PHARMOCOKINETICS: 0GENERAL

PRINCIPLES OF IV ANESTHETICS

No single anesthetic agent is perfect

The ideal IV anesthetic:
 Hypnosis
 Amnesia
 Rapid onset (time of arm-brain circulation)
 Propofol has become the “GOLD
STANDARD” (rapid onset – recovery after
bolus - redistribution and utility as continuous
infusion)
IV anesthetics have a rapid onset, rapidly distributing to
higher perfused and vessel-rich tissues,
Their lipophilicity allows for rapid crossing of the
blood–brain barrier. The slight delay between target
blood concentration and effect organ (brain) response is
known as Hysteresis, occurs because of differences
between peak plasma concentration and peak drug
concentration in the brain, and terminated by the
redistribution.
Initial bolus – desired plasma concentration –
redistribution (initial clearance), if in infusion, the
rate should be decreasing to maintain the desired
blood concentration.

Bolus- rapid increase of blood concentration and

decreases over time, first phase rapid onset, second
phase: slow distribution, third phase: elimination.

The three-compartment model is used to describe the behavior of an

IV anesthetic,
The first administration, fills the central compartment, then is
distributed to the peripheral compartments, starting to the smallest
ones to the largest, one rapid and the other slowest
The rate of distribution can be matched with an appropriated
infusion rate, that allows to maintain the desired blood concentration,
over time it will begin to accumulate because of the less removal
from the central circulation, with prolonged time due to the
contributions of the stored anesthetic it will require less infusion to
maintain the target blood concentration, but also leads to a longer
awakening time.

This leads to the concept of half time (time required to reduce the
plasmatic concentration of the drug to 50%, after stopping an
infusion) and elimination half time (time required to excrete or
metabolize the 50% of the drug out the body)

PROPOFOL
 (2,6-diisopropylphenol)  induction
 Rapid- onset  maintenance
 predictable context-sensitive half-time  (ICU) sedation
 rapid recovery  sedative-hypnotic
 antiemetic property  lipophilicity and relative insolubility in aqueous
solutions
anaphylactic reactions 1% propofol + 10% soybean oil + 2.25% glycerol + 1.2% egg phospholipid emulsifier +
ethylenediaminetetraacetic acid (EDTA) (milky white consistency

PHARMACOKINETICS
 hepatic metabolism (renal and pulmonary)
 water soluble protein inactivation
 renal excretion and a small fraction from feces
 hepatic and renal disease don’t affect the
metabolism significantly
 clearance rate (20-30 ml/ kg / min = 1.5 L/min)
 t ½ 2-4min (bi compartmental)
 t ½ 1-8 min – 30-70 min (tri compartmental)
 t ½ elimination 2-24 hrs

PHARMACODYNAMICS
 GABA inhibitory pathways
 α-adrenergic receptors
 Nmethyl-D-aspartate (NMDA) receptors
 low doses of propofol produce sedation
 mid doses paradoxical excitation may occur, where a patient disinhibited, has unpredictable movement, broken
speech, and is not readily arousable
 high dose of propofol leads to loss of consciousness, apnea, relative relaxation of muscles, loss of brainstem
reflexes, and subsequently necessitates airway support

CNS EFFECTS
 low dose increase in beta-waves
 induction dose deep non-REM sleep, low
frequency, high amplitude activity ↓β, ↑αδ
 low O2 consumption rate
 ↓ ICP - ↓ CBF
 ↓ CPP
 Antioxidant properties
 Generally considered an anticonulsivant
 Can cause dependence
 Physostigmine reversible (cholinomimetic)
CARDIOVASCULAR EFFECTS
 Dose dependent
 ↓ systolic/diastolic pressure without tachycardia
 ↓ cardiac output
 ↓ stroke volume
 ↓ vascular resistance
 Arterial vasodilation and venodilation
 Ø baroreceptor response
 Suppression on supraventricular tachycardia

