APEX IV anesthetics & Franco PP

Chemical name of propofol

2,6-diisopropylphenol

GABA (4)

Inhibitory

most abundant inhibitie receptor

distributed throughout cns

almost all GA enhance GABA

NMDA (2)

Blockage 

Found pre, post, and extrasynaptically

Glycine and VG Na+ channels (4)

glycine locatlizes near cell body

inhibitory role- imobility

no ketamine activity

propofol + Na channel contributes to antiepileptic activity

Class of propofol

Isopropylphenol

Propofol formulation

1% solution in lipid emulsion of 10% soybean oil, 2.25% glycerol, and 1.2% purified egg lecithin

Long chain of triglycerides

prop pH and pKa

pH= 4.5-6.4

pKa=11

Diprivan pH and pKa

pH= 7-8.5

pKa=11

Preservative in Diprivan

Disodium edetate

Preservative in generic propofol

Sodium metabisulfite

MOA of propofol

Direct GABA-A agonist which increases chloride conductance and causes neuronal hyper polarization

Dose of propofol induction and infusion

1.5-2.5mg/kg IV for induction

25-200mcg/kg/min infusion

Onset of propofol

30-60 seconds

Duration of propofol

5-10 minutes

Propofol clearance/ metabolisjm

Liver (P450 blood flow dependent) and extra hepatic- lungs

Active metabolite of propofol

None

Brain concentration of propofol peaks at...

1 minute

-Blood concentration declines over time.

-There is a rapid distribution from the blood to the vessel rich group. Then from the VRG to the muscle and fat.

Awakening from propofol is due to...

redistribution out of the brain

WHy is prop favorable to contamination

EDTA

Pro of prop

rapid onset and recovery

Cons of prop (4)

narrow TI

HD/resp depressin

pain on injection 

Prop infusion syndrome

Cardiovascular effects of propofol

• Decreased BP (d/t decreased SNS tone and vasodilation),

• Decreased SVR

• Decreased venous tone, preload, and myocardial contractility

Respiratory effects of propofol

-Shifts CO2 response curve down and to the right (less sensitive to CO2) leads to respiratory depression/apnea

-Inhibits hypoxic ventilatory drive

CNS effects of propofol

-Rapid and pleasant LOC/emergence

-Dose dependent anxiolysis, sedation, and amnesia

- Decreased CMRO2, CBF, ICP, and intraocular pressure and CPP- autoregulation is maintained

-Can produce burst suppression/ Anticonvulsant properties, but myoclonus may occur (rare cases of seizures)

-NO analgesia

Why may urine be green with a propofol infusion?

Phenol excretion

Why may urine be cloudy with a propofol infusion?

Increased uric acid excretion (not suggestive of renal impairment or infection)

How does propofol have antioxidant properties?

It has free radical scavenging properties

Most people with an egg allergy are allergic to...

the albumin in egg whites

Is propofol safe to administer to patients with egg, soy and peanut allergies?

YES!

-Exception: patients allergic to lecithin in egg yokes (very rare) should not be administered propofol

An increased long chain triglyceride load impairs ___ and ___ which causes the muscle and cardiac cells to be starved of oxygen and leads to ___

-oxidative phosphorylation and fatty acid metabolism

-propofol infusion syndrome.

Risk factors for propofol infusion syndrome (8)

>4mg/kg/hr (>67mcg/kg/min)

Infusion >48 hours

Inadequate oxygen delivery

Sepsis

Continuous catecholamine infusions

High dose steroids

Significant cerebral injury

-More common in adults and elderly critically ill patients because prolonged propofol use with children is discouraged by the FDA

Clinical presentation of propofol infusion syndrome

-Acute refractory bradycardia L/T asystole, plus at least one of the following:

Metabolic acidosis (base deficit >10),

rhabdo,

enlarged/fatty liver,

renal failure

HLD

lipemia (cloudy plasma or blood) (early)

Treatment of propofol infusion syndrome (7)

Discontinue propofol,

maximize gas exchange,

cardiac pacing,

PDEIs,

glucagon,

ECMO,

renal replacement therapy

How does prop decrease BP

Decrease SNS, vasodilation, dec SVR, dec Venous return, and decrease myocardial contractility

Before removing propofol, the vial and rubber stopper must be cleansed with...

70% isopropyl alcohol

Propofol in a syringe/ open vial- must be discarded within...

6 hours

A propofol infusion and tubing from a vial must be discarded within...

12 hours

Prop pharmacokinetics (4)

Rapid metabolized in liver (elderly require less and children require more)

Accumulation with infusion elimination half life is 1-2 hours

reversibly binds to erythrocytes and plasma protein

highly lipid soluble

Which formulation of propofol should be avoided in asthmatics and infants? why?

