IV Anesthetic Agents

Surgery Before Anesthesia

 18th Century Surgery

Original in the Royal College of Surgeons of England, London.

Fun and Frolics led to Early Anesthesia
 Anesthesia

• Allow surgical, obstetrical and diagnostic procedures

to be performed in a manner which is painless to the
patient

• Allow control of factors such as physiologic functions

and patient movement
 Goals of General Anesthesia

 Hypnosis (unconsciousness)
 Amnesia
 Analgesia
 Immobility/decreased muscle tone
 (relaxation of skeletal muscle)
 Inhibition of nociceptive reflexes
 Reduction of certain autonomic reflexes
 (gag reflex, tachycardia, vasoconstriction)
Intravenous Anesthetics
 Ideal Intravenous anesthetic
 Water-soluble, no pain on injection

 Rapid onset, rapid recovery, little accumulation.

 little depression on respiratory-cardiovascular system.

 No nausea and vomiting,

 no interact with muscle relaxant,

 no release of histamine…….
 Pharmacological Principles
 IV anesthetics completely bypasses the process of
absorption, because the drug is placed directly into the
bloodstream.
 Highly perfused organs (vessel rich) including the brain
take up disproportionately large amount of drug
compared to less perfused areas (the muscle, fat, and
vessel-poor groups).
 Drugs bound to plasma proteins are unavailable for
uptake by an organ.
 Pharmacological Principles
 After the highly perfused organs are saturated
during initial distribution, the greater mass of the
less perfused organs continue to take up drug
from the bloodstream.
 As plasma concentration falls, some drug leaves
the highly perfused organs to maintain
equilibrium.
 This redistribution from the vessel-rich group is
responsible for termination of effect of many
anesthetic drugs.
 Pharmacological Principles
Compartment Model
 Offers a simple way to characterize the distribution of
drugs in the body
 Can be conceptualized as a group of tissues that posses
similar pharmacokinetics (Central and peripheral
compartments)
 Distribution phase vs. Elimination phase
 Intravenous Anesthetics
Barbiturates (Thiopental, methohexital)
 Depress the reticular activating system located in the
brain stem that controls several vital functions,
consciousness
 Affect the function of nerve synapses not axons
 Suppress transmission of excitatory neurotransmitter
and enhance transmission of inhibitory
neurotransmitter
 They are barbituric acid derivatives, substitution at the
number 5 carbon determines hypnotic potency and
anticonvulsant activity
Barbituric Acid
 Intravenous Anesthetics
Methohexital
 Methylated Oxybarbiturate.
 Methylation of an active barbiturate at position 1 (Methohexital)
will give a drug with increased incidence of excitatory side
effects.
 Methohexital is excreted in the feces
 Methohexital) may induce involuntary skeletal muscle
contractions.
 Dosage : IV 1-2 mg/kg
 Intravenous Anesthetics
Absorption (Barbiturates)
 Administered mostly IV for induction in adults and children
 Rectal thiopental or methohexital in children
 IM pentobarbital or secobarbital for premedication
Distribution
 Duration of action of highly lipid soluble is determined by
redistribution (Thiopental)
 Thiopental is highly protein bound (80%)
 Maximum brain uptake within 30s
 Induction dose depends on body weight and age
 The elimination half-life from 3-12 h
 Intravenous Anesthetics
Biotransformation
 Mainly hepatic oxidation to inactive water-soluble metabolites

 Methohexital is cleared by the liver 3-4 times more rapid than

thiopental
Excretion
 High protein binding decreases barbiturates glomerular filtration

 High lipid solubility tend to increase renal tubular reabsorbtion

 Renal excretion is limited to water-soluble end product of

biotransformation
 Methohexital excreted in feces
 Intravenous Anesthetics
 Effect on organ systems (Barbiturates)
Cardiovascular
 Decrease blood pressure and increase heart rate

