MCQ Quiz: Medicinal Chemistry of Drugs Used in ADHD

The medicinal chemistry of drugs used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) is a classic example of how small molecular modifications can significantly alter a drug’s pharmacological profile, duration of action, and clinical utility. As covered in the Patient Care VII: Brain and Behavior course, understanding the structure-activity relationships of stimulants and non-stimulants is key to grasping their mechanisms and place in therapy. This quiz will test your knowledge on the chemical scaffolds, stereochemistry, and metabolic pathways that define this important class of neuropsychiatric medications.

1. The chemical structure of amphetamine is based on which core scaffold?

• A. A benzodiazepine ring
• B. An indole scaffold
• C. A phenethylamine scaffold
• D. A piperidine ring

Answer: C. A phenethylamine scaffold

2. Stimulant medications like methylphenidate and amphetamine must be sufficiently lipophilic to achieve their effect. What is the primary reason for this physicochemical requirement?

• A. To improve water solubility for IV formulation.
• B. To allow the molecule to cross the blood-brain barrier and reach its targets in the CNS.
• C. To prevent metabolism by the liver.
• D. To ensure binding to plasma proteins.

Answer: B. To allow the molecule to cross the blood-brain barrier and reach its targets in the CNS.

3. The “Medicinal Chemistry of Drugs Used in ADHD” is a core lecture in which Patient Care course module?

• A. Module 5: Anxiety and Sleep-Wake Disorders
• B. Module 6: Epilepsy
• C. Module 7: Other Neuropsychiatric Disorders
• D. Module 2: Neurodegenerative Disorders

Answer: C. Module 7: Other Neuropsychiatric Disorders

4. What is the primary role of the basic amine functional group present in all stimulant medications?

• A. It is responsible for the drug’s color.
• B. It is protonated at physiological pH, allowing it to form an ionic bond with an acidic residue in the transporter binding site.
• C. It makes the molecule highly water-soluble.
• D. It is the primary site of glucuronidation.

Answer: B. It is protonated at physiological pH, allowing it to form an ionic bond with an acidic residue in the transporter binding site.

5. Lisdexamfetamine (Vyvanse) is a prodrug of dextroamphetamine. What is chemically attached to the dextroamphetamine molecule to make it a prodrug?

• A. A phosphate group
• B. The amino acid L-lysine
• C. A methyl group
• D. A glucuronide moiety

Answer: B. The amino acid L-lysine

6. From a medicinal chemistry perspective, what is the primary advantage of the prodrug design of lisdexamfetamine?

• A. It allows the drug to be administered intravenously.
• B. It requires enzymatic cleavage in the blood to release the active drug, providing a slower onset and longer duration of action.
• C. It makes the drug less potent.
• D. It completely eliminates all side effects.

Answer: B. It requires enzymatic cleavage in the blood to release the active drug, providing a slower onset and longer duration of action.

7. Amphetamine has a chiral center. The dextro-(S)-enantiomer is more potent as a CNS stimulant than the levo-(R)-enantiomer because it has a higher affinity for the:

• A. Serotonin transporter (SERT)
• B. Norepinephrine transporter (NET)
• C. Dopamine transporter (DAT)
• D. GABA-A receptor

Answer: C. Dopamine transporter (DAT)

8. Methylphenidate’s structure contains a piperidine ring, making it chemically distinct from amphetamine. Its primary mechanism of action is:

• A. Promoting the release of dopamine and norepinephrine.
• B. Acting as a reuptake inhibitor of dopamine and norepinephrine.
• C. Antagonizing dopamine receptors.
• D. Agonizing serotonin receptors.

Answer: B. Acting as a reuptake inhibitor of dopamine and norepinephrine.

9. Atomoxetine is a non-stimulant medication used for ADHD. Its chemical structure as an aryloxypropanolamine confers selectivity for which transporter?

• A. Dopamine transporter (DAT)
• B. Serotonin transporter (SERT)
• C. Norepinephrine transporter (NET)
• D. GABA transporter (GAT)

Answer: C. Norepinephrine transporter (NET)

10. The alpha-methylation on the side chain of the amphetamine structure serves what medicinal chemistry purpose?

• A. It makes the molecule inactive.
• B. It blocks binding to the dopamine transporter.
• C. It provides resistance to metabolism by monoamine oxidase (MAO), increasing its duration of action.
• D. It makes the molecule highly water-soluble.

Answer: C. It provides resistance to metabolism by monoamine oxidase (MAO), increasing its duration of action.

