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Pharm Drugs 1 > Benzodiazepines/Barbs/ Non-Barb Induction Agents > Flashcards

Benzodiazepines/Barbs/ Non-Barb Induction Agents Flashcards

1
Q

5 Pharmacological Effects of Benzos

A

anxiolysis, anterograde amnesia, anticonvulsant, muscle relaxant (spinal level only), sedation

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2
Q

Benzos do not produce skeletal muscle relaxation adequate for what

A

surgery

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3
Q

This action of benzos does not alter the dose of what class of drugs required for procedures/surgery

A

skeletal muscle relaxation effect does not alter the dose of Muscle Relaxants required for procedures/surgery

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4
Q

Benzo potential for tolerance and abuse is what relative to opioids/barbs?

A

less than that for opioids/barbs

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5
Q

how is the margin of safety for benzos (in regards to OD)?

A

greater margin of safety (“ceiling effect”)

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6
Q

Benzos and hepatic enzymes

A

benzos do NOT induce hepatic enzymes

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7
Q

benzos have replaced what drug class for these 2 things

A

replaced barbs for 1) premeds and 2) MAC sedation

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8
Q

What is specific to benzos that sets it apart from other drugs used for sedative properties?

A

benzos have a specific antagonist–winning.

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9
Q

Benzo structure

A

Benzene ring, fused with 7-member diazepine ring

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10
Q

Benzo Mechanism of Action

A

1) Facilitate the action of GABA at GABA-A
2) Increase the affinity of GABA for its receptor

note: does NOT activate GABA-A receptor

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11
Q

How do Benzos differ from each other?

A

Potency, Lipid Solubility, Pharmacokinetics

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12
Q

Benzos are generally what (pharmacokinetically)

A

1) highly lipid soluble

2) highly bound to plasma proteins (albumin)

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13
Q

Affinity for GABA-A enhances/ does what?

A

1) opening of Cl- channels (inhibitory)
2) increases Cl- gated conductance
3) hyperpolarization of the post-synaptic membrane
4) increases resistance of post-synaptic membrane to excitation

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14
Q

What is the principle inhibitory neurotransmitter in the CNS?

A

GABA

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15
Q

What do Benzos do with GABA?

A

They FACILITATE the actions of GABA at its receptor (GABA-A)

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16
Q

What constitutes the GABA receptor? Where does GABA bind?

A

5 subunits.

GABA binds at the two Beta sites (similarity to nicotinic receptor)

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17
Q

Sequence of Benzo Action.

A

1) Benzo binds to the GABA-A receptor
2) Cl- channels remain open, influx of Cl- (increased Cl- conductance)
3) hyperpolarization of post-synaptic membrane (cannot respond to further stimulation)

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18
Q

GABA-A is what, and contains what?

A

GABA-A is a macromolecule that contains distinct binding sites where GABA, Benzos, Barbs, and ETOH bind

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19
Q

Why are benzos used to treat withdrawal?

What can a combo of benzos and ETOH lead to?

A
  • Pharmacologically, there is cross-tolerance and synergy. Substitute one addiction with another temporarily.
  • combo can lead to OD/CNS depression
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20
Q

Where are GABA-A found? and what does this mean systemically?

A

on post-synaptic receptors in the CNS. So they have little effect outside of the CNS.

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21
Q

Describe the “ceiling effect” associated with benzos

A

Once the Cl- channel is open and the membrane is hyperpolarized, that’s it as far as the effect can go.
Thus, a fairly wide safety margin with benzos.

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22
Q

General Properties of Midazolam (Versed)

  • preparation
  • chemical structure
  • pharmacokinetics
A

1) water soluble preparation
2) Imidazole ring
3) 2-3x potency of diazepam
4) 0.9 - 5.6 min effect site equilibration
5) EXTENSIVE hepatic first-pass effect
6) 90- 98% protein bound
7) Rapid redistributon- short duration
8) T 1/2 Elimination = 1- 6.5 hrs

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23
Q

How much more potent is Versed (midaz) vs Valium (diaz)

A

2-3x more potent!!!

