Central Nervous

System Drugs

Dr/ Radwan El-Haggar radwanelhaggar@yahoo.com

Pharmacy10.jed@bmc.edu.sa

The central nervous system (CNS) is the part of the nervous

system that integrates the information that it receives from,

and coordinates the activity of, all parts of the body.

It contains the majority of the nervous system and consists of

the brain and the spinal cord.

Some classifications also include the retina and the cranial

nerves in the CNS.

Together with the peripheral nervous system, it has a

fundamental role in the control of behavior. The CNS is

contained within the dorsal cavity, with the brain in the

cranial cavity and the spinal cord in the spinal cavity.

In vertebrates, the brain is protected by the skull, while the

spinal cord is protected by the vertebrae, and both are

enclosed in the meninges.

Central Nervous System Drugs

I- CNS depressants:-

- Sedative and Hypnotic drugs.

- Anticonvulsant drugs.

- Anxiolytic drugs.

- Skeletal Muscle Relaxant drugs.

- Antipsychotic drugs.

- General Anesthetics.

II- CNS Stimulants:-

CNS depressants

A depressant, or central depressant, is a drug or endogenous

compound that lowers neurotransmission levels, which is to depress

or reduce arousal or stimulation, in various areas of the brain.

Depressants are also occasionally referred to as "downers" as they

lower the level of arousal when taken.

Stimulants or "uppers" increase mental and/or physical function are

the functional opposites of depressants.

Depressants when used, effects often include ataxia, anxiolysis, pain

relief, sedation or somnolence, and cognitive/memory impairment,

as well as in some instances euphoria, muscle relaxation, lowered

blood pressure or heart rate, respiratory depression, and

anticonvulsant effects, and even complete anesthesia or death at

high doses.

Depressants exert their effects through a number of different

pharmacological mechanisms, the most prominent of which

include facilitation of GABA or opioid activity.

CNS depressants

I- Sedatives and Hypnotics

A Sedative or tranquilizer compound is a substance that

induces sedation by reducing irritability or excitement.

A Hypnotic (also called soporific) is a substance that induces

sleep.

Because drugs in this class generally produce dose-dependent

effects, ranging from anxiolysis to production of

unconsciousness, they are often referred to collectively as

Sedative-Hypnotic drugs.

Small doses produce sedation.

Large doses produce sleep.

I- Barbiturates

Barbiturates are derivatives of barbituric acid.

They are drugs that act as central nervous system depressants, and

can therefore produce a wide spectrum of effects, from mild sedation

to total anesthesia.

They are also effective as anxiolytics, and anticonvulsants.

They have addiction potential, both physical and psychological.

Barbiturates have now largely been replaced by benzodiazepines in

routine medical practice - for example, in the treatment of anxiety and

insomnia – mainly because benzodiazepines are significantly less

dangerous in overdose. However, barbiturates are still used in general

anesthesia, and for epilepsy.

NH

NH

O

O O

Barbituric acid

Barbiturates potentiate inhibitory GABA receptors (γ-Amino

butyric acid ) (the principal inhibitory neurotransmitter in the

mammalian CNS) and inhibit excitatory AMPA receptors (α-amino-

3-hydroxy-5-methyl-4-isoxazole propionic acid) (a subtype of

glutamate receptor which is the principal excitatory neurotransmitter in

the mammalian CNS).

Mechanism of action

Tolerance and dependence

With regular use of Barbiturates, barbiturate dependence develops.

This in turn may lead to a need for increasing doses of the drug to

get the original desired pharmacological or therapeutic effect.

Barbiturate use can lead to both addiction and physical dependence,

and as such they have a high potential for abuse.

Psychological addiction to barbiturates can develop quickly.

Symptoms of an overdose typically include incoordination,

difficulty in thinking, slowness of speech, faulty judgment,

drowsiness, shallow breathing, staggering, and in severe cases

coma and death.

Overdose

NH

NH

O

O X

R 1

R 2

R 1

R 2

COOEt

COOEt

NH2

NH2

X

POCl3

Barbiturates or

Thiobarbiturates

Diethylmalonate

Derivative Urea or

Thiouera

+

General Synthesis of barbiturate

NH

NH

O

O O

1

234

5 6Barbituric acid: pyrimidine-2,4,6(1H,3H,5H)-trione

1. Non Aqueous titration:

• solution in DMF is titrated with NaOMe using thymol blue as

indicator.

2. Argentometric:

• An aqeous solution is titrated directly with AgNO3 in presence

of CO3-2. The first drop excess of AgNO3 form turbidity.

3. Gravimetrically: (for Sodium salts)

• Precipitation of free barbituric acid derivative using HCl,

the precipitate is extracted with organic solvent, evapourated

and weighted.

General methods of Assay

1- Long Acting Barbiturates:-

Classification of Barbiturates

Onset time:- one hour.

Duration of action:- 6-10 hours.

Barbital

(Barbitone) Metharbital

Phenobarbital

(Luminal ®) Mephobarbital

NH

NH

O

O O NH

N

O

O O

CH3

NH

NH

O

O O NH

N

O

O O

CH3

5,5-diethyl-1-methyl pyrimidine-

2,4,6(1H,3H,5H)-trione.

5,5-diethyl-1-methyl barbituric acid

They are used primarily as

anticonvulsant, sedative

and anxiolytic.

2- Intermediate Acting Barbiturates:-

Onset time:- half hour.

Duration of action:- 4-6 hours. Amobarbital

(Amytal ®)

Butabarbital

NH

NH

O

O O

They are used for the

treatment of severe insomnia

and relieving anxiety before

surgical procedures. NH

NH

O

O O

3- Short Acting Barbiturates:- Onset time:- 15 minutes.

Duration of action:- 1-2 hours. Secobarbital

(Seconal ®)

Pentobarbital

(Nembual ®)

NH

NH

O

O ONH

NH

O

O O

They are used for the

treatment of epilepsy,

insomnia and relieving

anxiety before surgical

procedures.

4- Ultrashort Acting Barbiturates (Thiobarbiturates):-

Onset time:- 30-45 seconds.

Duration of action:- 5-10 minutes. Thiamylal

(Surital ®)

Thiopental

(Thiopentone ®)

They are used commonly

in the induction phase of

general anesthesia. NH

NH

O

O SNH

NH

O

O S

Following intravenous injection the drug rapidly reaches the

brain and causes unconsciousness within 30–45 seconds. At

one minute, the drug attains a peak concentration of about

60% of the total dose in the brain. Thereafter, the drug

distributes to the rest of the body and in about 5–10 minutes

the concentration is low enough in the brain such that

consciousness returns.

SAR of Barbiturates

1. In position No. 5:-

Both hydrogen atoms at position 5 should be substituted

(pka ≈ 7.6). The unsubstituted or monosubstituted

(decrease the activity very much) are very acidic (pka

≈ 4) so the compounds are largely ionized at

physiological pHs, with little lipid soluble compound

available to cross the BBB.

