Sweatman - ADHD Drugs

Question 1

What causes ADHD?

Answer 1

• Thought to arise from a DELAY IN MATURATION of the brain, esp. the outer layer of the CORTEX, compared to chronological age
• Matures in a normal pattern, but is delayed, on average, by about 3 years -> most pronounced in areas involving thinking, paying attention, and planning
• Delayed maturation of the cortex overall, and abnormal growth pattern of the corpus callosum

Question 2

What drugs are used to treat ADHD?

Answer 2

• Amphetamine
• Dextroamphetamine
• Atomoxetine
• Clonidine
• Dexmethylphenidate
• Methylphenidate
• Guanfacine
• Haloperidol

Question 3

How effective are stimulants for treating ADHD?

Answer 3

• While they don’t “cure” ADHD, stimulants have proven effective in controlling some of the symptoms:
  
  1. 65% of kids show improvement in core symptoms
  2. 95% respond after trying out different drugs
• Tx failure is often a result of inappropriate drug mgmt, rather than inactivity of the drug -> drug therapy requires trial and error to adjust medication levels to the individual pt

Question 4

How long are stimulant 1/2-lives?

Answer 4

• 1/2-lives are short, necessitating frequent dosing or sustained release preparations
• Cleared rapidly from the body

Question 5

Is there a correlation between serum drug levels and adequacy of response to stimulants?

Answer 5

NO

Question 6

What are the 4 phases of ADHD mgmt?

Answer 6

1. Counseling
2. Titration
3. Maintenance
4. Potential termination

Question 7

What are the key features of the counseling phase of ADHD tx?

Answer 7

• Explaining rationale for medication and outlining (+) and (-) outcomes
• Alerting parents to which behaviors to monitor, what side effects to “look out” for, and how to deal with them
• Advising that both dose and timing will change as tx progresses; w/adequate activity, a move is made from short-acting to sustained release preps

Question 8

What stimulants are most commonly used in ADHD tx? Which one is the “best?”

Answer 8

• Methylphenidate, Dexmethylphenidate, Dextroamphetamine, and mixed amphetamine salts
• LITTLE OVERALL DIFFERENCE BETWEEN AGENTS IN INITIAL RESPONSE -> trial and error to find drug and dose that works (AE’s may differ)

Question 9

What are the 6 major side effects of stimulant tx for ADHD?

Answer 9

1. Appetite suppression
2. Delayed sleep onset
3. “Wearing off” phenomenon
4. Tics
5. Depression
6. Social withdrawal
   - NOTE: some of these can be reduced by dose and timing adjustments; others may require adjunctive drug therapy (i.e., with an alpha-2 agonist like Clonidine)

Question 10

How can appetite suppression be managed as an ADHD AE?

Answer 10

• Will DEC with time
• Try to time meals when med effect is minimal or worn off
• Make breakfast a major meal, prior to dosing
• Make favorite foods for lunch
• Offer substantial meal at bedtime

Question 11

How can delayed sleep onset be managed as an ADHD AE?

Answer 11

• Determine if problem pre-existed, in which case an afternoon does may help
• If real, consider DEC afternoon dosing
• Usual sleep hygiene maintenance: same bedtime routine, bed just for sleep, etc.
• Rarely consider a second agent, like Clonidine (alpha-2 antagonist) or Trazodone (SARI)

Question 12

How can the “wearing off” phenomenon be managed as an ADHD AE?

Answer 12

• Check dosing
• Consider 4pm dosing of short-acting agent
• Switch to longer-acting agents

Question 13

How can tics be managed as an ADHD AE?

Answer 13

• Check child for emergence of Tourette syndrome
• Simple tics are common (unrelated to drug)
• If troublesome or intractable, stop stimulant and consider adding or substituting with another agent (like centrally acting alpha-agonist) with consult

Question 14

How can depression be managed as an ADHD AE?

Answer 14

• Check timing of symptoms; if they concur with dosing, consider a different agent
• Make sure that attention problems were not really a mood problem, and consider consult

Question 15

How can social withdrawal be managed as an ADHD AE?

Answer 15

• Uncommon effect of zombie-like behavior due to excessive dosing
• Check timing of symptoms and dosing; DEC dose or INC intervals

Question 16

Describe the maintenance phase of ADHD tx.

