ANESTHESIA ORGANS EFFECTS

Cardiovascular System
Dr. Firmalino Arterial Pressure
Halothane
Anesthesia Desflurane
Suppression of pain of a surgical procedure Enflurane
Analgesia Sevoflurane
Loss of pain sensation from other causes Isoflurane
General Anesthesia Bradycardia
With loss of consciousness Halothane
Local Anesthesia Tachycardia
Patient is awake Isoflurane
Desflurane
No Effect on Rate
GENERAL ANESTHESIA Methoxyflurane
Sevoflurane
1. Inhalation Myocardial Depression
2. Parenteral All inhaled anesthesia
o IM GREATEST depression
o IV Enflurane
Halothane
LEAST depression
Stages of General Anesthesia
Nitrous oxide
1. Analgesia
Arrhythmia
2. Delirium/ excitement
Halothane
3. Surgical
4. Medullary paralysis
Respiratory
MOST depressant
PharmacoKINETICS of General Anesthesia
Isoflurane
1. Flow
Enflurane
o Anesthesia machine lungs blood brain
Depress mucocilliary function pooling of mucus (atelectasis,
metabolism elimination
pneumonia)
2. Factor
Bronchodilation
o Tension difference or partial pressure between alveoli
Halothane
and blood
Enflurane
o From higher to lower concentration
Irritation & coughing difficult induction
3. Uptake & distribution
Desflurane
4. Solubility
5. Concentration in inspired air
6. Pulmonary ventilation
Brain
7. Pulmonary blood flow Cerebral Blood Flow undesirable ICP
8. Arteriovenous concentration Enflurane (potential seizure)
9. Elimination Nitrous Oxide (least in cerebral blood flow)

HEPATOTOXIC
PharmacoDYNAMICS Halothane (Fatal hepatitis)
Mechanism of Action of GENERAL anesthesia
1. Depresses the activity of the neurons
NEPHROTOXIC
2. Interacts with lipid matrix of nerve membrane which leads to
Methoxyflurane
changes in ion flux
o RESULTS to membrane HYPERPOLARIZATION (inhibitory
Malignant Hyperthermia
action) via activation of ligand gated K+ channel linked
Halothane
to neurotransmitters (Ach, Dopamine, NE, Serotonin)
o TARGET: to activate GABA receptor Chloride channel Syndrome
(mediator of inhibitory synaptic transmission) o Hyperthermia
o RESULT: activity of neurons, sensory transmission o Tachycardia
o Rigidity
Ideal Characteristics of Inhalational Anesthetics: o Hypertension
o Hyperkalemia
Rapid & pleasant induction & recovery
o Acidosis
Rapid changes in depth of anesthesia
Due to free calcium in muscle
Adequate relaxation of smooth muscle
Treatment: DANTROLENE (prevents release of Calcium)
Absence of toxic effect
Wide margin of safety

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CHRONIC TOXICITY SEVOFLURANE
Mutagenicity no evidence o Non-irritant to airway
Fluroxene & ether (no longer used)
Carcinogenecity no evidence NON-HALOGENATED
Reproductive ETHER
st
Miscarriage o 1 anesthetic
Teratogenic o No longer used
Hematotoxic o Explosive & flammable
Nitrous Oxide (Megaloblastic Anemia) CHLOROFORM
o No longer used
CLINICAL USE o Non explosive & non flammable
Rarely used alone
Combined with IV anesthetics GASEOUS
Commonly used NITROUS OXIDE
o Nitrous oxide o Only inorganic gas w/ anesthetic property
o Desflurane o Non-explosive
o Sevoflurane o Potent analgesic
o Isoflurane o Weak anesthetic
o Halothane o No muscle relation
o No CVS effect
NOT USED ANYMORE o Anesthetic of choice, combined w/ Halothane
Methoxyflurane (nephrotoxic) CYCLOPROPANE
Chloroform (hepatotoxic) o No longer used
Cyclopropane & ether (explosive, flammable) o Explosive
o Flammable
CLASSIFICATION
Gas (Nitrous Oxide, Cyclopropane) INTRAVENOUS ANESTHETIC
VOLATILE LIQUID Usually used as ADJUNCT to inhaled anesthetics
HALOGENATED o Sometime used alone
o Halothane o Do not require anesthesia machine
o Isoflurane DRUGS used as IV ANESTHETICS
o Sevoflurane Barbiturates
o Methoxyflurane Benzodiazepine
o Enflurane Ketamine
o Desflurane Profopol
NON HALOGENATED Etomidate
o Ether Opiate
o Chloroform
SHORT-ACTING IV ANESTHETICS
HALOGENATED Rapid onset
HALOTHANE Out-patient
o Choice in ASTHMA (bronchodilation effect) Barbiturate Thiopental
o TOXICITY Ketamine
Arrhythmia, Hepatitis Profopol
Malignant hyperthermia Opiate
ENFLURANE
o CNS irritability seizure LONG-ACTING IV ANESTHETICS
o Nephrotoxic (fluoride byproduct) Slow onset
o Cardiac depression
Cant be used for induction
o salivation & tracheobronchial secretion
Maintenance if used w/ inhalation
o Non hepatotoxic
Pre-op meds relax patients & reduce anxiety
ISOFLURANE
Benzodiazepines (diazepam, midazolam, lorazepam)
o Non hepatotoxic
w/ retrograde amnesia patients do not remember the
o Non nephrotoxic
unpleasant surgery
o Non cardiotoxic
o Choice in CARDIAC SURGERY
ULTRA SHORT ACTING BARBITURATES
METHOXYFLURANE
THIOPENTAL
o Most toxic
o Onset: 10-20 seconds
DESFLURANE
o Last for: 20-30mins
o BP & CO
o For short procedures
o No hepatorenal toxicity
o Airway irritant

