Jack DeRuiter, Principles of Drug Action 2, Fall 2004

THE BARBITURATES

1. Barbiturate General Structure and Numbering

• Barbiturates contain a “balance” of hydrophilic (2,4,6-pyrimidinetrione ring structure)

and lipophilic (5,5’-substituents) functionality. The overall hydrophilic (polar) or
lipophilic (non-polar) character of the barbiturates is a function of:

- The hydrophilicity of the pyrimidinetrione ring which is a function of the number

of N-substituents and the pKa of the acidic proton(s), and
- The overall size and structure of the two substituents at the 5-position

O R5/R5' = Aromatic
4
R5
R3 = H or CH3 R3 or alkyl
N 5 R5'
3
6
X 2 N1 O
X = O or S
H
Barbiturate

2. Barbiturate Ionization, Acidity and Salt Formation

• Barbiturates containing at least one N-H hydrogen atom are acidic. Acidity results
from the ability of the N to lose hydrogen and the stabilization of the resulting
anionic charge of the conjugate base by resonance delocalization as shown below:
O
R5 O O O
R3 R5 R5 R5
N R5' R3 R3 R3
Base N R5' N R5' N R5'
X N O
X N O X N O X N O
H
Acid form
Conjugate Base Resonance Forms

• The relative acidity of different barbiturates is a function of the degree of N-

substitution and C-5-substitution as shown below (electron donors decrease acidity!):

O O O
H R5 R5
H H CH3
N H N R5' N R5'

O N O O N O O N O

H H H

Barbituric acid: pKa 4.12 5,5'-Disubstituted 3,5,5'-Trisubstituted

barbituric acid: pKa 6.5-8 barbituric acid: pKa > 8

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

- Barbituric acid (N- and C-5-unsubstituted) is the highly acidic (but not active as a
CNS depressant): See structures above
- Addition of substituents at the 5-position decrease acidity (raise pKa) due to the
electron donating effects (+I) of the 5-alkyl groups: See structures above
- Substitution at one ring nitrogen atom reduces acidity (raise pKa) due to the
electron donating effects (+I) of the N-alkyl group: See structures above
- Substitution at BOTH ring nitrogen atoms eliminates both acidic protons (non-
acidic)

• Due to the presence of one (or more) acidic protons, barbiturates can be converted to
water soluble salt forms by treatment with an appropriate base as shown below. Note
that the charge resides primarily on the more electronegative oxygen atom:

O O
R5 R5 O
R3 R3 R5
N R5' NaOH N R5' R3
N R5'
X N O X N O
HX or RCOOH (-) X N O
H (-) Na+
Na+
Acid form
Water insoluble Salt form (conjugate base)
Water soluble
3. Barbiturate Chirality and Stereochemistry

• The barbiturate ring system contains only one sp2 carbon atom and it is not chiral
unless 1) there are two different C-5 substituents AND 2). one ring nitrogen is
substituted as shown in the example below:

O O O CH2CH3 O CH2CH3
H H
H H H CH3
N H N N N

O N O O N O O N O O N O
H H H H
Achiral Achiral Achiral
Chiral C-5 carbon
(No chiral center) (No chiral center) (No chiral center)
(R&S enantiomers)
• The C-5 substituents may contain chiral (unsymmetrically substituted sp2 carbon
atom(s)) and in such cases the barbiturate is chiral. Some barbiturates have BOTH a
chiral C-5 atom AND a chiral side chain as shown in one example below:

CH3 CH3
O O O
H CHCH2CH3 CHCH2CH3
H H CH3
N H N CH2CH3 N CH2CH3

O N O O N O O N O
H H H
Achiral Chiral C-5 carbon and
(No chiral center) Chiral C-5 substituent chiral C-5 substituent
(R&S enantiomers) (4 enantiomers possible)

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

• Enantiomers display comparable physicochemical properties, passive membrane

permeability, intrinsic pharmacologic activities but may display differential
metabolism.