Polar functions at C5 abolish the activity.

Substitution by ethyl groups give optimal activity.

↑ the length of alkyl group → ↑ sedating effect.

↑ the number of carbon more than 6 produce

anticonvulsant effect.

Branched, cyclic or unsaturated substituent at C-5 → ↓

duration of action (due to increased metabolic rates).

NH

NH

O

O O

R 1

R 2

Barbiturates

1

2

34

56

SAR of Barbiturates

2. Substitution of N-1 by methyl group result in shortening

both onset and duration of action.

3. Substitution of N-3 by methyl group produce

anticonvulsant effect.

4. Presence of mono-phenyl substituent at C-5

(Phenobarbital) produce anticonvulsant effect.

5. Replacement of C-2 oxygen with sulfur give rapid onset

and short duration of action (Thiopental).

NH

NH

O

O O

R 1

R 2

Barbiturates

1

2

34

56

II- Non-barbiturates

O

NH2

NH

O

Br

CH3

CH3

12

3

4

A) Urea derivatives:-

It has a week hypnotic effect.

1- Carbromal

2-Bromo-2-ethyl-butryl urea

O

NH2

NH2

Urea

NH

O

O

CH3

CH3

CH3

1 2

34

5

6

B) 2,4-piperidinedione derivatives:-

Uses:-

It was used for treating insomnia.

Acts by mechanism similar to that of barbiturates.

But is now rarely used as it has been replaced by newer

drugs with fewer side effects, such as benzodiazepines.

1-Methyprylone

3,3-diethyl-5-methylpiperidine-2,4-dione

NH

Piperidine

NH

O

O

2,4-Piperidinedione

NH

O

CH3

O

C) 2,6-piperidinedione derivatives:-

It was introduced as a safe alternative to barbiturates to treat

insomnia.

However, it was just as likely to cause addiction and caused

similarly severe withdrawal symptoms.

1- Glutethimide

3-ethyl-3-phenyl-piperidine-2,6-dione

NH

Piperidine

NH

OO

2,4-Piperidinedione

Synthesis

O

CH3

O

NH2

H3C-O

NH

O

CH3

O

1- Ester hydrolysis

2- CyclizationGlutathemide

C ONH

2

O

CH

D) Alcohols and Derivatives:-

Uses:-

It was used for treating insomnia.

Regular use leads to drug tolerance, and it is usually not

effective for more than 7 days.

Prolonged use can lead to dependency.

1- Ethinamate (Valmid ®)

(1-ethynylcyclohexyl)carbamate

Synthesis

C ONH

2

O

CHO

NH2

Cl

C OMgBr

CH

1- Hydrolysis

2- Ethinamate

Cl3C

OH

OH

Cl3C-CHO.H

2O1

2

2- Chloral hydrate

2,2,2-trichloroethane-1,1-diol

Uses:-

It is used for the short-term treatment of insomnia and as a

sedative before minor medical or dental treatment.

Prolonged use can lead to dependency.

Mechanism of action:-

Chloral hydrate is converted in the body to trichloroethanol,

which is responsible for its activity via enhancing the GABA

receptor complex.

Cl3C-CH

2OH

Disadvantages:-

Produce GIT irritation, so the phosphate ester is used.

P OO

O

OH

Cl3C Na

+

3- Triclofos sodium

2,2,2-trichloroethanol dihydrogen phosphate

Uses:-

It is used for the short-term treatment of.

Prolonged use can lead to dependency.

Mechanism of action:-

Triclofos is considered as a prodrug that is converted in the

body to trichloroethanol, which is responsible for its activity

via enhancing the GABA receptor complex.

Advantages over chloral hydrate:-

No GIT irritation.

CNS depressants

II- Anticonvulsant drugs

Epilepsy is a common and diverse set of chronic

neurological disorders characterized by seizures.

Some definitions of epilepsy require that seizures be

recurrent and unprovoked, but others require only a single

seizure combined with brain alterations which increase the

chance of future seizures.

In many cases a cause cannot be identified; however, factors

that are associated include brain trauma, strokes, brain

cancer, and drug and alcohol misuse among others.

Antiepileptic

drugs

Epilepsy is usually controlled, but not cured, with

medication. However, more than 30% of people with

epilepsy do not have seizure control even with the best

available medications.

Surgery may be considered in difficult cases.

Epilepsies are classified in five ways:

1) By their first cause (or etiology).

2) By the observable manifestations of the seizures,

known as semiology.

3) By the location in the brain where the seizures originate.

4) As a part of discrete, identifiable medical syndromes.

5) By the event that triggers the seizures, such as reading

or music

Seizure types are organized firstly according to whether the

source of the seizure within the brain is localized (partial or

focal onset seizures) or distributed (generalized seizures).

1- Partial Seizures:-

The source of the seizure within the brain is localized

They are further divided on the extent to which awareness is

affected.

a- If it is unaffected, then it is a simple partial seizure;

(Retain of consciousness).

b- Otherwise it is a complex partial (psychomotor) seizure.

(Loss of consciousness).

2- Generalized Seizures:- A partial seizure may spread within the brain - a process known

as secondary generalization.

Generalized seizures are divided according to the effect on the

body but all involve loss of consciousness.

a- Petit mal epilepsy (Absence Seizures ).

Loss of consciousness without spasm or convulsions.

b- Grand mal epilepsy.

Involve muscle activity

myoclonic, clonic, tonic, tonic-clonic, and atonic seizures.

Mechanism of action of antiepileptic drugs:- Conventional antiepileptic drugs block sodium channels or

enhance ɣ-aminobutyric acid (GABA) function (the main

inhibitory neurotransmitter). Several antiepileptic drugs have

multiple or uncertain mechanisms of action.

II- Anticonvulsant drugs Antiepileptic

drugs

Some members of barbiturates show antiepileptic activity.

(Phenobarbital, Mephobarbital, metharbital,..)

* Barbexaclone (Maliasm®)

A salt compound of Phenobarbital and levo-propylhexdrine

(adrenergic agonist), which prevents the hypnotic effect of

phenobarbital and thus used only for its antiepileptic effect.

NH

NH

O

O O

NH

CH3

CH3

A- Barbiturates

By ring contraction the antiepileptic activity is increased.

NH

NH

O

O O

R 1

R 2O

NH

NH

NHR

2

R 1

OO NH

O

R 2

R 1

OO NH

R 2

R 1

OO

Replacement of of

1- NH 2- O 3- CH

Imidazolidinedione

Derivatives (Hydantoin)Oxazolidinedione

Derivatives

Pyrrolidinedione

(Succinamide) Derivatives

Barbituratesby

1- Phenytoin

B- Hydantoin

NH

NH

OO

5,5-diphenylimidazolidine-2,4-dione

Imidazolidinedione Derivatives

Mechanism of action:- Phenytoin acts through blocking sustained high frequency repetitive

firing of action potentials. This is accomplished by reducing the

amplitude of sodium-dependent action potentials through

enhancing steady state inactivation.

