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Psych/Neuro EXAM 2
Psych/Neuro EXAM 2 Schober Benzos/ADHD
21
Pharmacology
Graduate
08/25/2011

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Term
3 main GABA receptors
Definition
1) GABA-A
ligand-gated ionotropic chloride channel
highest CNS expression of the 3 main GABA receptor types
target of benzodiazepines (and many other compounds)
20 different GABA-A subtypes

2) GABA-B
metabotropic receptors (effects are through G-protein coupled signaling)
baclofen (a muscle relaxant) is a GABA-B agonist

3) GABA-C
ligand-gated ionotropic chloride channel
has function in vision (retinal expression)
not a receptor for benzodiazepines or barbiturates
Term
subunit structure of GABA-A receptor
Definition
the GABA-A receptor is comprised of 5 subunits
16 different subunits have been identified thus making the potential combinations of GABA-A subtypes very large, but only 20 different subtypes have so far been found
most of the subtypes are made of combinations of alpha, beta, and gamma subunits

channel activity is affected by many different compounds
there are many different modulators (affect chloride flux) of the GABA-A receptor
flumazenil blocks benzodiazepine binding and is used for benzodiazepine overdose management
furosemide is an antagonist of certain receptor subtypes
picrotoxin is an antagonist
Term
binding sites on the GABA-A receptor
Definition
[image]

GABA appears to interact with alpha and beta subunits triggering Cl channel opening resulting in membrane hyperpolarization
binding of BZDs to the alpha subunit or to an area of the alpha subunit near the gamma subunit facilitates the process of channel opening but does not directly initiate Cl current

GABA-A is the receptor for benzodiazepines (BDZs)

the receptor is composed of 5 subunits (most commonly alpha, beta, and gamma in the CNS)
there are 6 different alpha, 3 different beta, and 3 different gamma subunits that combine to make the 20 known GABA-A receptor subtypes

GABA-A is a Cl channel that can hyperpolarize the membrane thereby decreasing the ability of the neuron to reach threshold

BDZs bind to a different site than GABA
without the presence of GABA, BDZs have no effect on Cl conductance
strictly speaking, BDZs are allosteric activators not true agonists
Term
graph of BZD binding effects
Definition
[image]

the effect of midazolam as demonstrated above is representative of BDZs
midazolam shifts the dose-response curve to the left (larger Cl current at a given concentration of GABA)
BDZs are not true receptor agonists b/c BDZs cannot activate the receptor alone
however, BDZs are sometimes referred to as "GABA-A agonists" because of the positive allosteric effect on Cl current

barbiturates can directly activate (open) the channel without presence of BDZ = TRUE AGONIST
Term
pharmacologic effects of BZDs
Definition
REDUCE ANXIETY
potentiation of GABAergic neurotransmission in the limbic system relieves symptoms of anxiety -> general property of benzodiazepines
the current thought is excessive 5HT and to a lesser extent noradrenergic activity in the limbic system is the basis for anxiety disorders
sedative affect of BDZs is believed to be a distinct property from anxiolytic effects (thought to be mediated through different GABA-A receptor subtypes)
all BDZs have anxiolytic efficacy

SLEEP STAGES
decreased latency period (amount of time to fall asleep)
increase total sleep time
less REM, less stages 3-4, more stage 2 (not as deep of a sleep)

DECREASED ALVEOLAR VENTILATION
high doses -> decreased response to CO2 -> RESPIRATORY ACIDOSIS
the compensatory mechanism to respiratory acidosis involves the kidneys reabsorbing more bicarb trying to normalize the pH

CARDIOVASCULAR
high doses decrease BP
reflex tachycardia may occur

ANTICONVULSANT AND MUSCLE RELAXANT PROPERTIES
decrease seizure activity and muscle tone
anticonvulsant and myorelaxant properties are proposed to be mediated through different receptor subtypes
Term
benzodiazepines marketed for treatment of INSOMNIA
Definition
estazolam: tmax = 2h; t1/2 = 12-15h
flurazepam: tmax = 1h; t1/2 = 8h
quazepam: tmax = 2h; t1/2 = 39h
temazepam: tmax = 1.5h; t1/2 = 10-15h
triazolam: tmax = 1h; t1/2 = 2h

all BDZs have effect on sleep stages
these are marketed for insomnia b/c of their pharmacokinetic properties

sedation expected to occur at or before peak plasma concentration (tmax)

active parent drugs with long t1/2 or active metabolites with long t1/2 will cause daytime sedation and impairmnet, but may be useful when daytime anxiety is present

pharmacokinetics determine induction time, maintenance and daytime effect
Term
nonbenzodiazepine drugs that bind GABA-A receptors indicated for insomnia
Definition
zolpidem (ambien)
zaleplon (sonata)
eszopiclone (lunesta)

these drugs to not chemically resemble benzodiazepines but they bind the GABA-A receptor and have sedative effects

like BZDs, these three drugs have hypnotic effects and decrease sleep latency, but they have much less effect on sleep stages (little or no reduction in REM and stages 3-4 sleep)

not associated with daytime impairment

LACK OF OTHER THERAPEUTIC EFFECTS (lack myorelaxant and anxiolytic effects, and have little or no anticonvulsant effects)
Term
what subunit do BDZs and non-BDZ GABA modulators bind to on the GABA receptor?
Definition
the GABA-A receptor is composed of 5 subunits

2 subtypes are found in the CNS: alph1-beta2-gamma2 and alph2-beta3-gamma2
these subtypes mediate effects of BDZs and GABA momdulators (zolpidem)

the binding sites of these drugs are on the alpha subunits:
zolpidem has selectivity for alpha-1
BDZs bind both alpha-1 and alpha-2

[image]

