Pharmacology: Block 2: Drug Metabolism

Front 1

What is the first pass effect?

Back 1

The phenomena by which a drug is absorbed in the gut, and metabolized by the live before circulating systemically.

Front 2

What types of drug administration bypass the first pass effect?

Back 2

1. Distal rectal (associated with variable rates and extents of absorption among medications and persons)

2. Most injections.

3. Sublingual

4. Transbuccal

5. Topical

Front 3

What is one type of injection that does not bypass the first pass effect?

Back 3

Intra-peritoneal injection (commonly used in small animals).

Front 4

The basic anatomic unit of the liver is what shape?

Back 4

hexagonal.

Front 5

What is at the center of the hepatic triad?

Back 5

The central vein.

Front 6

What is at the periphery of the vertices of the basic anatomical unit of the liver?

Back 6

The hepatic arteries, portal veins, and bile ducts.

Front 7

What is the flow of blood within the basic anatomical unit of the liver?

Back 7

From the periphery (hepatic arteries, portal veins) to the central vein.

Front 8

Which has an area of lower oxygen tension, around the central vein or at the periphery?

Back 8

There is less oxygen tension around the central vein.

Front 9

What is the flow of bile in the liver?

Back 9

From the center (around the central vein) to the periphery.

Front 10

1. In a liver cell, where is most of the drug metabolizing machinery located?

2. What is this machinery/system called?

3. What are the enzymes that are associated with this system called?

Back 10

1. In the smooth endoplasmic reticulum.

2. The mixed function oxidase system.

3. Microsomal enzymes.

Front 11

What are the microsomal enzymes? (6)

Back 11

1. Cytochrome P450 (CYP)
2. Cytochrome b5
3. NAD reductase
4. NADH reductase
5. Glucuronyl transferases
6. Epoxide hydrases

Front 12

What is the most common goal of drug metabolism?

Back 12

To render a drug POLAR and MORE WATER SOLUBLE, therefore increasing excretion.

Front 13

A conjugated metabolite is most likely "conjugated" to what?

What happens to these conjugated metabolites?

Back 13

To glucuronic acid or sulfate.

Conjugated metabolites are actively secreted into the urine by transporters in the renal tubules.

Front 14

Increasing the solubility of a drug that is excreted in the bile would have what effect on the elimination of that drug?

Back 14

More water soluble --> decrease in reabsorption via the enterohepatic circulation --> increase in fecal excretion of the drug.

Front 15

What is meant by a "non synthetic" reaction?

Back 15

A nonsynthetic reaction is one that includes ocidation, reduction, or hydrolysis.

Front 16

What is meant by a "synthetic" reaction?

Back 16

A synthetic reaction is one in which a drug or metabolite is conjugated to another small molecule.

Front 17

What are the two most common nonsynthetic microsomal reactions?

What system deals with these?

Back 17

1. Aromatic hydroxylation
2. Aliphatic hydroxylation

Both catalyzed by CYP

Front 18

Describe the process of aromatic hydroxylation. Provide an example.

Back 18

Propanolol (beta-adrenergic antagonist)

oxidized at aromatic ring --> produces an epoxide --> unstable, so spontaneously forms a hydroxyl group on the aromatic ring.

Note: there is enormous individual variability in the metabolism of propanolol.

Front 19

Describe the process of aliphatic hydroxylation. Provide an example.

Back 19

Pentobarbital (barbiturate sedative)

aliphatic side chain is oxidized --> forms epoxide --> unstable, so spontaneously forms an alcohol.

Front 20

How does CYP deal with alkyl chains connected to nitrogen or oxygen atoms?

Back 20

CYP oxidatively removes them via N or O dealkylation.

Front 21

Describe N or O-dealkyation.

Back 21

Lidocaine (local anesthetic)

aliphatic hydroxylation of a carbon adjacent to N --> unstable epoxide --> spontaneous formation of hydroxyl group

--> hydroxyl group next to a O or N is unstable, so --> carbon-nitrogen/carbon-oxygen bonds spontaneously (non-enzymatically) break --> remove alkyl chain from the nitrogen/oxygen atoms

Front 22

Give an example of N-dealkylation.

Back 22

Lidocaine (a local anesthetic)

N-dealkyation of lidocaine yields a secondary amine and acetaldehyde.

Front 23

Give an example of O-dealkylation.

Back 23

Trimethoprim (an antibacterial agent)

The O-dealkylation of trimethoprim yields an added free hydroxyl group and formaldehyde.

Front 24

N-hydroxylation of a compound often results in formation of what?

Back 24

A product that is often more toxic than its parent compound.

Front 25

What is an example of N-hydroxylation?

Back 25

Urethane (a commonly used organic compound that is the building block of polyurethane)

N-hydroxylation of urethane leads to production of a hydroxylamine carcinogen.

