CENTRAL NERVOUS SYSTEM AGENTS

OBJECTIVES
 To state the pharmacological action and uses of group of drugs.
 To recognize basic general chemical structure of particular group of drugs.
 To describe the importance of chemical and physical properties of each class of drugs.
 To identify the functional groups responsible for physical activity of a class.
 To describe the influence of chemical, structure and physical properties on the stability,
chemical reactivity and dosage form design.
 To describe the structure activity relationship, SAR, of each class.
 To illustrate structural modification in drug design as a method of obtaining better
pharmacological effects of eliminating undesired effects.
SEDATIVES, HYPNOTICS AND ANXIOLYTICS
a. Anxiolytics
They control anxiety and tension in mild mental illness neuroses) and mild depression. They are
used in anxiety disorders, e.g. panic disorders, post-traumatic stress disorders, phobias and
obsessive compulsive disorders.

Anxiety It is an emotional state, unpleasant in nature, associated with uneasiness, discomfort and
concern or fear about some defined or undefined future threat. Some degree of anxiety is a part of
normal life. Treatment is needed when it is disproportionate to the situation and excessive. Some
psychotics and depressed patients also exhibit pathological anxiety. Antianxiety drugs produce a restful
state of mind without interfering with normal mental or physical functions.
Antianxiety drugs:
1. Benzodiazepines - Diazepam Chlordiazepoxide Oxazepam Lorazepam, Alprazolam
2. Azapirones - Buspirone, Gepirone, Ispapirone
3. Antihitamines – Hydroxyzine, sedative.
4. β blocker- Propranolol

b. Sedatives
A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may
be produced. Sedation refers to decreased responsiveness to any level of stimulation (decreased
reaction time); is associated with some decrease in motor activity and ideation.

They may be used as pre-anesthesia treatment.

They cause calming, soothing effect without causing sleep.
c. Hypnotics
Hypnotic- A drug that induces and/or maintains sleep, similar to normal arousable sleep. This is not to
be confused with ‘hypnosis’ meaning a trans-like state in which the subject becomes passive and highly
suggestible.

The sedatives and hypnotics are more or less global CNS depressants with somewhat differing time-
action and dose-action relationships. Those with quicker onset, shorter duration and steeper dose-

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response curves are preferred as hypnotics while more slowly acting drugs with flatter dose-response
curves are employed as sedatives. However, there is considerable overlap; a hypnotic at lower dose may
act as sedative. Thus, sedation—hypnosis—general anaesthesia may be regarded as increasing grades of
CNS depression. Hypnotics given in high doses can produce general anaesthesia. However,
benzodiazepines (BZDs) cannot be considered nonselective or global CNS depressants like barbiturates
and others. Treatment of insomnia is the most important use of this class of drugs.

Increasing the dose of anxiolytics may cause sedation or hypnosis or a sedative may cause
hypnotic effect. This is because the anxiolytic, sedative or hypnotic effect of a drug may be
dependent on its dose or inherent potency. A particular class of drugs may have compounds of
varying applications as anxiolytics, sedatives or hypnotics depending on the individual drugs’
potency, duration of action among other properties.

Sedatives, hypnotics and anxiolytics may be used as muscle relaxants, anti-consultants, pre-
anesthesia medication and diagnostic aids in psychiatry.

1) Classification of sedative hypnotics: benzodiazepines, barbiturates, aldehydes, alcohols,

piperidine dione derivatives, cyclic ethers, e.g. paraldehyde, carbamic acids, esters,
quinazolones, alkylamine antihistamines, inorganic salts like bromides, ramelteon, a
melatonin receptor agonist is a newer hypnotic drug, Antiepileptic drugs

Atypical agents: azaspirodecadiones(azapirones), imidazopyridines, pyrazalopyrimidines,

cyclopyrrolones.
1. BENZODIAZEPINES
Chlordiazepoxide and diazepam were introduced around 1960 as antianxiety drugs. Since then this class
has proliferated and has replaced barbiturates as hypnotic and sedative as well, because
1. BZDs produce a lower degree of neuronal depression than barbiturates.
They have a high therapeutic index. Ingestion of even 20 hypnotic doses does not usually
endanger life—there is no loss of consciousness (though amnesia occurs) and patient can be
aroused; respiration is mostly not so depressed as to need assistance.
2. Hypnotic doses do not affect respiration or cardiovascular functions. Higher doses produce mild
respiratory depression and hypotension which is problematic only in patients with respiratory
insufficiency or cardiac/haemodynamic abnormality.
3. BZDs have practically no action on other body systems. Only on i.v. injection the BP falls (may be
marked in an occasional patient) and cardiac contractility decreases. Fall in BP in case of
diazepam and lorazepam is due to reduction in cardiac output while that due to midazolam is
due to decrease in peripheral resistance. The coronary arteries dilate on i.v. injection of
diazepam.
4. BZDs cause less distortion of sleep architecture; rebound phenomena on discontinuation of
regular use are less marked.
5. BZDs do not alter disposition of other drugs by microsomal enzyme induction.
6. They have lower abuse liability: tolerance is mild, psychological and physical dependence, drug
seeking and withdrawal syndrome are less marked.