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24
Q

T1/2 Elimination of Versed

A

1- 6.5 hrs

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25
Q

Versed: Length of effect site equiibration

A

0.9- 5.6 minutes

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26
Q

Versed: % protein bound

A

90 - 98% protein bound

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27
Q

Why does Midazolam have a short duration?

A

rapid redistribution

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28
Q

Midazolam: Metabolism

A

1) Extensive hepatic metaboism
2) hydroxylation to water-soluble compounds:
1- and 4- hydroxymidazolam
3) active metabolite: 1-hydroxymidazolam
4) conjugated and excreted in urine
5) Renal failure does not affect Vd, T1/2E, or clearance

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29
Q

Metabolic mechanism/product of Midazolam

A
  • hydroxylation to water soluble compounds

- 1- and 4- hydroxymidazolam

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30
Q

Midazolam: Active Metabolite

A

1-Hydroxymidazolam

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31
Q

Midaz: Though it is conjugated and excreted in urine, Renal Failure does not affect what in this drug?

A

Vd, T1/2 Elimination, or Clearance

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32
Q

Midaz: CNS Effects

A

1) decrease CBF and CMRO2
2) does NOT produce isoelectric EEG
3) preserves cerebrovascular response to CO2
4) does NOT attenuate ICP response to laryngoscopy
5) potent anticonvulsant and amnestic
6) paradoxical excitement — RARE.

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33
Q

Midaz does not produce what on EEG?

A

isoelectric EEG

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34
Q

Midaz: ICP and Laryngoscopy

A

Midaz does not reduce ICP during laryngoscopy :(

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35
Q

Midaz: Respiratory/ Airway Effects

A

1) dose dependent decrease in ventilation
2) hypoxemia and hypoventilation enhanced in presence of Opioids

3) depresses swallowing reflex
4) decreases upper airway activity

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36
Q

Midaz: CV Effects

A

1) decreases SVR at induction dosage
2) BP consequently decreases
3) CO unchanged
4) Does not prevent HR and BP changes with intubation

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37
Q

Midaz does not do what to the CVS with intubation?

A

It does not prevent HR/BP changes during intubation

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38
Q

Midazolam (Versed): Uses

A

1) Premedication
2) IV Sedation
3) Induction
4) Maintenance

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39
Q

Midazolam: Doses

A

1) Premedication/ Pediatrics
- 0.25 - 0.5 mg/kg PO, MAX PO= 20 mg

2) IV Sedation/ Adults
- 1 - 2.5 mg IV (can give as high as 5 mg, PRN)

3) Induction
- 0.1 - 0.2 mg/kg over 30-60 sec

4) Maintenance: incremental or infusion

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40
Q

Valium (Diazepam) General Characteristics

A
  • highly lipid soluble with prolonged duration of action
  • highly protein bound
  • commercially prepared in organic solvents including propylene glycol and benzyl alcohol
  • viscous
  • pH 6.6 - 6.9
  • painful IV/IM injection
  • PO rapidly absorbed from GI tract
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41
Q

What are propylene glycol and benzyl alcohol, what are they used for, and what do they cause?

A

they are organic solvents used to prepare Diazepam/Lorazepam(PG only) that cause pain upon injection

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42
Q

Diazepam: Metabolism

A
  • oxidation, n-demethylation to desmethyldiazepam, oxazepam, and temazepam by hepatic microenzymes
  • conjugated to glucouronic acid prior to renal excretion
  • desmethyldiazepam (active metabolite) is oxidized, conjugated, and excreted in urine
  • Cimetidine [blocks secretion of acid in stomach] effect on metabolism: inhibits CYP-450
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43
Q

metabolic byproducts of Diazepam

A
  • desmethyldiazepam (active)
  • oxazepam
  • temazepam
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44
Q

diazepam metabolites are conjugated to what substance in order to be excreted?

A

glucouronic acid

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45
Q

what is the active metabolite of diazepam and how is it metabolized?

