General Pharmacology: Pharmacokinetics and Metabolism of the Barbiturates.

Pharmacokinetics and Barbiturates: Introduction and Overview:

Barbiturates: Although barbituric acid was the first barbiturate synthesized over hundred years ago, thiopental (Pentothal) has been clinical use for about 70 years in its use mark the beginning of IV anesthesia.

Barbiturate acid is composed of urea and melonic acid (cyclic ureide of malonic acid)

urea

malonic acid

⇄

barbituric acid

Urea

malonic acid

Barbituric Acid

Particularly advantageous characteristics of thiopental (Pentothal) (and methohexital (Brevital)) include rapid onset but short duration of action due to redistribution.

Furthermore, these agents appear relatively safe to use

As noted above the primary mechanism for termination of action of thiopental (Pentothal) and methohexital (Brevital) is redistribution from the brain to other compartments, as a result of equilibration.

This mechanism is distinct from metabolism as a means of terminating anesthetic effect.

Rapid onset is a characteristic of these agents and can be understood in terms of their chemical properties

To understand this aspect we need to consider the molecular characteristics of these drugs.

Barbiturates exists in two molecular forms, and enol and keto forms.

Enol forms for barbiturates are water-soluble at pH 10-11at 6% sodium carbonate.

Therefore, in the injected form the drug is not initially lipid-soluble and would not be expected to enter the brain readily.

Here is the structure of enol form for barbiturate acid:

Once in circulation, the enol form undergoes a structural change called "tautomerization" to a keto form which is more lipid soluble:

Specific pharmacological characteristics of different barbiturates are mainly due to chemical substitutions at the "5" position in the molecule.

Hypnotic properties are influenced by the nature of side chains at position 5.

Duration of action and potency are also affected by the length of site chains at position 5.

Here are some examples

Thioamylal:

Pentobarbital (Nembutal)

Methohexital (Brevital)

Rapidity of onset and duration of action (that is more rapid onset with a shorter duration) is significantly affected by a substitution at position 2:

Thiopental (Pentothal) and thioamylal exhibit a shorter duration of action and a rapid onset compared to secobarbital (Seconal) and pentobarbital (Nembutal)

Thiopental (Pentothal)

Side Chain Differences between Barbituric Acid Derivatives

barbital

phenobarbital

pentobarbital

sodium pentothal

Barbiturates as anesthetic agents: Thiopental (Pentothal) Pharmacokinetics⁵

Overview:
- Major factors that determine to the characteristic uptake for thiopental (Pentothal) include not only its intrinsic lipid solubility but also the concentration gradient between blood and tissue and importantly the extent of perfusion.
- For example, the brain received a significant percentage of cardiac output and is also relatively lipophilic.
  - As a result, there is a rapid rise in thiopental (Pentothal) brain concentration and as a result a short time to onset of anesthetic effect.
- On the other hand, there will also be a relatively rapid decrease in brain thiopental (Pentothal) concentration as a thiopental (Pentothal) equilibrates with other compartments, such as muscle initially and ultimately with other large but increasingly poorly perfused compartments.
- An understanding of thiopental (Pentothal) pharmacology begins with the recognition that the rapid time to onset is largely due to the lipophilic characteristic of the drug and the significant percentage of cardiac output that goes to the brain.
  - The second important aspect is the recognition that the short duration is due not to metabolism but to redistribution from the brain to other compartments.
Barbiturate pharmacology a summary of organ system and other effects:⁵
- CNS:
  1. Barbiturates may increase the patient's sensitivity to pain.
    1. Administration of barbiturates the patient in pain may result in agitation as opposed to sedation.
    2. This observation suggests that other drugs, for example opioids, might be appropriate to manage pain and then subsequently an assessment made concerning the need to sedate.
  2. Cerebral metabolism is depressed by barbiturates and barbiturate administration is associated with decreased cerebral blood flow and intracranial pressure.
    1. Changes in these parameters are of sufficient size to be important in neurosurgical cases.
- Cardiovascular effects:
  1. Slight myocardial depression is associated with some tachycardia (increased myocardial oxygen consumption)
  2. Peripheral vasodilation (venodilation) is a principal effect that, because of reduced preload, results in reduced cardiac output.
  3. These cardiovascular effects should be considered as important for the subgroup of patients who may be particularly sensitive to these hemodynamic effects.
    1. For instance patients with ischemic heart disease might be adversely affected by the increased myocardial oxygen requirement secondary to tachycardia.
    2. Similarly, a hypovolemic patient may be more sensitive to reduced preload due to increase peripheral capacitance.
      1. The peripheral vasodilation results in a hypotensive state which appears more pronounced in patients who were initially hypertensive compared to those who were normotensive.
- Pulmonary effects:
  1. Barbiturates are respiratory depressants.
    1. Depressed respiration can lead to apnea during induction
  2. Respiratory system responses to hypoxia and hypercarbia will be diminished following barbiturate administration.
  3. Laryngospasm may still occur because laryngeal reflexes are relatively less affected by the drug.
- Other:
  1. Reduced urine output may occur secondary to reduced renal blood flow (presumably due to depressed cardiac output)
  2. Vasodilation may increase heat loss to an extent that postoperative shivering may be worsened.
  3. As discussed earlier, barbiturate are absolutely contraindicated in patients who have abnormalities in porphyrin metabolism.
    1. Episodes of acute intermittent porphyria may be induced by barbiturates because of their effect in increasing aminolevulinic acid synthetase, which is the enzyme that catalyzes the rate-determining step in the porphyrin biosynthetic pathway.
- Although barbiturate are properly classified as sedative-hypnotic agents, they lack certain characteristics which are important for anesthesia, including analgesia and amnesia.
  - Other drug groups, such as the opioids, represent effective approaches to analgesia, whereas certain benzodiazepines are very effective amnestic and anxiolytic agents.
- Thiopental (Pentothal), however, is an effective anesthetic induction drug although other agents, such as propofol (Diprivan) are increasingly commonly used.