ADHD Drugs

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This PPT is part of a lecture given to second year pharmacy students in a pharmacology & toxicology class.

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  • Stevens-Johnson syndrome
  • DSM5 will now note: “Several noticeable inattentive or hyperactive-impulsive symptoms were present by age 12”
  • Detailed report at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5944a3.htm?s_cid=mm5944a3_wThis notes SES differences (higher rates for parents on Medicaid) but also SES (lower rates for Hispanic).
  • Differences were retained when potential confounds (group differences in body weight/medication) were included in the statistics.
  • Midsagital view of rat brain (bottom) and PET of human brain (upper right). VMAT2 is an integral membrane protein that transports monoamines—including dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles
  • tegmentum is Latin for covering. VTA is found in midbrain or mesencephalon.
  • Adrenergic receptors in heart increase rate of heart contractility. α1 also has subtypes: α1A, α1B, α1D as does α2 with α2A, 2B, 2C
  • Amphetamine was first synthesized in 1887 by the Romanian chemist LazărEdeleanu in Berlin, Germany. Benzedrine marketed by Smith Kline & French was originally a non-prescription drug used for bronchodialation for people with asthma. Some individuals used Benzedrine recreationally by cracking the container open and swallowing the paper strip inside, which was covered in Benzedrine.
  • Word recall was assessed by a word game with lists of 20 words. CPT test involved press a button if a 4 appeared but only if it was preceded by a 6. Interestingly, 12 of 14 children correctly identified the medication day.
  • Shortly after the first synthesis of amphetamine in 1887, methamphetamine was synthesized from ephedrine 1893 by Japanese chemist Nagai Nagayoshi.
  • Originally synthesized in 1944 and released in 1948.
  • General description of the study available here: http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr120101b.htm
  • Guanfacine is approved as a monotherapy and adjunct for ADHD. For Guanfacine, Intuniv is approved for ADHD but Tenex (same molecule) is approved for hypertension. NRI =Norepinephrine Reuptake Inhibitor. NET takes up both NE and some dopamine.
  • Note that the individually tailored dose in Combined was less than that in MM.
  • ADHD Drugs

