Block 1 Lecture 2 -- IN, metabolism, PK, grapefruit, antihistamines, membranes Flashcards
Advantages to IN delivery
1) direct access to brain via olfactory neurons
2) avoid first pass
Disadvantages of IN delivery
1) rapid delivery = hi strength of conditioning = hi abuse potential
2) must be highly soluble
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
xenobiotic:
substance foreign to body including most drugs and dietary items
2 mechanisms of metabolism:
1) Phase I Functionalization
2) Phase II Biosynthetic
Describe Phase I Functionalization metabolism.
oxidation via introducing/exposing a functional group
- dealkylation, epoxide hydrolysis
- OH, COOH, SH, O, NH2
By what reaction are prodrugs usually activated?
Phase I Functionalization
– amide or ester hydrolysis
What are the major CYP enzymes?
- 50% CYP3A4/5
- 20% CYP2D6
- 10% CYP2C8/9
What enzymes are involved in Phase II Biosynthetic metabolism?
1) UDTs
2) SULTs
3) GSTs
4) NATs
UDT:
uridine 5’-diphospho-glucuronosyltransferase
SULT:
sulfotransferase
GST:
glutathione-S-transferase
NAT:
N-acetyltransferase
What is the purpose of metabolism?
serves to protect from chemical insult
– increase hydrophilicity, inactivate
Where are efflux transporters densely located?
intestine, BBB, kidney, liver
What happens in Phase II metabolism?
glucuronidation, sulfation
loss of pharmacological activity, increased hydrophilicity
What happens to lipophilic compounds in the kidney?
undergo renal tubular reabsorption
What proportion of hydrophilic molecules are excreted unchanged renally?
25-30%
2 types of efflux transporters:
1) ABC/P-gp
2) SLC
What are SLCs?
solute-carrier transporters
– passive, symporters, antiporters
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
What component of grapefruit juice causes issues for drugs?
Naringin, 6,7-dihydroxybergomottin
How does clopidogrel interact with grapefruit juice?
Clopidogrel activated by 3A4
– grapefruit juice decreases 3A4 in intestine
What is histamine?
an endogenously-occurring (basophils, mast cells) biogenic amine with high levels in periphery and CNS, but does not cross BBB
H1 receptor location
endothelium, smooth muscle
H2 receptor location
stomach mucosa
H3 receptor location
CNS
H1 receptor (agonist) function
allergic response
- increased vascular permeability
- bronchiole contraction
H2 receptor (agonist) function
nausea and reflux
– increased GI activity and secretions
H3 receptor (agonist) function
wakefulness
– increases histamine release in the CNS
Characteristics of drug needed to cross BBB:
1) lipophilic/uncharged
2) MW
What percent of drugs on market cross BBB?
3%
Henderson Hasselbach equation
pH = pKa + log (A/HA)
pH of breast milk:
7.1
pH of blood:
7.4
pH of gastric juice:
1.4
What compounds have the greatest potential to concentrate in breast milk?
weak bases
Describe a nitrosation reaction.
Nitrite anion + 2º alkylamine –> N-nitrosamine
2nd gen. antihistamines are more selective for what receptors?
H1
MoA of naloxone:
competitive antagonist of mu-opioid receptor
Uses of naloxone:
- reversal of opiate overdoses
- - coformulation with other opiate agonists
Why is naloxone co-formulated with oxycontin?
naloxone not absorbed via GI
- can’t get high if IV
- decreases constipation and cramping
