CNS

• Human brain is very complex and composed of about 10 billion neurons with functional interdependence
• Mixtures of excitatory and inhibitory neurons exist in the human brain
• Excitation in the brain is brought by activation of excitatory neurons and blockade of inhibitory neurons
• Inhibition in the brain is accomplished by pre-synaptic inhibition and post-synaptic inhibition
• Neurotransmitters in the brain:

  • Acetylcholine: excitatory
  • Monoamines:
  • NA: excitatory (α1), inhibitory (α2)
  • Dopamine: inhibitory (D1, D2), sometimes excitatory (D3)
  • 5HT (serotonin): inhibitory (5HT-1A), excitatory (5HT-2A, 5HT-3, 5HT-4)
  • Histamine: excitatory (H1, H2), inhibitory (H3)
• Blood brain barrier:

  • Structure: capillaries closely joined, absence of pores
  • Function: does not allow polar molecules to pass through, protects the brain from peripheral endogenous substances
• Sites of CNS drugs action:

  • AP
  • Synthesis
  • Storage
  • Release
  • Reuptake
  • Degradation
  • Receptors/ion channels
• General characteristics of CNS drugs:

  • Variation in potency or efficacy
  • Effect additive to physiological state
  • Variable antagonism
  • Initial excitation at low doses of depressants
  • Prolonged depression after acute excessive stimulation
  • Withdrawal syndrome upon sudden discontinuation
• Ranges of effects:

  Coma ← anesthesia ← hypnosis ← sedation (@ low dose) → excitation → hyper-excitation → convulsion
• Classes of CNS drugs:

  1. General (non-selective) central depressants:

  • General anesthetics
  • Sedative-hypnotics
  • Aliphatic alcohols

  2. General (non-selective) central stimulants:

  • Blockade of inhibition: Strychnine, Picrotoxin
  • Direct neuronal excitation: Metrazole, Xanthines

  3. Selective CNS functions modifiers:

  • Psychoactive drugs
  • Anti-epileptics
  • Opioid analgesics
  • Antiparkinsonians
• General anesthetics:

  • Sequence of anesthesia: Pain neurons → Inhibitory neurons → Excitatory neurons → Motor neurons
• Clinical stages of anesthetics:

  • Stage I: stage of analgesia/induction
  • Stage II: stage of delirium/excitement
  • Stage III: stage of surgical anesthesia
  • Stage IV: stage of medullary paralysis
• Classes of general anesthetics:

  • Inhalational: Gaseous (e.g., Nitrous oxide), Volatile liquids (e.g., Diethyl ether, Halothane, Enflurane, Isoflurane)
  • Parentral: Basal anesthetics (e.g., Thiopental, Propofol), Neurolept analgesics (e.g., Droperidol + Fentanyl), Dissociative anesthetics (e.g., Ketamine)
• Inhalational anesthetics:

  • Mechanisms of action: Water theory, Lipid theory, Protein theory
• Factors affecting kinetics of anesthetics:

  • Pulmonary ventilation
  • Partial pressure of anesthetic
  • Blood: gas partition coefficient
  • Cardiac output (pulmonary blood flow)
  • Lipid: Gas partition coefficient
• Techniques of administration:

  • Open drop method
  • Anesthetic machine
  • Sub-methods of anesthetics machine: Open system, Closed system, Semi-closed system
• Potency of inhalational anesthetics:

  • Determined by lipid: gas partition coefficient
  • Expressed as MAC (mean alveolar concentration)
• Comparison of Inhalational anesthetics:

  • Properties comparison for Nitrous oxide, Ether, Halothane, Enflurane, Isoflurane
• Pre-anesthetic medication:

  • Sedatives, anxiolytics
  • Analgesics
  • Muscle relaxants
  • Atropine like drugs
  • Antiemetics
  • Basal anesthetics
  • H2 blockers
• Sedative-hypnotics:

  • Sedatives induce drowsiness/anxiolytic effect
  • Hypnotics induce sleep/used in insomnia
• Causes of insomnia:

  • Specific like pain
  • Nonspecific
• Factors affecting selection of hypnotics:

  • Nature of sleep disorder
• Properties of Ideal anesthetics:

