General Anesthetics Inhaled general anesthetics
loss of consciousness exhibiting each one of the
following physiologic components:
(2) Amnesia
Attenuation of autonomic responses to noxious
stimulation
Immobility in response to noxious stimulation
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Most general anesthetic agents are incomplete anesthetics
Analgesia and muscle relaxation may need to be supplemented with other drugs
Conscious sedation is an altered or diminished state of consciousness with each of the following physiologic components: (1) analgesia
(2) amnesia
(3) retained responsiveness to verbal commands
A reduction in skeletal muscle tone is not required and the danger of hypoxia is reduced. Only a limited suppression of sensory and autonomic reflexes is observed.
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Diethyl ether (ether)
No longer used today.
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Stage 1. Analgesia (Without loss of consciousness)
CNS mild depression at cortical neuron
Loss of pain sensation
Suitable for minor surgical procedures that do not require significant neuromuscular relaxation.
Stage 2. Delirium (Excitement stage)
CNS motor neuron depression,
Urination, delirium, uncontrolled muscle movements occur, amnesic!
Heart rate and B.P. also increase.
Efforts are made to limit the duration and severity of the stage and end with reestablishment of regular breath.
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Stage 3. Surgical Anesthesia Dividing 4 stages
(1) Loss of spinal reflexes
(2) Decreased muscle reflexes
(4) Loss of most muscle tone characters
regular breathing, loss of many reflexes, roving eyeball movements.
Stage 4. Respiratory (medullary) Paralysis
(1) Respiratory and blood pressure may become severely depressed
(2) vasomotor paralysis occurred (cardiac depression)
(3) no eye movement
Overdose or toxic level
stages of general
MAC (minimum alveolar concentration, analogous to ED50)
The alveolar partial pressure that required to produce immobility in 50% of people subjected to a surgical incision at 1 atomosphere.
The lower the number, then the higher the potency, and a relative low partial pressure will be sufficient to cause anesthesia.
Examples
10% MAC means 50% adult reach surgical stage at 0.1 atm.
Isoflurane: MAC 0.0114 atm (1.14%)
Nitrous oxide: MAC 1.01 atm (101%)
In general,1.3-fold MAC are suitable for surgical procedure (99% adult included)
Inhalation anesthetic potency
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Solubility
The ideal general anesthetic has low solubility in blood conveyed by blood/gas (in the lung) partition coefficient,
Drug has low blood solubility quick onset (easy to tissue!)
Table 22.1 properties of the inhaled anesthetics
Anesthetic MAC blood:gas oil:gas
N2O 104 0.46 1.1
Halothane 0.75 2.4 137
Enflurane 1.68 1.8 98
Methoxyflurane 0.16 16.0 970
Isoflurane 1.15 1.43 90.8
Sevoflurane 2.10 0.65 50
Desoflurane 7.3 0.42 18.7
Xenon 71 0.12 1.9
A.CHCl2CF2OCH3
B.CF3CHBrCl
C.CHClFCF2OCHF2
D.CF3CHClOCHF2
13
Oil: gas partition coefficient
The oil could be olive oil, blood, brain tissue, etc. at STP (25 oC, 1 atm).
Unit: LgasLoil -1 atm-1 or atm-1.
(oil/gas) increases, MAC decreases.
x partial pressure = concentration of anesthetic e.g. N2O, = 0.47 LN2OLblood
-1 atm-1, partial pressure = 0.5 atm
then, conc = 0.5 x 0.47 = 0.24 LN2OLblood -1 or 9.8 mM (dividing
by 24.5 L/mol); doubling the partial pressure will double the conc.
If a gas has high (means low partial pressure) need large amount of gas to be transferred to change the partial pressure
Most inhaled anesthetics has similar solubility in lean organs, but in fat vary as predicted by their oil:gas coeff.
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15
solubility in oil increases
The constant that represents the conc of anesthetic
at 1 MAC is 1.3 Lgas / Loil, or 0.05 M (dividing by the
volume of one mole gas, 24.5 L/mole)
If we know MAC = 1.3 / (oil/gas)
Low solubility in blood = fast induction and recovery
High solubility in blood = slower induction and recovery
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Stereochemical aspects
carbon.
simple lipid solubility theory
directly the Na-channel
Glycine
GABA
chains
20
21
Non-NMDA receptors: more permeable to Na+ & K+
than Ca2+
Kainate (K)-receptor
AMPA receptor
Metabotropic receptors
Activated by ACPD.
