Ala-D-Ser ligase, which synthesizes D-Ala-D-Ser (D-alanine-D-serine) dipeptides instead of the usual D-Ala-D-Ala in the peptidoglycan precursor, which has reduced affinity for vancomycin and is added to UDP-MurNAc-tripeptide.vanXY gene encodes a bifunctional D,D-dipeptidase and D,D-carboxypeptidase that hydrolyzes any remaining D-Ala-D-Ala dipeptides and removes D-alanine from peptidoglycan precursors (UDP-MurNAc-pentapeptide[d-Ala]), ensuring that only D-Ala-D-Ser is incorporated into the cell wall. Lastly, VanT encodes a serine racemase that is membrane-bound and supplies d-Ser for the synthesis pathway.