Classification of Anaesthetics | Drugs

After reading this article you will learn about the classification of anaesthetics.

Distribution of Volatile Anaesthetics:

Volatile anaesthetics are stable within the body and are eliminated in the same form in which they are inhaled. Their movement within the body confirms to the fundamental gas laws. A volatile anaesthetic affects the nervous tissue by reversible physical union with the vital cellular substance. It is in the state of gaseous equilibrium.

Volatile anaesthetic is effective by rate of administration given generally by inhalation. In the alveoli of lungs the anaesthetic gas diffuses through the separating membranes into the circulating blood of lung capillaries. According to gas law of Dalton and Henry, greater the concentration of anaesthetic gas in the alveolus, the greater is the partial pressure and that greater will be solubility in blood.

The gaseous anaesthetic being dissolved in the blood is transported to lipoidal tissues into which it differs as a result of greater solubility in fats than in a gaseous media. CNS contains more lipids than any other part of body and therefore, attracts more anaesthetic than any other system.

In addition, CNS is highly vascular, so that proportionately more anaesthetic is carried to that part of the body. This makes the CNS more susceptible than any other system to the effect of anaesthetic because of high vascularity and lipoidal content.

On the other hand, the anaesthetic will diffuse out of the brain more quickly than other tissues with smaller blood supply. During the administration, concentration gradient is higher in arterial blood than in tissues of the body and therefore, much of the anaesthetic in blood diffuses out into the tissues. The excretion of inhalant anaesthetic is mainly through the process of diffusion but in reverse direction and the rate depends upon the ventilation rate of lungs.

Chloroform (CHCI₃):

(Tri-chloromethane)

The use of chloroform in modern anaesthetic practice is obsolete. It was used in horses and has been replaced by halothane which is more safer anaesthetic. It is used to produce euthanasia (painless-death) for killing street dogs. The B.P. of chloroform is very high i.e., 61 °C. It produces phosgene which is very-very irritant. Ethyl alcohol is also used as a solvent or cleansing agent and as an ingredient in pharmaceutical formulations.

Pharmacological Actions:

Moderate potency, MAC value-0.77% as compared to 0.87% of halothane, more potent than halothane, more soluble than halothane, induction and recovery takes longer time, more toxic than ether on heart and kidney, pronounced cardiopulmonary inhibition; nephrotoxic and hepatotoxic produces central tubular necrosis of liver, fatty degeneration of heart, liver and kidney; produces all the four stages of anaesthesia, is not inflammable and explosive.

Death in Chloroform Anaesthesia:

during

(A) Induction stage because of reaching higher concentration in brain due to a result of initial breathe holding followed by deep inhalation. This causes ventricular fibrillation. Due to excitement and struggling epinephrine is released from adrenal medulla precipitating cardiac fibrillation.

Horses die after few inspiratory gasp. Adrenaline sensitizes heart to the action of chloroform.

(B) In deep stages of anaesthesia it causes increased respiratory depression, stage IV may come as a death.

(C) After 24-48 hours of post anaesthesia there is delayed chloroform poisoning. This occurs due to fatty degeneration of heart, liver and kidney and central lobular necrosis of liver.

Advantages:

(i) It is not flammable or explosive

(ii) Inexpensive.

(iii) Induction and recovery is rapid.

(iv) Easy administration (open method).

Disadvantages:

(i) Potential toxicity prevents its use.

(ii) It has also been proposed to be carcinogenic.

Uses:

(i) Brief anaesthesia (small period anaesthesia) for boar and stallion castration.

Ether:

It is highly flammable and explosive. Ether is oxidised to peroxide when exposed to air and moisture. It is irritant and onset of anesthesia is delayed. Ether vapour is ignited and may cause explosion and hence, not kept in refrigerator. Interference with electric relay mechanism of refrigeration (Never keep in refrigerator). Ether is metabolised to CO₂ which is non toxic.

External Use:

(i) Rubefacient when applied to skin and rubbed with friction.

(ii) Solvent of fat and inorganic matter and used as cleansing agent.

(iii) After oral administration, it is antispasmodic, carminative and diffusible, stimulant to heart.

Inhalation:

(i) Ether is safest of all general anaesthetics when used with pre-medicants.

(ii) Produces all stages of anaesthesia.

(iii) Satisfactory muscle relaxation (due to motor end plate action), neuro-muscular blocade, central effect, and adequate analgesia.

