Level-3

Pharmacology
Drugs affecting on Central Nervous System
Lecture 2: Sedative & Hypnotics

1
 Sedative-Hypnotic Drugs
The sedative-hypnotics are drugs that depress central nervous system (CNS)
function. With some of these drugs, CNS depression is more generalized than
with others. The sedative-hypnotics are used primarily for two common
disorders: anxiety and insomnia.
Agents given to relieve anxiety are known as antianxiety agents or
anxiolytics. Agents given to promote sleep are known as hypnotics.
The distinction between antianxiety effects and hypnotic effects is often a
matter of dosage: typically, sedative-hypnotics relieve anxiety in low doses
and induce sleep in higher doses. Hence, a single drug may be considered
both an antianxiety agent and a hypnotic agent, depending upon the reason
for its use and the dosage employed.
2
 A. Classification of Sedative-Hypnotic Drugs

1. Benzodiazepines (BDZ)
Classifications of (BDZ) According to Duration of Action :

Ultrashort(<6 h). Short (12-18h) Medium (24 h) Long (24-72 h)

1. Triazolam 1. Lorazepam 1. Alprazolam 1. Diazepam

2. Midazolam 2. Oxazepam 2. Nitrazepam 2. Chlorazepate
3. Temazepam 3. Chlordiazepoxide
4. Lormetazepam 4. Clonazepam
5. Estazolam 5. Flurazepam
6. Quazepam
3
7. Prazepam
1. Benzodiazepines (BDZ)
Classification of (BDZ) According to Uses

Sedative Hypnotics Anticonvulsant Preanaestheic

1. Diazepam 1. Diazepam 1. Diazepam 1. Diazepam
2. Chlordiazepoxide 2. Flurazepam 2. Lorazepam 2. Midazolam
3. Oxazepam 3. Nitrazepam 3. Clonazepam
4. Alprazolam 4. Alprazolam 4. Clobazam
5. Lorazepam 5. Temazepam
6. Triazolam
7. Estazolam
8. Quazepam
because of pharmacokinetic differences, individual benzodiazepines may differ in
4
clinical applications
 Mechanism of Action of Benzodiazepines

 Bzs binding to BZ receptors (BZ1 or BZ2)  facilitation of GABA action on

GABA receptors  chloride channels opening   chloride influx to the
cell  cell membrane hyperpolarization  inhibition of propagation of
action potential  inhibitory effect on different sites of the brain especially
motor cortex, and limbic system.

 Note that benzodiazepines do not act as direct GABA agonists—they simply

intensify the effects of GABA.

 Because benzodiazepines act by amplifying the actions of endogenous

GABA, rather than by directly mimicking GABA, there is a limit to how
much CNS depression benzodiazepines can produce. This explains why
benzodiazepines are so much safer than the barbiturates—drugs that can
5
directly mimic GABA.
GABA (γ- aminobutyric acid) is the major inhibitory neurotransmitter in the
mammalian CNS

Figure(1) GABAA-benzodiazepine receptor-chloride channel complex

6
Figure(2) Mechanism of Action of Benzodiazepines 7
 Pharmacokinetics of BZDs

1. Absorption
I. Oral absorption of some is rapid while that of others is slow Why?
Chlorazepate is a prodrug converted by acid hydrolysis in stomach to
form nordazepam (desmethyldiazepam) active metabolite  rapidly
absorbed
II. I.M injection
‾ Most of BZDs have irregular absorption due to binding to skeletal
muscle protein.
‾ Lorazepam is well absorbed ,so its useful in status epilepticus when
I.V is difficult.
III. I.V injection (Diazepam , lorazepam , Chlordiazepoxide, Midazolam)
8
 Pharmacokinetics of BZDs

2. Distribution:
BZDs are lipid soluble and widely distributed& Pass BBB

Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action).

Cross placental barrier during pregnancy and are excreted in milk (Fetal &
neonatal depression).

