principles of psychopharmacology in children and adolescents waqar waheed university of calgary
TRANSCRIPT
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Principles of Psychopharmacology in Children And Adolescents
Waqar WaheedUniversity of Calgary
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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 brain’s 3 basic functions
• Environmental influences of psychotherapy and pharmacological intervention have impact on these networks
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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
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Major Excitatory Neurotransmitter
• Glutamic acid (glutamatergic pathways)
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Major Inhibitory Neurotransmitter
• GABA, via interneurons in each of the aforementioned areas
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Neurons modulating these 4 neuronal systems
• Cholinergic-Basal forebrain/brainstem• Dopaminergic- S. Nigra/Ventral Teg. areas• Noradrenergic- Locus coeruleus• Serotonergic- Raphe Nuclei
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Neurotransmission at the synapse
• Receptor Types1. 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
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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
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Glutamate Receptors
• Ionotropic (increased intracellular Na+, Ca2+)– NMDA
• Agonist activity requires binding of glycine or glycine analogue to the receptor’s glycine site
• Blocked by PCP/ketamine at the receptor’s PCP site
– AMPA– Kainate
• Metabotropic– mGluR1-7
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Impact of Glutamate activity
• Excess stimulation of these neurons occurs in seizures/stroke resulting in neuronal death
• NMDAR PCP site blockade ---> 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
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? 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
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Major Inhibitory neurotransmitter• GABA comes from
– Glu by the action of enzyme – GAD
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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
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Acetylcholine
• ACh is crucial for memory and cognitive function
• Choline + Acetyl CoA—choline acetyltransferase Ach• ACh ---AChE(acetyl cholinesterase)--> Choline + acetate • Muscarinic receptors – metabotropic• Nicotinic receptors - ionotropic
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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)
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• Short range interneurons in striatum (modulate GABA-ergic neurons by opposing the effect of dopaminergic neurons)
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Serotonergic Neurotransmission
• Comes from tryptophan by the action of TPH• 2% of the body’s serotonin is in the
brain/spinal cord• Project from the mid-brain raphe nuclei to the
C, S, T, Cerebellum, Amygdala and Hippocampus
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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
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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)
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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
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• 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
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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
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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)
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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)
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Pharmacokinetics
• “What the body does to the drug”
– Absorption– Distribution– Metabolism– Elimination
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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)
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Cmax
• The peak plasma concentration achieved after the administration of a given dose of med (the “crest” level)
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Tmax
• The time it takes to reach Cmax after the med is administered
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t1/2
• The half-life of a med is the time it takes for the plasma concentration to be half of Cmax
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Clearance
• Rate at which the med is removed from the plasma
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Steady state concentration
• Dependent on the med’s– 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
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• 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.
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MEC
• Minimal Effective Concentration• The minimal plasma concentration of a med
which needs to be maintained to have some pharmacodynamic effect
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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)
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IV Med
• No “first pass” effect (no metabolism by liver before med gets in to the heart and onwards into the systemci circulation)
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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
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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)
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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
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Relatively more body water and less adipose tissue
• Less accumulation • Faster elimination
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More renal parenchyma
• Greater clearance capacity• Faster elimination• Shorter half-life
– Lithium in children (Vitiello et al 1998)
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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)
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CYP 3A
• Chromosome 7 • Metabolizes 40-50% of all drugs
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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. John’s wort)
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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/TCA’s– Haldol/risperidone/aripiprazole
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CYP 2D6
• Inhibitors– Bupropion/clomipramine/desipramine – SSRI’s– Haldol/thioridazine/perphenazine
• Inducers– None
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CYP 2D6 Polymorphisms
• Poor metabolizers– White/African – 10%– Asian- 1%
• Ultrarapid metabolizers– Ethiopian- 30%– White- 4%
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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
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Efflux Transporters (p-glycoproteins, p-gps)
• Substrates– Nortriptyline– Risperidone– Sertraline– Topiramate
• Inhibitors (fluoxetine, grapefruit juice, haloperidol, risperidone, olanzapine)
• Inducers (phenytoin, St, John’s wort)
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Other drug–drug 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
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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
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MEDICATION MANAGEMENT OF ADHD
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Medications for ADHD
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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
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Response to stimulants
• 75% respond to the first stimulant• Up to 90% respond if 2 stimulants are used
consecutively
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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)
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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)
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Less Common Side Effects
•Triggering psychosis•Making tics worse•Increased risk of seizures
•Suppression of growth
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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
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• 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
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Abuse Potential
• Stimulants- ++ High –Short acting forms > 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
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Side Effects of Non-Stimulants
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MEDICATION MANAGEMENT OFANXIETY DISORDERS
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GAD, SAD, Sep Anxiety Disorder• Fluvoxamine >
fluoxetine=sertraline=paroxetine=venlafaxine (Birmaher 2003, RUPP 2001, Walkup et al 2008, Rynn et al 2007)
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Selective Mutism
• Fluoxetine has shown benefit (Black and Uhde 1994)
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Panic Disorder
Paroxetine (Masi et al 2001) and citalopram (Lepola et al 1998) have shown benefit
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Specific Phobias
• Traditionally treated with targeted CBT
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OCD
• Meta-analysis (Geller et al 2003) indicates Clomipramine > all SSRIs (mostly=)
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PTSD
• RCTs (Cohen et al 2007 n=24, Robb et al 2008 n=131) 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.
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School refusal
• Imipramine (Gittelman-Klein and Klein 1971)
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MEDICATION MANAGEMENT OF PDD
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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– SSRI’s shown to reduce repetitive behaviors
(adults/adolescents/children)
• TCA’s, Alpha adrenergic agents have been shown to be helpful in HA, Inattention in pts.
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• 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
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PsychoPharmacology PDD• GABA-ergic system
– BZD’s 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 20–40 minutes “
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OTHER FOCI OF MEDICATION TREATMENT
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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
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Emergency management of aggression
• Risperidone M-tab– <20 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)
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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
• NBzRA’s – Zaleplon/Zolpidem/Zopiclone– Rebound insomnia if used intermittently
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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, Raynaud’s
• Other medications– Atypical antipsychotics/ Chloral hydrate – prn– SSRIs/TCAs – continuous daily administration
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Enuresis• Desmopressin- Tablets only (nasal spray has a black
box warning, risk of hyponatremia/seizures/death) – 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
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Drug induced Syndromes
• Serotonin, Neuroleptic malignant and anticholinergic syndromes have a number of common features–Hypertension
–Tachycardia
–Tachypnea
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Onset/Mental status
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Temperature/Pupils
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Skin/Muscle Tone
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Reflexes
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FDA Risk Categories
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•Most are Pregnancy Category C
• Except bupropion, clozapine, buspirone (B)
• Except paroxetine, classic mood stabilizers (D)
• Beenzodiazepines (D or X)