Exam 2

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121 Terms

1

What are the major inhibitory amino acids

GABA and Glycine

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2

What is GABA made from? Via what?

Glutamate via glutamic acid decarboxylase (GAD)

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3

GABA is transported into vesicles via _____

Vesicular GABA transporters (VGAT)

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4

GABA is removed from the synaptic cleft by...... (3 types of transporters)

GAT-1, GAT-2, GAT-3

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5

Removal on neurons:

GABA is either reloaded into vesicles or metabolized to glutamate and succinate by GABA aminotransferase (GABA-T)

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6

Removal on astrocytes:

Glutamate is converted to glutamine by glutamine synthetase --> glutamine can be released by astrocytes ---> taken up by neuron & converted back to glutamate --> remade into GABA

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7

To raise GABA at synapse:

- Block GABA-T (gaba stays & does not get picked up)

- Block GAT1, 2, or 3

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8

What happens to GABA release if you block GAD

decreased production of GABA --> less available in synapse

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9

What about blocking the vesicular transporter (GABA)

GABA is not present to be released (decreased GABA release)

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10

Why won't precursors to GABA work?

Glutamate: excitatory

Glutamine: too standard of a precursor (used for others)

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11

GABA A channels:

-Move ____ into cell

- ________ and ______ occurs at the postsynaptic cell

- __#_ subunits - Various combos of ___ subunits:

1. Cl-

2. Hyperpolarization

3. four: α, β, γ, δ

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12

Both Benzos and barbiturates are......

both have different what kind of binding sites

PAMS & allosteric (binds outside active site)

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13

BZD increases _______ of opening (only if ___ subunit is present)

BZD _____ a subset of GABAa receptors

frequency, γ, potentiate

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14

barbiturates increase ______ of opening

duration

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15

Both BZD & barbiturates have broadly ____ effects but _______ are much stronger.

depressive, barbiturates

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16

NAMS at BZD promote.......

anxiety, arousal, & seizures

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17

Vigabon

- treatment for epilepsy

- responsible for converting GABA transported into neurons into glutamate

-prevents GABA metabolism = increased presynaptic GABA levels

- can affect vision ---> impacts GABAergic interneurons in the retina.

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18

Carbamazepine

- treatment for epilepsy

-Stabilizes inactive state of sodium channels

- reduced neuronal firing

-potentiates SOME GABAa receptors

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19

Lamotrigine

- treatment for epilepsy

-a sodium channel blocker

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20

Ketogenic Diet and Epilepsy: potential mechanisms

- net increase of GABA levels --> suppresses neuronal firing

- inactivation of VGLUT --> less loading GABA in vesicles = lower GLU levels

-altered levels of other NTs (NE, adenosine or 5-HT)

-antioxidant effect

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21

Glutamate Cycle

-EAAT1 & 2 located on astrocytes

-EAAT3 located on presynaptic terminal of neuron

Astrocyte: GLU --> glutamine synthase --> glutamine -> goes through glutamine transporters --> neuron terminal

Neuron terminal Glutamine --> Glutaminase --> Glutamate

VGLUTs load glutamate through vesicles: GLU--> EAAT3 --> VGLUT --> Glutamate in vesicle

<p>-EAAT1 &amp; 2 located on astrocytes</p><p>-EAAT3 located on presynaptic terminal of neuron</p><p>Astrocyte: GLU --&gt; glutamine synthase --&gt; glutamine -&gt; goes through glutamine transporters --&gt; neuron terminal</p><p>Neuron terminal Glutamine --&gt; Glutaminase --&gt; Glutamate</p><p>VGLUTs load glutamate through vesicles: GLU--&gt; EAAT3 --&gt; VGLUT --&gt; Glutamate in vesicle</p>
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22

VGLUT1 knockout mice

survive birth but begin to die during the third week of life

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23

VGLUT2 knockout mice

die immediately after birth

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24

VGLUT3 knockout mice

are viable but completely deaf; the inner hair cells of the cochlea use glutamate as the neurotransmitter