3. Metabolism & Excretion : ALL BZDs are metabolized in the liver

Phase I: ( liver microsomal system)  active metabolites  elimination half

life of the parent compound  cumulative effect with multiple doses Except
No active metabolites are formed for Lorazepam , Lormetazepam
Oxazepam, Nitrazepam, Temazepam & Clonazepam.

Phase II: glucuronide conjugation and excreted in the urine.

9
Figure(3) Biotransformation of benzodiazepines. *, active metabolite

10
 Pharmacologic Effects of BZDs

1. Central Nervous System:

All beneficial effects of benzodiazepines, and most adverse effects, result

from depressant actions in the CNS. With increasing dosage, effects progress
from sedation to hypnosis to stupor.

Benzodiazepines depress neuronal function at multiple sites in the CNS.

They reduce anxiety through effects on the limbic system, a neuronal
network associated with emotionality. They promote sleep through effects on
cortical areas and on the sleep-wakefulness ―clock.‖ They induce muscle
relaxation through effects on supraspinal motor areas, including the
cerebellum. Two important side effects: confusion and anterograde
amnesia—result from effects on the hippocampus and cerebral cortex.
11
 Pharmacologic Effects of BZDs

2. Cardiovascular System:

When taken orally, benzodiazepines have almost no effect on the heart and
blood vessels. In contrast, when administered intravenously, even in
therapeutic doses, benzodiazepines can produce profound hypotension and
cardiac arrest.

3. Respiratory System

In contrast to the barbiturates, the benzodiazepines are weak respiratory

depressants. When taken alone in therapeutic doses, benzodiazepines
produce little or no depression of respiration—and with toxic doses,
respiratory depression is moderate at most. With oral therapy, clinically
significant respiratory depression occurs only when benzodiazepines are
combined with other CNS depressants (e.g., opioids, barbiturates, alcohol).
12
 Therapeutic Uses of BZDs
1. Anxiety disorders ,Panic ,Phobic ,Psychic depression: alprazolam
2. Sleep disorders (Insomnia).
 Triazolam: initiate sleep .
 Estazolam - Lorazepam – Temazepam-: maintain sleep.
3. To control withdrawal symptoms of alcohols .
 Use long acting BZDs e.g. diazepam
4. Treatment of epilepsy.
 Slow i.v. Diazepam – Lorazepam: Status epilepticus
 Oral Clonazepam is broad spectrum anti-epileptic
5. Muscle relaxation: in spastic states (Diazepam).
6. In anesthesia
 Preanaestheic medication: diazepam
 Induction of balanced anesthesia :Midazolam.
7. Along with analgesics, NSAIDs, spasmolytics , antiulcer and many other drugs
13 .
TABLE 1■ Applications of the Benzodiazepines

14
 Adverse Effects of BZDs
1. Ataxia (motor incoordination), cognitive impairment.

2. Anterograde Amnesia (impaired recall of events that take place after dosing).
Anterograde amnesia has been especially troublesome with triazolam [Halcion].

3. Sleep Driving and Other Complex Sleep-Related Behaviors. Patients taking

benzodiazepines in sleep-inducing doses may carry out complex behaviors and then
have no memory of their actions. Reported behaviors include sleep driving,
preparing and eating meals, and making phone calls. Because of the potential for
harm, benzodiazepines should be withdrawn if sleep driving is reported.

4. Paradoxical responses, including insomnia, excitation, euphoria, heightened anxiety,

and rage. If these occur, the benzodiazepine should be withdrawn.

5. Abuse: Because their potential for abuse is low, the benzodiazepines are classified
under Schedule IV of the Controlled Substances Act
15
 Use in Pregnancy and Lactation

 Use of benzodiazepines during the first trimester of pregnancy is associated

with an increased risk of congenital malformations, such as cleft lip, inguinal
hernia, and cardiac anomalies.

