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Home , Aprobarbital, Barbiturate, Hypnotic, Metharbital, Phenobarbital, Talbutal

Jack DeRuiter, Principles of Action 2, Fall 2004

THE

1. 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 R5' 3 5 6 XON X = O or S 2 1 H Barbiturate

2. Barbiturate Ionization, Acidity and Salt Formation

• Barbiturates containing at least one N-H 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 O O R5 O R R5 R5 R 3 R R 5 N R5' 3 3 R3 Base N R5' N R5' N R5' XON XON 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 R H R5 5 H H CH3 N R ' N H N R5' 5

OON OON OON H H H : pKa 4.12 5,5'-Disubstituted 3,5,5'-Trisubstituted barbituric acid: pKa 6.5-8 barbituric acid: pKa > 8

1 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 ): 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 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 R O R3 5 R5 R3 N R5' NaOH N R ' R3 5 N R5' XON HX or RCOOH XON (-) X N O (-) Na+ H 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 CH CH O O O CH2CH3 2 3 H H H H H CH3 N H N N N

OON OON OON OON 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

ON O OON OON 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)

2 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

• Enantiomers display comparable physicochemical properties, passive membrane permeability, intrinsic pharmacologic activities but may display differential .

4. Barbiturates and and Therapeutic Uses

• Barbiturates bind to the GABAA 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 Notes. The basic structural features required for general CNS depressant activity for the barbiturates are summarized in the following Figure: O O H H 3 CH3 H N H N 4 5 H Two 5-substituents required 2 for GABA activity (R5/R5')!!! 6 OON OO1 N H H N-1 Substituted Barbituric acid: Barbituric acid: No 5-substituents Inactive Inactive

O O H O H H H CH3 N CH CH H N H 2 3 N CH2CH3

OON OON OON CH H CH 3 5-Ethylbarbituric acid: 3 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

OON OON OON 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(CH )CH CH CH CH2CH3 3 2 2 3 CH2CH3 H CH3 N CH3 N CH2CH=CH2 N

SON OON OON 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 3 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

• The following indications apply to most barbiturates:

! : Although traditionally used as nonspecific CNS for daytime sedation, the barbiturates have generally been replaced by the .

! : Short-term treatment of , since barbiturates appear to lose their effectiveness in induction and maintenance after 2 weeks. If insomnia persists, seek alternative therapy (including nondrug) for chronic insomnia.

! Preanesthetic: Used as preanesthetic as indicated below.

! (mephobarbital, ): Treatment of partial and generalized tonic-clonic and cortical focal .

! Acute convulsive episodes: Emergency control of certain acute convulsive episodes (eg, those associated with , cholera, eclampsia, meningitis, tetanus and toxic reactions to or local ).

! Headache products

5. Barbiturate Products and Onset and Duration of Action

A. Long-Acting Barbiturates (Typically ): 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 (<40%):

O O O CH CH CH CH CH2CH3 2 3 2 3 CH H CH3 3 N N N CH2CH3

OON OON OON H H H Phenobarbital Mephobarbital

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B. Intermediate-Acting Barbiturates (/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! OON OON H H

O O CH2CH2CH(CH3)2 CH(CH3)CH2CH3 Ethyl H H N CH2CH3 N CH CH Substituted! 2 3 OON OON H H

C. Short-Acting Barbiturates (Typically sedative/): 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(CH )CH CH CH CH(CH3)CH2CH2CH3 H 3 2 2 3 H N CH2CH3 N CH CHCH3

OON OON H H (Ethyl Substituted) (Allyl substituted)

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D. Ultra-Short-Acting Barbiturates (Induction of ): 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(CH )CH CH CH 3 2 2 3 R5 H H H N CH2CH3 N CH CH CH 2 2 N R5'

SN O SON Na+-S N O H H Salt forms Thiopental (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. 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 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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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 OON OON H

O O R5 R5 R R 3 pH < 6 3 Decreased ionization N R5' N R5' Enhanced tubular reabsorption Decreased renal elimination OON OON H

______

Very Lipo Barb! Less Lipo Barb

CNS Redistribution phases: Conc.

