Opoids, benzodiazepines, and

other sedatives
By: Tseganesh B. (consultant
anesthesiologist)

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 Objectives
• At the end of this lecture, students will be able
to describe
– The pharmacokinetic and pharmacodynamic
principles of
• Opoids
• Benzodiazepines and other sedatives

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 Introduction
• The term “opiate” was originally used to refer
to drugs derived from opium, including
morphine, its semisynthetic derivatives, and
codeine
• The more general term “opioid” was
introduced to designate all drugs, both natural
and synthetic, with morphine-like properties,
including endogenous peptides.

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 Introduction…
• The nonspecific term “narcotic” has been used
to refer to morphine and morphine-like
analgesics
• However, because of its use in a legal context,
referring to any drug (including nonopioids,
such as cocaine) that can produce
dependence, the term narcotic is not useful in
a pharmacologic or clinical context

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 Introduction…
• In its broadest sense, the term opioid can
refer to agonists, partial agonists, mixed
agonist– antagonists, and competitive
antagonists

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 Introduction…
ENDOGENOUS OPIOIDS
• All of the endogenous opioids are derived
from three prohormones: proenkephalin,
prodynorphin, and pro-opiomelanocortin
(POMC)

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 Pharmacology
• Receptors: mu (μ1, μ2 ), kappa (κ), sigma (σ)
– Main MOA: μ-R agonism
• Other opioid receptors are delta (δ) receptors,
bound by enkephalins, and epsilon (ε) receptors,
bound by endorphin
• Can be administered PO, IV, IM, SC,
transcutaenous, transmucosal, epidural, IT

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 Pharmacology
• Inhibit ascending pathways
– Sensory neuron
– Substantia gelatinosa of dorsal horn
– Cortex: ↓ perception of pain

• Augment descending inhibitory pathways

– medulla

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 Elimination
• Elimination: biotransformation and excretion.
• are biotransformed in the liver by two types of
metabolic processes
– Phase I reactions include oxidative and reductive
reactions, such as those catalyzed by cytochrome
P-450 system, and hydrolytic reactions
– Phase II reactions involve conjugation of a drug or
its metabolite to an endogenous substrate, such
as D-glucuronic acid.

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 Biotransformation
• Remifentanil is metabolized via ester
hydrolysis, which is unique for an opioid.
• With the exceptions of the
– Normepridine (metabolite of meperidine) and
– the 6- and possibly 3-glucuronides of morphine,
• opioid metabolites are generally inactive

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 Excretion
• Opioid metabolites and, to a lesser extent,
their parent compounds are excreted
primarily by the kidneys

• The biliary system and gut are other routes of

opioid excretion.

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Pharmacokinetics

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Pharmacokinetics

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Context sensitive half time: “ the time required to achieve a 50%
decrease in concentration after stopping a continuous, steady-state
infusion.” 14
 CV Effects
• ↓ HR: due to ↓ sympathetic tone
– Except meperidine  atropine-like structure, ↑ HR
• ↓ BP: due to ↓ venous/arterial tone
• Myocardial ischemia
– ↓ HR, ↓ sympathetic tone, vasodilation  ↓
preload
– Favorable myocardial O2 supply/demand ratio
• QT prolonglation
– Methadone, meperidine, sufentanil
– Fentanyl and morphine are preferred 15
 Respiratory effects
• ↓ RR  ↓ MV

• ↓ response to CO2

• ↑ apnea threshold

• Abolish ↑ ventilation in response to hypoxemia

• Bronchospasm
– Morphine and meperidine
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Respiratory effects

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 CNS effects
• Sedation, hypnosis
• No amnesia
• ↓ MAC
• ↓ CMRO2, CBF, ICP
• Miosis (CN III, Edinger-Westphal nucleus)
– Mydriasis if ventilation is not controlled
• N/E via CTZ
• Seizures
– Due to neuroexcitatory effects of normeperidine
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 MSK Effects
• Skeletal muscle rigidity
– Involves muscles of trunk, extremities, upper airway
– On induction: difficult mask ventilation
– ↑ risk: extremes of age, Parkinson dz, critical illness
– Occurs with rapid administration of potent opioids
– Management:
• Administer slowly
• NM blockade/controlled ventilation
• Postop shivering: via κ receptors
– Meperidine 12.5-25mg IV
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 Other
• GI effects
– Ileus: ↑ non-peristaltic bowel tone
– Biliary spasm
• Contraction of sphincter of Oddi  ↑ CBD pressure  ↓
emptying of gallbladder or bile duct
• Associated with morphine use
• Tx: anticholinergics, CCB, NTG, glucagon, naloxone
• Endocrine effects
– ↓ stress response to surgery  ↓ cortisol release

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 Other
• Histamine release
– Non-IgE mediated histamine release from mast cells
• ↓ SVR  ↓ BP, ↑ HR
• bronchospasm
– Associated with morphine and meperidine
• Opioid-induced hyperalgesia
– Increased sensitivity to noxious stimuli
– Due to ↑ signaling at level of spinal cord
• NMDA receptor is involved

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 Other
• Dependence
– Presence of withdrawal symptoms if drug is
withheld
• Physical
• Psychological: craving for a drug (= addiction)
• Tolerance
– Need for ↑ dose of an opioid over time to
maintain the same desired analgesic effect

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Benzodiazepines

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 Outline
• Introduction

• Pharmacokinetics

• Pharmacodynamics

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 Introduction
• Are the most widely used sedative-hypnotics

• Benzodiazepines can be used for sedation before or

after surgery and can be used to induce and maintain
general anesthesia with other anesthetic drugs.

