OPIODS Listen to Audio -meperidine -morphine -fentanyl -sufentanil -alfentanil

-remifentanil mechanism of action structure-activity relationship pharmacokinetics

effects on organ systems drug interaction

MECHANISM OF ACTION
Four major types of opiod receptors: -mu receptors ( mu-1, mu-2) -kappa receptors
-delta receptors -sigma receptors
Endogenous peptides which bind opiod receptors: -endorphins -enkephalins
-dynorphins
Opiod- receptor activation:
-produces analgesia
-inhibits presynaptic release of acetylcholine and substance P in nociceptive neurons
-inhibits postsynaptic response to acetylcholine and substance P in nociceptive
neurons
-may involve changes in potassium and calcium ion conductance
-intrathecal and epidural administration of opiods can interrupt pain impulses at the
dorsal horn of spinal cord
-periaqueductal gray and nucleus raphe may also be involved in the analgesic effects
of opiods

STRUCTURE-ACTIVITY RELATIONSHIPS -chemically diverse group of

compounds which share a common opiod-receptor interaction

PHARMACOKINETICS
Absorption
-oral transmuscosal fentanyl citrate absorption is effective in producing analgesia and
sedation with onset approx 10 minutes
-transdermal patch of fentanyl is possible due fentanyl's low molecular weight and
high lipid solubility
-intramuscular injection of meperidine and morphine has peak effects after 20 - 60
minutes
-intravascular route of analgesics allows for more closer titration from a clinically
trained experienced practioner

Distribution -distribution half live is generally rapid (5 - 20 minutes) for all

analgesics except for morphine -morphine has a lower lipid solubility and crosses the
BBB more slowly therefore the onset and duration of action are prolonged
-fentanyl and sufentanil have high lipid solubility therefore have a rapid onset of
action and have a short duration of action
-alfentanil has less solubility compared to fentanyl but has a more rapid onset due its
high nonioned fraction at nl pH and small Vd

Biotransformation -mainly involves the liver -high hepatic extraction fraction ratio
therefore the clearance of opiods is generally dependant on hepatic blood flow

-meperidine is N-demethylated to normeperidine which is an active metabolite which

may be associated with seizure activity -morphine is conjugated with glucuronic acid
forming active metabolites of morphine 3-glucuronide and morphine 6-glucuronide

-metabolites of fentanyl, sufentanil, and remifentanil are inactive

Remifentanil -ultra short acting opiod

-has a unique ester structure allowing hydrolysis by nonspecific esterases in blood and
tissue -terminal elimination half-life less than 10 minutes -context-sensitive half-time
is approximately 3 minutes regarless on duration of infusion time -lack of drug
accumulation following repeated dosing or prolonged infusion -presumed extrahepatic
hydrolysis due to lack of toxic metabolites in hepatic dysfunctional patients -normal
response to remifentanil in patients with pseudocholinesterase deficiency

Excretion -primarily excreted by the kidneys in the urine -metabolites of morphine

and meperidine are eliminated by the kidneys with less than 10% excreted within the
bile -accumulation of morphine metabolites in renal failure patients may be associated
with narcosis and ventilatory depression -accumulation of merperidine metabolites in
renal failure patients may be associated with narcosis and ventilatory depression -late
secondary peak fentanyl plasma levels may occur upto 4 hours after the last
intrvenous dose -late secondary peak fentanyl plasma levels may be due to
exterohepatic recirculation or sequestered drug mobilization -sufentanil metabolites
are excreted in the urine and bile -remifentanil metabolites are excreted in the urine

PHARMACODYNAMICS Effects on organ systems

Central nervous system -reduce CMR02 -reduce CBF -reduce ICP -variable effects on
cerebral perfusion pressure (CePP) and ICP -pts with decreased intracranial
compliance may have significantly decreased CePP with an associated decreased
MAP w.opiods -stimulation of the medullary chemotrigger zone (CTZ) may be
associated with a high incidence of nausea and vomiting -potential for physical
dependance with repeated doses of opiods -not a reliable amnestic agent -use of
opiods in spinal and epidural anesthesia has helped to provide better pain management
-meperidine has local anesthetic properties when administered intrathecally

Cardiovascular system -generally cardiovascular function is not impaired -high doses

of opiods generally are associated with vagal mediated bradycardia (exception
meperidine) -meperidine in high doses is associated with an increase in heart rate due
to its structural similarities to atropine -opiods generally do not depress myocardial
contractility (exception meperidine) -mean arterial pressure may decline with opiods
due to bradycardia, venodilation or decreased sympathetic tone -meperidine and
morphine are more associated with histamine release which causes vasodilation and
profound decreased in BP -opiods in combination with volatile anesthetics may be
involved with significanty myocardial depression

Respiratory system -depress ventilatory function primarily respiratory rate -decreased

respiratory ventilatory response to a rising PaC02 level -increased apneic threshold
-decreased hypoxic drive -morphine and meperidine may be associated with
histamine-induced bronchoconstriction -may be involved with chest wall rigidity
severe enough to prevent adequate ventilation more common after large boluses
-chest wall rigidity can usually be corrected with either reversal or use of muscle
relaxants

Gastrointestinal -delay gastric emptying be decreasing peristalic contractions -opiod

induced contraction of the sphincter of Oddi may cause biliary colic

Endocrine -block the release of stress hormones elevated during surgery

(catecholamines, ADH, and cortisol) more than volatile anesthetics -blocking the
release of stress hormones is especially beneficial for ischemic heart diseased patients
going in for surgery Drug

