Sedative and hypnotic Drugs /Medicinal Chemistry III Dr.Narmin Hamaamin Hussen

1. Sedative / Hypnotic drugs
(CNS depressants Drug)
Dr.Narmin H.Amin
College of Pharmacy
Medicinal Chemistry III / 4th stage/ 1st Semester
Lecture 1
2021-2022

2. Introduction
➢ A Sedative drug decreases activity and excitement of the patient and calms anxiety by
producing mild depression of CNS without causing drowsiness or sleep.
➢ A Hypnotic drug produces drowsiness, forcing the patient to sleep by depressing the CNS,
particularly the reticular activity which influences wakefulness
Sedative Hypnotic
Sedatives in therapeutic doses are
anxiolytic agents
They are used for initiation and / or
maintenance of sleep. Its used for
insomnia
Most sedatives in larger doses produce
hypnosis
Hypnotics in higher doses produce General
anesthesia
Site of action is on the limbic system
which regulates thought and mental
function.
Site of action is on the midbrain and
ascending RAS which maintain
wakefulness. Ascending reticular activating
system (ARAS)

3. ▪ All sedative, hypnotic and GA depress the CNS .
▪ The same drugs are used to induce both sedation and hypnosis
▪ The observed effect depends on the dose given to patient .
➢ Small dose cause sedation (calmness)
➢ Medium dose cause hypnosis (sleepy)
➢ Larger dose causes surgical anesthesia
Dose dependent activity :

4. ➢ In the anxiety disorders that inhibitory/excitatory
equilibrium is twisted into increased glutamate level.
➢ There are various neurotransmitters that are involved in
anxiety such as serotonin, glutamate, gamma-amino butyric
acid, Cholecystokinnin, Adenosine etc.
➢ Some are inhibitory and some are excitatory. These
neurotransmitters might play role in upregulation or
downregulation of anxiety disorders
Role of different neurotransmitters in anxiety:

5. GABAA Receptors
▪ GABA system is important in the pathophysiology of anxiety and insomnia.
▪ GABA is the most common and major inhibitory neurotransmitter (NT) in the brain and it exerts its rapid
inhibitory action mostly through GABA receptors.
▪ GABAA receptor is the target for many anxiolytics and sedative–hypnotic agents including benzodiazepines,
barbiturates, zolpidem, zaleplon, eszopiclone, steroids, anticonvulsive agents, and many other drugs that bind
to different binding sites of the GABAA receptors in neuronal membranes in the CNS.

6. Classification of Sedative and Hypnotic Drugs

7. Benzodiazepines
▪ Benzodiazepines enhance the effect of the GABA at the GABAA receptor, resulting in sedative, hypnotic
(sleep-inducing), anxiolytic (anti-anxiety) anticonvulsant, and muscle relaxant properties
▪ Useful in treating anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal and preanesthetic
▪ They also induce sleep and increase overall sleep quality
▪ Are safer than barbiturate and not additive.

8. Mechanism of Action benzodiazepines

9. Numbering in Benzodiazepines
▪ Benzodiazepines (BDZs) are the bicyclic heterocyclic compounds in which benzene ring is fused to seven membered
diazepine ring containing two nitrogen.
▪ Numbering is started from adjacent nitrogen to the bridge heads and second nitrogen is given 4th position. That’s why
these drugs are called 1,4-benzodiazpines.
▪ Most benzodiazepines are 5-aryl-1,4-benzodiazepines and contain a carboxamide group in the seven-membered diazepine
ring structure.
benzene ring
Diazepine ring
A B
C

10. Why SAR is important?
▪ Studying of structural activity relationships (SAR) is very important to develop drugs with more selectivity to the
target or more potent or more active.
▪ Sometimes, SAR can also be used to improve duration of action and bioavailability.
▪ It can be used to prepare a series of drugs with common structural features prove to have significant activity.
Human GABAA receptor with diazepam

11. 1st position
▪ At 1st position, a small alkyl group is optimal for activity.
▪ For example, diazepam and temazepam has methyl group at 1st position.
Structure–activity relationships (SARs) of benzodiazepines

12. ➢ Also, flurazepam has diethylaminoethyl group but it
doesn’t add any advantage to their action.
➢ Alkyl group is not essential as few of the benzodiazepines
don’t have any alkyl at 1st position. For example,
benzodiazepines like oxazepam, lorazepam and nitrazepam
simply have hydrogen at 1st position.
1st position

13. 2nd position
▪ Second position is very important in view of pharmacological activity as the drugs bind to benzodiazepine receptor
through this group.
▪ A carbonyl group at 2nd position is essential for activity
▪ You can easily observe this group in many of the benzodiazepines such as diazepam, oxazepm etc.
2
1
3
4
5
6
7
8
9

14. 2nd position
➢ Here we can found two exceptions. First is at chlordiazepoxide and second at fused benzodiazepines.
▪ Chlordiazepoxide is the first benzodiazepine that was developed and it doesn’t have keto group at 2nd
position
▪ But in-vivo it can undergo oxidative deamination to produce demoxepam with keto group at second
position.
▪ This again proved that keto group at 2nd position is essential for activity.