Generic - the preservative metabisulfite is bronchial irritant and can precipitate bronchospasm. Benzyl alcohol should be avoided in infants

(Diprivan is ok to use because it contains disodium ethylenediamine tetraacetic acid (EDTA) as the preservative) and doesn’t cause bronchoconstriction

Dose of propofol to reduce itching from spinal opioids and cholestasis

10mg IV

Dose of propofol to treat PONV

10-20mg IV or an infusion of 10mcg/kg/min

How to decrease propofol pain on injection

-Inject into a larger, more proximal vein

-Lidocaine

-Give opioid prior to propofol

Chemical name of fospropofol and class

Chemical name:Phosphono-O-methyl 2,6 diisopropylphenol

Class: Isopropylphenol

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Formulation of fospropofol and benefits

Aqueous solution

-no pain/ burning on injection but causes burning vag/anal

-no preservative but doesnt support microbial growth the same way lipid emulsions do

MOA of fospropofol

Prodrug metabolized to propofol by the enzyme alkaline phosphatase present in vascular endothelium and liver

Thus, slower onset of action and longer duration.

Dose of fospropofol

Initial bolus: 6.5mg/kg IV

Repeat bolus: 1.6mg/kg not more than q4min

Onset of fospropofol

5-13 minutes

Duration of fospropofol

15-45 minutes

Metabolism of fospropofol yields...

propofol, formaldehyde, and phosphate

-Formaldehyde is metabolized in the liver to formate and excreted in the urine

Active metabolite of Fospropofol

propofol is active metabolite;

Fosopropofol is prodrug (inactive—> active)

Clearance of fospropofol

-Same as propofol

(CYP450 enzymes in liver and lungs)

Side effects of fospropofol

Genital and anal burning

Chemical name of ketamine

2(o-Chlorophenyl)-2(methylamino) cyclohexanone hydrochloride

-Has a ketone group and amine group

Class of ketamine

Arylcyclohexylamine

Phencyclidine derivative producing “dissociative anesthesia”

¡Induction + analgesia

¡Resembles catatonic state

¡Does not require lipid emulsion and produces profound analgesia at subanesthetic doses

ketamine use

¡Intense analgesia and prompt induction of anesthesia

¡Somatic > visceral pain

¡Blocks central sensitization and wind-up in dorsal horn of SC

¡Also prevents opioid-induced hyperalgesia

¡Increased secretions - consider Robinul

¡No pain with injection

¡Not a respiratory depressant

Formulation of ketamine

Aqueous solution, available as 1, 5, or 10%

Racemic mixture

pKa 7.5

not significantly protein bound

MOA of ketamine

-NMDA antagonist (antagonizes glutamate)

-Secondary receptors target: opioid, MAO, serotonin, NE, muscarinic, sodium channels

-PCP derivative- Dissociates the thalamus (sensory) from the limbic system (awareness)

Dose of ketamine

IV induction:

IV maintenance:

Low dose infusion:

Analgesia:

IM:

PO:

IV induction: 1-2 mg/kg

IV maintenance: 1-3 mg/min

Low dose infusion: 1-3 mcg/kg/min (opioid sparing effect)

Analgesia: 0.1-0.5 mg/kg

IM: 4-8 mg/kg

PO: 10 mg/kg

Onset of ketamine

IV/IM/PO

30-60 seconds IV

2-4 minutes IM

Variable PO

Duration of ketamine

10-20 minutes

Up to 60-90 minutes for return to full orientation

Ketamine clearance

Liver (CYP450) via demethylation

Chronic use will induce the enzymes leads to rapid escalation in tolerance

elimination half life= 2-3 hours

Active metabolite of ketamine

Norketamine - 1/3 to 1/5 the potency of ketamine, relies on renal excretion

CV effects of ketamine

-Increased SNS tone (good for hemodynamic instability, bad if severe CAD),

increases myocardial O2 requirements

Increases CO, HR, SVR, and PVR (caution RV failure)

-Subhypnotic doses usually do not activate the SNS (<0.5 mg/kg)

-Myocardial depressant in patients with depleted catecholamines (sepsis) or sympathectomy

Respiratory effects of ketamine

-Bronchodilation

-Maintains respiratory drive (possible brief apnea after induction)

-Does not shift the CO2 curve

-Maintains intact upper airway muscle tone/airway reflexes—> still rx aspiration

-Increases oral/pulmonary secretions (glycopyrolate helps)

CNS effects of ketamine

Increased CMRO2, CBF, ICP, intraocular pressure, — rapid delivery to brain

¡Peak [plasma] around 1 minutes IV and 5 minutes IM

-Nystagmus or blepharospasm (caution with ocular surgery that requires a still eye)

-Emergence delirium

¡Avoid in patients with acute intermittent porphyria

Ketamine effect on eeg

¡Increases cortical amplitude of SSEP’s

¡Auditory and VEP’s are decreased

¡Does not alter seizure threshold

How does emergence delirium present?