 Depression of the medullary vasomotor center vasodilates

periphral capacitance vessels, increases periphral pooling of
blood and decreases venous return to right atrium
 Cardiac output is maintained by rise in heart rate and increased
contractility
 Intravenous Anesthetics
Respiratory
 Depresses the medullary ventilatory center and decreases the
ventilatory response to hypercapnia and hypoxia
 Tidal volume and respiratory rate are decreased
Cerebral
 Constrict the cerebral vasculature and cause decrease in cerebral
blood flow and intracranial pressure
 Cerebral perfusion pressure increases cause the drop in ICP
exceeds the drop in arterial BP
 Decreases cerebral oxygen consumption (up to 50%)
 Have anti-analgesic effect by lowering the pain threshold
 Intravenous Anesthetics
Renal
 Reduces renal blood flow and glomerular filtration rate in
proportion to fall in BP
Hepatic
 Decreases hepatic blood flow

 Induction of hepatic enzymes, increases the rate of metabolism

of some drugs (Digitoxin)
 Combination with the cytochrom p-450 enzyme system interfere
with biotransformation of some drugs (TCA)
 Intravenous Anesthetics
Intra-arterial injection of Pentothal
(Complication)
 Cause gangrene and subsequent amputation
 Most commonly in the antecubital fossa
 Decreased arterial pulsation may conceal an arterial puncture
 Causes destruction of the endothelial lining and inner portion of
the muscular coat of the artery
 The result is thrombosis, circulatory obstruction and ischemia
 The degree of arterial destruction depends on the concentration
and volume of the drug injected
 Intravenous Anesthetics
 Clinically immediate severe burning pain radiates
distally from the site of injection
 The extremity may become markedly edematous
and progressively cadaveric
 Poor prognosis with rapid progression
 Management : the aim is to prevent thrombosis
 Surgical intervention, intra-arterial vasodilators,
sympathetic block, anticoagulation and
antispasmodics are the modalities for treatment
 Intravenous Anesthetics
 Elevation of the extremity to the level of the heart permit free
venous return and aid in preventing venous thrombosis
 Heat or cold should not be applied
 Hypotension should be treated with hydration to prevent
hemoconcentratin
 Good analgesic to control pain
 Alkylphenols-Propofol
Physical & Chemical properties
 Propofol consists of phenol ring & is
chemically described as 2, 6-di-
isopropylphenol.
 The colour of solution is Milky white and is available in
1% and 2% concentration.
 The formulation also contains soybean oil, Egg, Lecithin
& glycerol. So injection is painful.
 The propofol injectable emulsion is isotonic and has a
pH of 4.5-6.4.
 It is preservative free so should be used within 6hrs after
opening the vial because there have been death reports
following the use of contaminated solution of propofol (
as egg lecithin is a good media for bacterial growth ).
 To prevent this formulations have disodium edetate or
sodium metabisulfite as antimicrobials.
Mechanism of Action
 Specific mechanism is unknown. But it is mainly due to GABA
medaited.