11. Stereochemistry is critical for methylphenidate. The (d)-threo isomer (dexmethylphenidate) is:

• A. The inactive isomer.
• B. The pharmacologically active isomer responsible for the therapeutic effect.
• C. A toxic metabolite.
• D. A mixture of all four possible isomers.

Answer: B. The pharmacologically active isomer responsible for the therapeutic effect.

12. The alpha-2 adrenergic agonists, guanfacine and clonidine, have chemical structures that allow them to modulate norepinephrine signaling where?

• A. Primarily in the peripheral nervous system.
• B. At postsynaptic receptors in the prefrontal cortex.
• C. At the norepinephrine transporter.
• D. In the adrenal medulla.

Answer: B. At postsynaptic receptors in the prefrontal cortex.

13. A key principle of medicinal chemistry is structure-activity relationship (SAR). For stimulants, this means:

• A. All phenethylamines have the same activity.
• B. Small changes to the molecule’s structure can drastically alter its potency, selectivity, and duration of action.
• C. A drug’s structure is unrelated to its biological effect.
• D. The most complex structure is always the most potent.

Answer: B. Small changes to the molecule’s structure can drastically alter its potency, selectivity, and duration of action.

14. The metabolism of atomoxetine is highly dependent on which CYP450 enzyme, leading to pharmacogenomic considerations?

• A. CYP1A2
• B. CYP3A4
• C. CYP2C9
• D. CYP2D6

Answer: D. CYP2D6

15. Long-acting stimulant formulations (e.g., Concerta, Adderall XR) are a triumph of pharmaceutical chemistry. They are designed to:

• A. Provide a rapid onset followed by a controlled release of medication throughout the day.
• B. Be administered multiple times during the school day.
• C. Have a higher abuse potential.
• D. Be less effective than immediate-release formulations.

Answer: A. Provide a rapid onset followed by a controlled release of medication throughout the day.

16. The OROS® (osmotic release) system used in Concerta is a sophisticated formulation that uses an osmotic gradient to:

• A. Push the drug out of a laser-drilled hole at a controlled rate.
• B. Dissolve immediately in the stomach.
• C. Prevent the drug from being absorbed.
• D. Deliver the drug via inhalation.

Answer: A. Push the drug out of a laser-drilled hole at a controlled rate.

17. Why is an understanding of the medicinal chemistry of stimulants important for a pharmacist?

• A. To explain the differences in onset and duration between various long-acting products.
• B. To understand the basis for their abuse potential.
• C. To anticipate drug interactions based on metabolic pathways.
• D. All of the above.

Answer: D. All of the above.

18. The “pharmacophore” for a classical stimulant includes a benzene ring and a(n) ___________ separated by a two-carbon chain.

• A. carboxylic acid
• B. basic amine
• C. hydroxyl group
• D. ester group

Answer: B. basic amine

19. From a medicinal chemistry standpoint, the non-stimulant atomoxetine was designed to be selective for NET over DAT. This selectivity results in:

• A. A higher abuse potential.
• B. A much faster onset of action.
• C. A lower abuse potential compared to stimulants.
• D. A need for daily dosing at bedtime.

Answer: C. A lower abuse potential compared to stimulants.

20. The difference between Adderall® and Evekeo® is a matter of stereochemistry. Adderall® is a 3:1 mixture of dextro- and levo-amphetamine salts, while Evekeo® is a:

• A. Single enantiomer of dextroamphetamine.
• B. 1:1 mixture of dextro- and levo-amphetamine.
• C. Prodrug of amphetamine.
• D. Long-acting formulation.

Answer: B. 1:1 mixture of dextro- and levo-amphetamine.

21. The chemical properties of methylphenidate make it susceptible to what type of metabolism, forming ritalinic acid?

• A. Oxidation by CYP enzymes
• B. Hydrolysis of the methyl ester
• C. Glucuronidation
• D. Reduction of the piperidine ring

Answer: B. Hydrolysis of the methyl ester

22. Which functional group on the atomoxetine molecule is the primary site of its metabolism?

• A. The ether oxygen
• B. The aromatic ring (para-hydroxylation)
• C. The methyl group on the nitrogen
• D. The propyl chain

Answer: B. The aromatic ring (para-hydroxylation)

23. The “Foundations” courses in the curriculum, like Medicinal Chemistry and Pharmacology, provide the principles needed to understand drugs used in the Patient Care courses.