(iv) Does not produce cardiopulmonary inhibition rather stimulates in the induction stage.

(v) Cost is low or inexpensive.

(vi) Does not require complicated method of application.

Disadvantages:

(i) Potency low [MAC value high (3%)].

(ii) Induction and recovery slow because it is highly soluble in blood.

(iii) B.P-35° C, so difficult to use in hot climate, flammable and explosive.

(iv) Irritates mucous membrane of respiratory tract and increases the respiratory secretion.

Clinical Uses:

(i) Permits satisfactory anaesthesia in young pigs, dogs, calves and cats.

(ii) Good laboratory anesthetic (rat and mice).

Ether and Balanced Anaesthesia:

Methoxy Flurane:

It is not flammable and explosive. It can be used both in large and small animals anaesthesia for both induction and maintenance anaesthesia. It is most potent because MAC, value is least (0.23%).

Potency is inversely proportional to MAC value. It is cardio pulmonary inhibitor and causes circulatory and respiratory inhibition. It does not produce significant change in heart rate and blood pressure. It can produce cardiac erythmia which is abolished by atropine.

However, it produces hypotension. The induction and recovery is slow (disadvantage). Relaxation of skeletal muscle, loss of tone and analgesia are excellent. It is not a hepatotoxic. Renal toxicity is a real problem, it is metabolised in liver by the process of di-fluorination and de-chlorination and there is formation of di-chloroacetic acid. The extent of metabolism is very high i.e. 20%.

Advantages:

(i) Most potent, least MAC value.

(ii) Non flammable, non explosive.

(iii) Excellent muscle relaxant and analgesic activity.

(iv) Involuntary excitement is less (stage II does not occur).

(v) Not toxic to liver.

Disadvantages:

(i) Slow induction and recovery.

(ii) Pronounced cardiopulmonary inhibition.

(iii) Potential renal toxicity.

Contraindication:

May not be used in renal dysfunction.

Clinical Uses: Cattle:

(i) Slow induction and recovery of anaesthesia, so it is mainly used as maintenance anaesthetic.

(ii) Pentobarbital sodium (i.v.) should be given for induction followed by 1-30% methoxy-flurane to maintain the anaesthesia.

Horse:

It is not used as general anaesthetic in horse. Halothane is preferred over meth-oxy-flurane in equine.

Pig:

(i) Meth-oxy-flurane (3%) and N₂O (70%) should be given for induction of anaesthesia.

(ii) To maintain anaesthesia N₂O (70%) and O₂ (30%) mixture is used.

Sheep and Goat:

(i) Pentobarbital (20 mg/kg, i.v.) is given for induction (stage I and II).

(ii) For maintenance (stage III and IV) 2-3% meth-oxy-flurane is given.

Dog and Cat:

(i) Preanesthetic is followed by meth-oxy-flurane.

(ii) Xylazine is very good premedication in case of dogs.

(iii) Ketamine is preferred as premedication in cats.

(iv) For induction and maintenance, meth-oxy-flurane is used.

Birds:

meth-oxy-flurane is used for induction and maintenance anaesthetic.

Halothane:

It is non-flammable and non-explosive anaesthetic. Metabolism of halothane is through the process of de-fluorination and de-chlorination (dehalogenation).

Pharmacological Action:

(i) Potency of halothane is next to meth-oxy-flurane and chloroform (meth-oxy-flurane (0.23%) < Chloroform (0.77%) < halothane (0.87%).

(ii) The induction and recovery of anaesthesia is rapid because of moderate degree of solubility

(iii) Excitement and struggling of stage II are absent which is an advantage.

(iv) Cardiac arrhythmia may occurs during induction. Bradycardia and hypotension may occur.

(v) Respiratory depression is also marked.

(vi) Increased cardiopulmonary inhibition i.e. in plane III and IV.

(vii) Muscle relaxation and analgesia adequate.

(viii) Post anaesthetic nausea and vomition are less troublesome.

(ix) Less side effects.

(x) Hepatotoxicity is not a problem in veterinary anaesthesia.

Advantages:

(i) Moderate potency.

(ii) Induction and recovery is relatively a rapid process.

(iii) Non-flammable and non-explosive.

(iv) Relatively non-irritant. It produces less respiratory tract secretion (no laryngeal spasm) and salivation.

(v) It is used for both induction and maintenance anaesthetic but preferably it should be used as maintenance anaesthetic.