 Use near term can cause CNS depression in the neonate. Because they may
represent a risk to the fetus, most benzodiazepines are classified in U.S. Food
and Drug Administration (FDA) Pregnancy Risk Category D . a Five of these
drugs— Estazolam, Flurazepam, Quazepam, Temazepam, And Triazolam are
in Category X .

 Benzodiazepines enter breast milk with ease and may accumulate to toxic
levels in the breast-fed infant. Accordingly, these drugs should be avoided by
nursing mothers.
16
 Tolerance and Physical Dependence

Tolerance :No tolerance develops to anxiolytic effects, and tolerance to hypnotic

effects is generally low. In contrast, significant tolerance develops to antiseizure
effects.

Physical Dependence. When benzodiazepines are discontinued following short-

term use at therapeutic doses, the resulting withdrawal syndrome is generally
mild and often goes unrecognized. Symptoms include anxiety, insomnia,
sweating, tremors, and dizziness. Withdrawal from long-term, high-dose therapy
can cause more serious reactions, such as panic, paranoia, delirium,
hypertension, muscle twitches, and outright convulsions. Symptoms of
withdrawal are usually more intense with benzodiazepines that have a short
duration of action. e.g. alprazolam [Xanax, Xanax XR, Niravam]
17
 Interactions of BZDs

1. BZDs + CNS depressants alcohol, antihistamines →↑↑ depressant effect

2. BZDs + ketoconazole, erythromycin and others →↑plasma

concentration of BZDs

3. BZDs + Cimetidine, isoniazid and oral contraceptives→↓ plasma

concentration of BZDs

18
 Benzodiazepines antagonist

1. Flumazenil( Anexate ®).I.V or infusion (0.3-1mg)

Absorbed orally; oral bioavailability is ~16%, but it is not used orally. On

i.v. injection, action of flumazenil starts in seconds and lasts for 1–2 hr;
elimination t½ is 1 hr, due to rapid metabolism.

 Mechanism of action: Competitive antagonists as well as inverse agonists

for the BZD receptors.

 Therapeutic Uses

1. Acute BZD toxicity (comatose patients).

2. Reversal of BZD sedation after endoscopy, dentistry.

 Adverse effects Flumazenil is safe and well tolerated

19
2. Barbiturates
 Are derivatives of barbituric acid

 Second choice as sedative – hypnotic

 Its members end with the suffix (barbital

or barbitone)

 They have a low margin of safety

compared with benzodiazepines and the
newer hypnotics.

 Serious suicide potential

20
 Classification of Barbiturates
 On the basis of duration of action
1. Long-acting( 6-8 h): Example, Barbitone & Phenobarbitone
2. Intermediate acting(4-6h):Example, Amobarbitone.
3. Short-acting(2-4h):Example, Pentobarbitone & Secobarbitone
4. Ultra short-acting(20-30min):Example, Thiopental sodium, Hexobarbitone

 On the basis of clinical use

1. Long-acting are used as anticonvulsants,e.g. phenobarbitone.
2. Intermediate and short-acting ones are hypnotic, e.g. Secobarbitone.
3. Ultra short acting groups are intravenous anesthetics,e.g. Thiopental sodium

21
 Mechanism of Action of barbiturates
 Facilitate the actions of GABA at multiple sites in the central nervous system
 In contrast to benzodiazepines they increase the duration of the GABA-gated
chloride channel opening
 Activating chloride channels(GABA-mimetic action) and inhibit Ca2+
dependent release of neurotransmitters.
 At high concentrations, the barbiturates directly →Inhibiting voltage sensitive
Na+ and K+ channels
A dose-dependent effect on multiple neuronal targets appears to confer the
ability to produce any grade of CNS depression

