Transcript Time to Sleep Anesthesia Pharmacology Review

Time to Sleep
Anesthesia
Pharmacology Review
JASON F HEUER, MSN, CRNA
Pharmacokinetics
▪ The effect of the body on a drug from administration to elimination
▪ Allows for determining properties of drug molecules such as halflife, onset, duration of effects, drug dosing, among others.
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Routes
Solubility
Absorption
Distribution
Metabolism
Elimination
Half-life
Volume of Distribution
Pharmacodynamics
 The effect of a drug on the body
 Major goal to determine the proper drug dose to elicit desired
effect while avoiding toxicity.
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Receptor Theory- “Lock and Key” model
Agonists/Antagonists
Receptor Regulation
Receptor Types – (i.e. Ligand-gated ion channels, G-protein coupled receptors)
Cultural, Environmental, and Genetic Influences
▪ Factors include age, gender, body weight, allergies, smoking,
dietary habits, and concurrent medications.
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Influence on biochemical enzyme systems – (i.e. cytochrome P-450 system)
Dietary Influences – vitamin K, Herbal supplements, phytochemicals
Alcohol consumption – acute vs. chronic
Smoking – Increased dosages of NMB, opioids, sedatives needed
Genetic Influences – Malignant Hyperthermia
Benzodiazepines
• MIDAZOLAM (VERSED)
• LORAZEPAM (ATIVAN)
• DIAZEPAM (VALIUM)
• ALPRAZOLAM (XANAX)
BENZODIAZEPINE ANTAGONIST
• FLUMAZENIL (ROMAZICON)
Benzodiazepines
▪ Represent class of drugs that possess varying degrees of anxiolysis, sedation,
and anticonvulsant actions; spinal cord-mediated skeletal muscle relaxation; and
amnestic properties.
A) Clinical Uses: 1) anxiety 2) insomnia 3) seizure 4) muscle spasm
B) Routes: oral, IM, IV, intranasally, and rectally
C) Onset/Peak: IV- circulated to brain within seconds; Oral- peak plasma levels achieved
in 1-2 hours; IM- well absorbed and peak plasma levels achieved in 30-90 minutes.
D) MOA: promote binding of the major inhibitory neurotransmitter gamma-aminobutyric
acid (GABA) to GABAA subtype receptors in cerebral cortex, cerebellar cortex, and thalamus. Binding
results in extended opening of chloride channels, causing hyperpolarization of postsynaptic cell
membrane and making cells LESS EXCITABLE.
Benzodiazepines
E) Metabolism: undergo hepatic metabolism by the cytochrome P-450 induction
system. Some, such as Diazapam, have active metabolites that can still produce sedative
effects, resulting in elimination half-life up to 20 hours. Midazolam has active metabolites that
are quickly conjugated and exhibit no secondary effects after metabolism.
Midazolam half-life = 1.7 – 2.6 hours
F) Physiologic Effects: Reduction in cerebral oxygen metabolism and cerebral blood
flow. Provide some cerebral protection against hypoxia and useful anticonvulsants for seizures.
Little effect on cardiovascular system. Cardiac output not altered and changes in blood pressure
due to changes in SVR. Respiratory depression observed in patients with existing respiratory
disease. Increasing PaCO2 levels can cause respiratory depression. Synergistic effect with
narcotics. Benzodiazepines depress swallowing reflex and upper airway activity, increasing risk of
pulmonary aspiration.
G) Elimination: Eliminated through renal system. VOD, half-life, and clearance
unaffected with renal insufficiency. Renal failure may enhance metabolite accumulation.
Benzodiazepines
H) Adverse Effects and Contraindications: Most significant concern is respiratory
depression. Less common are venous irritation, weakness, headache, blurred vision, N & V, and
epigastric distress. FDA categorizes BZ’s as either Category D or X, which means potential for harm in
unborn has been demonstrated (floppy infant syndrome, neurodevelopmental delays, motor
impairment). Adverse effects increased in elderly population, resulting in potential cognitive
symptoms postoperatively.
Flumazenil (Romazicon): only known antagonist approved by FDA that inhibits the
effects of BZ’s. Competitively inhibits activity at GABA/benzodiazepine receptor complex. Can be
administered IM or IV. Caution must be used as half-life of benzodiazepines is longer than half-life of
Flumazenil (0.7 – 1.3 hours), thus resedation can occur. Patients should be monitored closely
following administration.
Anesthetic Induction Agents
• PROPOFOL (DIPRIVAN)
• ETOMIDATE (AMIDATE)
• KETAMINE (KETALAR)
Anesthetic Induction Agents-PROPOFOL
 Represent drugs that induce loss of consciousness and facilitate intubation and
subsequent airway management. Paradigm shifting from one of primarily agents to
achieve anesthetic induction to that of total IV anesthesia (TIVA).
PROPOFOL
A) Clinical Uses: Induction and maintenance of general anesthesia, sedation,
hypnosis.
B) Routes/Dosages: IV; Induction of general anesthesia achieved with IV dose
of 1.5-2.5 mg/kg. Pediatric patients require a larger induction dose due to a larger VOD
and elevated clearance rate, whereas elderly patients generally require induction dose
reduced by 25-50%. Maintenance of general anesthesia with Propofol accomplished at
rates between 100-300 mcg/kg/min. Maintenance of sedation for MAC or ICU typically
accomplished at 25-100 mcg/kg/min.
C) Onset: produces unconsciousness in 30 seconds
PROPOFOL
D) MOA: exerts its sedative-hypnotic characteristics predominantly on
GABAA receptors within CNS, permitting increase of chloride transmembrane
conduction, allowing for hyperpolarization and inhibition of neurons.