Sodium channels exist in three main conformations

1.Resting state 2.Open state 3.Inactive state.

Phenytoin binds preferentially to the inactive form of the sodium

channel.

Sodium channels are

1.Closed channels 2.Open channels

3.inactive channel (phenytoin effect)

The mechanism of action of phenytoin sodium.

Used for the treatment of epilepsy (alone or in combiantion).

Comital® (Phenytoin + Mephobarbital)

Comital-L® (Phenytoin + Mephobarbital + Phenobarbital)

Uses:-

It has a narrow therapeutic index, thus used in combination.

Disadvantages:-

Synthesis:-

OH

O OEt

O

NH2

NH2

NH

NH

OO

+

Non-aqueous titration as acid (Compound + AgNO3 in

pyridine, the liberated nitric acid is titrated with NaOH

Assay:-

2- Fosphenytoin

N

NH

OO

O

POH

OH

O

(2,5-dioxo-4,4-diphenyl-imidazolidin-1-yl)

methoxyphosphonic acid

Fosphenytoin is a water-soluble phenytoin

prodrug used only in hospitals for the

treatment of epileptic seizures.

Include rash, severe allergic reactions, drug-induced gingival

enlargement, hypertrichosis, exfoliative dermatitis, pruritis,

hirsuitism, drug-induced lupus, teratogenic and carcinogenic effects.

Side effects:-

Activity:-

Off-label use of Fosphenytoin.

2- Ethotoin

N

NH

OO

CH2-CH

3

3-ethyl-5-phenyl-

imidazolidine-2,4-dione

3- Mephenytoin

N

NH

OO

CH3

CH3-CH

2

3-ethyl-5-phenyl-

imidazolidine-2,4-dione

Used for tonic-clonic and partial

complex seizures.

Ethotoin lacks phenytoin's side effects

of gingival hyperplasia and hirsutism,

however it is less effective.

Mephenytoin is more toxic and was

only considered after other less toxic

anticonvulsants had failed.

It can cause potentially fatal blood

dyscrasia in 1% of patients.

1- Trimethadione

C- Oxazolidinedione Derivatives

N

O

OO

CH3

CH3

CH3

3,5,5-trimethyl-oxazolidine-2,4-dione

It is most commonly used to treat epileptic conditions that are

resistant to other treatments.

If administered during pregnancy, fetal trimethadione syndrome

may result causing facial dysmorphism (short upturned nose,

slanted eyebrows), cardiac defects, intrauterine growth

retardation (IUGR), and mental retardation.

Fetal trimethadione syndrome

2- Paramethadione

N

O

OO

CH3

CH3

CH3

5-ethyl-3,5-dimethyl-oxazolidine-2,4-dione

It is used for treatment of absence epilepsy.

It is associated with fetal trimethadione syndrome, which is

also known as paramethadione syndrome

N

O

OO

CH3

CH3

CH3

OH

O

CH3

CH3

OEt

O

NH2

NH2

[(CH3)

2SO

4]

Trimethadione

+1- Condensation

2- Methylation

Synthesis:-

3- Ethadione

N

O

OO

CH3

CH3

CH3

3-ethyl-5,5-dimethyl-oxazolidine-2,4-dione

It is used for treatment of epilepsy.

N

O

OO

CH3

CH3

CH3

OH

O

CH3

OEt

CH3

O

NH2

NH2

[(CH3)

2SO

4]

Paramethadione

+1- Condensation

2- Methylation

Synthesis:-

D- Succinimide Derivatives

NH

OONH

O

OH

O

OH

Pyrrolidine Pyrrolidinedione

SuccinimideSuccinic acid

They are less toxic and more potent than Oxazolidinediones.

They are used for treatment of absence epilepsy.

Pyrrolidinedione

Derivatives

Synthesis:-

NOO

CH3

H3C-NH

2

O

OH

O

OH

Phenylsuccinic acid

Methyl amine

Phensuximide

1- Phensuximide

NOO

CH3

1-methyl-3-phenyl-pyrrolidine-2,5-dione

Synthesis:-

NOO

CH3

CH3

H3C-NH

2

O

OH

O

OH

CH3

Methyl amine

Methuximide

NOO

CH3

CH3

1,3-dimethyl-3-phenyl-pyrrolidine-2,5-dione

More potent than Phensuximide and it is

used for treatment of absence epilepsy.

The has long duration of action due to its

pharmacologically active metabolite, N-

desmethylmethsuximide.

2- Mesuximide

Synthesis:-

NOO

CH3

CH3

CH3

H3C-NH

2

O

OH

O

OH

CH3

CH3

Methyl amine

Ethosuximide

3-ethyl-3-methyl-pyrrolidine-2,5-dione

3- Ethosuximide

NH

OO

CH3

CH3

Most active succinimide derivative and it

is used for treatment of absence epilepsy.

Could be used in combination with

phenoparpital or phenytoin for treatment

of petit mal and grand mal epilepsy.

Other Anticonvulsants

Carbamazepine is typically used for the

treatment of epilepsy and neuropathic pain.

1- Carbamazepine (Tegretol®)

N

O NH2

a- Carboxamides

Carbamazepine stabilizes the inactivated state of Voltage-gated

sodium channels, making fewer of these channels available to

subsequently open. This leaves the affected cells less excitable until

the drug dissociates.

Carbamazepine has also been shown to potentiate GABA receptors.

Mechanism of action :-

Common adverse effects may include drowsiness, headaches and

migraines, motor coordination impairment, and/or upset stomach.

Less common side-effects may include cardiac arrhythmias, and blurry

or double vision anemia or agranulocytosis.

Side effects:-

Synthesis:-

N

O NH2

N

H

NH3 / EtOH

O

Cl Cl

N

O NH2

N

O NH2

O

N

O NH2

OHOH

Carbamazepine

Epioxidation Epioxide

Hydrase

10,11-epioxide

(Active metabolite)

10,11-trans-diol

(inactive metabolite)

Metabolism:-

Oxcarbazepine is an anticonvulsant and mood-stabilizing drug,

used primarily in the treatment of epilepsy.

It is also used to treat anxiety and mood disorders.

2- Oxcarbazepine

N

O NH2

O

N

O NH2

OH

Metabolism

Oxcarbazepine Eslicarbazepine

(Active metabolite)

Oxcarbazepine is considered as a prodrug which is activated to

Eslicarbazepine in the liver

Oxcarbazepine acts by the same mechanism as Carbamazepine

Gabapentin was originally developed to treat epilepsy, and currently

is also used to relieve neuropathic pain.

1- Gabapentin

O

OHNH

2

O

OHNH

2

GABA Gabapentin

b- GABA Analogs

Gabapentin interacts with voltage-sensitive calcium channels in

cortical neurons. Gabapentin increases the synaptic concentration of

GABA, enhances GABA responses at non-synaptic sites in

neuronal tissues, and reduces the release of mono-amine

neurotransmitters.

