This document discusses various classes of sedative-hypnotic drugs, including barbiturates and benzodiazepines. It provides details on the classification, mechanisms of action, structure-activity relationships, metabolism and adverse effects of barbiturates. Barbiturates such as phenobarbital, amobarbital and pentobarbital are described according to their duration of action. Their mechanisms involve facilitating GABA neurotransmission. However, barbiturates now see minimal use due to risks of tolerance, dependence and toxicity. Newer drugs like zolpidem and zaleplon were developed to avoid these issues.

1. SEDATIVE -HYPNOTIC DRUGS
(PART TWO)
Dr.Narmin Hamaamin Hussen
College of pharmacy/University of Sulaimani
Medicinal chemistry III / 4th stage/ 1st semester
Lecture 2
2021-2022
Phenobarbital

2. Classification of Sedative and Hypnotic Drugs

3. Barbiturates
▪They are effective as anxiolytics, hypnotics, anticonvulsants and
analgesics.
▪Unlike benzodiazepines, they bind at different binding sites and
appear to increase the duration of the GABA-gated chloride
channel openings.
▪ They have addiction potential, both physical and psychological.
▪Thus Benzodiazepines have largely replaced them in term of
sedative-hypnotic.

4. Barbiturate General Structure and Numbering
▪ Barbituric acid is the parent compound of barbiturate drugs.
▪ Barbiturates are cyclic ureides which are the derivatives of barbituric acid (2,4,6-
trioxohexahydropyrimidine).
▪ The barbiturates are 5,5-disubstituted barbituric acids.
▪ All barbiturates are derivatives of barbituric acid (2,4,6-trioxyhexahydropyrimidine).
▪ Barbituric acid itself does not possess any hypnotic properties.
Synthesis of Barbituric acid
▪ Barbituric acid may be described as a "cyclic ureide of malonic acid.
▪ Barbituric acid derivatives or barbiturates are prepared from malonic acid or its esters
by condensation with urea (or a urea derivative) and phosphorous oxychloride(POCl3).
▪ The compound was first synthesized by Adolf van Baeyer in 1864.

5. Structure–Activity Relationships of Barbiturates
1st position , 3rd position and 5th position
➢ Activity requires a balance of acidic and lipophilic properties.
▪ To make the drug sufficiently acidic, both or at least one of the two nitrogen must be
unsubstituted .
▪ To make drug sufficiently lipophilic, the two hydrogen atoms at position 5 : 5 must have the
appropriate substituent (e.g., alkyl or aryl groups) .
The type of substituent's control 2 aspects of the drug:
✓ Potency
✓ Duration of Action.
Barbituric acid
No 5-substituents
Inactive
because not lipophilic enough
Acidity (pKa) 4.01
5-substituted
Inactive
because not lipophilic enough
1,5-Disubstituted
Inactive
because not lipophilic enough
N-1, N-3 Disubstituted
Inactive
(Non-acidic!!!!)
5,5-Disubstituted Barbiturate
Active
weak acids (pKa about 8)
1,5,5-trisubstituted
Active
1,3,5,5-tetrasubstituted
Inactive
(Non-acidic!!!!)

6. Acidity of barbiturates
1st position and 3rd position
▪ The acidity value within certain limits to give proper ratio of ionized (dissociated) and unionized forms, which is
important to cross blood brain barrier (BBB).
▪ It takes approximately 40%–60% dissociation to enable a barbiturate to cross BBB and exert effects on CNS.
Determination of the pKa can thus be predictive of the CNS activity.
▪ The relative acidity of different barbiturates is a function of the degree of N-substitution and C-5-substitution as shown
below:
Barbituric acid easily undergoes
ionization at plasma pH 7.4 , due
to which , it cannot cross BBB and
hence pharmacologically
inactive
5,5-disubstituted and 1,5,5-trisubstituted Barbituric acids are present in
unionized forms at plasma PH because of their high PKa values which can
easily cross BBB and hence pharmacologically active

7. Acidity of barbiturates
▪ Barbiturates containing at least one N-H hydrogen atom are acidic. Acidity results from the
ability of the N to lose hydrogen and stabilization of the resulting anionic charge of the
conjugates base by resonance.
▪ The keto – enol tautomerism in barbituric acid is favoured by the presence of two
electronegative amido nitrogens flanking the C-2or C-4 carbonyl carbon,
▪ Keto-enol tautomerization allows formation of water-soluble barbiturate salts.
Enol form
1st position and 3rd position

8. ▪ Methylation of one of the imide hydrogens enhances onset and reduces duration of action
1st position
Methylphenobarbital
Methylation position 1
pKa= 7.4 pKa= 8

9. 2nd position (thiobarbiturates)
▪ Replacement of C-2 O by S → ↑ lipid solubility.
▪ Thiopental (Pentothal) and thiamylal (Surital) are called thiobarbiturates because they possess a sulfa molecule and
are quite similar pharmacologically.
▪ Thiopental used as IV anesthetics due to rapid onset & quick brain levels achieved.
• Thiamylal used as IV administration, the onset of action of these drugs is rapid (within 30 to 40 seconds) and of short
duration.
▪ Introduction of more sulfur atoms (2,4-dithio derivatives) destroys potency, due to decreased hydrophilic character
beyond required limits.