  • Sedative effects
  • Analgesic effect
  • Muscle relaxant effect
  • Vagolytic effect
  • Non-irritant property
  • Rapid induction and reasonable recovery
  • No gastric regurgitation in prolonged surgery
• Nature of sleep disorder:

  • Difficulty in falling asleep
  • Difficulty in maintaining asleep
• Factors affecting dose of hypnotics:

  • Characteristics of patient's daily activity:
  • For students: lower dose of hypnotics
  • For housewives: higher dose of hypnotics
  • Past experience with medication:
  • Tolerance may require higher doses
  • General patient attitude to drugs:
  • Positive
  • Negative
• Classes of hypnotics:

  • Barbiturates:
  • Ultrashort acting: Thiopental, Methohexital, Thiamylal
  • Short to intermediate acting: Pentobarbital, Secobarbital, Hexobarbital
  • Long acting: Phenobarbital, Barbital
  • Benzodiazepines:
  • Short acting: Oxazepam, Triazolam, Lorazepam, Alprazolam
  • Long acting: Diazepam, Temazepam, Flurazepam, Chlorazepam
  • Newer hypnotics: Zolpidem, Zaleplon, Eszopiclone
• Comparison between barbiturates and benzodiazepines:

  • Barbiturates:
  • Mechanism: Increase GABA effect
  • Effects: Sedation, hypnosis, anesthesia, REM phase, hangover, nightmares
  • Indications: Sedatives, hypnotics, basal anesthetic, antiepileptic
  • Benzodiazepines:
  • Mechanism: Activate B-receptors
  • Effects: Sedation, hypnosis, anesthesia, REM phase, hangover, nightmares
  • Indications: Short acting for sedatives, hypnotics, long acting for antiepileptic
• Barbiturate poisoning:

  • Symptoms: Decreased respiratory rate, body temperature, blood pressure
  • Treatment: Supportive care with artificial respiration, symptomatic treatment including removal of poison through gastric lavage and urine alkalinization
• Withdrawal syndromes with barbiturates:

  • Symptoms: Excitement, insomnia, convulsions
  • Treatment: Gradual withdrawal, replacing with long-acting barbiturate
• Alcohols:

  • Obtained through brewery, winery, distillation
  • Arabs introduced distillation but also banned alcohol
  • Ethanol kinetics: Absorbed from alveoli and GIT, metabolized by alcohol dehydrogenase to acetylaldehyde and further to acetic acid
  • MEOS: Metabolism in the liver, excreted in urine and alveoli
• Ethanol pharmacological effects:

  • Increase acetylcholine release, saliva, acid secretion
  • Vasodilation leading to decreased body temperature
  • Decreased ADH release leading to increased urination
  • Impairs mental capacity, slurred speech, fluent language
• Ethanol indications:

  • Locally as antiseptic/disinfectant
  • In methanol poisoning
  • Toxicity symptoms: Alcohol smell, hepatitis, drunkenness, appetite suppression
  • Treatment: Withdrawal, alcohol antabuse (disulfiram)
• Methanol:

  • Wood alcohol leading to blindness due to formic acid
  • Treated with ethanol
• Central stimulants:

  • Analeptic-convulsants: Strychnine, Picrotoxin, Metrazole, Necketamide, Doxapram
  • Methylxanthines: Caffeine, Theophylline, Theobromine
• Strychnine:

  • Blocks glycine, produces tonic-clonic convulsions
  • Used as a rodenticide, treated with artificial respiration, diazepam, and gastric lavage
• Picrotoxin:

  • Inhibits GABA, produces clonic uncoordinated convulsions
  • Antagonized by barbiturates
• Metrazole:

  • Also called leptazole/pentylenetetrazole
  • Used as a diagnostic tool
• Nicketamide:

  • Stimulates medullary center and carotid arteries
  • Used as a respiratory stimulant in chronic bronchitis for short term
• Doxapram:

  • Acts by direct neuronal stimulation
  • Used to stimulate respiration, wider safety margin
• Methylxanthines sources:

  • Coffee (caffeine), Cola drinks (caffeine), Tea (theophylline, caffeine), Cocoa (caffeine, theobromine)
  • Mechanisms of action: Stimulate cortex, inhibit phosphodiesterase enzyme, release catecholamine from adrenal medulla