E) Metabolism: Hepatic metabolism is extensive and rapid.
Cytochrome P-450 hydroxylation of Propofol into active metabolite one-third as
potent occurs. Although controversial, pulmonary uptake and elimination may be
responsible for extrahepatic metabolism. Unique characterstic is there is rapid
redistribution of Propofol away from effect site (brain) to less well-perfused tissues
(muscle), which accounts for rapid decline in plasma levels. Allows for rapid
reawakening when compared to other IV induction agents.
PROPOFOL
F) Physiologic Effects: decreases cerebral blood flow, ICP, and CPP. Significant
cardiovascular effects produce decrease in BP, CO, and SVR due to relaxation of vascular
smooth muscle and inhibition of sympathetic nervous system. Negative inotropic effect and
depression of baroreceptor reflex, causing bradycardia and possible asystole. Causes dosedependent depression of ventilation, leading to apnea in 25-35% of patients who receive
induction dose. Sedative infusions depress tidal volumes and respiratory rate, resulting in
hypoxia and hypercarbia. **Antiemetic and anticonvulsant properties
G) Elimination: Primarily renal with evidence of pulmonary elimination. Rapid
redistribution and metabolism responsible for characteristic rapid reawakening, with no
evidence that hepatic or renal dysfunction impacts this.
H) Adverse Effects and Contraindications: Pain on injection; strongly supports
bacterial growth (12 hour expiration with EDTA); Relative contraindication (reduced dose) in
patients with hypotension, decreased CO, or hemorrhagic shock. Propofol infusion syndrome
(>24 hrs) described as unexplained tachycardia, metabolic acidosis, myocardial dysfunction, and
possible rhabdomyolysis in patients receiving infusion.
ETOMIDATE
ETOMIDATE
A) Clinical Uses: Used as an alternative to Propofol when hemodynamic stability
is critical. Not to be used for prolonged sedation. Does not provide analgesia.
B) Routes/Dosages: IV; Induction of general anesthesia achieved with IV dose
of 0.2-0.4 mg/kg.
C) Onset: reaches brain concentrations within 1 minute
D) MOA: exerts its sedative-hypnotic characteristics predominantly on
GABAA receptors within CNS, permitting increase of chloride
transmembrane conduction, allowing for hyperpolarization and inhibition of
neurons.
ETOMIDATE
E) Metabolism: Rapid awakening primarily due to redistribution of the
active drug to neurologically inactive sites. Full recovery result of rapid hepatic
metabolism that occurs by hydrolysis and plasma esterases.
F) Physiologic Effects: Etomidate is a vasoconstrictor and decreases
cerebral blood flow by 35%, thus reducing ICP. CPP is maintained. May produce
convulsion like EEG patterns thus exercise caution in focal epileptic patients.
Relatively cardiovascular stable even in presence of existing CV disease.
Considered induction agent of choice for patients with CV disease because
Etomidate possesses minimal alpha-adrenergic agonist properties. Although
apnea is a possibility, respiratory suppression less dramatic when compared with
other induction agents.
ETOMIDATE
G) Elimination: Primarily renal; Less than 3% of drug recovered unchanged in urine,
whereas 85% of inactive metabolite in urine and 13% in bile. Distribution half-life of
approximately 2.6 minutes, and elimination half-life of approximately 5 hours.
H) Adverse Effects and Contraindications: The primary restricting factor for
Etomidate as an induction agent is its ability to suppress adrenocortical function (adrenal
glands) after a single dose. May last between 5-24 hours and results in diminished cortisol and
aldosterone levels. Morbidity and mortality increased in septic patients who receive one-time
dose of Etomidate.
KETAMINE
KETAMINE
A) Clinical Uses: Induction of anesthesia with hemodynamic instability; chronic
pain; useful with the difficult to manage patient and short painful procedures such as
dressing changes for the burn patient.
B) Routes/Dosages: IV, IM; Induction of general anesthesia achieved with IV
dose of 1-2 mg/kg, or IM 4-8 mg/kg
C) Onset: peak plasma concentrations within 1 minute IV and 5 min
following IM administration
D) MOA: interacts with multiple binding sites throughout the body
including: N-methyl-D-aspartate (NMDA), nicotinic and muscarinic
cholinergic, monoaminergic, and opioid receptors. Also interacts with
voltage gated Na and Ca receptors.
KETAMINE
E) Metabolism: Biotransformation of Ketamine occurs in the liver and
produces several active metabolites. Intial pathway is Cytochrome P-450 into
Norketamine which is 1/5 – 1/3 as potent as Ketamine. Initial awakening is due
to redistribution to nonactive compartments.
F) Physiologic Effects: increases cerebral blood flow as much as 60%,
potentially putting patients with elevated ICP at risk. May play a neuroprotective
role due to effect at NMDA receptors implicated as source of cerebral ischemic
damage. Direct negative inotropic effects, but overshadowed by stimulation of
SNS, resulting in elevation of hemodynamic parameters. Systemic and pulmonary
pressures, heart rate, CO, and myocardial oxygen demand all elevated within 3-5
min. Effect on ventilation minimal. Increased salivary production and secretion.
Upper airway reflexes remain intact and a potent bronchial dilator. Emergence
phenomena have an occurrence rate between 5-30% described as floating, vivid
dreams, and hallucinations. May inhibit platelet aggregation.
KETAMINE
G) Elimination: Primarily renal; Less than 4% recovered unchanged in urine, whereas
less than 5% found unchanged in fecal excretion.
H) Adverse Effects and Contraindications: Potential for increasing ICP.
Increased salivary production may lead to coughing, laryngospasm, and aspiration. Production
of “dissociative” state a limiting factor for use. Administration of benzodiazepine been shown to
significantly decrease occurrence of emergence delirium.
