DRUG DISTRIBUTION, METABOLISM & ELIMINATION

Question 1

Drug distribution and absorption:

Answer 1

Drugs with their non polar form diffuse across plasma membranes and are absorbed into the blood stream

Drugs in their non polar form are also easily distributed through the body tissues

As for absorption, only unbound drug molecules are distributed

Question 2

What is drug distribution?

Answer 2

Only unbound drug molecules can be distributed to body tissues

Blood flow, organ size and physical properties of the drug dictate distribution

Reversible process of a drug moving from the bloodstream to target sites

Question 3

What are the mechanical barriers?

Answer 3

• blood brain barriers
• fetal placenta barrier
• intestinal epithelium
• hepatic cells

^P-glycoproteins^

Question 4

What is parenteral administration?

Answer 4

Drugs distribute to target tissues and exert a biological (therapeutic) effect

Question 5

What is oral administration?

Answer 5

• drugs are first distributed to the liver via the hepatic portal circuit
• a fraction of the dose is metabolized “first pass effect” and no longer available to exert a biological response
• bioavailability of the drug is thereby reduced

Question 6

Steps of distribution:

Answer 6

1. Oral drug taken by patient
2. Drug absorbed across intestinal mucosa
3. Drug enters portal circulation and travels to the liver
4. On first pass through the liver, drug is metabolized to less active forms
5. Drug metabolites (less active) leave the liver for distribution to tissues

Question 7

What is drug metabolism?

Answer 7

Process by which drugs are bio transformed into water soluble compounds that are easily excreted by the kidneys

Question 8

Are most drugs lipid soluble at a physiological pH?

Answer 8

YES

Question 9

Why is metabolism necessary?

Answer 9

• the kidneys can only excrete water soluble substances
• metabolism not only inactivates the drugs, but also converts lipid soluble drugs into water soluble metabolized to facilitate excretion

Question 10

What is hepatic drug metabolism?

Answer 10

• critical mechanism for terminating drug action
• facilitates the elimination of drugs from the body

Question 11

Phase 1 reaction of metabolism:

Answer 11

The drug may be unchanged, activated or transformed into an inactive metabolite.
- transform non polar molecules into polar molecules by adding a polar functional group (OH-, -SH, -NH2)
- can increase, decrease or have no effect on a drugs biological activity

Question 12

Phase 2 reaction of metabolism:

Answer 12

Conjugation usually results in an inactive metabolite, but occasionally active metabolites are created (ex.morphine)

Conjugate a drug with a very water soluble compound to form a high water soluble metabolite

The product is excreted by kidneys

The metabolite is typically inactivated

Question 13

What is oxidation?

Answer 13

Catalyzed by oxidative enzymes

Question 14

What is hydrolysis?

Answer 14

Chemical decomposition process that uses water to split the chemical bonds of a drug

Question 15

What is reduction?

Answer 15

ADDITION (gains) of electrons

Question 16

What is cytochrome P450 enzymes?

Answer 16

Replace a -CH or -NH group in a molecule with an -OH group

Question 17

What is cytochrome P448 enzyme?

Answer 17

Insert an oxygen atom between two carbons that are connected by a double bond

Question 18

What is the function of rifampin?

Answer 18

• increases the synthesis of CYP enzymes
• increased metabolism decreases the plasma concentrations of co-administered drugs (ex. Antidepressants, estrogens, anti arrhythmic)

Question 19

What is the function of erythromycin?

Answer 19

• inhibits the activity of CYP enzymes
• decreases metabolism increases the plasma concentrations of co administered drugs

Question 20

What other enzymes are in phase 1 reactions?

Answer 20

Liver alcohol dehydrogenase (LADH)

Aldehyde oxidase (AO)

• these enzymes can only oxidize alcohol (not multifunction oxidases)

Monoamine Oxidase
- critical in termination of monoamine neurotransmitters (dopamine, norepinephrine, serotonin)

Question 21

Do all drugs undergo phase 2?

Answer 21

NO!!!!

Question 22

What are examples of phase 2 enzymes?

Answer 22

Glucuronyl transferase
- replaces OH or SH group with GLUCRONIC ACID
N-acetyltransferase
- replaces OH, SH or NH 2 group with ACETATE
Sulfotransferase
- replaces an OH or SH group with acetate
Glutathione S-transferase
- forms an adduct between the drug and glutathione

Question 23

What happens with overdose in metabolism of acetaminophen?

Answer 23

• NAPQI levels to rise
• glutathione stores become depleted
• cell death, an irreversible process, leading to liver damage
• symptoms of liver failure

Ethanol is an induced of phase 1 metabolic reactions

Question 24

H,w do we protect the liver in the context of acetaminophen overdose?

Answer 24

We can administer a drug that quickly acts as a replacement for glutathione

Question 25

What is Acetylcysteine?

Answer 25

• administered intravenously
• contains SH group
• binds to NAPQI and prevents damage to hepatocytes

Question 26

Excretion of drugs in the kidneys:

Answer 26

• primary site of drug excretion
• drugs must be ionized and polar
• solubility of drugs can be manipulated by shifting pH of urine
  —Aspirin overdose
  —Sodium bicarbonate

Question 27

Excretion of drugs in the intestines:

Answer 27

• some highly fat soluble metabolites are eliminated via the bile and excreted in feces
• do to high fat solubility, drugs may be re absorbed in the GI tract, prolonging drug action
• excretion will eventually occur through the kidneys