10. Barbiturate binding site
Thiopental

11. Lipophilicity of barbiturates
➢ In general, increasing lipophilicity, increases hypnotic potency and the onset of action and decreases the duration of
action.
The number of carbon atom at C-5
▪ Side chains at position 5 are essential for activity .
▪ The total number of carbon atoms present in the two groups at carbon 5 must not be less than 4 and more than 10 and
influences onset of action and duration.
▪ Sedative and hypnotic activity increases with lipid solubility until the total number of carbon atoms of both substituents at
C-5 is between 6 and 10.
▪ Long chains are readily oxidized and thus produce short-acting barbiturates.
➢ Example: Secobarbital, Pentobarbital (Secobarbital contains total 8 carbons at C-5, where as Pentobarbital contains
total 7 carbons. Hence, secobarbital is more active than Pentobarbital)
▪ Short chains at carbon 5 resist oxidation and hence are long-acting. Example: Barbital
Total carbon Duration of action
7-9 Rapid onset and shorter
duration
5-7 Intermediate duration of
action
4 Slowest onset and longest
duration of action( two
ethyl group) e.g. Barbital
5th position:

12. 5th position:
Branched chain isomer:
▪ Within the same series, the branched chain isomer has greater lipid solubility and activity, and
shorter duration of action than the straight chain isomer.
▪ The greater the branching, the more potent is the drug (e.g., pentobarbital > amobarbital).
Log P = 2.10
Pentobarbital Amobarbital

13. Alkyl or Aryl substitution at position 5:
➢ Presence of an alkyl or aryl substitution at position 5 confers sedative –hypnotic and
anticonvulsant properties .
▪ Barbiturate with single 5-phenyl substituent have selective anticonvulsant activity.
▪ Ex: Phenobarbital ( 5-phenyl-5-ethylbarbituric acid).
➢ The 5,5-diphenyl derivative has less antiseizure potency than does phenobarbital and is
virtually devoid of hypnotic activity.
➢ Aromatic and alicyclic moieties exert greater potency than the corresponding
aliphatic moiety having the same number of carbon atoms

14. ▪ Double bonds in the alkyl substituent groups produce compounds more readily vulnerable to tissue
oxidation ; hence, they are short-acting.
Double bonds or unsaturated alkyl groups :
Short Duration of Action (Less Than 3 Hours)
Short-acting, and has a rapid onset of action
IV: 2 to 10 minutes
✓ Introduction of a halogen atom into the 5-alkyl substituent ↑ the potency.
✓ Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and SO3H) in the 5-alkyl moiety reduces potency
considerably.
5th position:

15. Classification of Barbiturates
Barbiturates are classified according to their duration of action into:
1. Long duration of action (> 6 hours).
2. Intermediate duration of action (3-6 hours).
3. Short duration of action (< 3 hours)
4. Ultrashort duration of action (intravenous anesthetics)

16. Barbiturates with a Long Duration of Action (More Than 6 Hours):
1-Mephobarbital.
▪ Mephobarbital, 3-methyl-5- ethyl-5-phenylbarbituric acid (metharbital), is metabolically N-
demethylated to phenobarbital, which many consider to account for almost all of the activity.
▪ Its principal use is as an anticonvulsant.
2- Phenobarbital.
▪ Phenobarbital, 5-ethyl-5-phenylbarbituric acid (Luminal), is a long-acting sedative and hypnotic.
▪ It is also a valuable anticonvulsant; especially in generalized tonic–clonic and partial seizures.
▪ Metabolism to the phydroxylphenyl compound followed by glucuronidation accounts for about 90% of a dose.

17. Barbiturates with an Intermediate Duration of Action (3–6 Hours):
1- Amobarbital, 5-ethyl-5-isopentylbarbituric acid (Amytal), and its water-soluble sodium salt.
2- Butabarbital sodium, is water-soluble sodium salt of 5-sec-butyl-5-ethylbarbituric acid
(Butisol Sodium).

