3. Induction Agents

• Induction


  The process of inducing anesthesia
• Ideal IV induction agent


  • Rapid onset – high brain-drug concentration
  • Steep dose-response curve
  • Minimal CV/Resp. depression
  • Decreases ICP/CRMO2
  • Short duration
  • Highly lipid-soluble
  • Minimal metabolism
  • Non-active metabolite
  • Effect terminated by redistribution
  • Freely eliminated
  • Minimal Side effects: PONV etc
  • Produce hypnosis, amnesia, analgesia and immobility
• Commonly used IV agents


  • Barbiturates
  • Sodium thiopental (Pentothal)
  • Methohexital (Brevital)
  • Isopropylphenols
  • Propofol (Diprivan)
  • Carboxylated imidazole
  • Etomidate (Amidate)
  • Phencyclidine
  • Ketamine (Ketalar)
  • Alpha2- Adrenergic agonist
  • Dexmedetomidine
  • Benzodiazepines

  
• Barbiturates


  Formed through combination of Urea + Malonic acid to form barbiturate ring
• Main groups of barbiturates


  • Oxybarbiturate
  • Thiobarbiturates
  • Thiopental
  • Methylbarbiturates
  • Methohexital
  • Methylthiobarbiturates

  
• Structure-activity relationship of barbiturates


  • The ring structure is the key to their specific activity
  • Substitutes on the ring dictate pro- or anti-convulsant properties
  • Induction drug
  • Sedative/hypnotic
  • Cerebral protection
  • Barb 'coma'
• Recreational use of barbiturates


  • The sedative/hypnotic properties of these oral drugs have led to a high abuse potential
  • Effect are similar to EtOH intoxication and have been described as a 'relaxed and euphoric state'
  • Risk is respiratory arrest
• Mechanism of action of barbiturates


  • Enhances the inhibitory effects of GABAA by potentiating the duration of openings of the Cl- channel
  • Depresses in the reticular activating system (RAS) in medulla oblongata
• Reticular Activating System (RAS)


  • Poorly defined network of neurons near the medulla
  • Primary importance has to do with arousal and alertness
• Sodium thiopental (Pentothal)


  • Oldest IV anesthetic drug still in use
  • Rapid onset due to high-lipid solubility and low degree of ionization at physiologic pH
• Sodium thiopental


  • Dissolved in an Alkaline solution of 2Na+CO3-2
  • Comes in a yellowish powder which needs to be reconstituted
  • Used within 24hrs of mixing
  • Racemic mixture of two enantiomers
  • S (-) > clinical effects due to being more potent at the GABAA
• Structure of sodium thiopental


  • R group substitutions at C5 – add anticonvulsive properties
  • At C2 replacing the O with a Sulfur increases lipid solubility – rapid induction
• Clinical uses of sodium thiopental

  • Induction of anesthesia
  • Treatment of increased ICP
  • Anti-convulsant
  • Cerebral protection
  • ↓ EEG
  • Executions
• Pharmacokinetics of sodium thiopental


  • Extensively binds to albumin 80%
  • Rapid onset due to high blood flow to brain and highly lipid-solubility
  • Cross BBB rapidly
  • Return to alertness afterwards is due to redistribution rather then metabolism
• Metabolism and elimination of sodium thiopental

  • Return of awareness afterwards is due to redistribution rather then metabolism
  • Completely metabolized in liver via CYP 450
  • Oxidation
  • High doses can saturate liver enzymes and lead to a build up of the drug
  • Unsuitable for maintenance of anesthesia due to cumulative properties
  • Renal elimination
• Clinical considerations for sodium thiopental


  • Cardio: ↓BP due to↓SVR; ↑HR
  • Exaggerated in pts w/ prior CV dysfunction
  • Resp: ↓MV due to ↓TV and ↓RR modest reduction in laryngeal reflexes
  • CNS: ↓ICP due to ↓CBF and ↓CMRO2
  • Depresses EEG
  • Hepatic: mild ↓HBF
  • Renal: mild ↓RBF and ↓GFR
  • Slight pain on injection
• Dosing of sodium thiopental


  • Dose: 3 – 5 mg/kg
  • 2nd dose 25% of original dose
  • Reduced in elderly, neonates, renal failure
  • Equation: Dose (mg) = 350 + kg – (2 x y/o) – 50 (female)
  • Onset ~ 1 – 2 min
  • DOA ~ 5 – 15 min
• Preparation of sodium thiopental


  • Alkaline solution
  • pH 10.5
  • Bacteriostatic
  • Tissue damage if injected intra arterial or outside of vein
  • No preservatives
  • Commercial preparation: 2.5% sodium thiopental
• Methohexital (Brevital)

  • Designed to be a short acting rapidly eliminated barbiturate
  • High lipid-solubility
  • Alkaline solution
  • Bacteriostatic
  • Tissue damage
  • Extensively bound 80%
• Structure of methohexital


  • Methylbarbiturate with a methyl group at N1 and oxygen at C2
  • β enantiomer is more potent and 4 – 5 times more active
  • Also associated with extensive motor activity

  
• Clinical uses of methohexital


  • Induction of anesthesia
  • Pro-convulsant
  • Activates epileptic foci
  • Seizure mapping
• Pharmacokinetics of methohexital


  • Extensively bound to serum albumin
  • Metabolized in liver by CYP 450
  • Clearance is higher and thus elimination half-time is shorter then pentothal
  • Suitable for maintenance