NMDA receptors Excitatory amino acid glutamate increases the
conductance to Na+.
Halothane blocks glutamate-stimulated depolarization of neurons
Isoflurane decreases glutamate release
Mostly remain silent at resting membrane potential,
Crucial for the induction of specific forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD)
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K-Channel
Enhance K-channel decrease of neuronal excitation
a2 agonist: dexmedetomidine modulates K-channel via G- protein coupled receptor.
Cl-channel
Drugs allosterically modulate GABAA receptors to open Cl- channel. Isoflurane and halothane enhance GABAA receptor.
N
N
CH3
CH3
H3C
H
H
Dexmedetomidine
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ion channels
Structural features of the homologous GABAA receptor and nicotinic acetylcholine receptor. Each receptor contains five subunits (the front one is removed for clarity) that cross the lipid bilayer and are arranged around a central ion channel. Each subunit is thought to have four transmembrane elements, as indicated in the left-most subunit. Agonist binding sites are thought to be formed at subunit interfaces in the extracellular portions of the receptors.
In the upper right hand panel, nicotinic acetylcholine receptors are excitatory channels permeable to cations. Their activation depolarizes neurons and muscles, making the generation of action potentials more likely.
In the lower right-hand panel, excitatory postsynaptic currents activated by acetylcholine are noncompetitively inhibited by anesthetics, and in single-channel currents, anesthetics cause frequent closures or block the opening of currents.
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ion channels
In the upper left-hand panel Activation of GABAAR hyperpolarizes neurons, making
the generation of action potentials less likely.
In the lower left-hand panel Inhibitory postsynaptic currents activated by GABA are
prolonged by anesthetics, resulting in supranormal chloride influx and reduced excitability.
GABA concentration–response curves are shifted leftward, so that low concentrations of GABA in cerebrospinal fluid may produce a chloride leak by means of extrasynaptic GABAA receptors, suppressing neuronal excitation. Studies involving chimeras and amino acid mutations suggest that anesthetics interact at GABAA-receptor sites formed between several transmembrane elements.
Anesthetics
rate is usually unchanged or slightly increased
Respiration
decreases medullary responsiveness to both
arterial carbon dioxide and hypoxic drive
mechanisms
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anesthesia with halogenated hydrocarbon
skeletal muscle contracture, accelerated
sarcoplasmic reticulum.
Oxidative decomposition to HCl, HBr, COCl2.
preservative: thymol to minimize decomposition.
permeate into rubber of device, tarnish metals, e.g. Fe,
Al, Cu etc.
Potent inhalational anesthetic
MAC of 0.75%
Prolonged emergence
Systemic Effects:
Depresses myocardium
Halothane Toxicities
Due to metabolites
Malignant Hyperthermia- - 1/60,000
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Not attack metals, but can permeate rubber (Par. Co. = 74),
prolong induction/recovery times as seen with halothane
Not used during labor (due to relaxing uterus)
A constitutional isomer of isoflurane
Isoflurane (1981) F3C-CHCl-O-CHF2 Fewer CV effects than eflurane
More pungent odor irritation to the throat/ respiratory tract
Safe with epi without concern for arrthymia
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Rapid induction and recovery popular in outpatient
surgical procedure
Not associated with hepatotoxicity or nephrotoxicity
Sevoflurane (1996) (CF3)2CH-O-CHF2
In comparison to older agents, ex. isoflurane or halothane, the most
important property of sevoflurane is its low solubility in the blood
more rapid uptake and induction than the 'older' agents, improved
control of depth of anaesthesia and faster elimination and recovery.
Advantage in pleasant odor, not irritating to respiratory tract
Low incidence of hepatotoxicity or nephrotoxicity.
