Introduction
Intravenous (IV) anesthetic agents are the most common drugs used in day-to-day anesthesia practice. It encompasses agents like sedative-hypnotics, anxiolytics, opioids, and muscle relaxants. The combination of all these agents is used to achieve the desired level of anesthesia and analgesia with minimal side effects collectively known as “balanced anesthesia.”
Classification
The IV anesthetic agents can be classified, as shown in the schematic flowchart below (Flowchart 9.1).
The sedatives and hypnotics can be further categorized into barbiturates and nonbarbiturates:
Barbiturates, for example, thiopentone, methohexitone.
Nonbarbiturates, for example, propofol, ketamine, etomidate.
Nonopioid IV Anesthetic Agents
Barbiturates
Thiopentone: Thiopentone is a barbiturate, and its introduction in 1934 by Water and Lundy has changed the face of modern anesthesia practice.
Physicochemical Properties
A rapid-acting barbiturate derived from barbituric acid. The substitution with a particular chemical group in barbituric acid imparts characteristic property to the parent compound:
Sulfur at second position—increases lipid solubility.
Aryl/alkyl group at fifth position—has hypnotic and sedative effects.
Increase in length of alkyl chain at fifth position—increases potency.
Phenyl group at fifth position—increases anticonvulsant activity (but no effect on hypnotic activity).
Methyl group on nitrogen—increases hypnotic potency but lowers the seizure threshold.
Preparation: Yellow amorphous powder (500- and 1,000-mg vial) prepared in the atmosphere of nitrogen and 6% anhydrous sodium carbonate is added to prevent precipitation of free acid by carbon dioxide from the atmosphere.
The powder is diluted to prepare a 2.5% solution (acidic pH of Ringer lactate can precipitate thiopentone; so it should not be used for dilution).
The 2.5% solution is highly alkaline with a pH of 10.4 and pKa of 7.6.
The freshly prepared solution should be used within 48 hours; however, it can be used for 1 week if refrigerated.
Mechanism of Action
It acts on GABAA receptors in the central nervous system (CNS) and causes the opening of chloride channels, leading to CNS depression through hyperpolarization of neurons.
At low-dose, it is GABA-facilitatory, while at higher doses, it acts as GABA-mimetic.
It also acts on glutamate, adenosine, and neuronal nicotinic acetylcholine receptors.
Pharmacokinetics
It has rapid uptake and rapid distribution out of the brain into inactive tissues, leading to unconsciousness in one brain-arm circulation time (i.e., 15 s) after an IV dose.
80 to 90% is bound to plasma proteins (mainly albumin).
99% of thiopentone is metabolized by the liver (low-hepatic extraction ratio and capacity-dependent elimination) and excreted through the kidney.
The prolonged infusion or repeated doses of thiopentone leads to its accumulation in muscle and fat. The thiopentone is released into circulation after stopping the infusion and causes delayed awakening.
With usual induction doses (4–5 mg/kg), it follows first-order kinetics (i.e., a constant fraction is cleared per unit time), while at higher doses (200–300 mg/kg), it follows zero-order kinetics (a constant amount is cleared per unit time).
The children and adults are similar in terms of protein binding and volume of distribution.
Increased protein binding in pregnant patients leads to longer elimination half-life.
Pharmacodynamics and Clinical Applications
It produces unconsciousness in 15 seconds after an IV dose.
It causes a dose-dependent decrement in cerebral metabolic rate, cerebral oxygen consumption, and intracranial pressure (ICP) and thus provides neuroprotection against partial cerebral ischemia (however, there is no neuroprotection in global ischemia).
At lower doses, barbiturates decrease pain threshold.
There is dose-related suppression of EEG.
There is a lower degree of amnesia compared to benzodiazepines.
Respiratory system
Dose-related central respiratory depression with increased susceptibility in patients with chronic lung diseases.
Respiratory depression correlates with EEG suppression and minute ventilation.
The peak respiratory depression occurs at
1 to 1.5 minutes of drug administration and returns to baseline within 15 minutes.
Thiopental causes “double apnea” in 20% of cases, which can be described as apnea of few seconds succeeded by few breaths of normal tidal volume, with subsequent prolonged apnea (25 s).
Cardiovascular system
It causes hypotension by the following mechanisms:
There is baroreceptor reflex-mediated tachycardia (avoid in patients with coronary artery disease [CAD]).
Prolongation of QT interval and flattening of T wave (so, it is not good for patients at risk of QT prolongation and ventricular arrhythmias).
Significant reduction in cardiac output (not good for hypovolemic patients).
Complications
The IV use of thiopentone can sometime result in local complications such as thrombophlebitis, tissue necrosis due to intramuscular (IM)/subcutaneous (SC) injection, but the most dreadful is an intra-arterial injection which needs special attention here.
Intra-arterial injection: The inadvertent intra-arterial injection (commonly happen when thiopentone is injected in antecubital fossa) can cause gangrene and loss of limb if timely diagnosis and intervention are not instituted. The high alkalinity and pH of blood lead to precipitation and crystal formation which, in turn, leads to vasospasm and thrombus formation with consequent ischemia. Utmost precautions should be taken to prevent such incidents, and these are as follows:
Once the intra-arterial injection has happened, the definitive measures include:
Leave the needle at its site and use it for all therapeutic injections.
