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Title: Principles of Psychopharmacology in Children And Adolescents


1
Principles of Psychopharmacology in Children And
Adolescents
  • Waqar Waheed
  • University of Calgary

2
Biochemical Neuroanatomy
  • 100 billion neurons
  • 1,000 to 10,000 connections with each other
  • Neuronal networks are arranged to govern human
    behavior (Mesulam, 1998) and the brains 3 basic
    functions
  • Environmental influences of psychotherapy and
    pharmacological intervention have impact on these
    networks

3
4 Major Anatomical Systems
  • Thalamus (S, A, V) and Primary Sensory Cortices
    (S1, A1, V1)
  • Association Cortex (Primary cortex, subcortical
    structures, limbic system) ?creates an internal
    representation of sensory info.
  • Medial Temporal Lobe-memory storage/retrieval,
    attaches limbic valence to sensory info.
  • Basal Ganglia- modulate cortical activity, CSTC
    loop

4
Major Excitatory Neurotransmitter
  • Glutamic acid (glutamatergic pathways)

5
Major Inhibitory Neurotransmitter
  • GABA, via interneurons in each of the
    aforementioned areas

6
Neurons modulating these 4 neuronal systems
  • Cholinergic-Basal forebrain/brainstem
  • Dopaminergic- S. Nigra/Ventral Teg. areas
  • Noradrenergic- Locus coeruleus
  • Serotonergic- Raphe Nuclei

7
Neurotransmission at the synapse
  • Receptor Types
  • 1. Presynaptic vs. Postsynaptic
  • 2. Ionotropic- fast, ion-gated-Class I
  • vs. Metabotropic- slow G-protein
    coupled- Class II
  • 3. Autoreceptors vs. heteroreceptors
  • Influenced further by
  • 1. Reuptake (not for neuropeptides)
  • 2. Degradation

8
Major Excitatory Neurotransmitter
  • Glutamic acid (Glutamate, Glu)
  • Glutamatergic neurons
  • Projection fibers (C-C, C-T, C-S, T-C, C-spinal)
  • Hippocampus (generation of memory, LTP)
  • Cerebellum

9
Glutamate Receptors
  • Ionotropic (increased intracellular Na, Ca2)
  • NMDA
  • Agonist activity requires binding of glycine or
    glycine analogue to the receptors glycine site
  • Blocked by PCP/ketamine at the receptors PCP
    site
  • AMPA
  • Kainate
  • Metabotropic
  • mGluR1-7

10
Impact of Glutamate activity
  • Excess stimulation of these neurons occurs in
    seizures/stroke resulting in neuronal death
  • NMDAR PCP site blockade ---gt psychosis
  • Hippocampus- NMDAR crucial for LTP
  • Substances binding at the NMDAR glycine site,
    (glycine, d-cycloserine) are associated with
    reduction in psychosis/negative symptoms in
    schizophrenia

11
? Intoxication
  • Within an hour (less when smoked ,snorted,or
    used intravenously) ,two (or more) of the
    following signs
  • (1) vertical or horizontal nystagmus
  • (2) hypertension/tachycardia
  • (3) numbness or diminished responsiveness to
    pain
  • (4) ataxia (5) dysarthria (6) muscle rigidity (7)
    seizures or coma (8) hyperacusis

12
Major Inhibitory neurotransmitter
  • GABA comes from
  • Glu by the action of enzyme
  • GAD

13
GABA Receptors
  • GABAA-(ionotropic) BZD vs. Barbiturates/Ethanol
  • Progabide binds between gamma and beta subunits ?
    increased intracellular Cl-
  • BZD bind to the alpha subunit and open the ion
    channel if a gamma subunit is present and GABA is
    bound to the beta subunit
  • Barbiturates/Ethanol bind near the ion channel
    and are not dependent on the presence of GABA
  • GABAB-(metabotropic) pre and post synaptic
  • Agonist - Baclofen

14
Acetylcholine
  • ACh is crucial for memory and cognitive function
  • Choline Acetyl CoAcholine acetyltransferase?
    Ach
  • ACh ---AChE(acetyl cholinesterase)--gt Choline
    acetate
  • Muscarinic receptors metabotropic
  • Nicotinic receptors - ionotropic