Disadvantages:

(i) Cardio pulmonary inhibition is pronounced.

(ii) It is expensive and thus should be used by semi-closed and closed system.

Clinical Use:

Cattle and Horse:

(i) Mainly used as maintenance anaesthetic in equine. Because of high cost not used for induction.

(ii) The induction is done with pentobarbitone sodium (i.v.).

(iii) Maintenance is done with N₂O and halothane. Because N₂O reduces the effect of halothane on inhibition of cardiopulmonary effect.

Sheep and Goat:

(i) As in cattle and horse.

(ii) Halothane + N₂O + O₂ is used as maintenance anaesthetic.

(iii) Similar procedure is adopted in dog and cat.

(iv) It is not a totipotent anaesthetic (stage III is absent).

Trichloroethylene:

It is a potent analgesic. It reacts with soda lime to form neurotoxins called di-chloro-acetylene which is toxic to cranial nerves. It produces poor muscle relaxation. It possesses increased cardiopulmonary inhibition. The use of tri-chlor-ethylene as anaesthetic is obsolete.

Enflurane:

It is a new inhalent convulsant anesthetic for use in humans. It is chemically 2- chloro-1, 1, 2-trifluroethyl difluoromethyl ether. It is a potent volatile anaesthetic and structural analog of methoxy flurane. It is colourless, nonflammable liquid. It is not metabolized and eliminated in expired air in the unaltered form.

Pharmacological Property:

(i) Increases CNS irritability.

(ii) It induces anaesthesia and amnesia by functional disruption.

(iii) Cortical hyper excitability is produced in humans.

(iv) At the concentration of 3.12% enflurane produces grandmal seizure like activity in horses.

(v) Twitching of facial muscles, neck, limbs and abdominal wall occurs.

(vi) Clinical Uses:

(i) Thiamylal or thiopental may be given prior to enflurane (muscle twitching does not occur).

(ii) Diazepam (anticonvulsant) is given (0.35 mg/kg i.m) 45 minutes before enflurane, minimizes CNS excitation in dogs.

(iii) Pretreatment of dogs with ethosuximide (anticonvulsant) is most effective drug in raising enflurane seizure threshold.

(iv) Moderate level of surgical anaesthesia is considered to be 1.5 MAC.

(v) Depresses cardiovascular function in the horse to a greater degree compared with halothane.

(vi) Respiration depression is observed with a reduction in rate and depth after increased concentration.

Advantages:

(i) Non-irritant to respiratory tract.

(ii) Renal impairment does not occur.

Iso-flurane:

Iso-flurane and enflurane are structural isomers. They contain the same number of atom of fluorine, chlorine, carbon, hydrogen and oxygen. It is non-flammable halogenated and most ideal with respect to biotransformation in humans. It is metabolised to inorganic fluoride and trifluoroacetic acid.

However, it is metabolised one-tenth that of enflurane and one hundredth that of halothane. It is not toxic to liver and kidney (due to less metabolism). It is mildly pungent similar to enflurane. The solubility of iso-flurane in blood is lower than halothane, enflurane or meth-oxy-flurane.

It has been approved by the FDA for anaesthesia in horses.

Pharmacological Properties:

(i) It is not convulsant anaesthetic like enflurane.

(ii) CNS irritability may be absent or reduced.

(iii) The MAC in healthy un-sedated horse is 1.31%.

(iv) Anaesthetic potency is greater than enflurane but less than halothane.

(v) In dog MAC is 1.5% and 1.6% in cat.

(vi) Depresses cardiovascular function equal to halothane but less than enflurane in horse.

(vii) The margin of safety is greater for the cardiovascular system than that of other potent inhalent anaesthetics.

(viii) Provides skeletal muscle relaxation for surgical procedure.

(ix) Recovery is shortest.

Gaseous Anaesthetics:

Nitrous oxide and cyclopropane are two important gaseous general anaesthetics given by inhalation.

Nitrous Oxide (N₂O):

It is grouped under major inhalent anaesthetics used in veterinary medicine. Its importance has increased with the introduction of meth-oxy-flurane and halothane in animal anaesthesia because nitrous oxide decreases the cardiac pulmonary depressant effect of meth-oxy-flurane and halothane. It is relatively insoluble in blood thus induction is rapid.

