Sedative and Hypnotics

Defination

• A sedative drug decreases activity and excitement of the patient and clams 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

Dose dependent activity

• All sedative, hypnotic and GA depress the CNS• 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

Utility

Sedatives counter various types of anxiety such as • Obsessive-compulsive disorder (OCD)• Post-traumatic stress disorder (PTSD)• Social anxiety disorder• Specific phobiasHypnotics is for insomnia. Insomnia is a condition where person is not able to fall sleep

Ideal properties of hypnotics

1. Cause a temporary decrease in the level of consciousness for the purpose of falling asleep without any alteration to sleep cycle

2. Must not decrease or arrest respiration, even at high doses

3. Cause no addiction, tolerance or dependence

• sleep cycle : Sleep proceeds in cycles of light sleep and deep sleep

• Light sleep – NREM sleep, lasts for about 90 mins

• Easy to wake in this period• Deep sleep – REM sleep, last 5 to 10 mins• Difficult to wake in this time

Drug classification

1. Barbiturates :Phenobarbitone*2. Benzodiazepines: Alprazolam, Diazepam,

Nitrazepam, Lorazepam3. Non-Benzodiazepines: zolpidem, Zalephon4. Others: paraldehyde, Glutethimide, Chloral

Hydrate5. Herbal sedatives: Ashwagandha, Valerian and

passiflora

Barbiturates

• All derivatives of Barbituric acid• They are CNS depressants. They are effective

as anxiolytics, hypnotics, anticonvulsants and analgesics.

• They have addiction potential, both physical and psychological.

• Thus Benzodiazipines have largely replaced them in term of sedative-hypnotic

Types

Barbituric Acid

Amobarbital Pentobarbital

Short actingIntermediate acting

Long-Acting

Thiopental sodium

Ultra shortacting

Phenobarbital

Factors effecting Duration of action as by the SAR

Phenobarbital Thiopental Sodium

Branched R group

Short ethyl chainTotal carbon = 2 (not counting aromatic)

Long chain of R groupTotal C = 7

Additional improvements to Thiopental Sodium tofurther decrease duration of action•N methylation (potency also inc)•Unsaturated R group

• Mode of action of barbiturates1. They have positive allosteric effect at GABA receptor.

They bind at a different site than GABA or Benzodiazepines and stimulate the pharmacologic action of GABA which is the principal inhibitory neurotransmitter in the CNS

2. They inhibit AMPA receptor, which binds glutamate which is principal excitatory neurotransmitter in the CNS

3. At higher does they inhibit Ca2+ dependent release of neurotransmitters

• Allosteric drugs bind the receptor at different site. They can both stimulate or inhibit the receptor function.

• Agonist can only stimulate the receptor function• Antagonist can only inhibit the receptor function

Structure-Activity Relationship• Barbituric acid itself does not possess any hypnotic properties. •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 unsubstitutedTo 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 drugPotencyDuration of Action.

N NH

O

O O

HN NH

O

O O

HN NH

O

O O

HN NH

O

O O

Inactive inactive coz not lipophilic enough

R R RR R

R

N N

O

O O

RR

R R

Inactive coz not acidic enough

activeactiveinactive coz not lipophilic enough

Barbituric acid

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

Contd...

Total carbon Duration of action

7-9 Rapid onset n shorter duration

5-7 Intermediate duration of action

4 Slowest onset and longest duration of action

Only one of the substituent groups at position 5 may be a cyclic group.

C

N C

C

CHNC2H5

O

O

O

CH3

Methylepentobarbital

Contd...

The branched chain isomer exhibits greater activity but shorter duration. The greater the branching, the more potent is the drug (e.g., pentobarbital > amobarbital).This Branched, cyclic or unsaturated alkyl groups reduce duration of action due to increased ease of metabolic inactivation

Pentobarbital Amobarbital

Contd...

(iv) Double bonds in the alkyl substituent groups produce compounds more readily vulnerable to tissue oxidation ; hence, they are short-acting.

Pentobarbital Sodium

Contd...

Aromatic and alicyclic moieties exert greater potency than the corresponding aliphatic moiety having the same number of carbon atoms.

