Perioperative care

Therapeutics 4 for PharmD

Spring 2023

Prof. Nailya Bulatova-Younes

 References
• Koda-Kimble: Perioperative Care.
• UpToDate. Perioperative medication
management
• UpToDate. Postoperative nausea &
vomiting
• Gan et al. Fourth Consensus Guidelines
for the Management of Postoperative
Nausea and Vomiting. Anesth Analg
2020;131:411–48.
 Perioperative Care
• Operating room (OR) is one of the most
medication-intensive settings in a hospital
• significant number of medications are
administered as single doses by anesthesia care
provider
• Major classes: 1. preoperative medications, 2.
IV anesthetic agents, 3. volatile inhalation
agents, 4. neuromuscular blocking agents, 5.
local anesthetics, 6. antiemetic agents, & 7.
analgesic agents
 Goals of Premedication
Major goal: to ↓ patient's fear & anxiety about his or her
upcoming surgery
• produce sedation
• provide analgesia
• produce amnesia
• facilitate smooth anesthetic induction
• ↓ anesthetic requirements
• prevent autonomic responses resulting in intraoperative
hemodynamic stability
• ↓ salivation & secretions, ↓ gastric fluid volume, &/or
↑gastric pH
- midazolam is the most commonly used premedicant
Indications, Routes of Administration, & Doses
of Preoperative Agents
Agent Indications Route Doses
s
Benzodiazepines
Diazepam (Valium) Anxiolysis, PO Adults: 5–10 mg
amnesia, sedation

Lorazepam (Ativan) Anxiolysis, PO 0.025–0.05 mg/kg (range, 1–4 mg

amnesia, sedation for adults)

IV Adults: 0.025–0.04 mg/kg;

pediatrics: 0.01–0.03 mg/kg (titrate
dose; max: 2 mg)

Midazolam (Versed) Anxiolysis, PO Adults: 20 mg; pediatrics: 0.5–0.75

amnesia, sedation mg/kg (max: 20 mg)
IM Adults: 0.07–0.08 mg/kg (max: 10
mg); pediatrics: 0.1–0.15 mg/kg
(max: 10 mg)

IV Adults: 1–2.5 mg (titrate dose);

pediatrics: 0.025–0.05 mg/kg
(titrate dose)
Indications, Routes of Administration, & Doses
of Preoperative Agents
Agent Indications Routes Doses

Opioids
Morphine Analgesia, sedation IM Adults: 2–4 mg; pediatrics: 0.02–
0.05 mg/kg
IV Titrate dose
Fentanyl Analgesia, sedation IV Adults: 25–100 mcg (titrate
(Sublimaze) dose); pediatrics: 0.05–2 mcg/kg
Anticholinergics
Atropine (A) Antisialagogue (S > IM/IV Adults: 0.4–0.6 mg; pediatrics:
G > A), sedation (S 0.02 mg/kg IM, 0.01 mg/kg IV
> A > G) (max: 0.4 mg)
Glycopyrrolate (G) Antisialagogue IM/IV Adults: 0.2–0.3 mg; pediatrics:
(Robinul) 0.005–0.01 mg/kg (max: 0.3 mg)
Scopolamine (S) Sedation, amnesia, IM/IV Adults: 0.2–0.4 mg; pediatrics:
antisialagogue 0.02 mg/kg IM, 0.01 mg/kg IV
(max: 0.4 mg)
Indications, Routes of Administration, & Doses
of Preoperative Agents
Agent Indications Route Doses
s
Dissociative Anesthetics

Ketamine (Ketalar) Sedation, amnesia, PO Pediatrics: 3–6 mg/kg

analgesia
IM Adults: 3–4 mg/kg; pediatrics: 2–4
mg/kg
IV Adults: 0.5–1 mg/kg

Gastric Motility Stimulants

Metoclopramide Reduce gastric PO Adults: 10 mg; pediatrics: 0.15

(Reglan) volume, antiemetic mg/kg
IV Adults: 0.1–0.2 mg/kg (10–20
mg); pediatrics: 0.1–0.15 mg/kg
Indications, Routes of Administration, & Doses
of Preoperative Agents
Agent Indications Routes Doses

H2-Receptor Antagonists

Cimetidine ↑ Gastric pH PO Adults: 300 mg; pediatrics: 7.5

(Tagamet) mg/kg
IV Adults: 300 mg; pediatrics: 7.5
mg/kg
Ranitidine (Zantac) ↑ Gastric pH PO Adults: 150 mg; pediatrics: 2
mg/kg
IV Adults: 50 mg; pediatrics: 0.5–1
mg/kg
Famotidine (Pepcid) ↑ Gastric pH PO Adults: 40 mg; pediatrics: 0.5
mg/kg
IV Adults: 20 mg; pediatrics: 0.25
mg/kg
Nizatidine (Axid) ↑ Gastric pH PO Adults: 150 mg
Indications, Routes of Administration, & Doses
of Preoperative Agents
Agent Indications Routes of Doses
Administration
Nonparticulate Antacids

