Psychopharmacology

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neurotransmitters included in depression

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neurotransmitters included in depression

  • Noradrenaline

  • Dopamine

  • Serotonin

  • Histamine

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Origin of Noradrenaline

Locus coeruleus

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Origin of Dopamine

Substantia nigra + VTA

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Origin of Serotonin

Raphe nuclei

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Origin of Histamine

Hypothalamus with tuberomammillary complex

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response

50% reduction in symptoms

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remission

all symptoms relieved (to 6 months)

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recovery

remission longer than 6-12 mths

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relapse

symptoms worsen before recovery (<6-12 mths)

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recurrence

symptoms worsen after recovery (>12 mths)

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11

patients given anti depressants respond in how many days/wks?

67% patients respond in 8 wks

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12

give stats of these 67% ppl when kept on/taken off drug

  • Taken off

    • 50% of 67% ppl (33%) will retain the effects for a year

    • other half will become depressed again in one year

  • Kept on

    • 10-15% relapse again in a year

    • 85% remain well

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what happens when patient is given placebo instead of medication in the first place?

  • 33% responders

  • 67% non - responders

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Monoamine hypothesis

depression is caused due to deficiency in one or more of the 3 catecholamines = serotonin, norepinephrine or dopamine

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mechanism of antidepressant medication

Need to increase the levels of one/combination of these hormones by:

  • blocking their reuptake pumps

  • inhibiting their oxidation by monoamine oxidation (MAOs)

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reuptake pump is responsible for what

decreases the level of serotonin available to post-synaptic membrane by taking up the serotonin back inside the axon terminal

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MAO function

  • responsible for degradation of catecholamines in the CNS

  • present both in cleft and within the axon terminal

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problems with the monoamine hypothesis

  • no antidepressant effect observed for certain drugs that increase the NTs (cocaine, methamphetamines)

  • long delay (2-3 wks) between increase in NTs and clinical effect

  • decreased levels of NTs have only been associated with only some types of depression

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serotonin functions

  • results in neurotransmission

  • changes the proteins made in neurons

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what are the effects of the neuronal proteins serotonin acts upon

  • responsible for long-term effect of antidepressants on mood

  • facilitate increased neurogenesis, therefore helps in improvements in behavioral/mood disorders

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4 points about Brain-derived Neurotrophic Factor (BDNF)

  • normally regulated by cell body of neuron by factors like monoamines, glutamates, other signals

  • can be reduced by stress

  • during depression ↓MAs = ↓BDNFs

  • responsible for allowing neurons to make new connections; consequence of this = improves depression

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does hippocampus become small or big during depression? why?

  • becomes small

  • bc the peptide factors are low

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what does amygdala do?

  • part of limbic system

  • associated w emotions like anger, pleasure, sorrow, fear and sexual arousal

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what effect does medication have on amygdalas of depressed indv?

  • olume medicated = amygdala vol ↑es

  • unmedicated = amygdala vol ↓es

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name diff classes of antidepressant drugs

  • MAO inhibitors = Classical (MAOi), Reversible (RIMA)

  • Tricyclic antidepressants

  • SSRI (Serotonin Selective Reuptake Inhibitors)

  • NDRI (Noradrenaline/Dopamine reuptake Inhibitors)

  • SNRI (Serotonin/Noradrenaline Reuptake Inhibitors) (Noradrenaline/Serotonin Specific Antagonists - NaSSR)

  • SARI (Serotonin Antagonists/Reuptake Inhibitors)

For bipolar disorder -

  • Lithium

  • Valproic Acid

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26

first clinically discovered antidepressants?

MAOis

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2 subtypes of MAOs?

  • MAO A

  • MAO B

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examples of MAOis

  • phenylzine (Nardine)

  • tranylcypromine (Parnate)

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Features + side effects of classical MAOis

  • non-selective = blocks both subtypes

  • irreversible inhibitors = this is why action is long lasting and ∴ takes considerable time to regenerate MAOs again

  • has severe interaction with food, drugs and wine

    • tyramine

    • drugs = TCA, sympathomimetic (both ↑es bp to vvvvv ↑↑↑↑ levels)

    • meperidine (Demerol) = fever

  • bc of so many side effects these drugs were no longer used

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Tyramine features

  • helps to regulate bp

  • acts as a sympathomimetic when ingested

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what is a sympathomimetic

mimics/stimulates adrenergic NS = raises bp to alarming levels

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Tyramine is present in (food items)

  • cheese

  • beer

  • liver

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Effect of MAOs on tyramine

helps in breaking down excess tyramine in body

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Effect of MAOis on tyramine in body

  • blocks tyramine

  • spikes bp

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explain tyramine + MAOi effect in detail

  • Tyramine ↑es release of NE

  • Irreversible MAOi-A inhibits MAO to break down tyramine to stop NE destruction

  • ↑es NE = can lead to dangerous elevations of bp => hypertension

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3 subtypes of MAOis?