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 CARDIAC MUSCLE Effects
LOCAL ANESTHESIA LOW concentration Anti-arrhythmic
HIGH dosage arrhythmia
Blocks nerve conduction locally, thus blocks pain sensation
thru SODIUM channel BLOCKADE CLINICAL PHARMACOLOGY
SHORT acting
CHEMISTRY o Procaine
o Chlorprocaine
ESTER
INTERMEDIATE acting
o Cocoine
o Lidocaine
o Procaine
o Mepivacaine
o Tetracaine
o Prilocaine
o Benzocaine
AMIDE LONG acting
o Lidocaine o Tetracaine
o Mepivacaine o Bupivacaine
o Bupivacaine o Etidocaine
o Etidocaine o Ropivacaine
o Prilocaine
o Ropivacaine ONSET
FASTER if MIXED with SODIUM BICARBONATE CO2
increases penetration of anesthesia into membrane
PharmacoKINETICS SLOW in INFECTION acidic inflammation
ABSORPTION
Local anesthesia has to stay where injected to sustain its ROUTES
effect Topical
Once absorbed losses its effect as a local anesthesia Local infiltration
& systemic effect or toxicity may potentially happen
Nerve block
More vascular tissue absorbs drug faster duration
Spinal intrathecal
is shorter
Epidural
Vasoconstrictor EPINEPHRINE delays absorption &
Caudal
prolongs local effect
TOXICITY
PharmacoDYNAMICS Only when the anesthesia is ABSORBED in circulation
Mechanism of Action CNS TOXICITY
Binding with SODIUM channel receptor of nerve LOW DOSE
membrane o Sleepiness
Blockade of the excitable membrane of axon = blocking o Lightheadedness
nerve impulse o Visual/ auditory disturbance
o Restlessness
Action of Local Anesthesia on Nerve o Circumoral/ tongue numbness
Both sensory & motor blockade HIGH DOSE
Motor Paralysis o Nystagmus
o Maybe undesirable in normal delivery w/c o Muscle twitching
require abdominal muscle contraction o Convulsion
o Desirable in abdominal operations like CS o CNS depression
(requires abdominal muscle relaxation) o Death
o PREVENTION/TREATMENT: Diazepam,
Actions on Nerve barbiturates, O2
Autonomic parasympathetic blockade NERVE TOXICITY
o vasoDILATION, HYPOtension Prolonged motor/ sensory with CHLORPROCAINE or
SEQUENCE of Blockade LIDOCAINE if used as spinal Anesthesia
o Autonomic
o Temperature CVS TOXICITY
o Pain Blocks SODIUM channel in heart pacemaker, excitability,
o Touch conduction
o Deep pressure Blocks CALCIUM channel depress contraction
o Motor (hypotension: BUPIVACAINE)
Except COCAINE (vasoconstriction & HYPERtension) blockade
Actions on Nerve of NE reuptake
In EXTREMITY Cause ischemia & ulceration if used in nasopharyngeal
o Proximal sensory fibers are located in the mucosa
st
OUTER layer blocked 1 before distal fibers

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 BLOOD TOXICITY
Methhemoglobinemia PRILOCAINE ANESTHESIA
ALLERGY th
Katzung 11 edition
Common with ESTERS (metabolized to P-aminobenzoic
acid which cause the allergy)
Physiologic state induced by GENERAL anesthesia
Analgesia
Amnesia
Loss of consciousness
Inhibition of sensory and autonomic reflexes
Skeletal muscle relaxation

Ideal anesthetic drug would induce:

Smooth & rapid loss of consciousness
Allowing prompt recovery after its administration is
discontinued
Wide margin of safety
Devoid of adverse effects

Balanced anesthesia techniques

Use of combinations of IV and inhaled drugs
Monitored anesthesia care techniques
Oral or parenteral sedatives in combination with local
anesthetics

TYPES of GENERAL ANESTHESIA

1. INTRAVENOUS anesthetics
Alone or in combination with other anesthetic & analgesic
drugs
Barbiturates (thiopental, methohexital)
Benzodiazepines (midazolam, diazepam)
Propofol
Ketamine
Opioid analgesics (morphine, fentanyl, sufentanil, alfentanil,
remifentanil)
Miscellaneous sedative-hypnotics (etomidate,
dexmedetomidine)

2. INHALED anesthetics
Most commonly used inhaled anesthetics:
o Isoflurane
o Desflurane
o Sevoflurane
Volatile liquids that are aerosolized in specialized vaporizer
delivery systems
Nitrous Oxide gas at ambient temperature & pressure,
adjuvant to volatile agents

Balanced Anesthesia
Combination of IV & inhaled
Sevoflurane (volatile anesthetics) induction of anesthesia
Propofol (intravenous anesthetics) infused for
maintenance of anesthesia
Muscle relaxants facilitate tracheal intubation & optimize
surgical conditions
Potent opioid & cardiovascular drugs ( blockers, 2 agonists,
Ca channel blockers) control transient autonomic
responses to noxious surgical stimuli