Sodium citrate/citric ↑ Gastric pH PO Adults: 30 mL

acid (Bicitra)
α-2 Agonists

Clonidine (Catapres) Anxiolysis, PO Adults: 0.2 mg;

potentiate action of pediatrics: 0.002–
anesthetic agents, 0.004 mg/kg (max:
sedation, analgesia 0.2 mg)
 Timing & Routes of
Premedication Administration
• Agents administered IV are often given after pt
arrives in OR,
• medications administered IM are usually
administered 30-60 min. before pt arrives in OR
• If possible, IM route should be avoided because
it is painful & undesirable for pt
• PO agents should be administered 60-90 min.
before pt's scheduled arrival in OR
 Drug Interactions
• can be advantageous & intentionally
produced, or they can be problematic
• E.g., pts must be closely monitored when
they concurrently receive BDZ & opioid for
premedication due to synergistic
respiratory & cardiovascular ADRs
• α-2 agonists, however, can ↓ requirements
for inhalational anesthetics & opioids
 Aspiration Pneumonitis
Prophylaxis
• Aspiration pneumonitis is potentially fatal
condition that occurs as result of regurgitation &
aspiration of gastric contents
• Aspiration of gastric contents is also important
risk factor for development of adult respiratory
distress syndrome (ARDS)
• Gastric pH of <2.5 & gastric volume >25 mL
have been accepted as cutoff values that place
pt at greater risk for severe pneumonitis should
aspiration occur
 Risk Factors for regurgitation &
aspiration
• ↑ gastric acid (e.g., PUD)
• ↑ intragastric pressure
(e.g., pregnancy, obesity)
• gastric or intestinal
hypomotility (e.g., DM)
• structural disorders (e.g.,
hiatal hernia)
• neuromuscular
incoordination
• depressed sensorium
- Pts undergoing
emergency surgery
frequently have full
stomachs
Measures to ↓ risk of
aspiration:
- rapid sequence induction
- effective application of
cricoid pressure
- maintaining patent upper
airway
- avoiding inflation of
stomach with anesthetic
gases
- inserting large-bore
gastric tube once airway
has been secured
- use of regional
 Medications
to ↓risk of aspiration
- Pharmacologic aspiration prophylaxis is not cost
effective & does not ↓ morbidity or mortality in
healthy pts undergoing elective surgery
- It should, however, be considered to prevent
morbidity (e.g., ARDS) in patients at risk for
aspiration
• Groups of medications that can ↓ the risk of
pneumonitis if aspiration occurs:
- antacids,
- gastric motility stimulants,
- H2RAs
 Medications
to ↓risk of aspiration
Antacids
• ↑ gastric pH to >3.5
• should be given as single dose (30 mL)~15-30 min.
before induction
• nonparticulate antacids (e.g., sodium citrate/citric acid
[Bicitra]) are the agents of choice (Why?)
Advantages:
1. no “lag time” for onset
2. are effective on fluid already in stomach
Disadvantages:
(a) short-acting buffering effect (shorter than surgical
procedure)
(b) potential for emesis (lack of palatability)
(c) possibility of incomplete mixing in stomach
(d) administration adds fluid volume to stomach
 Gastric Motility Stimulants
• Metoclopramide (Reglan) has no effect on
gastric pH or acid secretion
• ↓ gastric volume by promoting gastric emptying
• should be administered 60 min. before induction
of anesthesia when given orally or 15-30 min.
before induction of anesthesia if IV
• concomitant administration of anticholinergics
(e.g., glycopyrrolate, atropine), or prior
administration of opioids, can reduce lower
esophageal sphincter pressure, which can offset
effects of metoclopramide on upper GIT
 H2RAs
• ↓ gastric acidity & volume by ↓ gastric acid
secretion
• onset orally is 1-3 hrs; IV 30-60 min
• administration of tablets introduces particulate
matter into stomach, which can be detrimental if
aspirated
• after IV administration, cimetidine (Tagamet)
dose should be repeated in 6 hours if necessary,
whereas ranitidine (Zantac) & famotidine
(Pepcid) in 8 & 12 hours, respectively
 PPIs
• When effects of preoperative IV pantoprazole on
gastric pH & volume were compared with IV
ranitidine, there was no difference between
pantoprazole & ranitidine groups → there
appears to be no need to use more expensive
PPIs in patients at risk for pulmonary aspiration
 Selection criteria for anesthesia
• American Society of Anesthesiologists (ASA) physical
status class
• Medical conditions
• Degree of anxiety
• Age
• Surgical procedure to be performed
• Length of procedure
• Postoperative admission status (e.g., inpatient vs.
outpatient)
• Drug allergies
• Previous experience with medications
• Concurrent drug therapy
 Selection Criteria (cont’d)
• ASA-I pts are healthy with little medical risk
• ASA-V pts have little chance of survival
• These pts generally have limited physiological
reserve → cardiovascular depressant agent, for
example, can be harmful
• These pts are taking significant number of
medications → chances for drug interactions ↑
• Contraindicated medications: e.g., BDZs in
pregnancy
• A pt's age: elderly are often > sensitive to
preoperative opioids & BDZs, as well as to CNS
effects of anticholinergic agents
 Selection Criteria (cont’d)
• Painful procedures (e.g., vascular cannulation,
peripheral nerve block) - analgesic may be
warranted.
• Length & type of procedure: e.g., pt undergoing
emergency surgery who has not fasted is often
administered nonparticulate antacid because of
risk for aspiration of gastric contents
• In short duration, outpatient surgery, anesthetics
with long duration of action should be avoided
because residual effects can prolong discharge
time
• Drug allergies: genuine allergies must be
differentiated from ADRs, e.g., N&V from opioids
• If medication has caused trouble in the past, it
should be avoided
 IV Anesthetic Agents
General Anesthesia (GA)
• GA: state of drug-induced unconsciousness
• Other components of general anesthesia include
amnesia, analgesia, immobility, & attenuation of
autonomic responses to noxious stimuli
• IV induction agent is commonly administered for
initiation of general anesthesia
• The most commonly used for IV induction is propofol
• Less commonly used: methohexital, etomidate,
remifentanil, midazolam & ketamine
• Propofol can also be used to maintain GA: does not
accumulate during repeat or continuous dosing
Common Clinical Uses of IV Anesthetic Agents
Etomidate (Amidate) Midazolam (Versed)

IV induction Anxiolysis

Ketamine (Ketalar)a Amnesia

Analgesia Sedation

Sedation Propofol (Diprivan)a

IV induction Sedation

IM induction IV induction

Methohexital (Brevital)a Maintenance of general anesthesia

IV induction

Sedation

aDose-dependent effects; sedation at lower doses, anesthesia at higher doses.