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25

VGLUT blockers

should reduce levels of GLU released --> used to treat excitotoxicity

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26

NMDA & Long term potentiation

-NMDA receptor is located at post synaptic terminal & responds to GLU

-NMDA has a Mg2+ ion block

- Presynaptic AMPA receptors are activated --> allows influx of Na+

- At sufficient depolarization Mg2+ block is lifted from NMDA Channels

- subsequent stimuli allows for Na+ and Ca2+ influx through NMDA

-Ca2+ is linked to induction of long-term enhancement of signaling at the spine (LTP)

<p>-NMDA receptor is located at post synaptic terminal &amp; responds to GLU</p><p>-NMDA has a Mg2+ ion block</p><p>- Presynaptic AMPA receptors are activated --&gt; allows influx of Na+</p><p>- At sufficient depolarization Mg2+ block is lifted from NMDA Channels</p><p>- subsequent stimuli allows for Na+ and Ca2+ influx through NMDA</p><p>-Ca2+ is linked to induction of long-term enhancement of signaling at the spine (LTP)</p>
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27

AMPA-kines

drugs that enhance action of AMPA receptors

- maybe by reducing rate of desensitization

- maybe by acting as a PAM

- works in animal models & mixed results in humans

increased neurotransmission --> facilitate LTP --> increase cognitive function (thought to be used in neurodegenerative diseases)

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28

Zinc and NMDA-sensitive glutamate-gated channels (two mechanisms)

Zinc directly inhibits

1) High-affinity binding to N-terminaldomains of Glu NR2A subunits reduceschannel open probability

2) Low-affinity voltage-dependent binding topore-lining residues blocks the channel

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29

Doogie Mouse

NMDA receptor geneticaly altered to stay open longer, allowing more calcium influx, more robust LTP, and enhanced memory

NR2B subunit of NMDA receptor --> over expressed -> greater ratio of NR2B subunits = longer NMDA receptor opening

note: more sensitive to certain forms of pain

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30

Necrosis

Uptake: cell contents are ingested by macrophages with significant inflammation

Membrane: Loss of membrane integrity with cell lysis occurring

Organelles: organelle swelling + lysosomal leaking & random degradation of DNA

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31

Apoptosis

Size: cellular shrinkage with one cell being affected

Uptake: cell contents ingested by neighboring cells with no inflammatory response

Membrane: membrane blebbing & Apoptotic bodies forming

Organelles: mitochondria release prop-apoptotic proteins with the presence of chromatin condensation and non-random DNA degradation.

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32

How can ischemia cause an increase in glutamate release:

Ischemia = temporary stoppage of blood flow/oxygenation to tissue

- lack of O2 --> interferes with ATP production

- when ATP dependent ion pumps fail --> cell is depolarized

-voltage gated Ca channels open = intercellular Ca2+ levels rise

- stimulates glutamate release --> AVALANCHE

- glutamate activates AMPA & NMDA receptors --> Ca2+ influx in downstream neurons

-excitotoxicity

- second wave: cells that die of necrosis release glutamate into interstitial space, also exciting neighboring cells. --> advantage of having microphages/microglia absorb dying cells

Once blood flow returns --> reperfusion injury --> increased permeability of blood vessels = inflammatory response.

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33

Caffeine as an antagonist

blocks activity

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34

what type of receptors are Adenosine A1

G i/o coupled

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35

what type of receptors are Adenosine A2a

Gs coupled

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36

what type of receptors are Adenosine A2b

G s/q coupled

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37

what type of receptors are Adenosine A3

G i/q coupled

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38

Caffeine at higher doses

-Inhibition of phosphodiesterase: increase cAMP =paralysis in insects

- Blocking of GABAa receptors

- Stimulation of Ca2+ release

- enters toxic range

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39

Malignant hyperthermia

inherited disorder that causes a severe reaction to certain anesthetics

<p>inherited disorder that causes a severe reaction to certain anesthetics</p>
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40

Treatment for malignant hyperthermia

Dantrolene

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41

What genetic mutation is associated with malignant hyperthermia?