The potency of nitrous oxide is poorest with a MAC value of 105% (man), 188% (dog) and 205% (cat). Nitrous oxide induces only stage I and II. Therefore, it is least potent among all inhalent anaesthetics. It produces excitation instead of depression of CNS. If administered at higher atmospheric pressure nitrous oxide may produce cataleptoid like symptoms and seizures (convulsion). It does not affect the cardiopulmonary function.

Replease of epinephrine and norepinephrine does not sensitize myocardium to the action of nitrous oxide. This agent must be used in combination with oxygen to avoid induction of hypoxia. If hypoxia occurs it may injure the brain tissue irreversibly which is a great danger. 20% nitrous oxide with 80% oxygen produces only analgesia.

The concentration most commonly used is 30% nitrous oxide and 70% oxygen that produces analgesia and loss of consciousness in some patient. However, 80% nitrous oxide, and 20% oxygen produces analgesia and loss of consciousness in most patients but at this concentration there is danger of hypoxia.

Nitrous oxide does not affect liver and renal function. Muscle relaxation is poor and it may produce muscle twitch and seizure (in epileptic patient). Laryngeal spasm does not occur unless hypoxia is present. There is no side effect of post operative nausea and vomition.

Clinical Uses:

(i) Nitrous oxide and oxygen mixture can not be used alone in maintenance of anaesthesia. Therefore, nitrous oxide is commonly used with preanesthetic medication.

(ii) It has been used as maintenance anaesthetic in horses, pigs, ruminants, dogs and cats.

(iii) Nitrous oxide (low potency), nitrous oxide, oxygen and halothane (high potency) i.e., a triple mixture is used. Nitrous oxide reduces the MAC value of halothane with a decrease in dose to 25% and provides good effect.

(iv) Nitrous oxide, oxygen and meth-oxy-flurane is also used, but pre medication of atropine and acepromazine is given before administration.

Induction:

(i) Thiopental sodium (i.v) is given followed by nitrous oxide and oxygen.

(ii) Neurolept analgesic (droperidol + Fentanyl) is first given then N₂O + O₂.

(iii) In cat, ketamine (Dissociative anaesthesia) is followed by N₂O + O₂.

Cyclopropane (Tri-Methylene):

(i) B.P. —32.9°C.

(ii) Metabolised to CO₂ to the extent of 0.5%.

(iii) Rapid induction and recovery because it is almost insoluble.

(iv) Potency is least (MAC value is high i.e., 17.5%) which is 6-8 time less potent than ether (MAC value 2.3% in dog).

(v) Less irritable to mucous membrane of respiratory tract.

(vi) No renal and liver toxicity problem (least toxicity problem).

(vii) It has least effect on respiration, therefore, preferred in thoracic surgery.

(viii) Blood pressure is rarely affected.

Disadvantages:

(i) Flammable.

(ii) Very costly.

(iii) Muscle relaxation is poor.

(iv) There is tendency of capillary oozing because of vasodilation.

(v) Cumbersome method of administration (closed method with total rebreathing).

(vi) Mainly used in humans (use declined due to least potency).

(vii) May be used in small animals.

Intravenous Anaesthetics:

The stages of anaesthesia obtained after i.v. anaesthetics are similar to that of inhalants. However, one can proceed rapidly through induction with i.v. anaesthetics as compared to inhalent anesthetic. Stage II of anaesthesia is bypassed by i.v. anaesthetics. Therefore, struggling and excitement of induction is avoided.

Advantages of i.v. Anaesthetics:

(i) It is easy to administer.

(ii) It directly produces stage III of surgical anaesthesia.

(in) It is safe for patient, veterinarian and handlers.

(iv) It may be administered in the presence of diathermy or thermo-cautery.

(v) It provides smooth recovery (horses show excitement)

(vi) Nausea and vomition are absent (in some cases vomition may occur in recovery period).

(vii) Post anaesthetic period is free from complications.

(viii) It does not interfere with operative areas.

Disadvantages of i.v. Anaesthetic:

(i) Depth and level of anaesthesia is not controlled.

(ii) The overdose cannot be easily detoxified.

(iii) It provides moderate muscle relaxation.

(iv) It does not relax abdominal muscles.

Classification of i.v. Anaesthetics:

A. Barbiturates:

e.g., a. Pentobarbitone sodium (Nembutal)

b. Thiopental sodium (pentothal)

c. Thiamylal sodium

d. Thialbarbitone

e. Methohexital

B. Non-barbiturates:

e.g., a. Chloral hydrate

b. Chloral hydrate + Magnesium sulphate

c. Chloral hydrate + Magnesium sulphate + Pentobarbitone sodium.