4. Barbiturates and Mechanism of Action and Therapeutic Uses

• Barbiturates bind to the GABAA receptor which ultimately increases GABA-induced

Cl- currents. They bind at a site distinct from the BDZ binding site. Barbiturates also
may reduce glutamate-inducde depolization by acting as antagonists at AMPA-type
receptors. The actions of the barbiturates are described in more detail in the
Pharmacology Notes. The basic structural features required for general CNS
depressant activity for the barbiturates are summarized in the following Figure:
O O
H H
CH3 H 3
N H N 4 5 H Two 5-substituents required
2
for GABA activity (R5/R5')!!!
O N O O 1N
6 O
H H
N-1 Substituted Barbituric acid: Barbituric acid: No 5-substituents
Inactive Inactive

O O O
H H H
CH3 H H
N H N CH2CH3 N CH2CH3

O N O O N O O N O
CH3 H CH3
5-Ethylbarbituric acid:
N-1, N-3 Disubstituted Barbituric acid: Inactive 1,5-Disubstituted Barbituric acid:
Inactive Inactive

O O O
CH(CH3)CH2CH2CH3 CH2CH3 CH2CH3
H H H
N CH2CH3 N CH2CH3 N

O N O O N O O N O
H H H
Disubstituted Barbiturate: ACTIVE 5,5-Diethylbarbiturate: Disubstituted Barbiturate: ACTIVE
7 total Cs in 5,5-side chain: Weak activity Ethyl/Phenyl side chain:
Increased activity: Branching and unsatuation Long-acting
Short-acting Achiral
Chiral: R=S in activity

O O O
CH(CH3)CH2CH2CH3 CH2CH3 CH2CH3
H CH3 CH3
N CH2CH=CH2 N N

S N O O N O O N O
H H CH3
Disubstituted Thiobarbiturate: ACTIVE Trisubstituted Barbiturate: ACTIVE
1,3,5,5-Tetrasubstituted Barbiturate
Ultra-Short-acting Ethyl/Phenyl side chain: Inactive (Non-acidic!!!!)
Chiral: R=S in activity Long-acting
Achiral
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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

• The following indications apply to most barbiturates:

! Sedation: Although traditionally used as nonspecific CNS depressants for

daytime sedation, the barbiturates have generally been replaced by the
benzodiazepines.

! Hypnotic: Short-term treatment of insomnia, since barbiturates appear to lose

their effectiveness in sleep induction and maintenance after 2 weeks. If insomnia
persists, seek alternative therapy (including nondrug) for chronic insomnia.

! Preanesthetic: Used as preanesthetic sedatives as indicated below.

! Anticonvulsant (mephobarbital, phenobarbital): Treatment of partial and

generalized tonic-clonic and cortical focal seizures.

! Acute convulsive episodes: Emergency control of certain acute convulsive

episodes (eg, those associated with status epilepticus, cholera, eclampsia,
meningitis, tetanus and toxic reactions to strychnine or local anesthetics).

! Headache products

5. Barbiturate Products and Onset and Duration of Action

A. Long-Acting Barbiturates (Typically Anticonvulsants): Relatively slow onset (30-60

minutes) and relatively long duration (10-16 hrs)

- Structure: N-H or N-Methyl and C-5 side chains consisting of two ethyl groups, or an
ethyl and phenyl group. General Properties: Relatively low lipophilicity and low
plasma protein binding (<40%):

O O O
CH2CH3 CH2CH3 CH2CH3
CH3 H CH3
N CH2CH3 N N

O N O O N O O N O
H H H
Metharbital Phenobarbital Mephobarbital

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

B. Intermediate-Acting Barbiturates (Sedative/Hyponotics): Relatively slow onset (45-60

minutes) and intermediate duration (6-8 hrs)

- Structure: N-H and C-5 side substituents consisting of and ethyl or allyl group and a 3
to 5–carbon atom unit. General Properties: Intermediate lipophilicity and
intermediate plasma protein binding (50%)

O O
CH(CH3)2 CH(CH3)CH2CH3
H H
Allyl N CH2CH=CH2 N CH2CH CH2
Substituted!
O N O O N O
H H
Aprobarbital Talbutal
O O
CH2CH2CH(CH3)2 CH(CH3)CH2CH3
Ethyl H H
N CH2CH3 N CH2CH3
Substituted!
O N O O N O
H H
Amobarbital Butabarbital

C. Short-Acting Barbiturates (Typically sedative/hypnotics): Relatively rapid onset (10-

15 minutes) and relatively short duration (3-4 hrs)

- Structure: N-H and C-5 side chains consisting of ethyl or allyl and a 5 carbon unit.
General Properties: High lipophilicity and high plasma protein binding (70%).
Rapid distribution and redistribution

O O
CH(CH3)CH2CH2CH3 CH(CH3)CH2CH2CH3
H H
N CH2CH3 N CH CHCH3

O N O O N O
H H
Pentobarbital Secobarbital
(Ethyl Substituted) (Allyl substituted)

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

D. Ultra-Short-Acting Barbiturates (Induction of Anesthesia): Administered by injection

(as salts): immediate onset and very short duration.

