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ADHD Drugs

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

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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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