New5 Flashcards
1
Q
Anxiety core features
A
- Generalized anxiety - generalized worry, fatigue, concentration, sleep, irritability, and muscle tension.
- Panic disorder - anticipatory anxiety, worry about panic attacks, phobic avoidance,
- Social anxiety - social performance anxiety, worry about exposure, expected panic attacks, phobic avoidance/behavioural changes
2
Q
Brain Circuits Anxiety
A
- Fear - regulated by reciprocal connections between amygala and anterior cingulate cortex, amygdala, and orbitofrontal cortex. Specifically, overactivation of these circuits.
- Avoidance - connections between amygdala and periaqueductal gray matter.
- Endocrine output of fear - increase cortisol due to amygdala activation of HPA. Prolonged HPA activation an cortisol release can increase risk of CAD, DM2, and stroke. May also result in hippocampal atrophy.
- Autonomic output of fear - increase heart rate and blood pressure - regulated by connections between the amygdala and locus coerulues. Long term activation can increase risk of aterosclerosis, cardiac ischemia, change in BP and MI.
3
Q
GABA and anxiety
A
- GABA is a key neurotransmitter involved in anxiety and thus many anxiolytic drugs target it.
- It is the main inhibitory neurotransmitter. Play regulatory role in reducing activity of many neurons, including those in the amygdala.
4
Q
Treatment Anxiety
A
- Benzos - enhance phasic (fast) inhibitory actions of postsynaptic GABAA receptors within amygdala to blunt fear-associated outputs
- Alpha2-delta ligands - Gabapentin and pregabalin. Block release of excitatory neurotransmitters, such as glutamate, when neurotransmission is excessive.
- Serotonin - serotonin is main neurotransmitter than innervates the amygdala and CSTC (worry circuit). Thus, antidepressants are effective at reducing symptoms of anxiety and fear (SSRI and SNRIs).
5
Q
Noradrenergic Hyperactivity in anxiety
A
- NE has important regulatory input to the amygdala and to the prefrontal cortex, and thalamus in CSTC circuits.
- Excessive noradrenergic outputs from locus coeruleus can cause numerous peripheral manifestations of autonomic overdrive but can also trigger numerous central symptoms of anxiety and fear
- Symptoms of hyperarousal can be reduced in some via alpha1- adrenergi blockers such as prazocin
- Symptoms of fear and worry can be reduced via NE reuptake inhibitors
- *At the start, SNRIs and NET inhibitors can increase anxiety. However, overtime it will downregulate and desensitize post-synaptic NE receptors, such as Beta1 and reduce symptoms of fear and worry long term.
6
Q
ADHD Signals
A
- ADHD is a trio of symptoms - inattention, hyperactivity, and impulsivity
- Thought to be due to abnormalities in prefrontal cortex because most prominent symptoms are due to executive dysfunction.
- Patients with ADHD cannot activate prefrontal cortex areas appropriately in response to cognitive tasks of attention and executive functioning. May be due to DA and NE dysregulation that prevents proper “tuning” of pyramidal neurons in the prefrontal cortex. In normal brain, NE and DA in preforntal cortex stimulate receptors of postsynpatic neurons allowing for optimal signal transmission and neuronal firing. Imbalances in NE and DA cause inefficient informaiton processing in prefrontal circuits and thus produces symptoms of ADHD.
- In ADHD, level of NE and DA symptoms in prefrontal cortex we see deficient signalling and reduced stimulation of postsynpatic receptors. Thus, agents that can increase release of NE and DA or increase tonic firing will benefit patients with ADHD.
- However, also see increase NE and DA in ADHD stress stated. This may be why we see increase drug and alcohol abuse in this population.
- Thus, both too mcuh and too little stimulation of NE and DA can cause inefficient information processing.
7
Q
Stimulants
A
- When DA and NE are too low, strength of output to prefrontal cortex is also low leading to ADHD symptoms (low NE = signal reduced (can’t focus); low DA = noise increase (fidget/shift attnetion))
- Thus, to treat ADHD symptoms you can increase DA and NE to strengthen prefrontal cortical output.
