Psych Primer/ADHD Unit 3

Why is the BBB important

establishes and maintains microenvironment of the CNS, allowing for proper neuronal function

What molecules can diffuse through the BBB easily?

small lipophilic molecules, O2, and CO2

GLUT1 transporters bring what into the CNS?

Glucose

MCT1 transporters bring what into CNS?

lactate and amino acids

EAAT 1,2,3 transporters are responsible for transporting?

glutamate out of the CNS

ABC transporters do what?

limit drug penetration and removes toxic lipophilic metabolites

Anion transporters bring what into CNS?

thyroid hormone

LAT1 transporters bring in what?

levodopa (Good for parkinson’s)

function of astrocytes in CNS

assist in development/maintenance of BBB characteristics, moment-to-moment regulation of microvascular permeability, induce synapse formation

function of microglia in CNS

immune system of CNS

function of neurons in CNS

signaling cells of the brain, release neurotransmitters to relay message between nerves

What can cause physical breakdown of the BBB?

disruption of tight and adherent junctions, increase in bulk-flow fluid transcytosis, enymatic degradation

BBB breakdown leads to

leakage of proteins/RBCs, albumin-driven brain swelling, allows neurotoxic and vasculotoxic proteins to enter, reductions in blood flow leading to neurodegeneration

Steps of neurotransmission

precursor uptake, biosynthesis, storage, release, action, termination

Which NTs are excitatory?

Glutamate, Histamine

Which NTs are inhibitory?

Serotonin, GABA, Dopamine

Which NTs are both excitatory and inhibitory?

NE and acteylcholine

Which NTs have LGIC receptors?

ACh, 5-HT, Glutamate, GABA

Which NTs have GPCRs?

ACh, NE, DA, 5-HT, Histamine

Characteristic of LGICs

have fast synaptic transmission

Characteristics of GPCRs

slower effects, have secondary messenger cascades involving cAMP or PLC

When it comes to NT function, drugs can ehance or inhibit what processes?

Uptake of NT precursors, NT biosynthetic enzymes, NT storage, NT release, Post-synaptic NT receptors, Pre-synaptic NT receptors, NT transporter reuptake, NT metabolism

ADHD definition

characterized by impairment to regulate arousal and inhibit behavior according to socially acquired rules of conduct

Major neurotransmitters involved in ADHD

NE and DA

Core symptoms of ADHD

inattention, hyperactivity, and impulsivity

Symptoms of inattention in ADHD

careless mistakes, seems to not listen, difficulty organizing, loses things, forgetful, difficulty keeping attention, can’t finish tasks, avoids sustained attention tasks, easily distracted

Symptoms of hyperactivity/impulsivity in ADHD

fidgeting, restless, “on the go”, unable to stay seated, can’t engage in leisure quietly, excessive talking, blurting out, interrupting/intruding others, difficulty awaiting turn

How do we diagnose ADHD?

Patient must often have 6/9 symptoms in either/each domain for 6 months or more in 2 or more settings before the age of 12

How many symptoms must adults exhibit for diagnosis?

5/9 in either domain of inattention or impulsivity/hyperactivity

Goal of treatment in ADHD

Reduction in core symptoms (patient specific)

Treatment for 4-6 yo

Behavioral therapy, if ineffective and symptoms have persisted for 9 months then start on methylphenidate

Treatment for 6-12 yo

Stimulant and behavioral therapy

Treatment for 12-18 yo

Stimulant and behavioral therapy (treat predominant disorder first if present)

First line pharmacotherapeutic treatment for ADHD

Methylphenidate and Amphetamines (Stimulants)

MOA of Amphetamines (AMPH)

inhibits reuptake of primarily NE but also DA

MOA of Methylphenidate (MPH)

Inhibits NE and DA reuptake

ADME of MPH

readily absorbed, high distribution to brain, rapidly metabolized, excreted via urine

ADME of AMPH

readily absorbed, high distribution to brain, hepatic oxidation by CYP2D6, excreted by urine and is pH dependent, children excrete faster than adults

What is one big concern with Concerta?

do not give to GI issue patients, they will pass tab in stool

Why are PK profiles for different MPH and AMPH products so different?

To achieve desired effect over longer periods, the higher the concentration the more effective the drug is, some patients symptoms may be more prevalent at certain times of day

Most likely causes of ADHD

genetic predisposition, low levels of DA and NE, neurons need more DA and NE than normal

What other conditions should we evaluate prior to starting someone on a stimulant?

Cardiac conditions, including family history, physical exam and maybe even an EKG

Common ADRs of stimulants

insomnia, tachycardia, decreased appetite/weight loss, increased BP, irritability, GI upset

Rare ADRs of stimulants

priapism, zombie-like state, tics, hallucinations, skin discoloration with patch formulation, stunted growth

Efficacy monitoring parameters for ADHD meds

reduction of symptoms, rating scales

Safety monitoring parameters for ADHD

BP, HR, insomnia, weight loss

When do we evaluate monitoring/safety parameters in ADHD?

Monthly on initiation or medication changes, then every 3 months if things are going well

Second-line ADHD therapy

Atomoxetine and Viloxazine, guanfacine and clonidine, bupropion (adults mostly)