22
 Pharmacokinetics of barbiturates
 Absorption: they are well absorbed from the g.i. tract.
 Distribution: are widely distributed in the body . The rate of entry into
CNS is dependent on lipid solubility. Highly-lipid soluble thiopentone has
practically prompt entry, while less lipid-soluble ones (pentobarbitone) take
longer; phenobarbitone enters very slowly.
 Elimination Three processes are involved in termination of action of
barbiturates:
1) Redistribution It is important in the case of highly lipid-soluble thiopentone and
others. After their i.v. injection, consciousness is regained in 6–10 min due to
redistribution while the ultimate disposal occurs by metabolism (t½ of elimination
phase is 9 hours). Effect of single dose of short acting barbiturate may last just 6–
10 hours due to redistribution, while elimination t½ is 12–40 hours.
23
 Pharmacokinetics of barbiturates
2) Metabolism Drugs with intermediate lipid-solubility (short-acting
barbiturates) are primarily metabolized in liver by oxidation,
dealkylation and conjugation. Their plasma t½ ranges from 12–40 hours.

3) Excretion Barbiturates with low lipid-solubility (long-acting agents) are

significantly excreted unchanged in urine. The t½ of phenobarbitone is
80–120 hours. Alkalization of urine increases ionization and excretion.
This is most significant in the case of long-acting agents.

24
 Therapeutic Uses of barbiturates
Seldom used now & replaced by BZDs Except for

1. Thiopental: in febrile convulsion & Induction of anesthesia

2. Phenobarbitone in Grand mal epilepsy status epilepticus &

Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl
transferase activity) Because its enzyme induction → ↑metabolism of
bilirubin

25
 Adverse Effects of barbiturates

Depending on dose effects may vary, Drowsiness to unconsciousness, hangover,

nightmares, cold and clammy skin, rapid and shallow, respiration, thready pulse,
fall of BP, allergic skin rash.
Contraindications
1. Severe pulmonary insufficiency in COPD
2. Liver and kidney diseases  Defective Kinetics
3. Attacks of porphyria.
4. Head injuries  ↓ R.C
5. Old people ( mental confusion).
6. Extremities of age Defective Kinetics
7. Alone in pain  hyperalgesia
8. Pregnancy(addict baby)&Lactation(Neonatal asphyxia)& Shock (↓ Bl.p) 26
 Interactions of barbiturates

1. Barbiturates induce the metabolism of warfarin, steroids (including

contraceptives), tolbutamide, griseofulvin, chloramphenicol, theophylline→↓

reduce their effectiveness

2. Barbiturates + CNS depressants e.g. alcohol, antihistamines →↑↑

depressant effect

3. Barbiturates + Sodium valproate →↑plasma concentration of

phenobarbitone.

4. Phenobarbitone decreases absorption of griseofulvin from the g.i.t.

27
 Contrasts Between Benzodiazepines and Barbiturates

Area of Comparison Benzodiazepines Barbiturates

Relative safety High Low

Maximal ability to depress CNS function Low High

Respiratory depressant ability Low High

Suicide potential Low High

Ability to cause physical dependence Low High

Potential to develop tolerance Low High

Abuse potential Low High

Ability to induce hepatic drug metabolism Low High

28
 3. Non-Benzodiazepine BZD –GABA agonist
 Examples 1-Zolpidem (t½ 2hrs) 2-Zaleplon (t½ 1hrs)

 An imidazopyridine derivatives

 Mechanism of Action: Acts on benzodiazepine receptors (BZD preferentially the α1

subunit1) & facilitate GABA mediated neuronal inhibition.

 Its action is antagonized by flumazenil.

 Rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT

P450.

 In contrast to the benzodiazepines, zolpidem lacks anxiolytic, muscle relaxant, and

anticonvulsant actions because zolpidem doesn’t bind with all benzodiazepine

receptors. Rather, binding is limited to the benzodiazepine1 subtype of
benzodiazepine receptors.?
29
 3. Non-Benzodiazepine BZD –GABA agonist.
 Safety in pregnancy has not been established. According to the FDA, zolpidem may

pose a small risk of anaphylaxis and angioedema.

 Because the plasma t½ is short( 2- 4 h) , next day sedation is minimal, but morning

sedation or prolongation of reaction-time can occur if it is taken late at night.

