N01: Anesthetics

How do anesthetics work?

Among the general anesthetics, propofol (N01AX10), an intravenous hypnotic used for sedation and general anesthesia, potentiates the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABA_A receptor [2]. Etomidate (N01AX07) acts on the same receptor as a positive allosteric modulator, enhancing the effect of GABA [3].

Local anesthetics of the amide type, such as lidocaine (N01BB02), bupivacaine (N01BB01) and ropivacaine (N01BB09), are potent sodium channel blockers [4].

Efficacy

For propofol, the main clinical effect is loss of consciousness, which is hard to quantify. Most clinicians consider it a continuum of effects, most of which are binary, present or absent [2]. A binary endpoint is modeled as a probability: for propofol, the probability of being asleep was modeled against steady-state concentration in volunteers aged 25 to 81 years. The concentration giving a 50% probability of loss of consciousness fell from 2.35 µg/mL at 25 years to 1.25 µg/mL at 75 years, so older patients are more sensitive [5].

Several electroencephalogram (EEG)-based methods quantify the depth of anesthesia instead. The most used is the bispectral index (BIS), a unitless number from 0 to 100, where 100 means no hypnotic drug effect and 0 means no cerebral electrical activity. Most propofol pharmacodynamic studies have used a sigmoid E_max model, relating the drug effect to the concentration in a hypothetical effect site rather than directly to the blood concentration. The effect site equilibrates with plasma at a rate set by the constant k_e0, and published values for propofol range from 0.01 to 0.45 min^-1 [2].

Because k_e0 estimates had been reported to depend on the rate and duration of administration, one study gave healthy volunteers a 1-minute infusion on one occasion, and the same infusion followed by 29 minutes more on another. A standard effect compartment could not describe the delay in BIS for both regimens, while a two-compartment effect site significantly improved the predictions [6].

Some of these models run in target-controlled infusion devices, which compute the infusion rate needed to reach a chosen plasma or effect-site concentration. Propofol’s interactions with other hypnotics tend to be additive, and those with opioids highly synergistic. Response surface models describe these combined effects [2].

Safety

Propofol has a narrow therapeutic margin. Its main adverse effects are cardiopulmonary: loss of airway reflexes, slow or shallow breathing (hypoventilation) or even a pause in breathing (apnea), and low blood pressure (hypotension). The most common adverse effect is pain on injection. Propofol infusion syndrome, with severe acid build-up in the blood (metabolic acidosis), muscle breakdown (rhabdomyolysis), high blood potassium (hyperkalemia) and cardiovascular collapse, is rare but frequently fatal. It occurs mostly with prolonged, high-dose infusions in children, and the Diprivan package insert advises against more than 5 mg/kg/h for more than 48 hours [2]. Etomidate suppresses the outer layer of the adrenal glands (adrenal cortex) by inhibiting the enzyme 11β-hydroxylase, which makes it unsuitable for prolonged infusion and for critically ill patients [3].

Systemic toxicity after injection of a local anesthetic is infrequent. The onset of its central nervous system and cardiovascular effects has been tentatively linked to circulating drug concentrations [7]. At toxic concentrations, the amide local anesthetics cause severe irregular heart rhythms (arrhythmias) that can lead to cardiac arrest. At least at steady state, their toxicity is directly related to the unbound drug concentration. They are bound to serum proteins, mainly to alpha₁-acid glycoprotein (AAG), from 65% for lidocaine to more than 95% for bupivacaine and ropivacaine. AAG is an acute phase protein that rises quickly with inflammation, particularly after surgery. Neonates and infants have less AAG than adults, so a larger fraction of the drug is unbound [4].

References