• A. True
• B. False

Answer: A. True

24. The development of a transdermal patch for methylphenidate (Daytrana®) was a formulation strategy designed to:

• A. Increase the abuse potential.
• B. Bypass first-pass metabolism and provide a different pharmacokinetic profile.
• C. Make the drug less potent.
• D. Be used for only one day.

Answer: B. Bypass first-pass metabolism and provide a different pharmacokinetic profile.

25. A patient who is a CYP2D6 poor metabolizer taking atomoxetine would be expected to have:

• A. Lower plasma concentrations of the drug.
• B. Higher plasma concentrations and a greater risk of side effects like increased blood pressure.
• C. No change in plasma concentration.
• D. Faster clearance of the drug.

Answer: B. Higher plasma concentrations and a greater risk of side effects.

26. The medicinal chemistry of the alpha-2 agonists like guanfacine makes them useful for treating which specific symptoms of ADHD?

• A. Only inattention
• B. Only hyperactivity
• C. Impulsivity and hyperactivity
• D. They are not useful for any ADHD symptoms.

Answer: C. Impulsivity and hyperactivity

27. The term “racemic mixture” means a formulation contains:

• A. Only the active enantiomer.
• B. Only the inactive enantiomer.
• An equal (1:1) mixture of both enantiomers.
• D. A prodrug and its active metabolite.

Answer: C. An equal (1:1) mixture of both enantiomers.

28. Why can’t a prodrug like lisdexamfetamine be abused via snorting or injection?

• A. It is not a controlled substance.
• B. It requires enzymatic conversion in the blood to become active, bypassing these routes of administration for a rapid “high.”
• C. It is too large a molecule to be injected.
• D. It is insoluble in water.

Answer: B. It requires enzymatic conversion in the blood to become active, bypassing these routes of administration for a rapid “high.”

29. The pH of the urine can affect the excretion of amphetamine. Amphetamine is a weak base, so making the urine more _________ will increase its clearance.

• A. acidic
• B. alkaline (basic)
• C. neutral
• D. concentrated

Answer: A. acidic

30. The “Implement” step of the PPCP for ADHD management involves counseling on the medication. A key point for long-acting capsules is:

• A. To always crush or chew them for faster effect.
• B. To understand that some formulations can be opened and sprinkled on food, but the beads should not be crushed.
• C. To take them right before bed.
• D. To only take them on weekends.

Answer: B. To understand that some formulations can be opened and sprinkled on food, but the beads should not be crushed.

31. The core structure of the stimulant medications directly interacts with which part of the monoamine transporters?

• A. The extracellular loops
• B. The transmembrane domains that form the binding pocket
• C. The intracellular C-terminus
• D. It does not directly interact with the transporter.

Answer: B. The transmembrane domains that form the binding pocket

32. The medicinal chemistry design of atomoxetine makes it structurally similar to:

• A. Amphetamine
• B. The antidepressant fluoxetine
• C. Methylphenidate
• D. Guanfacine

Answer: B. The antidepressant fluoxetine

33. What is a key structural difference between dopamine and norepinephrine?

• A. Dopamine has a hydroxyl group on the benzene ring.
• B. Norepinephrine has a hydroxyl group on the beta-carbon of the side chain.
• C. Dopamine has a longer side chain.
• D. Norepinephrine has a methyl group on the amine.

Answer: B. Norepinephrine has a hydroxyl group on the beta-carbon of the side chain.

34. The medicinal chemistry of stimulants explains why they are contraindicated with which class of antidepressants?

• A. SSRIs
• B. TCAs
• C. MAOIs
• D. Mirtazapine

Answer: C. MAOIs

35. A key SAR principle for phenethylamine-type stimulants is that adding bulky groups to the amine:

• A. Increases stimulant activity.
• B. Decreases stimulant activity but may increase activity at other receptors (e.g., serotonin).
• C. Has no effect on activity.
• D. Makes the drug a non-stimulant.

Answer: B. Decreases stimulant activity but may increase activity at other receptors (e.g., serotonin).

36. The knowledge that stimulants are controlled substances and require careful dispensing is part of which foundational course?

• A. Principles of Pharmacy Law & Ethics
• B. Patient Care I
• C. Pathophysiology and Patient Assessment I
• D. Principles of Evidence-Based Practice

Answer: A. Principles of Pharmacy Law & Ethics

37. The development of dexmethylphenidate (Focalin®) from racemic methylphenidate is an example of:

• A. A prodrug strategy.
• B. A “chiral switch” to market a single, more active enantiomer.
• C. A new molecular entity.
• D. A generic substitution.