A

desmethyldiazepam is oxidized, conjugated, and then excreted in urine

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46
Q

what is the effect of Cimetidine on metabolism of diazepam?

A

it inhibits the CYP-450 system

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47
Q

Diazepam (and active metabolite) : Elimination T1/2

A
  • Diazepam= 21 - 37 hours in healthy; increases with age

- Desmethyldiazepam= 48 - 96 hours

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48
Q

Diazepam: CV Effects

A
  • minimal changes in SVR, BP, CO ( <20% change)

- other system effects similar to midazolam: aka “Does not prevent HR and BP changes with intubation”

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49
Q

Diazepam: Uses/Doses

A

Premedication/PO
- 10-15 mg

Premedication/IV
- 0.2 mg/kg (reduces MAC)

Induction
- 0.5- 1.0 mg/kg IV

Anticonvulsant
- 0.1 mg/kg IV

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50
Q

Diazepam: Uses

A
  • Premedication
  • Induction
  • Anticonvulsant (inhibit activity in Hippocampus and the Limbic System)
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51
Q

Ativan (Lorazepam): General Characteristcs

A
  • 5-10x the potency of Diazepam
  • MOST POTENT amnestic of the benzos used in anesthesia
  • Metabolites are pharmacologically INACTIVE
  • T1/2 Elimination= 10-20 hours
  • Metabolism less influenced by alteration in hepatic function, age, and other drugs
  • Propylene glycol as solvent (ouch)
  • slow onset limits usefulness (distinguishing feature)
    - 2 hrs to peak plasma concentractions
52
Q

Benzos: order of potency

A

1) Lorazepam #strongAF (5-10x potency of diazepam)
2) Midazolam #basicAF (2-3x potency of diazepam)
3) Diazepam #weakAF

53
Q

Lorazepam (Ativan) Dose/Max Dose

A

Premedication/PO

- 50 mcg/kg [0.05 mg/kg] max= 4 mg

54
Q

Lorazepam metabolism is less influenced by what

A

alterations in hepatic function, age, other drugs

55
Q

$192,526

A

The median annual Certified Nurse Anesthetist salary in Washington, DC is $192,526, as of September 27, 2017.

With a range usually between $176,944-$210,005 NOT including bonus and benefit information and other factors that impact base pay.

(are you re-motivated yet)

56
Q

What is the distinguishing feature of Ativan (Lorazepam)?

A

SLOW onset.
2 hours to peak plasma []

***this limits usefulness

57
Q

Romazicon (Flumazenil): General Characteristics

A
  • Imidazobenzodiazepine derivative
  • specific, competitive benzo antagonist with HIGH affinity for benzo receptor
  • antagonizes depression of ventilation and sedation
  • Hepatic metabolism and Renal excretion
58
Q

Romazicon (Flumazenil): Dose (Methods and Duration)

A

Reversal:
- 0.2 mg IV initial. [Wait 2 mins]
- 0.1 mg IV subsequent doses, 60 sec intervals
MAX= 3 mg/hr

Infusion:
- 0.1- 0.4 mg/hr [0.5- 1 mcg/kg/min]

Duration of action: 30-60 mins– may need to repeat or supplement

59
Q

Romazicon special use

A

differential diagnosis of coma
- give up to 5 mg

sidenote: *potential tx for alcohol abuse.

60
Q

Romazicon: Duration of action

A

30-60 minutes, may repeat or supplement

61
Q

Romazicon: Use in Post-Ops

A

use in post-ops does not reveal an acute anxiety and neuroendocrine stress response

62
Q

Lorazepam ET1/2

A

10-20 hrs

63
Q

Barbiturates: General Info

A
  • commercially prepared as sodium salts
  • highly alkaline (bacteriostatic) pH up to 11 (turns to acid in the body)
  • At room temp, prepared Thiopental is stable/sterile for 6 days
  • Racemic prep but L-isomer is the potent one
  • ALL barbs derived from barbituric acid
64
Q

What is barbituric acid?

