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Pharmacology > Biotransformation > Flashcards

Biotransformation Flashcards

1
Q

Importance of biotransformation

A

The processing of xenobiotics for elimination- xenobiotics are foreign compounds including environmental chemicals, food toxins, therapeutic drugs, and recreational drugs

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2
Q

Hydrophilic drugs

A

Polar, ionize in physiological pH, easily excreted, low therapeutic effectiveness, short half-life

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3
Q

Lipophilic drugs

A

Most drugs, can cross membranes to get to site of action, difficult to eliminate, must be processed to prevent toxicity

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4
Q

Functions of biotransformation

A

Metabolize, detoxify, and render drug less toxic (metabolism)
Eliminate the drug from the body (disposition)

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5
Q

Phases of biotransformation

A

Phase I- metabolism and detoxification

Phase II- elimination, makes drug more excretable

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6
Q

Most important cytochrome P450 families

A

CYP1, CYP2, CYP3, CYP4

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7
Q

Important CYP enzymes

A

CYP3A4- responsible for >50% of prescription drug metabolism, CYP2D6, CYP2C, CYP1A2, CYP2E1

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8
Q

Induction

A

Transcriptional activation of the enzyme

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9
Q

Tobacco smoke, charcoal broiled meat

A

Induces CYP1A

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10
Q

Barbiturates (anxiolytics)

A

Induces CYP2B1

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11
Q

Ethanol

A

Induces CYP2E1

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12
Q

Steroids

A

Induces CYP3A4

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13
Q

Fibrates (LDL lowering drugs)

A

Induces CYP4A

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14
Q

Cimetidine (gastric ulcer medication)

A

Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates

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15
Q

Ketoconazole (anti-fungal medication)

A

Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates

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16
Q

Macrolides (antibacterial)

A

Inhibitor, metabolized to reactive species, complex with heme iron and rend it catalytically inactive

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17
Q

Suicide inhibitors

A

Irreversibly inhibit CYP via covalent binding to the heme or protein portion of the enzyme

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18
Q

Phase I

A

Enzymes add polar group onto the drug to make it more polar (hydrophilic), allowing it to be conjugated, includes: oxidation, reduction, and hydrolysis reactions

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19
Q

Phase I enzymes

A

Most are heme protein mono-oxygenases of cytochrome P450 gene family

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20
Q

Phase II

A

Drugs that have undergone phase I may have chemical groups that allow them to conjugate with endogenous substances, conjugates are polar, often inactive, and readily excreted

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21
Q

Consequences of conjugation reactions

A

May lead to formation of reactive species responsible for drug toxicity

22
Q

Acetaminophen processing

A

95% goes through conjugation- glucuronidation, sulfation

5% goes through P450 metabolism- makes reactive agent NAPQI, GSH conjugates NAPQI for excretion

23
Q

Acetaminophen overdose

A

Conjugation reaction is saturated, more goes through P450 and saturates GSH conjugation, NAPQI accumulates, forms protein adducts in liver, hepatic necrosis, death

24
Q

Alcoholics and acetaminophen OD

A

More susceptible because ethanol induces the same P450 and shifts reaction of the drug to P450 metabolism

25
Q

Treating acetaminophen OD

A

Give N-acetylcysteine (NAC), provides SH group to bind toxic protein, creates cysteine conjugate for excretion, must give NAC within 8-16 hours

26
Q

2D6 polymorphism, PM phenotype

A

Associated with breast cancer relapse in those treated with tamoxifen, dependent on 2D6 metabolism

27
Q

2D6 polymorphism, UM phenotype

A

Displays in 1/3 of Ethiopians and Saudi Arabians, patients require 2-3x dose of nortriptyline (antidepressant), poor response correlates with higher suicide rates, prodrug codeine is metabolized faster to morphine, faster sedation

28
Q

2C19 polymorphism, PM phenotype

A

Poor metabolizer, occurs in 3-5% of Caucasians, 18-23% of Japanese, lack hydroxylation activity and S- and R-forms of mephenytoin accumulate, cause sedation and ataxia

29
Q

2C19 polymorphism, EM phenotype

A

Extensive metabolizer, S-form is hydroxylated by 2C19, conjugated by glucuronidation, excreted into urine, R-form is slowly demethylated into active nirvanol

30
Q

2C9 polymorphism

A

Impaired formation or inactive protein, occurs in 6-13% of Caucasians, increases patient sensitivity to warfarin, can lead to excessive bleeding and death

31
Q

Warfarin

A

Inhibits vitamin K epoxide reductase- required for recycling vitamin K which is crucial in activation of clotting factors, warfarin inhibits clotting

32
Q

Slow acetylators

A

Occur in 50% of Whites and Blacks, associated with higher incidence of isoniazid-induced peripheral neuritis, autoimmune disorders, bladder cancer

33
Q

Newborn child biotransformation

A

Capable of carrying out many, but not all biotransformation reactions

34
Q

Gray baby syndrome

A

Chloramphenicol (antibacterial) excretion requires oxidative transformation followed by conjugation, oxidative metabolite is toxic, can accumulate if not conjugated (newborns)

35
Q

Elderly biotransformation

A

Reduced metabolic capacity due to decline in liver mass, hepatic blood flow, reduced renal function, some take multiple medications that can contribute to drug-drug interactions

36
Q

Androgenic hormone levels

A

Associated with sex-dependent differences in drug metabolism

37
Q

Diet and environment

A

May alter biotransformation by inducing or inhibiting P450 enzymes

38
Q

Grapefruit juice

A

Inhibits CYP3A4

39
Q

St. John’s wart

A

Herbal medication for mood stabilization, induces CYP3A4

40
Q

Polycyclic aromatic hydrocarbons in cigarette smoke

A

Induces CYP1A1, CYP1A2, CYP2E1

41
Q

Lead

A

Induces heme-oxygenase enzyme, breaks down P450

42
Q

Drug-drug interactions, two drugs metabolized by the same enzyme

A

The drug with lower affinity accumulates and becomes toxic

43
Q

Drug-drug interactions, one drug induces the enzyme

A

Can increase or decrease the efficacy of the other drug

44
Q

Drug-drug interactions, one drug inhibits the enzyme

A

Reduces the metabolism of the other drug

45
Q

Rifampin (antibacterial) drug-drug interaction

A

Induces CYP3A4, increases the metabolism of estrogenic component of estrogen-based contraception

46
Q

Erythromycin (macrolide antibiotic) drug-drug interaction

A

Metabolized by CYP3A4, metabolite complexes with 3A4 and inhibits the enzyme, inhibits 3A4 metabolism of other drugs

47
Q

Methanol intoxication drug-drug interaction

A

Intoxication results in blindness/death due to toxicity of formaldehyde metabolite, ethanol competes with methanol for oxidation by alcohol dehydrogenase, delayed methanol oxidation reduces metabolite formation, allows time for renal excretion

48
Q

Liver diseases and biotransformation

A

Main site of biotransformation, liver diseases (hepatitis, cirrhosis, cancer) will decrease enzymes required for metabolism

49
Q

Cardiac diseases and biotransformation

A

Can compromise blood flow, reduce drug delivery to the heart for effect, reduce drug delivery to the liver for metabolism

50
Q

Thyroid diseases and biotransformation

A

Thyroid hormone regulates rate of metabolism, hyperthyroidism increases drug metabolism, hypothyroidism decreases drug metabolism

51
Q

Kidney diseases and biotransformation

A

Decreases drug excretion

Pharmacology (15 decks)

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