02 General Anaesthetic Agents

02 General Anaesthetic Agents

(2 Hours)

• Hydrocarbons and halogenated hydrocarbons

• Ethers and alcohols• Ethers and alcohols

• Ultra-short acting barbiturates

General Anaesthetics

• General anesthetics depress the central nervous system to a

sufficient degree to permit the performance of surgery and

other noxious or unpleasant procedures

• Not therapeutic or diagnostic

• General anesthesia may be defined as a state which includes

1. A reversible loss of consciousness

2. Inhibition of sensory and autonomic reflexes 2. Inhibition of sensory and autonomic reflexes

(including nociceptive reflexes)

3. Skeletal muscle relaxation

4. Anterograde amnesia (upon recovery)

[the extent to which any individual anesthetic drug can exert

these effects depend upon the drug, the dose, and the

clinical circumstances}

General Anaesthetics

• General anesthetics are drugs that act in the CNS. They produce reversible loss of consciousness, thereby causing a generalized loss of sensation.

• The general anesthetic effect involves the following components:

- loss of arousability in response to noxious stimuli – sedation and loss of anxiety

- loss of pain sensation (analgesia) in response to noxious stimuli

- loss of mobility (immobility) in response to noxious stimuli –- loss of mobility (immobility) in response to noxious stimuli –skeletal muscle relaxation

- loss of awareness and memory (amnesia)

- attenuation of autonomic responses to noxious stimuli i.e. troublesome reflexes

Not all anesthetics bring about all of these. Ex: barbiturates are not analgesics, but they will put you to sleep

SIGNS AND STAGES OF GENERAL ANESTHESIA (as described for

diethyl ether anesthesia)

1. Stage of analgesia:

• Pain sensation is lost, Consciousness is still kept, unaltered pupils

• Minor operations (e.g., removal of pharyngeal tonsils) can be performed in this stage.

2. Stage of delirium – consciousness is lost, however, there is:

• Disturbed consciousness: incoordinate movements, • Disturbed consciousness: incoordinate movements, incoherent talk

• Motor hyperactivity: muscle tone is increased, jaw becomes set, irregular breathing, vomiting, defecation

• Sympathetic hyperactivity: hypertension, tachycardia, dilation of pupils

• Hyperactivity is caused by blockade of small inhibitory neurons, such as the GABA-ergic Golgi II cells.

Stages of Anaesthesia

3. Stage of surgical anesthesia – in which surgery can be performed

• It starts with return of regular breathing. This stage is divided into 4 planes.

• As the anesthesia deepens, 3 changes occur gradually:

� The intercostal ventilation weakens, then ceases, and only the diaphragmatic ventilation remains.

� The pupil (constricted in plane 1) dilates gradually.

� Various reflexes disappear: - Corneal reflex: in plane 2 (no blinking upon stimulation of the cornea)upon stimulation of the cornea)

- Peritoneal reflex: in plane 3 (no abdom muscle contr upon peritstimulation)

- Pupillary reflex: in plane 4 (no pupillary constriction upon light)

• Loss of the pupillary reflex is a warning sign; the sign of hypoxia!!!

• Other warning signs:

- decreased BP, rapid pulse

- shallow, irregular ventilation, cyanotic skin

4. Stage of medullary paralysis

• Respiration ceases (respiratory center paralysis)

• The heart stops (vasomotor center paralysis)

Note: Inhalation anesthetics have a low therapeutic index, making these

the most dangerous drugs in clinical use!

To rescue the patient: Stop anesthetic administration, provide O2, apply

cardiopulmonary resuscitation!

To prevent stage-4: Monitor cerebral function using indices of EEG

activity

• These stages appear in diethyl ether anesthesia (no longer practiced).• These stages appear in diethyl ether anesthesia (no longer practiced).

• In modern anesthesia, the stage of delirium does not develop (i.e.,

"induction is smooth") because the anesthesia is induced rapidly with

an: - i.v. anesthetic (e.g., thiopental, propofol), or with a - rapidly acting

inhalation anesthetic (e.g., sevoflurane).

• Combination of i.v. and inhalation anesthetics is called balanced

anesthesia: the favorable properties of each agent are exploited while

the unfavorable ones are minimized.

Pre-anesthetics

• Preanesthetic medications – drugs given generally prior to

anesthesia (may be given during or after, as well) in order

to:

� Decrease anxiety

� Sedation� Sedation

� Provide amnesia

� Relieve pre-and post-operative pain

� Inhibit secretion

� Antiemetic

Preanesthetic Agents

Drug Classification Generic Name Desired Effect

Benzodiazepines Diazepam

Midazolam

Reduce anxiety, Sedation, Amnesia,

“Conscious sedation”

Antihistamines Hydroxyzine Sedation

Opioid analgesics Morphine

Meperidine

Fentanyl

Sedation to decrease tension,

anxiety, and provide analgesia

Fentanyl

Remifentanil

Phenothiazines Promethazine Sedation, antihistaminic, antiemetic,

decreased motor activity

Anticholinergics Atropine

Glycopyrollate

Inhibit secretion, bradycardia,

vomiting, and laryngospasms

GI Drugs Ondansetron

Ranitidine

Metoclopramide

Antiemetic

Decrease gastric acidity

Decrease stomach contents

Classification:

Minimum Alveolar Concentration

• The minimum alveolar concentration (MAC) is defined as the

concentration at 1 atmosphere of anesthetic in the alveoli

that is required to produce immobil ity in 50% of adult

patients subjected to a surgical incision.

• A further increase to 1.3 MAC frequently will cause immobility

in 99% of patients.

• At equilibrium, the concentration (or partial pressure) of an • At equilibrium, the concentration (or partial pressure) of an

anesthetic in the alveoli is equal to that in the brain, and it is

this concentration in the brain that probably most closely

reflects the concentration at the site responsible for the

anesthetic actions.