Answer: B. A “chiral switch” to market a single, more active enantiomer.

38. The physicochemical property of pKa is important for stimulants because it determines:

• A. The drug’s color.
• B. The degree of ionization at a given pH, which affects absorption and excretion.
• C. The drug’s potency.
• D. The drug’s mechanism of action.

Answer: B. The degree of ionization at a given pH, which affects absorption and excretion.

39. The medicinal chemistry of the non-stimulants offers an alternative for patients who:

• A. Cannot tolerate the side effects of stimulants.
• B. Have a history of substance abuse.
• C. Have a comorbid anxiety disorder.
• D. All of the above.

Answer: D. All of the above.

40. A pharmacist’s understanding of the various long-acting technologies is essential for counseling on:

• A. Proper administration.
• B. What the patient might see in their stool (e.g., the ghost shell of Concerta®).
• C. Why different products are not interchangeable.
• D. All of the above.

Answer: D. All of the above.

41. The cardiovascular side effects of stimulants (increased HR and BP) are a direct result of their chemical structure allowing them to enhance ________ signaling.

• A. serotonergic
• B. cholinergic
• C. noradrenergic
• D. GABAergic

Answer: C. noradrenergic

42. Which of the following is NOT a primary goal of medicinal chemistry in developing new ADHD drugs?

• A. To improve the side effect profile.
• B. To simplify the dosing regimen (e.g., once daily).
• C. To decrease the abuse liability.
• D. To make the molecule as non-selective as possible.

Answer: D. To make the molecule as non-selective as possible.

43. The “pharmacology of drugs used in ADHD” is a key lecture that provides the context for the:

• A. Medicinal chemistry of drugs used in ADHD.
• B. Law and ethics of ADHD management.
• C. Cost of ADHD medications.
• D. History of ADHD diagnosis.

Answer: A. Medicinal chemistry of drugs used in ADHD.

44. The fact that all stimulants are based on a similar pharmacophore explains why:

• A. They all have the exact same potency and duration.
• B. They share a similar side effect profile.
• C. They are all available over-the-counter.
• D. They do not require a prescription.

Answer: B. They share a similar side effect profile.

45. The conversion of lisdexamfetamine to dextroamphetamine is a ________ reaction.

• A. hydrolysis
• B. oxidation
• C. reduction
• D. conjugation

Answer: A. hydrolysis

46. Understanding that alpha-2 agonists must be tapered off slowly upon discontinuation is based on the chemical property that abrupt cessation can cause:

• A. Severe sedation.
• B. Rebound hypertension.
• C. An improved response.
• D. A severe rash.

Answer: B. Rebound hypertension.

47. The “Assess” step of the PPCP involves evaluating the current therapy. A pharmacist might use their medicinal chemistry knowledge to understand why:

• A. A patient is not responding to a standard dose (e.g., potential PGx issue).
• B. A patient is having a specific side effect (e.g., off-target activity).
• C. A long-acting formulation isn’t lasting long enough.
• D. All of the above.

Answer: D. All of the above.

48. What is the fundamental difference in the chemical interaction of amphetamine versus methylphenidate with the presynaptic neuron?

• A. Methylphenidate is primarily a reuptake blocker, while amphetamine is both a reuptake blocker and a releasing agent.
• B. Amphetamine is primarily a reuptake blocker, while methylphenidate is a releasing agent.
• C. There is no difference.
• D. Methylphenidate is an enzyme inhibitor.

Answer: A. Methylphenidate is primarily a reuptake blocker, while amphetamine is both a reuptake blocker and a releasing agent.

49. The development of non-stimulant options like atomoxetine was a medicinal chemistry effort to:

• A. Create a more potent stimulant.
• B. Provide a therapeutic alternative with no abuse potential.
• C. Create a cheaper version of methylphenidate.
• D. Find a drug that only needs to be taken once a week.

Answer: B. Provide a therapeutic alternative with no abuse potential.

50. Ultimately, understanding the medicinal chemistry of ADHD drugs empowers the pharmacist to:

• A. Question every prescription written for them.
• B. Provide a higher level of patient care through a deeper understanding of how these drugs work.
• C. Compound these medications from raw chemicals.
• D. Make definitive ADHD diagnoses.

Answer: B. Provide a higher level of patient care through a deeper understanding of how these drugs work.