Distribution phases:

1 8 16 Time (hrs) 7 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

Summary of Barbiturate Structure and Biodispostion

O O O R R5 5 R5 H CH3 H N R ' N R5' 5 N R5'

OON OON SON 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 Barb Barb ADMINISTRATION Barbbound Barbfree free bound PLASMA (pH 7.4) (Barbiturate pKa and Lipophilicity) Barbiturate pKa and Lipophilicity (C-5 groups) Distribution and Drug Interactions (ppb)

Barbfree Barbfree

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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7. Barbiturate Metabolism

A. Omega and Omega-1 Oxidation O CH2CH3 OH ω H -1 N CHCH2CHCH3 Enantiomeric possible CH O 3 OON CH2CH3 H H N CHCH2CH2CH3 CH3 OON O O CH2CH3 CH2CH3 H ω H H N CHCH2CH2CH2OH N CHCH2CH2COOH Examples: Most barbiturates CH3 CH3 OON OON H H

B. Aromatic O CH2CH3 NIH H Shift N

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

C. Alkene and Allylic Oxidation

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

OON O O O H Alkene R R OH H H Oxidation N CH CH CH Hydrase Examples: Secobarb, 2 2 N CH2CH CH2 Talbutal and Aprobarb OH OON OON H H Enantiomeric alcohols possible

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D. N-Oxidation

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

E. Desulfuration

O O CH2CH3 CH2CH3 H H N CHCH2CH2CH3 N CHCH2CH2CH3 CH3 CH3 SN O OON H H Thiobarbs

F. Oxidation N-Dealkylation

O O CH2CH3 CH2CH3 CH3 H N N

OON OON H H N-Methylbarbs

G. Hydrolysis O O O CH CH CH2CH3 CH2CH3 2 3 R R R N N N H ON O OO O NH OH NH2 2 H Most Barbs

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

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H. Examples of Barbiturate Metabolism and Metabolites Formed:

O CH2CH3 NIH H Shift N

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

OH [O] O CHCH3 H N O CH2CH3 H OH OON N H OON OH H Catechol ______

O CH3 CH3 N

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

OON OON H H Epoxide Hydrase [R] [O]

O O O CH OH OH CH3 3 CH CH3 3 N N

OON OON H H 11 Jack DeRuiter, Principles of Drug Action 2, Fall 2004

8. Barbiturates: Metabolic and Other Drug Interactions

Chronic administration of barbiturates (as well as , , 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, , contraceptive (oral), , digitoxin, doxorubicin, doxycycline, , , , , , , 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 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 () and that some substances (charcoal) may reduce the absorption of barbiturates.

Concomitant use may of barbiturates with may produce additive CNS effects and death. 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, , impaired psychomotor function, irritability, increased pain perception. • Dependence and Tolerance: • Respiration: Depressed, laryngospasm (major limitation!) • Peripheral : Depressed ganglionic transmission, decreased excitation at NN receptors (enhanced NMBA blockade) • Cardiovascular: Decreased cardiac contractility and cardiac output, increased PVR, decreased cerebral flow • Liver: Enzyme induction • Renal: Decreased GFR and 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 CH CH H H H H 2 3 N CH2CH CH2 N CH CHCH3 N CH2CH3 N

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

CH3 CH3 O O CH3 CH3 CH3 H N N H CH2CH3 OON OON CH H 3 . 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?

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

H CH3 . 7. Why does alkalinization of the urine enhance the renal 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?

CH3 CH O O O 3 CH3 CH H CH3 H 3 N H N N CH2CH3 CH2CH CH2 OON OON OON H CH3 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 ?

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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

SN O OON H A H B

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

OON OON H H C D 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?

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