• Thus, the MAC often is used as a measure of the potency of

individual anesthetic agents

Properties of the Inhaled Anesthetics

Minimum Alveolar Concentration

Minimum Alveolar Concentration

• When used in combinations, the MACs for inhaled anesthetics

are additive. For instance, the anesthetic depth achieved with

0.5 MAC of enflurane plus 0.5 MAC of nitrous oxide is

equivalent to that produced by 1.0 MAC of either agent alone.

• The combination of two anesthetics is a very common

practice, because this technique allows a reduction in the practice, because this technique allows a reduction in the

patient exposure to any one of the individual agents, thereby

decreasing the likelihood of adverse reactions.

• Many factors can influence the MAC via a number of different

mechanisms

Factors that may affect MAC:

Theories of Anaesthetic Action

• Anesthetics are a mainstay of modern medicine, but their

molecular mechanism of action is still not precisely known

• No single theory adequately explains how anesthetics exert their

pharmacological effects

• Our understanding on the mechanism of action of general

anesthetics has developed in stages:

1. Early 1900s:

Meyer-Overton Theory: Physico-chemical theoryMeyer-Overton Theory: Physico-chemical theory

• In the early 1900s Hans Meyer and Charles Overton suggested that

the potency of a substance as an anesthetic was directly related to

its lipid solubility, or oil/gas partition coefficient. This has commonly

been referred to as the “unitary theory of anesthesia.”

• They used olive oil, octanol and other “membrane-like” lipids to

determine the lipid solubility of the agents available at the time.

• Compounds with high lipid solubility required lower concentrations

( i.e., lower MAC) to produce anesthesia.

Theories of Anaesthetic Action

• This correlation is accurate for a broad range of general

anesthetics: alkanols, volatile agents, and barbiturates

• Also, volatile anesthetics are generally additive in their

effects: a mixture of a half dose of two different volatile

anesthetics was in fact equal to a full dose of either drug in

isolation

• However, it does not explain the drugs’ mechanism of action.• However, it does not explain the drugs’ mechanism of action.

• i.e. General anesthetics act by being dissolved in the lipid

membranes of the CNS neurones and anesthesia develops

when the anesthetic reaches a critical concentration in the

neuronal cell membrane

• However, it was unclear what GAs did in the membrane of

CNS neurons to cause anesthesia.

Theories of Anaesthetic Action

• Speculations: GAs cause physicochemical alterations. For example, they expand the membrane’s lipid layer upon being dissolved in it; increase the membrane fluidity by disturbing the ordered lipid structure;

• induce formation of water crystals (called clathrates) in the membrane; interact with the hydrophobic domains the membrane; interact with the hydrophobic domains of integral membrane proteins, e.g. ion channels

• In support of this theory, it was found that at high pressures (40–100 atmospheres) , the anesthetic actions of many of these agents could be partially reversed, presumably by compressing membranes back to their original conformation

Anomalies with unitary theories

• the unitary theory of anesthesia cannot adequately explain the

mechanism of action of the inhaled anesthetic drugs for a

number of reasons:

i) Some compounds do not obey the Meyer and Overton rule. For

example, not all highly lipid-soluble substances are capable of

producing anesthesia e.g. some halogenated alkanes predicted

to be potent anaesthetics based on their lipid solubility fail to to be potent anaesthetics based on their lipid solubility fail to

suppress movement in response to noxious stimulation at

appropriate concentrations. These compounds are therefore

termed non-immobilizers

The inhaled anesthetics do disrupt the lipid bilayer but it is

unclear if they make enough changes to effect cell signaling

Anomalies with unitary theories

(ii) The ability of general anaesthetics to perturb lipid membranes in

vitro can be reproduced by a temperature increase of less than

1oC, a change well within the physiological range and clearly not

sufficient to induce loss of consciousness per se.

(iii) Enantiomers have identical physicochemical effects in an achiral

environment (e.g. the lipid bilayer). However, in vitro and in

vivo studies demonstrate that enantiomers of many general

anaesthetics do not produce identical clinical effects. anaesthetics do not produce identical clinical effects.

• For example, the R isomer of etomidate is 10 times more potent

than its S isomer at potentiating GABA-A receptor activity.

• These differential effects suggest that the primary site of action

of such anaesthetics is not the lipid bilayer and provide

compelling evidence for specific interactions with

stereoselective binding sites (i.e. within proteins).

Anomalies with unitary theories

(iv) According to Meyer and Overton, the addition of

methylene groups to a homologous series of long chain

alcohols, or alkanes, should increase their lipid solubility and

thereby produce a corresponding increase in anaesthetic

potency. However, at a certain chain length (n = 10) addition

of further methylene groups does not produce the expected

increase in anaesthetic potency, i.e. there appears to be a ‘cut increase in anaesthetic potency, i.e. there appears to be a ‘cut

off’ effect above a certain molecular volume which is

indicative of anaesthetic agents interacting with binding

site(s) of finite dimensions.

Receptor Theories of General Anaesthesia:

• In a landmark series of experiments in the early 1980s, Franks

and Lieb demonstrated that the relationship reported by

Meyer and Overton could be reproduced using a soluble

protein.

• They demonstrated that a range of general anaesthetics acted

as competitive antagonists of the protein firefly luciferase.

Remarkably, inhibition of luciferase was directly correlated Remarkably, inhibition of luciferase was directly correlated

with anaesthetic potency providing persuasive evidence that

general anaesthetic drugs could selectively interact with

proteins.

• Of course, the next major hurdle involved identifying which

proteins within the mammalian CNS were responsible for

mediating the dramatic behavioural effects of general

anaesthetic drugs

Ion Channel and Protein Receptor Hypotheses

• More recently, investigators have determined the effects of anesthetics

on a number of protein receptors within the central nervous system.