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STAGES of ANESTHESIA (Guedels signs) o Blood:gas partition coefficient
Stage of ANALGESIA Useful index of solubility
Analgesia without amnesia Defines the relative affinity of an
anesthetic for the blood
Later in stage I: both analgesia & amnesia produced
DESFLURANE & NITROUS OXIDE
Stage of EXCITEMENT
Insoluble in blood
Delirious & may vocalized but is definitely amnesic
LOW blood:gas partition
Respiration: irregular both in volume & rate
coefficient
Retching & vomiting may occur
o LOW blood SOLUBILITY diffuses from the lung
To limit duration & severity: rapidly increasing the
into the arterial blood
concentration of agent
Few molecules are required to raise its
Ends: reestablishment of regular breathing
partial pressure
Stage of SURGICAL ANESTHESIA
Arterial tension rises RAPIDLY
Begins: recurrence of regular respiration o MODERATE HIGH solubility (halothane &
Extends to complete cessation of spontaneous respiration isoflurane)
(apnea)
More molecules dissolve before partial
Four planes: (changes in) pressure changes significantly
o Ocular movements Arterial tension of the gas increases LESS
o Eye reflexes rapidly
o Pupil size o NITROUS OXIDE
*signs of increasing depth of anesthesia Low solubility
Stage of MEDULLARY DEPRESSION Reaches high arterial tension RAPIDLY
Deep stage RAPID equilibration with the brain
Severe depression of CNS FAST onset of action
o Vasomotor center in the medulla
o Respiratory center in the brain stem B. Anesthetic CONCENTRATION in the INSPIRED AIR
o Direct effects on BOTH maximum tension (alveoli)
Anticholinergic drugs (atropine, glycopyrrolate) & rate of increase in its tension in arterial blood
Used to decrease oral & airway secretions o INCREASE CONCENTRATION
Treat BRADYcardia Increase the rate of induction by
Can also DILATE pupils increasing the rate of transfer into the
Opioid Analgesics blood according to Ficks law
Depressant effects on both the respiratory function & HR o MODERATE CONCENTRATION
Enflurane, Isoflurane, halothane
Most reliable indication that stage III is achieved: Advantageous
Loss of purposeful motor & autonomic responses to noxious Often administered in combination with
stimuli a LESS soluble agent (Nitrous Oxide)
Reestablishment of a regular respirator pattern Reduce time required for loss
of consciousness
Adequacy of the DEPTH of anesthesia is assessed by: Achievement of a surgical
Monitoring changes in respiratory & cardiovascular depth of anesthesia
responses to specific surgical stimuli
Changes in electroencephalographic based cerebral indices C. PULMONARY VENTILATION
Vital signs: most common method of assessing depth of o Rate of rise of anesthetic gas tension in arterial
anesthesia blood is DIRECTLY dependent on BOTH rate &
Automated cerebral monitoring techniques depth of ventilation
o EEG signals o INCREASE ventilation only a slight increase in
o Bispectral index arterial tension with LOW blood solubility
o Auditory evoked potential o HYPERVENTILATION INCREASES speed of
o Physical state index induction of anesthesia with inhaled anesthetics
o Cerebral state index that would normally have a SLOW onset
o State & response entropy (irregularity) of EEG o DEPRESSION of respiration(opioids) SLOWS the
waveforms onset of anesthesia

PharmacoKINETICS D. PULMONARY BLOOD FLOW

Uptake & Distribution of INHALED anesthetics
Concentration of inhaled anesthetic is proportional to its
partial pressure (tension)
A. SOLUBILITY
o One of the most important factors influencing the
transfer of an anesthetic from the lungs to the
arterial blood
o INCREASE (CO) SLOWS the rate of rise in
arterial tension (moderate-high blood solubility)
Exposes a larger volume of blood to the
anesthetic agent in the alveoli
increasing rate of rise in the arterial
tension of inhaled anesthetic
o Patients with circulatory SHOCK combined
effects of DECREASED CO (pulmonary blood flow)