    1. 1. Agents For ADHDBrian J. Piper, Ph.D., M.S. piperbj@husson.edu February 12, 2013
    2. 2. Goals• Pharmacy students should be: – familiar with ADHD-I, ADHD-HI, and ADHD-C – able to contrast the MOA, AE, and abuse potential of stimulant and non-stimulant pharmacotherapies for ADHD
    3. 3. History of ADHD • ≈1910: Minimal Brain Damage: inattentive, distractible, hyper/hypoactive • 1980: Attention Deficit Disorder: normal IQ, poor sustained attention, added to DSM III • 1994: ADD is removed from DSM IV • 2013: “Symptoms present by age” changed from 7 to 12Taylor (2011). Attention Deficit Hyperactivity Disorder, 3, 69-75.
    4. 4. ADHD: Inattentive
    5. 5. ADHD: Hyperactive/Impulsive
    6. 6. AHDH Epidemiology • Very common in children (6%) & adults (4%) • Substantial regional variability (Maine = 9.6%) • Males (4) > Females (1) • Moderate genetic component in malesVisser et al. (2010) MMWR, 59(44), 1439-1433. http://www.cdc.gov/ncbddd/adhd/prevalence.html
    7. 7. ADHD Combined: ↓Cortical Volume <- Controls <- ADHDCastellanos et al. (2002). JAMA, 288(14), 1740-1748.
    8. 8. Dopamine Transporter (DAT) Dopamine• Neuroanatomy: – Somas: substantia nigra – Axons: striatum• Functions: movement, mood, reward, cognition
    9. 9. Dopamine• Neuroanatomy: – Somas: Ventral Tegmental Area (VTA) – Axons: Nucleus Accumbens• Functions: movement, mood, reward, cognition
    10. 10. Dopamine • Neuroanatomy: – Somas: Ventral Tegmental Area (VTA) – Axons: Prefrontal Cortex (PFC) • Functions: movement, mood, reward, cognitionModified from Meyer & Quezner (2008). Psychopharmacology.
    11. 11. Norepinephrine • Neuroanatomy – somas: Locus Coeruleus – axons: Forebrain+ • Receptors: α1A,1B,1D, α2A,2B,2C, β1, β2, β3 • Function: attention, cardiacModified from Meyer & Quezner (2008). Psychopharmacology.
    12. 12. Amphetamine• History: – synthesized in 1883 – benzedrine in 1933• Indications: ADHD (age 3+ ), narcolepsy• MOA: – DAT inhibition & reversal – NET inhibition & reversal – VMAT2 inhibition – MAO inhibition (weak)
    13. 13. Amphetamine Neurobehavioral Effects ≠ Paradoxical• 14 Boys (age 6-12, IQ = 131) randomized to receive 5 mg/kg dextroamphetamine or placebo• Cognitive battery completed at 30 – 150 min post drugRapoport, J. et al. (1978). Science, 199, 563-566.
    14. 14. Methamphetamine• History: synthesized in 1893• Indications: ADHD, obesity• Metabolite: amphetamine• MOA: – DAT inhibition & reversal – NET inhibition & reversal – SERT inhibition & reversal – VMAT2 inhibition – MAO inhibition ( ? )
    15. 15. Methylphenidate • History: synthesized in 1944 • Adverse Effects: – nervousness – ↓ appetite/weight – ↑blood pressure/heart rate Leandro (& Marguerite) • MOA: Panizzon – DAT/NET inhibition – DA/NE release (moderate)http://www.cesar.umd.edu/cesar/drugs/ritalin.asp
    16. 16. Comparison (All Schedule II)• Amphetamine (Adderall):• Methamphetamine (Desoxyn):• Methylphenidate (Ritalin SR):
    17. 17. Monitoring the Future: “Amphetamines” = Adderall & Ritalin
    18. 18. Recreational Methamphetamine & 11 DAT Depletions [ C]d-methylphenidateVolkow et al. (2001). Journal of Neuroscience, 21(23), 9414-9418.
    19. 19. Stimulants & Neurotoxicity • Rats received doses, chosen to produce 2-5X plasma therapeutic levels of: – amphetamine (AMPH) – methamphetamine (METH) – methylphenidate (MPH) • Animals monitored for hyperthermia • Dopamine at 1 week: – MPH = controls – ↓ METH – ↓ AMPHLevi et al. (2012). Neurotoxicology & Teratology, 34, 253-262.
    20. 20. Diversion Proof? Lisdexamfetamine Guanfacine Atomoxetine DAT/NET,MOA D-amphetamine NRI prodrug α2A agonist ADHD (>6 yrs), ADHD, ADHDIndications hypertensionScheduled Yes, II No No Abuse potential, SuicidalWarning sudden death No thoughts/ behavior
    21. 21. Total estimated number of outpatient prescriptions for ADHD drug market drug products dispensed to the US children (ages 0–17 years) from US retail pharmacies. --------------------------------------------------------------------------------------------------- ↓ -------------------------------------------------------------------------------------------------- ↑ ↑ ↓Chai G et al. (2012). Pediatrics, 130, 23-31.
    22. 22. Treatment for ADHD (DiPiro) • “Multimodal treatment (parent training, family training, classroom interventions, contingency management) is crucial for an overall positive therapeutic outcome.” • Pharmacotherapies – 1st Line: methylphenidate or amphetamine – 2nd Line: atomoxetine or guanafacine or bupropion – 3rd Line: combine above or add tricyclic antidepressantCopheide & Pliszka (2011). In DiPiro’s Pharmacotherapy: A Pathophysiological Approach, p. 1088.
    23. 23. Treatment for Hyperkinetic Disorder (European) • 1st Line: Psychoeducation • 2nd Line: methylphenidate • 3rd Line: other stimulant • 4th Line: TCA, nicotine patchTaylor et al. (2004). Eur Child & Adolescent Psychiatry, 13(S1), DOI 10.1007/s00787-004-1002-x
    24. 24. Multimodal Treatment Study of Children With ADHD (MTA) • Children (7-10 y.o.) with ADHD-C (N=579) randomized for 14 months to: – Medication Management (MM): methylphenidate (37.7 mg/day), monthly monitoring of adverse effects (parent) – Behavioral Therapy (BT): summer camp (9 hours/day x 5 weeks) + parent training + teaching aid (60 days) – Combined (MM & BT): methylphenidate (30.5 mg/day), monthly monitoring of adverse effects (parent & teacher) – Community Care: treatment as usual in the community (67% pharmacotherapy)MTA Group (1999). Archives of Psychology, 56(12), 1073-1086.
    25. 25. Interpretation? • 1) All groups improved relative to baseline. • 2) Behavioral Treatment doesn’t work • 3) Medication Management > Other • 4) Behavioral Treatment = Community Care --------------------------------------------------------------------MTA Group (1999). Archives of Psychology, 56(12), 1073-1086.

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