• Features that support the likelihood of an interaction with a protein

include:

1) the steep dose–response curves observed,

2) the stereochemical requirements of various anesthetics,

3) the finding that increasing the molecular weight and corresponding

lipid solubility of an anesthetic may actually decrease or abolish

anaesthetic activity, and anaesthetic activity, and

4) the finding that specific ion channels and neurotransmitter receptor

systems are required for most of the observed effects of the anesthetics.

• What appears to be emerging as a central theme for the mechanism of

action of general anesthetics involves the interact ion of the anesthetics

with receptors that allosterically modulate the activity of ion channels

(e.g. , chloride and potassium) or with the ion channel directly (e.g. ,

sodium) .

• Many other mechanisms also are emerging to help explain the

mechanisms of act ion of the general anesthetics.

Ion Channel and Protein Receptor Hypotheses

• In the 1980s, Benzodiazepines (BZD) and barbiturates were discovered to produce hypnotic effect by activating the GABA-A receptors. GABA-A receptor (GABA-gated Cl- channel) activation causes Cl- influx, neuronal hyperpolarization and is inhibitory.

• GAs bind to GABA-A receptor in a hydrophobic pocket located in the tran-smembrane domain and stabilize the open form of the Cl-

channel – May this be a major mechanism underlying the 78-yr-old lipid theory?

• In the 1990s, it was discovered that it was not only BZD and • In the 1990s, it was discovered that it was not only BZD and barbiturates that activate GABA-A receptor, but most general anesthetics as well! Moreover, GAs were also discovered to affect other ligand gated ion-channels, thereby causing neuronal hyperpolarization

• In the Early 2000s, it was discovered that GAs also activate TREK-1, a two-pore-domain background K+ channel, causing K+ efflux and neuronal hyperpolarization. TREK-1 knock-out mice exhibit resistance to several volatile anesthetics

Ion Channel and Protein Receptor Hypotheses

Ion Channel and Protein Receptor Hypotheses

• The concept today: By acting on ligand-gated ion channels and

certain K+ channels, general anesthetics hyperpolarize

neurons and thereby inhibit synaptic transmission in the CNS.

• Unlike local anesthetics, general anesthetics do not inhibit

axonal conductance, as they do not affect the voltage-gated

Na+ channels at anesthetic concentrations

• Inhibition of synaptic transmission in specific brain areas by

GAs is responsible for the 4 components of the general

anesthetic effect:

Ion Channel and Protein Receptor Hypotheses

INHALATION ANESTHETICS

GENERAL PROPERTIES:

1. Chemical properties: More or less lipid soluble hydrophobic chemicals.

Lipid solubility determines both their potency and pharmacokinetics

2. Potency: The more lipophilic, the more potent they are (= the lower is

their MAC value). Nitrous oxide never used alone – low potency

anaesthetic Lipid solubilty

oil:gas part. Coeff.

Potency MAC value,

% conc

Blood:gas part.

Coeff.

Methoxyflurane 970 0.2 12Methoxyflurane 970 0.2 12

Halothane 224 0.8 2.3

Isoflurane 99 1.2 1.4

Enflurane 98 1.7 1.8

Sevoflurane 65 2.0 0.7

Desflurane 19 6.0 0.5

Nitrous Oxide 1.4 105* 0.5

INHALATION ANESTHETICS

3. Pharmacokinetics

• Absorption: - Mechanism: diffusion across the alveolar membrane (driven

by the concentration gradient); Speed: rapid (due to large alveolar surface,

short diffusion distance, and large blood flow)

• Distribution from the blood to tissues (including the brain):

Mechanism: diffusion (an equilibrative process); Speed: depends on the

degree of lipid solubility of the anesthetic:

- Less lipophilic drugs (e.g., desflurane) are less dissolved in blood lipids →

less retained in the blood → equilibrate rapidly between the blood and less retained in the blood → equilibrate rapidly between the blood and

Sssues, including the brain → the anestheSc concentraSon in the brain is

rapidly reached → rapid induction of anesthesia (at 1.3 MAC!)

- More lipophilic drugs (e.g., halothane) are more dissolved in blood lipids

→ more retained in the blood → equilibrate slowly between the blood and

Sssues, including the brain → the anestheSc concentraSon in the brain is

slowly reached → slow induction of anesthesia (at 1.3 MAC!)

• However, one may facilitate induction by: - transiently increasing the

inhaled conc. of the anesthetic - increasing the minute ventilation (by

hyperventilation)

INHALATION ANESTHETICS

• Elimination: - Mechanism: > largely by exhalation

> halothane is also eliminated by biotransformation (20-40%; forms a reactive metabolite)

- Speed of elimination determines the speed of recovery from anesthesia after GA inhalation is stopped:

> slow for highly lipophilic anesthetics, as they are retained the brain and adipose tissue

> rapid for less lipophilic anesthetics, as they are less retained the brain and adipose tissue

Specific Inhalational Agents:

1. Volatile liquids: a). Ethers b). Halogenated hydrocarbons:

halothane (Br-, Cl- and F-substituted) – highly lipid sol. c).

Halogenated ethers: - Cl- and F-substituted (more lipid sol.):

enflurane, isoflurane - Only F-substituted (less lipid soluble):

desflurane, sevoflurane

a. Ethers: No longer used!

i) Diethyl ether: CH3-CH2-O-CH2-CH3i) Diethyl ether: CH3-CH2-O-CH2-CH3

• Diethyl ether is not used nowadays mainly because of the

flammability and explosiveness of its vapor. Yet, it is still

instructive to learn, through the example of diethyl ether,

about what type of favorable and unfavorable properties the

inhalation anesthetics may have.

Ether

Other undesirable properties: - Light sensitive: light induces peroxidation of ether; ether peroxides are toxic (prevent by keeping in cans).

- Causes strong excitation during the stage of delirium.

- Irritates the airways → induces hypersecretion (like isoflurane and desflurane; prevented by atropine).

- Excites the vomiSng center → postoperaSve vomiSng.

Advantages: - Ether produces good muscle relaxation.Advantages: - Ether produces good muscle relaxation.