15
Cholinergic Neurons
  • Neurons in the basal forebrain (nucleus of
    Meynert/septal nuclei) project to frontal,
    parietal, and occipital cortex (modulate
    attention/novelty-seeking), as well as to the
    hippocampus/cingulate gyrus (modulate memory),
    providing virtually all of the acetylcholine
    (ACh) for the brain.
  • Dorsal midbrain neurons project to thalamus
    (regulation of sleep-wake sycles)

16
  • Short range interneurons in striatum (modulate
    GABA-ergic neurons by opposing the effect of
    dopaminergic neurons)

17
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18
Serotonergic Neurotransmission
  • Comes from tryptophan by the action of TPH
  • 2 of the bodys serotonin is in the brain/spinal
    cord
  • Project from the mid-brain raphe nuclei to the C,
    S, T, Cerebellum, Amygdala and Hippocampus

19
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20
Serotonin Receptors
  • 5-HT1 -metabotropic
  • Buspar (5 HT1A partial agonist), triptans (5 HT1D
    agonists)
  • 5-HT2 -metabotropic
  • LSD/psilocybin (5 HT2A partial agonists, in
    cortical neurons)
  • Atypicals (5 HT2 antagonists)
  • 5-HT3 - ionotropic

21
Dopamine Neurotransmission
  • 3 wide ranging projections
  • Nigrostriatal (SN to Caudate and Putamen)
    modulates the neuronal excitability of GABAergic
    neurons
  • Mesolimbic (VTA to Amygdala/Nucleus
    accumbens)-appetite/reward behavior
  • Mesocortical (VTA to frontal, cingulate and
    entorhinal cortices) fine tuning of cortical
    neurons, increasing the s-n ratio
  • 1 intermediate-length projection (HT-P)
  • 2 ultra-short systems (retina, olfactory bulb)

22
Dopaminergic Receptors
  • D1 family includes D1 and D5 receptors
  • D2 family includes D2,3,4 receptors
  • D1 - SN, striatum, olfactory tubercle, cortex
  • D2 - SN, striatum, olfactory tubercle, retina,
    pituitary (autoreceptors are D2)
  • D3 - Nucleus Accumbens
  • D4 on GABAergic neurons in SN, thalamus,
    hippocampus and cortex
  • D5 Hippocampus, cortex and hypothalamus

23
  • All are metabotropic receptors
  • DAT- blocked by cocaine/amphetamines/bupropion
  • COMT in synapse
  • MAO-B intraneuronally
  • Dopamine comes from tyrosine by the action of TH

24
Noradrenergic Neurotransmission
  • Neurons are in the locus coeruleus (LC) and in
    the tegmentum (nearly 50 in each location)
  • Functions
  • Arousal/vigilance
  • Selective attention/response to novel stimuli
  • Sleep cycles/appetite/mood/cognition
  • LC neurons project to the cortex, thalamus,
    hippocampus, cerebellum and spinal cord
  • Tegmental neurons project to the basal forebrain,
    hypothalamus and spinal cord

25
Noradrenergic Neurotransmission
  • Alpha1 receptors primarily post-synaptic
  • Alpha2 receptors primarily pre-synaptic
  • Agonists clonidine, guanfacine
  • Beta1 receptors are the primary beta receptor in
    the CNS
  • Antagpnists- propranolol
  • All receptors (alpha and beta are metabotropic)

26
Noradrenergic Neurotransmission
  • NE comes from dopamine by the action of DBH
    (release enhanced by stimulants)
  • Metabolized intra-synaptically by COMT
  • Metabolized intra-neuronally by MAO
  • Uptake by the presynaptic neuron by NET (blocked
    by desipramine, nortriptyline, venlafaxine,
    atomoxetine)

27
Pharmacokinetics
  • What the body does to the drug
  • Absorption
  • Distribution
  • Metabolism
  • Elimination

28
Factors Affecting Drug Movement/Availability
  • Molecular size/shape
  • Degree of ionization
  • Lipid solubility in ionized v non-ionized states
  • Binding to proteins
  • transmembrane movement is usually limited to
    unbound drug)
  • Paracelluar movement is usually possible except
    for areas with tight junction capillaries (B-B
    barrier)

29
Cmax
  • The peak plasma concentration achieved after the
    administration of a given dose of med (the
    crest level)

30
Tmax
  • The time it takes to reach Cmax after the med is
    administered

31
t1/2
  • The half-life of a med is the time it takes for
    the plasma concentration to be half of Cmax

32
Clearance
  • Rate at which the med is removed from the plasma

33
Steady state concentration
  • Dependent on the meds
  • Cmax
  • Tmax
  • t1/2 (independent of dose)
  • Clearance
  • Exact dosage (the higher the dosage, the greater
    the Cmax)
  • Frequency of dosing
  • Typically achieved after 4-5 half-lives

34
  • If a med is dosed at intervals greater then the
    t1/2, then the med continues to hit peaks and
    troughs never reaching a SSC or plateau.
  • Lack of SSC is not problematic for stimulant med
    dosing but is problematic for fluoxetine,
    lithium, etc.