C. Dissociation-anaesthetics:

e.g., a. Phencyclidine

b. Ketamine.

c. Tiletamine

D. Steroid anaesthetics:

e.g., Althesin

E. Neurolept anaesthetics:

e.g., a. Droperidol + Fentanyl

b. Droperidol + Fentanyl + N₂O (66%).

F. Miscellaneous Agents:

e.g., a. α-chloralose

b. Urathane

c. Etomidate

Barbiturates:

Barbiturates are derivative of barbituric acid or malonyl urea. Barbituric acid as such has depressant effect on CNS. The basic compound barbituric acid is the condensation product of urea and malonic acid and consists of a six membered ring structure (Fig. 7.1.). To make barbituric acid effective some substitution are made by replacement of the hydrogen atoms attached to carbon atom 5 and 2.

There are many barbituric acid derivative e.g. butabarbital, hexobarbital, methobarbital, talbutal. These derivatives of barbituric acid are seldom used in veterinary medicine. Most widely used barbituric acid derivatives are phenobarbital sodium, barbital sodium, amobarbital sodium, pento barbital sodium, secobarbital sodium, thiopental sodium, thiamylal sodium, thialbarbital sodium and methohexital sodium. The later mentioned barbiturates are widely used.

Chemistry:

Barbiturates are colourless, odorless, crystalline, white powders having a bitter taste (except sulfur containing barbiturates) and are sparingly soluble in water. They are hygroscopic and decompose after exposure to air, heat and light. Therefore, they are kept in dark bottles sealed ampules or coloured capsules.

Solutions of barbiturates decompose rapidly, however, solutions or certain thiobarbiturates entirely decompose in 36 hours at room temperature but will last longer if refrigerated. When the hydrogen’s on carbon 5 are substituted with an alkyl or aryl group, depressant activity on the CNS is possessed by the compound. A few barbiturates contain sulphur atom attached to carbon 2 in place of oxygen.

Barbiturates with carbon 5 substituted of are sparingly soluble in water. Solutions of barbiturates in water are weak acid and combines with sodium or other fixed alkalies to form water-soluble salts. The Na⁺ atom joins the oxygen atom of carbon 2. These salts form alkaline solution of a pH between 9 and 10.

Structure Activity Relationship:

(i) Both hydrogen atoms on carbon 5 must be replaced by an alkyl or aryl group for CNS depressant activity.

(ii) The substituting radicals on carbon 5 should contain a minimum of 4 and maximum of 9 carbons for obtaining optimal therapeutic effect. Addition of more than 9 carbons at C₅ leads to convulsant activity.

(iii) Unsaturated carbon chains are readily oxidised and act as short acting.

(iv) Short chains are more stable and therefore, act as long acting.

(v) Long chains are easily oxidised and act as short acting.

(vi) Branched chains provide shorter duration of action than straight chains.

(vii) Only one aryl radical should be attached to C₅.

(viii) Substitution of the oxygen atom on C₂ by a sulphur atom increases potency and instability but decreases duration of action of the compound.

(ii) Attachment of an alkyl group to one of nitrogen atoms at position 1 or 3 increases the anaesthetic potency and stimulates the CNS. If substitution is made in both nitrogen atoms convulsant activity is obtained.

Classification:

(i) Long acting Barbiturates (duration of action 6-12 hrs.). e.g., phenobarbital.

(ii) Intermediate or medium acting (duration of action 3-6 hrs.) e.g., Butobarbital, Pentobarbital.

(iii) Short acting (1-3 hrs), secobarbital, hexobarbital.

(iv) Ultra short acting (20-30 minutes), thiopental, thiabarbital, methohexital.

Pharmacological Action:

Barbiturates cause the reversible depression of the activity of all excitable tissues, primarily the CNS. The exact mechanism of action of barbiturates are not well known. However, it is believed that barbiturates facilitate inhibitory neuro- transmission in the CNS by interacting with proteins of the GABA and thus open chloride channels and hyperpolarize neuronal membrane.

Central Nervous System:

Barbiturates depress the CNS from a mild sedation to general anaesthesia. They depress the polysynaptic responses and thus delay the synaptic recovery. Small doses may have GABA like action.