  • Classical MAOis

  • MAO A specific inhibitors

  • MAO B inhibitors

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MAOi A features

  • metabolises MAOs closely related to depression => NA,5HT

  • reversible inhibitors

  • E.g. = Moclobemide

    • reversible, competitive inhibitor

    • removes tyramine effect danger

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MAOi B features

  • involved in metabolism of DA + protoxins (which become toxins when activated)

  • used in treatment of Parkinson’s

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5HT receptors can be found in

  • CNS

  • Blood vessels

  • Smooth muscle

  • Platelets

  • GI tract

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side effects of MAOis

Serotonin syndrome

  • excessive levels of 5HT

  • mild symptoms = ↑sed heart rate, sweating, dilated pupils, over responsive reflexes

  • moderate symptoms = high bp, hyperthermia; Mental changes = hypervigilance, agitation

  • severe symptoms = severe ↑se in heart rate + bp leading to shock

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TCA features

  • first tested as antipsychotics

  • block uptake of NA, 5HT, and DA

  • have many f gps

    • α1 adrenergic-R = antagonism

    • histamine1-R = antagonism

    • ACh muscarinic-R = antagonism

    • 5HT and NA = reuptake inhibition

  • 5HT and NA levels ↑se = depression lifts

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TCA function

  • ↑se level of NT retained in synaptic cleft by blocking reuptake pump

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TCA side effects

  • histamine-1 antagonism = ↑ appetite, ↓ metabolism causes weight gain + drowsiness

  • cholinergic (muscarinic) antagonism = constipation, blurred vision, dry mouth, drowsiness

  • α1 adrenergic antagonism (less extent) = dizziness, drowsiness, ↓sed bp

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autoreceptors

  • when receptors for own NT are present on presynaptic neuron which results in inhibition of the NT release

  • e.g., histamine autoreceptors

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mechanism of inhibition of autoreceptors

  • GPCRs linked by G proteins to an inward K+ rectifying channel

  • prevents depolarisation

  • inhibits NT release

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heteroreceptors

  • receptor for a MA diff from the NT made by the neuron is present on it

  • activation inhibits NTission from the neuron

  • e.g., non-histaminergic neuron

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effect of serotonergic neurons

  • project to higher brain centers

  • affects mood and has effects on secondary NTission

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how were SSRIs formed

  • by removing α1, muscarinic, histaminergic and NA reuptake blocker activities from TCA

  • only SRI was kept

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what normally happens in depressed ppl

somato-dendritic release of 5HT in raphe nuclei

  • SERT (serotonin transporter) takes up 5HT

  • 5HT1A dendritic autoreceptors take up 5HT to inhibit firing of serotonergic receptors

  • Axon collateral release of 5HT

  • serotonin available in the synaptic space ↓ses

  • hence depression

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mechanism of SSRI

  • binds to SERT, blocks it

  • ↑ses serotonin in somatodendritic region

  • downregulates 5HT1A receptors and hence they ↓se in no.

  • neuron gets disinhibited

  • firing rate of serotonin in synaptic space ↑ses

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reason for delayed onset of action of SSRIs

  • downregulation is mediated by genomic mechanisms

  • hence reduction of 5HT1A receptors is not immediate

  • ∴ delay in producing ↑se in serotonin at terminals occurs

  • hence delay in therapeutic effects/onset of action

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Neurogenic hypothesis

new neurons in adult brain needed for proper mood control + for antidepressant efficacy

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most prescribed class of antidepressants

SSRIs

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examples of SSRIs

  • fluoxetine - Prozac = long half-life (~ 4 days) same effect, less drug

  • sertraline - Zoloft

  • paroxetine - Paxil

  • citalopram - Celexa

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55

advantages of SSRIs

much much much safer than MAOis and safer than TCAs for overdose

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side effects of melatonin

  • disturbed circadian rhythm

  • nausea, anorexia, insomnia, sexual dysfunction

  • possibly ↑ed suicidal thoughts in young adults

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how do SSRIs disturb the circadian rhythm

  • serotonin = precursor to melatonin

  • in presence of SSRIs = 5HT is reduced in neuron and is instead synthesised and released