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 & INCREASE ventilation ACCELERATE induction
of anesthesia (halothane & isoflurane)
E. ARTERIOVENOUS CONCENTRATION GRADIENT
o Dependent mainly on uptake of the anesthetic by
the tissues (nonneuronal tissues)
o Venous blood RETURNING to the lungs may
contain significantly LESS anesthetic than arterial
blood
o GREATER difference in anesthetic gas tension
MORE time it will take to achieve equilibrium with
brain tissue
o Anesthetic entry into tissues is influenced by
factors that determine transfer of anesthetic from
lung to intravascular space
Tissue:blood partition coefficients
Rates of blood flow to the tissues
Concentration gradients
o INDUCTION PHASE (& initial phase of maintenance
period)
Tissues that exert greatest influence on
the arteriovenous anesthetic
concentration gradient are those that are
HIGHLY PERFUSED (brain, heart, liver,
kidneys, splanchnic bed)
Receive 75% of the resting CO
Volatile anesthetics w/ HIGH SOLUBILITY
in HIGHLY perfused tissues venous
blood concentration will initially be very
LOW & equilibrium with the arterial
blood is achieved SLOWLY
o MAINTENANCE of anesthesia with inhaled
anesthetics
Drug continues to be transferred at rates
dependent on solubility of the agent,
concentration gradient between blood
and tissue and tissue blood flow
Muscle & skin 50% of total body mass
Anesthetics accumulate more
SLOWLY
Receive only 1/5 of the resting
CO
Most anesthetic agents are HIGHLY
soluble in ADIPOSE tissues LOW blood
perfusion to theses tissues DELAYS
accumulation
Equilibrium is Unlikely to occur
with most anesthetics during a
typical 1-3 hour operation
ELIMINATION
Blood:gas partition coefficient
o One of the most important factors governing rate
of recovery
Other factors:
o Pulmonary blood flow
o Magnitude of ventilation
o Tissue solubility of the anesthetic
2 Features of the recovery phase
o Transfer of an anesthetic from lungs to blood can
be ENHANCED by INCREASING its concentration in
inspired air
Page | 6
Reverse transfer process cannot be
enhanced because concentration in the
lungs cannot be reduced below zero
o Beginning of recovery phase anesthetic gas
tension in different tissues may be quite variable
INSOLUBLE in blood (LOW blood:gas partion coefficients) &
brain eliminated at FASTER rates
RAPID WASH OUT RATE rapid recovery from anesthetic
effects
o Nitrous oxide
o Desflurane
o Sevoflurane
HALOTHANE 2x soluble in brain & 5x more soluble in
blood
o Elimination SLOW
Duration of exposure:
o MORE SOLUBLE (halothane, isoflurane)
Recovery is SLOW after PROLONGED
administration)
o Accumulation of anesthetics in muscle, skin & fat
INCREASES with PROLONGED exposure
Blood tension may DECLINE SLOWLY
during recovery (anesthetic eliminated
slowly)
CLEARANCE via the LUNGS
o Major route of elimination
o Hepatic metabolism may also contribute to
elimination
HALOTHANE
o Oxidative metabolism formation of
trifluoroacetic acid and release of bromide &
chloride ions
o LOW OXYGEN TENSION halothane is
metabolized to chlorotrifluoroethyl free radical
(capable of reacting with the hepatic membrane
components HALOTHANE-INDUCED HEPATITIS)
Isoflurane & Desflurane
o least metabolized of the fluorinated anesthetics
with only trace concentrations of trifluoroacetic
acid appearing in the URINE even after prolonged
administration
Enflurane & Sevoflurane
o metabolism results in the formation of fluoride ion
Methoxyflurane
o renal fluoride levels do not reach toxic levels under
normal circumstances
o 70% is metabolized by liver
o Released fluoride ions can produce nephrotoxicity
Sevoflurane
o Degraded by contact with the carbon dioxide
absorbent in anesthesia machines
o Yielding a vinyl ether (compound A) renal
damage if HIGH concentrations are absorbed
Extent of Hepatic Metabolism (ranking)
1. Methoxyflurane
2. Halothane
3. Enflurane
4. Sevoflurane
5. Isoflurane
6. Desflurane
7. Nitrous oxide not metabolized by human tissues |
bacteria in the GIT may be able to break down the
nitrous oxide molecule
jhojho terrobias.2016
PharmacoDYNAMICS
MECHANISM of ACTION
Both inhaled & IV depress spontaneous & evoke activity of
neurons in many regions of the brain
Meyer-Overton principle interactions of these agents
with the lipid matrix of the nerve membrane that were
thought to lead to secondary changes in ion flux
1. Primary molecular target of GENERAL anesthetics:
o GABAA receptor-CHLORIDE channel (major
mediator of inhibitory synaptic transmission)
o Pentameric assembly of 5 proteins derived from
several polypeptide subclasses
Inhaled anesthetics, barbiturates, benzodiazepine,
etomidate, propfol)
Facilitate GABA-mediated inhibition at
GABAA receptor
Both inhaled & IV with sedative-hypnotic properties
DIRECTLY activate GABAA receptors
o LOW concentrations: facilitate the action of GABA
to INCREASE CHLORIDE ion flux
Benzodiazepines (lack general anesthetic properties
diazepam, lorazepam)
o Facilitate GABA action but have NO direct actions
on GABAA receptors even at HIGH concentrations
in the absence of GABA
Ser270 & Ala291 critical for the enhancement of GABAA
receptor function by volatile anesthetics
KETAMINE
o Unique dissociate anesthetic with analgesic
properties
o Does not produce its effects vial facilitation of
GABAA receptor functions
o Its CNS activity appears to be related to
antagonism of the action of the GLUTAMIC ACID
(excitatory NT) on the N-methyl-D-aspartate
channel receptor
2. MEMBRANE HYPERPOLARIZATION (inhibitory) via
activation of POTASSIUM channels
o Linked to NT (Ach, dopa, NE, Serotonin)
o Inhaled anesthetics DECREASE the duration of
opening NICOTINIC receptor-activated cation
channels (action that DECREASES the excitatory
effects of Ach at cholinergic synapses)
o Most inhaled anesthetics INHIBIT nicotinic Ach
receptor isoforms (4 subunit)
3. Strychnine-sensitive GLYCINE receptor
o Another ligand-gated ion channel that may
function as a target for inhaled anesthetics
o Can elicit channel opening directly & independently
of their facilitatory effects on NT binding
Neurons in the SUBSTANTIA GELATINOSA of the DORSAL
horn of the spinal cord very sensitive to even LOW
concentrations of anesthetic drugs
Interrupts sensory transmission in the spinothalamic tract
(including nociceptive stimuli)
Neurons in the respiratory & vasomotor centers of the
medulla INSENSITIVE to the depressant effects of general
anesthetics
Page | 7
o HIGH concentrations activity is depressed
(cardiorespiratory collapse stage IV)
DOSE-RESPONSE CHARACTERISTICS: The Concept of Minimum
Alveolar Anesthetic Concentration & the Continuum of CNS
Depression
Quantal dose-response principles
o Useful estimate of anesthetic potency for both
inhaled & IV
INHALATION anesthesia
o Partial pressure of inhaled anesthetic in the brain
equals that in the lung when steady-state
conditions are achieved
Volatile anesthetic concentration percentage of the
alveolar gas mixture or partial pressure of anesthetic as a
percentage of 760mmHg
Minimum Alveolar Concentration (MAC)
o Median concentration that results in immobility in
50% of patients when exposed to a noxious
stimulus
o Surrogate measure of the anesthetic requirement
o MAC value >100% for Nitrous Oxide:
Least potent
Must be supplemented with other agents
to achieve full surgical anesthesia
o A dose of 1 MAC of any anesthetic prevents