Contd...

C

HN C

C

CHNC2H5

O

O

O

CNH

C

CC

HN C2H5

O

O

O

1 2

3

4

5

6

1

2

3

4

5

6

more potent than

Short chains at carbon 5 resist oxidation and hence are long-acting. Long chains are readily oxidized and thus produce short-acting barbiturates.

Pentobarbital SodiumBarbitalContd...

Inclusion of a halogen atom in the 5-alkyl moiety enhances activity.

Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and SO3H) in the 5-alkyl moiety reduces potency considerably.

Methylation of one of the imide hydrogens enhances onset and reduces duration of action

Methylepentobarbital Contd...

The replacement of O-atom with an S-atom, at C- 2 position of the barbiturates significantly enhances the lipid solubility. The resulting modified versions of the barbiturates thus obtained exert a rapid onset of activity by virtue of the fact that they attain maximal thiobarbiturate-brain levels. Therefore, such drugs as ‘thiopental sodium’ find their profuse and abundant application as ‘intravenous anaesthetics’.

Thiopental sodium Contd..

HC

HN C

C

CHN

SNa

O

O

C2H5

CH

(CH2)2CH3

CH3

Inclusion of more sulphur atoms (at C-2 and C-6) decreases activity. Likewise replacement of Oxygen with Nitrogen abolishes activity

N N

NH

O O

RR

R R

Inactive

Phenobarbital

• Phenobarbital or phenobarbitone is a barbiturate which is most widely used anticonvulsant worldwide and the oldest still commonly used.

Phenobarbital

C

C

NH

C

NH

C

O

O O

C2H5

• It also has sedative and hypnotic properties but, as with other barbiturates, has been outdated by the benzodiazepines for these indications.

• first-line for partial and generalized tonic-clonic seizures

• first line choice for the treatment of neonatal seizures

• Sedation and hypnosis are the principal side effects of phenobarbital. Also dizziness, nystagmus and ataxia are common.

• In elderly patients, it may cause excitement and confusion while in children, it may result in paradoxical hyperactivity.

• Overdose may also lead to pulmonary edema and acute renal failure

• It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of 2 to 7 days) and has very low protein binding• Phenobarbital is metabolized by the

liver, mainly through hydroxylation and glucuronidation• It is excreted primarily by the kidneys

Synthesis of Phenobarbi

tone

Benzyl cyanide

i)Acid hydrolysid

ii) EtOH

C C

O

CH2 CH2 C

O

OC2H5

Ethyl phenyl acetate

EtOHand Na(-OC2H5)

Diethyl oxalate

CH C OC2H5

O

C C OC2H5

O O

Distilled at 180OC

(-CO)

HC

C OC2H5

O

C OC2H5

O

CN

Phenyl malonic ester Diethyl phenyl-oxyalo-acetate

C2H5-Br(ethyl bromide)C2H5-ONa (sodium ethoxide)

C

C OC2H5

O

C OC2H5

OC2H5

H2N

C

O

NH2urea

-2 EtOHEthylphenyl malonic

ester

Phenobarbital

OC2H5

O

C2H5O

C

C

NH

C

NH

C

O

O O

C2H5

-HBr

Thiopental sodium

•Ultra short acting barbiturate (5-10 mins)•Rapid action (10 -15 sec) and rapid recovery•Used mainly as inducing anesthetic• has no analgesic properties• anesthetic state maintained by inhalation anesthetic eg N20•it is a poor muscle relaxant

HC

HN C

C

CHN

NaS

O

O

C2H5

CH

(CH2)2CH3

CH3

• it possesses potent anticonvulsant activity it may be given to treat epileptic seizures that do not respond to other therapy.