Interactions Opiods with MAO inhibitors may result in: -respiratory arrest
-hypertension -hypotension -coma -hyperpyrexia -opiods with benzodiazepines,
barbiturates, and other CNS depressants can cause synergistic cvs, resp, and sedative
effects
PHARMACOKINETICS how the body affects the drug Listen to Audio absorption
distribution biotransformation excretion compartment models

elimination = biotransformation + excretion

clearance measures the rate of elimination

absorption -routes of absorption: oral, sublingual, rectal, inhalational, transdermal,

subcutaneous, intramuscular, and intravenous
-process which the drug leaves the site of administration and enters the blood
circulation affected by:
-physical properties of drug (solubility, pKa, and concentration)
-physical properties of site of absorption (circulation, pH, surface area)

distribution
-major determinant of end-organ drug concentration affected by
-organ perfusion of the drug
-protein binding to the drug
-lipid solubility of the drug
-molecular size of the drug
-tissue binding of the drug organ perfusion of the drug
-highly perfused vessel rich groups (ex. brain) take up large amounts of
drug compared with less perfused organs (ex.muscles)
-amount of drug uptake from a highly perfused organ can large despite
having a relative small mass (ex. brain vs muscle groups) protein binding of the
drug
-protein binding of the drug to plasma proteins prevents uptake of the drug by the
organ despite the extent of perfusion to the organ
-decreased protein binding of plasma proteins to a drug creates increased amount
of free available drug for tissue uptake increased amount of free drug available for
tissue uptake occurs when:
-diminished plasma proteins (ex. hepatic failure: decreased synthetic function to
manufacture plasma proteins)
-protein binding sites occupied by other drugs (ex. competitive antagonist drugs)
Albumin plasma protein generally binds to acidic drugs (ex. barbituates)
Alpha1-acid glycoprotein (AAG) generally binds to basic drugs (ex. local
anesthetics)
Lipid solubility of the drug -lipid soluable, nonionized drugs pass freely through lipid
membranes (basic constituents of cellular membranes)
ex. lipid insoluable,
ionized drug has limited uptake through the BBB therefore will have diminished or no
effect on the CNS lipid soluable,
nonionized drug passes freely through the BBB and therefore may have profound
effects on the CNS
Molecular size of the drug -may also influence the distribution of the drug
Tissue binding of the drug -may also influence the distribution of the drug

Redistribution -responsible for the termination of action for many anesthetic drugs
once highly perfused organs of the vessel-rich group (ex.brain) become fully saturated
during the initial distribution:
-lesser perfused organs (ex.muscle groups, adipose tissue) continue drug uptake from
the systemic circulation
-plasma concentrations of the drug diminish in the systemic circulation from the slow
continual uptake of less perfused organs
-diminished plasma concentrations of drug in systemic circulation is no longer in
equillibrium
-therefore drugs from the highly perfused organ will redistribute into the plasma to
maintain equillibrium
-once the lesser perfused organs are saturated then there is less drug uptake from
systemic circulation
-plasma concentrations remain in equilibrium therefore diminished or no
redistribution occurs lack of redistribution:
-may prolong emergence since awakening is no longer dependant on redistribution
but instead affected primarily by drug excretion ex. infusion or multiple doses of
thiopental or fentanyl may have prolonged effects

Volume of distribution (Vd) -apparent volume a drug would have to be distributed

into to account for its plasma concentration Vd= dose of administered drug / plasma
concentration of the drug Small Vd: relative confinement of drug within the
intravascular space therefore high plasma concentration of drug causes: high protein
binding, ionization ex. pancuronium Vd = 10L in average sized person Large Vd:
high distribution of drug outside the intravascular space and therfore smaller plasma
concentration of drug causes: high lipid solubility, high peripheral tissue binding
ability ex. fentanyl Vd = 350 L in average sized person
Biotransformation -metabolic alteration of a substance generally to inactivate and
create a water soluable form for easy excretion via kidneys -primary organ of
biotransformation is the liver
Metabolic biotransformation has two phases:
-phase I reaction: oxidation/reduction, hydrolysis: conversion of intial drug into a
more polar molecule
-phase II reaction: conjugation reaction which couples an endogenous subtrate
creating a highly polar molecule polarized metabolic biotransformed molecule is then
able to be eliminated via the kidneys

Hepatic clearance
-rate of drug elimination due to liver biotransformation
-volume of plasma cleared of drug / time = ml/min
-affected by: hepatic blood flow and hepatic extraction

ratio hepatic extraction ratio: fraction of drug removed from the plasma by the liver

high hepatic extraction ratio: effecient removal of drug from plasma by the liver
clearance proportional to heptic blood flow
low hepatic extraction ratio: ineffecient removal of drug from plasma by the liver
clearance limited to hepatic enzyme capacity

Excretion -primary organ of excretion is the kidneys

-alterations in urine pH can alter renal excretion of drugs
-kidneys are also capable of secretion of some drugs
-altered pharacokinetics may occur with renal failure due to changes in protein
binding, Vd, and rates of clearance

-nonprotein bound drugs: freely cross from the systemic circulation into the
glomerular filtrate
-protein bound drugs: unable to cross glomerulus therefore unable to enter into filtrate

-nonionized fraction of the nonprotein bound drug which entered into the glomerular
filtrate becomes reabsorbed back into circulation –
ionized fraction of the nonprotein bound drug which enetered into the glomerular
filtrate is excreted via urine

Renal clearance rate of elimination of a drug due to kidney excretion

Compartment models
-conceptual compartments to describe the distribution and elimination of drugs from
the body central compartment: ex.plasma and vessel rich groups peripheral
compartment: ex.less perfused groups (ex. muscles, fat tissue)

Two Compartment model:

-distribution phase (alpha phase): redistribution of drug from the central compartment
to the peripheral compartment ex. redistribution of drug from the plasma or vessel-
rich groups (ex.brain) to the lesser perfused groups (ex.muscles.fat tissue)

-elimination phase (beta phase) : as redistribution slows, slow continual elimination of

drug from the central compartment first order kinetics: constant fraction/percentage of
drug distributed/metabolized per unit of time despite the plasma concentration zero
order kinetics: constant amount of drug metabolized per unit of time regardless of
plasma drug concentration

PHARMACODYNAMICS: how the drug effects the body Listen to Audio -studies
the therapeutic and toxic effects on the organ systems of the body -the drug effects on
the body determines the drugs' efficacy, potency, and therapeutic ratio -concerned
with mechanism of action, drug interactions, and structure-activity relationships
-parameters of pharmacodynamics is better understood by studying the dose-response
curves and drug receptors

