Pharmacology of Sedation Drugs

• Definition of conscious sedation = the reduction or abolition of the physiological & psychological responses to the stress of dentistry, without loss of consciousness, cooperation or protective reflexes i.e. people aren't put to sleep, just put into a state where we can do the work without them being scared
• Routes of drug administration:

  • Intravenous eg midazolam
  • Inhalational eg nitrous oxide
  • Oral eg temazepam
• Intraveous drug administration - eg midazolam:

  • Certain absorption
  • Action terminated by redistribution, metabolism & excretion
• Inhalational drug administration - eg nitrous oxide:

  • Rapid absorption & onset of sedation
  • Rapid elimination & recovery
• Oral drug administration - eg temazepam:

  • Tend to be given to pt's pre-sedation - like the night before, so that they can get a good night's rest and will willingly attend the appointment
  • Gastric absorption
  • Slow onset
  • Not very reliable action
• Benzodiazepines act on receptors in:

  • the cerebral cortex and motor circuits
  • the spinal cord and brain stem
• Benzodiazepines - mechanism of action:

  • Benzodiazepines work on receptors in the CNS to enhance the effect of GABA (gamma-aminobutyric acid)
  • GABA inhibits neurotransmission - slows down nerve transmission
  • GABA receptors located in cerebral cortex and motor circuits
  • Benzodiazepine receptors close to GABA receptors

  
• Benzodiazepines - clinical effect:

  • Anxiolysis (reduced fear)
  • Sedation (relaxed, slightly reduced consciousness)
  • Detachment (acute for 20-30 mins)
  • Amnesia (anterograde) - they'll forget everything that happens after administering the drug
  • Muscle relaxation
  • Disinhibition (opposite effect to what you want - may become agitated/violent)
  • Anti-convulsion (prevent or terminate convulsions)
  • Anaesthesia (high doses)
• Benzodiazepines - effect on pain experience:

  • Benzodiazepines are not analgesics
  • May influence response to pain (e.g. patients may move more during LA administration, higher doses of benzodiazepines)
• Pharmacology of midazolam:

  • Water soluble benzodiazepine
  • Water soluble at pH < 4.0
  • Lipid soluble at physiological pH allows penetration of blood-brain barrier
  • Non-irritant (painless injection)
  • Ampoules for dental use - 5mg in 5ml pH 3.5
  • Around 2-3 times as potent as diazepam
  • Elimination half-life 1.9 (+/- 0.9) hours
  • Metabolites - alpha-hydroxymidazolam - short half-life 1.25 hours - therefore has little effect on lengthening the effects of midazolam
• Pharmacology of midazolam:

  • Elderly pts markedly more sensitive to midazolam - more careful with administration
  • Metabolised mainly in liver
  • Half-life less affected by liver disease than other benzodiazepines
  • Excreted by kidney (pharmacokinetics little affected by renal disease in acute use)
• Benzodiazepines - side effects - respiratory depression:

  • Due to CNS depression and muscle relaxation
  • Respiratory muscles (diaphragm and intercostal muscles) are more relaxed and therefore not as effective
  • Decreases cerebral response to CO₂
  • Level of CO₂ in blood is what determines breathing rate - therefore breathing rate would decrease
  • Synergistic relationship with opiates (e.g. Morphine) - increases effects of both drugs if administered together
  • Increased depression in patients with respiratory system disease e.g. chronic bronchitis
• Benzodiazepines - side effects - cardiovascular effect:

  • Reduced blood pressure by decrease in vascular resistance
  • Smooth muscle in blood vessels relax - therefore decrease in blood pressure
  • Heart rate increases due to baroreceptor response - i.e. Trying to keep blood pressure up
  • Cardiac output unaffected
• Benzodiazepines - side effects - drug interactions:

  • Synergistic CNS depression with other CNS depressants e.g. Opiates, alcohol, anti-histamines
  • Erythromycin & cimetidine inhibit metabolism of midazolam
• Nitrous oxide - clinical use:

  • Inhalation sedation - paediatric dentistry
  • Titrated mixture of nitrous oxide & oxygen = Relative Analgesia Sedation
  • Equipment won't deliver more than 70% nitrous oxide
  • Good safety margin; there's always 30% oxygen being administered 
• Nitrous oxide - properties:

  • Colourless gas (sweet odour)
  • Supplied in light blue cylinders containing gas and liquid at 750 psi (pounds per square inch)
  • Density 1.5 times air - any excess gas = low level in room
  • Blood-gas solubility 0.47 at 37°C - so highly soluble in blood
  • Mean alveolar concentration = 105%
  • The level of gas that will produce anaesthesia in 50% of the population
  • So for most people it's impossible to achieve anaesthesia with nitrous oxide alone - other gases needed
  • Takes around 3 minutes to achieve full saturation in the blood - but the effects are apparent much quicker
• Nitrous oxide - clinical effects - nervous system:

  • Depressive & euphoriant effects
  • Sensations depressed = touch, pain, hearing, vision
• Nitrous oxide - clinical effects - cardiovascular system:

  • Minimal CVS effect (vasodilation)
  • Myocardial depressant at high dose
• Nitrous oxide - clinical effects - respiratory system:

  • Mild depression of alveolar ventilation and CO₂ response
• Nitrous oxide - clinical effects - clinical signs:

  • Analgesia - insufficient for carrying out painful procedures like extractions or drilling, but will help in the reduction of pain perception during injections
  • Relaxation (they'll feel warm)
  • Paraesthesia (tingling)
  • Sedation (dissociation)
  • Euphoria
  • Amnesia - only at high doses, most people remember everything
• Nitrous oxide - side effects:

  • Hazards to clinical & nursing staff (dental, anaesthetic, obstetric)
  • Chronic exposure to N₂O
  • Side effects due to:
  • Unscavenged clinics - where the N₂O is collected by a scavenging unit, preventing over-exposure to staff in clinic
  • N₂O abuse
  • Health & safety recommendations
  • Maximum 100ppm N₂O over 8-hour averaged period - anything beyond that is starting to get unsafe for operators to administer nitrous oxide
• Nitrous oxide - side effects - haematological problems:

  • Reacts with cobalt complexes & oxidises vitamin B₁₂ - this will lead to anaemia
  • Inhibits methionine synthetase, which is essential in the synthesis of DNA, therefore...
  • Impairs DNA syntehsis
  • Bone marrow depression
  • Inhibits haematopoiesis (formation of red blood cells) - pernicious-like anaemia
• Nitrous oxide - side effects - neurological disease:

  • Chronic exposure leads up to 4x increase
  • Peripheral neuropathy (paraesthesia)
• Nitrous oxide - side effects - hepatic disease:

  • 1.6x increase in liver disease with heavy exposure
• Nitrous oxide - side effects - reproductive problems:

  • Increased miscarriage - female dentists/dental nurses
  • Decreased fertility
  • Decrease in probability of conception in each menstrual cycle
• Nitrous oxide - reducing exposure:

  • Equipment
  • Nosemask & hoses (no leaks)
  • Technique
  • Discourge mouth breathing
  • Correct flow rate
  • Ventilation
  • Open windows and doors
  • Fans, laminar flow
  • Scavenging
  • Active scavenging of exhaled gas