Mutation affecting the RYR1 protein in skeletal muscle

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42

What are the two sites on the RYR1 protein responsible for controlling calcium concentration?

A-site and I-site

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43

What is the function of the A-site on the RYR1 protein?

Mediates RYR1 opening with high affinity for calcium

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44

What is the function of the I-site on the RYR1 protein?

Mediates RYR1 closing with low affinity for calcium

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45

What role does magnesium play in the function of the RYR1 protein?

Causes RYR1 protein to close by acting on the I-site

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46

MH: triggering agents

Caffeine, halothane, etc.

- acts by drastically increasing the affinity of the A-site for Ca while simultaneously decreasing the affinity of the I-site in mutant MH proteins.

- Also includes a greatly decreased affinity for Mg.

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47

End result of triggering agents (MH)

increased Ca release due to lowered activation and heightened deactivation threshold.

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48

Most & Least Potent hallucinogens

Most: LSD

Least: Mescaline

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49

How are most hallucinogens administered

they are ingested

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50

Duration of Hallucinogen Effects

begins at 30-90 mins --> LSD trip can last for 6-12 hours

- smoked DMT & Sativa: felt in secs --> peaks in minutes --> gone in an hour

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51

2C-x

Family of psychedelic phenethylamines originally synthesized byAlexander Shulgin

• Early pesticide work with Dow Chemical

• Systematically tested compounds on himself

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52

PCP and ketamine binding site/receptors

noncompetitive antagonists at NMDA receptors

inside the receptors ion channel, separate from the site at which glutamate or NMDA binds

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53

Chronic Use of PCP or Ketamine: negative effects

- Urological signs: bladder pain and incontinence

-deficits in memory/ other cognitive functions

- Grey and White matter abnormalities (chronic ketamine)

-Repeated administration of high doses of ketamine = apoptotic cell death in developing brains of rats and monkeys

This is concern because Ketamine is a common anesthetic agent for pediatric procedures

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54

How can you increase catecholamine synthesis?

administering a precursor

example: LDOPA & treating parkinson's disease

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55

Pathway to dopamine and NE

tyrosine --> TH --> DOPA --> AADC --> DA--> DBH --> NE

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56

Alpha-methyl-para-tyrosine (AMPT)

Blocks TH --> prevention of catecholamine synthesis

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57

After catecholamine synthesis.........

- catecholamines are packaged into vesicles

OR

- is broken down --> decreased levels = sedation and depression

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58

What drug blocks VMAT 2 & 2

reserpine

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59

What type of receptor subtypes are present in DA-ergic system? How many?

- metabotropic

- 5

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60

D1 & D5 (G...... coupled)

Gs coupled

also know as "D1 like"

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61

D2, D3, D4 receptors

separate family --> Gi/o coupled

Also know as "D2 like"

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62

dopaminergic system: D1 & D2 signalling

knowt flashcard image
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63

alpha1 receptors (four main areas)

1. Blood vessels: vasoconstriction, increased BP, increased contractibility of the heart

2. eye: Mydriasis (dilation)

3. bladder: relaxation

4. prostate: contraction

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64

alpha2 receptors (two main areas)

1. blood vessels: decreased blood pressure

2. smooth muscles (GI tract): decreased GI tone and motility

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65

beta1 receptors (2 main areas)

1. heart: increased heart contraction and increased heart rate

2. kidney: increased renin secretion, increased angiotensin, and increased blood pressure

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66

beta2 receptors (4 main areas)

1. smooth muscle (GI tract): decreased GI tone and motility

2. Lungs: bronchodilation

3. uterus: relaxation of uterine smooth muscle

4. Liver: activation of glycogenolysis, and increased blood sugar

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67

Alpha1 Adrenergic Blockers

opposite functions of sympathetic nervous system --> decreased smooth muscle contraction and blood vessel dilatation

treats hypertension and benign prostatic hyperplasia

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68

Beta1

main subtype of the heart

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69

propranolol: what does it block? What does it do?