 Mechanisms of Action
• BARBs & BDZs produce CNS depression by action on
GABA BDZ chloride ion channel receptor
• Site of action of etomidate (Amidate) & propofol
(Diprivan) is also at the GABA receptor
• Ketamine (Ketalar) acts at different site than other
induction agents. It produces dissociation between
cortex & thalamus within limbic system, resulting in
dissociative state: pt appears to be detached from his or
her surroundings. Ketamine-anesthetized pt's eyes are
often open & move from side to side. Ketamine also
produces analgesia & amnesia
 Pharmacokinetics
• the commonly used IV induction agents
have rapid onset of action & short clinical
duration (redistribution of drug from brain
to other tissue sites (e.g., muscle, fat)
• rapid metabolism can be significant factor
in the relatively shorter duration to full
recovery of propofol
• HW: Propofol infusion syndrome (from
https://www.openanesthesia.org/propofol_i
nfusion_syndrome_dx/)
Pharmacokinetic Comparison of Common IV Anesthetic Agents

Drug Half-Life Onset Clinical Hangover

(hours) (seconds) Duration Effectb
(minutes)a
Etomidate 2–5 ≤30 3–12 +
(Amidate)

Ketamine 1–3 30–60 10–20 ++ – +++c

(Ketalar)

Methohexital 4 ≤30 5–10 +

(Brevital)

Midazolam 1–4 30–90 10–20 +++d

(Versed)

