Term
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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 |
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Term
| subunit structure of GABA-A receptor |
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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 |
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Term
| binding sites on the GABA-A receptor |
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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 |
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Term
| graph of BZD binding effects |
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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 |
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Term
| pharmacologic effects of BZDs |
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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 |
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Term
| benzodiazepines marketed for treatment of INSOMNIA |
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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 |
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Term
| nonbenzodiazepine drugs that bind GABA-A receptors indicated for insomnia |
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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) |
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Term
| what subunit do BDZs and non-BDZ GABA modulators bind to on the GABA receptor? |
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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 |
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Term
| general pharmacokinetic properties of zolpidem, zaleplon, and eszopiclone |
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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 |
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Term
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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 |
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Term
| MOA of ramelteon (rozerem) |
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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 |
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Term
| histamine effects and receptors |
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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 |
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Term
| actions of histamine in the CNS |
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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 |
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Term
| results of H1 receptor blockers |
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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 |
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Term
| receptor mechanism of H1 anti-histamines (INVERSE AGONISTS) |
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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 |
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Term
| etiology of attention deficit hyperactivity disorder |
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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? |
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Term
| amphetamine and analogs used for ADHD treatment |
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Definition
amphetamine mixtures
dextroamphetamine (dexedrine)
methamphetamine (desoxyn)
methylphenidate (ritalin)
seemingly paradoxical effect of stimulants improves a disorder characterized by hyperactivity |
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Term
| sites and MOA of amphetamines |
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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 |
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Term
| effectiveness of reuptake inhibition of NE, DA and 5HT by amphetamines |
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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 |
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Term
| actions of trace amine associated receptors (TAAR) |
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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 |
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Term
| general effects of amphetamine and analogs |
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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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