- Methylpenidate and Amphetamine
8
Q
Methylphenidate
A
- Blocks transport of NE and DA via alloesteric modification
- Methylphenidate has d and i isomer - d is more potent for both NET and DAT binding. It is available as single enantimor or as d-methylphenidate
- Available in both immediate and controlled release
- Biphentin (biphasic) - 20-80mg
- Concerta (long-acting) 18-72mg
- Foquest (long-acting) 25-100mg
- Ritalin (short acting) - 10-30mg (adminster in divided doses 2-3)
9
Q
Amphetamine-Based Agents
A
- Blocks transporters on both NE and DA. However, unlike methylphenidate, amphetamine is a competitive inhibitior and pseudosubstrate for NET and DAT, binding at the same site that the monoamines bind to the transporter, thus prevennting NE and DA from reuptake
- At clinical doses, the action of methylphenidate vs. amphetamine are small. However, at high doses there are additional pharmacological actions of amphetamine.
- Followin competitive inhibition of DAT, amphetamine is acutally transported as a hitchhicker into teh presynaptic DA terminal. If there is sufficient quantities (i.e., abuse) amphetamine is also a competitive inhbitor of vescular transporter (VMAT2) for both DA and NE. Once, amphetamine gets a “ride” to synpatic vesicles it displaces the DA there and causes a flood of DA release. As DA accumulates in cytoplasm of presynaptic neuron the DAT reverses direction releasing DA into the synpase, and also opening presynaptic channels for further DA release.
- Has d and i enantiomers, with d being more potent for DAT binding and d and i being equally potent for NET binding, thus, d- amphetamine will have greater DAT action then mixed.
10
Q
Amphetamine agents
A
- Lisdexamphetamine (vyvanse) - 13-14h. d-amphetamine linked to lysine. It is not abosrbed until slowly cleared into active d-amphetamine in the stomach. Reduced potental for abuse. 30-70mg/day
- Dexedrine (immediate) - 3-5hr. 20-50mg (30 for children)
- Dexedrine (sustained) - 6-8hr. 20-50mg (30 children)
- Adderall (mixed salts) - 10-12hr . 30mg children; 50mg adults.
Avoid MOAIs and they can increase HTN effect. Caution with SSRIs and SNRIs because of risk of serotonin syndrome.
11
Q
Slow vs. Fast-release stimulates
A
- Rapid and high degree of DAT occupancy by stimulants by cause euphoria and lead to abuse.
- Slow and low of DAT occupancy are more consistent with symptoms improvement in ADHD (no highs)
- Firing pattern of DA will be tonic, regular, and non-fluctuating vs. rapid and high which will lead to pulsatile drug administration that causes intermittent DA release and cause the reinforcing and pleasurable effects.
12
Q
Noradrenergic treatment of ADHD
A
- Atomoxetine - selective norephinephrine reuptake inhibitor (SNRI). Since prefrontal cortex has low [DAT], DA is inactivated in this part of the brain by NET. So, inhibiting NET increases both DA and NE. However, since there are few NE neurons (and thus NETs) in the nucleus accumbens, inhibiting NET does not lead to an increase in either NE or DA in that area. Because of this, it has no potential for abuse.
- Bupropion - a weak NRI and a weak DAT inhibitor (NE-DA reuptake inhibitor) not approved for ADHD but can be considered
- Alpha-2A-adrenergic agonists
- Guanfacine - more selective for alpha2A receptor. Available in controlled release
- Clonidine - non-selective alpha2adrenergeric agonist. Binds to alpha2A, 2B, and Cb. It also binds to imidazoline receptors, which contribute to sedating and hypotensive effective. (Approved for HTN and off label ADHD).
13
Q
Alpha-2A-adrenergic agonists ADHD
A
- Alpha-2A-adrenergic agonists. Alpha2A receptors are widely distruted throughuot the CNS, with high leved in the cortex and locus coerulus. Thought to be primary mediators of effects of NE in prefrontal cortex.
- Alpha1 tends to have opposing mechanism (stress, comorbidity, and cognitive impairment). However, these receptors only predominate when NE release is high.
- Thus, selective NRIs at low doses will increae alpha2A to enhave cognitive performace, but at higher doses may cause cognitive impairment and sedation.
Alpha2 receptors are high in concentration in prefrontal cortex and low in nucleus accumbens
