Major & Minor Tranquilisers

Major and Minor Tranquilisers

1. History

 Herbal sedatives and Alcohol known and used for centuries.

Bromide first used 1853, and an account of Bromism in Evelyn Waughs "The Ordeal of Gilbert Pinfold". Before 1900, Chloral Hydrate, Paraldehyde, Urethan, and Sulfonal were in use.

Barbiturates first synthesised in 1864 on St. Barbaras Day (which celebrates the day long ago when the father of a 4th century virgin and martyr was struck dead by lightning after unjustifiably beheading same. Patron Saint of Gunners and Arsenals). Phenobarbital first used in 1912

Benzodiazepines first synthesised 1933, Chlordiazepoxide first clinically used in 1960.

Charpentier first synthesised and used Promethazine in the 1930's and Chlorpromazine in the 1950's. He was the first to note the "Neuroleptic" effects of these drugs, wherein the patient loses interest in their surroundings, emotions are dulled and spontaneous and complex movements are reduced, while there is no gross impairment of intelligence or the ability to perform tasks and unconditioned or reflex activity remains unimpaired.

2. Minor tranquilisers

Generally simple CNS depressants with relatively few sideffects, these drugs include:

Barbiturates
Benzodiazepines, eg Diazepam
Chloral Hydrate

A. Barbiturates

General anaesthetic agents with no known receptor sites; sedatives in low doses via GABA interactions possibly including weak interactions at the GABA receptor. Cannot be safely used in conjunction with alcohol and have low therapeutic index. Frequently used orally for successful suicides. Anxiolysis is not clearly seen, and euphoria and antalgesia may occur.

Mostly have medium to long durations of action:

• Phenobarbitone 24-96 hours
• Amylobarbitone 14-42 hours
• Pentobarbitone 21-42 hours
• Quinalbarbitone 20-28 hours

Unwanted side-effects include:

• Morning sedation
• Synergism with alcohol
• Hepatic MFO enzyme induction
• Interactions with anticoagulants, steroids, anticonvulsants, etc
• Tolerance and dependence
• Suicide and Overdose
• Porphyria

B. Benzodiazepines

Pharmacology

Structures of Benzodiazepines

Highly protein bound moderately lipid soluble drugs. Vd usually around 0.5-3.0 l/kg, peak plasma concentrations in 1-2 hours, high oral bioavailability. Duration of effect depends primarily on the rate of metabolism or conjugation of the predominate active metabolite, except with IV use where relatively brief responses are due to redistribution. Few drug interactions and no stimulation of mixed function oxidase systems (unlike barbiturates). Metabolised mostly in the liver; long half-life in the elderly. Nor-Diazepam (N-desmethyl-diazepam) is active with a half-life of 50 to 100 hours.

Act by polysynaptic pathway inhibition via interaction with specific receptors (GABA, BZ, Barbiturate modified Chloride channel) which enhance the inhibitory effect of GABA in the Reticular Activating System and Amygdala by increasing the open time of the Chloride channel. Barbiturates are synergistic (supra-additive) by increasing receptor affinity for Benzodiazepines. Inverse agonists cause wakefulness, anxiety, fear, and convulsions. The actions of both agonists and inverse agonists are reduced by benzodiazepine antagonsists such as flumazenil (Anexate). Two receptor subtypes; BZ1 in cortex, BZ2 receptors in the amygdala and hippocampus.

Main effects are:-

• CNS Depression - decreased anxiety, tranquility, sedation, anterograde amnesia, ultimately unconsciousness and respiratory depression. Anxiety reduced more than apparrent drowsiness. Sleep changes include delayed and reduced REM sleep and reduced stage 3 and 4 sleep, but increased overall sleep times.
• Anticonvulsant effects - mostly with Diazepam.
• Muscle relaxation - spinal polysynaptic pathway, ie no enhancement of NMBs.

Few sideffects when used as hypnotics - headaches, morning drowsiness, habituation (due in part to adaptive changes at the receptor and more efficient metabolism; documented to occur before 6 weeks), rarely problems with sleep apnoea patients and ataxia, delerium. For anxiolysis and sedation chronic administration is associated with habituation, strong tendency to dependence, and withdrawal associated with REM rebound, insomnia, hallucinations, nightmares and seizures.

IV use complicated by venous thrombophlebitis (and worse if intra-arterial injection) from carrier agents, potential for significant respiratory depression and airway obstruction, response variability, and hypotension from reduced sympathetic tone.

Le Page et. al. (Anaesthesiology 65:678-683 1986) gave 0.2mg/k Diazepam, 0.02 mg/k Flunitrazepam, and 0.2 mg/kg Midazolam IV to umpremedicated patients prior to CAGS and found that all patients were unrousable in 50 seconds, that apnoea was rare and respiratory rate largely unchanged, and that there was a 10-20% fall in arterial blood pressure and non-significant falls in SVR and CO witrh LVEF and EDV substantially unchanged. Severe cardiovascular depression is not seen in pure benzodiazepine overdose, so one can conclude that these agents do not cause direct myocardial depression.

