INTRAVENOUS ANESTHETICS -PRIS (associated with doses of 4 mg/kg/hr for >48 hours)

Section 4, Chapter 19 *Pharmacokinetics of Intravenous Drugs

-rapidly distribute to higher perfused and vessel-rich tissues

I. PHARMACOKINETICS: GENERAL PRINCIPLES OF -LIPOPHILICITY-> allows for rapid crossing of the blood brain barrier

INTRAVENOUS ANESTHETICS -HYSTERESIS-> slight delay between target blood concentration and

*Thiopental effect organ (brain) response

-rapid, smooth onset of sedative and hypnotic effects -> occurs because of differences between peak

-predctable pharmacokinetics plasma concentration and peak drug

-rapid and smooth emergence concentration in the brain

-long context sensitive half-life-> less ideal for use as an infusion -Termination of action of single bolus of drug-> occurs during

Table 19-1 Properties of the ideal Intravenous Anesthetic Agent redistribution of the anesthetic to lean tissues such as the muscle
I. Pharmacodynamic/pharmacokinetic properties -Initial or LOADING DOSE= establishes desired blood concentration of
Hypnosis and amnesia
Rapid onset (time of one arm-brain circulation) the drug
Rapid metabolism to inactive metabolites
Minimal cardiovascular and respiratory depression
No histamine release or hypersensitivity reactions RULE: The rate of infusion of an intravenous anesthetic for maintenance of
Nontoxic, nonmutagenic, noncarcinogenic
No untoward neurologic effects, such as seizures, myoclonus, antaanalgesia, anesthesia DECREASES, the LONGER the duration of an infusion to maintain
neurotoxicity
Other beneficial effects: analgesia, antiemetic, neuroprotection, the desired blood concentration
cardioprotection
Pharmacokinetic-based models to guide accurate dosing
Ability to continuously sly monitor delivery *Pharmacokinetics of intravenous anesthetics after BOLUS ADMINISTRATION
II. Physiochemical properties
Water-soluble 1) RAPID DISTRIBUTION PHASE
Stable formulation, nonpyrogenic
-rapid distribution of drug from the plasma to the peripheral tissues
Nonirritating: painless on injection
Small volume needed for induction 2) SLOW DISTRIBUTION PHASE
Inexpensive to prepare and formulate
Antimicrobial preparation - drug continues to distribute to other tissues concurrent with return of

drug to the plasma from the rapid distribution phase

3) TERMINAL PHASE

- also called ELIMINATION PHASE

-drug is eliminated from the body

*Pharmacokinetics of intravenous anesthetics as a CONTINUOUS INFUSION

-follows a THREE COMPARTMENT MODEL

-Rate of infusion is determined via the distribution of the drug to the peripheral

compartment and the elimination of the drug

Drug is administered-> fills the CENTRAL COMPARTMENT-> distributes

*Propofol to peripheral compartments (rapid and slow) -> drug accumulate at the
peripheral compartments-> REDISTRIBUTION of the drug from the
-the new gold standard in anesthetic practice peripheral compartments to the central compartment-> with prolonged
time, drug from peripheral compartments become greater-> less drug to
-rapid onset
be infused to maintain target blood concentration-> longer time to
rapid recovery after bolus administration from redistribution awakening

-utility as a continuous infusion

-antiemetic properties

-used in multiple settings:

1. Induction of anesthesia

2. Maintenance of anesthesia, either with volatile or as a *ELIMINATION HALFLIFE (t1/2) = time it takes for the plasma concentration of

component of TIVA a drug to decrease to 50% of its original concentration

3. Monitored anesthesia care (MAC) sedation fr minor procedures

-Side effects: hypotension, respiratory depression, pain with injection

*CONTEXT SENSITIVE HALFLIFE -clearance rate: 20-30 mL/kg/min

-time to achive a 50% reduction in concentration after stopping a -most common extrahepatic sites of metabolism: KIDNEYS and LUNGS

continuous infusion - Initial Distribution half-life of 2-4 minutes

-influenced by the DISTRIBUTIVE PROCESS, refer both the transfer of - Secondary Slow distribution half-life: 30-70 minutes

drug out of the plasma into peripheral compartments and the reverse - Context sensitive half-life: 40 minutes or less

process *PHARMACODYNAMICS

-Propofol have a SHORT CONTEXT SENSITIVE HALFLIFE compare to - Mode of action: enhancement of GABE inhibitory pathways