35
MEC
  • Minimal Effective Concentration
  • The minimal plasma concentration of a med which
    needs to be maintained to have some
    pharmacodynamic effect

36
Orally administered med
  • Absorption (passive or by active transport
    proteins)
  • A poorly absorbed durg will have lower Cmax and
    longer Tmax
  • Protein binding in circulation (no
    pharmacodynamic effect in this state)

37
IV Med
  • No first pass effect (no metabolism by liver
    before med gets in to the heart and onwards into
    the systemci circulation)

38
Compared with adults
  • Children have smaller body size
  • Children have more liver parenchyma, relative to
    body size
  • Children have relatively more body water and less
    adipose tissue
  • Children have more renal parenchyma relative to
    body size

39
Smaller body size
  • Smaller volume of distribution which leads to a
    higher peak plasma concentration
  • After a 20 mg dose of fluoxetine is administered
    to children, a twofold peak plasma concentration
    occurs as compared to adults (Wilens et al 2002)

40
More liver parenchyma
  • Greater first pass hepatic drug extraction
  • Reduced Bioavailability
  • Faster drug metabolism
  • Shorter half-life
  • Bupropion SR half-life in juveniles is
    approximately 12 hours as compared to 21 hours in
    adults (Daviss et al 2005) necessitating split
    dosing throughout the day

41
Relatively more body water and less adipose tissue
  • Less accumulation
  • Faster elimination

42
More renal parenchyma
  • Greater clearance capacity
  • Faster elimination
  • Shorter half-life
  • Lithium in children (Vitiello et al 1998)

43
Metabolism
  • Phase I oxidation/reduction/hydrolysis- to
    increase polarity CYP-450 enzymes
  • Phase II conjugation, UGT enzymes
  • Cytochrome P450 Enzymes
  • Families (1-4)
  • Subfamilies (A-E)
  • Specific enzyme coded by a specific gene (1 and
    up)

44
CYP 3A
  • Chromosome 7
  • Metabolizes 40-50 of all drugs

45
CYP 3A4
  • 6-12 months- 50 of adult levels
  • Puberty- 100 (exceeds adult levels in
    childhood)
  • Substrates
  • Sertraline/citalopram/fluoxetine
  • Zolpidem/trazodone/alprazolam/midazolam
  • Risperidone/seroquel/aripiprazole/haldol
  • Inhibitors (grapefruit juice, star fruit,
    fluvoxamine)
  • Inducers (CBZ, phenytoin, St. Johns wort)

46
CYP 2D6
  • Chromosome 22 (other members of the CYP 2 family
    are coded by genes on other chromosomes)
  • 1st month of life- 20 of adult activity
  • 10 years of age- 100
  • Substrates
  • Amphetamines/atomoxetine
  • Fluoxetine/fluvoxamine/paroxetine
  • Mirtazipine/venlafaxine/TCAs
  • Haldol/risperidone/aripiprazole

47
CYP 2D6
  • Inhibitors
  • Bupropion/clomipramine/desipramine
  • SSRIs
  • Haldol/thioridazine/perphenazine
  • Inducers
  • None

48
CYP 2D6 Polymorphisms
  • Poor metabolizers
  • White/African 10
  • Asian- 1
  • Ultrarapid metabolizers
  • Ethiopian- 30
  • White- 4

49
UGT based DD interactions
  • Uridine diphosphate glucoronyl transferases are
    the microsomal enzymes responsible for Phase-II
    glucuronidation
  • VPA inhibits and ethinyl estradiol induces UGT2B7
    for which lamotrigine is a substrate

