BIOM 3090 Study Guide - Final Guide: Haloalkane, Inhalational Anaesthetic, Anaesthetic Machine
9 Jun 2018
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Preanesthetics/anesthetics
Introduction to Anesthetics & Pre-anesthetics
Intro:
- many surgical procedures would be impossible without general anesthetics
- amputations, etc. carried out on conscious patients has been compared to medieval torture
Early general anesthetics: N2O (Nitrous oxide)
- known as medicine since 1863
- patients remain conscious (not a true general anesthetic), but alleviates anxiety and is an
excellent analgesic
- very safe; still use in dental clinics to alleviate anxiety & pain; sometimes used in hospitals
to reduce amount of hydrocarbon anesthetic required
- It is now known that many lipid-soluble volatile hydrocarbons will cause unconsciousness
- Only a few do so without causing irreversible damage (eg. Renal failure, etc)
o Gasoline sniffing; Northern Labrador
- All of the inhalants available by the 1950s had at least one of the following two major
drawbacks:
o Explosive when administered with oxygen
o Produce toxic metabolites
o They also tended to cause a dangerous degree of cardiorespiratory inhibition
because of the manner in which they were used
Halogenated hydrocarbon anesthetics – Halothane
- First synthesized in England and used clinically in 1956
- Ethane, with most hydrogens replaced with halogens
- Relatively safe, non-flammable, non-pungent anesthetic
- Revolutionized anesthesia → most current anesthetics are of this type
- Even safer hydrocarbons have now replaced it, especially isoflurane and sevoflurane
- Ether (ethoxyethane) is flammable, and can be explosive when mixed with O2
- Actual explosions were rare, but could be catastrophic
- Substituting halogens for hydrogens reduces the flammability of a hydrocarbon
- Halothane-oxygen mixtures are non-explosive, solving one of the major problems with
inhalants
- Unfortunately, halothane is relatively unstable
- Compared to bromide, chloride and especially fluoride ions bind with greater affinity to
carbon because the bonding pair of electrons is closer to the nucleus of the halogen
- Anesthetic compounds containing bromide (and even larger iodide) tend to be unstable
o * SMALLER halogens promote molecular stability
- Unfortunately, totally fluorinated compounds do not produce anesthesia, so some other
halogens and/or hydrogens are required
- Because halothane is somewhat labile, it is combined with a stabilizing molecule (thymol)
- Inhalant anesthetics stabilizers/preservatives such as thymol can, unfortunately, deposit in
anesthetic machines, causing valves to malfunction
- Halothane also gradually breaks down in the presence of soda lime, the CO2 absorbent
used in most machines, releasing a toxic compound
o Chemical stability increases the safety of inhalant anesthetics
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- To be both safe and effective, general anesthetics must inhibit cerebrocortical activity while
maintaining brainstem function (cardiovascular and respiratory system regulation)
- All areas of the brain are reversibly inhibited by general anesthetics in a dose-dependent
manner
- Fortunately, the cerebral cortex is most sensitive, and its function is virtually abolished at
concentrations that only partially inhibit brainstem functions
- The safety of general anesthetics is therefore dependent upon the extent to which
cardiovascular and respiratory functions are impaired at concentrations required to
maintain unconsciousness
- The other major safety issue relates to the toxicity of the inhalant’s metabolites
o Some inhalant anesthetics undergo hepatic biotransformation into toxic metabolites
o These metabolites are present in highest concentration in the organs of production
(liver) and excretion (kidney), and these are the organs most likely to be damaged
o In general, hepatic and renal toxicity are directly related to the extent to which the
inhalant is metabolized
o Halothane: up to 40% metabolized → significant hepatotoxicity
o Isoflurane: <0.2% metabolized → essentially no organ toxicity
- Another drawback of halothane is that it sensitizes the myocardium to epinephrine,
promoting arrhythmias (e.g. when epinephrine is released in response to hypoxia during
anesthesia)
- Early testing of various halogenated hydrocarbons revealed that those with an ether
linkage do not have this property
o The ether linkage (C-O-C) is therefore desirable for safety
The IDEAL inhalant anesthetic – Characteristics
- Produces unconsciousness while maintaining brainstem function (respiration, circulation)
- Negligible visceral toxicity (i.e. no metabolism → 100% of drug exhaled intact)
- Non-flammable, non-pungent odour
- Compatible with anesthetic machine material doesn’t degrade rubber or metal parts or
react with soda lime)
- Chemically stable without preservatives
- Potent
General anesthesia
- To permit major surgery – start with alert patient (usually)
o Administer sedative or anxiolytic + analgesic
o Induce unconsciousness
o Maintain in unconscious state
- Pharmacological approach
1) Premedicate patient
2) Induce general anesthesia rapidly using a short-acting injectable drug
3) Transfer to inhalant anesthetic for maintenance
4) Recovery
Anesthetics and Pre-anesthetics
1) Premeds including sedatives and the opioid analgesics
2) Induction agents
3) Inhalant anesthetics
4) Local anesthetics
Pre-anesthetics premeds
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- Premedication’s: a broad term that refers to a variety of injectable drugs administered
prior to inducing general anesthetic, in order to calm the patient, reduce the amount of
general anesthetic needed, and inhibit intra- and post-operative pain
- Main types:
o Sedatives/anxiolytics – to calm patient/reduce activity
o Hypnotics – to induce sleepiness
o Analgesics – to minimize/abolish intra- & post-op pain
- Most premedication’s also reduce the amount of general anesthetic needed to produce
unconsciousness → increases safety of the anesthetic procedure
- Sedatives/hypnotics
o Main types, for example:
▪ Phenothiazine’s
▪ Alpha2-agonists
▪ Benzodiazepines
▪ Barbiturates
Benzodiazepines (BZDs)
- Ex. diazepam, lorazepam
- Many others; differ mainly in duration of action (diazepam ~ 48h; lorazepam ~ 20h)
- Diazepam – trade name: Valium
o Useful pre-med effects:
▪ Anxiolytic/sedative
▪ Hypnotic
▪ Muscle relaxant
▪ Also has anticonvulsant effects
- Mechanism of action:
o Facilitates the binding of GABA (the major inhibitory NT in the brain) to its
receptor (GABA receptors, types A & B) through an allosteric binding site
o GABAAR is a hetero-pentameric ligand-gated chloride channel; binding of GABA to
the alpha subunit opens channel → hyperpolarizes cell → inhibits excitation
o The overall effect depends on the location of GABA receptors within the brain
(receptor expression is not uniform throughout the brain)
o At least 21 different genes encode GABAAR subunits
▪ Most common: 2 1 + 2 2 + 1 2
o Different subunit combinations produce hundreds of types of GABAARs with
different ligand binding affinities in different regions of the brain
▪ → Explains why one drug can produce very different effects in different
regions of brain, and why different drugs of the same class can produce
different effects
o When the mechanism of this synthetic drug class was first discovered, no
endogenous ligand for the allosteric GABAA receptor binding site was known
o Recently, endogenous endozepines have been discovered → bind to same site as the
benzodiazepines, but produce more focussed effects in brain because released
locally in small quantities
- Benzodiazepines
o Relatively safe because they do not directly activate GABAAR; GABA itself must be
present
▪ When used alone, therapeutic index is ~1000
o At the organ level, BZD have little effect on the CV system (unless pulmonary or CV
disease present)
o Dose-dependent respiratory depression, but little effect at therapeutic dosages
(therapeutic index: dosage for the effect you want)
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