IV Anesthetics- Medications

Redistribution, half life, and elimination half life of propofol?

• Redistribution

  • Initial rapid distribution half life is 1-8 min (intermediate – muscle)

  • Slow distribution half-life ≈30-70 min (vessel poor - fat)

• Elim t_1/2 = 4-23.5 hrs

Redistribution, half life, and elimination half life of etomidate?

• Redistribution

  • Initial rapid distribution half life is 2.7 min (intermediate - muscle)

  • Slow distribution half life ≈29 min (vessel poor - fat)

• Elim t_1/2 = 2.9 to 5.3 hrs (increased with higher doses)

Redistribution, half life, and elimination half life of etomidate?

• Redistribution

  • Initial rapid distribution half life is 2.7 min (intermediate - muscle)

  • Slow distribution half life ≈29 min (vessel poor - fat)

• Elim t_1/2 = 2.9 to 5.3 hrs (increased with higher doses)

Redistribution, half life, and elimination half life of ketamine?

• Redistribution

  • Not as fast as propofol and etomidate

  • half life= 11-16 min

  • Mentally alert 60-90 min but can be quite variable

• Elimination t1/2 3hrs

Redistribution, half life, and elimination half life of methohexital?

t ½- 2-4 min

elim t ½- 2-4 hrs

What was the original formula of propofol that is no longer used due to anaphylactoid reactions?

Cremophor EL

How was the original formula of propofol changed in 1982?

made into an emulsion (Disopropyl Intravenous Anesthesia AKA Diprivan)

WHat is propofol derived from and what is special about it?

• Alkylphenol

  • Very weak acid and nonionized at physiologic pH

  • Oils at room temp and insoluble in aqueous soln at room temperature

  • Highly lipid soluble

What is included in propofol to make it an emulsion?

• soybean

• glycerol

• lecithin (derived from egg yolks, egg whites are what typically cause egg allergies so little cross sensitivity with egg allergy)

cons of propofol?

need for antimicrobial agents bc the emulsion goes bad quickly (instable emulsion)

strict asepsis with drawing up/use

hyperlipidemia

What must be included on the label for a syringe of propofol?

• Initials, date, time & 12 hour expiration time

how much fat is in propofol?

0.1 g/mL

For pre-packaged syringes, how long are they good for?

14 dys if refrigerate and 48 hrs out of refrigeration

What preservatives are in each brand of Propofol and what are the cons of each:

• Diprivan

• Baxter

• Hospira

• Diprivan- Disodium edetate (ethylenediamine tetra-acetic acid [ETDA])

  • metal chelator

• Baxter- sodium metabisulfite

  • bad w sulfite allergy

  • asthma precautions

  • less pain on injection

• Hospira- Benzyl alcohol and sodium benzoate

  • gasping syndrome in peds

  • CNS depression, met acidosis and in extreme cases intracranial hemorrhage, hepatic & renal failure and CV collapse

  • High doses of benzyl alcohol and metabolites found in blood/urine

  • At risk: premature and low-birth weight infants

What 3 analogs of propofol are available?

ampofol (not available in US)

fospropofol (not available in US)

frensius (Used during US drug shortages)

WHat is special about ampofol?

• lower lipid formula- more drug less fat

• increased free drug

• increased pain on injection (need lidocaine)

• equipotent to propofol

• increased N/V

WHat is special about fospropofol disodium?

• prodrug (inactive until metabolized)

• hydrolized by endothelial alkaline phosphatases

• approved for MAC sedation at 6.5 mg/kg

• loss of conciousness in 10 mins (lasts 45 mins)

WHat is special about Frensius?

• contraindicated in soy or peanut allergies (according to some inserts, but is likely safe)

• contains medium and long chain triglyceride (should be used with caution in pts with fat metbaolism disorders or on TPN)

Peds, elderly, perfusion dependent, and hepatic pts can have altered metabolism to propofol, how is each one affected?

