Barbiturates

Adolf Johann von Baeyer (Fig. 1), Nobel Laureate in Chemistry, synthesised the first barbituric acid in 1864 through a reaction between malonic acid and urea. The name “barbiturate” was coined by von Baeyer himself from a combination of the words urea and Barbara since the compound was discovered on Saint Barbara’s Day. The first compound of the group with sedative properties was barbital or barbitone, also known as “Veronal”, and was discovered by Fischer  (Fig. 2) and his assistant, Dilthey, in 1902. This compound was insoluble, had a very slow onset of action and a prolonged effect, making it unsuitable for intravenous administration. It was used as an oral sedative and was exploited by many famous people to obtain states of unconsciousness or to commit suicide.

The first barbiturate for intravenous use, Somnifene, was only synthesised in 1920. This compound was created by Redonnet, who combined equal parts of Veronal and allylisopropylbarbituric acid. It was first used for a surgical operation in 1924 by Fredet and Perlis and continued to be employed for various years in France and Germany. Sodium amobarbital (Amytal) was described in 1923 and, in the following 4 years, became the most widely used intravenous anaesthetic in North America.

In 1926 pentobarbital (Nembutal) was introduced for experimental use and was adopted in veterinary clinical practice from 1930. Three years later Epivan sodium (hexobarbital) began to be used: this has a faster onset of action but causes involuntary muscle movements during induction, a characteristic shared by all methylated barbiturates. This compound remained very popular, particularly in Europe, until the introduction of thiopental. The thiobarbiturates were created by replacing an O₂ molecule in position C2 with a sulphur atom. The thiobarbiturates are more liposoluble and, consequently, more potent and faster acting. In 1935 Ernest Volwiler and Donalee Tabern (Fig. 3) synthesised a series of sulphur-containing barbiturates, including thiopental, which was to become the most widely used barbiturate in anaesthesia. Thiopental (at the time called thionembutal and later sodium pentothal) was spread by Waters and Lundy and became extensively used because of its rapid onset of action and brief duration of effects, without the above described excitatory effects of Epivan. In 1946 and 1948 two new, ultrashort-acting barbituric acid derivatives were introduced into veterinary practice: thialbarbital sodium and thiamylal sodium.

PHYSICO-CHEMICAL CHARACTERISTICS

Barbiturates are classified as hypnotic sedatives and are derived from barbituric acid, which consists of a pyrimidine nucleus formed from the condensation of malonic acid and urea. This nucleus does not have depressive effects on the central nervous system (CNS), By substituting an alkyl or an aryl group in position 1, 2 or 5, numerous compounds can be obtained which do have depressive effects on the CNS. If the side chain of radical 2 has between two and five carbon atoms, the speed and duration of action of the barbiturate are limited; if, however, this side chain is formed of more than five atoms of carbon, the depressive effect on the CNS decreases and the excitatory and convulsive effects increase. The substitution of an oxygen molecule in C2 with a sulphur atom potentiates the effect of the compounds, but reduces their duration of action, while adding an alkyl radical (in position 1 or 3) increases the anaesthetic power, although the combination tends to stimulate the CNS. Substituting both atoms leads to the formation of compounds with convulsive effects.

The salt solutions are alkaline and usually have a pH between 9 and 10. The most widely used compounds have a pH of 10 or higher and, for this reason, can cause severe tissue damage if injected perivascularly.

Several hundred barbituric acid derivatives have been synthesised, but only some of these have satisfactorily passed clinical experimentation. Of these, only the thiobarbiturate, thiopental (sodium pentothal) is commonly used for the induction of anaesthesia.

The barbiturates can be classified into four groups on the basis of their duration of action:

• Long-acting barbiturates: this group includes barbital and phenobarbital. They are characterized by slow induction after intravenous administration and are used mainly as sedatives and for the long-term control of epilepsy;
• Intermediate-acting barbiturates: this group includes amobarbital and probarbital;
• Short-acting barbiturates: this group includes pentobarbital and hexobarbital. Induction is fairly fast (30-60 seconds) after intravenous injection and the effect is prolonged for 1-3 hours. Pentobarbital is the most widely used of these compounds in veterinary practice and has been used both as a sedative and as a general anaesthetic;
• Ultrashort-acting barbiturates: this group includes thiopental, thiamylal and methohexital. They are compounds with a very fast onset of action (15-30 seconds) after intravenous injection and a short duration of effect (5-20 minutes): they are very widely used drugs in veterinary practice for the induction of anaesthesia and as anaesthetics for short procedures.

