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