RESPIRATORY EFFECTS
 Dose dependent
 HIGH DOSE apnea
 MAINTENANCE DOSE ↓ tidal volumes, ↑ RR
 Blunt response due to hypoxia due to side effects on chemoreceptors, as well as decreased respiratory response
to hypercarbia
 Potent bronchodilator

CLINICAL USES
 Rapid and smooth induction and emergence
 Sedative-hypnotic
 Induction dose 1-2.5 mg/ kg, loss of consciousness (3 μg/ kg)
  Elderly can be sensitive due to the cardiac effects
 Alcoholics need a higher induction dose
 Maintenance 100-200 μg/ kg/ min + inhaled anesthetics
 Malignant hyperthermia
 Sedation, minor procedures, off-site anesthetics, ICU sedation 25-75 μg/ kg/ min
 TIVA with Propofol alone—or together with opioids as part of balanced anesthetic—has been utilized
successfully for all types of surgery

SIDE EFFECTS
 Pain on injection site  Rhabdomyolysis
 PRIS (propofol infusion syndrome)  Hepatomegaly
 Metabolic acidosis  Renal failure
 Hyperkalemia  ECG changes
 Hyperlipidemia  Arrythmias, with progression to cardiac failure

ETOMIDATE

PHARMACOKINETICS
 D+ enantiomer of imidazole derivate
 Propylene glycol – veno-irritation and
phlebitis
 Quick onset
 Fast resolution
 Three compartment kinetic model
 Adrenal suppression with continuous infusion
 Hepatic metabolism
 Renal and bile excretion
 75% protein bound

PHARMACODYNAMICS AND CLINICAL USES

 GABA-A agonist
 potent vasoconstrictor reduces CBF, ICP, and CMRO2
 CPP is either maintained or increased
 Epileptogenic activity
 Undesirable inductor
 Increase of the of the latency intervals, measured in somatosensorial-evoked potentials
 Hemodynamically stable induction
 Less depression of the airway reflexes
 Relaxes the smooth vasculature of pulmonary vasculature

SIDE EFFECTS
 Adrenocortical suppression
 inhibits the activity of the enzyme 11β-hydroxylase and prevents the conversion of
cholesterol to cortisol

KETAMINE
 Phencyclidine (PCP; angel dust)
 “dissociative anesthesia”
 marked nystagmus
  significant analge sia and unconsciousness
 emergence delirium, hallucinations, and alterations in
mood and affect
 low-dose ketamine has an opiate sparing effect in the
management of acute pain
 antihyperalgesic, antiallodynic, or toleranceprotective

PHARMACOKINETICS
 chiral compound
 racemic mixture of S and R enantiomers
 IM 93% bioavailability
 transnasal administ ration has 25% to 50%  CSF levels were about 0.2 mg/mL 1 hour after
bioavailability dosing
 rectal or oral administration has 16%  α-elimination phase CNS to peripheral tissues
bioavailability (11 minutes)
 high lipid solubility  β-elimination phase is 2.5 hours
 low protein binding (20%)  metabolized primarily in the liver by
 rapid uptake cytochrome P-450 enzymes (CYP 3A4 > CYP
 fairly rapid redistribution 2C9 > CYP 2B6)
 onset 30-60 seconds  principal metabolite norketamine only has one-
 t ½ 10-15 min third to one-fifth the activity, eliminated by renal
 induction dose 0.5 to 2 mg/kg IV or 4 to 6 excretion
mg/kg IM  Due to its lipophilicity, ketamine is only
 Peak plasma levels averaged 0.75 mg/mL partially removed by dialysis

PHARMACODYNAMICS  Ketamine binds to μ, δ, and κ opioid receptors;