18. Barbiturates with a Short Duration of Action (Less Than 3 Hours):
Log P= 2.33
Log P= 2.10

19. Ultra Short acting barbiturate (5-10 mins) (intravenous anesthetics)
1- Thiopental Sodium :
▪ Replacement of C-2 O by S → ↑ lipid solubility.
▪ Rapid action (10 -15 sec) and rapid recovery .
▪ Used mainly as inducing anesthetic
▪ It has no analgesic properties
▪ Anesthetic state maintained by inhalation anesthetic eg N20(nitrous oxide)
▪ it is a poor muscle relaxant.
2- Thiamylal Sodium:
▪ Thiopental (Pentothal) and thiamylal (Surital) are called thiobarbiturates
because they possess a sulfa molecule and are quite similar pharmacologically.
▪ Following IV administration, the onset of action of these drugs is rapid (within
30 to 40 seconds) and of short duration.

20. 3- Methohexital sodium :
▪ It is a drug which is a barbiturate derivative. It is classified as short-acting, and has a rapid
onset of action.
▪ It is similar in its effects to sodium thiopental, a drug with which it competed in the market for
anaesthetics.
▪ Methohexital is primarily used to induce anesthesia.
Onset of action:
▪ Intramuscular—In pediatric patients, within 2 to 10 minutes
▪ Intravenous—Within 60 seconds

21. Metabolism of barbiturates
Aromatic Hydroxylation , Glucuronide and sulfate conjugates at position 5
➢ Phenobarbital
➢ Mephobarbital
Mephobarbital
Phenobarbital

22. Oxidation of a substituent at C-5 forms alcohols
➢ Secobarbital
➢ Amobarbital
▪ Oxidation of a substituent at C-5 forms alcohols, and these undergo further oxidation to form ketones or carboxylic
acids. The barbiturates containing a propene at the fifth position inactivates CYP450 by alkylation of the porphyrin
ring of CYP450
Secobarbital

23. Oxidative desulphation of 2-thio barbiturates
➢ Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted
unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in
concentrations approximately 3-10% that of the parent concentration.
Thiopental Pentobarbital
desulfuration

24. Now barbiturates get minimal use as sedatives & hypnotics (Why)?
1. They have higher toxicity, that cause greater CNS depression.
2. They induce many of the liver metabolizing enzymes.
3. Barbiturates cause tolerance and, often physical dependence.
✓ When an individual addicted to barbiturates, sudden withdrawal should be avoided, because it can
cause grand mal seizures, which lead to a spasm of the respiratory musculature, producing impaired
respiration, cyanosis, and possibly death.

25. ▪ Melatonin (N-acetyl-5-methoxytryptamine) is the hormone responsible for regulation of circadian and
seasonal rhythms.
▪ Their endogenous ligand, melatonin ,at times referred to as “the hormone of darkness,” is N-acetylated and
O-methylated product of serotonin found in the pineal gland and is biosynthesized and released at night
and may play a role in the circadian rhythm of humans.
▪ Melatonin synthesis is controlled by light–darkness cycles, increased during the night and suppressed during
the day , reaching a concentration peak at night (between 02:00 to 04:00).
▪ In the brain, three melatonin receptors (MT1, MT2, and MT3) have been characterized.
▪ Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be related to the
circadian rhythm. MT3 receptors may be related to intraocular pressure.
▪ However, it is a poor hypnotic drug because of its poor potency, poor absorption, poor oral bioavailability,
rapid metabolism, and nonselective effects.
Melatonin Receptor Agonist

26. ➢ Ramelteon:
▪ The melatonin molecule was modified mainly by replacing the nitrogen of the indole ring with a carbon to give an
indole ring and by incorporating 5-methoxyl group in the indole ring into a more rigid furan ring.
▪ It is a very potent & very selective ligand for the MT1 receptor is eight times more than that of MT2 receptor.
▪ Unlike melatonin, it is more effective in initiating sleep (MT1 activity) rather than circadian rhythm (MT2 activity).
▪ Importantly, this drug has no addiction liability (it is not a controlled substance).
▪ As a result, it has recently been approved for the treatment of insomnia.

27. Miscellaneous Sedative–Hypnotic Drugs
▪ A wide range of chemical structures (e.g., imides, amides, alcohols) can produce sedation and
hypnosis resembling those produced by the barbiturates
1-Amides and Imides:
➢ Glutethimide:
▪ Glutethimide, (Doriden), is one of the most active nonbarbiturate
hypnotics that is structurally similar to the barbiturates, especially
phenobarbital. Because of glutethimide’s low aqueous solubility,
its dissolution and absorption from the GI track
▪ Consistent with its high lipophilicity, it undergoes extensive
oxidative metabolism in the liver with a half-life of
approximately 10 hours.
▪ The product of metabolic detoxification is excreted after
conjugation with glucuronic acid at the hydroxyl group.
Metabolism of glutethimide

28. 2-Alcohols and Their Carbamate Derivatives:
A. Ethchlorvynol.
▪ Ethchlorvynol, (Placidyl), is a mild sedative–hypnotic with a quick onset and short duration of action (t1/2
5.6 hours).
▪ Because of its highly lipophilic character, it is extensively metabolized to its secondary alcohol (~90%)
prior to its excretion. It reportedly induces microsomal hepatic enzymes.

