Block 1 Lecture 2 -- IN, metabolism, PK, grapefruit, antihistamines, membranes

Question 1

Advantages to IN delivery

Answer 1

1) direct access to brain via olfactory neurons

2) avoid first pass

Question 2

Disadvantages of IN delivery

Answer 2

1) rapid delivery = hi strength of conditioning = hi abuse potential
2) must be highly soluble

Question 3

Ideal characteristics of a transmembrane drug product?

Answer 3

1) rapid acting, = to inj.
2) needleless
3) powder or aqueous soln
4) non-toxic to admin site
5) unit-dose, disposable
6) easy to administer
7) good shelf-life
8) durable design of product

Question 4

xenobiotic:

Answer 4

substance foreign to body including most drugs and dietary items

Question 5

2 mechanisms of metabolism:

Answer 5

1) Phase I Functionalization

2) Phase II Biosynthetic

Question 6

Describe Phase I Functionalization metabolism.

Answer 6

oxidation via introducing/exposing a functional group

• • dealkylation, epoxide hydrolysis
• • • OH, COOH, SH, O, NH2

Question 7

By what reaction are prodrugs usually activated?

Answer 7

Phase I Functionalization

– amide or ester hydrolysis

Question 8

What are the major CYP enzymes?

Answer 8

• • 50% CYP3A4/5
• • 20% CYP2D6
• • 10% CYP2C8/9

Question 9

What enzymes are involved in Phase II Biosynthetic metabolism?

Answer 9

1) UDTs
2) SULTs
3) GSTs
4) NATs

Question 10

UDT:

Answer 10

uridine 5’-diphospho-glucuronosyltransferase

Question 11

SULT:

Answer 11

sulfotransferase

Question 12

GST:

Answer 12

glutathione-S-transferase

Question 13

NAT:

Answer 13

N-acetyltransferase

Question 14

What is the purpose of metabolism?

Answer 14

serves to protect from chemical insult

– increase hydrophilicity, inactivate

Question 15

Where are efflux transporters densely located?

Answer 15

intestine, BBB, kidney, liver

Question 16

What happens in Phase II metabolism?

Answer 16

glucuronidation, sulfation

loss of pharmacological activity, increased hydrophilicity

Question 17

What happens to lipophilic compounds in the kidney?

Answer 17

undergo renal tubular reabsorption

Question 18

What proportion of hydrophilic molecules are excreted unchanged renally?

Answer 18

25-30%

Question 19

2 types of efflux transporters:

Answer 19

1) ABC/P-gp

2) SLC

Question 20

What are SLCs?

Answer 20

solute-carrier transporters

– passive, symporters, antiporters

Question 21

What are the effects of grapefruit juice on drug PK?

Answer 21

1) inhibits intestinal 3A4
2) decreases 3A4 expression in intestinal wall
3) induces efflux transporters

Question 22

What component of grapefruit juice causes issues for drugs?

Answer 22

Naringin, 6,7-dihydroxybergomottin

Question 23

How does clopidogrel interact with grapefruit juice?

Answer 23

Clopidogrel activated by 3A4

– grapefruit juice decreases 3A4 in intestine

Question 24

What is histamine?

Answer 24

an endogenously-occurring (basophils, mast cells) biogenic amine with high levels in periphery and CNS, but does not cross BBB

Question 25

H1 receptor location

Answer 25

endothelium, smooth muscle

Question 26

H2 receptor location

Answer 26

stomach mucosa

Question 27

H3 receptor location

Answer 27

CNS

Question 28

H1 receptor (agonist) function

Answer 28

allergic response

• • increased vascular permeability
• • bronchiole contraction

Question 29

H2 receptor (agonist) function

Answer 29

nausea and reflux

– increased GI activity and secretions

Question 30

H3 receptor (agonist) function

Answer 30

wakefulness

– increases histamine release in the CNS

Question 31

Characteristics of drug needed to cross BBB:

Answer 31

1) lipophilic/uncharged

2) MW

Question 32

What percent of drugs on market cross BBB?

Answer 32

3%

Question 33

Henderson Hasselbach equation

Answer 33

pH = pKa + log (A/HA)

Question 34

pH of breast milk:

Answer 34

7.1

Question 35

pH of blood:

Answer 35

7.4

Question 36

pH of gastric juice:

Answer 36

1.4

Question 37

What compounds have the greatest potential to concentrate in breast milk?

Answer 37

weak bases

Question 38

Describe a nitrosation reaction.

Answer 38

Nitrite anion + 2º alkylamine –> N-nitrosamine

Question 39

2nd gen. antihistamines are more selective for what receptors?

Answer 39

H1

Question 40

MoA of naloxone:

Answer 40

competitive antagonist of mu-opioid receptor

Question 41

Uses of naloxone:

Answer 41

• • reversal of opiate overdoses

- - coformulation with other opiate agonists

Question 42

Why is naloxone co-formulated with oxycontin?

Answer 42

naloxone not absorbed via GI

• • can’t get high if IV
• • decreases constipation and cramping