Sedative Hypnotics

These include 3 types of drugs;

• Benzodiazepines
• Barbiturates
• Miscellaneous agents

Benzodiazepines (BZ)

• These were introduced in 1960.
• These are most commonly used.

Mechanism of Action

• It is based on GABA receptors stimulation.
• GABA (amino acid) binds with receptors and chloride channels open and there is influx of chloride ions which leads to hyper-polarization of membrane and sedation occurs. This is normal phenomenon.
• Benzodiazepines facilitate this mechanism by facilitating the binding of GABA receptors to their receptors which lead to sustained hyper-polarization.
• It is dose dependent effect;
• Low dose…. Sedation
• High dose… Hypnosis
• If GABA concentration is low, BZ are not able to perform their action because these only facilitate binding not the release of GABA.

Classification of BZ

Their classification is based on duration of activity;

Short Acting BZ

• Drugs with half life less than 5 hours and include;
• Midazolam
• Triazolam

Medium Acting BZ

• Drugs with half life b/w 5-24 hours and include
• Alprazolam
• Lorazepam

Long Acting BZ

• Drugs with half life greater than 24 hours and include
• Diazepam
• Chlorodiazep

Flumazenil

• This drug is used to treat the toxicity of BZ b/c it is antagonist of BZ.

Effects of BZ

• These act as anti-convulsants and also reduce the anxiety.
• These are poor analgesic but good muscle relaxant.
• Effects on CVS and respiratory systems are negligible.

Therapeutic Uses

• Sedative and hypnotic
• Anti-convulsants
• Used for sleep disorders
• Pre-anesthetic
• Midazolam can be used as anesthetic agent.

Problem

• If used for longer duration, problem of dependency occurs and abrupt withdrawal leads to anxiety, convulsions and other withdrawal symptoms.

Barbiturates

• These are synthesized from urea and malonic acid.
• Urea and malonic acid combine to form Barbituric acid.
• Barbituric acid is not having hypnotic property.
• When hydrogen at 5^th carbon in Barbituric acid is replaced by other substitutes, then these have hypnotic property.
• If thiaurea is used instead of Urea, Thiobarbiturates are formed which are good lipid soluble. Sodium salts of Thio-barbiturates are used as injectable anesthetics.
• These are having dose dependent effect;
• Low dose…Sedation
• High dose…Hypnosis
• Higher dose…..Anesthesia
• In BZ, higher dose do not lead to anesthesia.
• So Barbiturates are used as general anesthetics.

Classification of Barbiturates

Their classification is also based on duration of activity;

Ultra-short acting

• Drugs with half life b/w 10-30 minutes and include;
• Thiopental
• Thiobarbitone
• hexobarbitone

Short acting

• Drugs with half life b/w 30min-3hours and include;
• Pentobarbitone
• Secobarbitone

Medium acting

• Drugs with half life b/w 3-6 hours and include;
• Butobarbitone
• Amylobarbitone

Long acting

• Drugs with half life more than 6 hours and include;
• Phenobarbitone
• Mephobarbitone

Effects of Barbiturates

• Sedation, hypnosis and anesthesia
• Anti-convulsants
• Poor analgesics
• Higher doses can lead to respiratory failure and death. To treat this, respiratory center stimulants (Doxapram) are used.

Therapeutic Uses

• Sedative, hypnotic and anesthetic
• Anti-convulsants (Phenobarbitone, Primidone)

Miscellaneous Drugs

• Chloral Hydrate through oral route can be given.
• Chlorobutanol
• Bromides
• Ethyl Alcohol
• Cannabis (Bhang)

Classification of Anesthetics

There are two bases for classification of general anesthetics;

• Physical
• Route of Administration

Inhalant Anesthetics

Anesthetics which are inhaled, reach the alveoli, exchanged with arterial blood and distributed to different body parts especially Brain are called as inhalant anesthetics.

There are 3 important phases of anesthesia;

• Induction
• Maintenance
• Recovery

Factors Affecting Anesthesia

• Blood Gas Solubility
• Potency
• Gas Lipid Solubility

Blood Gas Solubility

• More the solubility of the inhalant anesthetic, it will take more time to saturate and more time to depress the Brain and vice versa.
• So, more the solubility of an inhalant anesthetic, it will take more time for induction and recovery of Anesthesia.