Barbiturates are white powders with a bitter taste, except for the sulphated ones which are yellowish. The powder is usually reconstituted with water for injectable preparations to produce solutions of different concentrations; in small animal clinical practice solutions of thiopental 2% or 2.5% are normally used for dogs (20 or 25 mg, respectively, of thiopental per ml), and 1% or 1.25% for cats and small dogs. Barbiturate solutions break down rapidly (4-7 days) if they are not appropriately stabilised.

A decrease in the alkalinity of the solution causes barbiturates to precipitate as free acids; for this reason barbiturates must not be reconstituted with Ringer’s lactate solution or mixed with other acid solutions.

METABOLISM

Barbiturates (with the exception of phenobarbital) are metabolised predominantly by hepatic microsomes. The disappearance of pentobarbital from the plasma of dogs is due both to hepatic metabolism of the drug and to its distribution into muscles and adipose tissue. The speed with which the metabolism occurs depends on the species: in the dog, in 1 hour about 15% of the dose of pentobarbital is metabolised and the animal wakes when 30-40% of the dose has been metabolised. The products of metabolism are promptly eliminated in the urine and bile. The thiobarbiturates are inactivated predominantly in the liver, but also by extra-hepatic tissue, in particular the brain and kidneys. Hepatic metabolism is the most important mechanism of elimination of all the barbiturates with the exception of phenobarbital: this compound is eliminated mainly through renal excretion, a route of elimination also used by the other long-acting oxybarbiturates.

PHARMACOKINETICS

After intravenous administration, the barbiturates are distributed more or less uniformly in all districts of the body. The specific values of the volume of distribution (Vd) have not been determined for many barbiturates. These values differ not only depending on the particular drug, but also according to the species of animal in which they are used. The most important factors determining the plasma levels of a barbiturate are the dose administered, the route of administration and the speed of administration. Following intravenous injection, the effect and duration of action of the barbiturate depend on haemodynamic and biochemical factors: the degree of ionisation, liposolubility and plasma protein binding. The barbiturates are acids bound to sodium, producing sodium salts: dissolved in blood, they have an ionised form (39%) and a non-ionised form (61%). The ionised form reacts with the water dipole of the cell wall and does not penetrate quickly into the cell, unlike the non-ionised form which is pharmacologically active. If the pH of the arterial blood is 7.4, 61% of thiopental and 83% of pentobarbital is present in the active (non-ionised) form and the drug has a “normal” distribution between the cells of the CNS, producing the desired degree of anaesthesia. If, however, the pH decreases, as in respiratory or metabolic acidosis, the depth of anaesthesia increases, since the proportion of the ionised (or inactive) form increases, while if the pH increases, for example during hyperventilation or after the administration of alkalinising agents, there is higher proportion of the active form.

The speed of penetration of the drug across the blood-brain barrier is determined by the plasma concentration reached, which, in turn, is regulated by two factors: the dose administered and the speed of administration. The thiobarbiturates are initially present at high concentrations in highly vascularised tissues (e.g., the brain), causing rapid induction of general anaesthesia; subsequently they are redistributed in moderately vascularised tissues (e.g., muscles) with a consequent decrease in the cerebral concentration to levels that allow recovery of consciousness.

MECHANISMS OF ACTION

The main effect of barbiturates is depression of the CNS through interference of the passage of nerve impulses to the cerebral cortex. The degree of depression of the CNS can vary, such that the state induced can range from light sedation, through hypnosis, to surgical anaesthesia. The barbiturates have multiple mechanisms of action, not all of which are yet understood. The anaesthetic effect is caused by an increase in the inhibitory activity at the receptors for gamma-aminobutyric acid (GABA).

CLINICAL USE OF BARBITURATES

Barbiturates are used to induce sedation and hypnosis and as anticonvulsants. As sedatives, the barbiturates have been superseded by tranquillisers and sedatives that are more manageable and have fewer side effects. The barbiturate that is most widely u

sed for the induction and maintenance of anaesthesia is thiopental, because of its rapid onset of action (about 30-40 seconds), gentle induction and swift recovery of consciousness (10-15 minutes) after its administration. Thiopental does not have analgesic activity and must, therefore, be administered together with analgesics in order to obtain loss of reflex responses to painful stimuli. Maintenance of anaesthesia with thiopental is not recommended given the drug’s slow metabolism, which leads to the accumulation of the substance in various tissues, including adipose tissue, with consequent prolongation of the time to recover consciousness

ADMINISTRATION AND DOSE

In veterinary practice, barbiturates are used mainly by the intravenous route. The drug administration is titrated “to effect”, that is, the total dose of the drug administered depends on the depth of anaesthesia desired. The doses depend on the species, breed, individual characteristics, clinical conditions, state of sedation, etc.

