ADME (tox substances)

Compounds that are likely to undergo more extensive distribution INTO the BRAIN by passive diffusion would be?

more lipophilic

Modification of drugs by drug metabolizing enzymes (DMEs) usually (increases/decreases) elimination.

increases

Phase 1 metabolism is normally what reactions?

oxidation, reduction, hydrolysis

Phase 2 metabolism is normally what reactions?

sulfation, glucuronidation

What happens in the First Pass Effect?

drug goes to liver before reaching systemic circulation

metabolism -> inactive metabolite leads to what?

elimination

metabolism -> active metabolite leads to what?

therapeutic action

metabolism -> toxic metabolite leads to what?

tissue damage, cancer, death

DME inhibition (increases/decreases) metabolism?

decreases

DME induction (increases/decreases) metabolism?

increases metabolism

Morphine binds to what receptors?

opioid (mu)

Route of administration of morphine that has good absorption

oral

what route of administration of morphine bypasses absorption?

IV

Where is morphine distributed?

tissues with high blood flow

Does morphine distribute into CNS?

no because of BBB

What reaction occur in morphine metabolism?

glucuronidation

What metabolite of morphine produces analgesic effect?

M6G

Can M6G distribute into the brain?

yes, penetrates BBB

What kind of transport allows M6G to penetrate BBB?

Active transport (OATP, GLUT)

How is morphine primarily eliminated?

urine

Which metabolite of morphine is mainly in the elimination?

M3G

What is a natural occurring opiate?

codeine

What receptor does codeine bind to?

opioid

Is codeine a prodrug?

yes (must undergo metabolism)

What metabolizes codeine?

cytochrome P450 (CYP2D6 isozyme)

A person is taking codeine to get high at the same time as the antidepressant fluoxetine (CYP2D6 inhibitor). You would expect to see:

decreased euphoric response to codeine

What is a synthetic opioid?

fentanyl

What are some routes of administration for fentanyl?

IV, intranasal spray, patch, buccal

Which route of administration of fentanyl has poor bioavailability?

oral

Fentanyl goes through what kind of metabolism?

first pass (straight into liver)

fentanyl absorption speed and why?

fast absorption, high lipophilicity

Where and how fast is fentanyl distributed?

well-perfused tissues, quickly distributed

Can fentanyl cross BBB?

yes

Can fentanyl cross placenta?

yes

speed and what metabolizes fentanyl

fast, CYP3A4 isozyme

fentanyl is metabolized into what?

norfentanyl

is norfentanyl an active, toxic, or inactive metabolite?

inactive

How is fentanyl primarily eliminated?

urine

Grapefruit juice contains potent CYP3A4 inhibitors. What effect would be seen if a fentanyl user drank grapefruit juice (elimination and activity)?

decreased elimination

increased fentanyl activity

What is a vet medication that appeared as an additive in street opioids?

xylazine

Why is xylazine not approved for human use?

hypotension and CNS depression

Where does absorption of xylazine occur?

plasma conc.

speed and location of distribution of xylazine

fast, into brain (lipophilic)

What metabolizes xylazine?

hepatic CYPs

How is xylazine eliminated?

renal clearance

Routes of administration of THC absorption

inhalation, oral

What is bad about inhalation of THC?

loss due to pyrolysis

What is bad about oral administration of THC?

poor solubility, degrades in acid, high first pass

Where is THC distributed?

perfused tissues, brain, placenta

Where is THC accumulated?

adipose tissue

What metabolizes THC?

liver

speed and location of elimination of THC

slow, feces (most), urine (small amount)

Chemical properties of aliphatic alcohol (ethanol)

organic solvent, soluble in water and lipids

speed and location of absorption of ethanol

fast, GI tract (small intestine > stomach)

speed and location of distribution of ethanol

fast, tissues, BBB, placenta

Main site of metabolism of ethanol

liver

Reactions of ethanol metabolism

ADH, ALDH

Some individuals have an inherited deficiency in ALDH activity. This will make them (more/less/equally) susceptible to ethanol-induced adverse effects.

more

What is a treatment of ethanol abuse?

disulfiram

function of disulfiram

inhibits ALDH

What happens to acetaldehyde levels when inhibiting ALDH?

higher levels

higher levels of acetaldehyde does what to adverse effects?

increases adverse effects

how is ethanol primarily eliminated?

metabolism

small amounts in urine, breath, sweat, breast milk

what are 2 minor metabolites of ethanol?

ethyl glucuronide

ethyl sulfate

Where can ethyl glucuronide and ethyl sulfate be found?

urine (several days)

blood, hair (weeks to months)