A

urea+ malonic acid

65
Q

Barbiturates: Structure/Activity

- chemical characteristics of a potent barbiturate

A
  • substitutions as Carbon 2 and Carbon 5 have sedative/ hypnotic properties
  • long branched chain is more potent than a straight chain
  • L-isomers 2x potency of D-isomers
  • ALL are only available as racemic mixture
66
Q

Barbs: Branched Chain at Carbon 5

A

increases hypnotic activity

67
Q

Barbs: Phenyl group at Carbon 5

A

increases anticonvulsant activity (ex: PHENObarbital)

68
Q

Barbs: Methyl radical component

A

imparts convulsant activity (ex: METHOhexital)

- used in electric shock therapy or seizure induction

69
Q

Barbs: Sulfuration

A
  • fat soluble

- lipid solubility increase= shorter duration, more rapid onset, increased potency

70
Q

Barbs:

  • Oxygen at Carbon 2
  • Sulfur at Carbon 2
A
  • OXYbarbituate

- THIObarbituate

71
Q

Barbs: Order of Relative Potency (compared to Thiopental)

A

1) Thiopental [TPL] = 1
2) Thiamylal [Surital] = 1.1
3) Methohexital [Brevital] = 2.5 (excitatory side effects)

72
Q

Barbs: Mechanism of Action

A

1) decrease rate of GABA dissociation from its receptor (increases duration of GABA activated Cl- Ch opening, ENHANCING GABA activity)

2) Decrease transmission in the sympathetic ganglia
- -> hypotension

3) Mimics GABA at the receptor (direct activation of Cl- Channels)

4) Decreases post-synaptic membrane sensitivity to ACh
- (some muscle relaxation-not surgical depth)

5) Interaction with GABA receptor
- functional inhibition of post-synaptic neuron

6) Depress RAS
- –> Sleep. (cannot maintain arousal)

73
Q

Barbiturates: Pharmacokinetics

A
  • Rapid onset of action
  • Redistribution = rapid termination of effect
  • extensive metabolism
  • Fat : Blood partition coefficient= 11 (very fat soluble)
  • TPL= 70-80% protein bound
  • Ionization: TPL, pK=7.6
74
Q

Barbs: Metabolism

  • Oxybarbiturates
  • Thiobarbiturates
  • how much excreted unchanged
A
  • Oxybarbs: hepatic only
  • Thiobarbs: hepatic and extrahepatic
  • side chain oxidation at Carbon 5 to carboxylic acid terminates activity
  • Desulfuration, hydrolysis opens ring
  • water-soluble, renal excretion
  • <1% excreted unchanged
75
Q

Barbs: T1/2 Elimination

A
  • TPL= 11.6 hrs (hangover effect)
  • Prolonged in pregnancy due to increased protein binding
  • Methohexital= 3.9 hrs
76
Q

never let anyone treat you like a yellow starburst

A

you are a pink starburst.

77
Q

At room temp, prepared Thiopental is stable/sterile for how many days?

A

up to 6 days

78
Q

Thiopental Characteristics

A
  • 1/2T Elimination= 11.6 hrs (hangover effect)
  • prolonged in pregnancy due to increased protein binding
  • TPL= 70-80% protein bound
  • Ionization: pK=7.6
79
Q

Barbs: CNS Effects

A
  • Depresses level of consciousness
  • cerebrovascular constriction, reduced CBF, decreased ICP, decreased CRMO2
  • Can produce isoelectric EEG
  • Paradoxical excitement
  • Methohexital: excitatory skeletal movements (myoclonus) and hiccups
  • Cerebral protection (?)
  • Does not preclude SSEP monitoring
  • Small doses decrease the pain threshold “anti-analgesic” (@ subanesthetic doses)
  • no skeletal muscle relaxation
  • Decreases IOP
80
Q