(a) Sedation and Hypnosis:

The long and intermediate acting barbiturates are used for sedation and hypnosis. Therefore, phenobarbital is given for sedation and pentobarbital is used for induction and maintenance of sleep.

(b) Anaesthetic Effect:

Thiobarbiturates (short acting) after i.v. administration produce basal or general anaesthesia.

(c) Anticonvulsant Effect:

All barbiturates if given in anaesthetic doses inherit convulsions due to epilepsy and tetanus. Phenobarbital and mephobarbital are used to prevent grandmal epileptic seizures.

(d) Analgesic Effect:

Barbiturates lessen the pain sensation producing a loss of consciousness.

(e) Spinal Cord:

Barbiturates depress the polysynaptic and the monosynaptic reflexes of the spinal cord.

Cardiovascular System:

Barbiturates may cause a slight decrease in blood pressure and heart rate. Toxic doses of barbiturates produce hypotension for a longer period (i) due to direct depression of myocardium and the vasomotor centre (ii) hypoxia (iii) blockade of sympathetic ganglia.

Respiratory Center:

Therapeutic doses of barbiturates depress respiration slightly (not in cat). In cat the reticular formation feeds signals or impulses into the medullary control centres governing respiration, thus the cat reacts adversely to barbiturates. Therefore, anaesthesia must be induced with particular caution until learnt more above the sensitivity of the cat to barbiturates.

Subanaesthetic doses of barbiturates increase respiration rate. However, large doses are depressant to the respiratory centre in the medulla. Doses of barbiturates that induce deep surgical anaesthesia severelly depress the respiration producing dangerous hypoxia and respiratory acidosis.

Barbiturates inhibit respiratory centre at lower blood concentrations than that arresting the heart. Therefore, in case of respiratory arrest during barbiturate anaesthesia, respiration should be reestablished because the heart continues to function for a brief period.

Gastrointestinal Tract:

Sedative doses of barbiturates do not affect the motility or gastrointestinal tract.

Kidney:

Hypnotic dose of barbiturates do not affect the urine output. When barbiturates are given i.v. to produce anaesthesia cause decrease in urinary output (due to decrease in glomerular filtration rate). Acute barbiturate toxicosis is generally associated with oliguria (due to severe hypotension).

Liver:

In therapeutic doses barbiturates do not produce hepatic disorders. By combining with cytochrome P_-450 competitively interfere with the biotransformation of a number of substrates of this enzyme. Barbiturates, that do not undergo significant hepatic detoxification, stimulate the microsomal enzyme systems responsible for drug inactivation. Barbiturates also stimulate the hepatic metabolism of certain other agents.

Uterus and Fetus:

Sedative doses of barbiturates do not affect uterine activity. Anaesthetic doses depress the uterine concentration during parturition. Pentobarbital and thiopental in concentrations that do not produce maternal anaesthesia, inhibit fetal respiratory movements. Clinically, cesarean section performed solely under barbiturates anaesthesia depress the fetus and may cause 100% fetal mortality.

Metabolic Rate:

Sedative doses of barbiturates do not affect the basal metabolic rate. However, doses of barbiturates that produce surgical anaesthesia depress basal metabolism thus less body heat is produced during anaesthesia and there is excessive heat loss due to vasodilatation. Therefore, patient going under surgical anaesthesia must be kept warm especially when overdose is given.

Skeletal Muscle:

Barbiturates do not relax the abdominal musculature therefore, for getting more muscle relaxation, d-tubocurarine may be used. The photo-motor reflex should be checked to determine whether the animal is regaining consciousness when skeletal muscle relaxant is used with a barbiturate-anaesthetic. Barbiturates cause muscular ischemia during the recumbent phase of anaesthesia leading to post- anaesthetic forelimb lameness (due to weight of large animal lying in recumbent position).

Absorption:

Barbiturates are readily absorbed orally and intramuscularly. They are weak acids and maximum absorption occurs from the stomach specially in dogs. Sodium salts are uniformally and rapidly absorbed after oral administration. The rate of absorption is faster for short-acting and slower for long-acting barbiturates. After an i.v. injection pentobarbital in plasma reaches distribution in the brain within 3-4 minutes.

Distribution:

After absorption, barbiturates are distributed throughout the body. A fraction of the barbiturate in blood is reversibly bound to plasma albumin. They cross the placental barrier and may be secreted in milk. Their lipid solubility, degree of protein binding and per cent of ionization affect their distribution. The apparent values of volume of distribution differs in different species.

