PHRM845 Exam 4 (Yang) Flashcards
Stimulants and ADHD
Location of the reticular activating system (RAS)
Hypothalamus –> Cortex
What is the reticular formation?
The reticular formation contains the cell bodies and fibers of many of the serotonergic, noradrenergic, and cholinergic systems
Epidemiology of ADHD
-6.1 million children in US (3-17 y.o.) in 2016
-Males more likely than females
-Adult rates of ADHD estimated at 3-5%
-From 2002 to 2010, overall prescribing for ADHD increased 46%
-Women 2003-2015 increased Rx 344%
-25-29 increased 700%!
**The number of pts with ADHD has increased dramatically (May be due to environmental issues or because there is more awareness.
**Known as a childhood disease, but some adults are diagnosed
Causes of ADHD
-Majority from heritable (genetics) factors
-Also from low birth weight, fetal alcohol syndrome disorder, lead, smoking, and perinatal
-ADHD is NOT a single mutation/gene (small portion of different genes)
**Children with fetal alcohol syndrome, lead poisoning, and meningitis have a higher incidence of ADHD symptomatology.3,17 ADHD is associated with a variety of environmental risks, including obstetric adversity, maternal smoking, and adverse parent–child relationships
Pathophysiology of ADHD
-Genetic vs. Non-genetic factors
Implicated systems:
-Dopamine transporter, COMT, cholinergic receptors, cholesterol metabolism, CNS development, glutamate receptors.
-Environmental factors
-Imaging studies reveal reduced total brain volume and activity in key areas
Functional MRI shows high activity in patients without ADHD. For patients with ADHD, most of the brain has ____ activity, so we want to increase activity and fire more action potentials.
Low
What is occurring in a brain with ADHD.
A lack of connectivity between the prefrontal cortex and precuneus (located in the midline of the parietal lobe) is associated with failure of suppression of the default mode network (active during “resting state” when attention is not engaged), causing lapses in attention and inhibitory control.23 Recently, methylphenidate has been shown to decrease aberrant default mode network activation in children with ADHD.
Clinical presentation of ADHD
-Symptoms at ages 5-9 y.o. (generally before 12 for diagnosis)
-Six or more symptoms must be present
-Significant impairment in two or more settings (e.g., home vs. school)
-Symptoms documented by parent, teacher, and clinician (very potent drugs to tx ADHD, so we want documentation in different settings)
-Interferes with functioning and development
Symptoms of ADHD
Symptoms
-Inattention examples: difficulty organizing tasks/activities, does not seem to listen, easily distracted, loses things for activities
-Hyperactivity examples: fidgets or squirms
-Impulsivity examples: leaves seat, runs/climbs excessively (e.g., in the mouse model), interrupts
-Possible circuity mechanism: medial prefrontal cortex (mPFC) control might not be fully functional–if not enough inhibition, we do things we shouldn’t
**Alcohol inhibits the medial prefrontal cortex causing us to do funny things (ex: dance in front of the class)
**Don’t treat unless it impacts AODL
Stimulants (stimulate brain to make it more active)
-Methylxanthines (ex: caffeine)
-Indirect-acting sympathomimetics: stimulant compounds mimic the effect of endogenous agonists of the sympathetic nervous system
Pharmacology of methylxanthines
Antagonize Adenosine Receptors
Inhibit Phosphodiesterases: Increase cAMP (potentiate Gs-linked receptors)
Increase activity of ryanodine receptors, increasing intracellular Ca2+
Adenosine’s role in regulating excitatory neurotransmission, using glutamate as an example
In this example, glutamate excites a postsynaptic neuron by activating metabotropic glutamate receptors (mGluR1) [1]. ATP enters the synapse when glutamate is released. Adenosine formed from metabolism of ATP within the synapse [3] binds to postsynaptic A1 receptors [2], which open K+ channels to inhibit the neuron through hyperpolarization. Adenosine also activates presynaptic A1 receptors [4] to lower intracellular Ca2+ concentrations, thereby impairing further glutamate release. Activation of presynaptic A2 receptors has the opposite effect, enhancing glutamate exocytosis [11]. After uptake by ENT [5], adenosine is acted upon either by adenosine kinase (AK) [7] to form AMP, or by adenosine deaminase (ADA) [6] to form inosine. Adenosine also binds to neuronal postsynaptic A2 receptors (especially in the striatum) and to vascular A2 receptors to cause vasodilation [8]. A3 receptors [9] are not activated by normal concentrations of adenosine. During times of excessive catabolism (eg, seizures, hypoglycemia, stroke) when intracellular adenosine concentrations rise markedly, adenosine moves into the synapse through reverse transport via ENT [5]. Resultant stimulation of A1 and A2 receptors results in inhibitory actions to decrease oxygen requirements and to increase substrate delivery through vasodilation as described above. However, the resultant stimulation of A3 receptors [9] may contribute to neuronal damage and death. Xenobiotics in Table 14–12 act to inhibit adenosine uptake [5]; to inhibit ADA [6]; to inhibit AK [7]; to increase adenosine release; and to antagonize A1 [2,4] and A2 [8,11] receptors. ADP = adenosine diphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; ENT = equilibrative nucleoside transporter; G = G protein; IP3 = inositol triphosphate.
Adenosine receptors pharmacology of methylxanthines (A1)
A1 – Gi/o-linked, pre and post synaptic; inhibitory modulation of many neurotransmittersLocated in cerebral cortex, hippocampus, cerebellum, thalamus, brain stem, and spinal cord.
CNS Activation: sedation, neuroprotection, anxiolysis, temperature reduction, anticonvulsant activity, and spinal analgesia.
Peripheral Activation : bronchoconstriction, decreased glomerular filtration, decreased heart rate, slowed atrioventricular conduction, and decreased atrial myocardial contractility.
Adenosine receptors pharmacology of methylxanthines (A2 & A3)
A2A – Gs-linked, pre and post synaptic;
-Located in cerebral vasculature and striatum: vasodilation (Gs causes vasodilation)
-Heterodimerize with A1 and D2 dopamine receptors
-A2B – Gs-linked, mostly on glial cells function unknown
-A3 – Gq-linked, hippocampus and thalamus (only activated in states of excessive catabolism; e.g., seizures, hypoglycemia, stroke; not antagonized by methylxanthines)-function is not very well known
Effects of methylxanthines
-Mild cortical arousal
-Increased alertness
-Decreased fatigue
-Nervousness/insomnia
-Ionotropic/ chronotropic effects
-Vasoconstriction (cerebral vessels)
-Smooth muscle relaxation
-Diuretic actions