Dose-dependant respiratory depression with large inter-individual variation has been demonstrated in several studies. The slope of the Ve/PetCO2 line is reduced from about 2.3 l/min/mmHg by about 10-15% following 0.1 mg/kg IV diazepam (Anaesthesiology 64:460-465 1986) and by 50% within 3 minutes of 0.4 mg/kg IV. The depression is reduced by half after 30 minutes in healthy volunteers (Gross, Anaesthesiology 57:18-21 1982). It is not reversible by Naloxone.

Relaxation of Lower Oesophageal Sphincter Tone by about 50% following 10mg iv Diazepam has been shown by Brock-Utne (AIC 10:130-133 1982).

All reduce CMRO2 but do not interfere with cerebral autoregulation.

Use as premedication made difficult by response variability. These drugs are not general anaesthetics; ED95 for midazolam to prevent movement in response to incision is of the order of 1mg/kg! 

1. Diazepam

Lipid soluble, Vd 1.0-2.6 l/kg; Half-life 25-50 hours, longer in the elderly; 94-98% protein binding. Enterohepatic recirculation; metabolites active, include des-methyl diazepam (half-life 50-100 hours), oxazepam, temazepam, etc.

Dissolved in 40% Propylene Glycol, Ethanol, and Sodium Benzoate 10mg/2ml or Intralipid (Diazemuls - 5mg in 2 ml - slightly less potent, but venous thrombosis very much reduced (17% from 90%, Galletly, AIC 1985, 13)).

IM injections erratically and unreliably absorbed. After IV administration duration of action limited by redistribution and dependent on dose and sensitivity.

Duration of action after oral administration very variable, depending on rate of absorbtion and individual sensitivity. Kinetics are appropriate for use the night before surgery for anxiolysis and improved sleep. As a premed prolonged postop sedation may be a problem in sensitive or elderly patients.

IV useful for sedation, anxiolysis, and amnesia, in mildly unpleasant medical procedures, and with droperidol for neurolept. Unfortunately associated with thrombophlebitis (80% incidence if injected into small veins, most obvious at two weeks, reduced by dilute administration into large veins (Galletly, AIC 13:352-354 1985)) and airway/respiratory hazards especially in unskilled hands.

Arterial damage has been described by Rees (BMJ 20/7/80, pp289-90) and is typically late in onset. Usually pain is felt on injection but is not excruciating, however the patient returns 24 hours later with persistant pain even though the affected area may still appear normal. Symptoms worsen over 20-30 days. Persistant pain is common and amputations have been required. Treatment includes steroids, prostacycline and sympathetic blocks for vasodilation early on, and heparin or streptokinase for thrombosis. 

2. Lorazepam

Half life 10-20 hours; less redistributive effect on duration of action, no active metabolites. Inadvertent relative overdose will last a long time. Unwise to exceed 4mg orally in adult unless sensitivity to Benzodiazepines has been established. Slow onset. Rapid and complete absorbtion after IM injection.

Usual dose 1-4 mg. High oral biavailability and reliable IM absorbtion.

Different dynamics from Diazepam - less sedation, less respiratory depression, profound amnesia. Good antiepileptic.

Useful oral premedicatant when unpleasant procedures need to be performed on a co-operative patient as recall is reduced or absent while the patient is often reasonably alert. 

3. Nitrazepam

Vd 2.5-5 l/kg; half-life 20-40 hours; 83-88% protein bound; highly lipid soluble. Relatively short duration of action due to redistribution but long-term accumulation.

Used primarily as a hypnotic; no antiepileptic activity. 

4. Temazepam

Vd 0.8 l/kg; half-life 5-8 hours, 75% protein bound; soft capsules of 10mg in polyethylene glycol. Temazepam is mostly conjugated to glucuronic acid in the liver, some goes to oxazepam, and 5-10% is faecally excreted..

Newer "medium-duration" benzodiazepine primarily intended as a hypnotic. Doses capable of inducing sleep generally wear off in 3-4 hours and morning drowsiness is uncommon and certainly less than using chloral hydrate or amylobarbitone in equi-therapeutic doses. Significant residual effects can be documented in healthy patients only in doses exceeding 30mg.

Useful premed in dose 10-40mg. Dose has to be guessed at on basis of prior response to benzodiazepines, concomitant use of alcohol or other sedatives, age and size of patient, and even then response is variable. 

5. Oxazepam

 

Vd 0.7 l/kg, half-life 7-15 hours.

6. Triazolam

Half-life 3-4 hours.

7. Midazolam

Vd 0.8-1.9/kg; half-life 1-2.8 hours due to very rapid hepatic metabolism; 90% protein bound. Opening of the cyclic imidazole ring at pH < 4.0 increases water solubility in acidic solutions but enhances lipid solubility at body pH; hence supplied in water at pH 3.3. Reliable absorbtion following intramuscular injection.

Rapid metabolism to 1-hydroxymethyl midazolam with only 0.03% excreeted unchanged in the urine.

New, short-acting; twice as potent as diazepam; used parenterally for premedication, induction, or sedation.

8. Flumazenil

Similar structurally to midazolam with affinity but no action on the BZ receptor, ie competitve reversal of the effects of benzodiazepines. Onset 3-4 min after IV administration and short half-life (60 minutes). Expensive.