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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 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:
Unwanted side-effects include:
B. Benzodiazepines Pharmacology
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:-
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. C. Other sedative-hypnotics 1. Chloral Hydrate Chloral is an unstable oil of formula 2,2,2 trichoroacetaldehyde and is hydrated to CCl3CH(OH)2 as chloral Hydrate. Half-life 8 hours. Irritant to gastric mucosa, GI sideffects common if taken without food. No analgesic activity. Overdose causes cardiac and respiratory failure. Skin rash and allergy common. Use contra-indicated in patients with hepatic/renal/CVS inadequacy. Dependance and use for suicide rare. 2. Ethylchlorvinyl Half-life 5 hours. Hypersensitivity reactions common. 3. Methaqualone Half-life 20-60 hours; very addictive, especially with diphenhydramine. 3. Major tranquilisers Two major classes, the butyrophenones (ie droperidol and haloperidol) and the phenothiazines (ie Chlorpromazine) Characteristic Features:
There is minimal depression of spinal reflexes, intellect, anxiety, and task performance. Usually multiple drug effects are seen, ie anticholinergic (dry mouth, urinary retention, tremor inhibition, etc), alpha-adrenergic block (hypotension and inhibiting shivering), anti-dopaminergic (antiemetic , inducing Parkinsonism), antihistamine, etc., with varying degrees of each in any given drug. A. Butyrophenones Strong neuroloptic agents with profound antiemetic properties but less sedation, alpha-blockade, or respiratory depression than the phenothiazines. No amnesia. "Locked-in" sensation often recalled vividly by patients. Intense desire to say or do something cannot be expressed. Very unpleasant, particularly during painful procedures, where the outward calm belies inner turmoil. Hence best not used alone; preferably in combination with a benzodiazepine. Useful for antiemesis (small doses), sedating restless patients, neurolept analgesia, or as drug-induced restraint on the floridly psychotic. 1. Droperidol 10mg/2ml in water with lactic acid to adjust pH to 3.4 (soluble under pH4) Half-life 6-12 hours. Partial biliary ecretion. Major Tranquiliser with strong neurolept and anti-emetic actions and mild sedation and alpha-blockade. No analgesic actions. Decreases cerebral oxygen consumption and ICP slightly in normal people. Moderate tendency to Parkinsonian rigidity. Innovar is a mixture of Droperidol and Fentanyl which is in the ratio 2.5mg of droperidol to 50ug of fentanyl per ml and this seems illogical for IV use as there will be early (10-15 minutes) predominance of Fentanyl and thereafter predominantly Droperidol effects. Most logical neurolept method is to give Lorazepam premed for amnesia, then IV Diazepam and Droperidol with narcotics if pain is a problem as well. Close observation of the adequacy of respiration and measurement of blood pressure is essential. Slow recovery likely if large amounts of these long half-life drugs are used, rather negating the usefulness of the technique. 2. Haloperidol Less alpha blockade, more sedation, less neurolept potency. Otherwise very similar to Droperidol. B. Phenothiazines Variable degrees of neurolept, sedating, alpha-adrenergic block, anti-histamine, anti-dopaminergic, and anti-cholinergic actions. Useful drugs in anaesthesia for premedication, antiemesis, and sedation. In general the phenothiazines are the "dirtier" of the major tranquilisers and have multiple actions. Chlorpromazine "Largactil". The archetypal phenothiazine ("Largactil = Large actions"). Prochlorperazine "Stemetil". Commonly used anti-emetic. 12.5 mg/ml, 1ml amp. Trimiprazine "Vallergan" (7.5mg/5ml), "Vallergan Forte" (30mg/5ml). Typical dose for oral premedication in children 2-4mg/kg. Promethazine "Phenergan". 25mg/ml in 1ml and 2ml ampoules; 10mg and 25mg tablets. Quite sedating hence useful as a premed, especially with a history of vomiting. Perphenazine 4. Uses in anaesthesia A.Premedication Sedation and anxiolysis are desirable CNS actions of premedication. Early studies used observer assesment of both parameters, but subjective assessment by the patient often yields different results. Sedation is not necessarily associated with anxiolysis, particularly with Droperidol and the major tranquilisers (Forest, Anaesthesiology 47:241-247 1977), and this has been demonstrated also with benzodiazepines and narcotics. Amnesia due to benzodiazepines makes retrospective assessments of their effects difficult. Response variability can be minimised by ascertaining the patients prior response to CNS depressants, current benzodiazepine intake, degree of anxiety, and their age and build, and adjusting the dose accordingly. It is a problem only when either a definite effect is required and none occurs, and more importantly when a substantial and prolonged effect or significant sideffects occur. Problems with prolonged effect are minimised with short half-life agents. Anxiolysis due to Midazolam 0.07mg/kg was investigated using subjective VAS by Artru (AIC 14:152-157 1986) 60 minutes after either Midazolam or Placebo in adults with high pre-op anxiety scores. He found that although Midazolam obviously sedated patients, and that there was a reduction in anxiety score, the reduced anxiety score was not significant. Most studies are similar, in as much as about half show trends to reduced anxiety and about half are "significant". Comparitive data between benzodiazepines and narcotics is limited. Rita (Anaesthesiology 63:523-531 1985) compared morphine 0.15mg/kg to Midazolam 0.08mg/kg as im premedication in children of different ages. Overall good assessments of