¡visual, auditory, proprioceptive, and confusional illusions- Nightmares and hallucinations

Risk factors for emergence delirium with ketamine

Age >15, female, dose >2mg/kg, history of personality disorder

Most effective way to prevent emergence delirium with ketamine

Benzos - Midazolam is better than diazepam

Ketamine brings a risk of nightmares and hallucinations for up to...

24 hours- ranges from 5-30%

Ketamine and analgesia

-Provides analgesia and opioid-sparing effects (only induction agent that does this)

-Relieves somatic > visceral pain

-Blocks central sensitization and wind-up in the dorsal horn of the spinal cord

-Prevents opioid-induced hyperalgesia after remifentanil infusion

-Analgesic properties make it good for burn and chronic pain patients (subhypnotic doses are being used to treat severe depression)

Chronic ketamine use may cause...

ulcerative cystitis

DEXTROMETHORPHAN MOA

¡NMDA antagonist common in OTC cough suppressants

¡Equal potency to codeine as antitussive, but lacks analgesic or physical dependence problems

dextromethorphan SE

¡Excessive intake – HTN, tachycardia, somnolence, agitation, slurred speech, ataxia, diaphoresis, skeletal muscle rigidity, seizures, coma, and decreased core body temperature.

¡Psychoactive effects create abuse potential

True or False: Patients with a history of acute intermittent porphyria should NOT be administered ketamine.

True

Ketamine protein binding compared to other induction agents

Smallest amount of plasma protein binding (12%)

Induction agent with highest amount of protein binding

Propofol (98%)

-Diazepam 98%

-Midazolam 94%

-Dexmedetomidine 94%

-Lorazepam 90%

-Etomidate 75%

-Ketamine 12%

Chemical name of etomidate (Amidate)

R-1 methyl-1 a-methylbenzyl imidazole 5-carboxylate

Class of etomidate

what happens when in acidic pH and physiologic pH

Imidazole

Has carboxylated imidazole containing Water-soluble (acidic pH) ad lipid-soluble (physiologic pH)

-Acidic pH --> imidazole ring opens --> increased water solubility

-Physiologic pH --> imidazole ring closes --> increased lipid solubility

ETOMIDATE - Pharmacokinetics (3)

Large VOD – peaks around 1 minute

Highly protein bound

Redistribution and rapid metabolism by hydrolysis

Formulation of etomidate

2 forms:

-35% propylene glycol (venous irritation and injection pain)

-Lipid emulsion (less venous irritation and injection pain)

MOA of etomidate

GABA-A agonist

Dose of etomidate

0.2-0.4 mg/kg IV

Onset of etomidate

30-60 seconds

Duration of etomidate

5-15 minutes

Clearance of etomidate

Hepatic P450 enzymes and plasma esterases

-Rapid awakening d/t redistribution, NOT metabolism

Active metabolite of etomidate

None

CV effects of etomidate

-Hemodynamic stability with minimal changes HR, SV and CO

-Decreased SVR with small decrease BP

-Does not block SNS response to laryngoscopy (opioid or esmolol will help)

Respiratory effects of etomidate

Mild respiratory depression

CNS effects of etomidate

-Decreased CMRO2, CBF (cerebral vasoconstriction), and ICP

-CPP stable

-No analgesia

-May increase risk of seizure activity in susceptible patients

Which anesthetic agent increases mortaility in the patient with addisonian crisis?

A. Etomidate

Propofol

Dexmed

Midazolam

A. Etomidate

Pro of etomidate

hemodynamic stability

Con of etomidate

does not block effects of laryngoscopy

Key SE of etomidate

• Myoclonus

• PONV (more than any induction agent

• Suppression of adrenal function for up to 24 hours (avoid in sepsis and acute adrenal failure

• Acute intermittent porphyria

Myoclonus

Involuntary skeletal muscle contractions, dystonia, or tremor (not a seizure)

Mechanism of myoclonus

Unclear; Likely an imbalance between excitatory and inhibitory pathways in the thalamocortical tract

Etomidate and seizure activity

-No history of seizures

-History of seizures

-No history of seizure: etomidate does not increase the risk of seizure

-History of seizures: etomidate can increase epileptiform (seizure like) activity and possibly increase the risk of seizures (useful for mapping seizure foci)

Cortisol and aldosterone synthesis are dependent on which enzyme? Where is this located?

11-beta-hydroxylase

Possibly also 17-alpha-hydroxylase

Located in the adrenal cortex

How does etomidate cause adrenocortical suppression?

Inhibits 11-beta-hydroxylase and 17-alpha-hydroxylase

(this is why not cont infusion in ICU)