- Ether is a safe anesthetic. It does not have severe toxic effects (e.g., hepato- and nephrotoxicity), and it does not depress cardiac contractility and respiration markedly (mechanical ventilation is not required).

• In contrast, all halogenated inhalation anesthethics (as well as barbiturates and propofol) have respiratory depressive effect, necessitating mechanical ventilation. Halothane and enflurane (as well as barbiturates and propofol) also produce cardiodepressive(negative inotropic) effects.

Specific Inhalational Agents:

ii) Divinyl ether (Vinydan): CH2=CH-O-CH=CH2

• It is also rarely used due to its flammability. Differences from diethyl ether:

it is more potent than diethyl ether, and is less irritative to the airways.

May be used for short anesthesia to reach the stage of analgesia for a

short surgical intervention, e.g., for removal of pharyngeal tonsils.

b. Halogenated hydrocarbons:

i) Chloroform, CHCl3: Introduced in 1847 by James Simpson, a Scottish

obstetrician. Queen Victoria delivered her 8th child in chloroform

anesthesia (after which JS was knighted). Its sweetish odor made

chloroform popular, but it is no longer used because of its hepato- and chloroform popular, but it is no longer used because of its hepato- and

cardiotoxicity.

Its hepatotoxic metabolite is phosgene (once a suffocating chemical warfare

agent), an electrophilic acyl chloride, formed by oxidative

dehalogenation:

ii) Halothane (Narcotan) – It is the only inhalational anaesthetic

agent containing a bromine atom. Its use has been drastically

curtailed due to its idiosyncratic hepatotoxicity

Advantages: - It is non-flammable (just like any other

alogenated hydrocarbon and halogenated ether).

- It causes “smooth induction” with virtually no stage

of delirium.

Halothane

of delirium.

- It rarely induces postoperative nausea and vomiting.

- It has bronchodilatory effect, like all halog. inhal.

anesthetics – last resort in st. asthmaticus.

Disadvantages: - Insufficient decrease of muscle tone (easily overcome

by muscle relaxants). - Adverse effects: 2 common (predictable) and 2

rare (unpredictable).

Halothane

Common and predictable adverse effects of halothane:

(1) Cardiac adverse effects: cardiodepressive effect + arrythmogenic effect · Cardio-depressive effect is manifested in decreased heart rate and decreased contractility

˃ halothane decreases cardiac output by 20-50%, → Hypotension (can be beneficial because of decreased bleeding); ˃ Decreased splanchnic (visceral; renal, bleeding); ˃ Decreased splanchnic (visceral; renal, hepatic) blood flow

• However, cerebral blood flow (CBF) is increased due to dilataSon of cerebral vessels → ↑ intracranial pressure (ICP); * halothane (and other halog. inhal. anest., except isoflurane) is NOT suitable for brain surgery.

˃Slightly sensiSzes the heart to catecholamines → exogenous catecholamine may provoke arrhythmias (this is uncommon in children).

(2) Respiratory adverse effects: respiratory depressive effect +

depression of mucociliary function:

˃ Halothane reduces the respir. minute volume by inducing rapid

shallow respiraSon →↑ pCO2, ↓pO2; This necessitates assisted

ventilation (i.e., use of anesthesia machine which also contains a

ventilator).

˃ Halothane impairs the mucociliary clearance → mucus retenSon,

post-operative respiratory infections.

Halothane

post-operative respiratory infections.

Rare and unpredictable adverse effects of halothane:

(1) Halothane hepatitis – an immunologically determined reaction:

· An idiosyncratic reaction = rare (1 in 10 000 cases; higher after

repeated use), unpredictable reaction

· Symptoms start 2-5 days after anesthesia: fever, nausea; elevation

of ALT, eosinophilia

· Hepatic failure rate may be as high as 50%.

•· Mechanism: oxidative debromination (20% of dose) by CYP2El to

reactive trifluoro-acetylchloride (a reactive electrophilic acyl chloride) →

covalent binding to hepatic proteins = neoantigene formaSon → immune

hepatitis

Halothane

On theoretical basis, disulfiram pretreatment has been recommended

before halothane anesthesia to prevent hepatitis. Disulfiram is a

potent inhibitor of CYP2E1 (not only of aldehyde dehydrogenase) and

thus decreases formation of trifluoro-acetylchloride.

Halothane

(2) Malignant hyperthermia (MHT) – a genetically determined reaction:

• MHT may be caused by any halogenated inhalation anesthetic and also by succinylcholine. · Symptoms:

˃ Hyperthermia

˃Muscle rigidity → rhabdomyolysis → hyperkalemia, ↑CK, myoglobinuria → renal failure˃Muscle rigidity → rhabdomyolysis → hyperkalemia, ↑CK, myoglobinuria → renal failure

˃ Metabolic acidosis (caused by lacSc acid produced in the hyperactive muscles)

• Pathomechanism: inherited myopathy; caused by mutation of ryanodine receptor (RYR1), or of the dihydropyridine-sensitive L-type Ca2+-channels in the skeletal muscle, or by other unknown cause.

RYR1 is a Ca2+-release channel in the sarcoplasmic reticulum; RYR1

opens in response to -Ca2+ in the sarcoplasm.

• Halothane sensitizes the mutant RYR1 to Ca2+, thus triggering RYR1

opening and release of Ca2+ from the sarcoplasmic reticulum into the

sarcoplasm → muscle contrac=on →↑ - heat produc=on, etc.

˃Therapy:

- Stop delivery of the inhalation anesthetic, continue with N2O + an

Halothane

- Stop delivery of the inhalation anesthetic, continue with N2O + an

i.v. anesthetic.;

- Infuse NaHCO3 to correct acidosis and prevent myoglobin

precipitation in renal tubules.

- Decrease body temperature (with ice, or by gastric lavage with cold

water).

