Transcript PEDIATRIC PSYCHOPHARMACOLOGY

‫بسم هللا الرحمن الرحيم‬
PEDIATRIC
PSYCHOPHARMACOLOGY
Malek, A., M.D
Professor of Psychiatry
Child & Adolescent Psychiatrist
Tabriz University of Medical Sciences
[email protected]
The Role of Development
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Pharmacokinetic and Pharmacodynamic
Principles
“Pharmacokinetics describes what the body
does to a drug; Pharmacodynamics what a
drug does to the body”
PHARMACOKINETIC PRINCIPLES
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four functionally distinct phases:
Absorption & Distribution,
Metabolism & Excretion
Absorption and distribution are responsible for
determining the speed of onset of drug effect,
Metabolism and excretion terminate the action
of the pharmacologic agent
Absorption
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The major factors influencing
gastrointestinal absorption are:
PH-dependent diffusion
gastric emptying time
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Stomach contents tend to be less acidic
in children than in adults.
Theoretically this process could affect
anticonvulsants, amphetamines, and
antidepressants.
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Drugs such as phenothiazines can
absorbed or metabolized in the gut wall
be
This explain why some children either are
unusually resistant to phenothiazines or
require a large oral doses.
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Intestinal transit time is shorter in
young children, which could result in
incomplete uptake of slow-release
preparations
Distribution
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Numerous physical factors can influence the
distribution of a drug throughout the body:
the size of body water compartments and
adipose tissue depots,
cardiac output,
regional blood flow,
organ perfusion pressure,
permeability of cell membranes,
acid–base balance,
binding to plasma and tissue proteins
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The two most important factors
affecting distribution that change
substantially during development:
fat stores
the relative proportion of total body
water to extracellular water
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The proportion of body fat is
highest in the first year of life,
followed by a steady decrease
until an increase occurs prepubertally
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In children one would expect to find
a larger plasma concentration with
lipophilic drugs when compared with
adults after being given the same
weight-adjusted dose.
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The relative volume of extracellular
water is high in children and tends to
decrease with development.
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Drugs that are primarily distributed in
body water (e.g., lithium) can be
expected to have a lower plasma
concentration
in
the
pediatric
population compared with that in adults
because the volume of distribution is
higher in children.
Metabolism
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Most drugs are lipid soluble.
Lipophilic drugs need to be metabolized into
more polar or hydrophilic forms in order to
be effectively excreted
Enzymes that catalyze these metabolic
reactions are found in greatest abundance in
the liver, the main organ of drug
metabolism,
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Phase I metabolic reactions, including
hydroxylation , reduction , and hydrolysis,
convert drugs to forms more suitable
for elimination.
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Hepatic microsomal enzymes (the
cytochrome P450 system ) are
responsible for phase I reactions.
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In phase II reactions, conjugation of
metabolites generated in phase I takes
place with glucuronic acid, sulfate, or
others. Conjugated compounds are then
readily excreted in urine or other body
fluids.
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Some drugs are never metabolized in a phase
I reaction and instead simply undergo conjugation
by glucuronic acid.
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Drugs such as the 3-hydroxybenzodiazepines
(e.g., lorazepam, oxazepam) and lamotrigine
are rapidly cleared at equal rates regardless
of age as long as renal function is normal ,
and are thus preferred in instances of liver
insufficiency.
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In children: CYPs are more efficient than in
adulthood, and their activity declines to
adult levels after puberty.
In children: A larger liver:total body ratio
Practical implication:
In order to achieve therapeutic serum levels,
when compared to adults , children may
require higher weight-adjusted dosages.
Drug Interactions:
Focus on the Cytochrome P450 System
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Cytochrome-based metabolism of drugs
is influenced by genetic factors.
7% to 10% of whites have a genetic
deficiency of CYP 2D6 and are less
efficient in metabolizing 2D6 substrates,
including many psychotropic agents
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Some Asian individuals have a 2D6 variant
that causes them to be “somewhat slow”
metabolizers; they require lower dosing of
relevant drugs to achieve therapeutic blood
levels.
Cytochrome P450
Inhibitors and Inducers
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Drugs that interact with CYPs can
inhibit, induce, or have no effect on CYP
activity.
