Epilepsia

Volume 53, Issue s8

PHENOBARBITAL: THE CENTENARY

Free Access

How did phenobarbital’s chemical structure affect the development of subsequent

antiepileptic drugs (AEDs)?
Meir Bialer

First published: 03 December 2012

https://doi.org/10.1111/epi.12024

Cited by: 8

Address correspondence to Meir Bialer, School of Pharmacy, Institute for Drug Research, Faculty of Medicine,
The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E‐mail: bialer@md.huji.ac.il
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Summary
Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical
success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g.,
phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of
which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and
the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures
that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced
between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism‐unbiased
anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their
multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is
therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central
nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or
restless legs syndrome). The barbiturates were once used as sedative‐hypnotic drugs, but have been
largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used
worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will
answer a clinical unmet need and might make this old AED more attractive.

The following sixteen new antiepileptic drugs (AEDs) were approved between 1990 and 2012 by the
U.S. Food and Drug Administration (FDA) and/or by the European Medicines Agency (EMA):
eslicarbazepine acetate (ESL), felbamate (FBM), gabapentin (GBP), lacosamide (LCS), lamotrigine
(LTG), levetiracetam (LEV), oxcarbazepine (OXC), perampanel (PER), pregabalin (PGB), retigabine
(RTG) or ezogabine, rufinamide (RUF), stiripentol (STR), tiagabine (TGB), topiramate (TPM),
vigabatrin (VGB), and zonisamide (ZNS). ESL and STR are currently approved only in Europe. These
AEDs offer appreciable advantages in terms of their favorable pharmacokinetics, improved
tolerability, and lower potential for drug interactions. In addition, the availability of old and new AEDs
 with various activity spectra and different tolerability profiles enables clinicians to better choose an
AED according to the characteristics of individual patients (Perucca et al., 2007; Bialer & White,
2010).

The AEDs approved between 1990 and 2012 divide into two categories (Backonja et al., 2011; Bialer,
2006, 2012; Bialer & White, 2010):

 1

Completely new chemical structures (e.g., LCS, RTG, or PER);

 2

Derivatives of existing AEDs that are second‐generation or follow‐up compounds of established

AEDs, such as:

o a.

OXC and ESL, which are carbamazepine (CBZ) derivatives;

o b.

LEV, an ethyl derivative of the cognitive enhancer piracetam;

o c.

PGB, a follow‐up compound to GBP;

o d.

GBP enacarbil, a recently introduced GBP prodrug, approved by the FDA for treating restless legs
syndrome (2011) and postherpetic neuralgia (2012).

Although the new AEDs with a completely new chemical structure were developed empirically and in
many cases serendipitously, the purpose of their design was either to widen the CNS activity or to
improve efficacy, safety, and/or tolerability. The incentives for the design and development of second‐
generation AEDs were the following:

 1

Enhancement of brain penetration compared to the parent compound (e.g., PGB or GBP enacarbil
compared to GBP);

 2
 Elimination of parent compound toxic metabolite (e.g., VPA);

 3

Circumvention of the structural requirements for the teratogenicity of the parent compound (e.g., VPA)
(Bialer, 2006; Bialer & Yagen, 2007).

This article focuses on the chemical properties of the first established AED, the barbiturate
phenobarbital, and discusses how its chemical structure has affected the design and development of
subsequent new AEDs from both categories (completely new chemical structures and second‐
generation) (Bialer, 2006, 2012; Bialer & Yagen, 2007; Bialer & White, 2010). In addition to aspirin
(1899) and paracetamol or acetaminophen (first used in medicine in 1893 but only gained popularity
after 1949) (Grosser et al., 2011), phenobarbital is the only synthetic drug and the only barbiturate that
is still widely used worldwide 100 years after its introduction to the clinical practice.

Phenobarbital
Phenobarbital, 5‐ethyl‐5‐phenyl barbituric acid, is the second barbiturate in clinical use, introduced for
the treatment of epilepsy in 1912 following barbital (Veronal, or 5,5‐diethyl barbituric) that was
introduced in 1903 (Cozanitis, 2004).