- Inject dantrolene (blocks RYR1) to relax the skeletal muscle.

c). Halogenated ethers

Enflurane

• Halogenation was used to prevent inflammation in ethers

Enflurane (Ethrane) – Its use has been diminished.

• It combines some of the properties of diethyl ether and some of the properties of halothane.

Advantages:

• Like ether - Enflurane has a good muscle relaxant effect.

- Enflurane does not sensibilize the heart toward catecholamines.

• Like halothane - Enflurane is not flammable.

- Enflurane smoothly induces anesthesia.- Enflurane smoothly induces anesthesia.

Disadvantages:

• Like ether - Enflurane mildly stimulates the tracheobronchialsecretions.

- Enflurane may cause postoperative nausea and vomiting (10%).

• Like halothane - Enflurane decreases cardiac contractility (but not the heart rate) → it causes a moderate decrease in cardiac output and blood pressure.

- Enflurane depresses the respiraSon →↑pCO2; assisted venSlaSon is needed.

Enflurane

• Rare adverse effect: tonic-clonic seizures (specific for enflurane); sometimes only EEG signs appear.

• Characteristic EEG: high voltage-high frequency activity, “spike and dome complexes”. The seizures are of short duration, self-limiting and of no special concern.

• CAUTION: Hyperventilation should be avoided, because it causes hypocarbia (↓pCO2) which sensiSzes the CNS to enflurane-induced seizures.

• NOTE: CO2 in the brain causes two effects:• NOTE: CO2 in the brain causes two effects:

- Anticonvulsive effect (remember the carbonic anhydrase inhibitor acetazolamide also ↑CO2 and is used as an adjuvant to antiepipleptics); therefore, ↓CO2 is pro-convulsive.

- Vasodilatory effect; therefore, ↓CO2 causes vasoconstriction –desirable in brain surgery.

• Biotransformation of enflurane: 2-5% of dose undergoes dehalogenation (much less than halothane).

· Isoflurane

• (Forane; an isomer of enflurane) – The most commonly used volatile

anesthetic today

Its properties are very similar to those of enflurane, except for 5 main differences:

(1) Isoflurane’s dehalogenation in the body is only 0.2% – there is no reason to

fear toxic metabolite(s).

(2) Isoflurane does not cause cardiac depression → cardiac output is well

maintained. Nevertheless, it

- decreases BP because it reduces peripheral vascular resistance (including the

coronary)coronary)

- increases the heart rate, but arrhythmias are not precipitated.

(3) Isoflurane does not induce seizures.

(4) Isoflurane is a preferred anesthetic for BRAIN SURGERY for 2 reasons:

- It decreases O2 demand/utilization by the brain.

- Although isoflurane slightly ↑ the cerebral blood flow (CBF), the CBF and ICP

can be ↓ by inducing hypocarbia (low pCO2) with hyperventilation.

(Hypocarbia causes cerebral vasoconstriction.)

(5) An unfavorable property: isoflurane has pungent odor and irritates airways.

This necessitates induction with an i.v. anesthetic.

Methoxyflurane (Penthrane)

• used for inducing the stage of analgesia, but not for general anesthesia.

• It is the most lipid-soluble (oil:gas part. coeff. = 970) and the most potent

inhal. anesthetic (MAC = 0.2%).

• However, its use as a GA has been discontinued due mainly to its

NEPHROTOXIC effect:

- Clinical presentation: "High-output renal failure", a concentrating defect

(ADH-refractory polyuria).

- Mortality rate: 20%, survivors slowly recover (it may take years).

- Increased susceptibility: after long anesthesia, in patients with existing - Increased susceptibility: after long anesthesia, in patients with existing

renal disease, in older patents, and after treatment with CYP inducers.

- Mechanism: 50-70% of methoxyflurane (MF) undergoes bio-

transformation via CYP-catalyzed O-demethylation and subsequent

oxidative dehalogenations. Its extensive biotransformation is mainly due

to large accumulation of methoxyflurane in fat → prolonged release of

MF from the fat → prolonged delivery of MF to the liver for

biotransformation.

Methoxyflurane

• Nephrotoxic methoxyflurane metabolites: Methoxyfluoroacetic acid, dichloroacetic acid, oxalic acid, and fluoride ion. Note: Oxalic acid is also one of the nephrotoxic metabolites of ethylene glycol.

• Methoxyflurane is used extensively in the Australian Defence Force and Australian ambulance services as an emergency analgesic – in sub-anesthetic dose (given by a pipe-like inhaler) nephrotoxicitydoes not occur.

Desflurane and Sevoflurane

Common properties:

- Ethers containing only fluorine substitutions

- They have lower lipid solubility and blood solubility than halothane, enflurane and isoflurane (see table); consequently:

> they induce anesthesia more rapidly

> recovery from anesthesia is also more rapid

-They do not cause cardiac depression (like isoflurane), but they cause:

> hypotension (due to vasodilatation)> hypotension (due to vasodilatation)

> respiratory depression

- Dehalogenation: is negligible for desflurane (0.02%) and is little for sevoflurane (3%)

Differences:

- Desflurane induces anesthesia most rapidly out of all volatile liquid anesthetics (as it is the least lipophilic), yet it is not used for anesthesia induction because it irritates the airways and causes coughing, breath holding, secretions and laryngospasm. (It is also expensive, precluding its use in poor countries.)

In contrast, sevoflurane has a pleasant odor and can be used for induction.

- Sevoflurane can react with the CO2 absorber Ba(OH)2 (Baralyme) in the

anesthesia machine.

This may have two adverse outcomes:

(1) Sevoflurane causes an exothermic reaction with the CO2 absorber, which

is overheated, if desiccated → airway burns, igniSon, and explosion may

occur. Therefore, the CO2 absorber should not run dry!