Mechanism of action :-

Activity:-

Off-label use of Gabapentin.

2- Vigabatrin

O

OH

NH2

Mechanism of action :-

Vigabatrin is an irreversible suicide inhibitor of gamma-

aminobutyric acid transaminase (GABA-T), the enzyme

responsible for the catabolism of GABA, which increases

the level of GABA in the brain.

(RS)-4-aminohex-5-enoic acid

3- Gabaculine

O

OHNH

2

(RS)-5-amino-1-cyclohexa-1,3-

dienecarboxylic acid

Valproic acid could be used as an anticonvulsant and mood-

stabilizing drug, primarily in the treatment of epilepsy,

bipolar disorder and prevention of migraine headaches.

Could be used as acid, sodium salt (sodium valproate), or a

mixture of the two (valproate semisodium).

1- Valproic acid (Depakene ®) O

OH

c- Fatty acids

2-Propylpentanoic acid

Synthesis:- O

OHC

N

NaOH

Mechanism of action :-

The mechanism of action of valproate is not fully understood.

Its anticonvulsant effect is attributed to the blockade of voltage-

dependent sodium channels and increased brain levels of gamma-

aminobutyric acid (GABA).

2- Progabide OH

FN

NH2

O

Cl

Mechanism of action :-

Progabide is a prodrug of gamma-aminobutyric acid (GABA).

Progabide has been investigated for

many diseases besides epilepsy,

including Parkinson's disease,

schizophrenia, clinical depression,

and anxiety disorder.

CNS depressants

III- Anxiolytic drugs

Anxiety is an unpleasant state of inner turmoil, often

accompanied by nervous behavior, such as pacing back and

forth, somatic complaints.

Anxiety is a mood. When it becomes a mental disorder, that

is, characterized by excessive, uncontrollable and often

irrational worry about everyday things that is

disproportionate to the actual source of worry, it is

diagnosed as generalized anxiety disorder.

Minor

Tranquilizers

Anxiety is distinguished from fear, which is an appropriate

cognitive and emotional response to a perceived threat and

is related to the specific behaviors of fight-or-flight

responses, defensive behavior or escape. Anxiety occurs in

situations only perceived as uncontrollable or unavoidable,

but not realistically so.

David Barlow defines anxiety as "a future-oriented mood

state in which one is ready or prepared to attempt to cope

with upcoming negative events," and that it is a distinction

between future and present dangers which divides

anxiety and fear.

In a 2011 review of the literature, fear and anxiety were said

to be differentiated in four domains:

1. Duration of emotional experience.

2. Temporal focus.

3. Specificity of the threat.

4. Motivated direction.

Fear is defined as short lived, present focused, geared

towards a specific threat, and facilitating escape from threat;

while anxiety is defined as long acting, future focused,

broadly focused towards a diffuse threat, and promoting

excessive caution while approaching a potential threat and

interferes with constructive coping.

An anxiolytic (also antipanic or antianxiety agent) is a

medication or other intervention that inhibits anxiety.

Anxiolytic medications have been used for the

treatment of anxiety and its related psychological

and physical symptoms.

Some recreational drugs such as beverage alcohols

(which contain ethanol) induce anxiolysis.

Bright light therapy and other interventions have also

been found to have an anxiolytic effect.

Beta-receptor blockers such as propranolol and

oxprenolol, although not anxiolytics, can be used to

combat the somatic symptoms of anxiety.

Classes of Anxiolytic drugs

Benzodiazepine are psychoactive drugs with the core chemical

structure is the fusion of a benzene ring and a diazepine ring.

N

NR 7

R 1 R

2

R 2`

1 2

3

456

7

8

9

1`

2`

3`4`

5`

6`

A- Benzodiazepine

Benzodiazepines enhance the effect of GABA at the GABAA

receptor, resulting in sedative, hypnotic (sleep-inducing),

anxiolytic, euphoric, anticonvulsant, and muscle relaxant

properties.

These properties make benzodiazepines useful in treating

anxiety, insomnia, agitation, seizures, muscle spasms, alcohol

withdrawal and as a premedication for medical or dental

procedures.

Benzodiazepines are categorized as either short-, intermediate-,

or long-acting.

Short- and intermediate-acting benzodiazepines are

preferred for the treatment of insomnia.

Longer-acting benzodiazepines are recommended for the

treatment of anxiety.

Benzodiazepines work by increasing the efficiency of GABA,

to decrease the excitability of neurons.

This reduces the communication between neurons and, therefore,

has a calming effect on many of the functions of the brain.

Mechanism of action

Side effects

They include drowsiness, dizziness, and decreased alertness and

concentration. Lack of coordination, impairment of driving

skills, decreased libido and erection problems.

Depression and disinhibition may emerge. Hypotension and

suppressed breathing may be encountered with intravenous use.

Less common side effects include nausea and changes in

appetite, blurred vision, confusion, euphoria, depersonalization

and nightmares.

Tolerance, dependence and withdrawal

Chronic use of benzodiazepines result in the development of

tolerance and dependence.

Discontinuation of benzodiazepines or abrupt reduction of the

dose, even after a relatively short course of treatment (three to

four weeks), may result in two groups of symptoms rebound

and withdrawal.

Rebound symptoms are the return of the symptoms for which

the patient was treated but worse than before.

Withdrawal symptoms are the new symptoms that occur when

the benzodiazepine is stopped. They include insomnia, gastric

problems, tremors, agitation, fearfulness, and muscle spasms.

The less frequent effects are irritability, sweating,

depersonalization, derealization, hypersensitivity to stimuli,

depression, suicidal behavior, psychosis and seizures.

The symptoms of benzodiazepines overdose may include;

drowsiness, slurred speech, nystagmus, hypotension, ataxia,

coma, respiratory depression, and cardiorespiratory arrest.

Combining benzodiazepines with alcohol, opiates or tricyclic

antidepressants markedly raises the toxicity.

Overdose

Because of their muscle relaxant action, benzodiazepines in

people with myasthenia gravis, sleep apnea, bronchitis, and

Chronic obstructive pulmonary disease (COPD).

Individuals with a history of alcohol, opioid and barbiturate

abuse should avoid benzodiazepines, as there is a risk of life-

threatening interactions with these drugs

Contraindications

Chlordiazepoxide was the first benzodiazepine to be synthesized

and the discovery of chlordiazepoxide was by pure chance.

It has a medium to long half-life but its active metabolite

(Desmethyldiazepam / Nordiazepam) has a very long half-life.

The drug has anticonvulsant, anxiolytic, hypnotic and skeletal

muscle relaxant properties.

N

N+

Cl

NH

O

Chlordiazepoxide

Chlordiazepoxide

N

NCl

OH

Nordiazepam

(active metabolite)

Diazepam is mainly used to treat anxiety, insomnia, and

symptoms of acute alcohol withdrawal.