movement in response to surgical incision in 50%
of patients
o Individual patients may require 0.5-1.5 MAC
o MAC values DECREASE in elderly patients & with
HYPOthermia
Not affected greatly by sex, height,
weight
o Chronic use of centrally active drugs, alcohol abuse
& pregnancy INCREASE the anesthetic requirement
o IV drugs (opioid, sympatholytics, sedative-
hypnotics) administered as adjuvant to the volatile
anesthetics, MAC is DECREASED in a dose-related
fashion
Inspired concentration should be
DECREASED
IV anesthetics produce similar dose-dependent continuum of
CNS depression
o LOW concentration produce anxiolytic & light
levels of sedation
o INCREASED produce a progressively
INCREASING DEPTH Of sedation
ORGAN SYSTEM EFFECTS of INHALED ANESTHETICS
A. CARDIOVASCULAR
Decrease MAP
o Halothane
o Desflurane
o Enflurane
o Sevoflurane
o Isoflurane
Halothane & Isoflurane
o Reduced arterial pressure caused by reduction in
CO
Isoflurane, Desflurane, Sevoflurane
o Depressant effect on arterial pressure decrease in
systemic vascular resistance with minimal effect on
CO
jhojho terrobias.2016
 Change in HR
o Directly altering rate of sinus node depolarization
o Indirectly shifting the balance of ANS activity
BRADYCARDIA Halothane
o Direct vagal stimulation
Increase HR
o Isoflurane
o Desflurane
Transient sympathetic activation with
elevation of catecholamine levels increase
HR & BP
All inhaled anesthetics tend to increase Right atrial
pressure (dose-related) depression of myocardial
function
GREATER myocardial depressant effects
o Enflurane
o Halothane
Depress the myocardium (concentration-dependent)
o Nitrous oxide
o Combination with potent inhaled (volatile)
anesthetics minimize cardiac depressant effects
(anesthetic-sparing effect)
Factors that influence cardiovascular effects of inhaled
anesthetics
o Surgical stimulation
o Intravascular volume status
o Ventilator status
o Duration of anesthesia
Hypercapnia releases catecholamines
o Attenuate the decrease after 5 hours of anesthesia
Concomitant use of blockers reduces adaptive
effect
Halothane & Isoflurane
o Sensitize the myocardium to circulating
catecholamines
Ventricular arrhythmias
o Patients with cardiac disease given with
sympathomimetic drugs or high circulating levels of
endogenous catecholamines (anxious patients, use
of epi-containing local anesthetics, inadequate
intraoperative anesthesia/analgesia, with
pheochromocytoma)
B. RESPIRATORY
All inhaled anesthetics (except nitrous oxide)
o Dose-dependent decrease in tidal volume &
increase in respiratory rate (decrease in minute
volume)
All volatile anesthetics respiratory depressant
Isoflurane & enflurane most depressant
Volatile anesthetics
o Increase apneic threshold
o Decrease ventilator response to hypoxia
Ventilator depressant effects of inhaled anesthetics
counteracted by surgical stimulation
Depress mucociliary function in airway
Prolonged anesthesia pooling of mucus = atelectasis
& postoperative respiratory infection
Halothane & sevoflurane bronchodilation
o Induction agents of choice (airway problems
asthma, COPD, bronchitis)
Page | 8
C. BRAIN
Decrease metabolic rate of the brain
More soluble volatile agents increase cerebral blood
flow (decrease cerebral vascular resistance)
Increase cerebral blood flow
o Undesirable to patient with increase ICP (brain
tumor or head injury)
Volatile anesthetic-induced increases in cerebral blood
flow increase cerebral blood volume = increase ICP
Nitrous oxide
o Least likely to increase cerebral blood flow
LOW concentrations all halogenated agents have
similar effects on cerebral blood flow
HIGH concentrations increase cerebral blood flow is
LESS with less soluble ages (desflurane & sevoflurane)
D. KIDNEY
Decrease GFR & renal blood flow
Increase filtration fraction
E. LIVER
Concentration-dependent decrease in hepatic blood
flow (15%-45% below the preinduction value)
F. UTERINE SMOOTH MUSCLE
Nitrous oxide
o Little effect on uterine musculature
Halogenated anesthetics
o Potent uterine muscle relaxants
o Concentration-dependent fashion
o Useful: intrauterine fetal manipulation or manual
extraction of a retained placenta
But can lead to intrauterine bleeding
TOXICITY
A. HEPATOTOXICITY (Halothane)
Postoperative hepatic dysfunction associated with
o Blood transfusions
o Hypovolemic shock
o Other surgical stresses
Obese patients
o Most susceptible especially when exposed more
than once in a short period of time
In animals: formation of reactive metabolites that either
cause direct hepatocellular damage or initiate immune-
mediated response
TFA (trifluoroacetylated proteins) during
biotransformation
B. NEPHROTOXICITY
Metabolism of Methoxyflurane, Enflurane, Sevoflurane
= formation of fluoride ions
Methoxyflurane and Enflurane
o Metabolized in part by renal enzymes generating
fluoride ions intrarenally
Sevoflurane degradation by carbon dioxide
absorbents in anesthesia machines = formation of
haloalkene, compound A (metabolized by renal -lyase
to form thoacylhalide = proximal tubular necrosis)
Renal dysfunction (methoxyflurane) caused by
inorganic fluoride released during the extensive
metabolism of this anesthetic by hepatic & renal
enzymes
jhojho terrobias.2016
 C. MALIGNANT HYPERTHERMIA BARBITURATES
Autosomal dominant genetic disorder of skeletal muscle
Thiopental most commonly used
that occurs in susceptible individual undergoing general
Thiamylal identical to thiopental
anesthesia with volatile agents & muscle relaxants
THIOPENTAL
(succinylcholine)
o IV bolus injection rapidly crosses BBB
Rapid onset of tachycardia & hypertension
o Rapidly diffuses out of the brain
Severe muscle rigidity
o Redistributed to muscle & fat
Hyperthermia
o Single dose brief period of unconsciousness
Hyperkalemia o Metabolized at the rate of only 12-16% per hour
Acid-base imbalance with acidosis that follows exposure o Less than 1% excreted unchanged by the kidney
to 1 or more of the trigerring agents o LARGE doses: dose-dependent DECREASES in
Increase in free calcium concentration in skeletal muscle arterial BP, SV, CO
cells o Potent respiratory depressant = transient apnea &
TREATMENT: lowering sensitivity of medullary respiratory center
o Dantrolene (to reduce calcium release for the to CO2
sarcoplasmic reticulum) METHOHEXITAL
o Appropriate measures to reduce body o Shorter-acting
temperature o Rapid elimination
o Restore electrolyte and acid-base balance o Can cause central excitatory activity (myoclonus)
o Useful for neurosurgical procedures involving
D. CHRONIC TOXICITY ablation of seizure foci
a. Mutagenicity o Drug of choice: undergoing ECT
NEITHER mutagens nor carcinogens o For short ambulatory procedures
Plasma:brain equilibrium occurs rapidly (<1min) high lipid
solubility
b. Effects on reproductive organs cerebral blood flow but less than O2 consumption
Risk of abortion higher in pregnant ICP & blood volume are NOT increased: THIOPENTAL
patients who underwent anesthesia & desirable drug for patient w/ cerebral swelling (head trauma,
surgery not related to pregnancy brain tumors)
c. Hematotoxicity hepatic blood flow & GFR
Nitrous oxide Prolonged exposure Produce no AE on hepatic or renal function
DECREASES methionine synthase activity
Can exacerbate acute intermittent porphyria (inducing
= MEGALOBLASTIC anemia
production of hepatic -aminolevulinic acid (ALA) synthase)

