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
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xenobiotic:
substance foreign to body including most drugs and dietary items
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2 mechanisms of metabolism:
1) Phase I Functionalization
2) Phase II Biosynthetic
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Describe Phase I Functionalization metabolism.
oxidation via introducing/exposing a functional group
-- dealkylation, epoxide hydrolysis
-- + OH, COOH, SH, O, NH2
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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
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What enzymes are involved in Phase II Biosynthetic metabolism?
1) UDTs
2) SULTs
3) GSTs
4) NATs
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UDT:
uridine 5'-diphospho-glucuronosyltransferase
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SULT:
sulfotransferase
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GST:
glutathione-S-transferase
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NAT:
N-acetyltransferase
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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
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What happens in Phase II metabolism?
glucuronidation, sulfation
(loss of pharmacological activity, increased hydrophilicity)
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What happens to lipophilic compounds in the kidney?
undergo renal tubular reabsorption
18
What proportion of hydrophilic molecules are excreted unchanged renally?
25-30%
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2 types of efflux transporters:
1) ABC/P-gp
2) SLC
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What are SLCs?
solute-carrier transporters
-- passive, symporters, antiporters
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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
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What component of grapefruit juice causes issues for drugs?
Naringin, 6,7-dihydroxybergomottin
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How does clopidogrel interact with grapefruit juice?
Clopidogrel activated by 3A4
-- grapefruit juice decreases 3A4 in intestine
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What is histamine?
an endogenously-occurring (basophils, mast cells) biogenic amine with high levels in periphery and CNS, but does not cross BBB
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H1 receptor location
endothelium, smooth muscle
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H2 receptor location
stomach mucosa
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H3 receptor location
CNS
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H1 receptor (agonist) function
allergic response
-- increased vascular permeability
-- bronchiole contraction
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H2 receptor (agonist) function
nausea and reflux
-- increased GI activity and secretions
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H3 receptor (agonist) function
wakefulness
-- increases histamine release in the CNS
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Characteristics of drug needed to cross BBB:
1) lipophilic/uncharged
2) MW
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What percent of drugs on market cross BBB?
3%
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Henderson Hasselbach equation
pH = pKa + log (A/HA)
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pH of breast milk:
7.1
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pH of blood:
7.4
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pH of gastric juice:
1.4
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What compounds have the greatest potential to concentrate in breast milk?
weak bases
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Describe a nitrosation reaction.
Nitrite anion + 2º alkylamine --> N-nitrosamine
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2nd gen. antihistamines are more selective for what receptors?
H1
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MoA of naloxone:
competitive antagonist of mu-opioid receptor
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Uses of naloxone:
-- reversal of opiate overdoses
-- coformulation with other opiate agonists
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