Propofol 0.5–7 ≤45 5–10 0–+

(Diprivan)
aTimefrom injection of agent to return to conscious state.
bResidualpsychomotor impairment after awakening.
cWhen ketamine is administered as the induction agent (e.g., 5–10 mg/kg IM).
dWhen midazolam is administered as the induction agent (e.g., 0.15 mg/kg IV).
ADRs & Costs of IV Induction Agents
Adverse Etomidate Ketamine Methohexital Midazolam Propofol
Effect (Amidate) (Ketalar) (Brevital) (Versed) (Diprivan)
Adrenal +a
suppression
Cerebral + + + +
protection
Cardiovascul ++ + ++
ar depression
Emergence ++ +
delirium or
euphoria
Myoclonus +++ + ++ +
N&V +++ ++ ++ +
Pain on ++ + ++
injection
Respiratory ++ ++ +/++ ++
depression
Relative cost ++ ++ +++ + +
aNot shown to be clinically significant in single dose.
+ to ++++, likelihood of adverse effect relative to other agents (or increasing cost for cost
comparison); –, no effect.
 Agent Selection
• Pt characteristics:
1. history of PONV
2. allergy profile
3. psychiatric history
4. cardiovascular status
• Circumstances associated with surgery:
1. postoperative admission status (inpatient vs. outpatient)
2. placement of IV line
3. duration of surgery
4. extubation status at the end of procedure
• Cost: older agents (e.g., thiopental, methohexital) priced
higher per single induction dose than newer agents
(e.g., etomidate, propofol).
Volatile Inhalation Agents
• 4 agents are available: desflurane, sevoflurane,
isoflurane, & enflurane
• are administered into lungs via anesthesia machine →
it is easy to ↑ or ↓ drug levels in body
• it is common to use combination of drugs (= balanced
anesthesia) intended to take advantage of smaller
doses of each drug
• E.g,, midazolam is used to produce sedation, anxiolysis,
& amnesia → thiopental or propofol → neuromuscular
blocking agent (e.g., succinylcholine) →rapid loss of
consciousness & muscle relaxation → endotracheal
intubation → volatile inhalation agents to provide
maintenance of general anesthesia + reflex suppression
(e.g., ↓ BP & heart rate)
• Opioids (e.g., fentanyl) also can induce reflex
suppression →↓ total anesthetic requirements
 Uses
• primarily to maintain GA
• sevoflurane also to induce general anesthesia via face
mask
• desflurane & sevoflurane, because of their low blood
solubility, are ideally suited for maintenance of GA in
ambulatory surgery patients & for inpatients when rapid
wake-up is desired (e.g., neurosurgery procedures)
Site/MoA
• MoA is not fully understood, these agents are believed to
disrupt neuronal transmission in discrete areas
throughout CNS by either blocking excitatory, or
enhancing inhibitory transmission through synapses.
• ion channels (especially GABA receptors) are likely
targets of action
 Anesthesia Machine & Circuit
• 3 parts of the anesthesia machine are critically
important:
1. flow meters regulate amount of nitrous oxide
(anesthetic gas), air & oxygen delivered to pt
2. vaporizers regulate concentration of volatile
inhalation agent administered to pt
3. carbon dioxide absorber, which contains either
soda lime or Baralyme, removes carbon
dioxide from exhaled air
• Mixture of nitrous oxide & oxygen is commonly
used → flows to one of vaporizers →“picks up”
anesthetic vapor of volatile inhalation agent →
mixture exits vaporizer → ultimately delivered
to patient via endotracheal tube or face mask
• Exhaled air from pt, which contains volatile
inhalation agent & carbon dioxide, is returned
to circuit
Pharmacologic & Pharmacokinetic Properties of Volatile Inhalation Agents
Property/Effect Desflurane Sevoflurane Isoflurane Enflurane
MAC in O2 (adults) 6.0 1.71 1.15 1.7
Blood/gas partition 0.42 0.69 1.46 1.91
coefficienta
Brain/blood partition 1.29 1.7 1.6 1.4
coefficientb
Muscle/blood partition 2.02 3.13 2.9 1.7
coefficientc
Fat/blood partition 27.2 47.5 45 36
coefficientd
Metabolism 0.02% 3% 0.2% 2%
Molecular weight (g) 168 201 184.5 184.5
Liquid densitye 1.45 1.505 1.496 1.517
aThe greater the blood/gas partition coefficient, the greater the blood solubility.
bThe greater the brain/blood partition coefficient, the greater the brain solubility.
cThe greater the muscle/blood partition coefficient, the greater the muscle solubility.
dThe greater the fat/blood partition coefficient, the greater the fat solubility.
eDensity determined at 25°C for desflurane, isoflurane, and enflurane and at 20°C for
sevoflurane.
MAC, minimum alveolar concentration to prevent movement in 50% of subjects.
 Potency
• is compared in terms of minimum alveolar concentration
(MAC)
• MAC is alveolar concentration of anesthetic at one
atmosphere that prevents movement in 50% of subjects
in response to painful stimulus (e.g., surgical skin
incision)
• The lower agent's MAC, the greater is anesthetic
potency
• Value of 1.3 MAC is required to produce immobility in
95% of pts, whereas 1.5 MAC is required to block
adrenergic response to noxious stimuli.
• Addition of second agent ↓ required concentration of first
agent.
• Isoflurane has the lowest MAC & desflurane the
highest
 Pharmacokinetics (cont’d)
• Agents with low blood solubility will equilibrate quickly &,
as a result, have a faster wash-in (onset)
• Low-solubility agents are also more rapidly washed out
(eliminated) because more of agent is removed from
blood in one passage through lungs
• Desflurane & sevoflurane's solubility is lower than
isoflurane's for blood & muscle → quicker responses to
intraoperative concentration changes + faster
emergence & awakening from anesthesia & more
rapid return to normal motor function & judgment when
compared with isoflurane
• Metabolism: desflurane is metabolized least
 Pharmacologic Properties
• Depress ventilation (↑ PaCO2) & dilate constricted
bronchial musculature: dose-dependent
• Administration of pungent agent by mask for induction
can cause coughing, breath-holding, laryngospasm, &
salivation
• ↓ myocardial contractility & arterial BP: dose-dependent
• Isoflurane can ↑HR → cardiac output is usually
maintained
• Desflurane can activate sympathetic nervous system
→transient ↑ BP & HR when concentrations are rapidly ↑
• Enflurane can sensitize myocardium to
arrhythmogenic effects of epinephrine
• All agents ↓ cerebral metabolic rate & produce
cerebral vasodilation → ↑cerebral blood flow & volume
 Pharmacologic Properties
(cont’d)
• Enflurane can cause tonic-clonic seizure
• All agents produce muscle relaxation →↑
neuromuscular block
• Agents relax uterine smooth muscle → perinatal blood
loss
• All agents have been implicated in malignant
hyperthermia (MH) & are contraindicated in MH-
susceptible patients
• All agents are associated with postoperative nausea,
vomiting (PONV) & shivering
• Opioids, BDZs, α-2 agonists, & neuromuscular blocking
agents potentiate effects → their administration permits