50
Efflux Transporters (p-glycoproteins, p-gps)
  • Substrates
  • Nortriptyline
  • Risperidone
  • Sertraline
  • Topiramate
  • Inhibitors (fluoxetine, grapefruit juice,
    haloperidol, risperidone, olanzapine)
  • Inducers (phenytoin, St, Johns wort)

51
Other drugdrug Interactions
  • Pharmacodynamic Interactions (which occur at
    active sites)
  • Citalopram tramodol (serotonergic analgesic) ?
    Serotonin Syndrome
  • Vs, the following non-CYP 450 pharmacokinetic
    interaction
  • Lithium ibuprofen (deceased renal Li clearance)
    ? Lithium toxicity

52
Indications for Therapeutic Drug Monitoring
  • Inadequate response
  • Higher than normal dose requirement
  • Serious/persistent adverse effects
  • Toxicity
  • Suspected non-compliance
  • Suspected drug-drug interactions
  • Changing brands
  • Other illnesses

53
MEDICATION MANAGEMENT OF ADHD
54
Medications for ADHD
55
Stimulants Dosing/MOA
  • Precise mechanisms have not been confirmed
  • MPH? prevents DA and NE re-uptake
  • Up to daily max of 2 mg/kg,
  • Amphetamine based? promote pre-synaptic vesicle
    release of DA and NE
  • Up to daily max of 1 mg/kg

56
Response to stimulants
  • 75 respond to the first stimulant
  • Up to 90 respond if 2 stimulants are used
    consecutively

57
Non-stimulants Dosing/MOA
  • Strattera- increases NE
  • 0.5 mg/kg/day x 3d then 1.2 mg/kg/day (qd or bid
  • Bupropion- Increases NE and DA
  • XR form, 150 mg qam (children) for adolescents,
    increase to 300 mg qam after 3-4 weeks if partial
    benefit
  • Venlafaxine - Increases Serotonin (at low doses)
    and NE (at high doses) (37.5 mg- 300 mg qd, XR
    form)
  • Clonidine- Central pre-synaptic alpha adrenergic
    receptor agonist (0.025 0.3 mg/d, usually tid)

58
Common Side effects of Stimulants
  • Loss of appetite/Weight loss
  • Insomnia (less if taken early)
  • Increased heart rate/blood pressure
  • Affective flattening
  • Nausea/vomiting/diarrhea (less if with food)

59
Less Common Side Effects
  • Triggering psychosis
  • Making tics worse
  • Increased risk of seizures
  • Suppression of growth

60
Comparison of Stimulants
  • Short acting forms usually last 3-4 hours
  • Associated with rebound effects
  • Lower cost
  • Greater abuse potential
  • Multiple dosing through the day

61
  • Long acting forms usually last 8-10 Hours
  • Usually are better tolerated
  • Greater cost
  • Relatively lesser abuse potential
  • Ease of administration- No school doses required

62
Abuse Potential
  • Stimulants- High
  • Short acting forms gt long-acting forms
  • 29 of students taking prescribed stimulants in
    one study reported they gave away, were forced to
    give away, sold, or were robbed of their
    medication. (Poulin, 2001)
  • Street Value of Dexedrine 5 for a 5 mg tab
  • Non-Stimulants- Low

63
Side Effects of Non-Stimulants
64
MEDICATION MANAGEMENT OFANXIETY DISORDERS
65
GAD, SAD, Sep Anxiety Disorder
  • Fluvoxamine gt fluoxetinesertralineparoxetineven
    lafaxine (Birmaher 2003, RUPP 2001, Walkup et al
    2008, Rynn et al 2007)

66
Selective Mutism
  • Fluoxetine has shown benefit (Black and Uhde
    1994)

67
Panic Disorder
  • Paroxetine (Masi et al 2001) and citalopram
    (Lepola et al 1998) have shown benefit

68
Specific Phobias
  • Traditionally treated with targeted CBT

69
OCD
  • Meta-analysis (Geller et al 2003) indicates
    Clomipramine gt all SSRIs (mostly)

70
PTSD
  • RCTs (Cohen et al 2007 n24, Robb et al 2008
    n131) did not show superiority of sertraline
    over PBO, CBT Steiner et al 2007 showed
    superiority of high dose VPA (500-1500 mg) over
    low dose VPA (250 mg)
  • Open label studies (n of 6-28) of clonidine,
    propranolol, CBZ, citalopram, risperidone,
    quetiapine and clozapine demonstrated benefit in
    symptom reduction.

