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Pharmacology > Sedative Hypnotic > Flashcards

Sedative Hypnotic Flashcards

1
Q

Propofol

[[Diprivan]]

A

2,6 -di-iso-propohenol

Preservative;
disodium edetate EDTA
[[diprivan version of propofol preservative]]
** different than generic brand preservative**

has to have preservative bc very easy to grow bacteria in medium it comes in

oil at room temp
insoluble in aqueous solution
**very lipid soluble

Made up of;
-1.2% egg –>egg yoke
[[assess for egg YOKE allergy; out people ate allergic to egg white]]

  • 10% soybean oil
  • 2.25% glycerol base solution [[causes pain on injection]]

can increase plasma glycerides with prolonged infusion

medium propofol comes in supports bacterial growth–> need preservative

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2
Q

Propofol

[[GENERIC]]

A

preservative;
sodium metabisulfite

CAN CAUSE BRONCHOSPASM

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3
Q

Ampofol

A

Low lipid formulation;
5% soy
0.6 egg lecithin

NO PRESERVATIVE needed

*HIGHER incidence of pain on injection

so expensive

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4
Q

Aquavan

A

Prodrug
inactive compound; metabolized in body to produce a drug

gets into body and transformed into propofol but monester

hydrolysis in plasma can be unpredictable
*PROBLEM arrises bc
huge variability in end effect

slower onset
higher Vd
higher potency

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5
Q

PROPOFOL Mechanism of Action

A

GABAa receptor [[MAIN]]

some activity at Glycine

*Allosteric agonist
decreases rate of dissociation of GABA at GABA a receptor
[[increases affinity of GABA; increasing duration of drug effect ]]

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6
Q

PROPOFOL Pharmacokinetics

A 
Large Vd
[[3.5 - 4.5 L/kg]]
uses 2-3 compartment model for distribution
[[vessel rich, vessel poor, muscle]]
*very lipophilic

clearance exceeds hepatic blood –> capacitance dependent
[[hepatic extraction ratio less than 0.3]]

E 1/2 t; 0.5 - 1.5 hours
[[very quick on and off]]

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7
Q

Propofol clearance is

A

Capacitance dependent

capacity-dependent elimination
[[hepatic extraction ratio less than 0.3]]

increased clearance of propofol with;

  • increased enzyme activity
  • decreased protein binding
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8
Q

Factors that affect elimination of Propofol

A

weight
[[obese, larger fat stores, longer duration of action]]

coexisting disease

age
[[younger more muscular person will need more]]

co-administration of other drugs

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9
Q

Propofol CNS effects

A
  • activates Chloride Channel of Beta1 subunit of GABA a receptor
  • minimal NMDA inhibition
  • rapid onset
  • decreases CBF, CPP,ICP, CMR02
  • VERY cerebral protective
  • resembles Vit E; more cerebral protection

-suppresses EEG burst
[[safe in seizures]]

  • at sub-doses can cause muscle twitching, clonus, hiccuping
  • hallucinations at sub anesthetic doses
  • opisthotonos [[eye movement]]
  • decreases IOP
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10
Q

Propofol ED95

A

effective dose in 95%

*highest in toddlers
decreases with age and little babies

*in elderly and babies; give it slowly and titrate to effect; once they fall asleep stop giving it

[[toddlers need more bc of CO, rapid circulation gets to liver quicker]]
^higher dose in toddlers

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11
Q

Propofol can cause

A

MYOCLONUS;
un-purposeful movement
muscle twitching

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12
Q

Respiratory effects of Propofol

A
  • Apnea after induction dose
  • Decreases TV and RR

-decreased ventilatory response to C02 and hypoxemia
^as C02 rises pt will become acidotic

-Bronchodilation
[[less using generic brand; (sodium metabisulfite preservative) that can cause bronchospasm]]

Hypoxic vasoconstriction [HPV] remains intact
-protective mechanism of lungs that better perfuses areas that are ventilated and shunts 02 away from poorly aerated areas