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Halothane: CHBrCl-CF3
malignant hyperthermia, body temperature raises due to
consumption of O2 & CO2 increases
Methoxyflurane: CHCl2CF2-O-CH3
Most potent agents (MAC, 0.16%)
The highest solubility in blood induction/recovery slow
Chemically unstable & toxic metabolites seldom used in
clinic
A.CF3CHBrCl
B.CHClFCF2OCHF2
C.CHCl2CF2OCH3
D.CF3CHFOCHF2
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Laughing gas, N2O ( ?)
mostly used in dental and labor procedures used in combination to decrease the dose of other anesthetics
Toxicity: inactivate the cofactor (vitamin B12) of methionine synthetase and thymidylate synthetase, resulting in impairment of myelin and DNA synthesis.
Ethyl ether, Et-O-Et
Limited use in human
anesthetics
Although halogenations of hydrocarbons and ethers increase anesthetic potency, it also increase the potential for inducing cardiac arrhythmias in the following order F<Cl<Br<I
Ethers that have an asymmetric halogenated carbon tend to be good anesthetics (such as enflurane).
Halogenated methyl ethyl ethers (enflurane and isoflurane) are more stable, are more potent, and have better clinical profile than halogenated diethyl ethers.
Fluorination decrease flammability and increase stability of adjacent halogenated carbons.
Complete halogenations of alkane and ethers or full halogenations of end methyl groups decrease potency and enhances convulsant activity. Fluoroethyl (CF3CH2OCH2CF3) is a potent convulsant, with a median effective dose (ED50) for convulsions in mice of 0.00122 atm.
The presence of double bonds tends to increase chemical reactivity and toxicity.
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Supplement general anesthesia
Maintain general anesthesia
Stimulates GABAA receptor
Poor water solubility; uses as 1 ~ 2% emulsion.
Rapid onset, short duration of action, rapid smooth recoveries w/o hangover‘
Mild to moderate hypotension, may produce bradyarrhythmias
Respiratory depressant, may produce apnea
Poor analgesic (need high dose)
OH
Propofol
Fospropofol
formulation concerning for propofol
propofol (+ formaldehyde & phosphate)
form), cause longer-lasting effects
Less hallucination than PCP
Side effects: interfere with steroidogenesis
Clomethiazole
As hypnotic inducing sleep latency after long-term use
N
N
O
EtO
The ultra-short acting barbiturates are useful for the induction of surgical anesthesia, producing unconsciousness within 10 - 30 seconds following IV administration.
If administered too rapidly or in large dosages, both respiratory and cardiovascular depression may be observed.
NH
Dissociative anesthetics
Dissociative anesthetics
Ketamine: inducing amnesia; less potent than PCP; short duration, thus not easy to be detected from urine
PCP: phencyclidine (peace pill, angel dust, --)
Dextromethorphan (with high dose):
producing feelings of detachment-dissociation from the environment and self with a cataleptic gaze! (a dissociation between the thalamocortical and limbic system)
But these mind-altering effects are not hallucinations.
MOA: altering distribution of the glutamate throughout the brain.
(Glutamate is involved in perception of pain, responses to the environment, and memory.)
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perceives time, motion,
think and communicate
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DXM
"I would stay up two, three days at a time, just re-dosing myself. I was pushing almost two dosing myself. I was pushing almost two- thousand thousand milligrams, which is, I mean, enough for four or milligrams, which is, I mean, enough for four or five people to take at a time. The more I took, the five people to take at a time. The more I took, the better I felt because I was really chasing better I felt because I was really chasing something, I guess you'd say. I was trying to get something, I guess you'd say. I was trying to get back to that same feeling from the first time I back to that same feeling from the first time I experienced it. But the more I took, the better I experienced it. But the more I took, the better I felt, the more relaxed I became. Well, at least I felt, the more relaxed I became. Well, at least I thought I was relaxed. My friends and family all thought I was relaxed. My friends and family all said that I was off the wall and that I was actually said that I was off the wall and that I was actually insane."
-Shawn, age 23 Shawn, age 23
www.dxmstories.com
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CH 3
CH 3
NH 2
Narcotic analgesics: morphine or meperidine Clinic use: reduce pain, anxiety, the amounts of
anesthetics used.