Barbs: CV Effects

A
  • Depression of medullary vasomotor center and decreased SNS outflow from CNS–> peripheral vasodilation –> preload decreases
  • SBP decreases, compensatory HR increase in normovolemic patients –> activation of SNS peripherally
  • Myocardial depression minimal
  • If SNS not intact or hypovolemia, or large dose given to reduce ICP, will see a significant decrease in BP or myocardial depression
  • HISTAMINE release with RAPID IV administration
  • Oral barbiturates produce minimal CV effects!!!
81
Q

Barbs: Respiratory Effects

A
  • Dose dependent depression of medullary and pontine ventilatory centers
  • decreased ventilatory response to hypoxia and hypercapnia
  • Apnea
  • Depression of laryngeal and cough reflexes incomplete
  • Note: if dose not large enough, can actually see a STAGE 2 response to airway manipulation (increased risk of laryngospasm, bronchospasm)
82
Q

Barbs: Other Effects

A
  • Hepatic enzyme induction with chronic use
  • increases metabolism of oral anticoags, phenytoin, TCAs, corticosteroids, Vit K
  • accelerated production of heme by stimulation enzyme (D- aminolevulinic acid synthetase) —> avoid in pts with porphyrias
  • Venous thrombosis
  • Readily crosses placenta
  • pts treated with barbs for seizure metabolize drugs 2x as fast as expected, especially evident in muscle relaxants
  • N/V incidence higher than midaz and prop but lower than etomidate, ketamine, and volatiles
  • Enhance their own metabolism (enzyme inducers)
  • tolerance develops more rapidly to barbiturates (moreso than can be explained by induction of hepatic enzymes, dose requirements may increase 6-fold)
  • Allergy 1:30,000 (high mortality), anaphylaxis
83
Q

Methohexital CNS Effects

A

excitatory skeletal movements (myoclonus) and hiccups

84
Q

Most potent barbiturate enzyme inducer

A

phenobarbital

85
Q

Barbiturates increase the metabolism of what

A

oral anticoags, phenytoin, TCAs, corticosteroids, Vit K

86
Q

Patients treated with Barbs for seizure disorder exhibit this characteristic

A

They metabolize drugs 2x as fast as expected, especially evident in muscle relaxants

87
Q

Barbiturate Allergy

A

1: 30,000, high mortality
- presents as anaphylaxis
- allergy usually in atopic patient– multiple allergies with prior TPL exposure

88
Q

Barbs: Usage and Doses

A

Induction of GA

 - TPL = 3-5 mg/kg/ IV - Decrease dose with age and first trimester of pregnancy

 - Methohexital= 1-2 mg/kg IV
            - 20 - 30mg/kg PR in peds

Duration of single IV induction dose is 5-8 minutes (bc redistribution)

89
Q

Not to be mixed with Barbiturates

A
  • Opioids, catecholamines, NMBs, Midazolam (acidic)
  • pancuronium, vecuronium, atracurium, alfentanil, sufentanil,
  • LR solution (acidic) will cause precipitation
  • if reconstituting powder, must use steril H20 or NS
90
Q

Barbs: Intra-Arterial Injection

A
  • IMMEDIATE intense vasoconstriction, pain
  • Mechanism: crystalline precipitation in arterial vessel, inflammatory response, vasoconstriction, microembolization

Treatment:

  • dilute with NSS
  • phenoxybenzamine
  • prevent thrombosis (heparin, urokinase)
  • brachial plexus or stellate ganglion block (sympathectomy)
  • Papaverine 40-80 mcg in 10-20 mL saline
  • 5-10mL lidocaine 1% (can cause seizures)
91
Q

General Characteristics: Propofol (Diprivan)

2,6-di-iso-propophenol

A
  • Oil at room temp (lipid soluble)
  • Supplied as 1.2% egg, 10% soybean oil, 2.25% glycerol base solution
  • Supports bacterial growth
  • discard after 6 hrs of drawing up
  • Can increase plasma glycerides with prolonged infuction
  • Caution: Egg YOLK allergies (anaphylactoid reactions have been reported)
  • Diprivan- EDTA (disodium edetate)
  • Propofol (generic)- sodium metabisulfite–> Bronchospasms!
92
Q