Opioid Agonists, Antagonists, and
Agonist-Antagonists
 FENTANYL
 MORPHINE
 HYDROMORPHONE (DILAUDID)
 REMIFENTANIL
 MEPERIDINE
 NALBUPHINE
 NALOXONE (NARCAN)
MECHANISMS OF PAIN
Nociception is the process in which painful stimuli are detected,
transduced, and transmitted peripherally and in the CNS.
Tissue injury activates inflammatory process which results in influx of
mediators into injured tissue. Signals initiated in peripheral
nociceptors are carried to dorsal horn of spinal cord. Output neurons
from dorsal horn ascend spinal cord via A-delta and C-fibers in the
spinothalamic tract to the thalamus and finally somatosensory cortex.
Opioid receptors affect transmission of painful stimuli by opening Na,
K, and Ca channels, thus decreasing the firing of action potentials in
neurons.
CONSEQUENCES OF PAIN
Acute pain found to stimulate neuroendocrine stress response, increasing
adrenergic neural activity, sympatethic tone, and catecholamine
concentration.
CV-related effects include hypertension, tachycardia,and increase
myocardial O2 demand and irritability, which can precipitate myocardial
ischemia and infarction.
From respiratory standpoint, pain increases minute ventilation in response
to increase in body O2 consumption
When surgery involves abdominal or thoracic cavities, respiratory effects
include hypoventilation, decreased tidal volume, ability to cough, and the
development of atelectasis.
Additional adverse responses include anxiety, sleep disturbances, and
depression.
OPIOID RECEPTORS
Three different opioid receptors discovered in the 1970’s in different
parts of brain.
µ1 (mu) and µ2 most related to analgesia. Other effects include
respiratory depression, bradycardia, GI dysmotility, sedation, and
euphoria. µ receptors located in cerebral cortex, thalamus,
hypothalamus, midbrain, pons, medulla, dorsal horn of spinal cord,
and peripheral tissues among others.
Activation of κ (kappa) opioid receptors also associated with analgesia,
although not as strongly as µ or delta receptors. Also associated with
dysphoria.
Multiple more opioid receptors have been identified.
FENTANYL
A) Clinical Uses: Rapid onset and short duration make it an ideal opioid for
acute pain and balanced anesthetic. Blunt sympathetic stimulation during direct
laryngoscopy, suppress stress response, sedation, premedication in elderly.
B) Routes/Dosages: IV, SQ, intrathecal, or epidural. Fentanyl is 100 times
more potent than Morphine and is more specific for µ receptors than other receptors. 100
mcg – 1 mg for induction of GA
100 mcg of Fentanyl equivalent to 10 mg Morphine
C) Onset: Onset almost immediate with duration of effects 30
minutes to 1 hour.
D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-
channels to inhibit firing of AP’s in pain pathways.
FENTANYL
E) Metabolism: Most IV Fentanyl metabolized on first pass in the liver
by cytochrome P-450 system (CYP3A4). Fentanyl least affected by genetic
variability in CYP system, making it good choice for perioperative analgesia.
F) Physiologic Effects: Bradycardia, minimal if any negative
inotropic effects, primarily provides hemodynamic stability with
induction of GA. Exogenous opioids reduce production of cortisol.
G) Elimination: Primarily renal; 75% cleared in urine, mostly
of metabolites. 10% unchanged in urine.
H) Adverse Effects: Opioid-induced sedation, respiratory
depression (attributed to µ2 receptors on brainstem), biliary spasm,
decrease GI motility, nausea, increase chest rigidity
MORPHINE
A) Clinical Uses: Intermediate acting opioid that can be used intraoperatively or
postoperatively. Is the gold standard all other opioids in comparison.
B) Routes/Dosages: IV, PO, intrathecal, or epidural (Preservative-free
Duramorph, Astromorph) Fentanyl is 100 times more potent than Morphine and is
more specific for µ receptors than other receptors. 100 mcg – 1 mg for induction of GA
100 mcg of Fentanyl equivalent to 10 mg Morphine
C) Onset: 5-10 minutes, duration 2-4 hours.
D) MOA: interacts with opioid receptors(primarily µ) in CNS, opens K-
channels to inhibit firing of AP’s in pain pathways.
MORPHINE
E) Metabolism: Primarily phase 2 metabolism via glucuronic
acid, leading to development of morphine-3-glucuronide M3G and
M6G (active metabolites that make of 70%). M6G provides
analgesia and can accumulate with renal disease.
F) Physiologic Effects: Bradycardia, minimal if any negative
inotropic effects, primarily provides hemodynamic stability with
induction of GA. Exogenous opioids reduce production of cortisol.
G) Elimination: Primarily renal
H) Adverse Effects: Renal buildup of active metabolite M6G.
Hydromorphone should be considered as intermediate opioid in
patients with decreased renal function.
HYDROMORPHONE – DILAUDID
A) Clinical Uses: Intermediate acting opioid that can be used
intraoperatively or postoperatively. Particularly useful for treating moderate to
severe pain.
B) Routes/Dosages: IV, PO;
1.5 mg Dilaudid equivalent to 10 mg Morphine.
100 mcg of Fentanyl equivalent to 10 mg Morphine
C) Onset: 5 minutes, duration 4-5 hours.
D) MOA: interacts with opioid receptors(primarily µ) in CNS,
opens K-channels to inhibit firing of AP’s in pain pathways.
HYDROMORPHONE – DILAUDID
E) Metabolism: Primarily phase 2 metabolism via glucuronic
acid. Lacks active metabolites that accumulate with renal disease.