Adolf von Baeyer reported the discovery of barbituric acid or malonylurea in 1864 and Mulder
subsequently confirmed its chemical structure in 1873 (Vida & Gerry, 1977). There are three
hypotheses about the origin of the term “barbiturates” (Dundee & Mellroy, 1982; Lopez‐Munos et al.,
2005):

 1

von Baeyer is said to have used this name for sentimental reasons, in honor of his friend Barbara
(Cohen, 1943);

 2

von Baeyer’s discovery was on December 4, the feast day of Saint Barbara, patron saint of artillery
men, tunnel diggers, and firemen. Therefore von Baeyer designated his malonylurea barbituric acid
(Sharpless, 1970; Cozanitis, 2004);

 3

The term was inspired by the “barbed” appearance of the crystals of these ureic compounds or uredines
(Fieser, 1944). In any case, it is clear that the combination of the terms “barb(ara)” and “urea” forms
the basis for the name barbiturates (Lopez‐Munos et al., 2005).
However, barbituric acid per se does not possess CNS activity, probably due to its lower lipophilicity
compared to its alkyl or aryl derivatives, namely the barbiturates. Fischer and von Mering
(1903) employed a condensation reaction to synthesize barbituric acid, using diethyl malonic acid and
urea; this was not only a practical method for synthesizing barbiturates but was also coupled with the
revolutionary discovery that barbital possesses hypnotic properties. Having visited Verona earlier, von
Mering thought it appropriate to name the new compound after this city; thus barbital became Veronal.
Another theory is that the name Veronal (from the Latin versus, meaning true) was coined by Fischer,
who claimed to have found the “true” hypnotic compound (Sneader, 1985). Veronal was manufactured
by E. Merck (Germany) and by Winthrop in the United States. Thus began the barbiturates era
(Table 1) (Cozanitis, 2004). In his memoirs, the Nobel laureate Emil Fisher mentioned Veronal only in
passing, since it was the synthesis of enzymes that most interested him (Cozanitis, 2004).
Table 1. Chemical structures, pharmacokinetics, and pharmacodynamic properties of barbiturates that are
currently available commercially (asterisks denote chiral centers, partly based on Mihic & Haris, 2011 )

Barbiturates were introduced into clinical practice during the first decade of the 20th century. Their
history as AEDs began with a report from Hauptmann (1912) that a patient with epilepsy had fewer
seizures when given phenobarbital for sedation. In 1919, Horlein at Bayer introduced phenobarbital
(Luminal), and the patent rights were granted to Bayer in 1916. Phenobarbital was rapidly recognized
as a better and safer AED than bromides; consequently it replaced bromides, which had been the only
AEDs used since 1857. Phenobarbital had a more prolonged pharmacologic action than its predecessor
and soon became the “king of the barbiturates,” both in the hospital and in outpatient care (Shorter,
1997).
Veronal and phenobarbital were the first barbiturates to be accepted by the international
pharmacopoeia. Acceptance in Britain and the United States was in 1914 and 1923, respectively.
Phenobarbital is considered as a sedative rather than hypnotic substance and, according to its
Controlled Substances Act grouping, it has low abuse potential. Tolerance in patients treated with
phenobarbital has been reported but the addiction to phenobarbital was questionable (Cozanitis, 2004).

Phenobarbital is a weak acid (pKa = 7.3) that is sparingly soluble in water (1 mg/ml).
Phenobarbital sodium salt (PB‐Na) has a better water solubility than phenobarbital per se (free acid)
and consequently, has been used in phenobarbital parenteral preparations. Nevertheless, a
phenobarbital injection is not an aqueous solution but contains 20% PB‐Na in a mixture of 90%
propylene glycol and 10% water at pH = 10–11 (Bialer, 2009). Phenobarbital’s pKa (−log of the
dissociation constant − Ka) is similar to that of the physiologic blood pH, and therefore phenobarbital
is 50% ionized and 50% nonionized at pH = 7.3, but the ratio of ionized to nonionized phenobarbital
changes according to the physiologic pH (Anderson & Levy, 1995).