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13
Q

PROPOFOL DOSE

A

INDUCTION
1 - 2.5 mg/kg

as high as 3mg/kg in TODDLERS
[[higher CO, gets to liver faster]]

GA Maintenance Infusion;
100 - 300 mcg/kg/ min

Sedation Infusion;
25- 100 mcg/kg/min

Amnestic Dose;
>30 mcg/kg/min

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14
Q

Propofol CV effects

A

25-40% decrees in BP
^thats a lot for a prone patient
**mush greater drop in SVR than with Sodiumpentothal [[barbiturate]]

dose dependent
myocardial depression

vasodilation [[decreases SVR, SV, CO]]

HR doesn’t change [[baroreceptor inhibitory]]
*not great for cardiac pt

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15
Q

Other effects of propofol

A

-Does not potentate muscle relaxants

-MYOCLONUS
[[pt not moving its myoclonus]]
^more myoclonus than with thiopental but less than with etomidate

  • pain on injection
  • antiemetic and antipruritic [[itching]]

readily crosses placenta; rapidly removed from fetal circulation [[no long term effects]]

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16
Q

Metabolism of Propofol

A

conjugated in liver by CYP450 system to water soluble compounds
[[liver function does NOT affect rate of metabolism]]

highly metabolized
less than 3% excreted unchanged

active metabolite
[[4-hydroxypropofol]]
*very weak

Renal excretion
[[renal failure doesn’t affect clearance]]

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17
Q

Propofol in patients with liver/ kidney issues

A

its very safe; can use

just reduce dose

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18
Q

Propofol active metabolite

A

4-hydroxypropofol

[[1/3 as potent]]

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19
Q

Etomidate

[[Amidate]]

A

**drug of choice for CV patient

carboxylated imidazole derivative

imidazole; parent compound C3H4N2

come in propylene glycol solver
[[hurts on injectioon]]

pH 6.9 [[water soluble in solution]]

very lipid soluble

Dextro isomer is the active hypnotic

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20
Q

Etomidate Mechanism of Action

A
  • binds to specific site on GABAa receptor

- increases the affinity of GABA to GABAa

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21
Q

Etomidate Pharmacokinetics

A

RAPID onset
highly lipid soluble

weak base pH 8.2

LARGE Vd; 2.5 - 4.5 L/kg
[[redistribution terminates the hypnotic effect; this is what causes people to wake up]]

E1/2 t; 3-5 hours

Hight hepatic extraction ration
>7
changes in liver blood flow WILL effect duration

75% protein bound

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22
Q

Etomidate hepatic extraction ratio

A

> 7
hepatic blood flow dependent
changes in liver blood flow effect elimination

increased blood flow increased elimination
decreased blood flow decreased elimination [[prolonged effects]]

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23
Q

No induction drugs provide

A

Analgesia

must give pain med

**except ketamine; provides analgesia

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24
Q

Etomidate CNS effects

A

Rapid LOC

Cerebral vasoconstriction
[[decreased CBF, CMR02, ICP}}

decreases IOP

increases EEG activity
in epileptogenic foci [[people prone to epilepsy]]
^rare association with grand Mal seizure in those patients

also produces anticonvulsant properties

produces myoclonus

**NO analgesia

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25
Q

Etomidate Respiratory Effect s

A

minimal depression on ventilatory response to C02
^maintains response to C02

increase RR
can stimulate ventilation
[[useful when maintenance of spont ventilation is desired]]

decreases TV [[more shallow breathing]]

Hiccups, coughing

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26
Q

Patient has a crappy heart

A

give Etomidate

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27
Q

Etomidate CV effects

A

MINIMAL

lack of effect of ANS–> SNS, baroreceptors

***HR, ABP, PAP, CO, SVR, PVR unchanged

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28
Q

Etomidate Endocrine effects

A

dose dependent reversible inhibition of 2 enzymes in biosynthesis of cortisol/ aldosterone

11- beta hydroxyls [[major]]