15. ➢ Fused benzodiazepines like alprazolam, midazolam and triazolam interact with GABA receptors through triazole or imidazole
ring.
2
2
2
interactions between alprazolam with the
GABA A receptor
2nd position
Imidazolobenzodiazepine Triazolobenzodiazepine

16. 3rd position
▪ This position is very important in view of pharmacokinetics.
▪ It is obvious that drugs or metabolites which are highly polar can undergo direct conjugation and hence directly excreted.
▪ A polar functional group at 3rd position increases excretion thereby decrease duration of action.
▪ Drugs like lorazepam, oxazepam and temazepam have hydroxyl group at 3rd position making all these drugs polar and easily
excretable. Hence all these drugs have short duration of action
3
3
3

17. ➢ Oxazepam and lorazepam are highly polar and can be excreted without phase I metabolism.

18. ➢ Temazepam also shows a little phase I reaction. It undergoes demethylation and converted into oxazepam and then
excreted

19. 3rd position With Carboxylic acid
➢ Clorazepate dipotassium
▪ Inactive itself, it undergoes rapid decarboxylation by the acidity of the stomach to nordazepam (a major active
metabolite of diazepam), which has a long half-life and undergoes hepatic conversion to active oxazepam.
▪ Despite the polar character of the drug as administered, because it is quickly converted in the GI tract to an active
nonpolar compound, it has a quick onset, overall long half-life, and shares similar clinical and pharmacokinetic
properties to chlordiazepoxide and diazepam
Metabolism of Clorazepate dipotassium

20. 3rd position Without hydroxyl group
▪ Benzodiazepines without the hydroxyl group are nonpolar and undergoes Phase I and Phase II metabolic
pathways: hepatic oxidation and reduction (by cytochrome P450) and glucuronide conjugation.
▪ Most benzodiazepines are lipophilic, in the nonionized form and thus well absorbed from the GI tract, whereas
the more polar compounds (e.g., those with a 3-hydroxyl group) tend to be absorbed more slowly than the more
lipophilic compounds.
▪ These drugs tend to be highly bound to plasma proteins; in general, the more lipophilic the drug, the greater the
binding.
▪ The more lipophilic a benzodiazepine, the higher the rate of absorption and faster the onset of clinical action.
For example, diazepam and midazolam have the highest lipid solubility and therefore also the quickest onset of
action
▪ Drugs like Chlordiazepoxide, diazepam, nitrazepam, Prazepam, Halazepam and Flurazepam, without hydroxyl
group at 3rd position making all these drugs nonpolar and slowly excretable. Hence all these drugs have long
duration of action.

21. ▪ Chlordiazepoxide hydrochloride,(Librium), is well absorbed after oral administration. The half-life of chlordiazepoxide is
6 to 30 hours.
▪ N-demethylation and hydrolysis of the condensed amidino group are rapid and extensive, producing demoxepam as a
major metabolite. Demoxepam can undergo four different metabolic fates. It is converted principally to its active
metabolite nordazepam, which is also a major active metabolite of diazepam, clorazepate, and prazepam.
▪ Nordazepam, in turn, is converted to active oxazepam, which conjugated to the excreted glucuronide.
▪ Because of the long half-life of parent drug and its active metabolites, this drug is long acting.
▪ As with diazepam, repeated administration of chlordiazepoxide can result in accumulation of parent drug and its active
metabolites, and thus cause excessive sedation.
➢ Chlordiazepoxide hydrochloride
Active metabolite

22. Diazepam
▪ Diazepam (Valium) is prototypical and was the first
member of the benzodiazepine-2-one group to be
introduced. It is very lipophilic and is thus rapidly
and completely absorbed after oral administration.
▪ Maximum peak blood concentration occurs in 2
hours and elimination is slow, with a half-life of
about 46 hours.
▪ As with chlordiazepoxide, diazepam is metabolized
by N-demethylation to active nordazepam, which is
3-hydroxylated to active oxazepam by CYP2C19
and CYP3A4.
▪ Like chlordiazepoxide, repeated administration of
diazepam leads to accumulation of an active
nordazepam
Nordazepam
Metabolism of Diazepam

23. ➢ Triazolobenzodiazepine :
Metabolism of Triazolobenzodiazepine and Imidazolobenzodiazepine:
➢ Alprazolam is one of the drugs widely used for anxiety
disorders. It is a medium acting benzodiazepine with
duration of action as 24 hrs. Hence it is given once a daily.
➢ Triazolam is a ultra short acting benzodiazepine with
duration of action less than 6 hrs. Due to short action it
can be used as hypnotic.
Imidazolobenzodiazepine:
➢ Midazolam is not used anxiolytic but used in induction of
anaesthesia by IV route.