use of lower dosages of volatile inhalants →↓ adverse
effects
 HW:
• Rapid Sequence Induction (from
https://emedicine.medscape.com/article/80
222-overview)
Neuromuscular Blocking Agents
Uses
• primarily as adjunct to GA to facilitate
endotracheal intubation & to relax skeletal
muscle during surgery under GA. Skeletal
muscle relaxation optimizes surgical field for
surgeon & prevents pt movement as a reflex
response to surgical stimulation.
• in ICU to paralyze mechanically ventilated pts
• have no known effect on consciousness or pain
threshold → adequate sedation & analgesia
must be ensured when neuromuscular blocking
agents are administered to ICU pts
 MoA
• N: 2 molecules of Ach bind to Ach subunits of nicotinic
cholinergic (NChR) receptors located on motor nerve
end plate → receptor conformational change → influx of
sodium & potassium into muscle cell → membrane
depolarizes → muscle contracts
• 2 classes of neuromuscular blocking agents :
depolarizing & nondepolarizing
• Succinylcholine, the only depolarizing agent, acts like
Ach to depolarize membrane. Because itis not
metabolized as quickly as Ach at neuromuscular
junction, its action at receptor persists longer than Ach
→ persistent depolarization of motor end plate because
sodium channels cannot reopen until motor end plate
repolarizes → sustained skeletal muscle paralysis
[preceded initially by fasciculations (transient twitching of
skeletal muscle)]
• nondepolarizing agents act as competitive antagonists to
Ach → prevent Ach binding → no depolarization of
muscle membrane → no muscle contraction
Classification of Neuromuscular Blocking Agents
Agent Type of Block Clinical Duration Structure
of Actiona
Atracurium - Intermediate Benzylisoquinolinium
(Tracrium)
Cisatracurium - Intermediate Benzylisoquinolinium
(Nimbex)
Pancuronium - Long Steroidal
(Pavulon)
Rocuronium - Intermediate Steroidal
(Zemuron)
Succinylcholine + Ultrashort Acetylcholine-like
(Anectine,
Quelicin)
Vecuronium - Intermediate Steroidal
(Norcuron)
aTime from injection of agent to return to twitch height to 25% of control (time at which
another dose of agent will need to be administered to maintain paralysis); in general,
clinical duration of a standard intubating dose of ultrashort agents ranges from 3 to 5
minutes, intermediate agents from 30 to 40 minutes, and long agents from 60 to 120
minutes.
+, depolarizing; –, nondepolarizing.
 Adverse Effects
• cisatracurium (Nimbex) & vecuronium (Norcuron) are
devoid of clinically significant cardiovascular effects &
are the agents of choice for pts with unstable
cardiovascular profiles
• succinylcholine (Anectine, Quelicin):
- significant number of ADRs: hyperkalemia; arrhythmias;
fasciculations; muscle pain; myoglobinuria; trismus; ↑
intraocular, intragastric, & intracranial pressures, can
trigger MH
- bradycardia, hyperkalemia & MH crisis are potentially life-
threatening
- is still used today because of rapid onset & ultrashort
duration of action & ability to be administered IM in
children in emergent situation when IV access has not
been established
 Drug Interactions
• volatile inhalation agents potentiate neuromuscular
blockade produced by nondepolarizing agents → lower
dose of the latter can be used
• other agents potentiating effects of neuromuscular
blocking agents include aminoglycosides, clindamycin,
magnesium sulfate, quinidine, furosemide, lidocaine,
amphotericin B, & dantrolene
• carbamazepine, phenytoin, corticosteroids (chronic
administration), & theophylline antagonize effects of
neuromuscular blocking agents
 Reversal of Neuromuscular
Blockade
• Anticholinesterases (e.g., neostigmine, edrophonium,
pyridostigmine) inhibit acetylcholinesterase, which
degrades Ach, & are used to reverse paralysis produced
by nondepolarizing agents
• Anticholinergic agents are coadministered (in same
syringe) with anticholinesterases to minimize other
cholinergic effects (eg,bradycardia, bronchoconstriction,
salivation, increased peristalsis, nausea, vomiting)
caused by ↑ Ach concentration
• Atropine is administered with edrophonium, &
glycopyrrolate with neostigmine or pyridostigmine
(Why?)
• reversal of neuromuscular blockade, as a general rule, is
not attempted until spontaneous recovery is well
established
• before extubation, adequacy of reversal is assessed with
peripheral nerve stimulator & by clinical assessment
 Depolarizing Agent c/i
1. skeletal muscle myopathies
2. after acute phase of injury (i.e., 5-70 days) following
major burns
3. multiple trauma
4. extensive denervation of skeletal muscle, or upper motor
neuron injury
5. in children & adolescents (except when used for
emergency tracheal intubation or when immediate
securing of airway is necessary)
6. hypersensitivity to drug
7. MH-susceptible patients
• In case of c/i to succinylcholine, rocuronium (Zemuron)
(the fastest onset time of nondepolarizing agents) can
be used
- Its longer clinical duration of action could be concern if
airway cannot be secured immediately or if procedure is
shorter than duration of intubating dose of rocuronium
 Local Anesthetics (LA)
Local & Regional Anesthesia
• For epidural anesthesia, LA is administered into
epidural space (between dura & ligament covering spinal
vertebral bodies & disks)
• For spinal anesthesia, LA is injected into CSF within
subarachnoid (intrathecal) space
• By injecting LA in tissue near specific nerve or nerve
plexus, anesthesia can be provided for carotid
endarterectomy (cervical plexus), upper extremity
surgery (brachial plexus), or hand surgery (ulnar, median
&/or radial nerve)
• IV regional anesthesia can be selected to ↓ or avoid
GA complications such as postoperative pain, N&V &
laryngeal irritation, or dental complications
Epidural vs spinal analgesia
Local infiltration, nerve block &
IV regional anesthesia
 LA (cont’d)
• Peripheral nerve block is not associated with bowel
obstruction or urinary retention, & it provides
postoperative analgesia (when long-acting LA are used)
• spinal or epidural anesthesia: (+) ↓ of stress response
to surgery, improvement in cardiac function in pts with
IHD, fewer postoperative pulmonary complications,
potentially favorable effects on coagulation (< risk of
VTE), & ability to continue epidural analgesia into
postoperative period
• (-) of spinal, epidural, or peripheral nerve block:
additional time & manipulations required to perform it,
possible pain from invasive catheter placements or
injections, slow onset of effect, possible failure of
technique, & toxicity from absorption of drugs
• Local infiltration anesthesia can be used to provide
localized anesthesia to allow minor procedure (e.g., a
deep laceration repair)
 Clinical Uses of Local Anesthetic Agents