Anticholinergics: atropine or scopolamine inhibit secretion in respiratory tract & to avoid
cholinergic-mediated hypotension and slower heartbeat
Muscle relaxants: (rapid onset): succinylcholine or mivacurium
(long-acting): pancuronium, vecuronium
Benzodiazepines - Diazepam, midazolam, lorazepam
The BZDs are useful for the induction of surgical anesthesia or conscious sedation. Midazolam is the preferred (drug of choice). The BZDs provide sedation and amnesia, but lack analgesic activity.
The actions of the BZDs can be terminated by the specific BZDs receptor antagonist, flumazenil.
a2-adrenergic agonists: clonidine or dexmedetomidine
provides sedation, reducing the amount of dose of anesthetic and analgesic.
Actions: stimulating a2-receptor in the locus coeruleus ().
N
N
Also a hypnotic for short term effectiveness for sleep induction
Onset: 1 hr; duration: 4~8 hr
A weak acid (pKa 3.5~4.4)
Active form: trichloroethanol (T1/2: 8~ 11 hr)
Exerts barbiturate-like effects on GABAA receptor
Cl H Cl
ether
A methoxyflurane
B halothane
C isoflurane
D sevoflurane
A
B
C
D
A
B
C
A.Isoflurane
A. Desflurane
B. Halothane
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Three general objectives
techniques
techniques that minimize the surgical stress
response
without loss of consciousness
Same:
Blockade of nerve conductance loss of motor and sensory functions
Difference:
without impairment of consciousness and vital central functions.
binding to sodium channel, reducing Na+ passage thru pores, but without affecting the resting potentials
General anesthetics
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Cocaine:
the active principle of the coca leaf, anesthetic effects on the tongue
First use by an ophthalmologist in 1884.
Hydrolytic products: ecgonine, benzoic acid, methanol.
Procaine, benzoic acid derivative, is the prototype of local anesthetic.
Low potency, short duration
adding epinephrine: prolong duration
potency.
O N
N H
amide-type agent
N H
Phenol
with a minimal effect on the motor fibers.
Rapid onset
current mainly by protonated form of anesthetic agents
Most anesthetic agents, pKa 7.5 ~ 9.0
At pH 7.4, the % of protonated form (by Henderson-
Hasselbalch Eq: pKa = pH + log [acidic]/[basic] )
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amide or ester linkage
incidence of allergy
lipophilic portion
increasing affinity for the binding to
the Na+ channel
Na+ channel
amide-type local anesthetic drugs
center Lipid center: carbocyclic or heterocyclic
Hydrophilic center: 2- or 3-amines
Ester and amide are bioisosteric
Bridge: short CH chain or oxygen, nitrogen or sulfur
As increasing molecular weight and lipid solubility becoming more potent as local anesthetics
demonstrating prolonged binding to the sodium channel
more toxic when released into the systemic circulation
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the anesthetic actions
pain transmitted by myelinated Ad fibers
Order of onset: unmyelinated C fibers > small
myelinated fibers > large fibers
Most anesthetics pKa ~ 8.5, slightly soluble in water;
most marketed as aqu solution containing
vasoconstrictors!
Vasoconstrictors
related to vasopressin)
Agents with low pKa and high lipid solubility more
rapid onset
Time taken for the onset be reduced by the use of
H2CO3 form of drug! no increasing of toxicity;
reducing the pain associated with injection
Doubling a dose does not double the time of action
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excitability, and the conduction of the myocardium
Sometimes, low conc admin by infiltration CV
collapse & death
Some agents act as antiarrhythmic by blocking Na, K, Ca
channels of heart muscle
Amide types
(2) Mepivacaine - moderate duration of action
(3) Bupivacaine - long duration of action
Hint: All the amide local anesthetic contain an i in the
prefix before -caine. The ester local anesthetics do not
contain an i in the prefix portion of the generic name.
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Pharmacokinetics
Duration of action: determined by its retention at the site of administration
Termination of local anesthesia: dependent upon tissue blood flow
Toxicity: determined by its plasma conc.
All local anesthetics (with the exception of cocaine) produce local vasodilatation Vasoconstrictors such as Epi (1:100,000),
phenylephrine (1:20,000), or NE (1:100,000) prolong the duration of action of local anesthesia, esp for short- acting agents, e.g. procaine and lidocaine
The slower systemic absorption of a local anesthetic also reduces plasma drug conc, reducing CV and CNS toxicity.