 Antagonism of the NMDA
 also has clinical effects at opioid, noradrenergic,
cholinergic, nicotinic, and muscarinic receptors.
 binds preferentially to the NMDA receptors on
inhibitory interneurons in the cortex, limbic
system, and hippocampus
 promote uncoordinated increase in neuronal
activity and an active EEG pattern, and produce
unconsciousness.
 nociception
 Ketamine binds to an interchannel site of the
NMDA decreases the amplification of repeated
stimulation of the NMDA receptor
 Ketamine has been found to bind to opioid,
noradrenergic, and cholinergic
 receptors
CLINICAL USES
ANESTHESIA
 dissociative amnestic
 Induction doses of ketamine are 1 to 2 mg/kg, onset of 1 minute and a duration of 10 to 20 minutes
 good choice for anesthetic induction in the hemodynamically unstable patient
 unsuitable for some cardiac patients
however this does not account for its analgesic
effects.
 The primary analgesic mechanism of ketamine
is believed to be in the prevention of developing
hyperalgesia.
 causes stimulation of CNS noradrenergic
neurons and inhibition of catecholamine uptake,
which provokes a hyperadrenergic state (with
increased release of norepinephrine, dopamine,
and serotonin).
 effect on noradrenergic neurons is partly
responsible for the hypnotic, psychic, and
analgesic effects observed
 affects CNS cholinergic neurons, and the
anticholinergic physostigmine can antagonize
the hypnotic effects of ketamine.

SEDATION
 burn patients during wound care
  pediatric patients for painful procedures such as
reduction and casting of bone fractures in the
emergency department
ANALGESIA
 acute postoperative pain
 lower pain scores and decrease opiate
requirements
 prevention of hiperalgesia and decreases in
central nervous system sensitization
CHRONIC PAIN
 preventing hiperalgesia
 Intranasal ketamine was found to significantly
lower the intensity of breakthrough pain
DEPRESSION
 treatment for major depression
 decreased depression symptoms and suicidal
ideation within 1 hour
  of administration

SIDE EFFECTS
SNC CARDIOVASCULAR
 psychogenic reactions  increased heart rate and increased blood pressure
 hallucinations and out-of-body experiences  direct myocardial depression
 lateral gaze nystagmus  cardiovascular collapse
RESPIRATORY
 maintains spontaneous respiration
 Hypoxia
 Bronchodilator
 increased salivation – laryngospasm
INTRACRANEAL PREASSURE/SEIZURE
ISSUES
 not recommended in patients with elevated ICP
 neuroprotective
 associated with epileptiform activity on EEG;
however
DEXMEDETOMIDINE
α2-adrenergic agonist similar to clonidine, it has seven to eight times greater affinity for the α2-
adrenergic receptor it’s usually used in ICU sedation in mechanically ventilated patients, for
procedural sedation, and as a component of general anesthesia

PHARMACOKINETICS
 rapid distribution phase
 distribution half-life of approximately 6 minutes
 elimination halflife of approximately 2 hours
 state volume of distributions of approximately 118 L
 0.2 to 0.7 μg/kg/hr IV infusion for up to 24 hours
 protein binding is 94%
 complete biotransformation with very little unchanged dexmedetomidine in the urine and
feces.
 direct glucuronidation and cytochrome P450-mediated
 metabolism
 terminal elimination half-life is approximately 2 hours
 clearance≈ 39 L/hr, (lower in hepatic impairment)

PHARMACODYNAMICS
 α2-adrenergic receptors in the spinal cord and brain
 effects are primarily at the locus coeruleus that activates sleep centers in the brain
 resembles non-REM sleep
 bradycardia and hypotension (7 mmHg decrease in systolic blood pressure and a
decrease in mean heart rate of 1 to 8 bpm)

CLINICAL USES
 sedation for mechanically ventilated patients in the ICU
 ICU sedation in neurosurgery
 analgesic properties, and can reduce opiate requirements in ICU patients who are
mechanically ventilated
 procedural sedation
 sedation during awake fiberoptic intubation
  MAC sedation alone or in combination
 0.5 to 1 μg/kg loading dose over 15
minutes, followed by an infusion of 0.3 to
0.7 μg/kg/hr.
 anesthetic adjuvant for regional anesthesia.

