Induction Agents, Drugs and classifications

Induction agents, Classification drugs, Thiopentone, Propofol, Ketamine, Etomidate and Benzodiazepines

1. Intravenous induction Agents Monnaf Ali Msc in OTAT BDIPS, Charusat University.

2. CLASSIFICATION Barbiturates:   Non barbiturates: Thiopentone   • Ketamine   Methohexitone   •  Propofol • Etomidate • Opioids • Benzodiazepines

3. Intravenous anesthetics are used in anesthesia for: Induction: Most commonly used intravenous(IV) anesthetic for induction is propofol  is Indications for induction with thiopentone in present day anesthesia are very limited. Ketamine is used only in specific situations. Since opioids and benzodiazepines are required in very high doses for induction therefore they are seldom used for this purpose.  For analgesia (largely opioids). As a sole  anesthetic  agent for minor procedures, e.g. ketamine or propofol +fentanyl. For amnesia (mainly benzodiazepines).  To blunt cardiovascular response to intubation(opioids). For sedation (mainly benzodiazepines).

4. THIOPENTONE Thiopentone was the first intravenous anesthetic used in clinical practice by Water and Lundy in 1934. It is an ultra short-acting barbiturate. Chemically it is sodium ethyl  thiobarbiturate . BARBITURATESTHIOPENTONE iopentone was the rst intravenous anestheticused in clinical practice by Water and Lundyin 1934. It is an ultra short-acting barbiturate.Chemically it is sodium ethyl thiobarbiturate. Physical and Chemical Properties  z  Available as yellow amorphous powder as0.5 g and 1.0 g vial to which 20 mL of sterile water for injection is added yielding aconcentration of 2.5% and 5% respectively(5% solution is further diluted to make it 2.5%solution). e solution is not stable and shouldbe used within 48 hours (but can be used for1 week if refrigerated or till precipitateappears). It should not be prepared with ringerlactate otherwise it will get precipitated due toacidic pH of ringer lactate solution.  z  It is sulfur analog of pentobarbitone. Sulfur isadded to increase the lipid solubility  .  z  The ultrashort duration of thiopentone isbecause of methyl group added to it.  z  It is available as sodium salt   to make it watersoluble but this increases the alkalinity ofsolution. pH of sodium thiopentone (2.5%)solution is 10.4 (highly alkaline) .  z  6% anhydrous sodium carbonate is added topowder to prevent the formation of free acid bycarbon dioxide from atmosphere.  z  It is prepared in the atmosphere of nitrogen. Anesthetic Properties andPharmacokinetics Unconsciousness is produced in one arm braincirculation time, i.e. 15 seconds and inductionis largely smooth (however sometimes may beassociated with initial excitatory responses). he elimination half-life of thiopentone is10.4 hours  but consciousness is regained after15–20 minutes because of redistribution  which CHAPTER 12 Intravenous Anesthetics                                                                                                                                                                                                          

5. Physical and Chemical Properties Available as yellow amorphous powder as 0.5 g and 1.0 g vial to which 20 mL of sterile water for injection  . It is sulfur analog of pentobarbitone . Sulfur is added to increase the lipid solubility. The ultra short duration of  thiopentone is because of methyl group added to it. It is available as sodium salt  to make it water soluble but this increases the alkalinity of solution. pH of sodium thiopentone (2.5%)solution is10.4 (highly alkaline). It is prepared in the atmosphere of nitrogen.

6. Mechanism of action:   Blockade of excitatory neurotransmitters action like acetylcholine and glutamate. Enhancement of inhibitory action of GABAa . Doses: Adults : 3-5 mg/kg iv Children: 5-7 mg/kg iv

7. Anesthetic Properties and Pharmacokinetics: Unconsciousness is produced in one arm brain circulation time, i.e. 15 seconds and induction is largely smooth. The elimination half-life of thiopentone is10.4 hours but consciousness is regained after15–20 minutes. Protein binding:  In blood 80–90% of thiopentone is bound to plasma proteins, mainly to albumin. Metabolism: Thiopentone is metabolized in liver Eliminated : Through kidneys.

8. Side effects: Myocardial depression Transient apnea Venous thrombosis Allergic reactions Bone marrow suppression, Leucopenia Contraindications: Porphyria (Hepatic enzyme inducer) Shock, Status asthmaticus Uncompensated CCF, Pericardial temponant .

9. PROPOFOL What is Propofol? Propofol is a short-acting intravenous anesthetic agent commonly used for induction and maintenance of general anesthesia. It is also used for sedation in intensive care units (ICU) and during some medical procedures.