Agent Primary Clinical Use

Esters
Chloroprocaine (Nesacaine) Epidural
Cocaine Topical
Tetracaine (Pontocaine) Topical, spinal
Amides
Bupivacaine (Marcaine, Sensorcaine) Local infiltration, nerve block, epidural, spinal
Lidocaine (Xylocaine) Local infiltration, nerve block, spinal, epidural,
topical, intravenous regional
Mepivacaine (Carbocaine, Polocaine) Local infiltration, nerve block, epidural
Ropivacaine (Naropin) Local infiltration, nerve block, epidural
 Uses of LAs
• LAs are mainstay of analgesia because they
prevent initiation or propagation of electrical
impulses required for peripheral & spinal nerve
conduction
• LAs are often given in combination with other
agents, such as sodium bicarbonate (to ↑ speed
of onset & ↓ pain on local infiltration),
epinephrine (to prolong duration of action & to
delay vascular absorption of LA → minimizing
plasma concentration & systemic toxicity), or
opioids (to provide analgesia by a different
MoA).
 MoA & ADRs
• reversibly bind to & block Na channels in nerve
membranes, ↓ rate of rise of AP → propagation of
electrical impulses is prevented
• C fibers (pain transmission & autonomic activity) appear
to be the most easily blocked → fibers responsible for
touch & pressure sensation (A-α, A-β, & A-Δ) → those
responsible for motor function (A-α & A-β)
• blockade of sensory, motor, or autonomic fibers may
result in ADRs such as paresthesia, numbness &
inability to move extremities, hypotension, & urinary
retention
• systemic effects (e.g., seizures or cardiac arrhythmias)
are related to inherent cardiac & CNS safety margins
• ropivacaine, like bupivacaine, has long duration of
action but has milder CNS & cardiac toxicity with less
motor blockade
• inadvertent IV administration of ropivacaine can produce
seizures
 Allergic Reaction
• Ester-type LAs (benzocaine, procaine, tetracaine)
produce most of the allergic reactions, which is probably
caused by their metabolite, para-aminobenzoic acid
(PABA)
• True (systemic) allergy to amide-type LAs is extremely
rare & may be due to preservative (methylparaben or
other substances that are structurally similar to PABA) or
to accidental intravascular injection of epinephrine-
containing LA
• Pt with known allergy to ester-type LA can safely receive
amide-type agent (preservative-free, epinephrine-free)
 Toxicity
Factors that influence
toxicity of LAs:
1. total amount of drug
administered
2. presence or absence of
epinephrine
3. vascularity of injection
site
4. type of LA used
5. rate of destruction of drug
6. age & physical status of
pt
7. interactions with other
drugs
• systemic absorption of LA is
positively correlated with
vascularity of injection site (IV
> epidural > brachial plexus >
SC)
• end-stage pregnancy, older
age, hepatic/renal dysfunction,
& advanced HF can result in
toxicity → doses should be
reduced
• toxic levels of LAs are most
often achieved by unintentional
intravascular injection
• systemic toxicity of LAs - CNS
& CVS: tinnitus,
lightheadedness, metallic
taste, tingling, numbness, &
dizziness. Hypotension →
tremors, seizures, arrhythmias,
unconsciousness, &
cardiac/respiratory arrest
 Physicochemical Properties
Affecting Action
• amide-type LAs are metabolized primarily by
microsomal enzymes in liver
• lidocaine (CYP3A4), levobupivacaine (CYP3A4,
CYP1A2), & ropivacaine (CYP3A2, CYP3A4, &
CYP1A2) → inducers or inhibitors of these
enzymes could affect metabolism of these drugs
• ester-type LAs are hydrolyzed by plasma
cholinesterase &, to < extent, cholinesterase in
liver
• agents that are highly protein bound typically
have longer duration of action
• agents with lower pKa (pH at which 50% of drug
is present in unionized form & 50% in ionized
form) typically have faster onset of action
 Physicochemical & Pharmacokinetic Properties of LAs (cont’d)