Low solubility inhalant anesthetic

• Low the solubility of inhalant anesthetic, minor change in concentration will lead to greater change in depth of anesthesia.
• Low solubility inhalant anesthetics include Nitrous oxide, Ether, Halothene, Fluorine.

Potency

• It is the ability of the drug to depress the CNS. It is measured by MAC value.
• MAC (Minimum Alveolar Concentration)
• Minimum concentration in alveoli which can induce anesthesia in 50% of the patients
• Lower the MAC value, more potent is the anesthetic agent.
• MAC value of drugs is in following order;
• Methoxy Fluorine < Halothene < Isofluorine < Ether < Nitrous Oxide

Gas Lipid Solubility

• If a drug is more lipids soluble, it will take more time for induction and recovery. Its value is in the following order;
• Nitrous Oxide > Isofluorine > Halothene > Ether > Methoxy Fluorine

Examples of Inhalant Anesthetics

Volatile

Chloroform, Ether mixture, Halothene, Isofluorine, N-fluorine, Methoxy fluorine, vinyl ether

Gaseous

Cyclopropaine, Nitrous Oxide

Chloroform

• In 1847, it was used as general anesthetic. It is still in use.
• In 1846, ether was used as general anesthetic.
• If it is used externally, it is rubifacient.
• If it is used by oral route, it has anti-spasmatic (Muscle relaxant), anti-zymatic (stop production of gas) and carminative (removal of gases) effects.
• If inhaled, it induces anesthesia. It induces rapid induction. It gives good analgesia and muscle relaxation.
• It can also cause irritation in alveoli. So, Bronchial and salivary secretions are increased and there is possibility of pneumonia. So, along with this drug, Head should be down and atropine can also be used.
• It also induces hepato-toxicity, myocardial sensitization to epinephrine. So, there are chances of Cardiac Arrhythmia.
• It is non-explosive and non-inflammable.

Ether

• It increases bronchial and salivary secretions when inhaled due to irritation.
• Good analgesic and relaxant
• Induction is slow.
• It is inflammable and explosive.
• Low toxicity problem. So, mixture of chloroform and ether is best combination as an anesthetic.
• ACE (alcohol, chloroform and ether mixture) in the ratio of 1:2:3 is also available.

CycloPropaine

• Inflammable, explosive
• Good analgesic and relaxant
• Can cause myocardial sensitization

Nitrous Oxide (Laughing Gas)

• It induces light anesthesia (pleasant induction).
• Used in humans
• Low toxicity
• Rapid induction and recovery

Injectable Anesthetics

These are of two types;

Depressants

• Barbiturates (thiopental, pentobarbitone, secobarbitone, hexobarbitone)
• Chloral-hydrate
• Etomidate
• Midazolam

Dissociative

• Phencyclodine
• Ketamine
• Tiletamine
• These induce superficial sleep. There is good analgesia, poor relaxation and poor hyporeflexia.
• Myotonia, reflexes and amnesia is also present.
• Eyelids remain open and there are chances of corneal ulceration. So, use some ointment to close eyes.
• Use some tranquilizers or sedatives
• Ketamine and Xylazine combination is best.
• Ketamine is used in veterinary practice.

Examples of Injectable Anesthetics

Thiobarbitone

• It induces rapid and smooth induction and recovery.
• Its termination of effect is due to Re-distribution (It is lipid soluble. So, highly perfused organs like brain receive more concentration and then drug moves to periphery).
• Give less dose of this drug.

Pentobarbitone

• It is metabolized

Propofol

• It induces smooth & rapid induction and recovery.
• Its termination of effect is due to metabolism because drug moves to all body parts.

Chloral-Hydrate

• It induces slow induction but prolonged recovery.
• Termination is due to metabolism.
• Hypnotic in nature due to metabolite called Trichloro Ethanol.
• Perivascular leakage also leads to necrosis.
• Still used in equines.
• Pre-anesthetic agents are used with these drugs.