(2) In the basic CO2 absorber, sevoflurane is dehydrofluorinated to form

“compound A”, which is nephrotoxic in rodents, but is much less toxic in

humans. Nevertheless, 2 L/min fresh gas flow rate is prescribed during

sevoflurane anesthesia in order to dilute the exhaled compound A in the

Desflurane and Sevoflurane

sevoflurane anesthesia in order to dilute the exhaled compound A in the

inhaled gas.Rats convert

Compound A

into a reactive

nephrotoxic

metabolite.

However,

humans form

this harmful

metabolite at a

low rate

2. Anaesthetic gases

Cyclopropane – an obsolete agent.

• Not used because - it is flammable and explosive,

• - it sensitizes the heart to catecholamines, and can induce arrhythmias, including ventricular fibrillation.

Nitrous oxide (N2O) – called "laughing gas”, as it causes euphoria.

• It is the least lipid soluble and least potent inhalation anesthetic (MAC = 105%).

• As a sole anesthetic, it could be used reliably only under hyperbaric conditions.

• Advantages:• Advantages:

- N2O is nonflammable, not explosive.

- It lacks harmful effects under proper use.

- It does not induce malignant hyperthermia.

- Of the inhalation anesthetics, N2O is least likely to increase cerebral blood flow and intracranial pressure.

- It promotes induction and recovery when combined with halothane.

• Disadvantages:

- N2O is very weak → used only in combinaSon with other general anesthetics.

- It has no muscle relaxant acSvity → use muscle relaxant.

- It may cause 3 adverse effects:

(1) Diffusional hypoxia" occurs when N2O inhalation is discontinued and air inhalation is started.

• Reason: N2O is rapidly released from the blood into the alveolar space

• → it dilutes O2 there →↓ alveolar pO2 →↓ arterial pO2. Easily prevented by O2 inhalation.

(2) Expansion of closed air pockets in the body by replacing the N2 in these closed air spaces.

• Reason: Large amounts of N2O moves into the pocket readily, while N2moves out from the pocket into the blood slowly, due to the much lower

Nitrous oxide (N2O)

• Reason: Large amounts of N2O moves into the pocket readily, while N2moves out from the pocket into the blood slowly, due to the much lower blood/gas partition coefficient for N2 (0.01) than for N2O (0.5).

• Air pockets: occluded middle air, cyst in the lung or kidney, pneumothorax, and formed during pneumoencephalography. Avoid N2O in these conditions!

(3) N2O oxidizes Co(I) to Co(III) in methylcobalamin (= methyl-vitamin B12)

• → inacSvates methylcobalamin for use by methionine synthase(methylates homocys to methionine) This may be harmful only after extremely prolonged or repeated use of N2O.

• Consequence: symptoms of vit. B12 deficiency - megaloblastic anemia

- neuropathy (demyelinization = funicular myelosis)

Nitrous oxide (N2O)

Clinical use (and abuse) of nitrous oxide:

• (N2O is supplied in gas tanks containing 70% nitrous oxide; NITRALGIN gas):

• - For anesthesia, in combination with other inhalation anesthetics (e.g., halothane, enflurane, isoflurane)

• The MAC value of the anesthetic is reduced by 60% when 70% N2O is added → unwanted effects of the combined anesthetic (e.g., circulatory respiratory depression) are also reduced.reduced.

• - For inducing euphoria in order to relieve chronic pain (<50% N2O is used):

> in patients with tetanus (for days),

> in cancer patients with pain.

Abuse of nitrous oxide in medical personnel: as N2O (laughing gas) induces euphoria; addiction may occur.

Part C. INTRAVENOUS ANESTHETICS

I. GENERAL PROPERTIES OF I.V. ANESTHETICS

1. Chemical properties

· I.v. anesthetics are relatively hydrophobic and lipophilic compounds.

· Chemical classes: - Barbiturates: thiopental, methohexital

- Others: propofol, etomidate, ketamine

2. Mechanism of action

· All (except ketamine) activate the GABA-A receptor.

· Barbiturates also inhibit the neuronal N-type acetylcholine receptor.

· Ketamine inhibits the NMDA-type glutamate receptor.

3. Pharmacokinetics – only two phases, i.e. distribution and elimination3. Pharmacokinetics – only two phases, i.e. distribution and elimination

a). Tissue distribution and redistribution of i.v. anesthetics:

· IMMEDIATELY AFTER I.V. INJECTION, they distribute rapidly to the well-perfused Sssues, including the brain → general anesthesia occurs rapidly (within ~ 1 min)

· LATER, they redistribute to the less well-perfused tissues, such as the muscle, skin and adipose Sssue. These have large mass → remove the anestheSc from the brain → the paSent wakes up in a few minutes.

• The anesthetic action of i.v. anesthetics is terminated by redistribution, not by elimination. The rate of redistribution is quite similar for all i.v. anesthetics; therefore, after a single anesthetic dose, their duration of action is also similar (i.e., 5-10 min).

Part C. INTRAVENOUS ANESTHETICS

The rate of redistribution of i.v. anesthetics may decrease in patients

with:

- decreased tissue perfusion (e.g., in cardiac failure and septic shock)

- decreased muscle and adipose tissue mass (e.g., in elderly or

malnourished patient).

• In such conditions, the dose of i.v. anesthetic should be lowered lest

the anesthesia should be too long.

b). Elimination of i.v. anesthetics:

· All i.v. anesthetics are eliminated by biotransformation, e.g., by CYP-· All i.v. anesthetics are eliminated by biotransformation, e.g., by CYP-

catalyzed oxidation (barbiturates, ketamine), glucuronidation

(propofol), and hydrolysis (etomidate).

· There are significant differences in the rate of elimination of i.v.

anesthetics; this is reflected in their elimination half-lives (T1/2β):

- Thiopental is eliminated very slowly: T1/2β = 12 hrs! (Thiopental is

biotransformed slowly.)

- The others are eliminated relatively rapidly: T1/2 = 1-4 hrs.

Propofol is eliminated most rapidly (by glucuronidation); T1/2β= 1-2 hrs.