 In contrast to zolpidem, zaleplon has a very rapid onset and short duration of action,

and hence is good for helping patients fall asleep, but not for maintaining sleep.

 Used for short-term treatment of insomnia(1-2weeks)

 Eszopiclone is approved for treating insomnia, with no limitation on how long it can

be used

 The most common adverse effect of Eszopiclone is a bitter aftertaste

30
 4.Melatonin& Melatonin Congeners

 Melatonin

- Its hormone of the pineal gland which is secreted at night.

- It is N-acetyl-5-methoxy tryptamine.

 Mechanism of action Activates MT1,MT2 and MT3 receptors in the CNS

- Uses : used for treatment of jet-lag symptoms, shift workers and elderly hypnotic
dependent insomniacs.

- Since melatonin secretion declines with age, it has been claimed that melatonin.
supplementation might delay ageing.

- Dose :3 mg tab, one tablet at evening daily.

- Side effect: Lowering of seizure threshold and psychiatric changes.

31
 4.Melatonin& Melatonin Congeners

Drug: Ramelteon

Pharmacokinetics

- Oral activity, bioavailability is < 2% , t1/2 of ~2 hours

- forms active metabolite via CYP1A2 with longer half-life 2-5 hers

Mechanism of action

- Activates MT1 and MT2 receptors in the CNS.

Effects

- Rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms

- has minimal potential for abuse, is not a controlled substance, and regular use does
not result in dependence
32
 4.Melatonin& Melatonin Congeners

Drug: Ramelteon

Toxicity: Dizziness, fatigue somnolence,, endocrine changes(decreases in

testosterone and increases in prolactin).

Interactions:

- Fluvoxamine ciprofloxacin inhibits metabolism.

- Rifampin induce metabolism.

FDA pregnancy category C

33
 5. 5-HT-receptor agonist

 Drug: Buspirone

 Pharmacokinetics: Oral activity ,forms active metabolite, short half-life 2-4

hrs.

 Mechanism unclear: Partial agonist at 5-HT receptors but also affinity for D2
receptors.

 Effects

- Slow Onset (1–2 Weeks) Of Anxiolytic Effects

- Minimal Psychomotor Impairment →No Additive

- CNS Depression With Sedative-hypnotic Drugs

34
 5. 5-HT-receptor agonist

 Drug: Buspirone

 Uses Generalized anxiety states but not phobias

 Toxicity : Tachycardia, paresthesias, gastrointestinal distress

 Interactions:CYP3A4 inducers and inhibitors

 FDA pregnancy category B

35
6. An orexin antagonist

Suvorexant [Belsomra] is a sedative that selectively blocks receptors for orexin,

a neurotransmitter in the brain that promotes wakefulness. The drug is
approved for treating chronic insomnia characterized by difficulty with sleep
onset and/or sleep maintenance. Similar to the benzodiazepine-like drugs,
suvorexant is regulated as a Schedule IV substance.

Adverse Effects

The most common side effects are somnolence, headache, dizziness, diarrhea,
dry mouth, and cough. Hallucinations, sleep paralysis (an inability to speak or
move for up to several minutes during sleep-wake transitions), and vivid,
disturbing perceptions have been reported by some patients
36
 6. Miscellaneous Sedative-Hypnotic Drugs
1. Antidepressants: Trazodone and Doxepin.

2. Antihistamines

Two Antihistamines—Diphenhydramine [Nytol, Sominex, others] and Doxylamine

[Unisom]—are FDA approved for use as ―sleep aids‖ and can be purchased
without a prescription. These drugs are less effective than benzodiazepines and
benzodiazepine-like drugs, and tolerance develops quickly (in 1 to 2 weeks).
Daytime drowsiness and anticholinergic effects (e.g., dry mouth, blurred vision,

urinary hesitancy, constipation) are common.

3. Alternative Medicines

Valerian Root, Chamomile, Passionflower, Lemon Balm, And Lavender—have very

mild sedative effects, but proof of benefits in insomnia is lacking.
37
Thank you

38