press above to begin

• Usually one enantiomer will be more effective than its mirror structural image-- suggesting a more complementary fit between the drug with its receptor binding region.

  • Examples:

    • S(+)- methacholine enantiomer > 250 times more potent than the R(-) enantiomer form

    • Ketamine (Ketalar): (+) enantiomer more potent, less toxic then the (-) enantiomer; however, the drug is used as the racemate (includes both enantiomeric forms)

• Other enantiomeric differences important in anesthesia:

  • Cardiotoxicity associated with bupivacaine is probably due to the d-bupivacaine (Marcaine) isomer, perhaps because d- bupivacaine (Marcaine) occupies the sodium channel longer than l- bupivacaine (Marcaine).

  • Ropivacaine (Naropin), related to bupivacaine (Marcaine), is synthesized as a single enantiomer, exhibiting decreased cardiotoxicity.

  • Cisatracurium (Nimbex), an atracurium (Tracrium)  isomer, does not promote histamine release.

  • d- propranolol (Inderal) is the form than blocks beta-adrenergic receptors; however, both enantiomers exhibit "local-anesthetic" effects.  The antiarrhythmic properties of propranolol (Inderal) therefore, depending on concentration, may include both beta adrenergic blockade, at lower concentrations (d-propranolol (Inderal)), as well as a direct membrane effect which is not require stereoselectivity.

  • Recently, a drug, dexmedetomidine (Precedex), which has been approved by the FDA for sedation of critically ill patients in the ICU setting, is a good example of a drug which, in the l-, form has no effect on halothane (Fluothane) MAC; however, the d- form dramatically reduces halothane (Fluothane) MAC.  

    • Dexmedetomidine (Precedex), presently used (on-label) in the ICU setting, exhibits the ability to produce a state of patient "tranquility"in which patients appear asleep but are easily aroused and exhibit no significant respiratory depression. These pharmacological characteristics suggest possibly wider future usage.

    • The example in which the d- form of dexmedetomidine (Precedex) significantly reduces the halothane (Fluothane) MAC value serves to reinforce the idea of that anesthetic requirements are influenced importantly by other drugs which may be concurrently used.  Other examples in which such interactions are prominent include benzodiazepines and opioids.

  • Naturally occurring agents used in anesthesia are typically stereospecific because enzymes exhibit stereoselectivity:

    • Examples:

      • l- morphined- tubocurarine 

• ³Mechanistic implications of enantiomer-selective biological effects:

  • Concerning the mechanisms of anesthetic action, an important aspect was derived from the observation that there was a significant correlation between anesthetic potency and lipid solubility (Meyer-Overton rule).  Generally, this rule had been applied to inhaled anesthetics rather than  intravenous drugs. Lipid solubility is an important physical-chemical property of drugs that is important in getting the drug to the site of action (lipid bilayer-based membrane structure).

  • How anesthetics work however does not appear to be explained solely on the basis of lipid solubility.

  • A clue comes from the observation that some anesthetics exhibit some degree of enantiomer-selectivity.  Examples of such agents include barbiturates, etomidate (Amidate), and isoflurane (Forane). Enantiomer-selectivity suggests a protein (receptor) involvement since presumably proteins exhibit the degree of molecular specificity required to select preferentially one enantiomer from another in terms of biological efficacy.  

  • A more general point, is that the way biological specificity works depends upon precise 3-D alignment of molecular groups and therefore is intrinsically, most of the time, stereoselective -- that is, preferring one stereoisomer over the other.  Such selectivity is reflected not only in one drug enantiomeric form being either more potent or less potent than another but also in the body prefers one amino acid isomer over another (typically the in l- form). Recall that this specificity is embedded at the deepest levels of enzyme, transport proteins, and nucleic acid interactions with biomolecules.

• ³Examples of anesthetic interaction-receptor sites:

  • Transmitter-gated ion channels

  • GABA (gamma-aminobutyric acid) and glycine receptors

    • At anesthetic concentrations, all intravenous anesthetic drugs enhance GABA_a (subtype a) receptor-mediated effects.  Recall that GABA systems are inhibitory

  • Some anesthetic agents inhibits excitatory responses associated with nicotinic, cholinergic receptor activation,  whereas others inhibits ionotropic glutamate receptor types (glutamate is an excitatory neurotransmitter)

  • Anesthesia action may be based on both activating inhibitory  neurotransmitter-receptor CNS systems and inhibiting excitatory neurotransmitter-receptor CNS systems.