Inject heparin to prevent thrombus formation.
Papaverine or 1% lignocaine to cause local vasodilation.
Relieve vasospasm with stellate ganglion block if the above measures do not work.
Prescribe oral anticoagulants and follow-up in consultation with the vascular surgeon.
Methohexitone
It is an ultrashort-acting barbiturate with an anesthetic effect lasting for 2 to 5 minutes. It is twice as potent as thiopentone. The epileptogenic potential of methohexitone makes it an attractive choice for ECT.
Nonbarbiturates
Propofol: Propofol is popularly known as “milk of anesthesia” among anesthesia providers. It was discovered in 1970 by John B. Glenn and approved by the Food and Drug Administration (FDA) in 1989 for clinical use.
Physicochemical Properties
It is an alkylphenol, and its chemical name is 2,6-diisopropyl phenol.
It is milky white in appearance due to scattering of light by the lipid droplets.
Constituents of 1% propofol preparation are as follows:
10% soyabean oil (emulsifier).
1.2% purified egg phospholipid (emulsifier).
2.25% glycerol (to maintain tonicity).
Because of the risk of bacterial contamination, EDTA/sodium metabisulphite is added as a bacteriostatic agent, and it is recommended to discard the propofol vial after 6 hours of opening it.
Mechanism of Action
The main site of action is the beta-subunit of GABAA receptors. It is GABA-facilitatory in a lower dose and GABA-mimetic with higher doses. The other receptors are:
Pharmacokinetics
It is oxidized to 1,4-diisopropylquinol in the liver, followed by conjugation with glucuronic acid and consequent excretion through kidneys.
The major site of metabolism is the liver (high-hepatic extraction ratio, so the metabolism is hepatic blood flow-dependent). The other sites are kidneys and lungs.
The context-sensitive half-life is 40 minutes after 8 hours of infusion.
The dose requirement decreases with age.
The children require a higher dose than adults because of the larger volume of distribution and rapid clearance of the drug.
Pharmacodynamics
The hypnosis onset occurs in one brain-arm circulation time (30 s), with peak effect at 90 to 100 seconds.
Effect on EEG shows an initial rise in alpha rhythm, followed by a shift to gamma and theta rhythm.
It causes a dose-dependent decrease in cerebral metabolic oxygen consumption, cerebral blood flow, and ICP; however, its role in neuroprotection is controversial.
It is a dose-dependent anticonvulsant; grand mal seizures have been described in the literature.
It has abuse potential; however, the evidence for it among the general public is scarce.
It causes a remarkable decrease in intraocular pressure (30–40%).
The awakening and orientation occurs at a plasma concentration of 1.6 and 1.2 µg/mL, respectively.
The endpoint of induction is the loss of response to verbal commands, and it correlates with the plasma level of 2.3 to 3.5 µg/mL (propofol alone).
Cardiovascular system
It causes significant hypotension by decreasing systolic, diastolic, and mean arterial pressure. It occurs through the following mechanisms:
It blunts baroreceptor reflex (so no significant tachycardia in response to hypotension).
The hemodynamic response to propofol lags behind the hypnotic effect.
Other effects
It does not enhance neuromuscular blockade produced by muscle relaxants.
No effect on evoked responses.
Does not trigger malignant hyperthermia.
No effect on corticosteroid synthesis or adrenocorticotropic hormone (ACTH) stimulation.
It decreases chemotaxis of neutrophils but has no effect on phagocytosis and killing.
Uses
Induction of anesthesia: 1 to 2.5 mg/kg
(adults), 2 to 3 mg/kg (children), 1 to 1.75 mg/kg (>60 years).
Maintenance of anesthesia: Dose (50–150 µg/kg/min with opiates or nitrous oxide).
For sedation in intensive care units: Dose (25–75 µg/kg/min).
In combination with remifentanil for total intravenous anesthesia (TIVA).
As an antiemetic: 10 to 20 mg IV can be repeated every 5 to 10 minutes or infusion of 10 µg/kg/min.
Side Effects
Pain at injection site is quite common, and the following measures can decrease it:
Use of water-soluble preparation (e.g., fospropofol).
Addition of lidocaine to the syringe of propofol.
Use of opiates/nonsteroidal anti-inflammatory drugs (NSAIDs)/ketamine/esmolol/clonidine/dexamethasone.
Risk of bacterial contamination and sepsis.
A rare lethal syndrome which occurs mostly in critically ill patients who receive it for sedation at doses 4 mg/kg/hr for more than 48 hours.
The risk factors for propofol infusion syndrome are:
Treatment of propofol infusion syndrome includes:
Pharmacokinetics
It can be given through IV/per oral/ rectal route.
Context-sensitive half-life is less than propofol.
It is metabolized into carboxylic acid and ethanol in the liver through ester hydrolysis and excreted in urine and bile.
Use of continuous infusion is limited by adrenal suppression caused by etomidate.
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