Barbiturate Anesthetics in animals

Barbiturate Anesthetics in animals

Barbiturate Anesthetics in animals are derived from the non-depressant barbituric acid which is a combination of malonic acid and urea. Barbiturates are bitter tasting white powders. Salts containing sulfur have a yellowish tint. They are hygroscopic and will decompose on exposure to air, heat and light. 

Structure activity relationship

To be hypnotically effective, both the hydrogen atoms on carbon5 must be replaced by an alkyl or aryl group. To obtain optimal therapeutic results, the substituting radicals on carbon 5 should contain a minimum of 4 and a maximum of 9 carbons. Addition of more carbon leads to convulsant activity.

Unsaturated carbon chains are more readily oxidized and hence are short acting. Short chains are more stable and hence are long acting and Long chains are easily oxidized and are short acting.

Branched chains tend to be shorter in action than straight chains. Only one aryl radical should be attached to carbon 5. Replacement of the oxygen atom on carbon 2 by a sulphur atom increases the potency and instability and shortens the duration of action of the compound. Barbiturates containing oxygen in carbon 2 are called oxybarbiturates and those containing Sulphur are called thiobarbiturates.

Attachment of an alkyl group to one of the N-atoms (position 1 or 3) increases the anaesthetic potency and tends to stimulate the CNS. Substitution in both the N-atoms produces a convulsant.

Replacement of the oxygen on carbon 2 by an HN= group destroys the hypnotic activity of the molecule.

Mechanism of action of barbiturates

Bind to GABA receptors → increase the duration of Cl­^– channel opening → exert facilitation of GABA binding.

At high concentration directly increase Cl^– conductance and inhibit Ca ⁺⁺ dependent release of neurotransmitters, Also depress glutamate-induced action potentials and At very high concentration affect K⁺ and Na⁺ channels.

Action of Barbiturate Anesthetics in animals

1. CNS – Depression ranging from mild sedation to anesthesia
2. Depression of motor areas leads  to control convulsions
3. Depression of sensory areas leads to anesthesia
4. Subtherapeutic doses – hyperalgesia observed
5. Respiration – slight depression. On intravenous administration it produces more severe depression than oral
6. Cardiovascular System – myocardial depression. Normal rhythm. Large doses results in  hemodilution,
7. CVS effects depend on other co-drugs, eg. Acepromazine, dose of barbiturate and condition of the animal
8. GI tract – Initial depression followed by  increase of tone and motility
9. Kidney and liver – not significant. But metabolism and excretion affected if there is any defect in these organs
10. Uterus – At anesthetic doses – depress uterine contraction. Cross placenta and depress fetal respiration. Not preferred for caesarean sections. If it is to be done, surgery completed very quickly and respiration of young one stimulated to overcome depression
11. Skeletal muscles – poor relaxation. Additional relaxants are needed

Pharmacokinetics of barbiturates

1. Absorption—readily absorbed from GI tract when given orally
2. Distribution– Cross BBB. High levels reached in brain, liver and kidney. Lipid soluble and redistribute to muscle leading to decrease  in plasma level of barbiturate.
3. Large store in adipose tissue.
4. Animal seems to recover once the plasma level goes down
5. Then sedate and drowsy as the drug keeps coming back to circulation from storage resulting in  long periods of CNS depression
6. Repeated doses end up in  cumulation.
7. Once stores are saturated can cause severe depression of CVS and respiration
8. Excretion – renal, after oxidation in hepatic and extra-hepatic sites
9. Barbiturates – known inducers of microsomal enzymes. Induces its own metabolism resulting in tolerance to the effects. Tolerance disappears after withdrawal of the drug.
10. Cats are sensitive to the respiratory depression and dogs to the CVS depression of barbiturates
11. Antidote – Bemegride. a CNS stimulant

Barbiturate Anesthetic drugs

Thiopentone, Thiamylal, Thialbarbitone, Methohexitone and Pentobarbitone are barbiturate anesthetic drugs. some of important drugs from this category described below-

Thiopental

Tiopental is an ultra short acting, most commonly used in veterinary medicine and is considered the prototype drug of its class. It is also the standard drug for induction of anaesthesia.

• CNS: Dose dependent depression: mild sedation to deep hypnosis  and surgical anesthesia. Depress both sensory and motor cortex.
• CVS: Rapid IV injection causes sharp, but transient fall in BP. High doses cause prolonged fall in BP (due to vasodilatation and depression of vasomotor center and heart).
• Respiratory system: slight depression at anesthetic dose, but respiration failure at high dose.
• Kidney: No significant effect at anesthetics doses, but high doses causes oliguria/anuria.
• Uterus and foetus: depress parturient uterine contractions. Also cross placenta causes depression of foetal respiration and death of foetus in utero.
• Skeletal muscle: No relaxation.
• Smooth muscle: No significant effect, except in GIT where tone and motility are slightly reduced.

