Pharmacology Exam 1

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