Stimulants and Drugs of Abuse - Proteau

Question 1

What stimulants use 1A2?

Answer 1

Caffeine, theophylline, MDMA

Question 2

What stimulants use MAO?

Answer 2

Mescaline

Question 3

What stimulants use 2D6?

Answer 3

MDMA, atomoxetine

Question 4

What stimulants use esterases?

Answer 4

Methylphenidate

Question 5

What drug uses hydrolysis and oxidation? What induction and inhibition properties does it have?

Answer 5

Modafinil. It inhibits 2C19 moderately and induces 3A4 moderately.

Question 6

Why does THC have so many different metabolites?

Answer 6

Because it can be oxidized in multiple areas.

Question 7

How is nabilone different than THC?

Answer 7

It has fewer sites of oxidation because of the double-bonded oxygen (blocking allylic P450 oxidation) and the double methyl group (blocks benzylic oxidation)

Question 8

What structural feature seems to contribute to the euphoric effects of the cannabinoids?

Answer 8

The closed ring contributes to the euphoric effects. Opening the ring in cannabidiol seems to be the reason there are no euphoric effects.

Question 9

What is something that could affect the metabolism of caffeine?

Answer 9

It is metabolized by 1A2, which can be induced by cigarette smoke. SO smokers usually need to drink more caffeine to feel the effects than non-smokers. There are also genetic polymorphisms associated with 1A2, so caffeine can affect people differently.

Question 10

What is caffeine metabolized to?

Answer 10

1A2 to paraxanthine (3 methyl is preferentially removed), then to 1-methyl uric acid (7 methyl removed).

Question 11

How is theophylline structurally similar to caffeine?

Answer 11

Same except it has the 7-methyl removed.

Question 12

What is theophylline used for?

Answer 12

A bronchodilator to treat asthma.

Question 13

What is the metabolism of theophylline?

Answer 13

1A2 can help it undergoes metabolism to 1- or 3-methylxanthine or 1,3-dimethy uric acid.

Question 14

What structural feature of amphetamine blocks MAO metabolism?

Answer 14

The alpha methyl.

Question 15

Does the S or R enantiomer of amphetamine have greater CNS stimulant effects?

Answer 15

The S has greater stimulant effects.

Question 16

What metabolism does amphetamine undergo?

Answer 16

P450 de-amination reaction to phenylacetone (inactive)

Question 17

What is the lysine prodrug of dextroamphetamine? What enantiomer(s) is/are used?

Answer 17

Lisdexamphetamine (S enantiomer)

Question 18

What is the prodrug of both amphetamine and theophylline? What is required to release the active component?

Answer 18

Fenethylline. P450 oxidative release is required (slow). It is schedule I in US.

Question 19

How is amphetamine modified to get phentermine?

Answer 19

Add 2nd alpha-methyl, which further decreases the rate of metabolism. There are reduced stimulant properties compared to amphetamine (less habit-forming).

Question 20

What drugs are used to manage obesity?

Answer 20

Phentermine, Diethylpropion

Question 21

What does N-methylation do to amphetamine?

Answer 21

It increases the CNS activity and increases the abuse potential. (This is methamphetamine). The lipophilicity is increased, which gives it more rapid CNS access.

Question 22

In methamphetamine, which isomer has greater stimulant properties?

Answer 22

The S isomer has greater stimulant properties. The R enantiomer is levmetamphetamine, which was formerly in Vick’s vapor inhaler. (This would make you test positive for meth).

Question 23

What does carbonyl substitution on the beta carbon do? Bulky diethyl group substitution?

Answer 23

Both reduce stimulant properties.

Question 24

Diethylpropion has what properties compared to amphetamine?

Answer 24

Decreased stimulant and decreased potential relative to other amphetamines. Used to manage weight-loss.

Question 25

What is the active ingredient in peyote cactus?

Answer 25

Mescaline

Question 26

What structural features does mescaline have?

Answer 26

Alkoxy aromatic ring substituents. Leads to psychotomimetic and hallucinogenic effects (5HT effects). Poor oral activity.

Question 27

What metabolism does mescaline go through?

Answer 27

Rapid MAO metabolism (A and B)

Question 28

What is MDMA an irreversible inhibitor of?

Answer 28

2D6

Question 29

How is MDMA metabolized?

Answer 29

MDMA uses 2D6 and 1A2 to remove catechol.

Question 30

What does COMT do?

Answer 30

Removes H and add CH3 to O-ring.

Question 31

What part does COMT play in the metabolism of MDMA?

Answer 31

It forms HMMA from the 2D6 and 1A2 product.

Question 32

What does oxidation do to the MDMA metabolite?

Answer 32

It forms an orthoquinone metabolite (two double-bonded oxygens). This possibly contributes to neurotoxic effects.

Question 33

What drug has a capped catechol that helps contribute to good oral activity and good CNS access?

Answer 33

MDMA

Question 34

What is methylphenidate formulated as?

Answer 34

R,R and S,S racemates. Dexmethylphenidate is active, and available as a separate product.

Question 35

What metabolism does methylphenidate undergo? What product does it form?

Answer 35

T1/2 = 2-3 hours, using esterase to form ritalinic acid (inactive)

Question 36

What antidepressant is also an irreversible inhibitor of CYP2D6 like MDMA?

Answer 36

Paroxetine

Question 37

What is atomoxetine

Answer 37

A selective NE reuptake inhibitor. A non-stimulant treating ADHD.

Question 38

What metabolism dose atomoxetine undergo?

Answer 38

2D6 major metabolism to 4-hydroxyatomoxetine (active) and then glucuronidation to an inactive product.

Question 39

What is the half-life of atomoxetine?

Answer 39

EM = 5 hours, PM = 20 hours

Question 40

What structural features is this lacking to be an antidepressant?

Answer 40

Lacking EWGs on rings that would make it an SSRI. Does not inhibit 2D6.

Question 41

What is the half-life of the active metabolite of atomoxetine?

Answer 41

6-8 hours

Question 42

What does modafinil treat?

Answer 42

Narcolepsy. It promotes wakefulness through an unclear mechanism.

Question 43

What is modafinil formulated as?

Answer 43

As a racemic mixture. Lone electron pair occupies fourth site. Both enantiomers are active, but R has the longer half-life of 15 hours (3-fold over S). R also has better pharmacodynamics than the mixture.

Question 44

What is the metabolism of modafinil?

Answer 44

1) Hydrolysis of primary amide 2) Oxidation to the sulfone (both are inactive)

Question 45

What is the name of the separately marketed R enantiomer of modafinil?

Answer 45

Armodafanil (Nuvigil)

Question 46

What are the induction/inhibition properties of the modafinil enantiomers?

Answer 46

- Induce 3A4 moderately | - Inhibit 2C19 moderately

Question 47

What drug has a slighter longer duration and is improved over THC?

Answer 47

Nabilone. It is improved because it varies less in its oxidative potential.

Question 48

What drug is in clinical trials for treating certain types of seizures?

Answer 48

Cannabidiol.