• peds- has a higher volume of distribution (needs higher dose)

• elderly, debilitated, and trauma- decreased clearance (lower dose by 25-50%)

• perfusion dependent- can impair clearance by decreasing hepatic blood flow (lower dose)

• hepatic- clearance is unchanged but t1/2 is slightly prolonged (may need to decrease dose)

how is propofol metabolized?

• liver (CYP2B6, UGTHP4, CYP2C6)

• conjugated with glucuronide and sulfate (50%)

• creates inactive metabolites (1-glucuronide, 4-glucuronide and 4-sulfate conjugates)

• less than 3% excreted unchanged

clearance of propofol?

clearance exceeds hepatic blood flow so it is also cleared by the kidneys (30%) na the lungs (20-30%)

Is propofol highly protein bound?

yes, concentrations increased if albumin is low

Induction dose, maintenance dose, and infusion doses for propofol?

• Induction

  • 1 – 2.5 mg/kg

• Maintenance of GA

  • Initial: 100-200 mcg/kg/min then decrease

• IV sedation

  • Initial: 25-75 mcg/kg/min for conscious then dec

  • Initial: 100-150 mcg/kg/min for deep then dec

MOA of propofol?

• potentiates GABA at beta-subunits (GABA-a) in the hippocampus to inhibit ACh release in the hippocampus and prefrontal cortex

• alpha-adrenoreceptor has indirect rols in sedation

• widespread inhibition of NMDA (modulates Na)

• direct depressant on spinal cord (Glycine receptor)

CNS effects of propofol

• Anxiolysis, sedation, amnesia

• Reduction in cerebral blood flow (CBF)

• decreased Cerebral metabolic rate of oxygen consumption (CMRO₂)

• decreased Intracranial pressure (ICP)

• decreased Cerebral perfusion pressure (CPP)

• decreased intraocular pressure (IOP)

• These effects are due in part to the decreased MAP, depressed metabolic rate and cerebral vasoconstriction

• EEG-burst suppression at high doses

• anticonvulsatn

  • shorten seizures (BAD FOR ECT)

  • seizures have been reported in rare cases

• cerebral vasoconstriction

  • can be used to treat intractable migraines

    *all dose-dependent

WHat dose of propofol can be given for intractable migraines?

20-30 mg every 3-4 mins (400 mg max)

Non-hypnotic effects of propofol

• excitatory phenomenon

  • choreiform movements or opisthotonos on emergence (rare)

• antipruritis

• burning of perineal region (only with Fospropofol, but has less pain on injection)

• antiemetic

• sense of well being

WHat causes propofols antiemetic effects? WHat dose should be given for these effects?

10-20 mg q 5-10 min or 10 mcg/kg/min

decreases serotonin in postrema, depressed the CTZ and vagal nuclei, and decreases glutamate and aspartate release in olfactory cortex

Why does propofol stimulate a sense of well-being?

increased dopamine in nucleus accumbens (similar reaction to drug abuse or pleasure seeking behavior)

How does propofol effect the respiratory system

• apnea- dependent on dose, speed of injection, and other meds

• decreased Vt- 100mcg/kg/min decreases it by 40%

• decreased rate- above dose decreases it by 20%

• depresses response to hypoxia- direct action on carotid body chemoreceptors

• decreases response to CO2

• bronchodilating- minimal (no histamine)

How does propofol effect the cardiovascular system

• decreases BP- SBP by 25-40%

• decreases CO, CI, SVI, and SVR

  • vasodilation, decreased sympathetic tone, direct myocardial depression

• decreased myocardial blood flow

• decreased myocardial oxygen consumption

• decreased HR - esp in presence of opioids, dex, and in peds (may want to give glycopyrrloate in peds)

• propofol infusion syndrome

What is propofol infusion syndrome

at high doses or when used long term metabolic acidosis, hyperlipidemia, rhabdo can occur leading to acute refractory bradycardia to asystole

which medication decreases intraocular pressure the most: etomidate, propofol, or thiopental

propofol

Hoe can propofol effect your urine?

phenolic metabolites can create a green urine color (benign)

MOA of etomidate

enhances GABA a receptor facilitation

What is etomidate a derivative of?

imidazole (with 2 isomers)

what are the 2 isomers of etomidate?