• It is stored as a solid white salt and needs to be prepared in sterile water to inject the patient

• Rapid recovery not due to rapid metabolism• It is due to lowered concentration caused by

redistribution of drug from brain to blood. This is made possible becoz of the salt form of drug

• Dose: 3 to 7 mg/kg. • It does not have any direct toxic effects on

the liver or kidney• Although it crosses the placenta it is a safe

agent for induction in pregnancy

Synthesis of Thiopental sodiumi) Preparation of Diethyl ester of ethyl-(1-methyl butyl) malonic acid

C2H5 O C

C

O

O

OC2H5

Na

C2H5 O C

C

O

O

OC2H5

C2H5-BrEthyl Bromide

- NaBr

C2H5 O C

C

O

O

OC2H5

C2H5

C-CH2-CH2-CH3

2-Bromopentane

- HBrCH3

C2H5 O C

C

O

O

OC2H5

C2H5

H

Sodium MetalDiethyl malonate

Diethyl ester ofethyl malonic acid

C-CH2-CH2-CH3CH3

Br

Diethyl ester of ethyl-(1-methyl butyl) malonic acid

H

H

Na

H

-H

ii) Preparation of Thiopental sodium

C2H5 O C

C

C

O

O

OC2H5

C2H5

C-CH2-CH2-CH3

CH3Diethyl ester of ethyl-(1-methyl butyl) malonic acid

C

NH2

NH2

S

HN

C

HN C

C

C

S

O

O

C2H5

- 2 EtOH

NaOH

N

C

HN C

C

C

HS

O

O

C2H5

C-CH2-CH2-CH3

CH3

C-CH2-CH2-CH3

CH3

Thiourea

Keto formEnol form

HN

CH

HN C

C

C

NaS

O

O

C2H5

C-CH2-CH2-CH3

CH3

Thiopental sodium

Thiamylal

• Ultra short acting barbiturate• Rapid action but not rapid recovery due to high

lipophilicity and subsequent drug accumulation in the fatty tissues

• Used mainly as inducing anesthetic in lab animals• anesthetic state maintained by inhalation

anesthetic eg N20• Use limited to Veterinary field. Only its sodium

salt is used in humans

Benzodiazepines• Chemically they are a fusion of a benzene ring and a diazepine ring

• Benzodiazepines enhance the effect of theGABA 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• are safer than barbiturate and not additive

MOA of benzodiazepines1. They have positive allosteric effect at GABA receptor. They bind at a different site than GABA or Benzodiazepines and stimulate the pharmacologic action of GABA which is the principal inhibitory neurotransmitter in the CNS

2. They block reuptake of Adenosine which is sedating neurotransmitter, thus promoting its sedative action.

Attach to and directly block the Acetylcholine (ACh) receptors in the hippocampus thus causing amnesia. (Hippocampus is where memory is stored and processed. This is how date rape drug Flunitrazepam works)

SAR of benzodiazepinez

R2= carbonyl group( C=O)

Mostly Cl or NO2 is used at position 7

But para substitution (position 4’) decreases activity

(Note--> inclusion of OH,NH3,SO4,PO4, COOH groups increase polarity)

Types of benzodiazepines

Half life exampleLong acting > 24 hrs Diazepam,Nitrazepam

chlordiazepoxide, flurazepam

Intermediate acting 12-24 hrs alprazolam, lorazepamclonazepam, flunitrazepam,

Short acting < 1-12 hrs midazolam and triazolam.

Based on drug elimination (metabolism + kidney filtration), 3 category of benzodiazepines exist

longer-acting benzodiazepines are recommended for the treatment of anxietyShort- and intermediate-acting are preferred for the treatment of insomnia;

Midazolam

• Midazolam has a rapid onset of action, high effectiveness and low toxicity level and fast recovery time

• Properties: It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties

• Uses: Used for treatment of acute seizures, moderate to severe insomnia and for inducing sedation and amnesia before medical procedures

• used mostly as a premedication for sedation and less commonly for induction or maintenance of anesthesia.