Propofol: Mechanisms of Action

A
  • Receptor interactions:
    • GABA-A (minor)
    • Glycine (major)
  • decrease rate of dissociation of GABA from GABA-A
  • no spinal cord depression
93
Q

Propofol: Pharmacokinetics

A
  • Vd= 3.5- 4.5 L/kg
  • Clearance exceeds hepatic blood flow
  • 2-3 compartment model of disctribution
  • weight, coexisting disease, age, co-admin of other drugs affect pharmacokinetics
  • T1/2 Elimination= 0.5 -1.5 hours
  • Age affects ED95 –> ED95 highest in toddlers, decreases with age. Elderly must reduce dose.
94
Q

Prop: CNS Effects

A
  • Cl- channel activation of Beta-1 subunit of GABA and slight NMDA inhibition
  • Rapid onset, one arm-brain circulation
  • Decreases CBF, ICP, CMRO2, and CPP –> cerebral protective
  • EEG burst suppression
  • Age affects ED95 –> ED95 highest in toddlers, decreases with age. Elderly must reduce dose
  • Hiccups/muscle twitching can occur
  • Hallucinations, opisthotonos (eye rolls)
  • Decreases IOP
  • Antioxidant effect –> resembles Vit E –> cerebral protective
95
Q

Prop: Respiratory Effects

A
  • Apnea following induction dose
  • Decreases ventilatory response to CO2 and hypoxia
  • PaCO2 rises, pH decreases
  • bronchodilation in COPD patients (not with metabisulfite)
  • HPV remains intact (hypoxic vasoconstriction)
96
Q

Prop: CV Effects

A
  • 25-40% decrease in BP –> greater than with STP
  • Dose Dependent myocardial depression and vasodilation result in:
    - similar decreases in SV, CO, and SVR
    - HR unchanged (baroreceptor inhibition)
97
Q

Prop: Other Effects

A
  • does NOT potentiate muscle relaxants!
  • Myoclonus: incidence higher than twith TPL but less than with etomidate and brevital
  • Pain on injection
  • anti-emetic and anti-pruritic at sub-hypnotic doses (10 mg) –>unknown mechanism
  • amnestic at > 30 mch/kg/min
  • Crosses placenta but rapidly removed from fetal circulation
98
Q

Prop: Uses and Doses

A

Induction:

 - 1 - 2.5 mg/kg 
 - Toddlers: high as 3 mg/kg d/t pharmacokinetic differences
 - 1 mg/kg won't do much unless its an oldie

GA Maintenance Infusion:
- 100-300 mck/kg/ min

Sedation:
- 25-100 mcg/kg/min

99
Q

Prop: Metabolism

A
  • conjugated in liver to water soluble
  • CYP-450
  • liver function does not affect rate of metabolism***
  • mostly inactive metabolites
  • 4- hydroxypropofol is 1/3 as potent
  • renal excretion: CRF doesn’t affect clearance
  • Highly metabolized, less than 3% unchanged
100
Q

Etomidate (Amidate): General Characteristics

A
  • Carboxylated Imidazole derivative
  • Imidazole refers to the parent compound C3H4N2
  • Propylene Glycol solvent (ouch)
  • pH= 6.9
  • water soluble in solution, but at physiologic pH becomes highly lipid soluble
101
Q

Etomidate: Mechanism of action

A
  • selective GABA-A
  • binds to a specific site on the receptor
  • increases the affinity of GABA to GABA-A
102
Q

Etomidate: Pharmacokinetics

A
  • onset of action rapid (one arm-brain circulation)
  • highly lipid soluble
  • weak base, pH=8.2
  • Vd= 2.5-4.5 L/kg
  • Redistribution terminates hypnotic effect
  • 3 Compartment model
  • T1/2 Elimination = 3-5 hrs
  • High hepatic extraction ratio and clearance–> blood flow determines extraction/clearance
  • 75% protein bound
103
Q