R(+)- 10-20 fold greater hypnotic potency

S(-)

usually in a racemic mix

how is etomidate metabolized?

in the liver by ester hydolysis creating inactive water soluble metabolites

How is etomidate effected by cirrhosis?

Vd is doubled prolonging the T ½ by twice the normal (clearance remains the same)

Standard induction dose of etomidate?

0.2-0.3 mg/kg

CNS effects of etomidate

• decreased CBF

• decreased CMRO2

• vasoconstriction- maintains CPP and MAP

• elevated ICP

• EEg- burst suppression w induction dose

• grand mal seizures (controversial)

  • does NOT alter seizure length for ECT

• myoclonic movements (most common with this drug)

• enhances NMDRs slightly

Cardiovascular effects of etomidate

• used for CV disease or hypovolemic pts:

  • less than 10% decrease in MAP

  • no histamine release

  • lack of depression of SNS

  • alpha 2 and beta agonist
    

Respiratory effects of etomidate

dose dependent effects similar to propofol, but less effects

which medication is the most immunologically safe?

etomidate

Cons of etomidate

• burning on injection

• higher N/V

• endocrine effects

  • suppresses cortisol and aldosterone

  • blocks 11- beta- hydroxylase and 17- alpha- hydroxylase

    • decreases steroids (cortisol, cortisone, and aldosterone)

  • *effects last about 4-8 hrs but are reversible, not usually an issue unless pt is septic, hemorrhaging, or on infusion which is not available in US)

why is there so much pain with injection of etomidate?

normal solution is unstable so propylene glycol is added, causing burning

How to decrease myoclonus with etomidate

pre-treat with fentanyl, midazolam, or dexmedtomidine

WHen is etomidate contraindicated?

acute porphyria and adrenal suppression

what is ketamine derived from?

Arylcyclohexylamine (2 isomers in a racemic mix)

WHat preservative is in ketamine?

benzethonium

metbaolism of ketamine

liver (CYP 450) demethylated to norketamine (metabolite 20-30% of activity of parent) then hydroxylated to hydronorketamine and conjugated to a glucuronide derivative that can be excreted in urine

what is protein binding of ketamine?

12% (low)

What are the 2 isomers of ketamine?

S+- more analgesic effect, faster clearance, and fewer side effects

R- - causes more delirium

MOA of ketamine

• non-competative antagonist of NMDA

• acts as opioid on mu, delta, and kappa receptors

• muscarinic antagonist- emergence delirium, bronchodilation

• sympathomimetics- increased HR and BP

How is the cataleptic state of ketamine created?

dissociative anesthesia creates a dissociation between the thalamonecortical and limbic systems

• suppresses the cortex and thalamus

• stimulates the limbic (hippocampus)

induction and subanesthetic/ sedation and ERAS dose of ketamine

• Induction: 1-2 mg/kg IV or 4-6 mg/kg IM

  • 1 mg/kg labor induction

• subanesthetic- 

  • 0.1-0.5 mg/kg or 100-500 mcg/kg

• ERAS

  • 0.4 mg/kg/hr (IBW) IV infusion

  • Stopped 1 hr before end of case

CNS effects of ketamine

• increased CBP/ICP

  • Traditionally thought to be C/I in head trauma and increased ICP – but is safe if ventilation is controlled

  • Can also be blocked with prior use of benzodiazepines

• increased CMRO2

• eyes remain open and pupils dilate

• EEG- aless suppression compared to inhaled and other IV

• BIS- no change or increase with small analgesic doses

Respiratory effects of ketamine

• central and minimal

• apnea- high doses

• bronchial smooth muscle relaxation- increased compliance

• lacrimation, salivation, and muscle tone increase

  • treat with glycopyrolate (0.1-0.2 due to increased HR) or atropine

  • salivation can cause issues in peds (laryngospasm)

