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218 General Anesthetics

Injectable Anesthetics

Substances from different chemical classes suspend consciousness when given intravenously and can be used as injectable anesthetics (A). Like inhalational agents, most of these drugs affectconsciousness onlyandare devoid of analgesic activity (exception: ketamine). The effect appears to arise from an interaction with ligand-gated ion channels. Channels mediating neuronal excitation (NMDA receptor, see below) are blocked, while the function of channels dampening excitation (GABAA receptor, p.222; and, for three drugs, additionally also the glycine receptor) is enhanced allosterically.

Most injectable anesthetics are characterized by a short duration of action. The rapid cessation of action is largely due to redistribution: after intravenous injection, brain concentration climbs rapidly to effective anesthetic levels because of the high cerebral blood flow; the drug then distributes evenly in the body, i.e., concentration rises in the periphery, but falls in the brain—redis- tribution and cessation of anesthesia (A). Thus, the effect subsides before the drug has left the body. A second injection of the same drug would encounter “presaturated” body compartments and thus be dif cult to predict in terms of effect intensity. Only etomidate and propofol may be given by infusion over a longer period to maintain unconsciousness. If no additional inhalational agent is employed, the procedure is referred to as total intravenous anesthesia (TIVA).

Thiopental and methohexital belong to the barbiturates,which, depending on dose,produce sedation, sleepiness, or anesthesia. Barbiturates lower pain threshold and thereby facilitate defensive reflex movements; they also depress central inspiratory drive. Barbiturates are frequently used for induction of anesthesia.

Ketamine has analgesic activity that persistsup to1hour after injection, wellbeyond the initial period of unconsciousness (~ 15 minutes only). On regaining consciousness,

between outside reality and inner mental state (dissociative anesthesia). Frequently there is memory loss for the duration of the recovery period; however, adults in particular complain about distressing dreamlike experiences. These can be counteracted by administration of a benzodiazepine (e.g., midazolam). TheCNSeffectsofketamine arise,in part, from an interference with excitatory glutamatergic transmission via ligand-gated cation channels of the NMDA subtype, at which ketamine acts as a channel blocker. The nonnatural excitatory amino acid N- methyl D-aspartate (NMDA) is a selective agonist at this receptor. Ketamine can induce release of catecholamines with a resultant increase in heart rate and blood pressure.

Propofol has a remarkably simple structure resembling that of phenol disinfectants. Because the substance is water-insoluble, an injectable emulsion is prepared by means of soy oil, phosphatide, and glycerol. The effect has a rapid onset and decays quickly, being experienced by the patient as fairly pleasant. The intensity of the effect can be well controlled during prolonged administration. Possible adverse reactions include hypotension and respiratory depression, and a potentially fatal syndrome of bronchospasm, hypotension, and erythema.

The anesthetic effect of (+)-etomidate subsides within a few minutes owing to redistribution of the drug. Etomidate can provoke myoclonic movements that can be prevented by premedicationwith a benzodiazepine or an opioid. Because it has little effect on the autonomic nervous system, it is suitable for induction in combination anesthesia. Etomidate inhibits cortisol synthesis in subanesthetic doses and can therefore be used in the long-term treatment of adrenocortical overactivity (Cushing disease).

Midazolam is a rapidly metabolized benzodiazepine (p.224) that is used for induction of anesthesia. The longer-acting lorazepam is preferred as an adjunctive anesthetic in prolonged cardiacsurgery with cardiopulmonary bypass; its amnesiogenic effect is

theLuellmann,patie t mayColorexperienceAtlas of Pharmacologya disconnection© 2005pronouncedThieme.

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

 

 

Injectable Anesthetics

219

A. Termination of drug effect by redistribution

 

 

 

 

 

 

 

 

CNS:

 

 

 

 

High concentration

 

 

 

 

 

 

 

 

in tissue

 

 

 

 

 

relatively

 

 

 

 

 

 

 

 

 

 

 

high

 

 

 

 

Relatively large

 

 

 

 

 

blood flow

 

 

 

 

 

 

 

 

 

 

 

 

 

amount of drug

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

i.v. injection

 

 

 

 

 

 

 

 

Periphery:

 

 

 

 

 

 

 

 

 

 

 

relatively

 

 

 

 

 

 

 

 

 

 

 

low blood flow

 

 

 

Relatively small

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

amount of drug

 

 

 

 

ml blood

 

 

 

 

mg drug

 

 

 

 

 

min x g tissue

 

 

 

 

min x g tissue

 

1. Initial situation

 

 

 

 

 

 

2. Preferential accumulation

 

 

 

 

 

 

 

 

 

 

of drug in brain

 

 

 

 

 

 

 

Decrease

 

 

 

 

Low concentration

 

 

 

 

in tissue

 

 

 

 

in periphery

 

 

 

 

 

concentration

 

 

 

 

 

 

 

 

 

 

Further

 

 

 

 

 

 

 

 

 

 

 

increase

 

 

 

 

 

 

 

 

 

 

 

in tissue

 

 

 

 

 

 

 

 

 

 

 

concentration

 

 

 

 

 

 

3. Redistribution

 

 

 

 

 

 

4. Steady state of distribution

 

 

B. Intravenous anesthetics

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NH

CH3

 

O

CH2

CH3

 

 

O

 

 

 

 

 

Ketamine

 

 

 

 

 

 

 

 

 

 

 

N

CH2

CH3

 

Cl

 

O C

 

 