  • ∴ less of it is available for production of nor melatonin

  • ∴ less melatonin

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58

features of NDRI

  • used to stop smoking bc = ↑sed dopamine levels help in reducing craving

  • e.g., bupropion = Wellbutrin, Zyban

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side effects of NDRIs

  • feeling of restlessness

  • high bp

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features of SNRI

  • inhibit reuptake of 5HT, NA and some DA

  • effects on reuptake NTs vary acc to dose = 5HT → NA → DA

  • claim to produce more rapid effect = 1 wk

  • e.g., venlafaxine = Effexor

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side effects of SNRIs

  • nausea

  • dizziness

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what is disinhibition

antagonists of a heteroreceptor prevent inhibitory effects of the agonist

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SNDI features

  • α2 antagonists = block α2 receptor-mediated -ve feedback inhibition (essentially blocks both auto and heteroreceptors to)

  • ↑se release of NA and 5HT

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5HT1D

presynaptic + dendritic autoreceptor for serotonergic neurons

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5HT1A, 5HT2A/B

postsynaptic stimulatory receptor

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5HT2C

postsynaptic stimulatory heteroreceptor on adrenergic and dopaminergic neurons

hence, inhibit NTission

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67

mechanism of action of SNDIs/NaSSAs + example

boosts NTs 5HT and NE by:

  • blocking α2 adrenergic presynaptic autoreceptor

    • ↑ses NE NTission (disinhibition)

  • blocking α2 adrenergic presynaptic receptor on 5HT neurons (heteroreceptors)

    • ↑ses 5HT NTission

  • E.g., Mirtazapine

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what do SNDIs also acts as and how

  • act as NaSSAs by blocking certain 5HT receptors (helps prevent many side effects)

    • 5HT2C antagonist = more NA secretion → anxiolytic

    • 5HT2A + 5HT2C antagonist = reduces insomnia, sexual dysfunction

    • 5HT3 antagonist = reduces nausea and GI upset

  • blocks H1 receptors to reduce insomnia

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how do SARIs work

  • highly sedating = excellent non-dependence, hence hypnotic

  • has v little α1, H1 and HT2A+C antagonism + SRI

  • ↑se 5HT levels + block 5HT2A+C which are resp for side effects caused by excess 5HT present

  • combining SRI with 5HT2A+C antagonism leads to antidepressant function w/o sexual dysfunction, anxiety, or insomnia

  • dosing of the drug will determine if its primarily pro-sleep (hypnotic) (25-150mg) or antidepressant (150-600mg)

  • e.g., Trazodone

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how does combining SRI with 5HT2A+C antagonism in SARIs prove to be helpful

  • combining SRI with 5HT2A+C antagonism leads to antidepressant function w/o sexual dysfunction, anxiety, or insomnia

  • dosing of the drug will determine if its primarily pro-sleep (hypnotic) (25-150mg) or antidepressant (150-600mg)

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what will happen if SARI trazodone if combined w SSRIs/SNRIs?

  • can potentially treat insomnia + anxiety associated w depression itself ++ prevent it too caused by more 5HT

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side effects of SARIs

  • low level of α1 antagonist activity = can cause hypotension

  • metabolite is active

    • trazodone is converted into active metabolite called meta-chloro-phenyl piperazine (mCPP)

  • has high affinity for 5HT2A+C, 5HT1A

    • acts mostly as agonists in these

    • can result in anxiety in some

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73

two mood stabilisers (simply used for maintenance in bipolar)

  • lithium

  • valproic acid

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74

how does Li work as a mood stabiliser

mechanism

  • Li enters via Na channel

  • blocks both inositol phosphatase that dephosphorylates

    • IP2 → IP1

    • IP1 → free inositol

  • hence blocks inositol signaling cascade in brain

  • blocks regeneration of PIP2

  • affects central adrenergic, muscarinic and serotonergic NTission

  • promotes GABA-ergic NTission

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features of Li as mood stabiliser

  • mainly used as prevention + maintenance for bipolar (not for people at the height of mania)

  • long half-life

  • narrow therapeutic window → hence patients have to be highly monitored

  • anxiety is treated by

    • ↓se in NE effects

    • ↑se in 5HT effects

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side effects of Li

  • nausea

  • polyuria (↑se in peeing) + thirst

  • tremor

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Valproic acid features

  • elevation of GABA conc

  • inhibition of neuronal voltage-gated Na+ channels

  • act as anticonvulsants

  • highly effective

  • 1st choice for

    • rapid cycling

    • mixed mania

    • mania w hallucinations

    • delusions

    • an option if patient cannot tolerate side effects of Li

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anxiety (physical) symptoms

headache, sweating, palpitations, dyspepsia, etc., all in rxn to a perceived threat which is vague, internal + unknown

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what causes anxiety, panic attacks, tremors, etc

monoamines from locus coeruleus activate the amygdala which causes these

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how do you inhibit activation of amygdala

by using benzodiazepines (GABA)

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81

most abundant inhibitory NT in CNS

GABA = amino butyric acid

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what is GABA synthesized and destroyed by

synthesize = from glutamate via glutamic acid decarboxylase

destroy = by GABA transaminase

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83

BZD potentiate activation of what

GABA A receptors

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84

BZD are +ve/-ve AMs?