F) Physiologic Effects: Bradycardia, minimal if any negative
inotropic effects, primarily provides hemodynamic stability with
induction of GA. Exogenous opioids reduce production of cortisol.
G) Elimination: Primarily renal
H) Adverse Effects: Opioid-induced sedation, respiratory
depression (attributed to µ2 receptors on brainstem), biliary spasm,
decrease GI motility, nausea, increase chest rigidity
REMIFENTANIL
A) Clinical Uses: As an infusion intraoperatively
B) Routes/Dosages: IV, 0.1 – 0.5 mcg/kg/min as part of
balanced anesthetic
C) Onset: almost immediate, duration 5-10 minutes; half-life
10-20 minutes
D) MOA: interacts with opioid receptors(primarily µ) in CNS,
opens K-channels to inhibit firing of AP’s in pain pathways.
REMIFENTANIL
E) Metabolism: Breakdown occurs by hydrolysis by esterases
present in tissue and blood. Renal and hepatic disease states do not
affect metabolism.
F) Physiologic Effects: Boluses can lead to significant
respiratory muscle rigidity and apnea.
G) Elimination: Primarily renal
rigidity
H) Adverse Effects: Significant bradycardia, increased chest
MEPERIDINE
 Use had decreased significantly due to increased awareness of the
risk of toxicity related to metabolite normeperidine.
 Increased levels of normeperidine associated with seizures.
 The American Pain Society recommends not using meperidine in
patients with Sickle Cell, CNS disorders, renal disease, or in
children.
 When combined with MAO inhibitors, multiple adverse effects
include severe respiratory depression, hypotension, and coma.
 Meperidine administration is more effective treatment for
shivering than equianalgesic doses of other opioids. Reduces
shivering threshold.
AGONIST-ANTAGONISTS- NALBUPHINE (NUBAIN)
 A synthetic opioid agonist-antagonist that has strong κ agonist
binding and is a µ receptor antagonist.
 Provides analgesia with less risk of respiratory depression. Can
also immeliorate adverse effects such as itching, respiratory
depression.
 Recommended IV dose is 10 mg for 70-kg adult.
 Onset is 2-3 minutes with duration of analgesic activity 3-6 hours.
OPIOID ANTAGONIST – NALOXONE (NARCAN)
 Naloxone is first-line opioid antagonist used for patients with
respiratory depression or significant sedation resulting from opioids
 Strong competitive antagonist for µ receptors, but also has antagonist
effects at other opioid receptors.
 The average serum half-life is 64 minutes, thus redosing may we
warranted if longer duration opioids were administered.
 Naloxone typically provided as 0.4 mg/ml and should be diluted in 10
mL saline (0.04mg/ml) and administered 0.5 mL at a time to prevent
development of severe pain and withdrawal manifestations (seizures,
arrhythmias).
NONOPIOID ANALGESICS
 ASA, ACETAMINOPHEN, IBUPROFEN
 KETOROLAC (TORADOL)
 KETAMINE
 CENTRALLY ACTING ALPHA-2 AGONISTS
1) Clonidine 2) Dexmetotomidine (Precedex)
KETOROLAC (TORADOL)
A) Clinical Uses: Indicated for short-term management of
moderate-severe acute pain as sole drug, or in combination with
opioids.
B) Routes/Dosages: IV, IM, PO, Intraarticular.
Ketorolac 30 mg IM produces analgesia equivalent to Morphine 10 mg
Patients age 16-64 years and weigh ≥ 50 kg with normal renal function
can receive 120 mg per day IV, not to exceed 5 days. No more than 60
mg/day with impaired renal function, elderly, and weight.
C) Onset: Onset dose dependent and ranges from 30 min –
1 hour. Peak effect for IV or IM Ketorolac is 1-2 hours.
D) MOA: inhibition of prostaglandin synthesis by competitive
blocking of the enzyme cyclooxygenase (COX). Ketorolac is a nonselective COX inhibitor
KETOROLAC (TORADOL)
E) Metabolism: Metabolized primarily by phase 2 glucoronic acid
conjugation; Clearance less than opioids, but further reduced in the elderly.
Elimination half-life about 5 hours.
F) Physiologic Effects: Antipyretic, anti-inflammatory, and
analgesic. Inhibits platelet thromboxane production and platelet
aggregation. Decreased prostaglandin synthesis produces negative effect
on the gastric mucosa (GI ulcers, bleeds). May cause renal toxicity by
inhibiting renal prostaglandins directly involved in maintenance of renal
hemodynamics. Has little to no effect on biliary tract dynamics.
G) Elimination: Primarily renal
H) Adverse Effects: Bleeding, renal toxicity, bronchospasm in
patients with asthma, ASA sensitivity, GI ulcers
Inhalation Anesthetics
 NITROUS OXIDE
 HALOTHANE
 SEVOFLURANE
 DESFLURANE
 ISOFLURANE
Inhalation Anesthesia
Introduction of inhaled anesthetics dates back to 1500’s and synthesis of ether.
Nitrous oxide synthesized in 1774.
Ether inhalation was successfully used for surgical procedures as early as 1842
by Crawford Long.
Until the 1920-30’s, chloroform and ether were principal anesthetizing agents.
1940’s-50’s saw the development of early modern inhaled anesthetics.
Halothane introduced in 1953 and rapidly displaced all other agents as the
primary inhaled anesthetic (later found to induce significant hepatic toxicity)
The inhaled anesthetics used in modern anesthesia care include nitrous oxide,
isoflurane, desflurane, and sevoflurane.
Inhalation Anesthesia
A single mechanism of action still not discovered explaining the effects of
inhaled anesthetics.
Many theories point to multiple anesthetic molecule – receptor interactions that
include inhibition of neurotransmitter release, neurotransmitter inactivation,
voltage gated ion channels, GABA and NMDA receptors, etc. Ultimate action
seems to occur on neuronal membrane proteins in CNS.