 

 

 

 

 

Etomidate

 

NaS

CH

(CH2 )2

CH3

 

 

 

CH3

 

N

 

 

 

 

 

 

 

NMDA receptor

 

N

N

 

 

H

 

 

 

 

 

 

 

 

O CH3

 

 

 

blockade

 

 

CH

 

H3C

N

Sodium thiopental

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

CH3

OH

CH3

 

 

 

 

N

CH2

CH

 

CH2

 

 

 

 

 

Cl

N

 

H3C

CH

 

CH CH3

 

 

NaO

 

 

 

 

 

 

 

 

F

CH

C

C

CH2

CH3

 

 

 

 

 

 

N

 

 

Propofol

 

 

 

 

 

 

 

 

 

H3C

O CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

Activation of

 

 

Activation of

 

 

Sodium methohexital

 

 

 

Midazolam

 

glycine receptors

 

GABAA receptors

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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220 Psychopharmacologicals

Sedatives, Hypnotics

During sleep, the brain generates a patterned rhythmic activity that can be monitored by means of the electroencephalogram (EEG). Internal sleep cycles recur 4–5 times per night, each cycle being interrupted by a rapid eye movement (REM) sleep phase (A). The REM stage is characterized by EEG activity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of individual muscle groups against a background of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle. Frequent interruption of sleep will, therefore, decrease the REM portion. Shortening of REM sleep (normally ~ 25% of total sleep duration) results in increased irritability and restlessness during the daytime. With undisturbed night rest, REM deficits are compensated by increased REM sleep on subsequent nights (B).

Hypnotic drugs can shorten REM sleep phases (B). With repeated ingestion of a hypnotic on several successive days, the proportion of time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which tapers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unrefreshing. Thus, the attempt to discontinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence.

Benzodiazepines and benzodiazepine-like substances are the hypnotics of greatest therapeutic importance. They display a positive allosteric action at the GABAA receptor (p.222). The formerly popular barbiturates have become obsolete because of their narrow margin of safety (respiratory arrest after overdosage). Barbiturates can also activate GABAA receptors allosterically; however, this action does not occur at benzodiazepine

binding sites. At high dosage, barbiturates can apparently produce an additional direct GABA agonist effect.

Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects. At higher dosage, both groups promote the onset of sleep or induce it (C). At low doses, benzodiazepines have a predominantly anxiolytic effect.

Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action; cerebral activity is not globally inhibited (the virtual impossibility of respiratory paralysis negates suicidal misuse) and autonomic functions, such as blood pressure, heart rate, or body temperature, are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates.

Zolpidem (an imidazopyridine), zaleplone (a pyrazolopyrimidine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, can bind to the benzodiazepine site on the GABAA receptor (p.222). However, their effects do not appear to be identical to those of benzodiazepines. Thus, compared with benzodiazepines, zolpidem exerts a weaker effect on sleep phases, supposedly carries a lower risk of dependence, and appears to have less anxiolytic activity. Heterogeneity of GABAA receptors may explain these differences in activity. GABAA receptors consist of five subunits that exist in several subtypes.

Antihistaminics are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p.118), in which case their sedative side effect is used as the principal effect. The hypnotic effect is weak; adverse effects (e.g., atro- pine-like) and corresponding contraindications need to be taken into account.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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Benzodiazepines

221

A. Succession of different sleep phases during night rest

 

Waking

 

 

state

 

 

Sleep

 

REM

stage I

 

 

 

Sleep

 

 

stage II

 

 

Sleep

 

 

stage III

 

 

Sleep

 

 

stage IV

 

 

REM-sleep = Rapid Eye Movement sleep

NREM = No Rapid Eye Movement sleep

 

B. Influence of hypnotics on sleep phases

REM

 

 

 

 

 

 

 

NREM

 

 

 

 

 

 

 

Proportion

 

5

10

15

20

25

30

 

 

Nights

Nights

Nights after

 

 

 

 

 

without

with

withdrawal

 

 

 

 

 

hypnotic

hypnotic

of hypnotic

 

 

 

 

 

 

 

 

 

 

 

C. Concentration dependence of effects

 

 

 

 

Barbiturates:

 

 

 

 

 

Pentobarbital

Effect

 

 

 

 

 

 

O

 

 

 

 

 

Paralyzing

 

N

C2H5

 

 

 

 

 

HO

CH

CH3

 

 

 

 

 

N

 

 

 

 

 

H

O C3H7

 

Pentobarbital

 

 

 

Benzo-

 

 

 

 

Anesthetizing

 

 

 

 

 

 

 

 

diazepines:

 

 

 

 

 

 

 

 

 

 

 

Brotizolam

 

 

 

 

 

 

 

H3C

N

N

 

 

Zolpidem

 

 

 

 

N

 

 

 

Hypnogenic

 

S

 

 

 

 

 

 

 

 

 

 

 

 

 

Br

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

Cl

 

 

 

 

 

 

Imidazo-

 

 

 

 

 

Hypnagogic

 

 

 

 

 

 

 

 

pyridines:

 

 

 

 

 

 

 

Zolpidem

 

 

 

 

 

 

 

 

CH3

 

 

 

 

 

Sedating

 

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

N

CH2

 

 

Triazolam

 

 

Anxiolytic

 

 

 

 

 

 

 

 

C

O

 

 

 

 

 

 

 

 

 

 

 

 

N

CH3

 

 

 

Concentration in blood

CH3

CH3

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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