It is also used as a premedication for inducing sedation, and

anxiolysis before certain medical procedures (e.g., endoscopy).

Five Types of benzodiazepine

i- 2- Keto / benzodiazepines

1- Diazepam (Valium®)

N

NCl

OCH

3

Diazepam is a long-acting "classical"

benzodiazepine.

It is metabolized into several active

metabolites.

Synthesis:-

N

NCl

OCH

3

OCl

NH2

O

O

NH2

CH3

(MeO)2SO

2+

1- Condensation

2-

Diazepam

2- Prazepam (Centrax®)

N

NCl

O Prazepam is a prodrug for nordiazepam

which is responsible for most of the therapeutic

activity of prazepam rather than prazepam

itself.

It is also metabolised into 3-hydroxyprazepam

which is further metabolised into oxazepam.

3- Flurazepam (Dalmane®)

N

NCl

O

NCH

3

CH3

F

Flurazepam is a long-acting

"classical" benzodiazepine.

Flurazepam generates an active

metabolite with a very long elimination

half-life of 40–250 hours.

Flurazepam is a unique benzodiazepine in that it is a partial

agonist of benzodiazepine receptors whereas other benzo-

diazepines are full agonists of benzodiazepine receptors.

ii- 3-Hydroxy / benzodiazepines

1- Temazepam (Restoril®)

N

NCl

OCH

3

OH

Temazepam is an intermediate-acting 3-

hydroxy hypnotic of the benzodiazepines.

It is a metabolite of diazepam.

2- Oxazepam (Noripam®)

N

NCl

OH

OH

Oxazepam is a metabolite of diazepam,

prazepam and temazepam.

Both have moderate amnesic, anxiolytic,

anticonvulsant, hypnotic, sedative and

skeletal muscle relaxant properties.

3- Lormetazepam

N

NCl

OCH

3

Cl

OH

Lormetazepam is a drug which is a short

to intermediate acting 3-hydroxy

benzodiazepine derivative.

It possesses hypnotic, anxiolytic,

anticonvulsant, sedative and skeletal

muscle relaxant properties..

Synthesis:-

N

NCl

OCH

3

Cl

OHAc2O

N

NCl

OCH

3

Cl

2- NaOH

1-

Lormetazepam

4- Lorazepam

N

NCl

OH

Cl

OH

Lormetazepam is a high-potency,

intermediate-duration, 3-hydroxy

benzodiazepine drug.

It possesses hypnotic, anxiolytic,

anticonvulsant, sedative and skeletal

muscle relaxant properties.

Synthesis:-

N

NCl

OH

Cl

OHAc2O

N

NCl

OH

Cl

2- NaOH

1-

Lorzepam

iii- 7-Nitro / benzodiazepines

1- Nitrazepam

N

N

OH

O2N

Nitrazepam possesses hypnotic, anxiolytic,

anticonvulsant, sedative and skeletal

muscle relaxant properties.

2- Nimetazepam

Nimetazepam is an intermediate-acting 7-

nitro benzodiazepine derivative.

it is partially metabolised to Nitrazepam .

N

N

OCH

3

O2N

3- Clonazepam

N

N

OH

O2N

Cl

4- Flunitrazepam

N

N

OCH

3

O2N

F

iv- Triazolo / benzodiazepines

1- Triazolam

NCl

Cl

NN

NCH3

Triazolam possesses hypnotic, anxiolytic,

anticonvulsant, sedative and skeletal

muscle relaxant properties.

Synthesis:-

NCl

Cl

NN

NCH3

NCl

Cl

NS

O

NH

NH2

NCl

Cl

NNH

NH

CH3

O

Cyclization

at 250 Co

2- Alprazolam

NCl

NN

NCH3

3- Estazolam

NCl

NN

N

v- Imidazo / benzodiazepines

1- Midazolam

NCl

F

N

NCH3

Midazolam possesses potent anxiolytic,

amnestic, hypnotic, anticonvulsant, skeletal

muscle relaxant, and sedative properties.

2- Climazolam

NCl

Cl

N

NCH3

Triazolam is used in veterinary medicine

for anaesthetising animals.

2,3-benzodiazepine derivatives

1- Tofisopam

N

N

CH3

CH3

OCH

3

OCH

3

O

CH3 O

CH3

Midazolam, like other benzodiazepines,

possesses anxiolytic properties but unlike

other benzodiazepines it does not have

anticonvulsant, sedative, skeletal muscle

relaxant, motor skill-impairing or amnestic

properties.

SAR of Benzodiazepines

N

NR 7

R 1 R

2

R 2`

1 2

3

456

7

8

9

1`

2`

3`4`

5`

6`

1. Benzodiazepine nucleus is essential for activity.

2. Substitution on N-1 should be with small alkyl group.

3. Carbonyl function at C-2 gives optimal activity.

4. Substitution at C-3 with OH group reduces the duration,

while alkyl substituents decreases the activity.

SAR of Benzodiazepines

5. Double bond between C-4 and C-5 is important for activity,

thus saturation of this double bond decreases affinity.

6. Phenyl substituent at C-5 promotes activity. ortho mono or

disubstituent with electron withdrawing groups increase the

potency, while p-substitution decreases it.

7. Substitution at C-6, C-8, or C-9 decrease the activity.

8. Substitution with electron withdrawing group at C-7 (mainly

Chloride) increases the anxiolytic activity.

9. 2,3-benzodiazepine derivatives maintain the anxiolytic effect

but decrease other CNS depressant properties (Tofisopam).

Buspirone functions as a serotonin 5-HT1A receptor partial

agonist, activation of these receptors results in decreased

neuronal activity.

N

N N

NN

O

O

B- Serotonergic antidepressants

a) Serotonin 5HT1A- Receptor agonists

1- Buspirone (Buspar®)

The first arylpiperazine

approved for clinical use.

It is also used as antidepressant

Classes of Anxiolytic drugs

Synthesis:-

N

N N

NN

O

O

O

O

O

N

N N

NNH

2

SAR:-

1. The aryl portion is typically a phenyl, substituted phenyl, or a

heteroaryl group e.g pyrimidinyl.

2. The intact piperazine ring gives optimal binding to 5HT1A-receptor.

3. A spacer that separates the N4-nitrogen atom of the piperazine and

the terminus should be a chain of 2-5 Carbon atoms.

4. The terminus is typically an amide or imide, but it is not required for

receptor binding

O

O

O

NH

F

b) Serotonin Re-uptake inhibitors

1- Paroxetine (Paxil®)

Paroxetine is used to treat major depression,

obsessive-compulsive disorder, panic

disorder, social anxiety, and generalized

anxiety disorder.

Synthesis:-

O

O

OH

O

O

O

NH

F

NH

F

OH

+- DCC

N

NH

S

N

O

OCH3

C) Miscellaneous anxiolytics

1- Afobazole

Afobazole produces anxiolytic and

neuroprotective effects without any

sedative or muscle relaxant actions.