Dose-response curves -relationship between the drug dose and the pharmacologic
effect on the organ systems of the body
-extrapalating information from the dose-response curve allows for the following
parameters:
efficacy: the maximal pharmacological effect of a particular drug on the body median
effective dose
(ED 50): dose of a given drug required to create a given effect in 50% of the
population median lethal dose
(LD50): dose of a given drug that leads to death in 50% of the population therapeutic
index ratio of median lethal dose: median effective dose (LD50: ED50)

Drug receptors -macromolecules which interacts with a drug to facilitate a

charecteristic intracellular change -mechanism of action generally depends on the
drug interacting with the receptor
Agonist: endogenous and or exogenous substances which bind directly to receptors
and create direct cellular changes in physiology -endogenous agonist (ex. hormone)
-exogenous agonist (drug)

Antagonist: endogenous and or exogenous substance which bind to the receptor

however do not create a direct cellular change Competitive antagonist: reversibly
binds to receptors that can be displaced by higher concentrations of agonist
Noncompetitive antagonist: irreversible binding to receptors such that even higher
concentrations of agonist does not reverse blockade
Benzodiazepines Listen to Audio midazolam (versed) diazepam (valium) lorazapam
(ativan) mechanism of action structure-activity relationships pharmacokinetics effects
on organ systems drug interactions

MECHANISM OF ACTION
-interact with receptors in the CNS (mainly the cerebral cortex) which facillitate
GABA conductance of chloride ions intracellular
-affects the membrane polarization which inhibits normal neuronal function hence
generally causes sedative effects

STRUCTURE-ACTIVITY RELATIONSHIPS
-benzene ring + seven membered diazepine ring
-potency and biotransformation affected by varying positions of substitutions on the
ring structures
ex.midazolam exist as a imidazole ring at a physiologic pH which allows for IV
injection for less painful than other benzodiazepines
midazolam exist as a open water soluable molecule at a more acidic environment
short-acting potent benzodiazepine which is very lipid soluable with rapid
redistribution

PHARMACOKINETICS
Absorption: -commonly administered: orally, IM, and IV
-orally: diazepam and lorazepam well absorbed by the GI tract: peak levels 1
hour, and 2 hours, respectively
midazolam not approved by USDA although more commonly used for oral
premedication of pediatric patients
-intramuscular: diazepam is painful and unpredictable when given IM IM
midazolam and lorazepam well absorbed with peak levels in 30 and 90 minutes,
respectively intravenous:

midazolam exist as imidazole ring at physiologic pH which is very lipid soluable with
rapid onset

Distribution
-diazepam is lipid soluable therefore rapidly penetrates the BBB
-midazolam is initially water soluable at low pH but then closes at physiologic pH and
becomes highly lipid soluable
-lorazepam is moderately lipid soluable therefore has a slower onset of action
associated with a slower uptake from the brain redistribution for benzodiazepines is
rapid and is responsible for awakening of the patient from sedation initial distribution
half life is 3-10 minutes

Biotransformation
-benzodiazepines are metabolized by the liver to form water soluable glucuronide end
products
-phase I metabolites of diazepam are active therefore may have prolonged effects
elimination half life of diazepam: 30 hours elimination half life of lorazepam 15 hours
elimination half life of midazolam 2 hours elimination half life and Vd account for the
differing times
ex. midazolam has a very high hepatic extraction ratio

Excretion
-metabolites mainly excreted in the urine
-renal failure pts may have prolonged sedative effects after recieving midazolam
due to the accumulation of a conjugated metabolite
-conjugated metabolite: alpha-hydroxymidazolam

PHARMACODYNAMICS Effects on Organ Systems \

Central nervous system
-reduce CMR02 -reduce CBF -reduce ICP (less reductions than from barbituates)
-effective in preventing and controlling grand mal seizures
-antegrade amnesia

Cardiovascular system
-at inductions doses: minimal cardiodepressant effects
-slight decline in blood pressure, cardiac output, and peripheral vascular resistance
-heart rate may increase perhaps from drug induced vagolysis
-midazolam may reduce blood pressure more than diazepam

Respiratory system
-blunted reponse to increasing PaCO2
-ventilatory depressant effects
-careful titration especially with midazolam

Drug Interactions:
Diazepam: cimetidine reduces metabolism due to inhibition of cytochrome p450
heparin increases the free drug concentration by displacing diazepam from binding
proteins
Midazolam: erythromycin decreases metabolism therefore an increases of 2-3 times
the prolongation
BARBITURATES Listen to Audio Thiopental Pentobarbital Phenobarbital
Methohexital Secobarbital Thiamylal mechanism of action structure-activity
relationships pharmacokinetics effects on organ system drug interactions

MECHANISM OF ACTION
-depress the reticular activating system (RAS) within the brainstem
-preferentially affect the function of nerve synapses rather than axons at clinical
concentrations
-supress transmission of excitatory neurotransmitters (ex. Acetylcholine)
-enhance transmission of inhibitory neurotransmitters (ex. GABA)

STRUCTURE-ACTIVITY RELATIONSHIPS derivatives of barbituric acid

-hypnotic potency from C5 substitution
-anticonvulsant activity from C5 substitution ex. adding a phenyl group instead of C5
-lipid solubility increased from C2 substitution ex. adding a sulfer group instead of C2
-shorter duration of action from methyl substitution at the N1 position

PHARMACOKINETICS
Absorption -most frequently administered intravenously for induction of general
anesthesia in both pediatric and adult patients
Distribution -duration of action generally determined by redistribution of the highly
soluable barbiturates (ex. thiopental, thiamylal, methohexital)
-rapid brain uptake of thiopental due to high lipid solubility and high nonionized
fraction despite high protein binding
-maximal brain uptake of thiopental within 30 seconds
-loss of consciousness generally within 30 seconds
-awakening generally within 20 minutes
-elimination half life of thiopental approximately 3-12 hours