17-alpha hydroxyls [[minor]]

prevents the conversion from cholesterol to cortisol

**need cortisol to manage stress

one shot deal in OR clinical significane is not that big a deal

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29
Q

Etomidate use can result in what

A

adrenocortical suppress for 4-8hrs

reduces mineralococorticoid and cortisol production

dose dependent etomidate can reversible inhibit 2 enzymes in the biosynthesis of cortisol and aldosterone

[[prevents conversion of cholesterol to cortisol]]

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30
Q

Etomidate effects on N/V

A

High incidence

give antiemetic

[[propofol has anemic properties]]

31
Q

Etomidate DOSES

A

induction; 0.2 - 0.6 mg/ kg
[[typical dose; 0.3 mg/kg]]

Maintenance; 10 mcg/ kg/ min
^with N20 and OPIOD
[[no analgesia effect]]

sedation; 5 - 8 mcg/ kg/ min
^for short procedure

Rectal 6.5 mg/kg in Peds

32
Q

Etomidate

Other effects

A

High incidence of NV

Higher incidence of myocluns
[[dis-inhibition of extrapyrmadial system in CNS

Enhances NMDR activity
[[mech of action is still GABA]]

33
Q

NMDA receptor

A

Remember

to activate need;
2 glutamate
2 glycine

allows cations; NA, K, Ca to pass
also need AMPA to remove MG pore blocker

34
Q

Metabolism of Etomidate

A

liver;
ester hydrolysis of N- dealkylation to carboxylic acid

biotransformation 5x faster than thiopental [[barb]]

85 % excreted by kidneys
13% biliary excretion
2% excreted unchanged
[[safe in renal failure only 2% excreted unchanged]]

35
Q

Ketamine

[[Ketalar]]

A

phencyclidine derivative

lipid soluble

prepared in acidic solution

racemic mixture of equal parts R and S enantiomers

s-enantiomer has been isolated
*more potent analgesic
[[undergoes faster metabolism and has lower incidence of emergence delirium]]

36
Q

Ketamine Mechanism of Action

A

interacts with many receptors
-NMDA receptors;excitatory ligand gated channel
[[glutamate and glycine bind to NMDA]]

-Opioid Mu, Delta, Kappa, Sigma[[not an opioid receptor]]

-Monoaminergic;
descending inhibitory pathways for pain
[[activates to fight pain]]

-inhibits Muscarinic -
antagonists
antiCHOLINERGIC
[[G alpha q or G alpha i]]
q --> increased Ca
i --> inhibits; decreased cAMP [[constricts]]
^but Ketamine inhibit this

-inhibits Calcium Channels

37
Q

Ketamine on NMDA receptor

A

activates NMDA receptors

opening of non selective cation channel [[Na, K, Ca]]

Ca flux through NMDA receptors is whats thought to play the critical role in synaptic plasticity [[learning and memory]]

NMDA is both ligand gated and voltage dependent

38
Q

Whats the effect of Ketamine on an NMDA receptor

A

Ketamine inhibits the spinal NMDA receptor;
glutamate [[primary excitatory NT; play an important role in spinal nociceptive [[pain]] pathways

allows for management of post pain

39
Q

Ketamine Metabolism

A

**active metabolite

First pass effect

metabolized by hepatic microsomal enzymes
hydrolysis to form
N-demethylation

**active metabolite;
norketaminie
^minimally active only about 20%
then hydroxylated to;
hydroxynorketamine

conjugated to water soluble
Kidneys excrete in urine

body clearance is roughly equal to liver blood flow

**changes in liver blood flow effect clearance!

40
Q

changes in liver blood flow can effect clearance of what drugs

A

KETAMINE and PROPOFOL

41
Q

Ketamine pharmacokinetics

A

2 compartment model
[[vessel rich and vessel poor]]

High lipid solubility [[potent]]

RAPID onset; pKa 7.5
^peak plasma concentration occurs within 1 min of IV

SHORT duration [[protein binding]]

