Pharmacodynamics / Individual Factors Affecting Drug Metabolism (4)

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The process by which a drug leaves the blood stream and enters the extracellular fluid and/or the cells of the tissues

drug distribution

Acidic drugs bind to _____ (protein) and basic drugs to _____ (protein).

plasma albumin

alpha1-acid glycoprotein

Are bound or unbound drugs pharmacologically active?

unbound drugs

How can maternal sulfonamides increase the risk of bilirubin encephalopathy in the newborn?

sulfonamides displace unconjugated bilirubin from albumin

What type of drugs are associated with redistribution?

highly liposoluble drugs administered rapidly by IV injection or inhalation

Can liposoluble or non-liposoluble drugs cross the blood-brain barrier?

liposoluble drugs

List 2 processes involved in drug elimination.

metabolism

excretion

Explain why lipophilic compounds are not easily excreted.

lipophilic compounds are reabsorbed through the tubular membranes

List 4 ways by which drug biotransformation can alter drugs.

List 5 phase 1 reactions.

oxidations

reductions

decarboxylations

deaminations

hydrolytic reactions

Pharmacologically inactive compound converted to biologically active metabolites

prodrugs

List 2 processes that are often involved in the activation of prodrugs.

hydrolysis of an ester

hydrolysis of amide linkage

- cyclophosphamide

What type of reactions are involved in phase 2 reactions?

conjugation reactions

List 5 molecules involved in phase 2 reactions.

glucuronate

acetate

glutathione

amino acids

sulfate

What are the 2 most active drug-metabolizing centers within a given cell?

ER (phase 1)

cytosol (phase 2)

What is the main enzyme system responsible for phase 1 reactions?

cytochrome P450 system
- superfamily of heme proteins present in bacteria, fungi, insects, plants, fish, and mammals

Cytochrome P450 general reaction

- the reaction is a monooxygenation
- the enzyme is a monooxygenase because it incorporates only one of the two oxygen atoms into the substrate

What form of the cytochrome P450 heme iron is required to metabolize drugs?

reduced to the ferrous state (Fe2+)

Sequences that are greater than _____% identical belong to the same family.

40%

Sequences that are greater than _____% identical are in the same subfamily.

55%

Humans have _____ families of cytochrome P450 genes divided into _____ subfamilies.

18

43

What CYP450 enzyme metabolizes approximately 50% of all drugs?

CYP3A4

List 3 drugs that are typical inducers of the cytochrome P450 system.

phenobarbital

rifampin

carbamazepine

- P450 enzyme induction typically occurs via increased transcription

List the 3 xenobiotic receptors.

aryl hydrocarbon receptor (AhR)

pregnane X receptor (PXR)

constitutively active receptor (CAR)

AhR inducers (2) and gene targets (3)

polycyclic aromatic hydrocarbons

2,3,7,8-Tetrachlorodibenzo-p-dioxin

PXR inducers (3/5) and gene targets (2)

CAR inducers (2) and gene targets (2)

List 2 important clinical consequences of enzyme induction.

a drug can increase its own metabolism

a drug can increase the metabolism of a coadministered drug

List 3 drugs that inhibit cytochromes P450.

What is the function of multi-drug resistance protein 1 (P-glycoprotein)?

actively transports compounds back into the intestinal lumen

What type of antibiotics can inhibit MDR1?

macrolide antibiotics
- also inhibits CYP450

What xenobiotic receptor transcriptionally regulates MDR1?

PXR

- drugs that induce P450 enzymes via the PXR pathway also induce MDR1 (protective)

Identify the toxic intermediate involved in the metabolism of acetaminophen.

Acetaminophen overdose antidote

N-acetylcysteine
- supplies cysteine for glutathione production
- mops up NAPQI

Variation in proteins involved in drug metabolism or transport

pharmacokinetic variation

Variation in drug targets or pathways associated with those targets

pharmacodynamic variation

List a CYP enzyme and protein inhibited by grapefruit juice.

CYP3A4

MDR1

- felodipine is an anti-hypertensive drug

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