- Structure: N-H with a thiocarbonyl and C-5 side chains consisting of ethyl or allyl
with a 5 carbon unit. General Properties: Very high lipophilicity and high
plasma protein binding (>70%). Rapid distribution and redistribution.
O O O
CH(CH3)CH2CH2CH3 CH(CH3)CH2CH2CH3 R5
H H H
N CH2CH3 N CH2CH CH2 N R5'
S N O S N O Na+-S N O
H H
Thiopental Salt forms
Thiamylal
(Ethyl substituted) (Allyl Substituted)

6. Barbiturate Disposition

A. Administration and absorption: Oral and parenteral dosage forms are typically
formulated as water soluble salts. These compounds are sufficiently lipophilic (C-5
alkyl, and aryl groups) to facilitate absorption from sites of adminstration.

B. Distribution: Plasma protein binding and CNS distribution and redistribution

correlates with lipophilicity which, in turn, is determined by the hydrophobic character of
the C-5 substituents. This effects onset and duration of action, as well as drug interactions
based on competitive plasma protein binding:

Onset of Action: Related to route of administration and barbiturate lipophilicity.

More lipophilic barbiturates are distributed more rapidly to the CNS and thus
have a more rapid onset. Onset of action for oral or rectal administration varies
from 20 to 60 minutes. For IM administration, onset is slightly faster than the oral
route. Following IV administration, onset ranges from almost immediate for
pentobarbital sodium and secobarbital to 5 minutes for phenobarbital sodium.
Maximal CNS depression may not occur for >= 15 minutes after IV
administration of phenobarbital sodium.

Plasma Protein Binding: More lipophilic drugs are more highly palsma protein
bound. More highly bound drugs generally are eliminated more slowly (not
filtered through the glomerulus) and are metabolized more slowly:

Barb + Drug PB Drug + Barb PB

(free) (bound) (free) (bound)

Duration of action (half-life) is largely dependent on redistribution. More

lipophilic barbiturates undergo more rapid secondary distribution (redistribution)

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

to non-target tissues (adipose tissue) and thus their action is terminated more
readily. Barbiturates are cleared from plasma by hepatic metabolism and direct
renal elimination, and these processes clear drug from the body.

C. Metabolism: Through secondary hepatic metabolic inactivation barbiturates lose

their affinity for the GABA receptor complex and thus CNS depressant activity.
Oxidative and conjugative reactions also result information of metabolites that are more
polar, less protein bound and more readily eliminated renally. (See metabolic reactions).

D. Elimination: Barbiturates and their metabolites are eliminated primarily renally by

glomerular filtration. Since the barbiturates are weak acids, the rate of elimination can be
altered by fluctuations in urinary pH:

O O
R5 R5
R3 R3 Enhanced ionization
N R5' pH > 8 N R5'
Decreased tubular reabsorption
Enhanced renal elimination
O N O O N O
H

O O
R5 R5
R3 R3
Decreased ionization N R5' pH < 6 N R5'
Enhanced tubular reabsorption
Decreased renal elimination O N O O N O
H

_________________________________________________

Very Lipo Barb!

Less Lipo Barb

CNS Redistribution phases:

Conc.

Distribution phases:

1 8 16
Time (hrs)
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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

Summary of Barbiturate Structure and Biodispostion

O O O
R5 R5 R5
H CH3 H
N R5' N R5' N R5'

O N O O N O S N O
H H H
Barbiturates N-MethylBarbs Thiobarbiturates
- Increased lipophilicity - Increased lipophilicity - Increased lipophilicity
with increased Cs at C-5 - Decreased acidity - Increased acidity

CNS (TARGET TISSUES)

GABA
Barbfree Receptor
Complex
(Base Barbiturate Structure)

BLOOD-BRAIN BARRIER
(Barbiturate pKa and Lipophilicity)
Distribution Redistribution

OTHER TISSUES (NON-TARGET)

ABSORPTION
Barbbound Barbfree Barbfree Barbbound ADMINISTRATION
PLASMA (pH 7.4)
(Barbiturate pKa and Lipophilicity)
Barbiturate pKa and Lipophilicity (C-5 groups)
Distribution and Drug Interactions (ppb)

Barbfree Barbfree
LIVER
KIDNEY
Barbmetabolites Barbmetabolites

Barbiturate pKa and Lipophilicity Rate of Clearance:

Specific functional groups at C-5 - Barbiturate pKa and Polarity
- Potential Drug Interactions - Urinary pH
- Rate of Clearance

ELIMINATION
(URINE)