CLINICAL USE of INHALED ANESTHETICS BENZODIAZEPINES

Volatile anesthetics rarely used alone for induction &
maintenance except in children Diazepam, lorazepam, midazolam
o Preanesthetic medication and adjuvants during
Combined with IV agents (balanced anesthesia technique)
surgical procedures under local anesthesia
Desflurane & Sevoflurane low blood:gas coefficient (more
Drug of choice: PREMEDICATION
rapid recovery and fewer postoperative adverse effect)
Diazepam & lorazepam not water soluble
o IV use needs non-aqueous vehicles (causes pain
and local irritation)
INTRAVENOUS ANESTHETICS Midazolam water-soluble, benzodiazepine of choice for
parenteral administration
(thiopental, methohexital, etomidate, ketamine, propfol) o More rapid onset
o Shorter elimination HL (2-4hours)
Most IV anesthetics lack antinociceptive (analgesic) Slower onset of CNS depressant effects
properties Reach plateau @ a depth of sedation that is inadequate for
Potency is adequate for short superficial surgical procedures surgical anesthesia
when combined with Nitrous oxide or local anesthetics or LARGE doses prolongs the post-anesthetic recovery
both period and can produce a high incidence of anterograde
Adjunctive use of potent opioids: amnesia
o Improved cardiovascular stability FLUMAZENIL (antagonist) to accelerate recovery
o Enhanced sedation o Multiple dosing to prevent recurrence of the CNS
o Perioperative analgesia depressant effects
o Enhance ventilator depressant effects
o Increase postop emesis
Benzodiazepines
o Provide anxiolysis, sedation, amnesia as part of
inhalational, IV or balanced
o Slower onset
o Slower recovery

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OPIOID ANALGESICS
HIGH doses have been used in combination with LARGE
doses of BENZO to achieve a general anesthetic state
(cardiac surgery or other major surgery)
REMIFENTANIL potent & extremely short-acting to
minimize residual ventilator depression
HIGH doses chest wall (& laryngeal) rigidity; acute
tolerance, postoperative morbidity & mortality after
cardiac surgery
LOWER doses of FENTANYL & SULFENTANIL
o used as adjunct to both IV & inhaled anesthetics to
provide perioperative analgesia
ALFENTANIL & REMIFENTANIL
o Shorter-acting
o Co-induction agents with IV sedative-hypnotics
anesthetics
o Rapid onset of action
REMIFENTANIL
o Rapidly metabolized by esterases in the blood &
muscle tissues
o Does not interfere with the clearance of other
compounds metabolized by plasma cholinesterase
(esmolol, mivacurium, succinylcholine)
Can be administered @ LOW doses:
o Epidural & subarachnoid (spinal) routes to produce
postop analgesia
FENTANYL & DROPERIDOL (butyophenone related to
haloperidol) = analgesia & amnesia and combined with
Nitrous Oxide provide a state referred to as
NEUROLEPTANESTHESIA
PROPOFOL
(2,6 diisopropylphenol)
Onset same as barbiturates KETAMINE
Recovery is more rapid
Reduced postop nausea & vomiting & a sense of well-being
Used for both induction & maintenance of anesthesia
Agent of choice: AMBULATORY surgery
Monitored anesthesia care technique & in diagnostic suites
for procedural sedation
Effective in producing prolonged sedation in critical care
settings
Can lead to delayed arousal prolonged use
Prolonged use of HIGH-dose propofol infusions for sedation
of critically ill young children = severe acidosis in presence of
respiratory infections & neurologic sequelae upon
withdrawal
Distribution HL: 2-8 minutes
Redistribution HL: 30-60minutes
Rapidly metabolized in the liver (10x faster than thiopental)
Excreted in the urine as glucuronide & sulfide conjugates w/
less than 1% of parent drug excreted unchanged
Produces a dose-related depression of central ventilator
drive & transient apnea
Marked decrease in BP during induction of anesthesia
through decreased peripheral arterial resistance and
venodilation
Direct negative inotropic effect
Pain @ the site of injection most common AE of bolus
administration
Admixture or pretreatment with LIDOCAINE (20-50mg)
most effective approach to minimize the pain on injection
FOSPROPOFOL water-soluble prodrug of propofol
o May ameliorate some of the problems associated
with propofol
ETOMIDATE
Carboxylated imidazole
Limited cardiovascular reserve
Major advantage: minimal cardiovascular & respiratory
depression
Produces a rapid loss of consciousness with minimal
hypotension even in elderly patients with poor
cardiovascular reserve
HR unchanged
Apnea low
No analgesic effects
Coadministration of opioid analgesics is required to
decrease cardiac responses during tracheal intubation &
lessen spontaneous muscle movements
Initial dose recovery is less rapid compared with propofol
Distribution is rapid
Extensively metabolized in the liver & plasma to inactive
metabolites
2% excreted unchanged in the urine
Pain on injection
Myoclonic activity
Postoperative nausea & vomiting
Adrenocortical suppression via inhibitory effects on
steriodogenesis with decreased plasma levels of cortisol after
single dose
Prolonged infusion in critically ill patients hypotension,
electrolyte imbalance, oliguria (adrenal suppressive effects)
2 isomers (S(+) and R(-) ketamine)
Dissociative anesthetic state
o Catatonia
o Amnesia
o Analgesia
o With or without loss of consciousness (hypnosis)
Arylcyclohexylamine related to phencyclidine (PCP)
MOA: blockade of the membrane effects of the excitatory NT
GLUTAMIC acid @ the NMDA receptor subtype
Highly lipophilic
Rapidly distributed into well-perfused organs (brain, liver,
kidney)
Urinary & biliary excretion
Only IV anesthetic that possess both anesthetic & analgesic
properties
Ability to produce dose-related cardiovascular stimulation
HR, Arterial BP, CO
Peak: 2-4 minutes after IV bolus injection
Slowly decline to normal values over the next 10-20mins
Cardiovascular effect: stimulating the central sympathetic
nervous system
o Inhibiting reuptake of NE @ sympathetic nerve
terminals
in plasma epi & NE after IV bolus as early as 2 minutes
cerebral blood flow, oxygen consumption, ICP
Potentially dangerous: ICP
RR