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 Introduction…
• The benzodiazepines used in anesthesia are classified
as:
– Short acting- (midazolam, flumazenil)
– intermediate- (diazepam)
– long-acting (lorazepam)

• Although benzodiazepines can be used as hypnotics,

they are primarily used as premedicants and
adjuvant drugs because of their anxiolytic, sedative,
and amnestic properties

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 Introduction…

All benzodiazepines have the following properties.

 Sedative
 Anxiolytic
 Hypnotic
 Amnestic (anterograde)-inability to remember events
occurring during the drug's duration of action
 Anticonvulsant
 spinally mediated muscle relaxant
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 Pharmacokinetics
Mechanism of action
• Benzodiazepines selectively attach to alpha
subunits to enhance the chloride channel
gating function of the inhibitory
neurotransmitter GABA.

• Benzodiazepines undergo hepatic metabolism

via oxidation and are conjugated to form
glucuronide which are excreted in urine.
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 Pharmacokinetics…
• All three drugs are highly protein bound, mainly to serum
albumin.

• highly lipophilic, with midazolam having the highest lipid

solubility.

• Although they are used as parenteral formulations, all three

drugs are absorbed after oral administration.

• Other possible routes of administration include

intramuscular, intranasal, and sublingual.
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 Pharmacokinetics…
• The highly lipid-soluble benzodiazepines
rapidly enter the CNS, which accounts for their
rapid onset of action, followed by
redistribution to inactive tissue sites and
subsequent termination of the drug effect.
• Metabolism of benzodiazepines occurs in the
liver through microsomal oxidation (N-
dealkylation and aliphatic hydroxylation) or
glucuronide conjugation.
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 Pharmacokinetics…
• Microsomal oxidation, the primary pathway
for metabolism of midazolam and diazepam, is
more susceptible to external factors such as
age, diseases (hepatic cirrhosis), and the
administration of other drugs that modulate
the efficiency of the enzyme systems.

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 Pharmacodynamics
Central nervous system
• CMR02 is mildly depressed along with CBF and ICP,
much less than barbiturates.
• Not known to be significantly neuroprotective.
• Amnestic, anticonvulsant, hypnotic, muscle relaxant,
and sedative effects in a dose dependent manner.
• Reduced cerebral oxygen consumption, cerebral
blood flow and ICP.

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Pharmacodynamics…
Cardiovascular System
• Minimal change in BP, HR, and CO. However, with
combination of opioids, SVR and BP can decrease.

• Mild systemic vasodilation and reduction in cardiac

output; heart rate usually unchanged.

• In the presence of heart failure, the decrease in preload

and afterload may be beneficial in improving cardiac
output.

• The cardiodepressant effect of benzodiazepines may be

more marked in hypovolemic patients.
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Pharmacodynamics…
Respiratory System
• Normal response to C02 is minimally affected.
• Mild dose-dependent decrease in respiratory rate
and tidal volume
• But the respiratory depressant effect is enhanced in
patients with:
– chronic respiratory disease
– Co-administered with opioid analgesics( results in
synergistic depressant effects )
• They also depress the swallowing reflex

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Midazolam
• Short-acting benzodiazepine

Preoperative Medication
Midazolam is the most commonly used oral preoperative
medication for children is effective for producing sedation
and anxiolysis

Intravenous Sedation,
Induction of Anesthesia can be induced by administration
of midazolam, 0.1 to 0.2 mg/kg IV, over 30 to 60 seconds

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Midazolam…
Maintenance of Anesthesia
• Midazolam may be administered to supplement
opioids, propofol, and/or inhaled anesthetics during
maintenance of anesthesia.

Postoperative Sedation
• Compared with diazepam, midazolam is two to three
times as potent
• Emergence time from midazolam is increased in elderly
patients, obese patients, and in of severe liver disease.
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Diazepam
• Diazepam is the benzodiazepine most likely to be
selected for abolishing seizure activity (0.1 mg/kg
IV).

• To inhibit seizures diazepam selectively inhibits

activity in the limbic system, particularly the
hippocampus.

• Contains propylene glycol a tissue irritant that

causes pain on injection and venous irritation
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Lorezepam
• Lorazepam is a more potent sedative and
amnesic than midazolam and diazepam

• Has a prolonged duration of action of which

limits its usefulness for preoperative
medication when rapid awakening at the end
of surgery is desirable.