• MOA- alloteric GABAA enhancer

Diazepam• Long acting benzodiazepine (>20 hrs)• due to high blood protein binding of 98.5% which reduces rate of

elimination and it’s metabolic product is also active• Properties: It has anxiolytic, anticonvulsant, hypnotic -

sedative, skeletal muscle relaxant, and amnestic properties • Uses :anxiety, panic attacks, insomnia, seizures , muscle

spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, opiate withdrawal syndrome

• Not used for long term epilepsy due to development of tolerance• Avoid during pregnancy• MOA – Allosteric GABAA enhancer

Lorazepam• high-potency, intermediate acting

duration benzodiazepine drugProperties: anxiolysis, short term

amnesia, sedation/hypnosis, anticonvulsion, muscle relaxation Uses: • short-term treatment of anxiety, insomnia, acute seizures,

sedation of aggressive patients• to decrease the likelihood of agitation and seizures in

patients who have overdosed on stimulant drugs• lorazepam has advantage over diazepam, as in

– Better at ending seizures and– more prolonged anticonvulsant effect

Lorazepam

• lorazepam is removed from the blood more rapidly than many other benzodiazepines, there is less chance that lorazepam concentrations in blood will reach high levels and become toxic

• MOA- alloteric GABAA enhancer

Alprazolam

• It belongs to intermediate acting benzodiazepine • Properties: It has potent anxiolytic, amnestic, hypnotic,

anticonvulsant, skeletal muscle relaxant, and sedative properties

• Main uses: Alprazolam is used for the treatment of anxiety disorders and panic attacks

• can cause fetal abnormalities and should not be used in pregnancy

• It is excreted in breast milk and should not be used by women who are nursing

• MOA- alloteric GABAA enhancer

Nitrazepam

• A long acting benzodiazepine• Properties: It has anxiolytic, anticonvulsant, hypnotic -

sedative, skeletal muscle relaxant, and amnestic properties • Uses: Nitrazepam is used to treat short-term sleeping

problems (insomnia) and short term management of epilepsies

• Nitrazepam is not suitable for use in the elderly, children, pregnant women, or those with chronic obstructive pulmonary disease

• MOA- alloteric GABAA enhancer

Barbiturates vs Benzodiazepines

Barbiturates BenzodiazepinesThey cause high physiological and psychological dependence

They cause very less physiological and psychological dependence

Long term use avoided due to toxicity Long term use is relatively safeSleep induced by it causes hangover effect after waking up

Sleep induced by it is just like natural sleep and is refreshing to wake up

Increase duration of GABA Cl channel opening

Increase frequency of GABA Cl channel opening

High Respiratory depression Manageable Respiratory depression

Different alpha units of GABAA have different effects

GABA A receptors containingalpha 1 subunits are involved in sleep.

GABA A receptors containing alpha 2 or alpha 3 subunits are involved in anxiety.

GABAA Alpha 1 Selective Hypnotics – MOA of Zaleplon and Zolpidem

• The GABAA receptor contain 6 different alpha subunits

• Benzodiazepines bind to four of GABAA alpha subunits: alpha 1, alpha 2, alpha 3 and alpha 5.

• Each of these subunits is associated with different effects, and thus benzodiazepines not only cause sedation but are also anxiolytic, cause muscle relaxation, and have alcohol potentiating actions.

• The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep).

Advantages over benzodiazepines• A relatively short half life so one does not wake up

with a "hangover" the following day• Having little effect on sleep staging, allowing the

individual to obtain approximately the same amount of time in each stage of sleep as one would without the medications

• Less likely to cause addiction, withdrawal, or tolerance relative to older sleeping medications.

• These drugs are very lipophillic which increases absorption into brain

• They are metabolized by liver into water soluble metabolites which is rapidly cleared out in urine and thus avoid accumulation

Zolpidem Zalephon

• Zalephon : hypnotic dose 6-10 mgUsed as hypnotic drugGood at inducing sleep but not good at maintaining it since it has short elimination half life• Zolpidem : hypnotic dose 5-10 mgUsed as hypnotic drug Slower acting but maintains effect overnight period due to long elimination half life

Paraldehyde• Paraldehyde is the cyclic trimer of acetaldehyde

molecules. It is a colorless liquid and sparingly soluble in water and highly soluble in alcohol.