Anaesthetic properties
 It is a sedative hypnotic used in the induction and maintenance
of anesthesia.
 Induction is achieved in one brain arm circulation time i.e. 15
seconds. Consciousness is regained after 2-8 minutes due to
redistribution.
 Elimination half life is 2-4 hrs, recovery is rapid & associated
with less hangover than thiopentone.
 It has no analgesic property.
 It is not a muscle relaxant.
Metabolism
 It is chiefly eliminated by hepatic
conjugation to inactive metabolites which
are excreted by the kidney.
 Elimination half life is 2-4 hrs ,recovery is
rapid.
 All metabolic products of propofol are
inactive.
 Systemic Effects
Cardiovascular
 Hypotension produced is significant & it also impairs baroreceptor
response to hypotension.
Respiratory
 The first respiratory disturbance after a bolus dose of propofol is a
profound fall in tidal volume leading to apnea in many patients.
There has been no accompanying cough or hiccup and otherwise
anesthesia is smooth.
 Induces bronchodilatation.
Cerebral
 It also has cerebral protection effect by decreasing cerebral oxygen
consumption, cerebral metabolic rate and intracranial pressure.
 It is also a reliable amnestic agent.
 It can sometimes produce muscle twitching & myoclonic activity.
Eye
 Reduces intraocular pressure.
GIT
 It is anti-emetic
Immunologic
 It is antipruritic.
DOSAGE AND ADMINISTRATION
 Healthy Adults Less Than 55 Years of Age: 40 mg
every 10 seconds until induction onset (2 to 2.5 mg/kg).
 Elderly, Debilitated, or ASA III/IV Patients: 20 mg
every 10 seconds until induction onset (1 to 1.5 mg/kg).
 Cardiac Anesthesia: 20 mg every 10 seconds until
induction onset (0.5 to 1.5 mg/kg).
 Neurosurgical Patients: 20 mg every 10 seconds until
induction onset (1 to 2 mg/kg).
 Pediatric - healthy, 3 years of age or older: 2.5 to 3.5
mg/kg administered over 20-30 seconds.
 Indications
 Because of its early induction, early & smooth
recovery, inactive metabolites & anti emetic
effects it is,the IV agent of choice for day care
surgery.
 Along with opioids (alfentanil or remifentanil ) it
is the agent of choice for total intravenous
anaesthesia (TIVA).
 Propofol injection can be used to produce
sedation in ICU patients.
 Agent of choice for induction in susceptible
individuals for malignant hyperthermia.
 Advantages of propofol over
thiopentone
 Rapid and smooth recovery.
 Completely eliminated from body in 4
hours so patient is ambulatory early.
 Anti-emetic.
 Anti-pruritic.
 Bronchodilator.
 Disadvantages
 Apnea is more profound and longer.
 Hypotension is more severe.
 Injection is painful.
 Solution is less stable (6 hrs).
 Chances of sepsis with contaminated solution is high.
 Myoclonic activity.
 Sexual fantasies and hallucination.
 Expensive than thiopentone.
 Allergic reactions in individuals who are allergic to egg lecitin.
 Propofol addiction has also been reported.
 Propofol infusion syndrome: It is very rare but is a lethal
complication. Usually seen if infusion is continued for more than
48 hrs & is much more common in children.
 Etomidate
 Etomidate is a carboxylated imidazole
derivative. Etomidate has anesthetic and
amnetic properties, but has no analgesic
properties
 Uses
 Etomidate is commonly used in the
emergency setting as part of a rapid sequence
induction to induce anesthesia or for
conscious sedation. It is often used in this
setting since it has a rapid onset of action and
a low cardiovascular risk profile, and
therefore is less likely to cause a significant
drop in blood pressure than other induction
agents
 It is the agent IV anesthetic agent of choice
for aneurysm surgery & patients with cardiac
disease.
 Dosage
 The anaesthetic induction dose for adult
humans is 0.3 mg/kg intravenously, with a
typical dose being 20 mg. In common with all
induction agents, etomidate causes loss of
consciousness after one arm-brain
circulation time.
 At the typical dose, anesthesia is induced for
about 5–10 minutes even though the half-life
of drug metabolism is approximately 75
minutes. This is because etomidate is
redistributed from the plasma to other
tissues.
 Metabolism

 Etomidate is highly protein bound in blood

plasma and is metabolised by hepatic and
plasma esterases to inactive products with a
redistribution half-life of 2–5 minutes and an
elimination half-life of 68–75 minutes.
 Actions and effects
 Etomidate does not cause significant cardiovascular or
respiratory depression, but may cause a brief period of
apnea.
 The decrease in cerebral blood flow produced by
etomidate is approximately the same as that produced
by thiopental
 Etomidate slightly lowers intracranial pressure and it
usually causes a moderate decrease in intraocular
pressure
 Side effects ( disadvantages)
 Adrenocortical suppressioin on long term
infusion.
 Nausea & vomiting. ( 40 %)
 Has very high incidence of myoclonus.
 High incidence of thrombophlebitis.
 It can cause vitamin C deficiency & platelet
dysfunction.
 May produce pain on injection
 No analgesia.
 Hiccups are common.
 Contraindications and
precautions
 Use of etomidate is not recommended since data
are insufficient to support its use in obstetrics,
including cesarean section deliveries
 It is not known whether etomidate is distributed
into breast milk. However, problems in humans
have not been documented
 Appropriate studies with etomidate have not
been performed in children up to 10 years of
age . Safety and efficacy have not been
established.

