Thursday, 11 December 2014

Pharmacology of General Anestehtics

General anesthetics are drugs generally used for the purpose of reversible loss of consciousness (especially in case of surgery). Before studying general anesthetics it's mandatory to understand the stages of anesthesia in human being.

Stages of Anesthesia:

Stages of anesthesia

Pharmacokinetic principles of volatile anesthetics:

  • Anesthetic first saturates the alveoli. After the saturation of alveoli, it enters the blood.
  • This depends upon blood/gas partition coefficient.
  • Higher the blood/gas coefficient more time will be required for the saturation of blood (Induction time high).
  • After saturation of blood, anesthetics enter in the tissue (including brain) & anesthesia achieved.
  • This also depends on tissue/blood partition coefficient.
           Minimum alveolar concentration (MAC): Concentration at 1 Atm. pressure of a anesthetic in              the  alveoli that is required to produce immobility in 50% of adult patients subjects to surgery.
  • Increase to 1.3 MAC = Immobility in 99% patients.
  • As at equilibrium, con. in alveoli is equal to the con. in brain (site of action), hence MAC is used represent the potency of anesthetic.
Factors influencing MAC:

a) Increased MAC: 
  • Increased catecholamines level CNS.
  • Hypernatremia
  • Hyper thermia
b) Decreased MAC: 
  • Alcohol
  • Clonidine
  • Lidocaine
  • Opoids
  • Decreased catecholamine in CNS
  • Hypotension
  • Hypoxia

Theories about the mechanism of anestehesia:

a) Meyer-Overton theory: In 1900, Hans Meyer & Charles Overton suggested that the potency of a substance (anesthetic) is directly proportional to its lipid solubility/partition coefficient (unitary theory of anesthesia).
  • Later, postulated, anesthetics interacts with hydrophobic portion of membrane ----> distortion of Na+ pumps ------> Anesthesia.
  • In the presence of anesthetics, membrane bloat & squeeze over Na+ channels ----> Interferes with depolarization.
  • Not all lipid soluble anesthetics are potents.
b) Stereochemical aspects: Isolurane, Desflurane, Enflurane all contains chiral carbon ------> (+) Isoflurane is more potent than (-).

c) Ion Channel & protein receptor hypothesis:
  • Chloride Channels:
    Chloride channels
    This is the most common route of mechanism of action of general anesthetics. Inhalation anesthetics acts by increasing GABA con. at GABAa receptor & stabilizing the GABA-receptor complex. There are two receptors : GABAa & Glycine, both of which are inhibitory in nature. Isolfulrane, Benzodiazepine,& barbiturates acts by this mechanism.

  • Sodium channels: 
    Sodium Channel
    Most important is ligand gated Na+ channel in N-methyl-D-aspartate (NMDA) receptor complex. Halothane & Ketamine antagonise this receptor.

  • Potassium Channels:
    Potassium Channels
    These act by increasing K+ con. in ECF from ICF. Opoid analgesics & alpha receptor2 agonists acts by this pathway.

Classification of General anesthetics:

Classification of general anesthetics

Pharmacology of individual class of general anesthetics:

a) Inhalation anesthetics:

1. Nitrous Oxide: (70% N2O + 25-30% O2 + 0.2-2% potent anesthetic)
  • Alone not used as low potency.
  • Induction & recovery quick (low blood solubility).
  • Thiopentone is used along for induction.
  • Low effect on respiration, BP % heart.
2. Ether (Ethyl ether): 
  • Potent anesthetic.
  • Increased blood solubility.
  • Increased irritation & inflammable (Not used in developed countries).
3. Halothane: 
  • Potent anesthetic.
  • 2-4% for induction & 0.5-1% for maintenance.
  • Cough suppression & bronchodilation- Suitable for asthamtics.
  • During labour: Increased delivery & blood loss.
  • Malignant hyperthermia: Abnormal RyR (Ryanodine receptor) Ca channels. Increased release of Ca2+ -------> Increased muscle contraction & heat (Succinyl choline increase the symptoms). IV dantrolene + O2 inhalation is used for the treatment.
4. Isoflurane (Sofane):
  • Isomer of enflurane.
  • Safer in patients with myocardial ischemia.
  • Preferred for neurosurgery.
5. Desflurane:
  • Very low blood solubility.
  • Other properties similar to isoflurane.
b) Intravenous anesthetics:

i) Inducing agents:

1. Thiopentone Sodium:
  • Ultrashort acting thiobarbiturate. High solubility in water & must be prepared fresh.
  • Increased lipid solubility reaches brain quickly.
  • Poor analgesic.
  • Thiopentone & succinylcholine reacts chemically- Should not be mixed in same syringe.
2. Propofol:
  • Superceded Thiopentone sodium.
  • Bradycardia common otherwise safe drug.
ii) Slower acting drugs:

1. Benzodiazepines:
  • Poor analegiscs.
  • Diazepam- Most common.
  • Lorazepam- 3 times more potent than diazepam,
  • Midozalam- Slower & faster acting.
2. Ketamine:
  • Dissociative anesthesia.
  • Feeling of dissociation from one's body.
  • Acts at cortex & subcortical region.
  • Increased heart rate, blood pressure & carbon monoxide (Dangerous in hypertensives).
  • Related to hallucinogen phenytoin.
3. Fentanyl: Related to pethidine.

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