THIOPENTAL -Other mode of actions:

-REMIFENTANIL= best illustrates the principle of context sensitive halflife 1) Alpha-adrenergic receptor agonism

-ultra short opioid agonist 2) NMDA receptors agonism

-ester component 3) Alteration of central cholinergic transmission

-rapidly eliminated via metabolism by nonspecific plasma - Initial low doses-> SEDATION

esterases - Increase doses-> PARADOXICAL EXCITATION (disinhibition,

-has a context sensitive halflife INDEPENDENT of the duration of unpredictable movement, broken speech, not readily arousable)

infusion -HIGH DOSES-> LOSS OF CONSCIOUSNESS, apnea, relative

-Elimination time of 3 MINUTES is the same for a 1 hour infusion relaxation of muscles, loss of brainstem reflexes

as is for a 10 hour infusion 1) CENTRAL NERVOUS SYSTEM EFFECTS

*Target Controlled Infusion (TCI) - At lower dosages-> increase in beta wave activity

-anesthesiologist sets the TARGET BLOOD or BRAIN -After induction dosages-> deep non-REM sleep, with progressively

CONCENTRATION increase low-frequency and high-amplitude activity

-incorporates: BURST SUPPRESSION

1) patient factors (age, height, sex, weight) - marked by period of electrical inactivity with alternating higher

2) the amount of drug that has been delivered frequency activity

3) amount of drug that has accumulated in the tissues -employed as NEUROPROTECTIVE measure prior to aneurysm

clipping

II. PROPOFOL (2,6-diisopropylphenol) - attained at concentration of propofol (8 mcg/ml) that are

-pharmacokinetic profile: significantly higher than the blood concentrations needed to

1) desirable rapid onset reach the initial stages of GENERAL ANESTHESIA (3

2) predictable context sensitive half-life mcg/mL)

3) raid emergence from anesthesia NEUROPROTECTIVE EFFECTS:

-favorable side effects profile - lower cerebral metabolic oxygen consumption rate

-anti-emetic property (CMRO2)

Ingredients: - decrease ICP by lowering cerebral blood flow (CBF)

1) 1% propofol - lowers cerebral perfusion pressure

2) 10% soybean oil-> can cause microbial growth - antioxidant properties-> free radical scavenger

3) 2.25% glycerol-> contributes to pain at injection - attenuating excitotoxic glutaminergic pathways-> lowers

4) 1.2% egg phospholipid emulsifier-> can cause microbial growth programmed apoptosis

5) EDTA-> deter microbial growth - anti-inflammatory (decreasing TNF-alpha)

*PHARMACOKINETICS ANTICONVULSANT PROPERTY:

-primarily metabolized by the LIVER, and subsequently its inactive and - At induction doses-> BURST SUPPRESSION occurs->

water-soluble metabolites are excreted by the kidneys Limited epileptiform activity

- small amount is excreted in oth urine and feces - successfully used to treat status epilepticus

-liver and kidney disease have not been noted to alter pharmacokinetics - RARELY the anesthetic of choice for induction of

significantly anesthesia for ECT-> SHORTENS SEIZURE

 DURATION tourniquet

2) CARDIOVASCULAR EFFECTS 4) Pretreatment with opioids

- DOSE DEPENDENT and more significant after an induction dose than 5) Diluting the emulsion and changing the lipid solvent

during a continuous infusion -PROPOFOL INFUSION SYNDROME

- characteristic DROP IN SYSTOLIC & DIASTOLIC BP without the - characteristics: unexplained metabolic acidosis, hyperkalemia,

expected increase in heart rate hyperlipidemia, rhabdomyolysis, hepatomegaly, renal failure, and most