Max.
Recommended
Doseb

With
Poten Plain Epinephr
Agent pKa cy Toxicity Onset Durationa (mg) ine (mg)
Amides
Bupivacaine (Marcaine, 8.1 High High Slow Long 175 225
Sensorcaine)
Lidocaine (Xylocaine) 7.8 Moder Modera Fast Moderate 300 500
ate te
Mepivacaine (Carbocaine, 7.7 Moder Modera Moder Moderate 300 500
Polocaine) ate te ate
Ropivacaine (Naropin) 8.1 High Modera Slow Long 300 –
te
 Antiemetic Agents & Postoperative
Nausea & Vomiting (PONV)
Impact of PONV
• overall incidence is 25-30% - highly undesirable
anesthetic & surgical outcome
• pts who develop PONV are greatly dissatisfied with their
surgical experience & require additional resources such
as nursing time & medical/surgical supplies
• typically lasts <24 hours
• symptom distress can continue at home
• nausea is a separate subjective sensation & is not
always followed by vomiting. Nausea can be as or more
distressing to pts. as vomiting.
 and/or
motion
sickness

The panel considers patients with 0–1, 2 or 3, and more risk factor
as “low,” “medium,” and “high” risk categories, respectively.
Risk score for POV in
children
• Simplified risk score from
Eberhart et al to predict
the risk for POV in
children.
• 0, 1, 2, 3, or 4 risk factors
correspond to POV risks
of approximately 10%,
10%, 30%, 50%, or 70%,
respectively. POV
indicates postoperative
vomiting
Copyrights apply
Copyrights apply
Copyrights apply
 5-HT3 Receptor Antagonists
Timing of Administration
• Ondasetron, dolasetron, granisetron,
tropisetron – 1st gen.
• Ramosetron, palonosetron - 2nd gen.
• All are most effective in the prophylaxis of
PONV when given at the end of surgery.
Adverse Events: all except palonosetron
affect the QTc interval.
 NK1 Receptor Antagonists
• Aprepitant, fosaprepitant, casopitant,
vestipitant
• > effective against POV than nausea
• Rolapitant is long acting, t1/2~180 hrs
• May be effective in postop delayed N&V
 Corticosteroids
Dexamethasone
• effectively prevents nausea and vomiting in
postoperative patients.
• for patients at increased risk for PONV is
recommended after anesthesia induction rather than
at the end of surgery.
• Preoperatively enhances the postdischarge quality of
recovery in addition to reducing nausea, pain, and
fatigue.
• Use in labile diabetic patients is relatively
contraindicated
• Concerns of increased bleeding risk and hypokalemia
 DA antagonists
Amisulpride.
• a DA2 & DA3 receptors antagonist, oral
antipsychotic, may be used IV (at induction)
• Not associated with EPS, sedation or LQTc
Droperidol
• Is most effective when administered at the end
of surgery.
• Several studies have documented the equal QTc
effects of droperidol versus ondansetron.
 DA antagonists (cont’d)
Haloperidol
• The timing of haloperidol IV at induction versus
end of surgery administration did not affect
PONV risk
• Useful in established PONV
• May be given PO
• Sedation
Metoclopramide
• Not very efficacious
 DA antagonists (cont’d)
Perphenazine
• atypical antipsychotic & DA receptor antagonist.
• may be effective for the prophylaxis of PONV
without increase in drowsiness or sedation.
 Antihistamines
Dimenhydrinate
• Effective for prophylaxis
Diphenhydramine
• Was effective at higher doses
Promethazine
• Effective for both prevention & treatment
• HW: FDA black box warning regarding this
agent???
 Anticholinergic
Transdermal Scopolamine
• Is useful as an adjunct to other antiemetic
therapies.
• The patch effectively prevented nausea and
vomiting postoperatively up to 24 hours.
• It can be applied the evening before surgery or 2
to 4 hours before the start of anesthesia due to
its 2- to 4-hour onset of effect.
• TDS is useful for control of nausea in the setting
of PCA.
 Combination of Agents
• because cause of PONV is likely multifactorial, a
combination of antiemetic agents (from different
classes) is more efficacious for preventing
PONV in high-risk pt
• E.g., dexamethasone 4 mg IV can be
administered at beginning of surgery (just after
induction of anesthesia) & 4 mg IV ondansetron
should be administered ~30 min. before end of
surgery
• if alternative agent (to ondansetron &
dexamethasone) or 3rd agent is warranted,
transdermal scopolamine patch can be placed
within 2 hrs before induction of GA
Copyrights apply
 Treatment of PONV
• rescue antiemetic is more efficacious if it works
by different mechanism of action than
prophylactic antiemetic
• e.g., prophylactic dexamethasone &/or
ondansetron were used →N&V occured in
recovery room → prochlorperazine or
metoclopramide may be appropriate
• diphenhydramine or promethazine would also be
appropriate choices for rescue in such case
• it is important to assess for postoperative factors
that could ↑ likelihood of PONV: if postural
hypotension is present, IV fluids & ephedrine
would be appropriate therapy
• PONV is also related to degree of pain
 Anesthetic Agents With Low
Incidence of PONV
• when propofol is used for both induction &
maintenance of anesthesia, it reduces risk of
PONV similar to administration of single
antiemetic
• because perioperative administration of opioids
is associated with PONV, use of NSAIDs (e.g.,
parenteral ketorolac intraoperatively &
postoperatively), when appropriate, can reduce
need for postoperative opioids
• surgical wound infiltration with long-acting LA,
such as bupivacaine, should also be used, as
needed, to reduce postoperative incisional pain
Analgesic Agents & Postoperative
Pain Management
 Management Options
(a) systemic administration of opioids, NSAIDs, &
acetaminophen
(b) on-demand administration of IV opioids (PCA)
(c) epidural analgesia (continuous & on-demand,
usually with opioid/LA mixture)
(d) local nerve blockade such as local infiltration or
peripheral nerve block
(e) application of heat or cold, guided imagery,
music, relaxation, or other nonpharmacologic
intervention
Management Options (cont’d)
• For pts with mild to moderate postoperative pain, LA
wound infiltration/peripheral nerve blockade, or NSAID or
acetaminophen are appropriate
• For moderate postoperative pain, less potent oral
opioid, such as hydrocodone or codeine, is added.
• For moderate to severe pain, IV opioid (e.g., morphine,
hydromorphone), epidural containing LA & opioid, or
peripheral nerve block with LA is necessary.
- Analgesia for acute pain in perioperative setting is best
achieved by using multimodal (balanced) approach with
combination of two or > analgesic agents that have
different mechanisms of action or that are administered
by different techniques
 Patient-Controlled Analgesia (PCA)
• small, frequent IV opioid doses, as seen in PCA,
minimize peaks & valleys in serum concentrations seen
with relatively larger intermittent IM or IV doses
→avoiding ADRs & inadequate pain relief
• small, frequent, pt.-controlled dosing of opioids is able to
move plasma concentration from being subtherapeutic to
above minimum effective plasma concentration that will
provide effective pain relief
• if pt becomes sedated, self-administration of additional
pt-controlled bolus doses will stop →serum opioid
concentration falls to safe level
• infusion pump, with programmed on-demand dose &
number of minutes between allowable doses (lock-out
interval), is equipped with a button that pt presses to
receive dose
 Patient Selection
• pts receiving PCA therapy must be able to understand
concept behind PCA & to operate drug administration
button
• pts must be alert & oriented before being put in control of
his/her own pain management
• Pt must be able to comprehend verbal &/or written
instructions regarding function & safety features of
infusion pump & how to titrate drug as needed for
satisfactory analgesia
• PCA is not indicated in pts who are expected to require
parenteral opioids for analgesia for <24 hrs because
these pts will generally be able to tolerate oral
analgesics shortly after surgery
 Patient Instructions
• pt should be informed that if he/she administers too large
of amount of prescribed opioid analgesic, he/she should
fall asleep & will not press button
• when this ADR has worn off, he/she will wake up
• family members must not push button for pt
• pt should know that he/she may have to press button
several times (after lock-out interval has passed) before
pain is relieved
• pt must also be informed that he/she may require a
larger PCA dose, so it is important to assess pain relief
from “usual” dose most pts are initially started on
following surgery
• pt should understand possible ADRs of PCA medication
& what can be done to prevent & treat these effects, as
well as advantages of providing with adequate analgesia
(e.g., early ambulation).
• pt should be told of negligible risk of “narcotic” addiction
 Choice of Agent
• morphine is the most common choice for PCA,
although fentanyl & hydromorphone can be used
• morphine-6-glucuronide is active metabolite of
morpine that can accumulate in pts with renal
failure
• hydromorphone is not metabolized to active
metabolite, & fentanyl is metabolized to inactive
metabolites
 Adult Analgesic Dosing Recommendations for Intravenous Patient-
Controlled Analgesiaa
Demand Dose
(mg)
Usual Lock-Out
Drug Concentration Usual Range Interval (min)
Fentanyl (as citrate) 10 µg/mL 0.01– 0.01– 10
(Sublimaze) 0.02 0.04
Hydromorphone 0.2 mg/mL 0.2–0.3 0.1–0.4 10
hydrochloride (Dilaudid)
Morphine sulfate 1 mg/mL 1–2 0.5–2.5 10