Front 26

Give an example of desulfuration and describe the mechanism.

Back 26

Thiopental (an IV anesthetic) --> pentobarbital (active)

sulfur atom oxidized --> forms an unstable sulfoxide intermediate --> spontaneous rearrangement --> the sulfur is replaced by an oxygen.

Front 27

Give an example of dehalogenation and describe the mechanism.

Back 27

Carbon tetrachloride (used to be used in dry cleaning) --> trichloromethanol (less toxic) and Cl-

halogen atom oxidized --> unstable intermediate --> carbon-halogen bond breaks --> halogen atom removed.

Front 28

What to the letters and numbers in CYP3A4 indicate?

Back 28

CYP3A4

3 = Family (>40% amino acid homology)

A = Subfamily (>55% amino acid homology. Same subfamily indicates occurrence on the same chromosome)

4 = Individual enzyme.

Front 29

More polymorphisms than any other CYP enzyme.

Back 29

CYP2D6

Front 30

The most versatile drug metabolizing enzymes in the CYP system.

Back 30

CYP3A4, CYP3A5

Front 31

Important CYP enzyme for carcinogen activation.

Back 31

CYP1A

Front 32

Metabolize many CNS active agents.

Back 32

CYP2C9

Front 33

CYP alcohol metabolism.

Back 33

CYP2E1.

Front 34

CYP11B1

Back 34

steroid 11beta-hydroxylase.

Front 35

CYP17

Back 35

steroid 17alpha-hydroxylase.

Front 36

If a drug has been tested in animal models, why is it generally assumed to be safe for human use?

Back 36

Because the CYP enzymatic pathway in humans and all other lower forms of life is so similar.

Front 37

In what conditions are reduction reactions thought to be more common?

Back 37

When tissue oxygen tension is low.

Front 38

Give an example and explain the mechanism of a nitro reduction.

Back 38

Nitro group (NO2 esp those bound to aromatic rings) is reduced --> highly reactive free radical product formed.

This product can bind covalently with cellular macromolecules. This may cause cellular necrosis or
mutagenesis.

Example: Nitrofurantoin (ABX for UTI)


In the case of nitrofurantoin, it is excreted so quickly that little metabolism occurs.

Nitrofurantoin is not toxic as long as you have functional kidneys.

Front 39

Give an example and explain the mechanism of a azo reduction.

Back 39

Reduction of azo bond (N2) --> formation of two primary amine derivatives.

Example: Sulfasalazine (an agent used in the txt of IBS) --> cleaved --> sulfapyradine (ABX) + 5-aminosalicylic acid (anti-inflammatory agent)

Front 40

Where are azo reactions likely to occur in the body?

Back 40

Azo reactions only occur rarely in mammaliam cells. They are much more likely to be catalyzed by azo reductases in gut bacteria

Front 41

Explain reductive dehalogenation and give an example.

Back 41

Reductive dehalogenation yields highly reactive free radicals. Can cause a non-enzymatic, spontaneous reaction.

Example: carbon tetrachloride

Front 42

Explain the action of epoxide hydrase and give an example.

Back 42

Stable epoxide + epoxide hydrase --> diol --> formation of stable epoxide derivatives.

Example: Benzo[a]pyrene (cigarette smoke, charred meats) --> epoxide hydrase --> CYP --> stable epoxide that can travel into the nucleus. One of the most potent carcinogens yet discovered.

This is why charring food and inhaling smoke is harmful.

Front 43

Explain the action of the glucuronyl transferases. Give an example.

Back 43

Catalyze the attachment of glucuronic acid, usually at the site of a hydroxyl group.

Example: Morphine (can be glucuronidated at either the #3 or #6 position). Morphine-6-glucuronide is more potent than morphine.

UDP-glucose + morphine --> morphine-3-glucuronide

Front 44

What is considered to be the primary microsomal synthetic reaction?

Back 44

Glucuronyl transferase reactions.

Front 45

What are the very basic steps of the CYP pathway?

Back 45

1. Drug (R) binds to Fe3+.

2. NADPH reduces Fe3+R to Fe2+R.

3. Oxygen binds Fe2+R to make O2-Fe2+R.

4. NADH reduces O2-Fe2+R to an unknown intermediate.

5. Oxygen is split and water is produced.

6. Epoxide is formed.

7. R-OH is formed.

Front 46

What are the two major sources of NADH and NADPH?

Back 46

1. Glycolysis (90%) (Embdem-Meyerhof pathway)

2. Pentose phosphate shunt (10%).

Front 47

What is the only source of NADPH?

Back 47

The pentose phosphate shunt.

Front 48

Glucose-6-phosphate dehydrogenase (G6PD) is often lacking in which populations?

Back 48

Black Africans and southern Europeans living near the Mediterranean.