This makes it more selective in action

than many currently used drugs.

2- Meprobamate

O

NH2

O O NH2

O

CH3

CH3

Meprobamate is used as an anxiolytic drug.

It was the best-selling minor tranquilizer for

a time.

It is a known drug of abuse and dependence.

4- β-Blockers

O NH

CH3

CH3

OH

Propranolol

Officially, β-blockers are not

approved for anxiolytic use by

the FDA.

3- Some Antihistaminics

N

NO

OH

Cl

Hydroxyzine

Hydroxyzine is classified as an

antihistamine, antipsychotic,

and anxiolytic.

5- future drugs

CL-218,872

NN

N

NF

F

F

CH3

CL-218,872 has sedative, hypnotic,

anxiolytic, and anticonvulsant.

L-838,417

O NN

N

N

N

N N

CH3

CH3

CH3

CH3

F

F

L-838,417 is an anxiolytic drug

used in scientific research.

CNS depressants

IV- Skeletal Muscle Relaxants

A muscle relaxant is a drug which affects skeletal muscle

function and decreases the muscle tone.

It may be used to decrease symptoms such as muscle spasms,

pain, and hyperreflexia.

The term "muscle relaxant" is used to refer to two major

therapeutic groups: Neuromuscular blockers and Spasmolytics.

Neuromuscular blockers act by interfering with transmission at

the neuromuscular end plate and have no central nervous system

(CNS) activity.

They are often used during surgical procedures and in intensive

care and emergency medicine to cause temporary paralysis.

Spasmolytics, also known as "centrally acting" muscle

relaxants, are used to decrease musculoskeletal pain and spasms

and to reduce spasticity in a variety of neurological conditions.

While both neuromuscular blockers and spasmolytics are often

grouped together as muscle relaxants, the term is commonly used

to refer to spasmolytics only.

Spasmolytics are commonly prescribed for low back pain or

neck pain, fibromyalgia, tension headaches and myofascial pain

syndrome.

Muscle relaxants are not recommended as first-line agents; in

acute low back pain, they are not more effective than

paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs),

and in fibromyalgia they are not more effective than

antidepressants.

Nevertheless, some (low-quality) evidence suggests muscle

relaxants can add benefit to treatment with NSAIDs. In general,

no high-quality evidence supports their use. No drug has been

shown to be better than another, and all of them have adverse

effects, particularly dizziness and drowsiness. Concerns about

possible abuse and interaction with other drugs, especially if

increased sedation is a risk, further limit their use. A muscle

relaxant is chosen based on its adverse-effect profile, tolerability,

and cost. The following classes could be used as Muscle

relaxants

Benzodiazepine derivatives

α2-Adrenergic receptor agonists

Hydantoin derivatives

O

NH

O O NH2

O

CH3

CH3

CH3

CH3

Skeletal Muscle Relaxants

1- Carisoprodol (Soma®)

Carisoprodol is available by itself

or mixed with aspirin, codeine

and/or caffeine.

Carisoprodol has been withdrawn

due to its abuse potential as a

prodrug of Meprobamate.

Synthesis:-

O

NH

O O NH2

O

CH3

CH3

CH3

CH3

O

NH

O OHCH3

CH3

CH3

CH3

O

O NH2

CH3

+- DCC

N

CH3

CH3

2- Cyclobenzaprine (Amrix®)

Cyclobenzaprine, is a muscle relaxant

medication used to relieve skeletal

muscle spasms and associated pain in

acute musculoskeletal conditions.

Synthesis:-

N

CH3

CH3

O

N

CH3

CH3

BrMg+1- Hydrolysis (HCl)

2- Dehydration (-H2O)

CH3

CH3

OO

NH

O

3- Metaxalone (Skelaxin®)

Cyclobenzaprine, is a muscle relaxant

used to relax muscles and relieve pain

caused by strains, sprains, and other

musculoskeletal conditions.

Synthesis:-

CH3

CH3

OO

NH

O

CH3

CH3

OH

O

NH

O Cl + - HCl

OCH

3

OOH

O

NH2

O

4- Methocarbamol (Robaxin®)

Methocarbamol is a central muscle

relaxant used to treat skeletal muscle

spasms.

Synthesis:-

Mechanism of action:-

Methocarbamol acts as GABAA receptor agonist resulting in an

exaggerated effect of GABA which occurs naturally in the brain.

OCH

3

OOH

O

NH2

O

OCH

3

OOH

OH

COCl2

NH3

1-

2-

O

NH

O

Cl

5- Chlorzoxazone (Paraflex®)

Chlorzoxazone is a centrally acting muscle

relaxant used to treat muscle spasm and the

resulting pain or discomfort.

Could be used in combination with

Paracetamol, but it is not recommended

due to increased risk of hepatotoxicity.

Synthesis:-

O

NH

O

Cl

OH

NH2

ClCOCl

2

O

CH3

NCH

3

CH3

6- Orphenadrine (Norgesic®)

Orphenadrine is an anticholinergic drug of

the ethanolamine antihistamine class with

prominent CNS and peripheral actions

used to treat painful muscle spasms, other

similar conditions, as well as the treatment

of some aspects of Parkinson's Disease.

Synthesis:-

O

CH3

NCH

3

CH3

Cl

CH3

NCH

3

CH3

OH+-HCl

CNS depressants

V- Antipsychotic Agents

Antipsychotics are a class of psychiatric medication primarily

used to manage psychosis (including delusions, hallucinations, or

disordered thought), in particular in schizophrenia and bipolar

disorder.

Major

Tranquilizers

Neuroleptics

Antipsychotics could be used for the treatment of.

- Schizophreni - Bipolar disorder

- Dementia - Unipolar Depression

- Obsessive-compulsive disorder

Medical uses

Mechanism of action

It was proven that less dopamine released in the prefrontal cortex

in the brain, and excess dopamine released from all other

pathways, is linked to psychotic experiences, caused by abnormal

dopaminergic function as a result of patients suffering from

schizophrenia or bipolar disorder.

All antipsychotic drugs tend to block D2 receptors in the dopamine

pathways of the brain.

Antipsychotics (in particular atypical neuroleptics) also antagonize

5-HT2A receptors which have been associated with schizophrenia

and other psychoses, including depression.

Classification of Antipsychotics

I- First Generation Typical antipsychotic

A- Butyrophenone derivatives

1- Haloperidol

N

O

F

OH

Cl

Haloperidol

Haloperidol is an antipsychotic medication used in the

treatment of schizophrenia and acute psychosis.

It functions as an inverse agonist of dopamine.

Side effects:- include Dystonia, Muscle rigidity,

hypotension, Dry mouth and Blurred vision.

It is a potent and long-

acting neuroleptic, used as

an antipsychotic in the

treatment of schizophrenia.

2- Bromperidol

N

O

F

OH

Br

Bromperidol

N

O

F

N

NHO

Droperidol

3- Droperidol

It is an antipsychotic.

medication used in the

treatment of schizophrenia.