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 7. A specific BZD antagonist flumazenil is available which can be used in case of poisoning.

They differ in absorption, duration of action and other pharmacokinetic factors.

Chlordiazepoxide- It was the first to be discovered.

Physico-chemical characteristics of benzodiazepines

1. Are unstable in light and oxygen because of excess electron contributed by the aromatic
rings and the hetero atoms.
2. They undergo degradation in aqueous solutions. Diazepam in aqueous solution
undergoes hydrolysis in water to give benzophenone.
Because of the above reasons, they should be protected from light, air and moisture.
Variations in physico-chemical characteristics contribute to differences in pharmacokinetic
properties of BDZs.
Most of them are lipophilic hence readily absorbed from the GIT. The more lipophilic ones enter
the CNS rapidly and have a faster onset of action.
The long activity ones are good for anxiety while short acting ones are better for insomnia.

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STRUCTURE ACTIVITY RELATIONSHIP
a. An aromatic ring or hetero aromatic ring A is necessary for activity. Aromatic ring confer
better activity than hetero aromatic ring.
b. An electron withdrawing group at -C – 7, e.g. a halogen or nitro group increases activity.
Electron donating group at C-7 decreases activity.
c. Substitution at any other position of ring A reduces activity.
d. A proton accepting group at C – 2 confers good activity.
e. C – 3 hydroxyl substituted compounds are as active as non hydroxylated analogs but are
excreted faster hence they have a short duration of action, e.g. lorazepam.
f. An alkyl group at N-1 increases activity whereby an ethyl group gives optimal activity.

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 Increasing the chain length decreases activity. However, substituents that are
metabolically removed can be used while retaining activity, e.g. prazipam which
becomes metabolized when it gets into the body.
g. An additional ring may be introduced whereby position 1 and 2 are part of that ring
yielding active compounds (Posn 1 and 2 of ring B are part of a fourth ring) e.g.
triazolam, alprazolam.
h. At position 5 of ring B, a phenyl substituent gives optimal activity.
i. Ortho but not para substitution on ring C is acceptable. An electro negative substituent,
e.g. fluoride or chloro at the ortho position. Any substitution in meta or para decreases
activity.
j. Ring C may be isosterically substituted, e.g. with pyridine ring in bromazepam.
k. Removal of the keto group at position 2 removes activity.
l. OH at posn 3 decreases activity and duration of action but decreases side effects, e.g.
lorazepam and oxazepam.
m. Introduction of –COOH group at position 3, e.g. in the clozapate increases DOA.
Clorazepate is a pro drug which is metabolized to N-desmethyl diazepam (nordiazepam),
an active metabolite.
METABOLISM
Oxidation
N-dealkylation, aromatic and aliphatic hydroxylation. The metabolites are conjugated with
glucoronic acid.

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Action and uses of benzodiazepines
Generally used as Anxiolytics. They interact with BDZ receptors in the CNS through the major
neurotransmitter in the CNS, GABA.
They bind to the GABA receptors thus causing an increase in Cl- ions entry into the cell and this
causes hyperpolarity and thus leads to a slow transmission of nerve impulse.
The long acting BDZ include flunitrazepam (Rohypnol®), clorazepate (a pro drug),
flurazepam(pro-drug).
The short acting BDZ are metabolized into inactive metabolites. They include triazolam (less
than 4 hours) midazolam (3 hours), lorazepam.
The BDZs used as anxiolytics: include the short acting lorazepam and oxazepam and the longer
acting diazepam, alprazolam, bromazepam,clorazepate, chlordiazepoxide and clobazam.
Hypnotics: diazepam, flurazepam, nitrazepam, flunitrazepam, temazepam, triazolam,
midazolam
For panic disorders: clonazepam, diazepam and lorazepam.

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For epilepsy/anticonvulsant: clonazepam, clobazam. Lorazepam & diazepam are used in status
epilepticus.
BDZs – are used as pre-anaesthetic medication.
Flumazenil - used as an antidote for benzodiazepines. It is used to reverse effects of BDZ.