Higher brain and heart concentrations for a given dose in the following conditions:
-hypovolemic shock: central compartment volume contraction
-severe liver disease: low serum albumin
-acidosis: decreased nonionized fractions

Biotransformation
-primarily involves hepatic oxidation to create inactive water soluable metabolites of
barbiturates
-methohexital is cleared from the liver 3-4 x's more rapidly than thiopental due to
methohexitals high hepatic extraction

Excretion -renal excretion is limited to water soluable end products of hepatic

biotransformation -high protein binding decreases the glomerular filtration of
barbiturates -high lipid solubility increases the renal tubular reabsorption of
barbiturates -methohexital is exreted via feces

PHARMACODYNAMICS Effects on the Organ Systems

Central nervous system
-decreased CBF and ICP via cerebral vascular constriction
-possible increased cerebral perfusion pressure due a greater decrease in ICP
compared to the decrease in MAP
-decreased CBF avoids a cerebral injury due to a corresponding decrease in CMR02
-may provide cerebral protection from transient focal episodes of cerebral ischemia
(ex.cerebral embolus)
-does not protect the brain during global complete cerebral ischemia
-may occasionaly have an antianalgesic effect, lowering the threshold to pain stimuli
-grand mall seizures are generally rapidly controlled with small doses of thiopental

Cardiovascular system -decrease in blood pressure with induction doses due to

increased venous capacitance via vasodilation
-vasodilation occurs do to depression of the medullary vasomotor center therefore
decreases preload to the right atrium
-decreased blood pressure stimulates an intact baroreceptor which results in
tachycardia
-cardiac output generally is maintained with the compensatory increase in heart rate
secondary to the decreased blood pressure
-cardiac output can dramatically decrease in which the baroreceptors and no longer
intact or diminished generally cardiac output changes with administration of
thiopental are reflective of: -volume status -basline autonomic tone -pre-existing
cardiovascular disease

Conditions in which cardiac output may decrease dramatically with the administration
of thiopental: -hypovolemia -heart failure CHF -beta blockade

Respiratory system -decreases and blunts the medullary ventillatory center response to
hypercarbia and hypoxia -possible upper airway obstruction with sedation -apnea
generally follows induction doses -decreased tidal volume and respiratory rates
associated with emergence and awakening of barbiturates possible bronchospasm
during induction using thiopental may be from: -excessive cholinergic nerve
stimulation -histamine release -direct bronchial smooth muscle stimulation
Hepatic system -decreased hepatic blood flow -stimulating hepatic enzymes increases
rate of metabolism of some drugs (ex. digitoxin) -inhibition of cyto p450 slows the
rate of metabolism of some drugs (ex. TCA)
-may stimulate the enzyme aminolevulinic acid synthase which forms porphyrins
which may precipitate acue intermittent porphria

Renal system -decreases renal blood flow and GFR proportionally to the decrease in
mean arterial pressure

Drug Interactions -contrast media -sulfonamides -drugs which compete for the same
binding sites of protein binding molecules may increase the free fraction of
barbiturates

Potentiate the sedative effects of barbiturates: -ethanol -antihistamines -cns depressant

medications
Propofol Listen to Audio mechanism of action structure-activity relationships
pharmacokinetics effects on organ systems drug interactions
MECHANISM OF ACTION -may involve facilitation of GABA mediated inhibitory
neurotransmitters
STRUCTURE-ACTIVITY RELATIONSHIPS 2,6-diisopropylphenol consist two
isopropyl groups attached to a phenol ring -potency, induction and recovery
charecteristics are affected by altering the side-chain length on the alkylphenol of
propofol -packages as 1% aqueous solution
PHARMACOKINETICS
Absorption -only available for intravenous administration -induction of general
anesthesia
Distribution -rapid onset due to high lipid solubility -onset nearly as rapid as
thiopental with a one arm-to-brain time -short initial redistribution time of about 2-8
minutes leads to rapid awakening after a single bolus -good anesthetic agent for
outpatient services due to less hangover sensation compared with thiopental and
etomidate -elderly patients: may require a smaller induction dose due to a smaller Vd
-female patients: may require a larger dose than males and may have a more rapid
awakening
Biotransformation -conjugation of propofol in the liver results in inactive metabolites
which are then to be eliminated by renal clearance
-extrahepatic metabolism is implicated due to the clearance of propofol exceeding the
hepatic blood flow
-very high clearance rate of propofol allows for a rapid recovery even after a
continous infusion
Excretion -primarily renal excretion of metabolites of propofol in the urine -chronic
renal failure does not appear to affect the clearance of propofol
Pharmacodynamics
Effects on Organ Systems Central nervous system -decreases CBF -decreases ICP
-patients with increased ICP, propofol may cause a critical reduction of CePP < 50
mmHg due to a decrease in MAP
-may provide cerebral protection in focal ischemia of the brain similar to barbiturates
-antiemetic and antipruritic properties of propofol provide good charecteristics for
outpatient based anesthesia
-anticonvulsant properties -may be associated with an excitatory phenomena during
induction (ex. muscle twitching, spontaneous movement, hiccuping)
-subcortical glycine antagonism may be the cause of hiccuping associated with
propofol induction
Cardiovascular system -decrease in mean arterial blood pressure -decrease in systemic
vascular resistance SVR -decrease in preload -decrease in myocardial contractility
-hypotension generally more profound with propofol than with thiopental
-inhibits normal function of baroreceptors in response to decreased MAP, therefore
leads to lack of reflex tachycardia

Decreased cardiac output and perhaps even bradycardia may be more associated in the
following patients:
-extremes of age
-negative chronotropic medications taken by patient
-procedures involved with oculocardiac reflex

Factors exacerbating hypotension associated with propofol induction include:

-large doses of propofol
-rapid injection of propofol
-old age

Respiratory system
-profound respiratory depressant
-generally causes apnea during induction doses of general anesthesia
-decreased hypoxic ventilatory drive even with subanesthetic doses during an infusion
for conscious sedation
-associated with less wheezing in both asthmatic and nonasthmatic patients with
induction doses of propofol compared to thiopental
ETOMIDATE Listen to Audio mechanism of action structure-activity relationships
pharmacokinetic effects on organ systems drug interactions MECHAMISM OF
ACTION -depresses reticular activating system (RAS) -mimics the inhibitory effects
of GABA primarily binding to GABA type A receptor -associated with myoclonus
incidence of 30-60% due to disinhibitory effects on the extrapyramidal motor system
STRUCTURE-ACTIVITY RELATIONSHIPS -carboxylated imidazole ring -lipid
solubility at physiologic pH -water soluable at acidic pH -usually pain on injection
due to propylene glycol in which etomidate is dissolved in PHARMACOKINETICS
Absorption -only in intravenous form -used primarily for induction of general
anesthesia Distribution -very rapid onset of action due to high lipid solubility and
high nonionized fraction at physiologic pH -rapid emergence is due to redistribution
leading to decreasing plasma concentrations Biotransformation -rapid hydrolysis of
etomidate to inactive metabolites by the hepatic microsomal enzymes and plasma
esterases -rate of biotransformation of etomidate is five times more rapid than for
thiopenthal Excretion -primarily excreted in the urine PHARMACODYNAMICS
Effects on Organ Systems Central nervous system -decreases CMR02 -decreases CBF
-decreases ICP -generally well maintained CePP due to minimal CVS effects
-enhances somatosensory evoked potentials (SSEP) -naseau and vomitting more
common with etomidate than other induction agents Cardiovascular system -minimal
effects on CVS -may have a slight decline in MAP due to mild reduction in the
peripheral vascular resistance -myocardial contractility and cardiac output generally
well maintained -not associated with histamine release Respiratory system -less effect
on ventilation than other induction agents (ex. barbiturates,benzodiazepines and
propofol) -often induction doses of etomidate when used alone may still not result in
apnea Endocrine system -enzymes involved in cortisol and aldosterone synthesis may
transiently inhibited with induction doses of etomidate -adrenocortical suppresion
may occur with long term infusion of etomidate Drug Interactions Fentanyl:
increases both plasma levels and half life of etomidate Opiods: decreases myoclonus
of etomidate induction
KETAMINE Listen to Audio mechanism of action structure-activity relationships
pharmacokinetics effects on organ systems drug interactions
MECHANISM OF ACTION -dissociative amnesia which dissociates the thalamus
from the limbic system -primary receptor involved: NMDA receptor antagonist -other
possible receptors involved:calcium regulated receptors, muscarinic receptors, opiod
receptors, monoamine oxidase receptors
STRUCTURE-ACTIVITY RELATIONSHIPS -phenycyclidine structural analogue
-probable stereotactic receptor involvement with increased potency and and decreased
psychotomimetic side effects
PHARMACOKINECTICS
Absorption -administered either intravenously or intramuscularly
-intramusclular administration leads to peak plasma levels within 10 - 15 minutes

Distribution -rapid brain uptake due to high lipid solubility, less protien binding and
equally ionized at physiologic pH
-ketamine-induced increased CBF and cardiac output contribute to increased brain
uptake -distribution half life is 10 - 15 minutes

Biotransformation -biotransformation occurs in the liver -some metabolites may

retain anesthetic activity ex. norketamine: approximately 1/3 the anesthetic potency of
ketamine -multiple doses may induce hepatic enzyme activity which may develop
tolerance -relatively short elimination half time (2 hours) due to a high hepatic uptake
-hepatic extraction ratio of 0.9 Excretion -excretion by kidneys

PHARMACODYNAMICS Effects on Organ Systems

Central nervous system -increases CMR02 -increases CBF -increases ICP
-therefore should be avoided in patients with space occupying lesions
-increased subcortical electrical activity associated with myoclonus activity
-possibe undesirable psychotomimetic side effects during induction or emergence
-premedication with benzodiazepines helps to lessen or avoid the undesirable side
effects
Cardiovascular system Indirect cardiovascular effects by: -central stimulation of the
sympathetic nervous system -inhibiting reuptake of norepinephrine -therefore
indirectly increases mean arterial pressure, heart rate, and cardiac output
Ketamine avoided in patients with CAD, uncontrolled hypertension, heart failure, and
arterial aneurysms because:
-increased pulmonary artery pressure associated with increased sympathetic tone
 -increased myocardial work associated with increased sympathetic tone
Direct myocardial depressant effects of large doses of ketamine may be due to:
-calcium transient inhibition -may unmask the blocked sympathetic tone
which occurs in cases such as spinal cord transection
-exhaution of catecholamine stores which may occur in cases of severe end
stage shock
-ketamine may be considered an induction drug of choice in acute
hypovolemic shock patients such as trauma patients
Respiratory system -generally induction doses of ketamine used alone has minimal
effects on ventilatory drive -potent bronchodilator: good induction agent for asthmatic
patients -upper airway reflexes generally stay intact although patients at risk of
aspiration should be intubated -associated with increased salivation therefore
premedication with an anticholingeric agent (ex.glycopyrrolate) may be useful