aAnalgesic doses are based on those required by a healthy 55- to 70-kg, opioid-naive
adult. Analgesic requirements vary widely between patients. Doses may need to be
adjusted because of age, condition of the patient, and prior opioid use.
 Use of a Basal Infusion
• As rule of thumb, opioid-naïve pt experiencing
acute pain (that can change quickly) should only
receive about one-third of her average hourly
usage as a continuous infusion or 1 mg/hour of
morphine (or its equivalent, which would be 0.2
mg/hour for hydromorphone) in addition to
demand dose of by PCA
 Epidural Analgesia
Advantages & Disadvantages
• epidural analgesia can offer superior pain relief over
traditional parenteral (IM & IV PCA) analgesia
• continuous epidural infusions offer advantage over
intermittent epidural injections because peak & trough
concentrations of drugs are avoided
• epidural catheter placement is invasive procedure that
can result in unintentional dural puncture, causing
postdural puncture headache, insertion site inflammation
or infection, &, rarely, catheter migration during therapy
& epidural hematoma
 Patient selection for epidural
analgesia
• Pts undergoing abdominal, gynecologic, obstetric,
colorectal, urologic, lower limb (e.g., major vascular), or
thoracic surgery are excellent candidates for epidural
pain management
• Absolute c/i include severe systemic infection or infection
in area of catheter insertion, known coagulopathy,
significant thrombocytopenia, recent or anticipated
thrombolytic therapy, full (therapeutic) anticoagulation,
uncorrected hypovolemia, pt refusal, & anatomical
abnormalities that make epidural catheter placement
difficult or impossible
 MoA of opioids & LAs for
epidural analgesia
• opioids & LAs are administered alone or in combination
in epidural infusions
• opioids in epidural space are transported by passive
diffusion & vasculature to spinal cord, where they act at
opioid receptors in dorsal horn
• after epidural administration, opioids can reach
brainstem sites by cephalad movement in CSF
• lipophilic opioids (fentanyl, sufentanil) have substantial
systemic absorption from epidural space
• opioids selectively block pain transmission & have no
effect on motor, sensory, or autonomic function
• LAs act on axonal nerve membranes crossing through
epidural space
• LAs produce sensory, motor, or autonomic blockade
 Epidural anesthesia (cont’d)
• most often, opioids & LAs are combined in same
solution because they act synergistically,
allowing administration of < doses of each drug
to ↓ risk of ADRs while providing effective
analgesia
• bupivacaine is commonly chosen as LA
because it can preferentially block sensory fibers
(producing analgesia) without significantly
blocking motor fibers
• choice of opioid is based on pharmacokinetic
differences: highly lipophilic opioids such as
fentanyl & sufentanil have faster onset of
action, shorter duration of action (from a single
dose), < dermatomal spread & > systemic
absorption
 Epidural anesthesia (cont’d)
• fentanyl & bupivacaine are commonly admixed
in 0.9% sodium chloride
• preservative-free preparations of each drug
should be used (HW: Why?)
 Pharmacokinetic Comparison of Common Epidural Opioid
Analgesics
Partition Onset of Action Duration of Dermato
Coefficie of Bolus Action of Bolus mal
Agent nta (minutes) (hours) Spread
Fentanyl 955 5 3–6 Narrow
(Sublimaze)
Hydromorpho 525 15 6–17 Intermed
ne (Dilaudid) iate
Morphine 1 30 12–24 Wide
Sulfate
(Duramorph)
Sufentanil 1,737 5 4–7 Narrow
(Sufenta)

aOctanol/water partition coefficient; used to assess lipophilicity; higher numbers

indicate greater lipophilicity.
 ADRs of epidural opioids
• pruritus (almost all opioids)>
frequent than with IV
• antihistamines (e.g.,
diphenhydramine) can provide
symptomatic relief
• other ADRs: N&V, sedation,
confusion, constipation, ileus,
urinary retention, & respiratory
depression
• respiratory depression can occur
up to 12-24 hrs after single bolus
of morphine or within hours to 6
days after beginning continuous
infusion of fentanyl/bupivacaine -
regular assessments of sedation
level & rate & depth of
respirations safely detect
respiratory depression from
opioids
 ADRs of epidural LAs
• hypotension, urinary retention, lower limb paresthesias
or numbness, & lower limb motor block
• depending on degree of numbness & motor block, pt
may have difficulty ambulating
• Monitoring for efficacy & ADRs of epidural analgesia
should include pain intensity & quality, response to
treatment, number of on-demand requests (if PCA is
being used), analgesic consumption, BP, heart rate,
respiratory depth & rate, level of sedation, urinary output,
presence of numbness/tingling, inability to raise legs or
flex knees/ankles (lumbar epidural placement), &
temperature
Adjunctive LMWH Administration
• It is safe to leave epidural catheter in place as
long as the first dose of LMWH is administered
6-8 hrs postoperatively. The second dose should
be administered no sooner than 24 hrs after the
first dose
• Timing of the catheter removal should be
delayed for at least 10-12 hr after the last dose
of LMWH, with subsequent dosing occurring a
minimum of 2 hours after catheter has been
removed.
• There may be greater risk of spinal hematoma
when LMWH is administered twice a day
 Case study
• An 28-year-old lady who had recently started the oral
contraceptive was admitted with severe abdominal pain
& proceeded to have a laparotomy.
• Anaesthesia was induced using thiopental &
succinylcholine, & was maintained with isoflurane.
• A normal appendix was removed.
• Post-operatively, the patient’s abdominal pain worsened
& was not significantly improved with a morphine
injection.
• A nurse reported that the patient’s urine appeared dark
in colour & her blood pressure was high.
 Case study (cont’d)
Question
• What is the likely post-operative diagnosis & what may
have precipitated this?
Answer
• Acute intermittent porphyria in association with:
• oral contraceptive pill;
• thiopental.
• Opiates, such as morphine & pethidine, are thought to
be safe in porphyria. (Ectopic pregnancies should always
be considered sexually active female patients with
abdominal pain.)
 Homework:
1. Acute intermittent porphyria causes
and manifestations (from
http://www.msdmanuals.com/professional
/endocrine-and-metabolic-
disorders/porphyrias/acute-porphyrias)
2. Drugs unsafe in porphyria (from
http://www.msdmanuals.com/professional
/endocrine-and-metabolic-
disorders/porphyrias/acute-
porphyrias#v983912)