Large Vd 3 L/kg

E 1/2 t; 2 - 3 hours

42
Q

Onset determined by

A

pKa

43
Q

Duration determined by

A

protein binding

44
Q

Potency determined by

A

lipid solubility

45
Q

Sedative hypnotics all have a LARGE

A

Vd

propofol 3.5 - 4.5 L/kg

etomidate 2.5- 4.5 L/kg

ketamine 3 L/kg

46
Q

Sedative hypnotics are have a fairly SHORT

A

E1/2 t

propofol E1/2 t; 0.5 - 1.5 hours

etomidate E1/2 t; 3 -5 hours

Ketamine E1/2 t; 2-3 hours

Dex E1/2 t; 2-3 hours

47
Q

Ketamine CNS effects

A

crosses BBB

biggest difference ****Depresses neuronel function in;
cerebral cortex
thalmaus

stimulates neuronal function in hippocampus
[[dissociative state]]

onset 30 seconds
max effect within 1 min of IV injection
pKa 7.5 [[very close to pH 7.4]]

termination of effect is rapid after single bolus
[[15 min r/t redistribution]]

  • amnesia but not as much as benzos and propofol;
48
Q

What induction drugs produce amnesia

A

Benzos
[[versed, atiivan, valium]]

propofol
>30mcg/kg/min

ketamine but not as much

49
Q

what is the biggest difference with ketamine vs other induction drugs

A

Depress neuronal activity in cerebral cortex
thalamus

and stimulates the hippocampus
[[dissociative state]]
ex. hear red but associate it was something else, feel like you aren’t you; your body does belong to you

sub anesthetic doses need to be careful
[[lights down, minimal stim, decrease noise]]

*benzos can help with dissociative state
[[give versed then induce with ketamine]]

also ketamine increases
ICP
CBF
CMR02
IOP
50
Q

Ketamine CNS effects

A

nystagmus [[eye movement]]
pupil dilation

salivation
lacrimation

myoclonus
increased skeletal muscle tone

****ketamine increases
CBF
ICP
CMR02 
IOP
^this is why we dont use in neuro patient

emergence reaction from dissociative state
[[out of body experience, dreaming, excitement, illusion, euphoria, fear

51
Q

Is emergence delirium with ketamine common

A

10-30 % of patients who receive Ketamine as part of anesthetic experience emergence delirium

*give premed of benzo and it will help with this

52
Q

Who should you avoid using ketamine in?

A

patients with increased ICP/ tumor

and psych patients bc of emergence delirium

53
Q

Ketamine DOSE

A

spinal analgesia IV;

0.2 - 0.5 mg/kg

54
Q

Ketamine activity at Mu receptor

A

mu receptor in spinal cord is where activity is coming from

s- enantiomer is better at analgesia

55
Q

S enantiomer of ketamine

A

higher affinity as NMDA receptor

better at analgesia
and less emergence delirium
[[R enantiomer better for depression but causes more emergence delirium]]

56
Q

Ketamine Respiratory effects

A

MINIMAL

**really good for asthmatic and COPD patient

sympathomimetic
[[increases SNS activity
activate B2 –> bronchodilator ]]

however;
increases PVR and salivation
**avoid in pulmonary HPTN

57
Q

Why is ketamine good for asthmatics but not good for a BPD baby

A

its a Sympathomimetic
^Increases SNS activity to bronchioles
**Bronchodilation

but increases PVR
avoid in pulmonary HPTN

58
Q

Ketamine CV effects

A

Sympathomimetic
[[NMDA effect]]

**not peripheral effect
think activity in nucleus tractus solitairus

increases
BP, HR and CO
[[only if pt has good norepi stores]]

inhibits the reuptake of norepi

increases myocardial work from the sympathetic nervous system activity

ketamine on it own is a
CARDIAC DEPRESSANT
[[remove your SNS activity]]
ketamine will depress CV system

elderly, trauma patient with decreased SNS outflow
[[critically ill pt will decreased norepi stores –> ketamine is doing to depress CV system]]

59
Q

Ketamine CV effects if SNS activity is impaired

A

elderly pt
trauma ot
critically ill pt

anyone with deceased SNS outflow; ketamine will be a direct myocardial depressant

only reason ketamine isn’t a myocardial depressant in healthy individuals is bc of indirect SNS activity

60
Q

Ketamine Dose

A

sedative/ analgesic
0.2 - 0.5 mg/kg

induction ;
IV; 1 - 2 mg/kg
IM; 4 -8 mg/ kg

maintenance;
1 - 2 mg/kg/ hr

PO and nasal
6 mg/ kg
[[first pass effect]]

61
Q

So to summarize who is Ketamine contraindicated in?