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 Upper airway muscle tone is well maintained and airway
reflexes are usually preserved
Postop disorientation, sensory & perceptual illusions, vivid
dreams (EMERGENCE PHENOMENA)
Diazepam, Propofol given before admin of ketamine
o Reduces incidence of these AE
Useful: poor-risk geriatric patient
o High-risk patients in cariogenic or septic shock
(cardiostimulatory properties)
LOW doses: for outpatient anesthesia in combination with
propofol (monitored anesthetic technique) & children
undergoing painful procedures
S (+) isomer possesses psychotomimetic side effects
LOCAL ANESTHESIA
Nociception pain awareness
o Mediated by nerve ending receptors in peripheral
tissues
o Transmitted to the CNS by primary afferent fibers
o Relayed by secondary afferent fibers to the brain
Reversibly block impulse conduction
SODIUM channels primary means of action potential
generation
Block pain sensation from specific areas of the body
(sympathetic vasoconstrictor impulse)
st
Cocaine 1 local anesthetic
CHEMISTRY
Lipophilic group (aromatic ring)
Ester links more prone to hydrolysis (shorter duration of
action)
Weak bases
Usually made available as salts to increase solubility and
stability
In the body: uncharged base or cation
Cationic form most active form at the receptor site
because it cannot readily exit from closed channels
Uncharged form rapid penetration of biologic membranes
Less effective when injected into infected (ACIDIC) tissues
smaller percentage of local anesthetic is nonionized &
available for diffusion across the membrane in an
environment with low extracellular pH
PharmacoKINETICS
Usually administered by injection into dermis and soft tissues
around nerves
ABSORPTION
Factors in Systemic absorption:
o Dosage
o Site
o Drug-tissue binding
o Local tissue blood flow
o Use of vasoconstrictors (epi)
o Physiochemical properties
More rapid absorption
o Application to a highly vascular area (tracheal
mucosa or tissue surrounding intercostal nerves)
Block of large nerves
o Maximum blood levels decrease according to the
site of administration
Intercostal (highest)
Caudal
Epidural
Brachial plexus
Sciatic nerve
EPINEPHRINE (vasoconstrictor)
o Reduce systemic absorption of local anesthetics
(decreasing blood flow)
o Important with intermediate or short durations of
action
o Procaine, lidocaine, mepivacaine
o Spinal anesthesia act directly on the cord to
both enhance and prolong local anesthetic
induced spinal anesthesia
2 adrenoceptor inhibits release of
substance P
reduce sensory neuron firing
Clonidine & dexmedetomidine prolong local anesthetic
effect in subarachnoid space and on peripheral nerves
Epinephrine combination of reduced systemic absorption,
enhanced local neuronal anesthetic uptake, 2 receptor
activation
o Prolonging local anesthetic effect up to 50%
Vasoconstrictors
o Less effective in prolonging anesthetic action of
bupivacaine and ropicavaine
More lipid-soluble, long-acting
Highly tissue bound
Cocaine
o High surface (topical) activity
o Intrinsic sympathomimetic properties
DISTRIBUTION
Widely distributed after IV bolus administration
Sequestration in lipophilic storage sites (fats)
Initial rapid distribution brain, liver kidney, heart
Slower distribution phase muscle & GIT
METABOLISM & EXCRETION
Converted in the liver (amide type) or plasma (ester type)
water-soluble metabolites
Excreted in the urine
Acidification of urine
o Promotes ionization of the tertiary amine base to
more soluble water charged form = rapid
elimination
ESTER TYPE
o Hydrolyzed very rapidly in the blood by
butyrycholinesterase (pseudocholinesterase) to
inactive metabolites
o PROCAINE & CHLOROPROCAINE
Very short plasma HL (<1min)
AMIDE TYPE
o Hydrolyzed by liver cytochrome P450
o Prilocaine (fastest) > lidocaine > mepivacaine >
ropicavaine = bupivacaine & levobupivacaine
(slowest)
o Toxicity to patients with hepatic disorder
Decreased hepatic elimination in reduced hepatic blood flow

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PharmacoDYNAMICS
MECHANISM of ACTION STRUCTURE-ACTIVITY CHARACTERISTICS of LOCAL ANESTHETICS
Blockade of voltage-gated SODIUM channels Smaller & more highly lipophilic = FASTER rate of interaction
o Depolarization: Na close (inactivate); K open with SODIUM channel receptor
o Outward flow of K: repolarizes membrane Lidocaine, Procaine, Mepivacaine
Disruption of SODIUM channel function: o More water soluble
o Biologic toxins: Batrachotoxin, aconitine, Tetracaine, Bupivacaine, Ropivacaine
veratridine, scorpion venoms o Less water soluble
Bind to receptors and prevent activation o More potent
Prolonged influx of Na depolarizing o Longer durations
membrane o Bind more extensively to proteins and can be
o Marine toxins: tetrodotoxin & saxitoxin displaced from these binding sites by other
Block Na channels by binding to the protein-bound drugs
channel receptors near the extracellular
surface OTHER ACTION on NERVES
Resemble local anesthetics Not limited to the desired loss of sensation from sites of
o TTX-resistant neurons noxious stimuli
Responsible for pain transmission Spinal anesthesia
Primary targets for local anesthetics in o Motor paralysis may impair respiratory activity
producing spinal (subarachnoid) o Residual autonomic nerve blockade can lead to
anesthesia hypotension, urinary retention
Local anesthetics bind to receptors near the INTRAcellular Direct application to the nerve root
end of the SODIUM channel and block the channel in a time o Smaller B & C fibers are blocked first
and voltage-dependent fashion o Motor function blocked last
INCREASE concentration
o Increase threshold for excitation 1. Effect on fiber DIAMETER
o Impulse conduction slows Block small fibers distance can passively
o Rate of rise of the action potential declines propagate an electrical impulse is shorter
st
o Action potential amplitude decreases Small-diameter fibers 1 to fail to conduct
o Ability to generate an action potential completely electrical impulses
abolished Myelinated nerves atleast 2 & 3 successive
Myelinated fibers critical length (2-3 nodes) nodes must be blocked
Blockade is VOLTAGE and TIME dependent Preganglionic B fibers are blocked before the
o Low affinity for local anesthetics smaller unmyelinated C fibers
Channels in rested state 2. Effect of Firing FREQUENCY
Predominate at more negative Blockade is more marked at HIGHER frequencies of
membrane potential depolarization
o Higher affinity Sensory (pain) fibers have a high firing rate and
Activated (open state) long AP duration
Inactivated channels Motor fibers fire @ a slower rate and have shorter
Predominate at more positive membrane AP duration
potential Type A delta & C fibers smaller-diameter fibers
o Effect of given drug concentration is more marked that participate in high-frequency pain
in rapidly firing axons transmission
Refractory period LENGTHENED o Fibers are blocked earlier and with lower
Nerve conducts fewer electrical impulses concentrations
ELEVATED extracellular CALCIUM 3. Effect of Fiber POSITION in the Nerve Bundle
o Partially antagonizes action of local anesthetics Large nerve trunks
st
o Calcium-induced increase in the surface potential o Fibers located circumferentially 1 to
on the membrane be exposed
INCREASE in extracellular POTASSIUM Extremities
o Depolarize the membrane potential o Proximal sensory fibers outer portion
o Favor inactivated state of the nerve trunk
o Enhancing effect of local anesthetics o Distal sensory innervation central core
SPINAL ANESTHESIA of the nerve
st
o Local anesthetics can inhibit transmission via: Sensory analgesia 1 develop PROXIMALLY
SUBSTANCE P (neurokinin 1) 4. Effects on OTHER EXCITABLE Membranes
NMDA receptors Weak direct NM blocking effects
AMPA receptors Widely used as antiarrhythmic agents at
o Contribute to the analgesia (subarachnoid concentrations LOWER Than those required to
administration) produce nerve block
Block other ion channels
o Nicotinic acetylcholine channels (spinal cord)