SIDE EFFECTS
 hypotension,
 bradycardia - cardiac arrest
 dry mouth
 nausea
 hypertension

BENZODIAZEPINES
Anxiolysis + anterograde amnesia + sedation +
hypnosis
Muscle
relaxants and anticonvulsants

PHARMACOKINETICS
highly protein-bound (less drug is free to cross the blood–brain
barrier)
and highly lipophilic (rapid-onset of action)
Metabolism - hepatic cytochrome P450 system via
oxidation and glucuronic conjugation.

PHARMACODYNAMICS AND CLINICAL USES

most commonly used parenteral benzodiazepines
1. lorazepam
2. diazepam
3. midazolam
Lorazepam and diazepam are not soluble in water and often cause vein irritation due to the propylene glycol admixture, an
alternative formulation are available as a lipid emulsion, but with a decrease in bioavailability. Midazolam is water-
soluble and undergoes conformational change in the bloodstream, becoming more lipophilic. Midazolam is manufactured
as an acidic formulation that may produce mild local tissue and vein irritation.
  GABA-A receptor complex
 decrease both the CMRO2 and CBF,
 maintain carbon dioxide
responsiveness

 anticonvulsants
 muscle relaxants (supratherapeutic
doses)
 hemodynamically stable induction

SIDE EFECTS
 Anaphylaxis
 Pain
 Thrombophlebitis

BARBITURATES
Used in clinical practice are the thiobarbiturates thiopental (2.5%) and thiamylal (2%), and the oxybarbiturate
methohexital (1%).
The thiobarbiturate solutions are produced as racemic mixtures, despite unequal potency between their two stereoisomers.
Methohexital has two chiral centers and four potential stereoisomers, but not all isomers are included in the final product.
Barbiturate solutions are highly alkaline, allowing for formation of water-soluble salts.

PHARMACOKINETICS
Primary metabolism, hepatic, yielding water-soluble inactive metabolites that are subsequently eliminated in urine and
bile
Thiopental has a relatively long elimination half-life (12 hours), and its clearance rate (3
mL/kg/min) is 10-fold longer than that of propofol. Methohexital elimination half-life (4
hours) is also shorter than thiopental, secondary to a more efficient hepatic extraction of the drug
(clearance rate 11 mL/kg/min).

PHARMACODYNAMICS
cortical and brainstem GABA inhibitory pathways, leading to loss of consciousness, as well as
respiratory and cardiovascular depression, inhibition of central excitatory pathways,
specifically those mediated by glutamate via NMDA receptors and acetylcholine

CNS
 EEG changes, dose-dependent
 low doses can generate a light level of
anesthesia often associated with a high-
frequency and low-amplitude EEG pattern
 higher doses, both burst suppression and an
isoelectric EEG can be attained
 Thiopental (anticonvulsant)- treatment of status
epilepticus, “smaller concentrations -
proconvulsant properties”
 decrease in CMRO2 that is dose-dependent
 decreased CBF and ICP.
 CPP is often unchanged or even impr
 Neuroprotective

CARDIOVASCULAR EFFECTS
  decreases MAP and cardiac output  respiratory depression dose-dependent
 reduction of venous vascular tone  central apnea
 Baroreceptor-mediated heart rate increase
 negative hemodynamic effects in patients with
underlying cardiovascular disease and in
hypovolemic states
RESPIRATORY SYSTEM EFFECTS

CLINICAL USES  Methohexital-induced pain on injection

 Tiopental- induction dose is 2.5 to 5 mg/kg,  Inadvertent arterial administration of thiopental
resulting in light stages of anesthesia in 15 to 30 has to be managed promptly - formation of
seconds, and deeper stages in 30 to 40 seconds crystals (vasospasm and thrombus formation),
that last for approximately 1 minute pain at the arterial site, and possible tissue
 Methohexital- shorter elimination half-life, necrosis
infusion doses of 50 to 150 μg/kg/min has been
used for maintenance of sedation and general
anesthesia
SIDE EFFECTS
 can cause discomfort