• Properties: It has an effective anticonvulsant, hypnotic and sedative

• MOA: Paraldehyde increases the effects of GABA, a inhibitory neurotransmitter that depresses CNS, at the GABAa receptor and decreases levels of glutamate, which is stimulatory neurotransmitter that excites CNS

Uses: •to induce sleep, and is also used to calm psychiatric patients•it is used to prevent hallucinations and tremors caused due to alcohol withdrawal•used to control seizures in infantsm not responding to phenobarbitone and phenytoin, • Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when the patient's breathing is already compromised.•It is very addictive and Paraldehyde also can stress the gastrointestinal tract so that a patient can develop ulcers

•Synthesis

H3C CH3

O

O O

O CH3H3C

CH3

H2SO4

ACETALDEHYDEPARALDEHYDE

Glutethimide

• Properties: sedative, hypnotic • Use: was used for insomnia but rarely prescribed today

just as likely to cause addiction and caused severe withdrawal symptoms as barbiturates.

• When taken with codeine, it stimulates metabolic conversion of codeine into morphine, which is used for its hallucinogenic effect

• MOA: It binds at the GABAa receptor which increases the effects of GABA which is a inhibitory neurotransmitter that depresses CNS

Chloral Hydrate• Synthesis 4 Cl2 + C2H5OH + H2O → Cl3CCH(OH)2 + 5 HCl

Chloral hydrate is metabolized to trichloroethanol, which is responsible for its physiological and psychological effects.Higher doses can depress respiration and blood pressure.Properties: seadtive, hypnotic Use: It has a very narrow therapeutic window making this drug difficult to use.

Instead benzodiazepines are preferred. • short time (no more than 2 weeks) treatment of insomnia • Used in organic synthesis as a reagentMOA: It binds at the GABAa receptor which increases the effects of GABA

which is a inhibitory neurotransmitter that depresses CNS

Cl C

Cl

Cl

CH

OH

OH

metabolizedCl C

Cl

Cl

CH2

OH

Trichloroethanol(Active compound)

Chloral Hydrate

Herbal sedatives

• Ashwagandha• Valerian• Passiflora

Ashwagandha

• Withania somnifera, also known as Ashwagandha, is a plant in Solanaceae or nightshade family.

Uses:• Ashwagandha is effective for insomnia but

does not act as a good sedative

Main compounds • Steroids :withaferin A• Alkaloids :anaferine

• MOA• increases the effects of GABA which is a

inhibitory neurotransmitter that depresses CNS by binding at the GABAa receptor

NH

NH O

anaferine

withaferin A

ValerianValerian (Valeriana officinalis), a member of the Valerianaceae family.chemical compounds responsible for sedative effect is Valerenic acidMOA:Enhances GABA effect on

GABAa receptor Uses: Alternate medicine for

Insomnia,anxiety OHO

H

Passiflora incarnata

• Use: Its herbal medicine is used to treat anxiety and insomnia.

• Active component in the extract is GABA itself• the anxiolytic effects were comparable to a 2

mg/kg of diazepam• MOA• Binds and GABAa receptor and depresses CNS

THANK YOU

Selectivity for GAB-A Receptor SubunitsGABA A receptors containingalpha 1 subunits are involved in sleep.

GABA A receptors containing alpha 2 or alpha 3 subunits are involved in anxiety.

Alpha 1 Selective Hypnotics - Zaleplon and Zolpidem

• The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep). This subunit is important for sedation and possibly for anticonvulsant and amnesic actions.

Existing Benzodiazepines are Non-selective

• Benzodiazepines bind to GABA-A alpha subunits: alpha 1, alpha 2, alpha 3 and alpha 5.

• Each of these subunits is associated with different effects, and thus benzodiazepines not only cause sedation but are also anxiolytic, cause muscle relaxation, and have alcohol potentiating actions.

The future of sedative-hypnoticsSelectivity for Phasic GABA Inhibition - Avoiding Addiction

Benzodiazepine sensitive GABA A receptors contain gamma and alpha (1 through 3) and alpha 5 subunits are intra-synaptic and mediate phasic inhibition triggered by peak concentrations of synaptically released GABA.

GABA A receptors containing alpha 4, alpha 6 , gamma 1 or delta subunits are located extrasynaptically and regulate tonic inhibition (tonic inhibition is not addictive).

Location of RAS in brain (no. 7)

RAS is brain centre for arousal and sleep cycle