The primary clinical measure of inhaled anesthetic’s potency is MAC (minimum
alveolar concentration)
MAC represents the percentage of agent required to abolish movement in
response to stimuli (skin incision) in 50% of patients.
MAC values: N2O-105%, Isoflurane-1.17%, Sevoflurane 1.8%, Desflurane-6.6%
Effects of Inhalation Anesthesia
Neurologic: decrease cerebral metabolic rate, can produce isoelectric EEG,
↑ ICP, ↓ CPP, potential neuroprotective effects
Cardiovascular: Predictable reduction in arterial BP by decreasing
afterload (SVR). Desflurane, Isoflurane may increase HR, possible
cardiprotection, ↑ arrhythmia generation, prolong QT
Respiratory: relax airway smooth muscle but ↑ airway resistance by
decreasing net lung volume. Pungency complications include resliratory
irritation with ↑ secretions, coughing, and laryngospasm.
Renal and Hepatic Systems: only Sevoflurane undergoes significant
metabolism, with up to 5% metabolized. Still associated with postop liver
dysfunction through metabolites such as Trifluoroacetate.
Malignant Hyperthermia
An inherited, potentially fatal syndrome that susceptible patients develop when
they receive inhaled anesthetics (Isoflurane, Sevoflurane, Desflurane), the
skeletal muscle relaxant Succinylcholine, and possibly N2O.
MH linked with mutations in the gene for the skeletal muscle, ryanodine (Ryr1)
receptor. Offending agents cause cascade of events that include uncontrolled
calcium release within skeletal muscle cell, leading to muscle rigidity and lifethreatening hypermetabolism.
The Midwest appears to have the highest incidence of MH in the US.
The caffeine-halothane contracture test is “gold standard” diagnostic test for MH
Symptoms due to hypercatabolic state causing very high temperatures, ↑ HR and
CO2 production, acidosis, rigid muscles, and rhabdomyolysis.
Malignant Hyperthermia
Treatment includes the following:
1) Discontinue agent and hyperventilate with 100% O2 at high flows.
2) Administer sodium bicarbonate, 1-2 mEq/kg IV
3) Administer muscle relaxant Dantrolene 2.5 mg/kg as soon as possible. If not
improving, administer up to 10 mg/kg.
4) Institute cooling measures (lavage, cooling blanket, cold IV solutions)
5) Administer inotropes and antiarrhytmics prn
6) Monitor and treat urine output, hyperkalemia, blood gases, clotting
abnormalities, etc.
7) 24-hour hotline available for consultation of suspected MH cases (1-800-MHHYPER)
Neuromuscular Blocking
Drugs
 DEPOLARIZING
 Succinylcholine
 NON-DEPOLARIZING
 Rocuronium
 Vecuronium
 Pancuronium
 Atricurium
 Cisatricurium
Mechanisms of Action
Skeletal muscle receives innervation from motor nerves that arise
from cell bodies in ventral horn of spinal gray matter.
Interaction between nerve and muscle occurs at neuromuscular
junction (NMJ), where nerve terminates near area on muscle fiber
called motor end plate.
Acetylcholine (ACh) produced by nerve interacts with nicotinic
receptors on motor end plate causing depolarization of motor nerve
axon and muscle fibers it innervates.
Enzyme acetylcholinesterase hydrolyzes ACh and choline/acetate
recycled into presynaptic nerve terminal.
DEPOLARIZING RELAXANTSSuccinylcholine
Unique mechanism of acting as an agonist at the nicotinic receptor on
NMJ
Succinylcholine comprised of 2 ACh molecules that mimics endogenous
ACh.
A) Clinical Uses: Short term muscle relaxation in anesthesia or
critical care, primarily for facilitation of endotracheal intubation, treat
laryngospasm, ECT.
B) Routes/Dosages: IV, IM, IO 0.5-2 mg/kg
C) Onset: Almost immediate; duration of action 2-5 min
D) MOA: interacts with nicotinic receptors on NMJ causing
muscle depolarization; the NMJ remains depolarized for minutes until
metabolized.
DEPOLARIZING RELAXANTSSuccinylcholine
E) Metabolism: Metabolized by breakdown of ester linkage by
plasma cholinesterase formed in liver. Unlike ACh and ACh-esterase.
F) Physiologic/Adverse Effects: Bradycardia developing into cardiac
arrest, hyperkalemia, muscle pains, ocular HTN, malignant hyperthermia,
prolonged paralysis.
Serum K+ rises by approximately 0.5 mEq/L. However, strong hyperkalemic
response seen in certain populations such as burn patients, muscular
dystrophies, immobility, and sepsis. Histamine release possible cause of
anaphylactoid reaction.
Malignant hyperthermia- Succinylcholine more potent trigger than volatile
agents.
No reversal for Succinylcholine-induced prolonged paralysis
Non-DEPOLARIZING RELAXANTSRocuronium, Vecuronium, Cisatricurium
Non-depolarizing muscle relaxants (NDMR) consist of 2
classes:
1) Aminosteroids- Rocuronium, Vecuronium, Pancuronium
2) Benzylisoquinolones- Atricurium, Cisatricurium
MOA: Antagonists at the nicotinic receptor, blocking the
binding of ACh and potential for muscle depolarization.
Clinical Uses: Short to long term muscle relaxation
NON-DEPOLARIZING RELAXANTS
Rocuronium prototype for Aminosteroid class. Intermediate duration with
faster onset (1-3 min) makes it a useful alternative to Succinylcholine for rapid
sequence intubation (RSI).