  • silent aspiration risk

• reflexes maintained, but may not be protective

cardiovascular effects of ketamine

• SNS stim- increase BP, HR, CO, contractility, and MCO2

• increased epi and norepi

  • anlso inhibs norepi reuptake

• increased pumonary vasc resistance

• *these effects can be blocked with alpha and beta blockers or Benzos

• *direct depressent effect can occur when combined with inhaled agents or depleted catecholamines

uses for ketamine

• Bronchospastic airway (asthma)

• Acute hypovolemia

  • Healthy trauma, shock

• CV instability

  • Cardiac tamponade

  • Restrictive pericarditis

  • Congenital R ®L shifts

• OB (0.5-1 mg/kg)

  • Severe hypovolemia/trauma

  • Acute hemorrhage

• Analgesia or adjuncts in regional anesthesia

  • Low doses

• Dental – physically/mentally challenged (IM)

• treat resistant depression

• PTSD- potentially better than versed

Which pre-treatment med can be given with ketamine to prevent emergence delirium

Versed or other sedatives

COntraindications to ketamine

• Increased ICP (unless pretreated)

• Ischemic heart disease

• Vascular aneurysms

• Recent penetrating eye injury (open globe)

• Schizophrenia

• Wolff-Parkinson-White syndrome 

• In patients who catecholamines are depleted, ketamine can be cardiac depressant (inhibiting norepi reuptake)

  • Chronic hypovolemia

  • Caution – if used in combination with tricyclic antidepressants

Who is more likely to experience emergence reactions to ketamine

• Adults, especially women

• Rapid administration and higher doses (sole anesthetic)

• People who dream a lot or personality disorders   

Which meds may worsen psychotropic efefcts of ketamine>

atropine and droperidol

MOA of dex

• alpha 2 agonist (1600 alpha2: 1 Alpha 1).

• major presynaptic inhibitor of exocytosis of NE (sympatholytic)

• causes sedation by inhibiting NE release inthe locus coeruleus in the spinal cord

• analgesic effect (thought to occur in spinal cord by inhib Ca activated K channels)

onset, T ½, elimination half life, and protein binding of dex

• onset- 15 min (peak 60)

• T1/2- 6 min

• elim T ½- 2 hrs

• 94% protein bound (high)

metabolism of dex

liver throughCYP 450 and glucuronide conjugation

CNS effects of Dex

• decreased CBF (vasoconstriction)

• sedation

• anxiolysis

• hypnosis

• analgesic

• sympatholytic

• most like normal non-REM sleep

dex loading and infusion dose

• Infusion loading dose: 1mcg/kg over 10 mins

  • Give slowly to avoid drop in HR and BP

• Followed by IV infusion rate

  • 0.2-0.7 mcg/kg/hr

CV and resp effects of Dex

• decrease HR and BP (decreasing NE)

  • biphasic response after bolus of 2 mcg/kg (vasoconstriction of alpha 2 in periphery before central action)

• no clinically sig resp effects

How to prevent emergence delirium using dex

• Decreases emergence delirium dosing

  • Titrate up 0.25-1 mcg/kg

drug class of droperidol

atypical antipsychotic (AKA neuroleptics)

What is innovar

combo of droperidol and fentanyl

CNS effects of droperidol

• acts centrally where dopamine, NE, and serotonin act

• May occupy GABA receptors

• marked tranquility and cataleptic immobility

  • can be reversed with physostigmine

CV and resp effects of droperidol

• vasodilation

• alpha adrenergic blocker

• decreases BP

• slight antiarrhythmic effects

• minimal resp effect

Major effect of droperidal

potent antiemetic by depressing the CTZ

Black box warning for droperidol

• Due to QT prolongation

• Fatal HR irregularities have occurred

• Only use if other antiemetics have failed

major side effect of droperidol

• extrapyramidal- dyskinesia, hallucinations, rare malignant neuroleptic syndrome

• common with pts taking butyrophenones and phenothiazines for psych disorders

• treat with dantrolene and bromocriptine (a central dopamine agonist)

What is the protein binding of ALL Benzos?