Front 49

Where do nonmicrosomal reactions occur?

Back 49

In the cytoplasm or in mitochondria.

Front 50

What are the important nonmicrosomal nonsynthetic reactions?

Back 50

1. Hydrolysis.
2. Monoamine oxidation.
3. Alcohol and aldehyde dehydrogenation.

Front 51

Explain ester and amide hydrolysis and give an example.

Back 51

Ester hydrolysis occurs in many different tissues besides the liver. Ester (very common in everyday foods) --> 2 OH groups.

Example: Procaine (a local anesthetic)

Amide hydrolysis: occurs mainly in the liver. Analogous to ester hydrolysis.

Example: Metabolism of lidocaine. N-dealkylation --> amide bond hydrolyzed --> formation of primary amine and carboxylic acid.

Front 52

Where are esterases located?

Back 52

Everywhere! Even in RBCs, skeletal muscle, etc.

Front 53

Where does most amide hydrolysis take place?

Back 53

Liver cytoplasm.

Front 54

What is the action of monoamine oxidase?

Back 54

Takes a free amine and converts to an aldehyde.

CYP can do this, but most amines never get to the liver.

Front 55

What is the danger associated with nonspecific MAO inhibitors?

Back 55

If you take a nonspecific MAO inhibitor, then you will have trouble detoxifying dietary amines (e.g. tyramine). Some of these amines are potent vasopressors.

Take MAOI, eat diet high in tyramine --> hypertensive crisis.

Some herbal products can have MAOI activity.

Front 56

Where are the two types of MAOs located?

Back 56

One in the liver and gut lining, another in the brain.

Front 57

What is the pathway for the metabolism of ethanol?

Back 57

Ethanol ---(alcohol dehydrogenase)---> acetaldehyde ---(aldehyde dehydrogenase)---> acetic acid (vinegar!)

Front 58

What is the function of disulfram?

Back 58

Ethanol ---(alcohol dehydrogenase)---> acetaldehyde ---(aldehyde dehydrogenase <DISULFRAM>)---> acetic acid (vinegar!) ---> Krebs cycle

Disulfram inhibits aldehyde dehydrogenase.

Front 59

What is an example of a reaction in the body that follows zero-order kinetics?

Back 59

The metabolism of ethanol. The concentration of the enzyme is rate-limiting.

Front 60

What are the side effects of disulfram?

Back 60

Taking disulfram inhibits aldehyde dehydrogenase. If the pt drinks, it causes a buildup of acetaldehyde that gives the pt a wicked hangover.

Front 61

What are the important nonmicrosomal synthetic reactions?

Back 61

1. Acetyl transferase
2. Sulfate transferase
3. Methyltranferase
4. Addition of glutathione.

Front 62

What is the action of acetyl transferase?

Back 62

Adds an acetyl group to an amine.

Example: procainamide --> N-acetylprocainamide (active, less toxic, acts by a different mechanism than procainamide).

Front 63

What is the action of a creation of a sulfate group?

Back 63

A sulfate group may be added to a hydroxyl group.

The sulfate group is dervived from phosphoadenosine phosphosulfonate (PAPS).

Example: acetaminophen --> conjugation to sulfate.

As the dose of acetaminophen is increased, a larger fraction of the metabolism proceeds via oxidation of the nitrogen via CYP2E1 --> unstable N-hydroxylated metabolite --> N-acetyl-p-benzoquinone imine (NAPQI) --> conjugated to glutathione --> --> production of mercapturic acid derivative

Front 64

What is glutathione?

Back 64

A tripeptide containing the amino acids glutamic acid, cysteine, and glycine.

Front 65

Most metabolites that result from conjugation to glutathione are hydrolyzed to what?

Back 65

Most are hydrolyzed to mercapturic acids.

Front 66

Explain the mechanism of glutathione conjugation. Give an example.

Back 66

As acetaminophen dose is increased, a larger fraction of the metabolism proceeds via oxidation of the nitrogen via CYP2E1 --> unstable N-hydroxylated metabolite --> N-acetyl-p-benzoquinone imine (NAPQI) --> conjugated to glutathione --> --> production of mercapturic acid derivative

Front 67

What is the action of methyltransferase?

Back 67

Catalyze the addition of a methyl group to a nitrogen, oxygen, or sulfur atom,

S-adenosylmethionine in the donor of the methyl group.

Example: Methylation of nicotine.

Front 68

What is induction?

Back 68

The process by which a xenobiotic compound causes an increase in the number of enzyme molecules.

All microsomal enzymes and some nonmicrosomal enzymes are subject to induction.

Example: barbituates are the prototypical inducers.