-Decrease in cardiac output, stroke volume, and systemic vascular importantly ECG changes

resistance - Mechanism: mitochondrial toxicity and uncoupling of the

- Decreases sympathetic activity and leads to indirect arterial vasodilation intracellular respiratory chain

and venodilation

- direct inhibition of baroreceptor response, leading to a diminished reflex III. ETOMIDATE

increase in heart rate -introduced last 1972 into anesthetic practice

3) RESPIRATORY EFFECTS *PHARMACOKINETICS

-DOSE-DEPENDENT -imidazole derivatives, not stable in neural pH solutions

- Diminished tidal volumes and increased RR - (+) propylene glycol, contribute to veno-irritation and phlebitis

- At induction doses, can cause APNEA - quick onset of action (vein to brain), fast resolution of effect secondary

-Has a direct effect on chemoreceptors -> blunted response to hypoxia to redistribution, follows the three-compartment kinetic model

- decreased response to HYPERCARBIA -limited continuous infusion use due to adrenal suppression

- POTENT BRONCHODILATOR - Metabolism: LIVER

*CLINICAL USES - Elimination: 80% at KIDNEYS, 20% at BILE

-INDUCTION DOSE in a healthy adult adult= 1-2.5 mg/kg - largely protein bound (75%)

-Loss of consciousness corresponds to a blood concentration level of 3

Initial distribution half-life 2.7 minutes
mcg/kg Redistribution half-life 29 minutes
-For elderly patients, have prolonged effects and increased sensitivity to Elimination half-life 2.9-5.3 hours
Volume of distribution 2.5-4.5 L/kg
propofol because of DECREASED CARDIAC OUTPUT and Induction dose 0.2-0.3 mg/kg
CLEARANCE

- For children, have a larger volume of distribution & quicker clearance, *PHARMACODYNAMICS and CLINICAL USES

resulting in increased requirement on a kilogram basis -Mechanism of action: binds as an agonist to the GABA-A receptor->

- For morbidly obese patients, lean body weight is used to calculate inhibitory influence on the brain

propofol dosing - potent VASOCONSTRICTOR-> reduces CBF, ICP and CMRO2

- Maintenance of GENERAL ANESTHESIA= 100-200 mcg/kg/min - minimal effect on MEAN ARTERIAL PRESSURE

- For ICU sedation= 25-75 mcg/kg/min - can achieve BURST SUPPRESSION with a concomitant decrease in

ICP

*SIDE EFFECTS -Associated with EPILEPTOGENIC ACTIVITY (excitatory spikes) on

- PAIN ON INJECTION EEG-> undesirable induction agent for NSS surgeries

- occurs in 60-70% of patients - Increases latency intervals measured on SSEPs

-Interventions: - Proconvulsant and lowers seizure threshold-> used or induction in ECT

1) pretreatment of local anesthetics, such as Lidocaine, in - Cardiovascular effects:

conjunction with venous occlusion using a tourniquet 1) minimal or nonexistent effects on MAP

(Modified Bier block) 2) minimal effects on pulmonary artery pressure (PA), pulmonary

2) Antecubital vein use as an alternative to smaller artery wedge pressure, central venous pressure (CVP), stroke

peripheral vein sites- most important nondrug volume, cardiac index, SVR, and pulmonary vascular

technique for minimizing pain on injection resistance

3) Pretreatment with Lidocaine without the use of

 - Respiratory effects:

1) preservation of airway reflexes

2) relaxation of the smooth musculature of the pulmonary

vasculature system

* SIDE EFFECTS

1) ADRENAL SUPPRESSION

- most significant adverse effect of ETOMIDATE

- inhibits the activity of the enzyme 11beta-hydroxylase->

PREVENTS CONVERSION OF CHOLESTEROL TO

CORTISOL

2) POSTOPERATIVE NAUSEA AND VOMITING

IV. KETAMINE