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CLINICAL PHARMACOLOGY of LOCAL ANESTHETICS Systemic local anesthetic drugs
Usual Routes of Administration o Adjuvants to the combination of TCA
o Topical (amitriptyline) & anticonvulsants (carbamazepine)
o Injection in the peripheral nerve ending (perineural who fail to respond to the combination of
infiltration) antidepressant & anticonvulsant
o Major nerve trunks (blocks)
o Injection into the epidural or subarachnoid spaces TOXICITY
surrounding spinal cord CNS
o IV regional anesthesia (BIER BLOCK) short surgical A. CNS toxicity
procedures involving upper &/ lower extremities Local anesthetics have the ability to produce in HIGH
o Local anesthetic infiltration of autonomic sympathetic plasma concentrations
fibers evaluate role of sympathetic tone (peripheral o Sleepiness
vasospastic disorders) o Light-headedness
o Injection in trigger points diagnostic & therapeutic o Visual & auditory distrubances
purposes (recurrent pain tactile stimulation) o Restlessness
SHORT-acting EARLY symptom of toxicity
o Procaine o Circumoral & tongue numbness
o Chloroprocaine o Metallic taste
INTERMEDIATE HIGHER concentrations
o Lidocaine o Nystagmus
o Mepivacaine o Muscular twitching
o Prilocaine When large doses are required:
LONG-Acting o Premedication of parenteral BENZODIAZEPINE
o Tetracaine (diazepam/midazolam)
o Bupivacaine SEIZURE
o Levobupivacaine o Hyperoxemia beneficial after onset of seizure
o Ropivacaine o Hypercapnia & acidosis may lower the seizure
Short & intermediate acting can be PROLONGED by threshold (hyperventilation)
increasing dose or adding a vasoconstrictor agent Increases blood pH
(EPINEPHRINE or Phenylephrine) Lowers extracellular potassium
o Slows the removal of local anesthesia Hyperpolarizes transmembrane potential
o Decreases the blood level & probability of Favors resting state of Na channels
cardiovascular & CNS toxicity Decreased local anesthetic toxicity
Onset can be ACCELERATED by adding SODIUM o Seizure-induced:
BICARBONATE (1-2ml) TX: IV anesthetic drugs
o Maximizes amount of drug in more lipid-soluble (thiopental, propofol,
(unionized) form) midazolam)
Repeated injections of local anesthetics = loss of Muscular manifestation TX:
effectiveness (ex. Tachyphylaxis) due to extracellular acidosis succinylcholine
o Deplete buffering capacity B. COCAINE
o Ensuing acidosis increases the extracellular cationic Can produce severe cardiovascular toxicity
form HPN, arrhythmias, acute myocardial failure
o Diffuses poorly = tachyphylaxis
o Common in CSF NEUROTOXICITY
Pregnancy HIGH concentrations
o Increase susceptibility to toxicity o Direct neural toxicity
o Epidural Bupivacaine cardiac arrest Chloroprocaine, Lidocaine
Topical local anesthesia o More neurotoxic when used for spinal anesthesia
o Requires rapid penetration across the skin or TRANSIENT RADICULAR IRRITATION
mucosa (neuropathic symptoms)
o Limited tendency to diffuse away from the site of o Pooling of high concentrations of local anesthetic in
application the cauda equina region
Cocaine
o Excellent penetration CARDIOVASCULAR
o Local vasoconstrictor Direct effects on cardiac and smooth muscle membranes
o Used for ENT procedures Indirect effects on autonomic nervous system
Local anesthetics have membrane-stabilizing effects (both Blockade of Na channels
parenteral & oral) o Depress cardiac pacemaker activity, excitability,
o Treat patients with neuropathic pain syndromes conduction
Involved uncontrolled, rapid, sensory, Except Cocaine
fiber firing o Can depress myocardial contractility,
o Produce direct arteriolar dilation = hypotension

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 COCAINE
o Blockade of NE reuptake= vasoconstriction & HPN
o Cardiac arrhythmias
Bupivacaine
o More cardiotoxic
o Bupivacaine-induced blockade of Na channels is
potentiated by long AP duration of cardiac cells
compared with nerve fibers
ECG: slow idioventricular rhythm with
broad QRS complexes
o Propofol can be useful in resuscitation

HEMATOLOGIC
Prilocaine (large doses)
o Accumulation of metabolite o-toluidine (oxidizing
agent capable of converting hemoglobin to
methemoglobin)
o Sufficient methemoglobin:
Cyanotic
Blood chocolate-colored
o Elevated methemoglobinemia
Decompensation in patients with
preexisting cardiac or pulmonary disease
TX: IV methylene blue or ascorbic acid

ALLERGIC REACTION
Ester type metabolized to p-aminobenzoic acid
o Responsible for allergic reactions

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