 Elderly patients are more sensitive to the

effects of etomidate than are younger
patients. In addition, geriatric patients are
more likely to have age-related hepatic
function impairment, which may require
reduction of dosage in patients receiving
etomidate
 Intravenous Anesthetics
 Ketamine
 Has multiple effects through the CNS including blocking
polysynaptic reflexes in the spinal cord and inhibiting
neurotransmitter effects in selected areas of the brain
 Ketamine dissociates the thalamus from the limbic cortex
 N-methyl-D-aspartae receptor antagonist
 Structurally analogue to phencyclidine
 Can cause hallucinogenic effects and nightmares
 Dose : Induction IV 1-2 mg/kg, IM 3-5 mg/kg
 Intravenous Anesthetics
Absorption
 Administered IM or IV with peak plasma level within 10-15 min
after IM injection
Distribution
 More lipid soluble and less protein bound than thiopental
 Distribution half-life is 10-15 min
Biotransformation and excretion
 Biotransformed in the liver to several metabolites some retain
anesthetic properties (norketamine)
 Short elimination half-life (2h)
 Excreted renally
 Intravenous Anesthetics
 Effect on organ systems
Cardiovascular
 Increases Blood pressure, heart rate, and cardiac output

 Increases pulmonary artery pressure and myocardial work

 Avoid in patient with coronary artery disease

Respiratory
 Minimal effect on the ventilatory drive

 Potent bronchodilator
 Intravenous Anesthetics
Cerebral
 Increase cerebral oxygen consumption, cerebral blood flow and
intracranial pressure
 Myoclonic activity is associated increased subcortical electrical
activity
 Undesirable psychotomimetic effects (illusions, disturbing,
dreams and delirium)
 Have analgesic effects
 Intravenous Anesthetics
Benzodiazepines
 Interact with specific receptors in the CNS mainly in the cortex
 Binding to receptors enhances the inhibitory effects of various
neurotransmitters (GABA)
 Flumazenil is a specific benzodiazepine-receptor antagonist that
effectively reverses most of the CNS effect
 Chemical structure includes a benzene ring and a 7-member
diazepine ring, substitution ay various positions on these rings
affect potency and biotransformation
Agent Use Route Dose
Premedication Oral 0.2-0.5 mg/kg upto 15
mg
Sedation IV 0.04-0.2 mg/kg
Diazepam
Induction of hypnosis IV 0.3-0.6 mg/kg

Premeditation IM 0.07-0.15 mg/kg

Sedation IV 0.01-0.1 mg/kg

Midazolam
Induction of hypnosis IV 0.1-0.4 mg/kg

Lorazepam Premedication Oral 0.05 mg/kg

(not
Recommended IM 0.03-0.05 mg/kg
in children) Sedation IV 0.03-0.04 mg/kg
 Intravenous Anesthetics
Absorption
 Administered orally, IM and IV for sedation or induction of GA
 Diazepam and Lorazepam well absorbed from GI tract, peak
plasma level in 1-2 h respectively
 Dose Medazolam : premedication IM 0.07-0.15 mg/kg, sedation
IV 0.01-0.1 mg/kg, Induction IV 0.1-0.4 mg/kg
Distribution
 Diazepam is lipid soluble and rapidly cross the blood brain
barrier, water soluble at low pH
 Redistribution is rapid for benzodiazepines (3-10 min)
 Highly protein bound (90-98%)
 Intravenous Anesthetics
Biotransformation
 Rely on the liver for transformation into water-soluble
glucoronide end products
 Slow hepatic extraction, long half-life for diazepam (30h)

Excretion
 Metabolites are excreted mainly in the urine

 Entrohepatic circulation produces a second peak in diazepam

plasma concentration 6-12h following administration
 Intravenous Anesthetics
 Effect on organ systems
Cardiovascular
 Minimal CVS depressant effects

 Arterial BP, Cardiac output, and PVR slightly decreased

 Heart rate sometimes increased

Respiratory
 Depresses ventilatory response to CO2

 Ventilation must be monitored

 Intravenous Anesthetics
Cerebral
 Reduces cerebral oxygen consumption

 Decreases cerebral blood flow and intracranial pressure

 Effective in preventing and controlling grand mal seizures

 Sedative dosages cause antegrade amnesia

 Intravenous Anesthetics
Opioids
 Classically known as narcotic analgesics

 Name derived from Poppy juice (opium), first obtained from the
capsules of the unripe oriental Poppy seed (papaver somniferum),
of which Morphine is the principal active ingredient.