  
• Clinical considerations for methohexital


  • Cardio: ↓BP & CO; ↑HR reducing baroreflex sensitivity
  • Resp: ↓MV due to ↓TV and ↓RR
  • CNS: excitatory movements
  • Slight pain on injection
  • Avoid in patients with high risk of psychomotor seizures or history of epilepsy
• Preparation and dosing of methohexital


  • Alkaline 1% solution
  • Must be reconstituted
  • Dose: 1.5 – 2.5 mg/kg
  • Infusion rate: 100 – 150 mcg/kg/min
• Contraindications for all barbiturates

  • Proven allergy or hypersensitivity
  • Acute intermittent porphyria
  • Disorder of enzyme in heme bio-synthetic pathway leading to build up of aminolaevulinic acid
  • AIP – Overproduction and accumulation
  • Abd pain, vomiting, neuropathy, weakness, cardiac arrhythmias, anxiety/depression, constipation/diarrhea
• Propofol (Diprivan)


  • Most commonly used IV induction agent
  • Highly lipid soluble
  • Nonionized
  • Neutral pH 7.4
  • Extensively bound (96%)
  • Antiemetic properties

  
• Structure of propofol


  • Propofol or 2,6 – diisopropylphenol developed in 1975
  • In 1983 Diprivan – lipid emulsion of 1% Propofol, soybean oil, egg phospholipid (lecithin), with glycerol and sodium hydroxide
  • Opaque white fluid
  • Initially no preservatives
  • Now EDTA is added to prevent bacterial growth
• Mechanism of action of propofol


  • Potentiation of GABAA receptor by enhancing the inhibitory effects of GABA
  • It binds to GABA receptor and keeps it open/activated longer
• Pharmacokinetics of propofol


  • Bound to both erythrocytes and serum albumin
  • After bolus dose, concentrations decrease rapidly due to extensive redistribution to peripheral tissues
  • Potential for accumulation
  • Return to central compartment is slower then rate of elimination
  • Persistence of clinical effects
• Metabolism and elimination of propofol


  • Rapidly metabolized in liver by hydroxylation and conjugation via CYP 450
  • Extrahepatic metabolism via kidney & GI
  • Metabolites are eliminated via renally
  • Context-sensitive ½ time ~ 20 min
  • Even after 8 hours of infusion
• Clinical uses of propofol

  • Induction of anesthesia
  • Smooth
  • IV "conscious" sedation
  • ICU sedation
  • Maintenance of anesthesia
  • Anticonvulsant
• Clinical considerations for propofol

  • Cardio: ↓SVR, ↓CO, ↓BP
  • Blunts normal baroreceptor response to ↓BP
  • Resp: ↓TV, ↓RR, apnea, suppresses airway reflexes
  • CNS: ↓CMRO2, ↓CBF will↓ICP,↓EEG, suppresses REM sleep, ~20% patients report dreaming, no analgesic properties, does not enhance NM blockade
  • Hepatic & Renal: minimal
  • Combination of opioids/BDZ – reduce dose requirements
  • Dose reduction in elderly and CV compromised
• Preparation and dosing of propofol

  • Commercial preparation: 1% Propofol, soybean oil and egg lecithin, EDTA as preservative
  • Dosing: 1.5 – 2.5 mg/kg
  • Infusion: 25 – 250 mcg/kg/min
• Propofol


  • Rapidly metabolized in liver by hydroxylation and conjugation via CYP 450
  • Extrahepatic metabolism via kidney & GI
  • Metabolites are eliminated via renally
  • Context-sensitive ½ time ~ 20 min
  • Even after 8 hours of infusion
• Clinical uses of Propofol


  • Induction of anesthesia
  • Smooth IV "conscious" sedation
  • ICU sedation
  • Maintenance of anesthesia
  • Anticonvulsant
• Propofol


  • Cardio: ↓SVR, ↓CO, ↓BP
  • Blunts normal baroreceptor response to ↓BP
  • Resp: ↓TV, ↓RR, apnea, suppresses airway reflexes
  • CNS: ↓CMRO2, ↓CBF will↓ICP,↓EEG, suppresses REM sleep, ~20% patients report dreaming, no analgesic properties, does not enhance NM blockade
  • Hepatic & Renal: minimal
• Propofol preparation


  • 1% Propofol
  • Soybean oil and egg lecithin
  • EDTA as preservative
• Propofol dosing


  • 1.5 – 2.5 mg/kg
  • Infusion: 25 – 250 mcg/kg/min
  • IVP Dose – 30 to 50 mg
  • Onset ~ 30 – 45 sec
  • DOA ~ 3 – 7 min
• Propofol contraindications


  • Pain on injection
  • Can be a good growth medium for bacteria
  • Used within ~12hrs
  • Metabolic acidosis
  • Propofol infusion syndrome (PIS)
  • Lactic acidosis s/p prolonged high-dose infusions
  • Hypersensitivity to propofol
  • Disorders of fat metabolism
• Fospropofol


  • Only propofol analog approved by FDA
  • A prodrug of propofol
  • Rapid cleavage by alkaline phosphatase to Propofol + Formaldehyde + Phosphate
  • 1 mg gives you 0.54 mg of propofol
  • Onset is slower and longer DOA
  • Used for sedation
  • No reported pain on injection