The dose necessary in healthy, not pre-medicated dogs to produce a state of unconsciousness sufficient to enable orotracheal intubation is 20-25 mg/kg, but the dose can be halved (8-12 mg/kg) if the animal is pre-medicated. Thus, the administration of potent sedatives (alpha₂-agonists with or without opioids), reduces the amount of anaesthetic necessary to 6-8 mg/kg in the dog and to 8-10 mg/kg in the cat.

Fig. 6. Approximate doses of thiopental (expressed in mg/kg) necessary to produce anaesthesia alone or after pre-medication with    various drugs in healthy dogs.

Considering the tissue damage that thiopental can cause and the severe consequences of perivascular administration (Fig. 7), it is recommended that this drug be administered through a cannula, which minimises the possibility of errors. In the case of extravascular injection, infiltrating the region with 1 or 2 ml of a solution of lidocaine hydrochloride 2% or hyaluronidase can mitigate the thiopental-induced damage.

The duration of effect of a single dose of thiopental (without pre-medication) is about 10-15 minutes. Various factors can cause differences in the response to a single dose of each of the barbiturates; these factors include age, sex, obesity, shock or hypovolaemia, liver dysfunction, hypothermia, acid-base disorders, uraemia and hypoproteinaemia.

NEGATIVE EFFECTS OF BARBITURATES

The main side effects of barbiturates are depression of the respiratory centre (particularly when the drug has been administered too fast or at high doses) and cardiovascular depression.

Both these effects are unpredictable and related to the above listed variables (dose, rate of administration, the animal’s condition, contemporaneous administration of other drugs, etc.).

In the case of marked overdose, death usually occurs from respiratory arrest, followed by cardiac arrest, although particularly high doses can depress the cardiocirculatory apparatus directly.

EFFECTS ON THE CENTRAL NERVOUS SYSTEM

As already mentioned, all barbiturates depress the CNS and, depending on the dose used, are able  to cause simple sedation or even comatose states. The barbiturates do, however, differ from each other for effective dose, speed of onset of action and duration of effect. These compounds depress the cortex, thalamus and motor areas of the encephalon. The reticular activating system of the mesencephalon seems to particularly sensitive to the depressant effects of barbiturates.

EFFECTS ON THE CARDIOVASCULAR SYSTEM

The barbiturates induce various effects on the cardiovascular system depending on the species of animal to which they are administered, the type of drug, its dose and its route of administration.

The vasomotor centre is particularly influenced by the high blood concentrations of thiopental that can be reached during rapid intravenous administration of large doses of the drug. The first effect of the drug is peripheral vasodilatation caused by depression of the vasomotor centre, which leads to pooling of blood in peripheral tissues and an abrupt fall in blood pressure, a decrease in venous return (preload) and, therefore, cardiac output. Systemic hypotension is more common when the drug is administered at high doses, at a fast rate and if the patient is already hypotensive or has heart failure.

Arrhythmias are common after the administration of thiopental and their appearance is promoted by the use of xylazine, halothane and adrenaline. The mechanism by which thiopental triggers arrhythmias remains unclear, but seems to be related to a decrease in permeability to potassium.

EFFECTS ON THE RESPIRATORY SYSTEM

Barbiturates induce depression of the bulbar respiratory centre and common side effects are, therefore, a reduction in the tidal volume and/or the development of brief periods of apnoea; a rapid administration of the drugs increases the incidence of these phenomena. As the plasma concentration decreases, respiration becomes regular again, although at a slower rate and with a lower minute volume.

Barbiturates also alter the threshold and sensitivity of the respiratory centre, as well as the aorto-carotid chemoreceptors, to CO₂, causing an attenuated respiratory response to high values of PaCO₂. The apnoea induced by barbiturates can be treated with controlled ventilation until spontaneous respiration is recovered.

HEPATIC EFFECTS

The liver is affected only marginally by the administration of thiopental. Any effects on this organ are due to the effects that the drug has on the cardiocirculatory apparatus: the decreases in cardiac output and blood pressure are reflected by a decrease in the perfusion of the liver.