Etomidate: CNS Effects

A
  • Rapid loss of consciousness after single dose
  • NO analgesia
  • direct cerebral vasoconstriction results in decreases CBF, ICP, CMRO2
  • reduces IOP
  • Increases EEG activity in epileptogenic foci
  • rare association with Grand Mal seizure
  • Myoclonic movement
  • also possesses anticonvulsant properties
104
Q

Etomidate: Respiratory Effects

A
  • minimal decrease in ventilatory response to CO2 (similar to benzos)
  • decreased Vt
  • increased RR
  • hiccups, coughing
105
Q

Etomidate: CV Effects

A
  • MINIMAL effect on CV function due to lack of effect on SNS and baroreceptors
  • HR, ABP, PAP, CO, SVR, PVR unchanged (THIS is what sets this drug apart!)
106
Q

Etomidate: Endocrine Effects

A
  • dose dependent reversible inhibition of 2 enzymes in biosynthesis of cortisol/aldosterone –> prevents conversion from cholesterol to cortisol
  • —-> MAJOR: 11-beta-hydroxylase
  • ————–> Minor: 17-alpha- hydroxylase
  • results in adrenocortical suppression for 4-8 hours, reduces mineralocorticoid and corticosteroid production
107
Q

Etomidate: Uses and Doses

A
  • when you can’t use propofol
  • GREAT drug for CV disease patients

Induction:
- 0.3 mg/kg (range 0.2-0.6 mg/kg)

Maintenance infusion:
- 10 mcg/kg/min with N20 and opioid

Sedation:
- 5-8 mck/kg/min for short procedure

Rectal:
- 6.5 mg/kg in Peds

108
Q

Etomidate: Other Effects

A
  • high incidence of N/V (30-40%) – one of the most potent!!!
  • Myoclonic movements (30-60%) – inhibits the extrapyramidal system
  • Enhances NMDR activity
109
Q

Etomidate: Metabolism

A
  • Liver, ester hydrolysis
  • N- dealkylation to Carboxylic Acid (H2CO3)
  • biotransformation 5x faster than TPL
  • 85% renal, 13% biliary excretion
  • 2% excreted unchanged
110
Q

Ketamine (Ketalar): General Characteristics

A
  • phencycline derivative (PCP)
  • Lipid soluble
  • prepared in acidic solution (for shelf-life, antibacterial)
  • racemic mixture (equal R,S enantiomers)
  • S-enantiomer more potent analgesic, undergoes faster metabolism and lower incidence of emergence delirium
111
Q

Ketamine: Mechanism of Action

A
  • Interacts with following receptors:
    - **Inhibits NMDA (ionotropic glutamte receptor) “anti glutamamte”
    - **    Opioid Mu receptor (Delta, Kappa, Sigma)
    - Monoaminergic- involves descending pathways (anti-nociception)
    - Muscarinic antagonist
    - Ca Channel Inhibition
112
Q

Ketamine @ NMDA Receptor

A
  • activation results in opening of ion channel that is nonselective to cations
  • flow of Na+ and small amounts of Ca+ into cell, and K+ out of cell
  • Ca++ flux through NMDARs though to play role in synaptic plasticity (mechanism for learning/memory)
    - -> remember long-term potentiation (inserting AMPA onto surface)
  • NMDA is BOTH ligand and voltage dependent
113
Q

Ketamine: Pharmacokinetics

A
  • 2 compartment model
  • highly lipid soluble
  • Vd= 3L/kg
  • Rapid onset (onset 30 secs, max effect 1 min)
  • Short duration (termination of effect is rapid after single bolus (15 min) due to redistribution )
  • T1/2 Elimination = 2-3 hours
114
Q

Ketamine: CNS Effects

A
  • Crosses BBB
  • depresses neuronal function in association areas of the cerebral cortex and thalamus
  • stimulates the hippocampus (limbic system)
    - ->dissociative state
  • Amnesia not as prominent as benzos
  • Nystagmus, pupil dilation
  • Salivation, lacrimation
  • increased skeletal muscle tone, non-purposeful movement
  • myoclonic activity
  • increases CBF, CMRO2, and ICP (not great for neuro pts)
  • increases IOP
  • Emergence reactions- common, 10-30% of pts
    - dreaming, out-of-body sense of floating, excitement, illusions, euphoria, fear
115
Q