0.6 – 1.2 mg/kg intubating dose, maintenance dose 10-20%
Dosing based on ideal body weight (IBW) rather than actual.
25% of neuromuscular recovery occurs in 20-45 minutes. (versus 40 min for
Vecuronium and 60-90 min for Pancuronium.
Metabolism by many means. 10-30% of aminosteroid relaxants undergo
metabolism by hepatic enzymes with remaining unchanged in bile or urine.
Low incidence of side effects. Minimal crossing of placenta and blood-brain
barrier, so no effect of fetus or cerebral function.
NON-DEPOLARIZING RELAXANTS
Atricurium and Cisatricurium prototypes for Benzylisoquinolines.
Because of organ-independent metabolism, these drugs are most desirable in
elderly or those with renal insufficiency.
Undergo ester hydrolysis and Hoffman elimination in the plasma, thus
providing no risk to patients with underlying liver or renal disease.
Histamine release from Atricurium make it less favorable choice in presence of
asthma, carcinoid tumor, and other histamine sensitive condition.
Cisatricurium twice as potent and no histamine release.
Atricurium 0.5 mg/kg intubation dose. Onset 2-3 min. 25% recovery 40 min
Cisatricurium 0.2 mg/kg intubation dose. Onset 2-3 min. 25% recovery 45-60 min
Precautions & Monitoring
Despite pharmacological reversal, the incidence of residual relaxation is high.
Residual relaxation postoperatively contributes to reduced hypoxemic drive,
pharyngeal dysfunction (airway protection), and great risk of respiratory
compromise.
Advanced age, abdominal/chest surgery, administration of opioids, OSA,
obesity all factors that may compound otherwise inconspicuous effect.
Ulnar nerve peripheral nerve monitoring most commonly used
Train-of-four count and ratio(T4 /T1) help determine subjective amount of
residual blockade
Can have 4/4 twitches with approximately 50% of receptors stilled blocked.
Reversal of Muscle Relaxation
ANTICHOLINESTERASES
 NEOSTIGMINE
 EDROPHONIUM
 PYRIDOSTIGMINE
 ALZHEIMERS DEMENTIA DRUGS
 Donepezil
 Rivastigmine
 Galantamine
Anticholinesterases-ACh-E inhibitors
A) Clinical Uses: Myasthenia gravis, Alzheimers, reversal of
muscle paralysis, glaucoma, tx of urinary retention or bowel evacuation,
anticholinergic toxicity, and organophosphate poisoning.
B) Routes/Dosages: Neostigmine 0.05 mg/kg or 5mg/100kg
C) Onset: 7-10 minutes
D) MOA: All anticholinesterases exert effects by inhibiting
endogenous enzyme acetylcholinesterase (Ach-E), thus allowing ACh to
build up within NMJ and compete with NDMRs for nicotinic and
muscarinic receptors.Work both pre- and post-synaptically to increase
bioavailability of ACh. Physostigmine only one to cross blood-brain
barrier for treatment of central anticholinergic crisis.
Anticholinesterases-ACh-E inhibitors
E) Metabolism/Elimination: Neostigmine undergoes
hydrolysis by cholinesterase as well as hepatic enzyme metabolism.
Renal clearance accounts for 80% of elimination within first 24
hours.
F) Physiologic/Adverse Effects: Actions on the
parasympathetic nervous system cause bradycardia, increased
salivation, bronchoconstriction, GI tract hypermotility. Conflicting
evidence regarding Neostigmine and increased PONV. Reports of
complete heart block, asystole and prolonged QT (especially in heart
transplant patients).
Always administered concurrently with anticholinergic drug
(Glycopyrrolate or Atropine) to offset muscarinic effects.
Cholinergic crisis
A toxic syndrome occurring as a result of overdose of anticholinesterases
(as in MG oral tx) or organophosphates (insecticides, lubricating oils, and
chemical nerve agents).
Effects manifest from excessive ACh at muscarinic and nicotinic receptors.
SLUDGEM - (Salivation, Lacrimation, Urination, Diaphoresis, GI, Emesis,
Miosis)
Edrophonium is anticholinesterase used to differentiate inadequate
anticholinesterase therapy vs cholinergic crisis in myasthenic patient. If
symptoms improve, r/t inadequate therapy. (1 mg IV every 1-2 min)
Treatment of cholinergic crisis is to use anticholinergics that cross the
blood-brain barrier (AFLOP-Atropine, Fluids, Oxygen, Pralidoxime)
Anticholinergics
 ATROPINE
 GLYCOPYRROLATE (ROBINUL)
 SCOPOLAMINE
 INHALATION AGENTS
 Ipratropium
 Tiotropium
Anticholinergics – Muscarinic Receptor Antagonists
A) Clinical Uses: Tx of bradycardia, concurrent use with anticholinesterase
for reversal of muscle paralysis, bronchodilation, prevention of motion-induced
nausea, preoperative to dry secretions
B) Routes/Dosages:
IV, IM Atropine 0.4 – 1 mg adults, 10-20 mcg/kg children
IV, IM Glycopyrrolate 0.1-0.4 as premedicant, 0.1 – 1.0 mg with reversal
IV, IM, ophthalmic, TD, PO- Scopolamine 0.3-0.6 mg adults IV or IM; transdermal patch 1.5
mg
C) Onset: Atropine onset approximately 1 minute with DOA 30-60 min
Glycopyrrolate onset 2-3 min with DOA 30-60 min
.
Anticholinergics – Muscarinic Receptor Antagonists
D) MOA/Physiologic Effects: competitively and reversibly bind
to muscarinic cholinergic receptors at PNS sites on smooth muscle,
cardiac muscle, and gland cells; as well muscarinic receptors in CNS.