Thiopental is metabolised slowly and, although redistribution is the main cause of recovery of consciousness, severe hepatic dysfunction, as occurs, for example, with porto-systemic shunts, can delay the recovery of consciousness.

RENAL EFFECTS

Barbiturates do not have direct effects on the kidney, but can reduce renal blood flow by as much as 40%. Sensitivity to barbiturates is increased in uraemic animals, in which the time to recover consciousness is prolonged. This phenomenon is related to the decreased capacity of acidic drugs, such as the barbiturates, to bind to plasma proteins. Barbiturates should, therefore, be used with caution and at minimal doses in uraemic animals.

By causing hypotension, barbiturates can indirectly provoke oliguria or anuria, an effect that becomes important if prolonged, as in the case of overdosage.

EFFECTS ON THE GASTROINTESTINAL TRACT

Ultrashort-acting barbiturates do not cause a prolonged decrease in the activity of the gastrointestinal tract. The incidence of gastro-oesophageal reflux after administration of a barbiturate was 17.6%. Contractility of the gastro-oesophageal sphincter is not altered.

METABOLIC AND ENDOCRINE EFFECTS

At anaesthetic doses, thiopental decreases basal metabolism, which, in association with peripheral vasodilatation and depression of the thermoregulatory centre, can cause a drop in body temperature. The animal’s body temperature tends to equilibrate with the environmental temperature during anaesthesia because of the decrease in thermogenesis and increased loss of body heat due to peripheral vasodilatation.

Thiopental causes a decrease in plasma cortisol concentration to below the basal level as a result of the general anaesthesia; however, it does not prevent the release of cortisol or aldosterone in response to surgical stress.

HAEMATOLOGICAL EFFECTS

Thiopental reduces the haematocrit and the white blood cell count, while its effect on total proteins is variable. The reduction in haematocrit seems to be due to splenic sequestration of red blood cells. This decrease increases the hydrostatic pressure and movement of fluids in the circulatory system.

PREGNANCY AND CAESAREAN DELIVERY

Barbiturates cause foetal depression characterized by a reduction of respiratory function, somnolence and decreased vitality; these effects are less evident when the dose is less than 4 mg/kg. The neonatal liver lacks the hepatic microsomal system involved in the metabolism of drugs such as barbiturates and renal function is also less efficient than that of the adult at eliminating the anaesthetic.

USE IN PAEDIATRIC AND ELDERLY SUBJECTS

Paediatric patients (more than 6-8 weeks) need higher doses of thiopental, probably because such animals have a larger central volume and more rapid hepatic clearance. In contrast, neonates and elderly subjects are very sensitive to thiopental and for this reason the dose must be reduced. Recover of consciousness can be delayed because of immature or altered renal and hepatic function and/or because a low concentration of plasma proteins.

EFFECTS ON THE EYE

Thiopental decreases intra-ocular pressure. Apart from the reduction in systemic arterial pressure, the mechanism for this decrease seems to involve depression of the areas of the CNS (diencephalon) that influence intra-ocular pressure.

CLINICAL USES

Barbiturates are used in veterinary anaesthesiology to produce a state of hypnosis and muscle relaxation sufficient to enable orotracheal intubation of the animal, which can then be maintained in an anaesthetised state with other specific drugs such as halogenated compounds.

FACTORS INVOLVED IN THE VARIABLE RESPONSE TO BARBITURATES

Besides the most important and already mentioned factors, such as weight, age, hepatic dysfunction and renal dysfunction, other factors are also able to alter the response to barbiturates:

• repeated doses: these can prolong the return to consciousness, because this is related mainly to tissue redistribution;
• chronic tolerance: barbiturates can induce liver enzymes, so frequent administration of short- or ultrashort-acting barbiturates can increase the capacity of the liver to detoxify these drugs;
• excited or frightened patients: such subjects often require higher doses of barbiturates to obtain a normal anaesthetic effect. This requirement is partly due to greater excitation of the CNS, but also to the greater blood flow to striated muscles (the “fight or flight” phenomenon) which occurs in frightened or excited animals as a result of stimulation of b₂receptors;
• substances that can potentiate the effects of the barbiturates: substances that break drug-protein bonds can increase the amount of unbound barbiturate and amplify its effects, while substances that are detoxified by the same hepatic metabolic pathways can prolong the anaesthetic effect of barbiturates.

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