blocks β-receptors in the heart, reducing contractile force

makes anxiety FEEL less overwhelming

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70

How do you make serotonin

Tryptophan —> TH —> 5-HTP —> AADC —> 5HT—> serotonin

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71

What will given Tryptophan do?

increase production of 5HT

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72

Serotonin Cycle:

5-HT released by vesicles —> 5HT transporter (SERT) takes it back into serotonergic neuron —> Transported into vesicles by VMAT2—> Metabolized by MAO to 5-HIAA

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73

What is the target for SSRIs

SERT

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74

What does reserpine do as a VMAT2 blocker

Depletes 5-HT —> is then broken down when not protected in vesicles

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75

Which MAO is located in neurons vs gilal cells?

MAO-A is located in neurons, MAO-B is located in gilal cells.

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76

Serotonin receptors and appetite (reduced food intake)

5-HT1B or 5-HT2C receptor agonists, and 5-HT6 antagonists produce
hypophagia (reduced food intake)

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77

Serotonin receptors and appetite (increased food intake)

5-HT1A agonists can lead to hyperphagia (increased food intake).

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78

Where are 5-HT3 receptors located?

On the peripheral terminals of the vagus nerve

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79

Chemo and 5-HT3 receptors

induces vomiting

antagonists can be used to treat the nausea

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80

Pathological Aggression

Prevalent in men —> comorbidity with a lot of things such as substance abuse, depression, and anxiety disorders.

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81

Pathological aggression: threat perception and risk assessments

alteration can affect aggression —> reactive aggression associated with poor recognition of facial cues

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82

Pathological aggression: circuit

amygdala —> orbito frontal and orbital prefrontal cortex (OPF cortex)

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83

Lesion of the OPF cortex……

massive agression

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84

Arsenic toxicity: target organs

Blood, Kidneys, CNS, digestive, and keratinized tissues

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85

Arsenic has a high affinity for a…..

sulfhydryl chemical group (thiol)

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86

Amino acids that contain sulfur:

cysteine and methionine

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87

Where are skin affects of arsenic seen at

hands and feet

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88

Arsenic poisoning: impedes….. and may also alter……

DNA repair system & DNA methylation (alters gene expression)

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89

Brain barrier to prevent metal insults from blood beyond the BBB

choroid plexus (CP)

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90

True or false: Cadmium can cross BBB

true

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91

cd concentration in blood is about —— times higher than found in the brain cortex

2.5x

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92

the CP contains abundant WHAT binding ligands

metal

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93

BBB and CP structures in young Individuals…. does it make it easier or harder for Cd to reach the brain

NOT FULLY DEVELOPED & EASIER —> DEVELOPMENTAL TOXIN

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94

Itai Itai disease

  • Chronic Cd poisoning that happened in japan

  • 1912-1942

  • ‘it hurts it hurts’ disease

  • Cd orginated from downstream of major mining site

  • Link to Cd was not id’ed until 1968

  • softening of the bone as Cd substitutes Ca

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95

Dimercaprol: what is it?

  • BAL

  • drug of choice fr treatment of gold, lead, arsenic, copper, and mercury toxicity

  • used as an antidote to the chemical weapon Lewisite

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96

How is Dimercaprol administered

Deep IM injection

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97

Dimercaprol: What does it do?

- Extracellular and intracellular cation scavenged

• Enhances fecal and urinary elimination

• Diffuses into brain and RBC's

  • IS TOXIC ITSELF WITH A NARROW THERAPEUTIC RANGE

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98

What else is Dimercaprol useful for?

Apparently also useful for some snake-bites
• Zinc-dependent metalloproteinases in viper venom
• Chelates the zinc

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99

EDTA

  • second line of treatment for lead toxicity

  • more effective when given early in acute poisoning

  • CHELATES ONLY EXTRACELLULAR LEAD

  • may also induce CNS toxicity if BAL therapy not initiated first

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100

EDTA —> when does therapy start? How is it administered?

  • 4 hrs after BAL is given

  • Only given via IV by continuous infusion

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