+ve = PAMs

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how do BZD act as PAMs for GABA A receptors

binds to allosteric site on receptor and ↑ses action of GABA A receptors, hence PAMs

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86

3 types of anxiolytics?

  • GABAergic

    • benzodiazepines

    • non benzodiazepines

  • Serotonergic

  • Noradrenergic antagonist

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BZD features

  • ↑ses effect of endogenous GABA

  • uses

    • reduction of anxiety + aggression

    • sedation + induction of sleep

    • muscle relaxants (central action)

    • as antiepileptic drugs

  • bind to GABA A α subunits: α 1, 2, 3 & 5

    • all are associated with diff effects and hence they have wide range of effects

  • E.g., Diazepam (Valium), Lorazepam (Ativan), Clonazepam

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what does Diazepam metabolize into? how does that help?

  • metabolises into active metabolite called Nordazepam

  • active metabolite has has longer half-life (bc its still biologically active)

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what is VLPO

  • Ventrolateral Preoptic Nucleus of the Hypothalamus (sleep center)

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2 main effects of BZD

  • anxiolytic effect = inhibit activation of amygdala by binding to the GABA A receptors in the amygdala

  • hypnotic effect = promote sleep by binding at GABA A-R in VLPO, causing sleepiness

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how does BZD affect sleep badly

ppl don’t get restful nights sleep on these, since they just induce sleep

stage 4 of deep sleep is never reached

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side effects of BZD

  • excessive drowsiness

  • ataxia (bc regular NTission of motor neurons is inhibited)

  • Dependence, tolerance (14) days and abuse

    • prolonged usage results in withdrawal

  • dangerous when combined w alcohol

  • possible anterograde amnesia

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non BZD features

  • rapidly becoming 1st line treatment of insomnia

    • induce sleep but don’t disrupt sleep cycle like BZD

  • demonstrate less unwanted cognitive, memory and motor side effects

  • better pharmacokinetics

  • rapid onset and short duration of action

  • e.g., zaleplon, zolpidem, zopiclone

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how does Zaleplon and Zolpidem aid as hypnotics

are α1 selective hypnotics

  • bind selectively to α1 subunit (sleep) of GABA A receptors

  • this subunit is imp for sedation and possibly for anticonvulsant and amnesic actions

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features of serotonergic anxiolytics

  • less sedative

  • less interaction w alcohol

  • less potential for abuse

  • there is delay in onset of action

  • E.g., Buspirone

    • 5HT1A partial agonist

    • interacts w somatodendritic -ve feedback receptors

    • ↓es release of 5HT by stimulating -ve feedback in controlled fashion

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side effects of serotonergic anxiolytics

  • vertigo

  • “woozy” feeling

    • probably due to interactions w postsynaptic 5HT1A receptors

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Noradrenergic anxiolytics features

  • reduces symptoms like = anxiety, tachycardia, dilated pupils, tremors, sweating

  • α2 agonist, e.g., clonidine

    • useful in reducing these symptoms

    • not v effective in reducing the emotional aspects of anxiety

  • β adrenergic antagonists, e.g., propranolol

    • useful in treatment of social phobia, stage-fright type of anxiety + anxiety associated w the memory of stressful events

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98

street drugs

  • anxiolytics

    • flunitrazepam = Rohypnol

    • GHB

  • Sympathomimetics

    • MDMA = ecstasy

    • Methamphetamine

    • Methylphenidate

  • Anesthetic

    • Ketamine

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99

flunitrazepam/Rohypnol (roofies) features

bzd used for

  • short-term treatment of insomnia

  • sedative hypnotic

  • preanesthetic medication

physiological effect is similar to diazepam but 10x more potent

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100

GHB

  • gamma hydroxybutyric acid

  • occurs naturally in mammalian brain

  • acts on GABA + GHB receptors, either directly or by converting GHB to GABA

  • synthesis = mixing gamma butyrolactone + NaOH is proper amts

  • often tinted blue with food coloring

  • danger lies in = possibility of ingesting impurities or unreacted substrates

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