71
School refusal
  • Imipramine (Gittelman-Klein and Klein 1971)

72
MEDICATION MANAGEMENT OF PDD
73
PsychoPharmacology PDD
  • Risperidone , approved by the FDA for treatment
    of irritability and other behavioral symptoms in
    children with ASD.
  • The serotonin system has been implicated, but a
    mechanism has not been defined
  • SSRIs shown to reduce repetitive behaviors
    (adults/adolescents/children)
  • TCAs, Alpha adrenergic agents have been shown to
    be helpful in HA, Inattention in pts.

74
  • Glutamate system
  • Amantadine (NMDA blocker) shown to reduce HA,
    inappropriate speech in children (DBPC)
  • D-cycloserine-(Partial NMDA agonist) shown to
    improve social responsiveness in children (SBPC)
  • Lamotrigine-(glutamate release blocker), no
    effect
  • Riluzole- (Glutamate antagonist) being studied,
    based on benefit in childhood onset OCD

75
PsychoPharmacology PDD
  • GABA-ergic system
  • BZDs known to cause disinhibition
  • GABA receptor blocker flumazenil has shown (Wray
    2000) benefit..
  • We undertook a randomized, double-blind, placebo
    controlled pilot study of the behavioral effect
    of the benzodiazepine antagonist, flumazenil in
    two children with autism. In one participant,
    there was a mild increase in Interpersonal
    engagement between 2040 minutes

76
OTHER FOCI OF MEDICATION TREATMENT
77
Emergency management of aggression
  • Lorazepam 0.5 mg 1 mg up to every hour, 4mg/24h
    max (children), 6 mg/24h max (adolescents)- main
    risk to monitor respiratory suppression
  • Haloperidol 1-5 mg q 1-2 hours (12-20 mg max/24h)
  • main risk- acute dystonia, managed with Cogentin
    0.5 mg PO/IM

78
Emergency management of aggression
  • Risperidone M-tab
  • lt20 kg 0.25 mg x 1, repeat after1h
  • 20 kg - 0.5 mg x 1, repeat after 1h
  • Olanzapine (Zydis)
  • 2.5 mg per hour up to max 10 mg per day
  • Olanzapine (IM)
  • 3 doses max per day of 2.5 5 mg, spaced at
    leats 2 h apart main risk hypotension
  • Avoid IM lorazepam IM olanzapine (at least 1h
    apart)

79
Insomnia
  • Antihistamines (diphenhydramine 25-50 mg qhs, PK
    interaction with fluoxetine)
  • Melatonin 3 mg (children) 6 mg (adolescents)- 1
    hour before bedtime
  • If delayed sleep phase is the concern, 0.5 mg 6-7
    hours before bedtime is recommended instead
  • NBzRAs Zaleplon/Zolpidem/Zopiclone
  • Rebound insomnia if used intermittently

80
Insomnia
  • Alpha 2 agonists- Clonidine- 2-3 hours before
    bedtime (0.025 - 0.1 mg), usually recommended
    daily, risk of rebound htn
  • avoid in DM, Raynauds
  • Other medications
  • Atypical antipsychotics/ Chloral hydrate prn
  • SSRIs/TCAs continuous daily administration

81
Enuresis
  • Desmopressin- Tablets only (nasal spray has a
    black box warning, risk of hyponatremia/seizures/d
    eath)
  • 0.2 mg po at bedtime (mandatory fluid
    restriction)
  • increase by 0.2 mg increments every 4 days up to
    a max of 0.6 mg in children, 0.8 mg in
    adolescents
  • stop after 1 week of max dose if no benefit
  • Imipramine- 0.5 mg/kg po qhs
  • Increase by 0.5-1 mg/kg/day up top a max of 2.5
    mg/kg/day
  • Stop after 2 weeks of max dose if no benefit

82
Drug induced Syndromes
  • Serotonin, Neuroleptic malignant and
    anticholinergic syndromes have a number of common
    features
  • Hypertension
  • Tachycardia
  • Tachypnea

83
Onset/Mental status
84
Temperature/Pupils
85
Skin/Muscle Tone
86
Reflexes
87
FDA Risk Categories
88
  • Most are Pregnancy Category C
  • Except bupropion, clozapine, buspirone (B)
  • Except paroxetine, classic mood stabilizers (D)
  • Beenzodiazepines (D or X)
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