• Dose of thiopentone
  • Dog &cat– 20-25 mg/kg
  • Pig– 10-12mg/kg
  • Calf/goat– 15-20 mg/kg
  • Horse– 10mg/kg
  • It is administered as 2.5% solution in small animals and as 5-10% aqueous solution in large animals.
  • ½ dose –fast IV then slow IV
  • NOT for SC or IM

Methohexital

Methohexital is more rapidly metabolized than the thiobarbiturates and the other oxybarbiturates because of its higher lipid solubility, which results from the addition of a methyl group. It is more potent than thiopental.

Like the thiobarbiturates, methohexital is safe for use during cesarean section. ii. It is safe for use in greyhounds and other sight hounds. Because of methohexital’s rapid redistribution and metabolism by the liver, recovery is quick.

Pentobarbital sodium

Pentobarbital sodium is used sedative hypnotic and general anesthetic in animals. It has a very low margin of safety, is the primary ingredient of euthanasia agents. Pentobarbital is occasionally used for IV anesthesia in dogs, cats, pigs, and small ruminants. Also used for seizure control when a long-acting drug is desired. Low doses administered IV may cause an excitement phase characterized by whining, paddling, and incoordination. Recovery is slow and characterized by paddling of the limbs and incoordination. Sedation, physical assistance, or both may be required to ensure a smooth recovery.

Long acting are the least lipid soluble and the slowest in their onset of action, but they have a long duration of action (6–12 hours). Phenobarbital is used primarily as an anticonvulsant at sub-anesthetic doses, not as a general anesthetic.

Non-Barbiturates Anesthetic drugs

these are the non-barbiturates anesthetic drugs in animals-

1. Phenol derivatives- propofol
2. Imidazole derivatives- etomidate and metomidate
3. Steroidal anesthetics- saffan (alphaxalone-alphadolone)
4. Chloral derivatives- chloral hydrates
5. Benzodiazepines- midazolam and diazepam
6. Opioid and neurolept analgesics-fentanyl, fentanyl- droperidol combination
7. Miscellaneous anesthetics- chloralose and urethane

Propofol (2,6-diisopropylphenol)

• An oily solution – highly lipid soluble, Available as an aqueous emulsion containing propofol (10 mg / ml), soybean oil (100 mg / ml), glycerol (2.5 mg / ml), egg lecithin (12 mg / ml) and Na OH (to adjust pH)
• Induces effects by enhancing inhibitory effects of GABA (from a different pathway from that of Benzodiazepines)
• On intravenous injection rapidly taken in by CNS — but rapidly redistributed to other parts of the body – high Volume of distribution
• Metabolized in liver and pulmonary tissues to respective  glucuronides and sulfates
• On CVS – mild hypotension, may sensitize heart to adrenaline arrhythmia
• On lungs – short periods of apnea
• Uses – for induction of anaesthesia—with intravenous bolus or infusion with dextrose
• In dogs – 5-7 mg/kg, dose  can be reduced  if premedicated with tranquilizers
• Cats – 5 – 8 mg /kg

Saffan (Althesin)

(9 mg alphaxolone + 3 mg alphadolone) both steroids

• High therapeutic index with wide margin of safety
• Good muscle relaxation
• Mild cardiovascular and Respiratory depression
• Can be given both by intravenous or intramuscular
• (5-6 mg /kg)
• No irritation on escape into subcutaneous sites
• Contraindicated in dogs – due to histamine release by the vehicle

Chloral hydrate

• Volatilizing crystalline substance
• Reduced to 2,2,2-trichloroethanol – which is the narcotic agent
• Hypnotic agent
• Slow onset –difficult to assess the depth of anaesthesia
• Perivascular escape severe reaction
• Used in Large Animals –sometimes with barbiturates
• 12% Chloral hydrate + 6% MgSO₄ intravenous in Large Animals for anaesthesia
• Has low margin of safety
• Not used now a days – since better agents are available

Chloralose

• Glucose + chloral hydrate
• Long shallow depth and slow recovery
• Not used

Urethane

Urethane is aCarcinogenic drug so discontinued in clinical practice.

Metomidate

• Non Barbiturate intravenous anaesthetic – imidazole product
• Developed as hypnotic in pigs
• Poor analgesia but strong muscle relaxation
• Remarkable stability of the CVS
• Used for restraint of birds apart from pigs

Etomidate

• Low CVS toxicity
• Release histamine but in general low respiratory depression
• Suppresses adrenocortical function
• Expensive and not popular