29. B- Meprobamate.
▪ Meprobamate, (Equanil, Miltown), is indicated as an antianxiety and a sedative hypnotic
agent.
▪ Meprobamate is also a centrally acting skeletal muscle relaxant.
▪ They have interneuronal blocking properties at the level of the spinal cord, which are
said to be partly responsible for skeletal muscle relaxation.
C-Carisoprodol.
▪ Carisoprodol, (Soma), is the mono-N-isopropyl–substituted relative of meprobamate.
▪ It is indicated in acute skeletomuscular conditions characterized by pain, stiffness, and
spasm.

30. 3-Aldehydes and Their Derivatives:
➢ Chloral Hydrate:
▪ Chloral hydrate, trichloroacetaldehyde monohydrate, CCl3CH(OH)2 , is an aldehyde hydrate stable
enough to be isolated.
▪ Chloral hydrate is unstable in alkaline solutions, undergoing the last step of the haloform reaction to
yield chloroform and formate ion.
▪ In hydroalcoholic solutions, it forms the hemiacetal with ethanol.
▪ Synergism between two different CNS depressants also could be involved.
▪ Chloral hydrate is a weak acid because its CCl3 group is very strong electron withdrawing.
▪ A 10% aqueous solution of chloral hydrate has pH 3.5 to 4.4, which makes it irritating to mucous
membranes in the stomach. As a result, GI upset commonly occurs for the drug if undiluted or taken on an
empty stomach.
Chloral hydrate
chloroform
ethanol

31. Metabolism of Chloral hydrate
▪ Chloral hydrate is very quickly converted to trichloroethanol, which is generally assumed to account for
almost all of the hypnotic effect.
▪ The trichloroethanol is metabolized by oxidation to chloral and then to the inactive metabolite,
trichloracetic acid, which is also extensively metabolized to acylglucuronides via conjugation with
glucuronic acid. It appears to have potent barbiturate-like binding to GABAA receptors.
▪ Additionally, ethanol, by increasing the concentration of nicotinamide adenine dinucleotide (NADH),
enhances the reduction of chloral to the more active metabolite trichloroethanol, and chloral can inhibit
the metabolism of alcohol because it inhibits alcohol dehydrogenase.
▪ Although an old drug, it still finds use as a sedative in nonoperating room procedures for the pediatric
patient

33. Newer Drugs:
Orexin Receptor Antagonists:
1- Belsomra(Suvorexant):
▪ Suvorexant, an orexin receptor antagonist (ORA), is the first in a new class of
drugs in development for the treatment of insomnia .
▪ It may help you fall asleep and stay asleep longer, so you can get a better
night's rest.
▪ Suvorexant belongs to a class of drugs known as sedative-hypnotics, approved
August 2014.
Orexin Receptor agonist Function:
▪ Orexin also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.
▪ The least common form of narcolepsy, type 1, in which the sufferer experiences brief losses of muscle tone (cataplexy), is
caused by a lack of orexin in the brain due to destruction of the cells that produce it.
Orexin receptor antagonist (ORA), is a new class of drugs in development for the treatment of insomnia.
▪ The drugs promote the natural transition from wakefulness to sleep by inhibiting the wakefulness-promoting orexin neurons
of the arousal system.

34. 2- Lemborexant (Dayvigo):
▪ The FDA has approved lemborexant (Dayvigo – Eisai), an orexin receptor antagonist, for
treatment of sleep-onset and/or sleep-maintenance insomnia in adults.
▪ It is the second orexin receptor antagonist to be approved for this indication; suvorexant
(Belsomra) was the first.
▪ DAYVIGO is contraindicated in patients with narcolepsy.
▪ U.S. FDA Approves lemborexant for the Treatment of Insomnia in Adult Patients - Dec 23,
2019.

35. ➢ Intermezzo(Zolpidem tartarate sublingual):
▪ Intermezzo® (zolpidem tartrate) sublingual tablet is indicated for use as needed
for the treatment of insomnia when a middle-of-the-night awakening is followed
by difficulty returning to sleep.
▪ Intermezzo is not indicated for the treatment of middle-of-the-night insomnia
when the patient has fewer than 4 hours of bedtime remaining before the
planned time of waking.
▪ Intermezzo is to be taken in bed when a patient wakes in the middle of the night
and has difficulty returning to sleep. Intermezzo should only be taken if the
patient has at least 4 hours of bedtime remaining before the planned time of
waking, approved November 2011.

36. ✓ What is the role of topological polar surface
area (TPSA) or Polar Surface Area (PSA) in
medicinal chemistry ?

37. END THANK YOU