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

PHS 931 > Block 1 Lecture 2 -- IN, metabolism, PK, grapefruit, antihistamines, membranes > Flashcards

Flashcards in Block 1 Lecture 2 -- IN, metabolism, PK, grapefruit, antihistamines, membranes Deck (42):
1

Advantages to IN delivery

1) direct access to brain via olfactory neurons
2) avoid first pass

2

Disadvantages of IN delivery

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

3

Ideal characteristics of a transmembrane drug product?

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

4

xenobiotic:

substance foreign to body including most drugs and dietary items

5

2 mechanisms of metabolism:

1) Phase I Functionalization
2) Phase II Biosynthetic

6

Describe Phase I Functionalization metabolism.

oxidation via introducing/exposing a functional group
-- dealkylation, epoxide hydrolysis
-- + OH, COOH, SH, O, NH2

7

By what reaction are prodrugs usually activated?

Phase I Functionalization
-- amide or ester hydrolysis

8

What are the major CYP enzymes?

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

9

What enzymes are involved in Phase II Biosynthetic metabolism?

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

10

UDT:

uridine 5'-diphospho-glucuronosyltransferase

11

SULT:

sulfotransferase

12

GST:

glutathione-S-transferase

13

NAT:

N-acetyltransferase

14

What is the purpose of metabolism?

serves to protect from chemical insult
-- increase hydrophilicity, inactivate

15

Where are efflux transporters densely located?

intestine, BBB, kidney, liver

16

What happens in Phase II metabolism?

glucuronidation, sulfation
(loss of pharmacological activity, increased hydrophilicity)

17

What happens to lipophilic compounds in the kidney?

undergo renal tubular reabsorption

18

What proportion of hydrophilic molecules are excreted unchanged renally?

25-30%

19

2 types of efflux transporters:

1) ABC/P-gp
2) SLC

20

What are SLCs?

solute-carrier transporters
-- passive, symporters, antiporters

21

What are the effects of grapefruit juice on drug PK?

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

22

What component of grapefruit juice causes issues for drugs?

Naringin, 6,7-dihydroxybergomottin

23

How does clopidogrel interact with grapefruit juice?

Clopidogrel activated by 3A4
-- grapefruit juice decreases 3A4 in intestine

24

What is histamine?

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

25

H1 receptor location

endothelium, smooth muscle

26

H2 receptor location

stomach mucosa

27

H3 receptor location

CNS

28

H1 receptor (agonist) function

allergic response
-- increased vascular permeability
-- bronchiole contraction

29

H2 receptor (agonist) function

nausea and reflux
-- increased GI activity and secretions

30

H3 receptor (agonist) function

wakefulness
-- increases histamine release in the CNS

31

Characteristics of drug needed to cross BBB:

1) lipophilic/uncharged
2) MW

32

What percent of drugs on market cross BBB?

3%

33

Henderson Hasselbach equation

pH = pKa + log (A/HA)

34

pH of breast milk:

7.1

35

pH of blood:

7.4

36

pH of gastric juice:

1.4

37

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

weak bases

38

Describe a nitrosation reaction.

Nitrite anion + 2º alkylamine --> N-nitrosamine

39

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

H1

40

MoA of naloxone:

competitive antagonist of mu-opioid receptor

41

Uses of naloxone:

-- reversal of opiate overdoses
-- coformulation with other opiate agonists

42

Why is naloxone co-formulated with oxycontin?

naloxone not absorbed via GI
-- can't get high if IV
-- decreases constipation and cramping