Front 69

What are some typical inducers of CYP? (extra credit)

Back 69

1. Barbituates

2. Anticonvulsants (phenytoin and carbamazepine) - inducers of CYP3A4/5

3. Polycyclic aromatic hydrocarbons in cigarette smoke /charred foods - induce CTYP1A (activates proto-carcinogens to carcinogens)

4. Rifampin (used to treat TB) - induces lots of CYP enzymes.

Front 70

What are some typical inhibitors of CYP? (extra credit)

Back 70

1. Imidazoles

2. Macrolide antibiotics (NOT azithromycin)

3. HIV protease inhibitors

4. Grapefruit juice - inhibits CYP3A4/5

5. Proadifen

Front 71

Where is MAO-B usually found?

Back 71

In the liver and brain

Front 72

Where is MAO-A usually found?

Back 72

In the gut.

Front 73

Selective MAO inhibitors inhibit what form of MAO?

Back 73

MAO-B

Front 74

What is another cell in the body that contains a CYP that is not present in the liver?

What compound does this CYP help metabolize?

Back 74

The clara cell of the lung contains CYP, as well as CYP4B1, an isozyme not found in the lung.

This CYP metabolizes styrene.

Front 75

What is an good example of when drug metabolism in an animal is different than that of a human?

Back 75

Metabolism of styrene. The clara cells of the lung produce a CYP that metabolize styrene.

Styrene is more toxic to rodents because they have much more CYP4B1.

Front 76

Vitamin D and CYP.

Back 76

Needs to be metabolized by CYP isozymes in the kidney and the liver.

Front 77

Where does hydrolysis of esmolol take place?

Back 77

Hydrolysis of esmolol (a beta-adrenergic antagonist) takes place in the RBC.

Front 78

Where does hydrolysis of succinylcholine take place?

Back 78

Hydrolysis of succinylcholine (a muscle relaxant) is catalyzed by a circulating plasma enzyme.

Front 79

What is a drug that can be oxidized by hemoglobin acting as an oxidase enzyme?

Back 79

Aniline (an organic chemical often used in dyes)

Front 80

What is the most common enzyme deficiency in humans?

Back 80

G6PD deficiency. Sex-linked. Common in sub-saharan Africa and southern Europe.

Exposure to certain drugs that increase rate of hydrogen peroxide generation ---G6PD---> hemolysis.

Front 81

What is the function of superoxide dismutase?

Back 81

Converts superoxide anion (O2-*) to hydrogen peroxide.

Front 82

What is responsible for hydrogen peroxide detox in the red blood cell?

Back 82

Glutathione peroxidase.

Note that it is not catalase. Even though the RBC has this, the Km is too high to be useful in detoxifying hydrogen peroxide in the red cell.

Front 83

People with G6PD deficiency usually have an abnormally low concentration of what in their RBCs?

Back 83

NADPH

Front 84

What disease is G6PD protective against?

Back 84

Malaria. The parasite can't make its own NADPH, so needs to get it from its host. But people with G6PD have low NADPH in their RBCs.

Front 85

What drugs should patients with G6PD avoid? (6, extra credit)

Back 85

1. Primaquine (an anti-malarial)

2. Nitrofurantoin (an antibacterial)

3. Phenacetin (an obsolete analgesic)

4. Sulanilamide, sulfacetamide, sulfapyradine (obsolete antimicrobials)

5. Naphalene (moth balls)

6. Fava beans

Front 86

What is porphyria?

Back 86

A disease due to a deficiency in one of the heme biosynthetic enzymes.

Front 87

What is the rate-limiting enzyme in heme synthesis? One important characteristic.

Back 87

delta-aminolevulinic acid (ALA) synthase

It is inducible.

Front 88

Injesting an inducer of ALA synthase in a patient that has enzyme deficiencies can cause what?

Back 88

Accumulation of ALA. Can cause three types of porphyria.

1. Acute intermittent porphyria (AIP)

2. Hereditary coproporphyria (HCP)

3. Variegate porphyria (VP)

Front 89

What medications should patients with porphyria avoid?

Back 89

Barbiturates.

Front 90

Pseudocholinesterase

Back 90

Metabolism of succinylcholine

Front 91

What demographic is a "fast" acetyl transfer-er?

Back 91

Asians

Front 92

People of what ancestry are "slow" acetylators?

Back 92

People of western European descent.

Front 93

What are some examples of substrates for acetyl transferase? (5, extra credit)

Back 93

1. Sulfonamides (antibacterial)

2. Aminosalicylic acid (anti inflammatory)

3. Isoniazid (anti mycobacterial)

4. Procainamide (antidysrhythmic)

5. Hydralazine (antihypertensive)

Front 94

What is a good example of an "active metabolite?"

Back 94

Diazepam (half life = 1 day) --> nordazepam (half life = 4 days)

During chronic therapy, most of the pharmacological effect is produced by the metabolite.

Front 95

How much methanol is adequate to produce permanent blindness?

Back 95

A tablespoon!