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95 Cards in this Set

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What is the first pass effect?
The phenomena by which a drug is absorbed in the gut, and metabolized by the live before circulating systemically.
What types of drug administration bypass the first pass effect?
1. Distal rectal (associated with variable rates and extents of absorption among medications and persons)

2. Most injections.

3. Sublingual

4. Transbuccal

5. Topical
What is one type of injection that does not bypass the first pass effect?
Intra-peritoneal injection (commonly used in small animals).
The basic anatomic unit of the liver is what shape?
hexagonal.
What is at the center of the hepatic triad?
The central vein.
What is at the periphery of the vertices of the basic anatomical unit of the liver?
The hepatic arteries, portal veins, and bile ducts.
What is the flow of blood within the basic anatomical unit of the liver?
From the periphery (hepatic arteries, portal veins) to the central vein.
Which has an area of lower oxygen tension, around the central vein or at the periphery?
There is less oxygen tension around the central vein.
What is the flow of bile in the liver?
From the center (around the central vein) to the periphery.
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?
1. In the smooth endoplasmic reticulum.

2. The mixed function oxidase system.

3. Microsomal enzymes.
What are the microsomal enzymes? (6)
1. Cytochrome P450 (CYP)
2. Cytochrome b5
3. NAD reductase
4. NADH reductase
5. Glucuronyl transferases
6. Epoxide hydrases
What is the most common goal of drug metabolism?
To render a drug POLAR and MORE WATER SOLUBLE, therefore increasing excretion.
A conjugated metabolite is most likely "conjugated" to what?

What happens to these conjugated metabolites?
To glucuronic acid or sulfate.

Conjugated metabolites are actively secreted into the urine by transporters in the renal tubules.
Increasing the solubility of a drug that is excreted in the bile would have what effect on the elimination of that drug?
More water soluble --> decrease in reabsorption via the enterohepatic circulation --> increase in fecal excretion of the drug.
What is meant by a "non synthetic" reaction?
A nonsynthetic reaction is one that includes ocidation, reduction, or hydrolysis.
What is meant by a "synthetic" reaction?
A synthetic reaction is one in which a drug or metabolite is conjugated to another small molecule.
What are the two most common nonsynthetic microsomal reactions?

What system deals with these?
1. Aromatic hydroxylation
2. Aliphatic hydroxylation

Both catalyzed by CYP
Describe the process of aromatic hydroxylation. Provide an example.
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.
Describe the process of aliphatic hydroxylation. Provide an example.
Pentobarbital (barbiturate sedative)

aliphatic side chain is oxidized --> forms epoxide --> unstable, so spontaneously forms an alcohol.
How does CYP deal with alkyl chains connected to nitrogen or oxygen atoms?
CYP oxidatively removes them via N or O dealkylation.
Describe N or O-dealkyation.
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
Give an example of N-dealkylation.
Lidocaine (a local anesthetic)

N-dealkyation of lidocaine yields a secondary amine and acetaldehyde.
Give an example of O-dealkylation.
Trimethoprim (an antibacterial agent)

The O-dealkylation of trimethoprim yields an added free hydroxyl group and formaldehyde.
N-hydroxylation of a compound often results in formation of what?
A product that is often more toxic than its parent compound.
What is an example of N-hydroxylation?
Urethane (a commonly used organic compound that is the building block of polyurethane)

N-hydroxylation of urethane leads to production of a hydroxylamine carcinogen.
Give an example of desulfuration and describe the mechanism.
Thiopental (an IV anesthetic) --> pentobarbital (active)

sulfur atom oxidized --> forms an unstable sulfoxide intermediate --> spontaneous rearrangement --> the sulfur is replaced by an oxygen.
Give an example of dehalogenation and describe the mechanism.
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.
What to the letters and numbers in CYP3A4 indicate?
CYP3A4

3 = Family (>40% amino acid homology)

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

4 = Individual enzyme.
More polymorphisms than any other CYP enzyme.
CYP2D6
The most versatile drug metabolizing enzymes in the CYP system.
CYP3A4, CYP3A5
Important CYP enzyme for carcinogen activation.
CYP1A
Metabolize many CNS active agents.
CYP2C9
CYP alcohol metabolism.
CYP2E1.
CYP11B1
steroid 11beta-hydroxylase.
CYP17
steroid 17alpha-hydroxylase.
If a drug has been tested in animal models, why is it generally assumed to be safe for human use?
Because the CYP enzymatic pathway in humans and all other lower forms of life is so similar.
In what conditions are reduction reactions thought to be more common?
When tissue oxygen tension is low.
Give an example and explain the mechanism of a nitro reduction.
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.
Give an example and explain the mechanism of a azo reduction.
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)
Where are azo reactions likely to occur in the body?
Azo reactions only occur rarely in mammaliam cells. They are much more likely to be catalyzed by azo reductases in gut bacteria
Explain reductive dehalogenation and give an example.
Reductive dehalogenation yields highly reactive free radicals. Can cause a non-enzymatic, spontaneous reaction.