It is also has antiemetic and

anesthesia .

Synthesis:-

N

O

F

N

NHO

O

F

Cl NH

N

NHO

Droperidol

+

- HCl

SAR:-

The attachment of the 3ry N-atom to the fourth C-atom of

butyrophenone is essential for activity.

Keto- function is important activity.

F atom in p-position gives the optimum activity.

F atom could be replaced by Methoxy (OCH3) group

without significant change in the activity.

Variations in length of the butyl chain leads to loss of the

activity.

Decanoate ester is a depot injectable form which is used as

maintenance therapy for 4 – 6 weeks

N

O

F

OH

Cl

B- Diphenylbutylpiperidine derivatives

1- Penfluridol

N

F

OH

CF3

F

Cl

Penfluridol

Penfluridol is an antipsychotic medication used in the

treatment of schizophrenia and acute psychosis.

Side effects:- include hypokinesia, hyperhidrosis, speech

disorder, hypotension, dry mouth and blurred vision.

2- Pimozide (Orap®)

N

F

F

NNH

O

Pimozide

Pimozide is used in its oral preparation in schizophrenia and

chronic psychosis.

Side effects:- include hypokinesia, hyperhidrosis, speech

disorder, hypotension, dry mouth and blurred vision.

Synthesis:-

N

F

N

NHO

F

F

Cl

F

NH

N

NHO

Pimozide

+

- HCl

C- Phenothiazines derivatives

1- Chlorpromazine (Largactil®)

N

S

Cl

NCH

3

CH3Chlorpromazine

It is used in the treatment of both acute and chronic

psychoses, including schizophrenia and the manic phase of

bipolar disorder.

Side effects:- include Sedation, weight gain, orthostatic

hypotension, dry mouth and blurred vision.

N

S

Phenothiazine

Abbreviated CPZ.

Chlorpromazine is classified as a low-

potency typical antipsychotic.

Synthesis:-

NH

S

Cl

N

CH3

CH3

Cl

N

S

Cl

NCH

3

CH3

+

- HCl

Chlorpromazine

2- Levomepromazine

N

S

O

N

CH3

CH3

CH3

Levomepromazine

3- Trifluoperazine

N

S

F3C

N

NCH

3Trifluoperazine

It is a low-potency antipsychotic

(approximately half as potent as

chlorpromazine).

It has a strong analgesic, hypnotic and

antiemetic properties..

4- Chlorpromazine (Largactil®)

More potent than CPZ about 50 times.

Its primary uses in medicine is in the treatment of

schizophrenia.

Fluphenazine decanoate used as depot injectable form for

prolonged duration.

Side effects:- include Sedation, weight gain, orthostatic

hypotension, dry mouth and blurred vision.

N

S

F3C

N

NOH

Fluphenazine

Synthesis:-

N

S

F3C

N

NOH

N

S

F3C

N

NH

OBr

CH3

O

Fluphenazine

1- (-HBr)

2- Hydrolysis

+

SAR:-

SNNN

H3C

H R

Site A

Site B Site C

X

It is postulated that phenothiazines interact with the receptor

at three distinct sites, A; B; and C.

The highest degree of specificity is required for site B

followed by C then A.

SAR:- Site A: The side chain basic nitrogen

NN

H3C

Site A

Bulky disubstitution reduce the activity.

If the substituent is a part of a ring the activity is retained.

Quaternization of the nitrogen atom reduce lipid solubility

resulting in decreased penetration to the brain and loss of

central activity.

In case of piperazine derivatives, the duration of action could

be increased by esterification of the N-hydroxy alkyl

substituent with long chain fatty acids (Fluphenazine

decanoate).

SAR:- Site B: The side chain

Three C-atoms chain is the optimal length for activity.

Two C-atoms chain results in moderate CNS activity,

predominant antihistaminic activity.

Free rotation of the side chain is necessary: Nonsubstituted β-

carbon gives best CNS activity, whereas introduction of

methyl substituent enhances the antihistaminic activity.

H R

Site B

N

S

CH2-CH-

Cl

N

CH3

CH3CH

3

Promethazine

(antihistaminic and antiemetic)

SAR:- Site C: The phenothiazine nucleus

SN

Site C

X

The phenothiazines are folded along the N-S

axis with the two flat benzene rings at right

angles.

Only position 2 is susceptible for substitution. Any

substitution at positions 1,3, or 4 or simultaneous substitution

on both rings give inactive compounds.

The nature of X substituent:

• Electron withdrawing (Cl, CF3, SO2N(CH3)2), will

increase the activity (CF3 is the optimal).

• Thioalkyl and acyl substituents give active compounds

with least side effects.

Ionizable groups e.g. OH reduce the activity.

D- Thioxanthenes derivatives

1- Chlorprothixene S

Cl

NCH

3

CH3Chlorprothixene

O SNH

NH

N

NH

O

O

Xanthene ThioxantheneXanthine

It is the prototype of this class.

It is used for treatment of schizophrenia.

It is also has anxiolytic and

anticholinergic effects.

Synthesis:-

S

Cl

NCH

3

CH3

S

Cl

HN-(CH3)

2

Chlorprothixene

S

F3C

N

NOH

Flupentixol

2- Flupentixol

It is used as a long-acting injection

given once in every two or three weeks

to individuals with schizophrenia.

It is also used in low doses as an

antidepressant.

Classification of Antipsychotics

II- Second Generation Atypical antipsychotic

1- Loxapine O

N

N

N

Cl

CH3

Loxapine

Loxapine is a typical antipsychotic

medication, used primarily in the

treatment of schizophrenia.

Loxapine may be metabolized by

N-demethylation to the active

metabolite Amoxapine, which is

also a tetracyclic antidepressant.

O

N

N

NH

Cl

Amoxapine

Synthesis:-

O

N

N

N

Cl

CH3

NH

O N

NCH

3

Cl POCl3

Loxapine

2- Zotepine

Zotepine is an atypical antipsychotic drug

indicated for acute and chronic

schizophrenia.

Side effects:- Tachycardia, weight gain,

orthostatic hypotension and Palpitations.

S

Cl

O

N

CH3

CH3

Zotepine

3- Ziprasidone

Ziprasidone is approved by the FDA in 2001 for the treatment

of schizophrenia, and acute mania.

Ziprasidone is also used off-label for depression, bipolar

maintenance, mood disorders, anxiety and dementia,

NH

N

N

NS

O

ClZiprasidone

4- Risperidone

Risperidone is is an atypical antipsychotic drug indicated for

acute and chronic schizophrenia.

It is a dopamine antagonist possessing antiserotonergic,

antiadrenergic and antihistaminergic properties.

N

N

N

NO

CH3

N

OF

Resperidone

5- Paliperidone

N

N

N

NO

CH3

N

OF

OH

Paliperidone

also known as 9-hydroxyrisperidone

A general anaesthetic is a drug that has the ability to

bring about a reversible loss of consciousness.