 “Opiates”: a term generally used for naturally occurring

substances with properties similar to Morphine.

 “Opioids” : refers to all naturally occurring and synthetic drugs

with an affinity for opioid receptors, and actions that can be
stereospecifically antagonized by Naloxone
 Intravenous Anesthetics
Mode of Action
 By interaction with Specific opioid receptors in the CNS ( brain
and Spinal Cord) and peripheral tissues ( somatic and
sympathetic nerves)

 Opioids Modify the complex emotional experience of pain as

well as affecting its transmission as a sensory modality.

 Their influence on the reactive component of pain (i.e. anxiety,

Fear and suffering) can greatly influence the patients’ ability to
tolerate pain.
 Intravenous Anesthetics
Opioid Receptors
Four major Types:

1- µ (mu): with µ-1 and µ-2 subtypes

2- К (kapa)
3- б (delta)
4- σ (sigma)

 The pharmacodynamic properties of specific opioids depend on which receptor is

bound, the binding affinity, and whether the receptor is activated.

 Opioid receptors can also be activated by some endogenous peptides (

Endorphins, enkephalins, and dynorphins)

 Opioid receptor activation inhibits the presynaptic release and post-synaptic response
to excitatory neurotransmitters (e.g. Acetyl-choline, substance P).
 Intravenous Anesthetics
Opioids classification
1- Agonists:
- Strong: Morphine, pethidine, Methadone, Fentanyl,…
- Moderate: Codeine, Oxycodone, Hydrocodone
- Weak: Propoxyphene

2- Mixed agonist/antagonist: Pentazocine, butorphanol,

nalbuphene, Buprenorphine, Nalorphine,…

3- Antagonists: Naloxone, Naltrexone, Doxapram, …

 Intravenous Anesthetics
 Agonist opioid drugs:

 Have linear Dose-Response relationship

 Stimulate µ and К receptors
 Antagonized by Naloxone and Nalorphine

 Agonist/Antagonist opioid drugs:

- Have a plateau or bell shaped Dose response curve

- Antagonists at µ receptor above low dose.
- Full or partial agonists at К receptor.
- Antagonized by Naloxone but not by Nalorphine.
 Intravenous Anesthetics
 Antagonist opioid drugs

- Naloxone has a higher affinity for µ receptor than for other

opioid receptors.
- Doxapram is used to treat the respiratory depression caused by
Buprenorphine since its effects are only partially reversed by
Naloxone.
 Intravenous Anesthetics
Receptor Clinical effect Agonist examples
µ (mu) - Supra-spinal analgesia (µ-1) Morphine
- Respiratory Depression (µ-2) Met-enkephalin
- Physical dependence Beta endorphin
- Muscle rigidity Fentanyl
К (kapa) - Sedation Morphine
- Spinal analgesia Nalbuphene
Butorphanol
Dynorphins
Oxycodone
б (delta) - Analgesia Leu-Enkephalin
- Behavioral Beta endorphin
- Epileptogenic
σ (sigma) - Dysphoria Pentazocine
- Hallucinations Nalorphine
- Respiratory stimulation Ketamine?
 Intravenous Anesthetics
Pharmacokinetics
 Distribution half lives of all opioids are fairly rapid: 5-20
minutes.
 Re-distribution is responsible for termination of action of small
doses
 Morphine has low fat solubility accounting for its slow onset and
prolonged duration of action.
 Most opioids depend on the liver for biotransformation, with
high hepatic extraction ratio.
 Morphine has both active and inactive metabolites
 Pethidine (Meperidine) is metabolized to the active
noremeperidine.
 Remifentanyl has a unique ester structure  rapid ester
hydrolysis: terminal elimination half life of 10 minutes.
 Intravenous Anesthetics
 Excretion of end products of opioids metabolism is mainly
through the kidney
 Noremeperidine has an excitatory effect on CNS leading to
Myoclonic activity and seizures that are not reversed by
Naloxone
 A late secondary peak in Fentanyl plasma level may occur 4
hours after last IV dose due to enterohepatic recirculation and
release of sequestered drug.
 Morphine-3-glucuronide is partly excreted in bile and cab be
broken down by intestinal bacteria, releasing morphine that may
be reabsorbed by Enterohepatic recirculation.
 Intravenous Anesthetics
CVS
 In general, Opioids do not
seriously impair the cardiovascular
System.
Meperidine ↑H/R, ↓cardiac contractility, Histamine release in some
individuals
Morphine ↓H/R at high doses (vagus mediated), histamine release