A

Neuro pt with increased ICP, tumor

eye surgery; increases IOP

Pt with pulmonary HPTN

pt with systemic HPTN

not intact SNS
elderly, trauma pt, critically ill

coronary artery disease
[[increases work of heart bc of SNS activity increased BP, HR, CO]]
vascular aneurysms
^increases BP

psych diseases or personality disorder
^emergence delirium

62
Q

Ketamine and MAO inhibitor

A

MAO break down epi and norepi

now we inhibit MAO and it increases epi and norepi bc not breaking it down
[[antidepressant drug]]

not we give them ketamine
that inhibits the retake of norepi
ALOT of norepi
alot of CV changes

63
Q

Dexmedetomidate

[[Precedex]]

A

water soluble

selective alpha -2 adrenergic agonist
[[G alpha i –> decreased cAMP, increases K conductance ]]
Decreases BP and HR

produces sedation that most closely mimics sleep
does this by impacting;
locus ceruleus [[where norepi is produced]]

and analgesia comes from dex acting on Mu receptor on spinal cord

64
Q

Alpha 2 adrenergic agonist

A

vasodilator
sedation
pain

65
Q

Locus ceruleus

A

area in brain that produces norepi

dex impacts this area and this is how it it able to closely mimic physiologic sleep

66
Q

Dex CNS effects

A

decreased CBF
without changing ICP and CMR02

decreases MAC of volatile agents and opioids
dex use with anesthetic gasses and opioids allows your to decrease the dose
[[inhibits CYP450, how opioids are metabolized, longer duration, decrease dose]]

decreases thermoregualtion
and inhibits shivering

67
Q

Dex CV effects

A

**bradycardia
decreased SVR and BP

bolus can increase BP and decrease HR
[[decreases CO]]

potential for severe bradycardia, heart block and systole

attenuate [[reduce]] CV effects with noxious stim
[[decreases catecholamine level during GA
^no HR change with intubation

68
Q

catecholamines

A

epi
norepi
dopa

69
Q

Dex Respirtaopry effects

A

decreased TV
no change in RR
^hypoxia from change in TV
[[have oxygen]]

no change in C02 drive

possible upper airway obstruction
[[have our airway equipment]]

70
Q

Dex metabolism

A

RAPID
conjugation
n-methylation
hydroxylation

metabolites cleared in urine and bile

90% protein bound
E1/2 t; 2-3 hours

inhibits CYP450
interferes with clearance of other drugs
[[opioids duration prolonged; decrease dose]]

71
Q

Dex Dose

A

ADJUNCT to GA
1 mcg/kg BOLUS over 10-15 min
0.2 - 1 mcg/kg/hr infusion

decreases MAC of volatile anesthetics and opioids
[[produces some analgesia at spinal cord, mimics physiological sleep bc works on alpha2 and can attenuate HR changes with intubation]]

72
Q

Why is Dex used

A

it most closely mimics physiological sleep

produces analgesia

decreases MAC for volatile anesthetics and opioids

attenuaste HR response to intubation

73
Q

Anipamezole

A

specific and selective antagonist for dexmetatomidine

will rapidly and effectively reverse sedative AND CV effects

74
Q

What induction drugs have antagonist

A

Barbiturates –> phenoxybenzamine
[[used to reverse effects of accidental arterial injection]]

Benzo –> Flumanezol
[[noncompetive antagonist]]

Dex –> Antipamezole
[[reverses sedation and HR]]

Pharmacology (7 decks)

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