-
Reduction
- Addition of hydrogen or removal of oxygen
- R-NO2 => R-NH2
- Enzyme is ____ reductase
-
Hydrolysis
- Breakdown of molecule to basic components with the addition of water
- Ester = body breaks down into acid and alcohol
- R-CO-O-C2H5 => R-CO-OH + HO-C2H5
- Enzyme is Esterase
-
Dehalogenation
- Removal of halogen groups
- R-C-CCL3 => HCL +R-C-CCL2
- Dehalogenase
-
Oxidation
- Opposite of reduction
- removal of hydrogen or addition of oxygen
-
Microsomal oxidation reactions
catalyzed by enzymes in the ER/microsome
-
Enzyme of microsomal oxidation reactions
- Cytochrome p450
- Mixed Function Oxidase
- Monooxygenase
-
cytochrome p450
- many members of this family
- CYP-#ABC
- Enzyme containes heme
- Iron is present in oxidized (Fe3+) or reduced form (Fe 2+)
- Reduced form has affinity for carbon monoxide
- absorbs light maximally at 450 nm (p=peak light absorption)
-
Mixed function oxidases
- require O2 to work
- require 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-OH
- Oxidation of an alkyl group
-
N-Dealkylation
- Ring-N-R => Ring-NH2 + R-OH
- Oxidation of R (Alkyl group)
-
S-Dealkylation
- Ring-S-R => Ring-SH + R-OH
- Oxidation 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 dehydrogenase
- R-OH => Aldehyde => Acid
- Aldehyde dehydrogenase
- Located in cytosol and mitochondria
- Cytosolic 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 oxidase
- present in the mitochondria
- Mono = 1 amino group
- Di = 2 amino groups
-
Purine oxidation
- chemical structure is the nucleus in caffeine, theophyline or hypoxanthine
- converts to uric acid
- metabolized by xanthine oxidase
-
xanthine oxidase
- catalyzes oxidation of purines
- present in the cytosol
-
inhibitor of xanthine oxidase
allopurinol
-
Cytosolic Enzymes
soluble fraction
-
Conjugation reactions
- Glucuronidation
- Sulfation
- Acetylation/acylation
- Glutathione conjugation reactions/mercapturic acid formation
-
Glucuronidation Reactions
- addition of glucuronic acid to the drug
- uses glycuronyl transferases
- high capacity, low affinity
-
UDPGA
uridinediphosphoglucuronic acid
-
Glucuronyl transferases
- moves glucuronic acid from UDPGA to the drug
- enhances water solubility of drug
- also present in microsomes
-
sulfation reaction
- addition of sulfate group to the drug molecule
- active sulfate compound required
-
PAPS
phosphoadenosinephosphosulfate
-
sulfur transferases/sulfur kinase
- trasfer sulfur from PAPS to drug in sulfation reaction
- present in cytosol
- high affinity, low capacity
- low amounts of PAPS limit the reaction
-
Acetylation
- two carbon compound added to the drug by acetyltransferase
- present in cytosol
-
acylation
- more than two carbons added to drug by acyltransferase
- present in cytosol
-
Glutathione conjugation reactions
involve the tri-peptide glutathione
-
glutathione
- tri-peptide
- cysteine - glutamate - glycine
-
Reduced form of glutathione
- CYS - SH or G-SH
- Interacts with drugs enzymatically or non-enzymatically
-
Oxidized form of Glutathione
- cross link between two glutathione molecules by S=S
- GSSG
-
Glutathione S Transferase
- found in the cytosol
- forms a glutathione adduct on the drug to be excreted
-
Mercapturic Acid Derivative
- Depends on the drug attached to glutathione
- drug is attached to glutathione
- body removes glycine and glutamate then reacts with cysteine via acetylation.
- Drug-S-CYS-NH-O-CO-CH3
-
Effect of diet on metabolism
- Diet effects proteins
- May change enzymes
- High protein, low carb may increase metabolism
- High 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 decreases
- decline in microsomal enzymes is more than in non-microsomal.
-
Environmental Effects on Metabolism
- Temperature
- Stress
- Smoking, first or second hand
- Genetics
- Disease states (liver = decrease metabolism)
-
Drug excretion
Termination of the drug by inactivation or redistribution
-
Major routes of excretion
- Renal
- Biliary (through the liver)
- Lungs (excretion of volatile molecules)
-
Minor routes of excretion
-
Major Mechanisms of Drug excretion in the kidney
- Filtration from blood to glomerulus
- Secretion from blood to glomerulus
- Reabsorption from urine to blood
-
Filtration from blood to glomerulus
- drug must be small
- must be free drug
- blood pressure pushes molecules out of blood vessel and into the nephron
- drug moves from high concentration to low concentration
-
Secretion of drugs
- Active transport process
- Carrier mediated process
- Involves saturability, specificity, energy
- moves from low to high concentration
- useful for drugs that cannot cross lipid membranes due to size or charge
-
Reabsorption of the drug
- from urine to blood
- drugs that are able to cross lipid membranes of the nephron
- Must be unionized to cross membrane
-
Mechanisms to keep drug in the urine
- Drug must be kept in the ionized form in the urine
- keep 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 urine
- drink a lot of fluids
- Ingest NH4CL (ammonium chloride) which acidifies urine
-
Mechanisms to keep a drug in the body
- Keep drug unionized
- Remove H+ from the urine (increase pH)
- Alkalinize the urine with sodium bicarb
-
Keep weak acid drug in the urine
- Alkalinize urine
- results in A- and H+
-
Biliary Secretion
- Carrier mediated
- could 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 liver
- Proteins of transport mechanisms decreased
- Energy diminished
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