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Lorezepam…
• A slow onset limits the usefulness of lorazepam for
(a) the intravenous induction of anesthesia,
(b) intravenous sedation during regional
anesthesia,
(c) use as an anticonvulsant

• As a result of slower onset times, diazepam and

lorazepam are rarely used for induction of general
anesthesia
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 SIDE EFFECTS OF BENZODIAZEPINES
• Fatigue
• Drowsiness
• Decreased motor coordination
• Impairment of cognitive function
• Anterograde amnesia
• Synergistic effects with other CNS depressants
• Potentiation of ventilatory depressant effects of
opioids
• Inhibit platelet aggregation
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Flumazenil…
Reverses the effects of benzodiazepines
• It is a specific competitive antagonist for
benzodiazepines
• Flumazenil (8 to 15 mcg/kg IV) may be useful
for treating patients experiencing delayed
awakening, but its duration of action is brief
(about 20 minutes) and resedation may occur.

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Context-sensitive half time

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Other Sedatives

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Clonidine
• is an a2-agonist, which is increasingly used as
a sedative in both mechanically and
spontaneously breathing patients.
• It is particularly useful if agitation is a feature
or after withdrawal of benzodiazepines or
opioids.
• It may be administered by bolus doses (50–
150 mg t.d.s.) or as an infusion.

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Clonidine…
• acts via stimulation of a2-receptors in the lateral
reticular nucleus of the medulla, resulting in
reduced sympathetic outflow, causing profound
analgesia and sedation without respiratory
depression
– it is safe in spontaneously breathing/extubated
patients.
• may also cause significant haemodynamic changes.
• an initial rise in arterial pressure, which is later
followed by a more prolonged fall.
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Clonidine…
• Bradycardiareduction in sympathetic tone
and an increase in vagal tone.
• abrupt withdrawalacute rebound
hypertensive crises
• has an elimination half-life of 8.5 h, 50% liver
dependent, to inactive metabolites, and the
rest is excreted into the urine.

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Dexmetatomidine ;Precedex
• Dexmetatomidine is a more potent a-agonist
than clonidine; it is showing promise as a
sedative agent in ICU and in paediatric
anaesthesia, due to its shorter elimination
half-life (2 h).
• was approved in 1999 by the FDA as a
sedative-hypnotic ‘
• is a centrally acting α2-agonist that inhibits
norepinephrine release.
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Dexmedetomidine…
• It is a sedative and opioid sparing analgesic
but does not have antiepileptic effect it does
not cause respiratory depression!
• Overall, patients are more easily arousable .
• It is the only sedative in the US approved for
sedation in non-intubated patients.

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Dexmedetomidine…
• Onset of sedation occurs within 15 minutes
peaks at 1 hour, and is widely distributed
throughout the peripheral tissues.
• It is metabolized by the liver and in patients
with normal liver function has a half –life of 3
hours

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Pharmacokinetics
• undergoes rapid hepatic metabolism involving
conjugation, N-methylation, and hydroxylation,
followed by conjugation.
• Metabolites are excreted through urine and
bile. Clearance is high, and the elimination
halftime is short.
• significant increase in the context-sensitive half-
time from 4 minutes after a 10-minute infusion
to 250 minutes after an 8-hour infusion.
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Pharmacodynamics
• produces its selective a2-agonist effects through
activation of CNS a2-receptors.
• Hypnosis presumably results from stimulation of a2-
receptors in the locus ceruleus, and the analgesic
effect originates at the level of the spinal cord.
• the sedative effect resembles a physiologic sleep state
through activation of endogenous sleep pathways.
• decreases CBF without significant changes in ICP and
CMRO2.
• Tolerance and dependence can occur.
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 CARDIOVASCULAR SYSTEM
• Dexmedetomidine infusion produces moderate
decreases in HR and SVR  decrease in BP.
• A bolus injection may produce transient increases in
BP
• Bradycardia associated with dexmedetomidine
infusion may require treatment.
• Heart block, severe bradycardia, or asystole may
result from unopposed vagal stimulation.
• The response to anticholinergic drugs is unchanged.

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 RESPIRATORY SYSTEM
• a small to moderate decrease in tidal volume
and very little change in the respiratory rate.
• ventilatory response to carbon dioxide is
unchanged.
• In addition, dexmedetomidine has a
synergistic sedative effect when combined
with other sedative-hypnotics.

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 Clinical Uses
• principally used for the short-term sedation of
tracheally intubated and mechanically
ventilated patients in an intensive care setting.
• In the operating room, dexmedetomidine may
be used as an adjunct to general anesthesia or
to provide sedation during awake fiberoptic
tracheal intubation or during regional
anesthesia.

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 Clinical Uses…
• When administered during general anesthesia,
dexmedetomidine (0.5- to 1-mg/kg initial dose
over a period of 10 to 15 minutes, followed by an
infusion of 0.2 to 0.7 mg/kg/hour) decreases the
dose requirements for inhaled and injected
anesthetics.
• Awakening and the transition to the postoperative
setting may benefit from dexmedetomidine-
produced sedative and analgesic effects without
respiratory depression.
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 References
• Miller’s Anesthesia, 7th ed., by RD Miller, 2009
• Basics of Anesthesia, 6E. Miller RD, 2011.
• Anesthesiology Review, 4E. Faust, 2015.

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