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

7. Barbiturate Metabolism

A. Omega and Omega-1 Oxidation

O
CH2CH3 OH
H
ω-1 N CHCH2CHCH3 Enantiomeric alcohols possible
CH3
O
CH2CH3 O N O
H
N CHCH2CH2CH3 H
CH3
O N O O O
CH2CH3 CH2CH3
H H H
ω N CHCH2CH2CH2OH N CHCH2CH2COOH
Examples: Most barbiturates CH3 CH3
O N O O N O
H H

B. Aromatic Hydroxylation
O
NIH CH2CH3
H
Shift N

O O O N O OH
CH2CH3 CH2CH3 H
H Aromatic H H
N N Phenol
Hydroxylation O
O N O O N O O
H CH2CH3 H
H H H
Hydrase N OH
Examples: Phenobarb Arene Oxide OH
and Mephobarb O N O
H
H Diol

C. Alkene and Allylic Oxidation

O
R OH
Allylic H
Oxidation N CHCH=CH2
Enantiomeric alcohols possible
O O N O
R
H H
N CH2CH=CH2

O N O
O O
H R O R OH
Alkene H
Oxidation Hydrase H
Examples: Secobarb, N CH2CH CH2 N CH2CH CH2
Talbutal and Aprobarb OH
O N O O N O
H H
Enantiomeric alcohols possible

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

D. N-Oxidation

O O
CH2CH3 CH2CH3
H H
N CHCH2CH2CH3 N CHCH2CH2CH3
CH3 CH3
O N O O N O
H OH
Most Barbs

E. Desulfuration

O O
CH2CH3 CH2CH3
H H
N CHCH2CH2CH3 N CHCH2CH2CH3
CH3 CH3
S N O O N O
H H
Thiobarbs

F. Oxidation N-Dealkylation
O O
CH2CH3 CH2CH3
CH3 H
N N

O N O O N O
H H
N-Methylbarbs

G. Hydrolysis
O O O
CH2CH3 CH2CH3 CH2CH3
R R R
N N N
H
O N O O O O
OH NH2 NH2
H
Most Barbs

O
O CH2CH3
CH2CH3 R
N
HO
H
O
O OH
OH

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

H. Examples of Barbiturate Metabolism and Metabolites Formed:

O
NIH CH2CH3
H
Shift N

O O O N O OH
CH2CH3 CH2CH3 H
H Aromatic H H
N N Phenol
Hydroxylation O
O N O CYP O N O O
H Epoxide CH2CH3 H
H H H
Hydrase N OH
Phenobarbital Arene Oxide OH
O N O
H
CYP H
(ω-1) trans-Diol

OH [O]
O
CHCH3
H O
N CH2CH3
H OH
O N O N

H O N O OH
H
Catechol
______________________________________________________________________
O
CH3
CH3
N

O N O
O
H
[O] [R]
O
CH3 O
H CH3
N CH3
N
Allylic
O N O N-Oxidation Oxidation O N O
H O HO
H
CH3
CH3
N
Alkene
Oxidation O N O
Allylic
O H Oxidation OH
CH3 O O
CH3 Hexobarbital CH3
N CH3
N

O N O O N O
H H
Epoxide
Hydrase [R] [O]

O
O O
CH3 OH OH CH3
CH3 CH3
N N

O N O O N O
H H
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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

8. Barbiturates: Metabolic and Other Drug Interactions

Chronic administration of barbiturates (as well as phenytoin, carbamazepine, rifampin)

results in “enzyme induction”, a drug–induced increase in the synthesis of the enzymes of
metabolism including MFOs, glucuronyl transferase, aldehyde dehydrogenase and delta-
aminolevulinic acid synthetase. Thus barbiturates can induce the metabolism of a variety
of drugs, including some beta-blockers, carbamazepine, clonazepam, contraceptive (oral),
corticosteroids, digitoxin, doxorubicin, doxycycline, felodipine, fenoprofen,
phenylbutazone, quinidine, theophylline, verapamil, etc. Generally then barbiturates may
enhance the clearance (and thereby decrease efficacy of these other drugs when used
concurrently.

Other drugs can also alter the metabolism of barbiturates. For example, chloramphenicol
and valproate can inhibit the metabolism of barbiturates when uswed concurrently. Also
rifampin, a potent enzyme inducer, may induce barbiturate metabolism.

There are some reports that barbiturates may interfere with the absorption of other oral
drugs (griseofulvin) and that some substances (charcoal) may reduce the absorption of
barbiturates.

Concomitant use may of barbiturates with alcohol may produce additive CNS effects and
death. Methadone actions may be reduced by barbiturates, but the CNS depressant
effects of meperidine may be prolonged. MAOIs also are reported to enhance the sedative
effects of barbiturates.