The V_d value of pentobarbital is 0.72 L/kg in goat after i.v. (30 mg/kg) administration. The half-life of pentobarbital in goat is 0.9 hour whereas in dog it is 8.2 hours.

Thiopental is highly lipid soluble and passes the blood brain barrier. Phenobarbital has low partition coefficient, penetrates the blood brain barrier more slowly. Therefore, phenobarbital takes 15 minutes or even more than this to depress CNS after i.v. administration.

Barbiturates remain in plasma both in ionized and non ionized state. The ionized form does not cross the biological membranes and can not be reabsorbed by the kidney tubules. The elevation of blood and urine pH increases the ionization of barbiturates and thus causes an efflux of barbiturates from the tissues into the plasma. Thus the increase in pH of blood and urine prevents their reabsorption by the kidney tubules and increases their excretion.

Metabolism:

They are metabolised by the microsomal enzymes in the liver. The inactive metabolites are conjugated with glucuronic acid are excreted through urine. Phenobarbital is excreted 25-30% unchanged of the dose administrated.

Therefore, in patients suffering from renal damage, it is safer to administer compounds like pentobarbital which are completely metabolized by the liver: Activity of drug metabolizing enzymes in hepatic microsomes may be affected by several factors.

New born and young animals possess less capacity to metabolize drugs. Hepatic microsomes are also depressed to a greater extent to metabolize the drug. Phenobarbital and phenytoin accelerate the liver microsomal activity, therefore, same drug and others may be metabolized at a greater rate. For example, phenobarbital stimulate the metabolism of other barbiturates. As a result animals become tolerant to these drugs because of a greater rate of metabolism.

The rate of metabolism varies between various species. Barbiturates are metabolized at slower rate to that in humans and takes longer time to metabolize barbiturates. Pentobarbital is metabolized slowly by humans (4%/hr) as compared with in dogs (15%/hr) and horses (50%). Ruminants metabolize pentobarbital at high rate.

Clinical Uses of Barbiturates:

(i) As an Anaesthetic:

Pentobarbital is used as anaesthetic in dog and cat.

(a) Dog:

For i.v. anaesthesia in dog pentobarbital (24-33 mg/kg in 3-6% aqueous solution) should be used (average i.v. dose is 30 mg/kg)

(b) Cat:

Pentobarbital at the dose of 25 mg/kg (i.v.) produces anaesthestia. An additional dose of 10 mg/kg if initial dose do not produce desired anaesthesia, is given i.v. One-half of the dose should be injected at a moderately fast rate so that the stage of excitement (stage II) of anaesthesia is bypassed.

Few seconds to 1 minute is allowed the drug to exert its full effect. Thereafter, the pentobarbital is injected to effect. It is administered slowly in repeated small amounts over a period of 2-4 minutes with continuous observation of reflexes and respiration until the desired depth of surgical anaesthesia is obtained.

(ii) As Anticonvulsants:

Phenobarbital is used in epilepsy.

(iii) Euthanasia:

Pentobarbital is commonly used for euthanasia of small animals (dog: 40-60 mg/kg).

(iv) As Sedative:

Pentobarbital is used for sedation in foals and small colts. It can also be used as sedative in large animals (1 to 4.4 mg/kg, i.v.)

Adverse Reactions:

(i) Intolerance

(ii) Allergic reaction

(iii) Megaloblastic anemia

(iv) Tolerance

(v) Drug interactions

(vi) Drug dependence

Non Barbiturates I.V. Anaesthetics:

Choral Hydrate:

It is among the first CNS depressant, which was used in veterinary surgery. Even to-day it is one of the best hypnotics available for large animals. Its use is very rare in small animals.

The salient features of chloral hydrate are given below:

Effect on CNS:

(i) Chloral hydrate mainly depresses the cerebrum.

(ii) It is not a good analgesic and muscle relaxants.

(iii) It is better sedative-hypnotic than anaesthetic because margin of safety is very narrow.

(iv) Do not depress sensory cortex up to the mark.

Uses:

(i) It is used for light sedative action and colic in horses with anti-zymotic and carminative agent.

(ii) Used in cattle to depress nervous excitement or even mania that may accompany acetonemia.

(iii) Used for hypnosis preceding local anaesthetic or regional anaesthetic in large animals.

(iv) Used as maintenance anaesthesia (ether and halothane) at the dose of 1 gm./9 kg body weight as 10% solution i.v.