Many of the most serious drug
interactions occur when a potent CYP
inhibitor is added to a drug that is a
substrate of that CYP and has a narrow
therapeutic index.
For example
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fluoxetine or paroxetine (potent inhibitors of
CYP 2D6) can increase the plasma
concentration of desipramine (a substrate
of CYP 2D6) about 400%.
Sertraline, a less potent inhibitor of
CYP2D6, increases desipramine levels only
25%.
fluvoxamine (a potent CYP3A inhibitor) can
double levels of phenytoin within hours.
For example
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glucuronidation (phase II) enzymes are also
susceptible to inhibition and induction.
As an example, lamotrigine is handled by
glucuronidation alone, and the addition of
valproate (a glucuronidation inhibitor) can
significantly elevate lamotrigine levels,
thereby
increasing
the
likelihood
of
developing
life-threatening
StevensJohnson syndrome.
Excretion
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The kidney is the most important organ
for drug excretion.
More efficient glomerular filtration rate
in children as compared to adults.
PHARMACODYNAMIC PRINCIPLES
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Dopaminergic /Serotonergic / Noradrenergic /
Cholinergic / Gabaergic Neurotransmission
Developmental changes in neurochemical
systems can influence both therapeutic
response and side effect profile.
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(a) Compared to adults, adolescents
have a higher risk of dystonic reactions
to neuroleptics.
(b) Prepubertal children are at a higher
risk for the activating side effects of the
selective serotonin reuptake inhibitors
(SSRIs).
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(c)
Developmental differences in
the maturation of
noradrenergic
pathways may explain why tricyclic
antidepressants are less effective in
children with depression as compared
to adults.
THANK YOU
FOR YOUR ATTENTION
Evidenced-Based
Clinical Decision Making
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Treatment plans should be grounded on
available empiric evidence.
A simple method for ranking available
treatments according to their level of
empiric support:
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Class A :medications with good empiric support,
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Class B :drugs with fair empiric support showing
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Class C :drugs with minimal empiric support, based
based on consistently positive results in randomized
controlled trials (RCTs).
positive, but inconsistent, results in RCTs or positive
results from small sample trials.
primarily on accumulated clinical experience from
case reports and open-label studies.
Examples: A level
Stimulants, Atomoxetine, and Clonidine for
ADHD;
 Fluvoxamine for OCD and other anxiety
disorders of childhood;
 Sertraline for OCD;
 Fluoxetine for depression;
 Risperidone, Haloperidol and Pimozide
for tic disorders.
 Risperidone for autism and disruptive
behavior
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Examples: B level
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Sertraline for depression;
Clonidine for tics;
Guanfacine for ADHD;
Lithium for aggression and conduct
disorder
Pharmacokinetic
in Children and Adolescents
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one basic observation is suggested
clinically: Children and adolescents
require larger, weight-adjusted doses of
most medications than do adults to
achieve comparable blood levels and
therapeutic effects
The Role Of Development
Pharmacokinetic
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Development can have a major impact
on pharmacologic effects .Thus,
children and adults may show divergent
responses to psychotropic drugs.
First, children often metabolize and
eliminate drugs from the body more
quickly than adults, resulting in shorter
drug half-lives.
a larger liver:total body ratio and more
efficient glomerular filtration rate in
children as compared to adults.
 practical implication:
In order to achieve therapeutic serum
levels, when compared to adults,
children may require higher weightadjusted dosages.
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A final theoretical consideration in
children and adolescents is the relative
permeability of the blood–brain barrier
when compared with that in adults.
SEVEN GUIDING PRINCIPLES
1-The Role of Development
2-Evidenced-Based Clinical Decision Making
3-Comorbidity
4-Target Symptoms and the Integration of Data
from Multiple Informants
5-Adverse Effects: Monitoring Risks and Benefits
6-The Role of Caregivers and the Meaning of
Medication
7-Combination of Therapeutic Modalities
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Most psychotropic drugs undergo both
phase I and phase II reactions.
A few drugs are metabolized by only
one CYP (e.g., desipramine).
Some others undergo phase II
conjugation only (e.g., lorazepam,
oxazepam, and lamotrigine are
glucuronidated only);