BZDs bind both GABA-A receptor subtypes thereby producing sedative, anxiolytic, and myorelaxant effects
non-BZD GABA-A receptor modulators have binding specificity for the alpha-1 subunit thus producing only sedative effects
Term
general pharmacokinetic properties of zolpidem, zaleplon, and eszopiclone
Definition
zaleplon has the lowest oral bioavailability

1-1.5 h to peak plasma concentration
3A4 major

eszopiclone longest elimination t1/2 (~5h)

60-90% protein bound
Term
MOA of melatonin
Definition
melatonin is produced by acetylation and methylation of serotonin

pineal gland secretion is controlled by light imput to the retina
during the day plasma levels of melatonin are low and during the night plasma melatonin levels are high

melatonin may help sleep problems associated with jet lag and shift work

it shortens latency and lengthens sleep duration

melatonin suppresses LH surge and other sex hormones

may increase REM sleep duration

useful in entrainment of blind patients
Term
MOA of ramelteon (rozerem)
Definition
melatonin derivative

ramelteon binds to MT1 and MT2 and is thought to mediate the sleep promoting properties

GI absorption is good but like melatonin it undergoes extensive first pass metabolism

good for reducing sleep latency, but not for maintenance of sleep

hydroxylated metabolite circulates in the plasma at higher concentration than parent drug but has much lower affinity for melatonin receptors
Term
histamine effects and receptors
Definition
lungs
effect: bonchoconstriction
clinical manifestation: asthma-like symptoms
receptor subtype: H1

vascular smooth muscle
effect: postcapillary venule dilation; terminal arteriole dilation
clinical manifestation: erythema
receptor subtype: H1

vascular endothelium
effect: contraction and separation of endothelial cells
clinical manifestations: edema, wheal response
receptor subtype: H1

peripheral nerves
effect: sensitization of afferent nerve terminals
clinical manifestations: itchiness, pain
receptor subtype: H1

stomach
effect: increased gastric acid secretion
clinical manifestation: peptic ulcer disease, heartburn
receptor subtype: H2

CNS
EFFECT: NEUROTRANSMITTER
CLINICAL MANIFESTATIONS: CIRCADIAN RHYTHMS, WAKEFULNESS
RECEPTOR SUBTYPE: H1, H3
Term
actions of histamine in the CNS
Definition
CNS histamine serves as a neurotransmitter

during the day histaminergic neurons are active (high histamine release from axon terminal)

during the night histaminergic neuron activity is low (little histamine release)

one of the areas that the histaminergic neurons innervate is the reticular activating system (RAS)
the RAS is located in the brain stem and controls arousal, motivation, and consciousness

there are H1 receptors located in the RAS
histamine release into the RAS (activation of H1 receptor) is associated with wakefulness
Term
results of H1 receptor blockers
Definition
the first generation antihistamines readily cross the BBB and block the H1 receptor in the RAS

these drugs also have antagonistic activity at muscarinic receptors (xerostomia, urinary retention, mydriasis)

cause sedation and drowsiness
Term
receptor mechanism of H1 anti-histamines (INVERSE AGONISTS)
Definition
antihistamines are INVERSE AGONISTS

[image]

A)
the H1 receptor can exist in 2 states, active and inactive without presence of ligand or drug
the 2 states are in an equilibrium (equal number of active and inactive receptors)
the active states means that the second messenger system is turned on (in this case it means more GTP-alpha) causing a baseline response in the cell or brain tissue

B)
histamine is an agonist
it binds to (has a higher affinity for) the active state of the receptor and stabilizes the receptor in the active state
more active receptor causes greater second messenger signaling causing greater response in the cell

C)
H1 antihistamines are inverse agonists
they bind to (have higher affinity for) the inactive state of the receptor and stabilize the receptor in the inactive state
the result is less second messenger signaling (more GDP-alpha) and less response in the cell or brain tissue
Term
etiology of attention deficit hyperactivity disorder
Definition
genetic:
concordance increases with genetic identity
polymorphisms in dopamine receptor subtypes and the dopamine transporter have been associated with ADHD; a specific mutation in the D4 receptor is 2 times more likely to be found in a patient with ADHD (D4 signals through Gi-alpha (cuppresses cAMP))

environmental:
lead
neonatal complications
fetal alcohol syndrome
parent-child relationship?
Term
amphetamine and analogs used for ADHD treatment
Definition
amphetamine mixtures
dextroamphetamine (dexedrine)
methamphetamine (desoxyn)
methylphenidate (ritalin)

seemingly paradoxical effect of stimulants improves a disorder characterized by hyperactivity
Term
sites and MOA of amphetamines
Definition
[image]

amphetamines have indirect sympathomimetic activity

amphetamines compete with monoamine reuptake and reverse the transporter

amphetamines enter the cytosol using the monoamine reuptake transporter and are transported into the vesicle (via VMAT) in exchange for NE and DA

the result is higher synaptic concentration of NTs
Term
effectiveness of reuptake inhibition of NE, DA and 5HT by amphetamines
Definition
the d-isomer of methylphenidate more effecely blocks NE and DA uptake; racemic methylphenidate is less potent than the d-isomer

uptake inhibition: NE>DA>5HT
Term
actions of trace amine associated receptors (TAAR)
Definition
found throughout the CNS and vasculature

bind trace amines, amphetamines, LSD, tyramine

these receptors may mediate many of the effects of amphetamine and analogs
Term
general effects of amphetamine and analogs
Definition
cardiovascular: increase systolic and diastolic

gastrointestinal - slow motility

fatigue and sleep - decreased (motor stimulation)

appetite - depressed, weight loss

similar effects to activation of the sympathetic nervous system

therapeutic goal: improve attention and reduce hyperactivity
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