Drug Interactions
-ketamine may prolong the effects of nondepolarizing muscle relaxants (NDMR)
-ketamine with theophylline combination may predispose patients to seizure activity
-ketamine may have less indirect cardiostimulatory effects when used with diazepam
-ketamine may have a prolonged elimination half life with use of diazepam
-ketamine generally has a more cardiodepressant effect when used with volatile
anesthetics (especially halothane)
-ketamine may have a prolonged duration when used with lithium
Inhalational Anesthetics
PHARMACOKINECTICS: Listen to Audio
-factors affecting inspiratory concentrations (FI)
-factors affecting alveolar concentrations (FA)
-factors affecting arterial concentrations (Fa)
-factors affecting elimination
FACTORS AFFECTING INSPIRED CONCENTRATIONS: (FI)
Inspired gas mixture generally depends on:
-fresh gas flow rate (FGF)
-volume of breathing circuit
-machine or breathing circuit absorption ex. high FGF lead to a smaller breathing
system volume and lower absortion by the circuit therefore the inspired gas
concentration will be closer to the fresh gas concentration
FACTORS AFFECTING ALVEOLAR CONCENTRATIONS (FA)
-uptake of anesthetics
-ventilation
-concentration effect
-second gas effect (concentrating effect, and augmented inflow effect)
FACTORS AFFECTING ARTERIAL CONCENTRATIONS (Fa)
-ventilation/perfusion mismatching
PHARMACODYNAMICS Listen to Audio
THEORIES OF ANESTHETIC ACTION
-unitary hypothesis
-critical volume hypothesis
-fluid theory of anesthesia
-lateral phase separation theory
MINIMUM ALVEOLAR CONCENTRATION (MAC)
-minimum alveolar concentration of an inhaled anesthetic which prevents movement
in 50% of patients in response surgical incision
-mirrors brain partial pressures
-allows for comparison of potency amongst differing anesthetic agents -provides a
standard for expiremental observations
MAC (awake): 0.3 MAC
MAC (amnesia): 0.5 MAC
MAC:(ED 50): 1.0 MAC
MAC (ED 95): 1.3 MAC
MAC (BAR): 1.5 MAC
MAC (BAR)= blockade of adrenergic response
Oxide Listen to Audio physical properties effects on organ system biotransformation
and toxicity contraindications drug interactions
Physical Properties
-MAC value: 105 %
-only inorganic gas used in the clincal practice of anesthesia
-colorless and nearly odorless
-nonexplosive, nonflammable (although may support combustion)
-gas at room temperature
-gas at ambient pressure
-critical temperature is above room temperature therefore can be kept liquid while
under pressure
-relatively inexpensive anesthetic agent
Effects on organ systems
Central Nervous System -increases CMR02 -increases CBF -increases ICP (mild)
Cardiovascular System
-in vivo: direct myocardial contractility depressant
-in vitro: stimulates sympathetic nervous system therefore increases cardiac function
-overall: minimal or slight change in cardiac function due to the two opposing forces
explained above patients with CAD or severe hypovolemia:
-may have unmasked myocardial depression
-resultant drop in arterial blood pressure may lead to myocardial ischemia and further
compromise on a already failing heart patients with preexisting pulmonary HTN or
Right sided CHF: -should avoid nitrous oxide due to increased pulmonary vascular
resistance via vasoconstriction of pulmonary artery

Respiratory System
-increases respiratory rate
-decreases tidal volume
-minimal change on minute ventilation
-minimal change on resting PaC02 levels
-hypoxic drive depressed by even low concentrations of nitrous oxide

Hepatic System -decreases hepatic blood flow but to a lesser extent than volatile
anesthetics

Renal System
-decreases renal blood flow secondary to increased renal vascular resistance
-decreased GFR and therefore decreased urinary output

Gastrointestinal System -may cause postoperative nausea and vomitting

-may stimulate the chemoreceptor trigger zone (CTZ) and vomitting center in medulla

Biotransformation and toxicity

-biotransformation limited < 0.01 % which undergoes reductive metabolism within
the GI anaerobic metabolism
-nearly all the nitrous oxide is eliminated through exhalation during the emergence of
anesthesia
-toxicity may occur by irreversibly oxidizing the cobalt atom of vitamin B12
-therefore nitrous oxide inhibits enzymes which are vitamin B12 dependant (ex.
methionine synthetase, thymidylate synthetase) methionine synthetase: involved in
myelin formation thymidylate synthetase: involved in DNA synthesis -prolonged
exposure of nitrous oxide may lead to bone marrow suppresion and neurological
deficiencies bone marrow suppresion: megaloblastic anemia neurologic deficiencies:
peripheral neuropathies, pernicious anemia
-possible teratogenic effects: therefore avoid in pregnant women

contraindications -nitrous oxide tends to diffuse into air-containing cavaties more

rapidly than nitrogen absorbed into the blood stream therefore has an expanding
capacity in air-containing cavaties such as: -air embolism -pneumothorax -acute
intestinal obstruction -intracranial air -pulmonary air cysts -intraocular air bubbles
-tempanic membrane grafting
Drug Interactions -prolongs muscle relaxation from nondepolarzing muscle
relaxants (NDMR) -attenuates the circulatory and respiratory effects caused by
volatile anesthetics
Halothane Listen to Audio physical properties effects on organ system
biotransformation and toxicity contraindications drug interactions
physical properties
-MAC value: 0.75 %
-vapor pressure: 243 mmHg at 20 degree celcius
-halogenated alkane
-nonflammable and nonexplosive agent due to the carbon-flouride bonds -amber-
colored bottles which contain thymol preservative slow the spontaneous oxidative
decomposition -least expensive volatile anesthetic

Effects on organ systems

Central Nevous System
-decreased CMR02 -increased CBF -increased ICP -altered/blunted cerebral
autoregulation
Cardiovascular System
-dose dependant reduction in mean arterial blood pressure -direct myocardial
depressant by interference of the sodium-calcium exchange and utilization of
intracellular calcium
-increases in right artrial pressure (CVP)
-coronary arterial blood flow decreases secondary to decrease in mean arterial
pressure
coronary arterial blood flow decreased despite halothane induced coronary artery
vasodilation
-generally well maintained perfusion to heart due to balance of decreased oxygen
demand with decreased blood supply to the heart
-inhibits normal baroreceptor reflex tachycardia in response to decreased mean
arterial pressure
-inhibited baroreceptor reflex may lead to junctional rhythms and bradycardia
-sensitizes myocardium to epinephrine-induced dysrhythmias, therefore avoid
epinephrine dosages > 1.5 ug/kg

Respiratory System
-increases respiratory rate
-decreases tidal volume
-resultant decreased alveolar ventilation
-elevated resting PaC02
-elevated apneic threshold
-blunted response to elevated PaC02 -potent vasodilator
-may reverse asthma-induced bronchoconstriction
-may be the most potent bronchodilator amongst the current volatile anesthetic agents
-depresses respiratory mucociliary clearance which may promote postoperative
atelectasis and hypoxia