the quality of sedation from both drugs were made in older children (more than 5 years old). Morpine caused more postop vomiting while midazolam was equal to control. Controls took longer to wake than unpremedicated patients. Midazolam was considered superior to morphine. Children under the age of 5 were more difficult to sedate, but midazolam was better than morphine. Longbottom (BrJA 56:179 1984) used psychometric tests as well as VAS to study Triazolam and showed that 0.25mg had effects for 3-4 hours while 0.5mg still caused impairment at 6 hours. They also found that an independant observers assessment of the degree of sedation correlated well with the psychometric tests (which clearly reflected the CNS actions of the drug), whereas in contrast the patients subjective assessment of sedation was subject to much wider variability and correlated poorly. Galletly (AIC 13:352-4 1985) showed that Diazepam 10 mg had less effect than 0.25mg of Triazolam (in fact little different than placebo) at all times and it appeared that about 20-30 mg of Diazepam would be equipotent. Midazolam 15mg im had greater effect sooner than 0.25mg Triazolam and had completely worn off by 4 hours. They felt that the dose of Midazolam was too high because of excessive sedation at 60 minutes and that the dose of Triazolam was also too high because of delayed effects. Temazepam is readily available and I use it a lot, finding that 10-20mg has little discernable effect except in sensitive patients, and that for substantial sedation 30-40 mg is required. Van Der Walt (AIC 15:151-162 1987) in two studies looked at premedication in children, particularly looking at the effect of Trimeprazine (Vallergan) and comparing it to narcotics, diazepam, and the addition of Droperidol. Trimeprazine 4mg/k compared to Diazepam 0.25mg/kg caused better preop sedation, and postop was associated with much less vomiting, reduced narcotic requirements, and more sedation. Three children of the 46 had untoward responses to Vallergan, ie very prolonged drowsiness, confusion, and one oculogyric crisis requiring drug treatment. The addidtion of Droperidol 0.2mg/kg caused more sedation, less vomiting and reduced narcotic requirements, but interestingly even in combination with hdiazepam had less effect than trimeprazine on its own. Van Der Walt commented on problems with Trimeprazine when very drowsy children are woken up, resulting in a disoriented struggling child. This is common in half asleep children and is seen also with benzodiazepaines. His second study clearly showed that trimeprazine causes much less vomiting postoperatively than Omnopon and Scopolamine or Diazepam premedication. He thinks that it is important to use fairly large (0.4mg/kg) doses of trimeprazine so that the child is extremely sleepy. Problems with trimeprazine include disorientation and delerium, excessive post-op sedation, oculogyric crises, and infrequently significant hypotension (Loan, BMJ 25/5/85 page 290). Finding veins can be difficult as the child often comes to theatre quiet but pale and shutdown peripherally. I don't know of anaesthetic data considering respiratory depression or cardiovascular effects of this drug. B. Sedation Sedation for unpleasant or painful procedures is sometimes provided by anaesthetists. Inhalational agents are commonly used in obstetrics and dentistry and as an adjunct to intravenous agents. Short-duration general anaesthetic agents are reducing the difference in recovery times between sedation and GA. The association between substantial sedation, major local anaesthetic blocks, and subsequent mortality has been documented in Anaesthesiology recently, and the hazards associated with excessive intravenous sedation by inexperienced surgeons or physicians performing the procedure are well known. The temptation to try "just a little sedation" for that horribly unfit patient you don't want to provide a GA for should be resisted. None the less there are times when a bit of sedation is quite appropriate and the problem is that there are a lot of drugs (diazepam, midazolam, methohexitone, propofol, hemineurin, fentanyl, droperidol, ketamine, etc) to choose from, and lots of studies showing how any drug works very well if used skilfully. The ideal agent should provide pleasant sedation, anxiolysis, amnesia, and analgesia, and have no respiratory or cardiovascular depression, vascular toxicity, or untoward sideffects. It should have a 15-30 minute duration of action following iv bolus (shorter duration really necessitates infusion for all but brief procedures), limited by metabolism rather than redistribution, and pharmacological antagonists should be available. All of the drugs mentioned before have differing strengths and weaknesses in each area, and it is also true that the requirements of different clinical circumstances vary widely. Hence the only appropriate solution is to use a drug or variable combination of drugs which best meets the clinical requirements. Experience with resuscitation and airway management and access to the relevant equipment is essential. Apart from ketamine and to a lesser extent the major tranquilisers, airway patency depends on the degree of sedation. Doses of benzodiazepines sufficient to render the patient unconscious always depress respiratory drive and airway reflexes. This is often annoying, particularly when lesser degrees of sedation disinhibit the patient and a little more requires you to provide airway support. Neurolept drugs are usefulwhen this occurs. Small doses of narcotics make sense in painful procedures, but iv they may provoke vomiting. Choice of agent should be appropriate to the duration of the painful stimulus.
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