Antimuscarinic agents block M2 receptors at the SA and AV nodes, thus
producing an increased HR.
They produce bronchodilation (COPD) and decreased airway resistance
Antimuscarinics decrease intestinal motility as well as greatly diminish
secretions from lacrimal, gastric, pancreatic, salivary, and bronchial
glands.
Varying degrees of excitement,depression sedation in the CNS; Have
been associated with increased incidence of postop delirium in elderly.
ATROPINE
Considered the prototypical antimuscarinic agent.
Of all the anticholinergic drugs, Atropine is the most effective for
treating bradycardia associated with vagal-mediated reflex
responses such as peritoneal stimulation, the baroreceptor reflex,
and eyeball pressure.
Because of its rapid onset of action, Atropine is best paired with
Edrophonium for skeletal muscle relaxant reversal.
GLYCOPYRROLATE (ROBINUL)
Does not cross blood-brain barrier thus minimal CNS effects.
Is a potent antisialagogue and used for specific procedures where
inhibition of salivary and tracheobronchial secretions is desired
without sedative effects.
Vagolytic effect on the heart is similar to the effects of equipotent
doses of Atropine but with delayed onset.
D/t slower onset and longer duration, Glycopyrrolate best used
with Neostigmine for reversal of muscle relaxation.
General rule: 0.2 mg Glycopyrrolate for every 1 mg Neostigmine.
SCOPOLAMINE
Crosses blood-brain barrier and CNS effects include drowsiness and
amnesia.
Transdermal preparation of Scopolamine proven effective for protecting
against motion-induced nausea and vomiting.
Antiemetic effects are prophylactic. Much less effective after PONV has
developed.
Is the most potent antisialagogue used in anesthesia. Scopolamine
depresses the RAS and has additive effects with opioids,
benzodiazepines, and anesthetics.
Caution warranted in patients with glaucoma d/t increase in IOP of
muscarinic receptor blockers, especially Scopolamine
Antiemetics
 ONDANSETRON
 DEXAMETHASONE
 BUTYROPHENONES
 Droperidol
 Haloperidol
Phenothiazines
Prochlorperazine (Compazine)
Promethazine (Phenergan)
POSTOPERATIVE NAUSEA AND VOMITING (PONV)
The general incidence of vomiting is believed to be 30%, nausea 50%, and in a
subset of high-risk patients as high as 80%.
Positive risk factors for PONV include:
 female sex, history of motion sickness, nonsmoking, younger age,
postoperative opioids, duration of anesthesia, type of surgery (laparoscopic,
chole, gynecological), use of volatile anesthetics and nitrous oxide, general vs
regional anesthesia.
Society for Ambulatory Anesthesiology released new guidelines in 2014
GUIDELINE: Reduce baseline risks factors that increase incidence of PONV:
1) Use regional over GA if possible 2) Preferential use of Propofol infusion
3) Avoidance of N2O
4) Avoid volatile anesthetics
5) Minimize perioperative opioids
6) Adequate hydration
POSTOPERATIVE NAUSEA AND VOMITING (PONV)
GUIDELINE: Administer PONV prophylaxis using 1-2 interventions in adults at
moderate risk for PONV.
Recommended pharmacologic anitemetics for PONV prophylaxis include:
 5-hydroxytryptamine (5-HT3 ) receptor antagonists (Ondansetron, Dolasetron)
 Neurokinin-1 (NK-1) receptor antagonists (Aprepitant)
 Corticosteroids (Dexamethasone, Methylprednisolone)
 Butyrophenones (Droperidol, and Haloperidol)
 Antihistamines (Meclizine)
 Anticholinergics (Scopolamine)
5-HT3 Serotonin Receptor Antagonists
(Ondansetron)
The emetic center consists of various scattered neurons throughout the body
that control the components of the vomiting act.
Sensory input from many areas of the body such as pharynx, GI tract, direct
stimulation of cerebral cortex, signals from sensory organ (sights, smells),
input from chemoreceptor trigger zone (CTZ) in the fourth ventricle, or inner ear
signal can all stimulate the emetic center to initiate vomiting.
Serotonin receptors located throughout GI tract and CTZ, thus blocking these
receptors greatly reduces the effects anesthetic drugs can have in inducing
PONV.
Although other drugs are more effective at treating nausea, 5-HT3 receptor
antagonists are of the most effective in treating vomiting.
5-HT3 Serotonin Receptor Antagonists
(Ondansetron)
Currently there are 6 different 5-HT3 receptor antagonists identified as having
efficacy in managing PONV.
Ondansetron was the prototype and is the “gold standard” by which other
antiemetics are compared.
Designated as a first-line treatment regimen for PONV.
The usual adult dosage is 4-8 mg over 2 to 5 minutes. Onset of action is 30
min with an elimination half-life of 4 hours.
Ondansetron is as effective as Dexamethasone and Haloperidol IV, with no
difference in effect on the QT interval (lengthening of QT has been reported).
Best administered within 30 min of end of surgery
2 most commonly reported side effects are slight headache and dizziness.
Corticosteroids – Dexamethasone (Decadron)
Has been shown to effectively prevent PONV
A prophylactic dose of 4 to 5 mg IV for patients at increased risk for PONV is
recommended after induction of anesthesia rather than at end of surgery.
For PONV prophylaxis, the efficacy of Dexamethasone 4 mg IV is similar to
Ondansetron 4 mg IV and Droperidol 1.25 mg IV.
More recent studies using the higher dose of 8 mg IV. Preoperative
Dexamethasone 8 mg may enhance the quality of recovery from anesthesia by
reducing nausea, pain, and fatigue.
Data on safety is inconclusive. In most studies, a single dose of perioperative
Dexamethasone does not appear to increase the risk of wound infection.