Hepatic System
-decreases hepatic blod flow proportional to decreases in cardiac output
-may impair hepatic metabolism and clearance of some drugs (ex. fentanyl,
phenytoin, and verapamil)
-may cause hepatic cellular dysfunction evidenced by minor elevation of liver
transaminases

Renal System
-decreases renal blood flow
-decreases GFR
-decreases urinary output
-filtration fraction is increased due to a greater decrease of renal blood flow compared
to the decrease in GFR

Neuromuscular
-potential triggering agent for malignant hyperthermia
-prolongs muscle relaxation from nondepolarizing muscle relaxants (NDMR)

Biotransformation and toxicity -halothane oxidized by the liver cyto p450 (2EI) to
trifluoroacetic acid metabolite which can be inhibited by disulfiram -presense of
ischemia may lead to reductive hepatotoxic metabolites of halothane which covalently
bind to macromolecules
Factors which may be associated with postoperative hepatic dysfunction: -viral
hepatitis -impaired perfusion to the liver -preexisting liver disease -hepatocellular
hypoxia -sepsis -hemolysis -drug induced hepatitis
Halothane hepatitis associations: -rare: 1 in 35,000 cases -multiple, short interval
anesthetic exposure -middle-aged obese females -familial history of halothane toxicity

contraindications
-patients with pre-existing unexplained liver dysfunction
-possibly in patients with intracranial mass lesions due to potential of increasing ICP
-patients with pheochromocytoma due to possible association of epinephrine induced
dysrythmias -cardiac patients who cannot tolerate direct cardiodepressant effects of
halothane
drug interactions
-beta blockers and calcium channel blockers exacerbate direct cardiodepressant
effects of halothane
-possible arterial pressure fluctuation and dysrhythmia effects with tricyclic
antidepressants and monoamine oxidase inhibitors
-possible severe ventricular dysrhythmias with combination of halothane and
aminophylline
Enflurane Listen to Audio physical properties effects on organ system
biotransformation and toxicity contraindications drug interactions
physical properties -MAC value: 1.7 %
-vapor pressure: 175 mmHg at 20 degrees celcius
-halogenated ether -mild, sweet odor -nonflammable at clinical concentrations

Effects on organ systems

Central Nervous System
-decreased CMR02 (unless seizure activity is induced)
-increased CBF
-increased ICP
-increased CSF secretion and increased resistance to CSF outflow
-association with tonic clonic seizure activity followed by high voltage high
frequency EEG patterns
-high concentrations of enflurane in the setting of hypocapnia may exacerbate
epileptiform activity

Cardiovascular System
-enflurane decreases both myocardial contractility and systemic vascular resistance
-lowered mean arterial pressure
-lowered cardiac output
-lowered myocardial oxygen consumption
-increase in heart rate due to decreased arterial pressure
-sensitizes myocardium to epinephrine induced dysrhythmias usually at a dose > 4.5
ug/kg
Respiratory System
-increases respiratory rate
-decreases tidal volume
-resultant decrease in alveolar ventilation
-increased resting PaC02
-decreased response to an elevated PaC02
-decreased/abolished hypoxic drive
-bronchodilation
-depressed mucociliary function

Hepatic System -decreases hepatic blood flow

Renal System -decreases renal blood flow
-decreases GFR
-decreases urinary output
-enflurane metabolites are nephrotoxic (discussed more in biotransformation and
toxicity)

Neuromuscular System -relaxes skeletal muscles -prolongs duration of

nondepolarizing muscle relaxants (NDMR)

biotransformation and toxicity -flouride ions are the metabolite of enflurane

-flouride ions concentrations are far less than metabolism of methoxyflurane -renal
dysfunction with the use and metabolism of enflurane is unlikely -nearly after 10
MAC-hours of enflurane, flouride ion concentrations were less than 40 umol/L in
healthy patients -flouride ion concentrations may lead to mild reduction concentrating
abilities of the renal tubules in values of 40 umol/L

contraindications -may best be avoided in patients with pre-existing renal disease

-may best be avoided in patients with history of seizure disorders -may best be
avoided in patients with history of increased ICP or decreased intracranial compliance

drug interactions -isoniazid induces deflourination of enflurane possibly from

stimulating the cytochrome P450 2EI -prolongs duration of nondepolarizing muscle
relaxants (NDMR)
Sevoflurane Listen to Audio physical properties effects on organ system
biotransformation and toxicity contraindications drug interactions
physical properties -MAC value: 2.0 % -vapor pressure: 160 mmHg at 20 degrees
celcius
-halogenated with flourine
-combination of blood solubility greater than desflurane and potency slightly lower
than enflurane
-nonpungent
-agent of choice for inhalation induction for both pediatric and adult patients
-rapid emergence due to rapid fall of alveolar concentration upon discontinuation
secondary to low blood solubility -association with greater incidence of delirium in
some pediatric patients which may be treated with small doses of fentanyl

effects on organ systems

Central nervous System -decreases CMR02 -increases CBF -increases ICP
-may impair cerebral autoregulation at high concentration levels > 1.5 MAC

Cardiovascular System -mild myocardial depression -decrease in systemic vascular

resistance which decreases arterial blood pressure -cardiac output not well maintained
due to no/or slight increase in heart rate
-QT interval may be prolonged

Respiratory System -increases respiratory rate -decreases tidal volume -resultant

decrease in alveolar ventilation -reverese bronchoconstriction

Hepatic System -maintains total hepatic blood flow and oxygen delievery to the liver
-decreases portal vein blood flow -increases hepatic artery blood flow

Renal System -renal blood flow slightly decreases -formation of compound A

metabolite of sevoflurane may inhibit renal tubular function (discussed in
biotransformation and toxicity)