24. ▪ Based on drug elimination (metabolism + kidney filtration), 3 category of benzodiazepines exist.
Half-life Example
Long acting More than 24 hrs. Diazepam, Nitrazepam
chlordiazepoxide, flurazepam
Intermediate acting 12-24 hrs. alprazolam, lorazepam
clonazepam, flunitrazepam
Short acting Less than 1-12 hrs. midazolam and triazolam
✓ longer-acting benzodiazepines are recommended for the treatment of anxiety
✓ Short- and intermediate-acting are preferred for the treatment of insomnia
3rd position

25. 4th position
▪ In all benzodiazepines we can observe an unsaturation at 4th and 5th position.
▪ This is essential for activity and saturation of this double bond may decrease the activity.
▪ Even shift of the double bond to 3rd and 4ht position decreases the activity.
4
5
Essential for
activity

26. 5th position
▪ A simple aromatic ring like phenyl group is optimal for activity.
▪ Again all benzodiazepines including fused benzodiazepine ring systems have a phenyl group at 5th position.
▪ For example, drugs like diazepam, nitrazepam, oxazepam, temazepam and chlordiazepoxide all have a phenyl group at 5th
position.
▪ Substitution on phenyl group also plays a key role in influencing activity
▪ .But all positions may not yield favourable results. Those drugs having phenyl group with ortho or diorhto substitution
with an electron withdrawing group found to increase activity. At the same time, para substitution decreases the activity.
Para

27. ▪ We can easily observe this in the names of few benzodiazepines.
▪ For example, flurazepam has fluoro group and clonazepam has chlorine group
✓ Note:
▪ This applies to above two drugs only. Don’t think that nitrazepam has nitro group on phenyl ring. Actually it has nitro
group at 7th position of the benzodiazepine ring.
▪
Similarly other drugs like triazolam and midazolam has chlorine and fluorine groups respectively at ortho position of the
phenyl ring.

28. 7th position
▪ This is again very important position to determine the potency of
benzodiazepine.
▪ Electron withdrawing groups like halogens or nitro group increase the
activity.
▪ Higher the electornegativity higher the potency
▪ Therefore nitrazepam is more potent than diazepam
▪ The EA property of the nitro group is associated with the fact
that all three atoms of this group are strongly electronegative
(χN = 3.04, χO = 3.44)
7

29. Nonbenzodiazepine Drugs
▪ Zolpidem (imidazopyridine) and eszopiclone
(cyclopyrrolone) are nonbenzodiazepines and have been
introduced as short and moderate-acting hypnotics,
respectively.
▪ Zolpidem exhibits a high selectivity for the α1 subunit
of benzodiazepine binding site on GABAA receptor
complex.
▪ Zolpidem has a rapid onset of action of 1.6 hours and
good bioavailability (72%), mainly because it is
lipophilic and has no ionizable groups at physiological
pH.
▪ It has short elimination half-life, because its aryl
methyl groups is extensively αhydroxylated to inactive
metabolites by CYP3A4 followed by further oxidation by
aldehyde dehydrogenase to the ionic carboxylic acid.
▪ The metabolites are inactive, short-lived, and
eliminated in the urine. Its half-life in the elderly or the
patients with liver disease is increased.
N-demethylation

30. ➢ Zaleplon
▪ Zaleplon is another short-acting nonbenzodiazepine hypnotic.
▪ Pharmacologically and pharmacokinetically, zaleplon is similar to zolpidem; both are hypnotic agents with short halflives.
▪ It also has selective high affinity for α1-subunit containing BzRs but produces effects at other BzR/GABAA subtypes as
well
▪ It is primarily metabolized by aldehyde oxidase to 5-oxo-zaleplon and is also metabolized to a lesser extent by CYP3A4.
N-demethylation yields desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-
desethylzaleplon.
▪ These oxidative metabolites are then converted to glucuronides and eliminated in urine.
▪ All of zaleplon’s metabolites are pharmacologically inactive. It may have a more rapid onset (about 1 hour) and
termination of action than zolpidem, and therefore, it is good to initiate sleep instead of keeping sleep

31. Benzodiazepines and related compounds can act as agonists, antagonists, or inverse agonists at the
benzodiazepine-binding site on GABAA receptor.
➢ Beta–carbolines
▪ Beta-carboline and benzodiazepine interactions with GABAA receptor-gated chloride channels.
▪ Its high affinity for Bz receptor.β–carbolines are negative modulators (inverse agonists) at
benzodiazepine modulatorysites.
▪ Negative modulators diminish the positive effect of GABA on chloride flux.

32. ➢ Fluoroquinolones
▪ FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions in July
10, 2018.
▪ Fluoroquinolones are antagonists of the GABA-A receptor, meaning that they prevent the binding of GABA and can displace
other molecules bound to the receptor, such as benzodiazepines.
▪ GABA is an inhibitory neurotransmitter and drugs which enhance its action, like benzodiazepines, cause sedation.
▪ The GABA receptor blockade caused by a fluoroquinolone results in a CNS stimulant effect, with neurological manifestations
ranging from mild insomnia and agitation to hallucinations and seizures.

33. Antidote for benzodiazepine toxicity
➢ Flumazenil
▪ Flumazenil, a specific benzodiazepine antagonist, is useful in reversing the sedation and
respiratory depression that often occur when benzodiazepines.
▪ Antagonist at the benzodiazepine receptor.