Answer 16

• Frequency of physician visits will decline once appropriate dose regimen (titration) is achieved
• Schedule II drugs, so physician visit essential for prescription refills
• Monitor medication effects and progress

Question 17

Describe the termination phase of ADHD tx.

Answer 17

• A decision to terminate therapy is based on a clinical trial off of the medication, and close monitoring for return of target symptoms -> tapered and withdrawn

Question 18

What is the CNS MOA of the amphetamines?

Answer 18

• Releases DA and NE

Question 19

What is the CNS MOA of Atomoxetine?

Answer 19

• Selective NE reuptake INH centrally and peripherally (SNRI)

Question 20

What is the CNS MOA of Dexmethylphenidate and Methylphenidate?

Answer 20

• Block reuptake of DA and NE

Question 21

What is the CNS MOA of Clonidine and Guanfacine?

Answer 21

• Animal studies show improved prefrontal cortical function through post-synaptic alpha-2-receptor agonist effects in the prefrontal cortex (PFC)

Question 22

What is the CNS MOA of Haloperidol?

Answer 22

• Blocks post-synaptic D2 receptors

Question 23

How do the ADHD drugs work (generally speaking)?

Answer 23

• By initiating catecholamine release from pre-synaptic NN terminals, or by blocking reuptake process that leads to termination of their synaptic activity

Question 24

How does duration of action affect tx for ADHD?

Answer 24

• SHORT-acting amphetamines: often used as INITIAL TX in small children (

Question 25

What are the principal drug interactions for the amphetamines?

Answer 25

• ACETAZOLAMIDE, Na-bicarbonate: alkaline urine favors reuptake of drug in renal tubules, INC serum drug levels
• AMMONIUM CHLORIDE: acidic urine favors renal elim, DEC serum drug levels
• CHLORPROMAZINE, Haloperidol: dopamine receptor blockers diminish effects of amphetamines
• DEXTROMETHORPHAN: INC impaired judgment, erratic euphoria, hallucinations (potentiation of effect)
• DIGOXIN: INC pro-arrhythmogenic effect (potentiation of effect)
• MAOI’s: INC serum drug levels and toxicity
• CYP2D6 inducers/INH (like Fluoxetine): serum drug levels INC or DEC

Question 26

What are the more and less common amphetamine AE’s?

Answer 26

• MORE: abdominal pain, HA, insomnia, loss of appetite, INC BP
• LESS: anxiety, emotional lability, nervousness, tachycardia, weight loss, HTN
• NOTE: tx with all stimulants associated with mild INC in BP and pulse; generally, this slight INC is NOT clinically significant

Question 27

How do you treat ADHD if stimulants don’t work?

Answer 27

• While stimulants control symptoms well in most pts with ADHD 10-30% of pts do not respond adequately to stimulant tx, or have intolerable side effects
• Non-stimulant meds are next best tx option for these pts
• ATOMOXETINE and, at times, BUPROPION and TCA’s: esp. useful with co-morbid substance use and mood disorders
• Non-stimulant meds are generally less effective in treating ADHD than stimulants

Question 28

What are the potential drug interactions with Atomoxetine and Methylphenidate?

Answer 28

• ALBUTEROL (A): accentuates CV AE’s (beta-2 agonist)
• EPINEPHRINE (A): further INC in BP
• MAOI’s (A + M): INC toxicity; allow 2-week interval between drugs
• ALCOHOL (M): INC production of toxic metabolite -> functional inability to concentrate (drive)
• PHENYTOIN (M): INC blood levels of Phenytoin in some pts
• ERGOTAMINE (anti-migraine with 5-HT, DA, and NE effects)/Pseudoephedrine: exacerbates pressor agent effect on BP
• CYP2D6 ind/INH (i.e., Fluoxetine): both serum drug levels INC or DEC

Question 29

What are the AE’s for Atomoxetine and Methylphenidate?

Answer 29

• ATOMOXETINE: dry mouth, HA, abdominal pain, DEC appetite, cough, somnolence, vomiting, insomnia
• METHYLPHENIDATE: HA, insomnia, DEC appetite (patch), N/V, abdominal pain
• NOTE: similar to those experienced with the amphetamines

Question 30

What are the contraindications to stimulant use?