Example: carbon tetrachloride
Explain the action of epoxide hydrase and give an example.
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.
Explain the action of the glucuronyl transferases. Give an example.
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
What is considered to be the primary microsomal synthetic reaction?
Glucuronyl transferase reactions.
What are the very basic steps of the CYP pathway?
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.
What are the two major sources of NADH and NADPH?
1. Glycolysis (90%) (Embdem-Meyerhof pathway)

2. Pentose phosphate shunt (10%).
What is the only source of NADPH?
The pentose phosphate shunt.
Glucose-6-phosphate dehydrogenase (G6PD) is often lacking in which populations?
Black Africans and southern Europeans living near the Mediterranean.
Where do nonmicrosomal reactions occur?
In the cytoplasm or in mitochondria.
What are the important nonmicrosomal nonsynthetic reactions?
1. Hydrolysis.
2. Monoamine oxidation.
3. Alcohol and aldehyde dehydrogenation.
Explain ester and amide hydrolysis and give an example.
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.
Where are esterases located?
Everywhere! Even in RBCs, skeletal muscle, etc.
Where does most amide hydrolysis take place?
Liver cytoplasm.
What is the action of monoamine oxidase?
Takes a free amine and converts to an aldehyde.

CYP can do this, but most amines never get to the liver.
What is the danger associated with nonspecific MAO inhibitors?
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.
Where are the two types of MAOs located?
One in the liver and gut lining, another in the brain.
What is the pathway for the metabolism of ethanol?
Ethanol ---(alcohol dehydrogenase)---> acetaldehyde ---(aldehyde dehydrogenase)---> acetic acid (vinegar!)
What is the function of disulfram?
Ethanol ---(alcohol dehydrogenase)---> acetaldehyde ---(aldehyde dehydrogenase <DISULFRAM>)---> acetic acid (vinegar!) ---> Krebs cycle

Disulfram inhibits aldehyde dehydrogenase.
What is an example of a reaction in the body that follows zero-order kinetics?
The metabolism of ethanol. The concentration of the enzyme is rate-limiting.
What are the side effects of disulfram?
Taking disulfram inhibits aldehyde dehydrogenase. If the pt drinks, it causes a buildup of acetaldehyde that gives the pt a wicked hangover.
What are the important nonmicrosomal synthetic reactions?
1. Acetyl transferase
2. Sulfate transferase
3. Methyltranferase
4. Addition of glutathione.
What is the action of acetyl transferase?
Adds an acetyl group to an amine.

Example: procainamide --> N-acetylprocainamide (active, less toxic, acts by a different mechanism than procainamide).
What is the action of a creation of a sulfate group?
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
What is glutathione?
A tripeptide containing the amino acids glutamic acid, cysteine, and glycine.
Most metabolites that result from conjugation to glutathione are hydrolyzed to what?
Most are hydrolyzed to mercapturic acids.
Explain the mechanism of glutathione conjugation. Give an example.
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
What is the action of methyltransferase?
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.
What is induction?
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.
What are some typical inducers of CYP? (extra credit)
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.
What are some typical inhibitors of CYP? (extra credit)
1. Imidazoles

2. Macrolide antibiotics (NOT azithromycin)

3. HIV protease inhibitors

4. Grapefruit juice - inhibits CYP3A4/5

5. Proadifen
Where is MAO-B usually found?
In the liver and brain
Where is MAO-A usually found?
In the gut.
Selective MAO inhibitors inhibit what form of MAO?
MAO-B
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?
The clara cell of the lung contains CYP, as well as CYP4B1, an isozyme not found in the lung.

This CYP metabolizes styrene.
What is an good example of when drug metabolism in an animal is different than that of a human?
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.
Vitamin D and CYP.
Needs to be metabolized by CYP isozymes in the kidney and the liver.
Where does hydrolysis of esmolol take place?
Hydrolysis of esmolol (a beta-adrenergic antagonist) takes place in the RBC.
Where does hydrolysis of succinylcholine take place?
Hydrolysis of succinylcholine (a muscle relaxant) is catalyzed by a circulating plasma enzyme.
What is a drug that can be oxidized by hemoglobin acting as an oxidase enzyme?
Aniline (an organic chemical often used in dyes)
What is the most common enzyme deficiency in humans?
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.
What is the function of superoxide dismutase?
Converts superoxide anion (O2-*) to hydrogen peroxide.
What is responsible for hydrogen peroxide detox in the red blood cell?
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.
People with G6PD deficiency usually have an abnormally low concentration of what in their RBCs?
NADPH
What disease is G6PD protective against?
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.
What drugs should patients with G6PD avoid? (6, extra credit)
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
What is porphyria?
A disease due to a deficiency in one of the heme biosynthetic enzymes.
What is the rate-limiting enzyme in heme synthesis? One important characteristic.
delta-aminolevulinic acid (ALA) synthase

It is inducible.
Injesting an inducer of ALA synthase in a patient that has enzyme deficiencies can cause what?
Accumulation of ALA. Can cause three types of porphyria.

1. Acute intermittent porphyria (AIP)

2. Hereditary coproporphyria (HCP)

3. Variegate porphyria (VP)
What medications should patients with porphyria avoid?
Barbiturates.
Pseudocholinesterase
Metabolism of succinylcholine
What demographic is a "fast" acetyl transfer-er?
Asians
People of what ancestry are "slow" acetylators?
People of western European descent.
What are some examples of substrates for acetyl transferase? (5, extra credit)
1. Sulfonamides (antibacterial)

2. Aminosalicylic acid (anti inflammatory)

3. Isoniazid (anti mycobacterial)

4. Procainamide (antidysrhythmic)

5. Hydralazine (antihypertensive)
What is a good example of an "active metabolite?"
Diazepam (half life = 1 day) --> nordazepam (half life = 4 days)

During chronic therapy, most of the pharmacological effect is produced by the metabolite.
How much methanol is adequate to produce permanent blindness?
A tablespoon!