Part C. INTRAVENOUS ANESTHETICS

• What is the implication of the differences in elimination rate?

• - Thiopental should not be given in continuous infusion to maintain anesthesia, because it would accumulate in muscle and fat, forming a depot in these tissues. After termination of the infusion, thiopental release from the depot tissues would maintain high blood and brain levels and therefore recovery would be extremely delayed. For this reason, thiopental is not useful for TIVA (Total IntraVenous Anaesthesia )– For the same reason, delayed this reason, thiopental is not useful for TIVA (Total IntraVenous Anaesthesia )– For the same reason, delayed recovery also follows repeated administration of thiopental in single i.v. doses.

• - The others (especially propofol) can be given in continuous infusion to maintain anesthesia, because they do not have a propensity to accumulate in the body, therefore their duration of action is only slightly prolonged after long-lasting infusion. For example, the patient wakes up in 10 minutes even if propofol is infused for 3 hours.

Part C. INTRAVENOUS ANESTHETICS

4. Clinical use

• All may be given as a single dose for:

- induction of anesthesia before inhalation anesthesia, if the inhal. anesthetic slowly induces anesthesia (e.g., halothane), or has unpleasant odor or airway irritating property (e.g., isoflurane, desflurane);

- short anesthesia for short surgery or painful intervention (e.g., reposition of a dislocated joint).(e.g., reposition of a dislocated joint).

- Some (especially propofol) may be given in continuous infusion to produce long-lasting anesthesia.

• After discontinuation of the infusion, the patient wakes up in 10 minutes even if propofol was infused for 3 hours. Propofol is the preferred i.v. anesthetic for TIVA (total intravenous anesthesia). At a lower dose rate, propofol is also used for continuous sedation of patients in ICUs.

II. SPECIFIC PROPERTIES OF I.V. ANESTHETICS

1. Barbiturates: thiopental (a thiobarbiturate) and methohexital

(an oxobarbiturate)

a. Dose for methohexital: 1-1.5 mg/kg iv, for thiopental: 3-5

mg/kg i.v.

b. Onset of action: ~20 sec; induction is rapid and smooth;

Duration of action: ~5-10 min, for both

c. Elimination:

• by CYP: - Thiopental: Oxidative desulfuration (the product is

pentobarbital, a hypnotic)

- Methohexital: N-demethylation

- Both: Hydroxylation on the aliphatic chains linked to C5 of the

barb. ring

• at different speed: - Thiopental: very slow, T1/2β = 12 hrs → not used

for TIVA

- Methohexital: faster, T1/2 = 4 hrs → may be given in infusion

1. Barbiturates

- Methohexital: faster, T1/2 = 4 hrs → may be given in infusion

(0.1-0.3 mg/kg/min) to maintain anesthesia.

d. Advantages of barbiturates:

• Barbiturates (unlike most halogenated inhalation anesthetics,

except isoflurane) ↓ the cerebral metabolic rate and O2 utilization by

the brain →↓ the cerebral blood flow →↓ intracranial pressure (an

advantage in brain surgery) →↓ intraocular pressure

• Barbiturates exert anSconvulsive effect → thiopental is valuable in

the treatment of status epilepticus

e). Disadvantages:

• Incompatibility: The injectable solution is basic (pH 10-11) as

barbiturates are dissolved as Na-salts; if mixed with acidic solutions (e.g., a

muscle relaxant, such as pancuronium bromide) the barbiturate

precipitates out as a free acid!

• Barbiturates exert vascular irritative effect:

- if the i.v. injected thiopental conc. is >2.5%, it may induce pain and

thrombophlebitis

1. Barbiturates

thrombophlebitis

- if injected intra-arterially, it induces endarteritis and gangrene!

(The pain resulting from the veno-irritative effect can be prevented by

prior injection of lidocaine.)

• Barbiturates induce respiratory depression (low minute volume) and

apnea at high dose. In asthmatics, they may induce ehistamine release and

wheezing.

1. Barbiturates

• Barbiturates induce hypotension by causing both: - vasodilatation, and - ve inotropic effect. Therefore, barbiturates should not be injected - too rapidly → excessive decrease in cardiac contracSlity, and - to a paSent who can not compensate for ↓ blood pressure, e.g. those with – hypovolemia, - cardiomyopathy, - coronary artery disease, - β-receptor blockade

• Barbiturates induce ALA synthetase, the first enzyme in hemesynthesis. This in turn will cause accumulation of porphyrins(neurotoxic byproducts of heme synthesis) in patients deficient in some downstream enzymes of the heme synthetic pathway. (neurotoxic byproducts of heme synthesis) in patients deficient in some downstream enzymes of the heme synthetic pathway.

• Thus barbiturates may precipitate widespread demyelinization in patients with:

˃ Acute intermiIent porphyria (deficiency in porphobilinogendeaminase), and

˃ Variegate porphyria (deficiency in protoporphyrinogen oxidase).

In these inherited porphyrias barbiturates are ABSOLUTELY CONTRAINDICATED!

2. Propofol (DIPRIVAN) = 2,6-diisopropylphenol

a. Dose: 1.5-2.5 mg/kg

b. b. Onset and duration of anesthesia: - after a bolus dose, anesthesia develops in ~20 sec, like for barbiturates

- recovery is > within 10 min after a 3-hr infusion; > within 40 min after an 8-hr infusion

c. Elimination: - by glucuronidation (mainly) and sulfation at the hydroxyl group

• - rapid: T = 2 hrs or less (However, it is longer in neonates • - rapid: T1/2β = 2 hrs or less (However, it is longer in neonates because of the low quantity of UGT in the newborn liver. Therefore, recovery may be prolonged in neonates.)

2. Propofol

d). Used for:

• TIVA in infusion (0.1-0.2 mg/kg/min); for example, TIVA is used by orthopedic surgeons in SCOLIOSIS CORRECTION SURGERY, which

- requires anesthesia for several hours, however,

- the patient has to be wakened up (by stopping propofol infusion) to test sensory and motor functions after reposition of the spinal column and before completing the surgery.