Chloral Hydrate and Magnesium Sulfate:

The combination of chloral hydrate and Magnesium sulfate is known as ‘Dank’s formulation’. Chloral hydrate (12%) and magnesium sulphate (6%) is given slowly i.v. (30 ml/min in horses) for anaesthesia in large animals.

With the appearance of stage of surgical anaesthesia, administration is discontinued. Surgical anaesthesia is indicated by absence of nystagmus and other reflexes. Initially it was thought that magnesium sulfate enhances the action of chloral hydrate but it is not true. Magnesium sulfate has got neuromuscular blocking activity, thus produces skeletal muscle relaxation.

Magnesium sulfate given alone produces only neuromuscular blockade and death due to asphyxia and thus is inhuman to use it as euthanasia agent. Chloral hydrate (12%) and magnesium sulfate (12%) of each 6 gm./ 100 kg body weight is given i.v. for anaesthesia in camel.

Chloral Hydrate, Magnesium Sulfate and Pentobarbital Sodium:

It is a good anaesthetic for horses and cattle. It is very cheap and consists of 30g chloral hydrate, 15g magnesium sulfate and 6.6 g pentobarbitone dissolved in 1000 ml water. The above combination is also known as Millenbruck and Wallinega formulation.

For general anaesthesia in horses 30-70 ml of the above solution /45 kg body weight is given i.v. The above solution must be used within 1 hour otherwise precipitate occurs. Duration of anaesthesia in horse is 30 minutes. The margin of safety is fair, Recovery is satisfactory. The recovery of muscle tone occurs along with the return of consciousness so that horses can stand on their legs immediately after recovery.

Clinical Uses:

(i) For sedative in horses,

(ii) For restraining and handling of cattle for diagnostic purposes.

(iii) Anaesthesia in birds. For this purpose chloral hydrate (21.3 g), pentobarbitone (4.8 g) and magnesium sulfate (10.6 g) are dissolved in 500 ml of distilled water. This aqueous solution is mixed with an aqueous solution of propylene glycol with 9.5% alcohol. The above preparation is injected into pectoral muscle of the bird in dose of 0.22-0.25 ml/100g.

Dissociative Anaesthetics:

Phencylidine hydrochloride and its congeners-ketamine hydrochloride and tiletamine hydrochloride are currently used as dissociative anaesthetic drugs in veterinary medicine. The term dissociative anaesthetic originated from the use of ketamine in human medicine. Dissociative anaesthesia is defined as the feeling of to be dissociated from or unaware of the environment during induction.

Ketamine Hydrochloride:

Ketamine is a general anesthetic which was first introduced in humans in 1965. In 1970 it was introduced for anaesthesia in the cat.

The important features of ketamine is as below:

(i) It induces stage I and II but not III and IV.

(ii) Ketamine does not act on ARS (Ascending reticular system) like other anaesthetics.

(iii) It produces depression of thalamoneocortical system and stimulation of limbic system. Therefore, due to dual action ketamine is called dissociative anaesthetic.

(iv) It induces ketalepsy, amnesia anaesthesia by functional disruption (dissociation) of CNS through marked CNS excitation.

(v) It produces dissociation/complete unawareness of environment due to amnesia/forgetfulness.

Action on C.V.S:

(i) Ketamine increases cardiac output, blood pressure, central venous pressure and heart rate.

(ii) Cardiac stimulating properties, proves it a good induction agent for poor- risk and hypovolemic patients.

(iii) It does not depress respiration, there is profound analgesia and amnesia, muscle relaxation is poor, induction rapid but recovery is prolonged, there is only little salivation which is not a problem, swallowing reflex is impaired.

(iv) It possess wide margin of safety i.e. 5 times than that of pentobarbitone.

Mechanism of Action:

Ketamine prevents reuptake of GABA by brain cells thus acts by GABA-mimetic mechanism. It also blocks neuronal transmission mediated by 5-HT, dopamine and norepinephrine across the synapses (nerve ending.)

Dose:

Cat:

(i) 44 mg/kg (i.m.)

(maximum dose 50 mg/kg)

Duration of action is shorter i.e. 30-45 min. If dose is increased further then duration of anaesthesia is increased.

(ii) In small animals it is given at the dose of 5-10 mg/kg (i.v.)

Sheep and Goat:

2 mg/kg body weight (i.v.)