10. Mechanism of Action (MOA) Propofol acts primarily on the GABA-A receptor in the central nervous system (CNS). It enhances the inhibitory action of the neurotransmitter gamma-aminobutyric acid (GABA) , leading to CNS depression. This results in sedative, hypnotic, and anesthetic effects. It has rapid onset (within 30 seconds) and short duration (5–10 minutes). Doses: For induction : 1.5- 2.5 mg/kg iv For conscious sedation : 25-100 ug/kg/min iv For maintenance of anaesthesia : 100-300 ug/kg/min iv For antiemetic effects : 10-15 mg/kg iv

11. Pharmacokinetics Absorption : Administered intravenously. It is highly lipophilic, which means it rapidly distributes into tissues with high blood flow, including the brain. Distribution : It has a large volume of distribution ( Vd ), especially in well-perfused organs like the brain, heart, and liver. Peak effect within 1 minute after IV injection. Metabolism : Propofol is primarily metabolized in the liver It has a half-life of about 2–4 hours in the body. Excretion : The metabolites are primarily excreted through the urine . Elimination Half time: 0.5 -1.5 hours

12. Side Effects Pain on injection Hypotension Respiratory depression Bradycardia Propofol infusion syndrome Allergic Cardiac arrhythmias Uses: Because of its shorter half life it is the agents of choice of induction. It is choice of day surgery because early and smooth recovery. Propofol is the choice of TIVA. Propofol infusion can be used to produce sedation in ICU. Use in induction.

13. ETOMIDATE Chemically it is an imidazole derivative. A short-acting intravenous anesthetic agent.

14. Mechanism of Action Acts on the GABA receptor to enhance inhibitory neurotransmission Pharmacokinetics Parameter Etomidate Route of Administration IV only Onset of Action 30-60 seconds Peak Effect 1 minute Duration 3-5 minutes Metabolism Hepatic + Plasma Esterases Excretion Renal (75%), Biliary (25%)

15. Dose: Induction dose: 0.2- 0.4 mg/kg iv Advantages It is most cardiovascular stable Minimal respiratory depression No histamine release Indirect coombs Test (ICT) Adverse Effects ⚠️ Adrenal suppression ⚠️ Myoclonus ⚠️ Pain at injection site ⚠️ Nausea & vomiting Use Aneurysm surgery and Patient with cardiac disease

16. Ketamine Ketamine is a dissociative anesthetic Discovered in 1962 , FDA-approved in 1970 Used for anesthesia , analgesia, and sedation Unique hallucinogenic and analgesic properties

17. Mechanism of Action Non-competitive NMDA receptor antagonist → Prevents glutamate transmission Dissociates the thalamus from the limbic system → Induces unconsciousness Also acts on: Opioid receptors (analgesia) Sympathetic nervous system (increased BP & HR) Parameter Ketamine Route of Administration IV, IM, Oral, Nasal Onset of Action IV: 30 sec, IM: 3-5 min Duration 10-15 min (IV), 20-30 min (IM) Metabolism Hepatic (CYP450 enzymes) Excretion Renal Pharmacokinetics

18. Doses Induction: 1-2mg/kg iv and 4-8 mg/kg IM For continuous infusion : 1-2mg/hr Analgesia : 0.2-0.5 mg/kg iv Indications Induction & maintenance of anaesthesia Pain management Procedural sedation Emergency & battlefield medicine

19. Side Effects ⚠️ Emergence delirium ⚠️ Hypertension & tachycardia ⚠️ Increased intracranial pressure (ICP) ⚠️ Nausea & vomiting Contraindications Hypertensive & cardiac patients Raised ICP (head injury, brain tumours) Psychiatric disorders (schizophrenia) Glaucoma (increased IOP)

20. BENZODIAZEPINES Benzodiazepines (BZDs) are a class of psychoactive drugs. - Used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants. - Act on the central nervous system (CNS) by enhancing GABA activity.

21. Classification of Benzodiazepines - Short-acting (e.g., Midazolam, Triazolam) - Intermediate-acting (e.g., Alprazolam, Lorazepam) - Long-acting (e.g., Diazepam, Clonazepam, Chlordiazepoxide) Mechanism of Action Benzodiazepines enhance the effect of GABA at GABA-A receptors. - Increases chloride ion influx leading to CNS depression. - Reduces neuronal excitability, producing anxiolytic and sedative effects.

22. Pharmacokinetics Absorption: Rapidly absorbed from the GI tract. Distribution: Highly protein-bound and lipophilic. Metabolism: Primarily metabolized in the liver via CYP450 enzymes. Excretion: Eliminated through urine. Clinical Uses Anxiety disorders Insomnia Seizures (e.g., status epilepticus) Muscle relaxation (e.g., spasticity conditions) Pre- anesthetic medication Alcohol withdrawal syndrome

23. Adverse Effects - Drowsiness and sedation - Dizziness and confusion - Respiratory depression (especially with other CNS depressants) - Dependence and withdrawal symptoms - Cognitive impairment (long-term use)

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