• Also used for continuous sedation in intensive care units (ICU) – be aware of the possibility of PRIS - Propofol Infusion Syndrome!

e). Advantages:

• Like barbiturates, propofol ↓cerebral metabolic rate, O consumption • Like barbiturates, propofol ↓cerebral metabolic rate, O2 consumption →↓ cerebral blood flow, intracranial and intraocular pressure

• Propofol has antiemetic effect

f). Disadvantages:

• Like barbiturates, propofol:

- has venoirritative effect → pain; prevented by lidocaine i.v.

- has respiratory depressive effect (stronger than barbiturates)

- decreases blood pressure because of vasodilatation and negative inotropic effect

2. Propofol

Two special disadvantages of propofol:

(1) Propofol is a water immiscible oily substance. Its emulsion is used as an i.v. anesthetic. Its solvent contains soybean oil, egg phospholipids and glycerol, which supports bacterial growth.

• Serious infections have occurred with the use of propofol that had been opened and contaminated.

• PROPOFOL SHOULD BE USED SHORTLY AFTER OPENING OR DISCARDED!

• To overcome this problem, the water soluble prodrug of propofol, fospropofol is now marketed as Lusedra in the USA. Fospropofol is fospropofol is now marketed as Lusedra in the USA. Fospropofol is the phosphate ester of propofol, which is hydrolyzed by alkaline phosphatase (AP) in the body, thus releasing propofol:

Because of the need of metabolic activation, fospropofol induces anesthesia only in 10

min time

2. Propofol

(2) Propofol Infusion Syndrome (PRIS): A rare, but potentially lethal adverse

effect that occurs with high dose (>4 mg/kg/hour) and long-lasting (>48

hrs) propofol infusion. The incidence of PRIS in American ICUs was 1.1% in

the 2000-2008. The lethality of PRIS cases was 18%.

• Mechanism: PRIS is caused by toxic effect of propofol on mitochondria,

mainly in skeletal and cardiac muscle. Propofol acts as a weak

protonophoric uncoupler: it diffuses into mitochondria, dissociates its

phenolic proton, thus dissipating the inwardly directed H+ gradient that

drives ATP synthase.

• In addition, propofol also inhibits mitochondrial electron transport.

• Consequences and signs of the mitochondrial toxicity of propofol:

i. Cardiac failure: acute refractory bradycardia (may lead to asystole),

hypotension, and ST elevation; ii. Rhabdomyolysis →↑serum K+, ↑serum

CK, myoglobinuria → renal failure; iii. Hepatomegaly with fatty liver

(probably caused by inhibition of fatty acid oxidation); iv.- High serum

triglyceride levels (may be an early marker; caused by inhibition of fatty

acid oxidation?); v. Lactic acidosis (pyruvate use by PDH complex is

impaired → pyruvate is reduced to lactate by LDH)

3. Etomidate (AMIDATE)

a. Dose: 0.2-0.4 mg/kg

b. Rapidly and ultra short acting (4-8 min) anesthetic – used mainly for

induction of anesthesia

c. Elimination: - by ester hydrolysis in the liver

• - rapid; T1/2β = 3 hrs → Etomidate could be given in infusion (10

mg/kg/min), yet prolonged infusion is contraindicated because it inhibits

cortisol synthesis and blunts the stress response (may increase mortality).

d. Other disadvantages:

• often induces nausea and vomiting• often induces nausea and vomiting

• causes pain on injection (like barbiturates and propofol; prevent it by

prior injection of lidocaine)

• appears to have pro-convulsive effect (contraindicated in seizures)

3. Etomidate (AMIDATE)

e). Advantages:

• Like barbiturates and propofol, etomidate causes:

• ↓ cerebral metabolic rate, O2 consumption

• →↓ cerebral blood flow, intracranial and intraocular pressure

• Unlike barbiturates and propofol (and the halogenated inhalation anesthetics), etomidate causes:

- little respiratory depression- little respiratory depression

- little or no decrease in blood pressure and may slightly increase the heart rate

• → the CARDIOVASCULAR FUNCTION IS STABLE during etomidateanesthesia

• → etomidate is usually reserved for patients at risk for hypotension and/or myocardial ischemia

4. Ketamine (KETALAR) – an NMDA receptor antagonist

a. Dose: 0.5-1.5 mg/kg

b. Onset of action: relatively slow (1-2 min)

• Duration of anesthesia: 10-15 min (the anesthesia is longer than that induced by other i.v. anesthetics)

c. Elimination:

• by CYP-catalyzed N-demethylation

• rapid: T1/2β = 3 hrs → can be infused (25-100 mg/kg min)

4. Ketamine (KETALAR)

d). Ketamine has 3 peculiar effects:

• Ketamine has analgesic effect that outlasts the anesthetic effect – an

advantage: Ketamine may be used by ambulance services for sedation and

pain suppression in patients.

• Ketamine may induce disagreeable dreams and hallucinations, when emerging

from the anesthesia. This occurs seldom in children → ketamine is a preferred

anesthetic in pediatric surgery (may be given in combination with a

benzodiazepine).

• Ketamine has indirect sympathomimetic effect because it ↓ neuronal reuptake • Ketamine has indirect sympathomimetic effect because it ↓ neuronal reuptake

of catecholamines both peripherally and centrally (like cocaine); the resultant

effects are:

- ↑ blood pressure; - ↑ heart rate, cardiac output, myocardial O2 consumption

- ↑ cerebral blood flow, - intracranial pressure; - pupillary dilation, nystagmus,

lacrimation; - bronchodilation

Consequently, ketamine is Indicated for patients:

- who are at risk for hypotension (like etomidate); - who are asthmatic

- Contraindicated for patients: - who are at risk for myocardial ischemia

- who have ↑ intracranial pressure