Neuromuscular System -adequate muscle relaxation allowing for intubation in

pediatric patients following inhalational induction

biotransformation and toxicity -sevoflurane is metabolized by hepatic microsomal

enzymes cytochrome P450 2EI into flouride ions -production of flouride ions are
potentially nephrotoxic inhibiting renal tubular concentrating ability at high
concentrations -has been no association with renal compromise with sevoflurane use
for general anesthesia Compound A: formed by sevoflurane degraded by soda lime
(CO2 absorbent) producing a nephrotoxic metabolite fluoromethyl-2,2-difluoro-1-
trifluoromethyl vinyl ether accumulation of compound A occurs with: -increased
respiratory gas temperature -low gas flow anesthesia -dry barium hydroxide absorbent
(baralyme) -high sevoflurane concentrations -long duration of anesthetic exposure
-recommended to use gas flows > 2 L/min and avoid in patients with pre existing
renal dysfunction

contraindications -patients with severe hypovolemia, suceptible to malignant

hyperthermia, and patients with intracranial hypertension

drug interactions -prolongs muscle relaxation from nondepolarizing muscle

relaxants (NDMR) -does not senstitize the myocardium to epinephrine induced
dysrhythmias
Isoflurane Listen to Audio Physical Properties Effects on organ system
Biotransformation and toxicity Contraindications Drug Interactions
Physical properties
-MAC value: 1.2 %
-vapor pressure: 240mmHg at 20 degrees celcius -pungent odor -nonflammable
-chemical isomer of enflurane
Effects on organ systems
Central Nervous System
-decreases CMR02 (at 2MAC produces electrically silent EEG which may provide
come cerebral protection against ischemia)
-increases CBF
-increases ICP (increased ICP may be reversed with hyperventilation)

Cardiovascular System
-in vivo: mild cardiac depressant
-decreased systemic vascular resistance
-resultant decrease in mean arterial blood pressure
-decreased arterial blood pressure stimulated the preserved carotid baroreceptor which
increases heart rate
-decreased arterial pressure and increased heart rate generally leads to a maintained
cardiac output
-rapid increase in concentration may transiently increase heart rate, arterial pressure
and norepinephrine levels
-coronary artery vasodilation (less than nitroglycerin effects)
-coronary steal phenomena possibilities Coronary steal phenomena: -coronary arteries
that have atherosclerotic plaque lesions generally are unable to further vasodilate
-therefore intense coronary artery vasodilation from normal vessels may divert blood
from fixed stenotic (maximally dilated) vessels -would lead to decreased coronary
blood flow to already ischemia stenotic vessels and increased blood flow to normal
vessels
Respiratory System -increased respiratory rate (tachypnea less pronounced with
isoflurane compared to other volatile anesthetics) -decreased tidal volume -resultant
decreased alveolar ventilation (more pronounced fall in minute ventilation due to less
increased respiratory rate) -blunted response to elevating levels of PaC02 or hypoxia
-good bronchodilator
Hepatic System -reduces hepatic blood flow -possibly better oxygen supply to liver
with isoflurane in comparison with halothane and enflurane -minimal effect on liver
function tests
Renal System -decreases renal blood flow -decreases GFR -decreases urinary output
Neuromuscular System -relaxes skeletal muscles biotransformation and toxicity
-isoflurane is metabolized in the liver to end products of trifluoracetic acid -flouride
ions rise but extremely unlikely to cause nephrotoxicity even in combination with
enyzme inducers -upto 20 MAC-hours of isoflurane may lead to flouride ion
concentration greater than 50 umol/L without detectable renal dysfunction -isoflurane
has limited metabolism which reduces the possible risk of significant hepatic
dysfunction
contraindications -no major contraindications -controvery regarding coronary steal
phenomena
drug interactions -epinephrine may be safely administered upto 4.5 ug/kg -prolonged
duration of action of nondepolarizing muscle relaxants (NDMR)
Desflurane Listen to Audio physical properties effects on organ system
biotransformation and toxicity contraindications drug interactions
physical properties
-MAC value: 6.0%
-vapor pressure: 681 mmHg at 20 degrees celcius
-substitution of isoflurane's chlorine atom for flourine creates desflurane -boils at
room temperature when located at high altitudes (ex. Denver, Colardo)
-requires a special vaporizer
-low solubility promotes rapid induction and emergence
-tighter control of anesthetic level due to alveolar concentration close to inspired
concentrations -blood-gas partition coefficient 0.42

Central Nervous System -decreases CMR02 -increases CBF -increases ICP

Cardiovascular System -decreased systemic vascular resistance leads to decreased

arterial blood pressure -decreased arterial blood pressure which stimulates
baroreceptors relex increase in heart rate -maintained cardiac output with decreased
arterial pressure and increased heart rate -rapid increases in desflurane concentrations
may lead to increased arterial blood pressure and heart rate -increased cardiac
parameters due to sudden increase in desflurane levels can be attenuated with:
fentanyl, esmolol or clonidine

Respiratory System -increased respiratory rate -decreased tidal volume -resultant

decreased alveolar ventilation -elevated resting PaC02 -decreased hypoxic drive
-blunted/decreased ventilatory response to elevated PaC02 -airway irritation
associated with: salivation, breathe holding, coughing, and laryngospasm
Hepatic System -no evidence of hepatic injury -normal post-operative liver function
test
Renal System -no evidence of nephrotoxic injury
Neuromuscular System -dose dependant decrease in train-of-four peripheral nerve
stimulation response -dose dependant decrease in tetanic peripheral nerve stimulation
response

biotransformation and toxicity -minimal metabolism of desflurane in humans

-degraded by dissicated carbon dioxide absorbents into clinically insignificant levels
of carbon monoxide
contraindications -general contraindications shared with other volatile anesthetics
-avoid in malignant hyperthermia, severe hypovolemia and patients with increased
intracranial hypertension
drug interactions -desflurane emergence in some pediatric patients has been
assoicated delirium -prolongs duration of nondepolarizing muscle relaxants (NDMR)
-epinephrine can be used safely in doses upto 4.5 ug/L