Ketamine: Respiratory Effects

A
  • minimal
  • no alteration in CO2 response
  • Bronchial smooth muscle relaxation (SNS activity)
  • Increase PVR
  • Increase salivation
116
Q

Ketamine: CV Effects

A
  • sympathomimetic- NMDA effect
    • NOT a peripheral effect bc of NMDA receptor activity in the nucleus tractus solitaries
  • increase BP, HR, CO
  • inhibit reuptake of NE
  • increases myocardial work and O2 consumption
    - –> ketamine is a DIRECT myocardial depressant, especially in critically ill patients with decreased NE stores
117
Q

Ketmaine: Uses and Doses

A

Spinal Anesthesia
- Dose 0.2- 0.5 mg/kg/IV

Mu Receptor Activity?
- S-enantiomer has some mu activity (spinal analgesia contribution)

NMDA antagonism
- S-enantiomer has high affinity for excitatory NMDA receptor in dorsal horn

Premedication, Sedation/Analgesic:
- 0.2-0.5 mg/kg

Induction:
- 1-2 mg/kg IV (4-8 mg/kg IM)

Maintenance:
- 1-2 mg/kg/hr

Can be administered PO, IV, IM, intrnasal
- PO/Intranasal dose= 6 mg/kg

118
Q

Ketamine: Contraindications

A
  • increased ICP
  • open eye injury
  • CAD (as sole anesthetic bc increases myocardial O2 consumption)
  • Vascular aneurysms
  • uncontrolled systemic or pulm HTN
  • certain psychiatric diseases
119
Q

Ketamine: Metabolism

A
  • first pass effect
  • hepatic microsomal enzymes
  • N-demethylation followed by hydroxylation
    - Norketamine- metabolite 1- only 20-25% activity of parent compound
    - Hydroxylated to hydroxynorketamine
  • conjugation to water soluble
  • urinary excretion
  • total body clearance is = to liver blood flow (changes in flow affect clearance)
120
Q

Precedex: General Characteristics

A
  • water soluble
  • produces sedation that most closely mimics sleep
  • Locus Ceruleus (hypnosis) produces a lot of epi
  • spinal cord analgesia
  • 90% protein bound
121
Q

Precedex: mechanism of action

A
  • selective Alpha-2 agonist (sedation, hypotension)

1620: 1 alpha-2: alpha:1

122
Q

Precedex: CNS Effects

A
  • decreased CBF without significantly changed ICP or CMRO2
  • Decreased MAC of volatile agents and opioid requirements
  • Depresses thermoregulation (hypothermia, depresses shivering)
123
Q

Precedex: CV Effects

A
  • decreased HR, SVR, BP
  • bolus can cause transient increase in BP but decreased HR
  • potential for severe bradycardia, heart block, asystole
  • attenuates CV responses to noxious stimuli
    • decrease catecholamine levels during GA
124
Q

Precedex: Uses and Doses

A
  • adjunct to GA (most common)

1 mcg/kg bolus over 10-15 minutes
0.2- 1 mcg/kg/ hr infusion

125
Q

Precedex: Antagonist

A

Atipamezole
- a specific and selective antagonist that will rapidly and effectively reverse sedative and CV effects of Precedex

(research in humans as potential anti-parkinson’s drug)

126
Q

Precedex: Metabolism

A
  • Rapid metabolism:
    • conjugation
    • N-methylation
    • Hydroxylation
  • inhibit CYP450- interferes with clearance of other drugs (opioids?!) but thats okay bc Dex has opioid-like effects so you can just decrease the amount of opioids you use.
  • Metabolites cleared in urine or bile
  • 90% protein bound
127
Q

Precedex: Pharmacokinetics

A
  • 90% protein bound

- T1/2 Elimination= 2-3 hrs

Pharm Drugs 1 (5 decks)

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