Answer 30

• ABSOLUTE: MAOI’s, psychosis, glaucoma*, existing liver disorders, hx of stimulant drug dependence
  
  1. Underlying cardiac conditions: family hx of early arrhythmic death, personal hx of structural abnormalities, palpitations, chest pain, SOB or syncope of unclear origin either before or during tx with stimulants (mild INC in pulse and BP)
• *Can induce transient mydriasis; in pts w/narrow angles, pupillary dilation can provoke attack of angle-closure glaucoma (should be avoided in pts with other forms of glaucoma too, if possible, bc mydriasis may occasionally INC intraocular pressure)

Question 31

What is the most common comorbid condition encountered in people with tics and Tourette syndrome?

Answer 31

ADHD

Question 32

What are the 3 best tx options for comorbid tics/Tourette syndrome and ADHD?

Answer 32

1. Alpha-2 agonists (Clonidine, Guanfacine) to significantly improve tics and ADHD
2. Stimulants have rapid activity against ADHD, but no activity against tics
3. Methylphenidate + alpha-2 agonist combo

Question 33

What drugs have the best outcomes for treating tics? What if the pt has ADHD?

Answer 33

• Antipsychotic agents have greatest effect in DEC tics in RCT’s, but tx decisions must be based on risks + benefits
• Antipsychotics have considerably worse side effect profile compared to alpha-2-agonist meds and behavioral therapy
• Alpha-2-agonists show similar or better benefit in DEC tics among subject with comorbid ADHD, but minimal benefits in those w/o ADHD

Question 34

What drugs used to tx ADHD can cause Tourette? Monitoring?

Answer 34

• Tics thought to result from excess dopamine levels causing dysfunction in cortical, subcortical, and thalamic areas of the brain, and in basal ganglia, and frontal cortical areas
• Drugs INC dopamine may cause their emergence
• Amphetamines, Dexmethylphenidate/methylphenidate
• Physicians should check child for emergence of TS; simple tics common and not necessarily associated w/stimulants
• If intractable, STOP STIMULANT and consider adding or substituting another agent (like centrally acting alpha-agonist), with consultation

Question 35

What is the potential for drug interactions with the alpha-2-agonists and Haloperidol?

Answer 35

• CLONIDINE/GUANFACINE: both C (2D6) and G (3A4) undergo hepatic metabolism, and list extensive drug-drug interactions, but greater for C (17 major) than G (1 major)
• HALOPERIDOL: metabolized by glucuronidation and CYP2D6 and 3A4; INH of 1 or more of these pathways may lead to INC H concentrations and potential for INC in QT prolongations (172 major drug interactions)
• NOTE: these interactions are primarily due to involvement of CYP system in the activation of these drugs

Question 36

What are the AE’s for the alpha-2-agonists?

Answer 36

• Skin reactions (patch)
• Dry mouth
• Somnolence
• HA
• Fatigue
• Drowsiness
• Dizziness
• Anxiety
• Abdominal pain

Question 37

What does amphetamine/Methylphenidate OD look like? Mgmt?

Answer 37

• Toxicity primarily prominent neuro and CV effects, but secondary complications can involve renal, muscle, pulmonary, and GI effects:
  
  1. Mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, mvmt disorders, seizures
• MGMT: supportive, with judicious use of BNZ’s
• NOTE: fatal intoxication with ADHD meds is very rare

Question 38

What does Atomoxetine OD look like? Mgmt?

Answer 38

• Toxicity is generally mild: drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia, HTN, seizure
• MGMT: largely supportive, with focus on sedation, and control of dyskinesias and seizures

Question 39

What does Clonidine OD look like? Mgmt?

Answer 39

• May produce paradoxical short-term HTN, but usually hypotension
• MGMT: Nitroprusside (NO release and vasodilation) for HTN
  
  1. Atropine (muscarinic antagonist), dopamine (pressors: induce vasoconstriction, elevating BP) for support of hypotension

Question 40

What does Guanfacine OD look like? Mgmt?

Answer 40

• Mixed picture, depending on central and peripheral effects
• Initial presentation may be drowsiness, lethargy, dry mouth, and diaphoresis
• CV effects may present as hypotension or HTN
• MGMT: largely supportive, with focus on support of BP