Studies do show significant increases in blood glucose 6-12 hours
postoperatively. Labile diabetic patients should be relative contraindication.
Butyrophenones- Droperidol, Haloperidol
Older, standard, neuroleptic-type antipsychotics that possess significant sedative and
antiemetic properties.
Protect against PONV-inducing effects of a variety of endogenous and exogenous agonists that
stimulate CTZ in the medulla.
Droperidol has been a useful first-line antiemetic since the 1970’s.
In 2001, FDA changed “black box” labeling requirement d/t reports of QT interval prolongation
and torsades de pointes.
Before administration of Droperidol, it is now recommended that a 12-lead ECG is performed.
If QT > 440 ms, than Droperidol should not be given.
ECG should be monitored for 2-3 hours following administration.
Because of potential for proarrythmic effects and death, Droperidol should be reserved for
patients who fail to respond to first-line agents.
Adult dose for PONV is 0.625 mg IV.
The use of Haloperidol as an IV antiemetic is not an FDA-approved indication.
Phenothiazines
Prochlorperazine (Compazine), Promethazine (Phenergan)
Similar to butyrophenones, the phenothiazines believed to exert their
antiemetic effects primarily by antagonism of central dopaminergic receptors
in the CTZ. They also antagonize histamine 1 and cholinergic receptors.
All phenothiazines are capable of producing extrapyramidal symptoms and
sedation.
Second or third-line antiemetics
Compazine has a more rapid onset and less sedating effect than Phenergan.
Compazine can produce CNS depression, hypotension, and EPS. Usual dose is
5-10 mg IV.
Phenergan long been used to treat PONV, breakthrough N&V in CINV, allergic
blood reactions and anaphylaxis. Usual dose is 10-25 mg IV.
Treatment of PONV
When N&V occur postoperatively, tx sould be administered with a different class
antiemetic than was given prophylactically. Multimodal combination therapy
recommended for all patients with moderate risk for PONV.
If none given, the recommended tx is a low-dose 5-HT3 receptor antagonist
Alternative tx for established PONV include Dexamethasone 2-4 mg IV, Droperidol
0.625 mg IV, or Phenergan 6.25-12-5 mg IV.
Propofol 20 mg bolus as needed can be considered for rescue therapy for patients still
in PACU. Antiemetic effect of single dose Propofol brief.
Repeating the medication given for PONV prophylaxis within the first 6 hours confers
no additional benefit.
Although isopropyl alcohol inhalation has not been shown to be effective for the
prophylaxis of PONV, it was effective in achieving a quicker reduction in nausea
severity compared with Phenergan or Ondansetron.
Drugs for BP Control
 ADRENERGIC AGONISTS
 Phenylephrine (Neosynephrine)
 Ephedrine
ADRENERGIC ANTAGONISTS AND MIXED ANTAGONISTS
 Beta-blockers
 Labetelol
 Ca2+ - channel blockers (Nicardipine)
OTHER
 Hydralazine
ADRENERGIC AGONISTS
The term adrenergic refers to the effects of epinephrine (adrenaline) on SNS,
as opposed to the cholinergic effects of acetylcholine on PNS.
Adrenergic receptors divided in 2 general categories: 1)alpha α 2)beta β
α1-receptors are adrenoreceptors located throughout smooth muscle, blood
vessels, gut, uterus, lung, and GI system. Activation increases intracellular Ca2+
which leads to muscle contraction. Associated with bronchoconstriction,
vasoconstriction, uterine contraction, and contraction of sphincters in GI and
GU tracts. Most important CV effect is vasoconstriction.
α2-receptors are located in brain, platelets, pancreatic cells, and blood vessels.
Responsible for some smooth muscle vasoconstriction. Stimulation of α2receptors in CNS causes sedation and reduced sympathetic outflow (Precedex).
ADRENERGIC AGONISTS
β1-receptors are located on heart and kidneys. Agonists at these receptors
cause ↑ HR, contractility, excitability, and conduction. ↑ RAAS and BP.
β2-receptors are located on bronchi, blood vessels, uterus, eyes, urinary tract.
Agonists relax vascular, bronchial, GI, and GU smooth muscles.
ADRENERGIC AGONISTS-Phenylephrine
Phenylephrine- a noncatecholamine with predominantly direct α1-agonist
activity.
Used to treat hypotension, as a nasal decongestant, mydriatic agent, and
relieve drug-induced priapism.
Primary effects is peripheral vasoconstriction with rise in SVR and arterial BP. Reflex
bradycardia can reduce CO.
Phenylephrine use in obstretric anesthesia controversial. Studies have shown that it
can be used to manage hypotension during OB anesthesia d/t less fetal acidosis
compared with Ephedrine. Does potentially cause ↓ uterine blood flow.
IV boluses of Phenylephrine (50-100 mcg) rapidly reverse reductions in BP caused by
peripheral vasodilation. Onset almost immediate.
A continuous infusion of 5-100 mcg/min or 0.25-1 mcg/kg/min to maintain arterial
BP at expense of renal blood flow.
ADRENERGIC AGONISTS- Ephedrine
Ephedrine – a mixed (direct and indirect) acting sympathomimetic
that acts as direct agonist at α and β receptors, as well releasing
catecholamines from vesicles (indirect).
Causes ↑ BP, HR, contractility, and CO. It crosses blood-brain barrier
and can act as CNS stimulant. Dilates bronchioles.
Used in tx of asthma d/t bronchodilator effects, manage
hypotension, nasal decongestant,
Considered as preferable for OB ansesthesia by some because it
does not decrease uterine blood flow.
In adults, IV bolus of 2.5-10 mg to maintain BP. Onset 2-3 minutes