Phenobarbital has a complete oral bioavailability (F = 100 ± 11%), very low total clearance (CL
= 0.06 ± 0.01 ml/min/kg) that is 75% (hepatic) metabolic and 25% renal, a volume of distribution
less than the total body water (V = 0.54 ± 0.03 L/kg), and a long half‐life (t1/2 = 99 ± 18
h) (Browne et al., 1985; Anderson, 2002). Phenobarbital is mainly metabolized to two inactive primary
metabolites: p‐hydroxy‐PB that is excreted in the urine as free and glucuronide conjugate, and an N‐
glucoside conjugate of phenobarbital (Anderson, 2002).

Sandberg (1951) postulated that in order to possess good hypnotic activity, barbituric acid must satisfy
two criteria: (1) it must be a weak acid, and (2) it must have a lipid/water partition coefficient within a
certain limit. Subsequently, the barbiturates were classified into potentially active and inactive classes.
In the active class (as hypnotics) there were 5,5‐disubstituted barbituric acids and thiobarbituric acids
as well as 1,5,5‐trisubstituted barbituric acids (Sandberg, 1951; Vida & Gerry, 1977). Substitution of
various alkyl and/or aryl moieties for the N and C‐5 hydrogens of barbituric acid yielded molecules
that varied considerably in their dominant pharmacologic effect on laboratory animals, including
inactive, sedative, and proconvulsant compounds (Prichard, 1980).

In 1922, Dox synthesized butabarbital (Table 1), a butyl analog of Veronal that was three times
stronger with a shorter duration of action and thus lower “rebound” possibility. In 1923, Shonle and
Molen synthesized amobarbital (Amytal) that was methyl homolog of butabarbital. Six years later,
Amytal sodium became the first ever barbiturate to be used as an intravenous anesthetic (Cozanitis,
2004; Lopez‐Munos et al., 2005).

The ease of substituting various moieties on position 5 of the barbituric acid molecule yielded over
2,500 barbiturates. About 50 barbiturates were marketed, and classified as short‐, medium‐, or long‐
acting sedatives (Cozanitis, 2004; Lopez‐Munos et al., 2005). Although the barbiturates were used
extensively in the first half of the 20th century as sedatives, hypnotics, and anesthetic drugs, today they
have been largely replaced in these roles by the safer benzodiazepines, except for a few specialized
uses. Currently, about eight barbiturates (Table 1) are sufficient to cover the therapeutic applications
(e.g., insomnia, anesthesia) that still require barbiturates (Lopez‐Munos et al., 2005). In contrast to
other barbiturates, phenobarbital is still the most widely used AED in the developing world and
remains a popular AED in many developed countries (Kwan & Broide, 2004). Phenobarbital’s
centenary will be celebrated in 2012 with a special Centenary Symposium during the 10th European
Congress on Epileptology (ECE) in London (September 30–October 4, 2012).

Other Phenobarbital Derivatives Used as AEDs

Mephobarbital
Phenobarbital’s success led to the development of other barbiturates as subsequent AEDs,
including the N‐methyl barbituric acid derivatives (Fig. 1): mephobarbital (N‐
methylphenobarbital), introduced in 1932 (Blum, 1932) and metharbital (5,5‐diethyl‐1‐
methylbarbituric acid), which was introduced in 1948 but never became popular (Eadie &
Hooper, 1995, 2002). Like phenobarbital, both mephobarbital and metharbital are water‐
insoluble weak acids with pKa values of 7.8 and 8.5, respectively. The introduction of the N‐
methyl group into the phenobarbital molecule breaks the symmetric axis possessed by
barbituric acid or phenobarbital. Consequently, unlike phenobarbital, mephobarbital is a chiral
compound containing one asymmetric carbon atom at position 5 of the molecule. It has been
used clinically as racemic mixtures [equal parts of (R)‐ and (S)‐enantiomers]. Lim and Hooper
(1989) and Hooper and Qing (1990) showed that mephobarbital metabolism is
stereoselective with (R)‐methylphenobarbital being metabolized by cytochrome P450
(CYP)2C19‐mediated aromatic hydroxylation (a genetic polymorphism‐susceptible metabolic
pathway coregulated by mephenytoin hydroxylation), whereas (S)‐methylphenobarbital
undergoes CYP2D6‐mediated demethylation to form phenobarbital (Lim & Hooper,
1989; Hooper & Qing, 1990; Eadie & Hooper, 2002). In contrast to phenobarbital,
mephobarbital is currently not widely used.