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Metabolism
p-aminobenzoic acid (PABA): competitively inhibits the actions of sulfonamides
Amide local anesthetics are metabolized in the liver.
Oxidation (CYP1A2) or N-dealkylation (CYP3A4)
Many of the metabolites of amide local anesthetics retain the ability to produce grand mal seizures and depress respiration.
Only a small fraction of local anesthetics (< 5%) are excreted unchanged in the urine.
Metabolic scheme of lidocaine
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CYP3A4
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Pharmacodynamics
As a general rule, small unmyelinated nerve fibers with slow conduction mediating pain are more sensitive to local anesthetics than larger myelinated nerve fibers with rapid conduction, mediating skeletal muscle contraction and proprioception().
The following functions are given in order of their sensitivity to blockade by local anesthetics: (1) pain
(2) touch
The toxicity of local anesthetics is determined by :
(1) the properties of the individual local anesthetic
(2) the rate of absorption of the local anesthetic into the
systemic circulation
uncommon
aminobenzoate (procaine, tetracaine).
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containing a p-aminobenzoic acid moiety, a common heptan () mediating anaphylaxis for sulfonamides, diuretics, and ester type local anesthetics.
For most forms of local anesthesia, procaine should not be used without a vasoconstrictor.
has largely been replaced by lidocaine, an amide local anesthetic
Tetracaine –
a long-acting ester-type
more potent and more prolonged anesthesia than procaine at the cost of increased systemic toxicity.
O N
N H
two metabolites lack anti-arrhythmic drug activity while retaining
CNS stimulatory activity.
administration of a vasoconstrictor
Avoid use lidocaine-epi mixture in areas with limited vascular supply
to prevent tissue necrosis
use of a vasoconstrictor prolongs its duration of action and
reduced peak systemic lidocaine conc
N H
Tocainide
Mepivacaine
Bupivacaine
a potent vasoconstrictor and has extreme abuse liability.
When used in the eye (cornea) or applied to mucous membranes repeated, the drug produces ischemic necrosis and destroy the cornea or nasal septum. This necrosis can also occur with local infiltration to produce nerve block.
An effective CNS stimulant and is the poster child of self- administering drugs with a high abuse potential.
Systemic administration is associated with hyperpyrexia (fever), hypertension, stroke, and sudden cardiac death.
Its sole legitimate medical use is restricted for surgery requiring incisions or manipulation of mucous membranes.
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Mepivacaine
duration of action
block as well as for spinal and epidural anesthesia.
has a greater systemic toxicity than lidocaine, but is
less toxic than bupivacaine.
duration of action.
significant amounts are allowed to enter the
systemic administration.
A Lidocaine
B Procaine
C Prilocaine
D Dibucaine
A.3-hydroxylidocaine
B.glycinexylidide
C.monoethylglycinexylid
ide
D.2,6-xylidine
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102
Articaine
Quick onset, short duration
Metabolism: by plasma cholinesterase
Study question:
with lidocaine and other amide-type local
anesthetics. Explain.
Articaine
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Benzocaine
lacking a positive charge, high concentrations are needed for efficacy (>10 %)
Used topically or in combination with menthol or phenol as OTC, i.e. gel, cream, ointment, ---
Chloroprocaine
Use by infiltration or regional and central nerve block
Cl-atom increases the rate (3-fold) of hydrolysis of ester by esterase
May be used in maternal or neonatal patients with minimal placental passage of chloroprocaine
O N
NH 2
Procaine, R = H (pKa 8.8) Chloroprocaine, R = Cl (pKa 9.0)
Benzocaine, R = C2H5 (pKa 2.8)
Butamben, R = n-C4H9 (pKa 2.5)
(103-1)
A. Lidocaine
B. Benzocaine
C. Bupivacaine
D. Cocaine
tissue without regard to the course of
cutaneous nerves.
Nerve block
anesthetic into tissue immediately adjacent to
a peripheral nerve or nerve plexus
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as the drug is a direct vasoconstrictor resulting
from an inhibition of norepinephrine uptake into
sympathetic neurons.
iontophoresis, a direct electrical charge forcing the
drug into cutaneous tissues.