Fentanyl, ↓H/R at high doses

sufentanyl,
Remifentanyl
alfentanyl
Combination ? Significant myocardial depression
with other
anesthetics
 Intravenous Anesthetics
Respiratory
 Depress ventilation, particularly respiratory rate.
 ↑Resting PaCO2 with blunted ventilatory response to CO2
challenge.
 Apneic threshold is elevated.
 Hypoxic drive is decreased.
 Histamine release - bronchospasm: (Morphine and
Meperidine).
 Chest wall rigidity: Fentanyl, sufentanyl, alfentanyl.
 Opioids effectively blunt the airway reflexes to airway
management.
 Intravenous Anesthetics
Cerebral
 Opioids are the mainstay of intra-operative pain management ( powerful
analgesics).
 In normal brains, Opioids- in general- reduce cerebral Oxygen
Consumption, blood flow, and intracranial pressure, but to a much lower
degree than barbiturates or benzodiazepines.
 Meperidine:? EEG activation.
 Stimulation of CRTZ Nausea & Vomiting.
 Opioids do not reliably produce amnesia.
 Opioids are recently effectively used in intra- thecal and epidural spaces
for analgesia.
 Meperidine: has local anesthetic qualities and effectively used
to treat shivering.
 Intravenous Anesthetics
Gastro-intestinal
 Contraction of sphincter of Oddi and biliary spasm .
 Constipation.

Genitourinary: Urine retention

Endocrine:
 More effective than inhalational anesthetics in blocking the
stress response to surgical stimulation.

Ophthalmic: Miosis.
 Intravenous Anesthetics
Concurrent use of:
 MAOI drugs Respiratory arrest, hypertension or
Hypotension, coma and Hyperpyrexia. (esp. with
Meperidine).
 Other Hypnotic and sedative drugs synergism in sedative,
cardiovascular, and respiratory effects.
 Erythromycin: impairment of alfentanyl biotransformation.
 Intravenous Anesthetics
 Dexmedetomidine
 Is a sedative medication used by intensive care units and
anesthesiologists, and is marketed under the brand name
Precedex
 It is relatively unique in its ability to provide sedation without
causing respiratory depression
 Its mechanism of action is agonism of alpha-2 receptors in
certain parts of the brain
 It is the S-enantiomer of medetomidine
 Has sedative, analgesic, sympatholytic, and anxiolytic
effects
 Intravenous Anesthetics
 Reduces the volatile anesthetic, sedative and analgesic
requirements of the patient without causing significant
respiratory depression
 Effective treatment for the dangerous cardiovascular symptoms
of cocaine intoxication and overdose
 Has an opiod sparing effect
 The recommended dosage is 1 µg/kg IV over 10 min
 Maintenance infusion rate of 0.2-0.7 µg/kg/hr
 Metabolized in the liver and its metabolite is eliminated in the
urine
 Side effects include bradycardia, heart block and hypotension
 Summary of Intravenous Anesthetic Agents
Drug Speed of Induction Main Unwanted Notes
and Recovery Effects

Thiopental Fast (accumulation occurs, Cardiovascular and Used as induction agent declining.
giving slow recovery) respiratory depression Decreases cerebral blood flow and
Hangover O2 consumption.

Etomidate Fast onset, fairly fast Excitatory effects during Less cardiovascular and
recovery induction and recovery, respiratory depression than with
Adrenocortical suppression thiopental, Causes pain at injection
site
Propofol Fast onset, very fast Cardiovascular and Most common induction agent.
recovery respiratory depression. Pain Rapidly metabolized; possible to
at injection site. use as continuous infusion.

Ketamine Slow onset, after-effects Psychotomimetic effects Produces good analgesia and
common during recovery following recovery, amnesia
Postoperative nausea,
vomiting and salivation
Midazolam Slower than other agents Little respiratory or cardiovascular
depression
Thank you