9. Barbiturate Adverse Reactions (See Pharmacology notes):

• CNS Actions: Drowsiness, hangover, impaired psychomotor function, irritability,

increased pain perception.
• Dependence and Tolerance:
• Respiration: Depressed, laryngospasm (major limitation!)
• Peripheral Nervous System: Depressed ganglionic transmission, decreased excitation
at NN receptors (enhanced NMBA blockade)
• Cardiovascular: Decreased cardiac contractility and cardiac output, increased PVR,
decreased cerebral blood flow
• Liver: Enzyme induction
• Renal: Decreased GFR and hypotension decreased urine volume

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SAMPLE BARBITURATE QUESTIONS

Answer questions 11-8 below for the following barbiturate derivatives (I-IV):

O O O O
CH(CH3)CH2CH2CH3 CH(CH3)CH2CH2CH3 CH(CH3)CH2CH3 CH2CH3
H H H H
N CH2CH CH2 N CH CHCH3 N CH2CH3 N

S N O O N O O N O O N O
H H H H
I II III IV

1. Which barbiturates above (I-IV) would yield water soluble salts if treated with
NaOH?

A. Only I
B. Only I and II
C. Only II and III
D. Only II, III and IV
E. All of the barbiturates above (I-IV)

2. Which barbiturates above (I-IV) would be appropriate for oral long-term treatment of
seizure disorders?

A. Only I
B. Only IV
C. Only III and IV
D. Only II and IV
E. Only II, III and IV

3. Which barbiturate above (I-IV) would have the shortest duration of action

A. I
B. II
C. III
D. IV

4. Which barbiturates above (I-IV) would be capable of forming epoxide metabolites by

oxidative metabolism (cytochrome-mediated oxidation)?

A. Only I
B. Only IV
C. Only I and II
D. Only I, II and IV
E. All of the barbiturates above (I-IV)

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

5. Why are the barbiturates shown below inactive as sedatives, anti-epileptics or

anesthetics?

CH 3
CH3 O
O
CH3
CH 3 CH 3
H N
N H CH2CH3
O N O
O N O
CH3
H
.
6. Which barbiturate below is more extensively bound by plasma proteins? What is the
therapeutic relevance of this? Why don’t the highly protein bound have significantly
longer durations of ation than those barbiturates less extensively bound?

CH 3
O O
CH3
H CH 3
N N
CH2CH3
CH 3
O N O O N O
H CH3
.
7. Why does alkalinization of the urine enhance the renal excretion of the barbiturates?

8. Which barbiturate below is a long-acting sedative? Rapid-acting sedative? More

extensively metabolized? Distributed and accumulated in adipose tissue most
extensively? Are these barbiturates primarily ionized or non-ionized at physiological
pH?

CH 3 CH3
O O O
CH3 CH3
H CH 3 H
N H N N
CH 2CH 3 CH2CH CH2
O N O O N O O N O
H CH 3 H

9. Why do the barbiturates decrease patient respons to warfarin? Why do they decrease
carbamazepine plasma levels? Why do they increase renal toxicity of
methoxyflurane?

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 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

10. What effect does N-substitution have on pKa? On lipophilicity?

11. Why are there four ω-1 oxidation products formed from racemic pentobarbital? Why
do desulfuration reactions limit the duration of action of the thiobarbiturates?

12. How does stereochemistry influence sedative activity? Distribution to the CNS?
Route of elimination?

13. For the compounds shown below, circle the appropriate response or responses. There
may be more than one correct answer, or no correct answer.

O O
CH(CH3)CH2CH2CH3 CH(CH3)CH2CH2CH3
H H
N CH2CH CH2 N CH CHCH3

S N O O N O
H H B
A

O O
CH(CH3)CH2CH3 CH2CH3
H H
N CH2CH3 N

O N O O N O

H H D
C

a. Which compounds yield a water soluble salt with NaOH?………....A B C D None

b. Which compounds are chiral?…………………………………..…..A B C D None
c. Which compounds are active CND depressants?……………..…….A B C D None
d. Which compound is longest acting?………………………..……….A B C D None
e. Which compound is shortest acting?………………………………...A B C D None
f. Which compound displays the lowest plasma protein binding?…..…A B C D None
g. Which compound is more hydrophilic?……………………………..A B C D None
h. Which compounds are eliminated primarily by renal mechanisms?...A B C D None

14. Draw the structure of the primary metabolites formed from D above by cytochrome-
mediated aromatic ring oxidation? Are these metabolites as active as the parent drug?

15. Draw the structure of the diol formed from alkene oxidation followed by hydrolysis
of compound A above.

16. Draw the omega and omega-1 oxidation products formed from cytochrome-mediated
oxidation of compound B above?

15