Anesthesiologists administer these drugs to induce or

maintain general anaesthesia to facilitate surgery.

Some of these drugs are also used in lower dosages

for pain management.

The biological mechanism(s) of the action of general

anaesthetics are not well understood.

CNS depressants

VI- General anaesthetics

Drugs given to induce or maintain general anaesthesia

can be either as gases or vapours (inhalational

anaesthetics), or as injections (intravenous anaesthetics

or even intramuscular).

It is possible to deliver anaesthesia solely by inhalation

or injection, but most commonly the two forms are

combined, with an injection given to induce anaesthesia

and a gas used to maintain it.

VI- General anaesthetics

I- Inhalational anaesthetic

Inhalational anaesthetic substances are either volatile

liquids or gases, and are usually delivered using an

anaesthesia machine.

An anaesthesia machine allows composing a mixture of

oxygen, anaesthetics and ambient air, delivering it to the

patient and monitoring patient and machine parameters.

Liquid anaesthetics are vapourized in the machine.

All of these agents share the property of being quite

hydrophobic.

A- Ethers

It is a colorless, highly volatile flammable liquid.

It is commonly used as a solvent and was once

used as a general anesthetic.

It has narcotic properties and has been known to

cause temporary psychological addiction.

O CH3

CH3

Diethyl ether

1- Diethyl ether

Methoxypropane was used as an alternative to

diethyl ether because of its greater potency.

As an anaesthetic it has been replaced by

modern halogenated ethers which are much less

flammable.

OCH

3CH

3

Methoxypropane

2- Methoxypropane

It is a highly fluorinated methyl ethyl ether used for

maintenance of general anesthesia.

It is a racemic mixture of (R) and (S) optical isomers

(enantiomers).

It has the most rapid onset and offset of the volatile anesthetic

drugs used for general anesthesia due to its low solubility in

blood.

Drawbacks: its low potency, its pungency and its high cost. It

may cause tachycardia and airway irritability when

administered at concentrations greater than 10 vol%.

F

O FF3C

F

Desflurane

3- Desflurane

(RS)- 2-(difluoromethoxy)-1,1,1,2-tetrafluoro-ethane

F

O FF3C

Cl

Isoflurane

4- Isoflurane

(RS)-2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane

Isoflurane is a halogenated ether used for inhalational

anesthesia.

It is completely nonflammable, (replaces the flammable

ethers).

Isoflurane is still frequently used for veterinary

anaesthesia.

It is a halogenated ether that was commonly used for

inhalational anesthesia.

It vaporizes readily, but is a liquid at room temperature.

Side effects:-

It produces a dose-related depression of myocardial contractility

with an associated decrease in myocardial oxygen consumption.

It has a nephrotoxic effect and cause acute renal failure.

lowers the threshold for seizures, (contraindicated with

epilepsy).

It is no longer in common use and is largely replacing halothane

as a general anesthetic.

F

O FF

Cl

F F

Enflurane

5- Enflurane

(RS)-2-chloro-1-(difluoromethoxy)-1,1,2-trifluoro-ethane

FOF3C

CF3

Sevoflurane

6- Sevoflurane

1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane

CH3

OCl

Cl

F F

Methoxyflurane

7- Methoxyflurane

2,2-dichloro-1,1-difluoro-1-methoxyethane

B- Haloalkanes

It is a potent anesthetic with a minimum alveolar

concentration.

It is not a good analgesic and its muscle relaxation

effect is moderate.

It is the only inhalational anesthetic agent

containing a bromine atom.

Br

ClF

F

F

Halothane

1- Halothane

Synthesis:-

Br

ClF

F

F

ClF

F

F

Br2,

Halothane

450 C

C- Others

It is commonly known as laughing gas due to the euphoric

effects.

It is a colourless, non-flammable gas, with a slightly sweet

odour and taste.

It is used in surgery and dentistry for its anaesthetic and

analgesic effects.

Nitrous oxide is most commonly prepared by careful heating

of ammonium nitrate, which decomposes into nitrous oxide

and water vapour

N N+

O

Nitrrous oxide1- Nitrous oxide

NH4NO

3 (S) H

2O (g) N

2O (g)+2

II- Injection anaesthetic

Injectable anaesthetics are used for the induction and

maintenance of a state of unconsciousness.

Anaesthetists prefer to use intravenous injections, as they

are faster, generally less painful and more reliable than

intramuscular or subcutaneous injections.

A- Barbiturates

Thiamylal Thiopental

NH

NH

O

O SNH

NH

O

O S

They are used commonly

in the induction phase of

general anesthesia.

B- Benzodiazepines

1- Midazolam NCl

F

N

NCH3

C- Neuroactive steroids

Neuroactive steroids (neurosteroids) rapidly alter neuronal

excitability through interaction with neurotransmitter-gated

ion channels.

Neurosteroids have a wide range of potential clinical

applications from sedation to treatment of epilepsy.

These compounds can act as allosteric modulators of

neurotransmitter receptors, such as GABAA.

1- Alfaxalone CH

3

CH3

HH

HOH

O

CH3

O

Alfaxalone

Alfaxalone is a neurosteroid

general anaesthetic.

It is used in veterinary anaesthesia

in both dogs and cats.

2- Minaxolone CH

3

CH3

HH

HOH

N

CH3

OCH

3

CH3

OCH3

Minaxolone

Alfaxalone is a neurosteroid

general anaesthetic.

D- Others

It could be used for neuroleptanalgesic anesthesia and

sedation in intensive-care treatment.

It is also has antiemetic and antipsychotic.

Side effects:- include Dysphoria, sedation, hypotension.

N

O

F

N

NHO

Droperidol

1- Droperidol

Ketamine is used in human and veterinary

medicine, primarily for the induction and

maintenance of general anesthesia.

Other uses include sedation in intensive care,

analgesia and treatment of bronchospasm.

Cl

N CH3

O

H

Ketamine

2- Ketamine (Ketalar®)

Synthesis:-

Cl

N CH3

O

H

Cl

N

CH3

OH

Ketamine

Ring expansion and rearrengement

Cl

N CH3

O

H

Esketamine

It is the S(+) enantiomer of the drug ketamine.

It is a general anaesthetic.

Esketamine is approximately twice as potent as racemic

ketamine.

As of July 2013, it is being tested in FDA clinical trials as

an antidepressant.

3- Esketamine

Fospropofol is a prodrug; it is metabolized

by alkaline phosphatases to an active

metabolite, propofol.

It is a water soluble of IV administration.

O

OP

O

O

O

CH3

CH3

CH3

CH3

Na+

Na+

Fospropofol

5- Fospropofol

Propofol is used for induction and

maintenance of general anesthesia.

It acts through potentiation of GABAA

receptor activity.

and also acting as a sodium channel

blocker

OH

CH3

CH3

CH3

CH3

Propofol

4- Propofol