Reduction
Addition of hydrogen or removal of oxygenR-NO2 => R-NH2Enzyme is ____ reductase
Hydrolysis
Breakdown of molecule to basic components with the addition of waterEster = body breaks down into acid and alcoholR-CO-O-C2H5 => R-CO-OH + HO-C2H5Enzyme is Esterase
Dehalogenation
Removal of halogen groupsR-C-CCL3 => HCL +R-C-CCL2 Dehalogenase
Oxidation
Opposite of reductionremoval of hydrogen or addition of oxygen
Microsomal oxidation reactions
catalyzed by enzymes in the ER/microsome
Enzyme of microsomal oxidation reactions
Cytochrome p450Mixed Function OxidaseMonooxygenase
cytochrome p450
many members of this familyCYP-#ABCEnzyme containes hemeIron is present in oxidized (Fe3+) or reduced form (Fe 2+)Reduced form has affinity for carbon monoxideabsorbs light maximally at 450 nm (p=peak light absorption)
Mixed function oxidases
require O2 to workrequire reducing agent, NADPH
Monooxygenases
use 1 oxygen atom
Side chain hydroxylation
R-CH2-CH2-CH2-CH3 => RCH2-CH2-CHOH-CH3
Aromatic hydroxylation
OH added onto aromatic ring
O-Dealkylation
Ring-O-R => Ring-O-H + R-OHOxidation of an alkyl group
N-Dealkylation
Ring-N-R => Ring-NH2 + R-OHOxidation of R (Alkyl group)
S-Dealkylation
Ring-S-R => Ring-SH + R-OHOxidation of R (Alkyl Group)
Sulfoxidation
Ring with S in the ring. S becomes double bonded to O. O ||/S\ => /S\
Aromatization
Alicyclic compound to aromatic by aromatase in the mitochondria.
Alcohol and Aldehyde oxidation reactions
Alcohol dehydrogenaseR-OH => Aldehyde => AcidAldehyde dehydrogenaseLocated in cytosol and mitochondriaCytosolic enzymes are more efficient than mito
specific inhibitors of alcohol dehydrogenase
pyrazoles
Specific inhibitor of aldehyde dehydrogenase
disulfiram
Mono and Di-amine oxidation reaction
monoamine oxidase and diamine oxidasepresent in the mitochondriaMono = 1 amino groupDi = 2 amino groups
Purine oxidation
chemical structure is the nucleus in caffeine, theophyline or hypoxanthineconverts to uric acidmetabolized by xanthine oxidase
xanthine oxidase
catalyzes oxidation of purinespresent in the cytosol
inhibitor of xanthine oxidase
allopurinol
Cytosolic Enzymes
soluble fraction
Conjugation reactions
GlucuronidationSulfationAcetylation/acylationGlutathione conjugation reactions/mercapturic acid formation
Glucuronidation Reactions
addition of glucuronic acid to the druguses glycuronyl transferaseshigh capacity, low affinity
UDPGA
uridinediphosphoglucuronic acid
Glucuronyl transferases
moves glucuronic acid from UDPGA to the drugenhances water solubility of drugalso present in microsomes
sulfation reaction
addition of sulfate group to the drug moleculeactive sulfate compound required
PAPS
phosphoadenosinephosphosulfate
sulfur transferases/sulfur kinase
trasfer sulfur from PAPS to drug in sulfation reactionpresent in cytosolhigh affinity, low capacity low amounts of PAPS limit the reaction
Acetylation
two carbon compound added to the drug by acetyltransferasepresent in cytosol
acylation
more than two carbons added to drug by acyltransferasepresent in cytosol
Glutathione conjugation reactions
involve the tri-peptide glutathione
glutathione
tri-peptidecysteine - glutamate - glycine
Reduced form of glutathione
CYS - SH or G-SHInteracts with drugs enzymatically or non-enzymatically
Oxidized form of Glutathione
cross link between two glutathione molecules by S=SGSSG
Glutathione S Transferase
found in the cytosolforms a glutathione adduct on the drug to be excreted
Mercapturic Acid Derivative
Depends on the drug attached to glutathionedrug is attached to glutathionebody removes glycine and glutamate then reacts with cysteine via acetylation.Drug-S-CYS-NH-O-CO-CH3
Effect of diet on metabolism
Diet effects proteinsMay change enzymesHigh protein, low carb may increase metabolismHigh carb, low protein my decrease drug metabolism
High Fat diet effects on metabolism
May induce metabolism of certain drugs by enducing specific enzymes
Effects of age on metabolism
drug metabolism decreasesdecline in microsomal enzymes is more than in non-microsomal.
Environmental Effects on Metabolism
TemperatureStressSmoking, first or second handGeneticsDisease states (liver = decrease metabolism)
Drug excretion
Termination of the drug by inactivation or redistribution
Major routes of excretion
RenalBiliary (through the liver)Lungs (excretion of volatile molecules)
Minor routes of excretion
SweatTearsSalivaMilk
Major Mechanisms of Drug excretion in the kidney
Filtration from blood to glomerulusSecretion from blood to glomerulusReabsorption from urine to blood
Filtration from blood to glomerulus
drug must be smallmust be free drugblood pressure pushes molecules out of blood vessel and into the nephrondrug moves from high concentration to low concentration
Secretion of drugs
Active transport processCarrier mediated processInvolves saturability, specificity, energymoves from low to high concentrationuseful for drugs that cannot cross lipid membranes due to size or charge
Reabsorption of the drug
from urine to blooddrugs that are able to cross lipid membranes of the nephronMust be unionized to cross membrane
Mechanisms to keep drug in the urine
Drug must be kept in the ionized form in the urinekeep pH low in the urine
Mechanisms to push drugs from blood to urine
increase the pH of the blood to make a basic drug move (unionized form) move into the urine
Hasten drug removal in the urine
Ionize the drug in the urinedrink a lot of fluidsIngest NH4CL (ammonium chloride) which acidifies urine
Mechanisms to keep a drug in the body
Keep drug unionizedRemove H+ from the urine (increase pH)Alkalinize the urine with sodium bicarb
Keep weak acid drug in the urine
Alkalinize urineresults in A- and H+
Biliary Secretion
Carrier mediatedcould administer a drug that has a higher affinity for a carrier for the drug you want to stay, to keep a drug in the system.
Diets that acidify urine
meat and fish
diets that alkalinize urine
dairy
competes with sodium for a carrier
lithium
Effects of aging on drug excretion
Diminished blood supply to kidney and liverProteins of transport mechanisms decreasedEnergy diminished