96-98%

MOA of benzos

bind with the BZD binding site on the alpha subunit of GABA-a to increase affinity fir GABA, increase frequency of Cl channel opening (hyperpolarize) (GABA-ergic

alpha 1 receptors mediate what effects for Benzos? alpha 2?

alpha 1- sedation, retrograde amnesia, and anticonvulsant (increased seizure threshold)

alpha 2- anxiolysis, spinal mediated muscle relaxant

CNS effects of benzos

decreased CMRO2

decreased CBF

increased seizure threshold

which benzo is better for an anticonvulsant?

midazolam > diazepam

Which alpha subunits interact with Benzos and where are they located?

alpha 1- most abundant found in the brain

alpha 2, 3, and 5- region specific

benzo effects are produced by receptor occupancy, which % create each effect?

20% anxiolysis

30-50% sedation

>60% unconsciousness

What is different about EEG effects of Benzos?

They have a ceiling effect and will NOT produce burst suppression

where are Benzo receptors located in the CNS?

• Hippocampus & amygdala

• Cerebral cortex

• Olfactory bulb

• Substantia nigra

• Lower brainstem and SC

metabolism of Benzos

undergoes microsomal oxidation in the liver follwed by glucuronide conjugation

which factors can effect metabolism of benzos

• Elderly

• Liver disease

• Malnutrition

• Coadministration with drugs that impair oxidation pathway

explain T ½ and elim T ½ of each benzo (midazolam, lorazepam, and diazepam)

all are highly protein bound so volume of distribution is similar, but clearance varies

• T ½:

  • midaz-7-15 mins

  • loraz- 3-10 min

  • diaz- 10-15 mins

• elim T ½

  • midaz- 1-4hrs (shortest)

  • loraz- 10-20 hrs

  • diaz- 20-40 hrs (longest)- highest lipid solubility

compare duration of action of the 3 main benzos

• Midazolam = 15-20 min (short)

• Diazepam = 15-30 min (intermediate)

• Lorazepam = 60-120 min (long)

CV efefcts of benzos

• decreased SVR

• decreased BP (minor)

  • synergistic lowering when used with opiates

• nitroglycerin effect- can increase CO by decreasing LVFP

resp effects of benzos

• apnea (greatest with midazolam)

  • additive effect with opioids

which benzo is most potent?

lorazepam- most potent

midazolam- twice as potent as diazepam (3-6 times the affinity for recptor)

comparison of metabolites between benzos

• Diazepam has active metabolites that prolong residual effects

• Midaz has a mild active metabolite

  • 20% of its potency –cleared quickly with little residual effect

  • 1-hydroxymethylmidazolam

midazolam doses: sedation, induction, maintenance, and oral

• Sedation

  • 0.5-1 mg

    • These are according to Miller, normally 1mg for old people and 2 mg for a healthy pt (up to 4 mg for a wild pt)

  • 0.07 mg/kg IM

• Induction

  • 0.05-0.15 mg/kg

• Maintenance

  • 0.05 mg/kg prn or 1 mcg/kg/min

• Oral dose

  • 0.5 mg/kg

what is the reversal agent for benzos? How does it work?

flumazenil- it is an antagonist at the BZD site and has a higher affinity for the site (minimal intrinsic effect)

contraindication to flumazenil

• Patients on BDZ for seizure control, ICP

• Tricyclic antidepressant overdose or poisoning

• Black Box Warning – risk of seizures

dosing of flumazenil

• Reversal of conscious sedation and general anesthesia

  • Initial dose 0.2 mg IV

  • May repeat 0.2 mg every 60 seconds to max of 1.0 mg

  • Continuous infusion: 0.5 – 1 mcg/kg/min

  • ****Max doses 1mg at a time or 3 mg/hr

• reversal of overdose

  • higher dose 0.5-3 mg

  • ---

    greater than 5 mg w/o response indicates other reason for sedation

duration of flumazenil

30-60 mins (may need to repeat doses q 20 mins