2. BARBITURATES
They are cyclic ureides (amides from uric acid) derived from malonic acid esters. They may also
be said to be substituted derivatives of barbituric acid which is obtained from urea and malonic
acid.

Barbiturates can be synthesized by diacylation of urea using malonic acid esters or by

substitution of barbituric acid.

They colourless crystalline compounds insoluble in water but whose sodium salts are soluble.
They are currently useful in severe intractable insomnia which occurs in patients already taking
barbiturates, e.g. anti epileptics. However, they may be used as sedatives, hypnotics,
anticonvulsants or anaesthetics. Their use as sedatives, hypnotics and anxiolytics has declined
because of the following;
I. They have low/narrow therapeutic index.
II. Toxicity
III. They have microsomal hepatic enzyme induction, i.e. drug interactions.
IV. They have high potential of abuse and dependence.
They are now used mainly in epilepsy and pre anaesthesia.
They are divided into:

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 a) Long acting.
b) Short acting/ ultra short acting.
c) Intermediate acting.

Long acting
Barbital
Phenobarbital
Mephobarbital

Intermediate acting
Amobarbital
Butabarbital

Short acting
Pentobarbital
Secobarbital

Ultra short acting (onset within minutes)

Thiopental
Thiamylal

Barbiturates
They are short acting and the ultra short acting are used in anaesthesia.
The long acting are useful in epilepsy- anticonvulsants.
The intermediate acting ones are used in severe intractable insomnia.
MOA
It involves BDZ – GABA chloride ionophore complex.
Barbiturates exert their effect by preventing the generation of excitatory potentials in post
synaptic cells of the ventricular activating system responsible for wakefulness.

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Physico-chemical properties of barbiturates.
Barbiturates are derivatives of barbituric acid which is pharmacologically inactive because of its
high polarity and thus can’t cross BBB.
Barbiturates exhibit keto tautomerization with the tri keto form being predominant.

Barbituric acid is a strong acid sometimes stronger than acetic acid. This is because of
tautomerism.
Substitution at C-5 reduces acidity.
The barbiturates in use are colourless to white crystalline solids and are sparingly soluble in
water but quite soluble in organic solvents.
Because of their weak acidic character, they form water soluble salts with alkaline metals, e.g.
Phenobarbital sodium.
In acidic medium or in presence of CO2, the sodium sodium salts precipitate as free acids.
Injectable forms are buffered, e.g. using K2CO3 to prevent this precipitate that is responsible
for pain and irritation on injection.
Heat, sodium chloride and dextrose catalyze the hydrolytic cleavage of barbiturate ring, due to
this, barbiturates are incompatible with dextrose and saline infusions.
The ring breaks at N1……..C2 or N1………C6 bond resulting in carbamide and urea derivative.
SAR
General structure

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Only 5-5 disubstituted barbituric acid, 5, 5 disubstituted thio barbituric acid and 1, 5, 5
trisubstituted barbituric acid compounds are active. This decreases polarity hence enhancing
lipophillicity. Therefore at C-5, both hydrogens in barbituric acid must be replaced for maximum
activity.
By increasing the chain length of the side chain of the substituents at position 5, we increase
activity of lipophillicity. Its lipophillicity increases the compound crossing the BBB (quick onset
of action) but also leave the CNS fast and are metabolized more rapidly. (Short duration of
action)
However, optimal activity lies for substituents bearing between 5-6 carbons of the chain length
thus beyond 6 carbons, there is increased hydrophillicity hence leads to decreased activity.
Replacement of carbon 2 by S, e.g. thiopentane shortens the onset and duration of action
because it increases lipophillicity – IV general anaesthesia use.
Branching, unsaturation and replacement of aliphatic side chains with aromatic or aryl cyclic
ring increases lipophillicity.
Alkyl substitution on the amide H increases lipid solubility giving a quick onset and short
duration. However, substitution on both N, destroys activity as the compounds are non acidic.
Stereoisomers have equal activity.
Synthesis of barbiturates
Barbiturates are synthesized by diacylation of urea or thiourea with appropriately substituted
malonic acid esters.
Example

Metabolism
40% of barbiturates are excreted unchanged.
Barbiturates are potent microsomal enzymes inducers especially phenobarbitone. This causes a
lot of drug interactions – warfarin, trifusions, diphenyl hydramine.
With exceptions of thio barbiturates, barbiturates are metabolized through C5 substituents.
Metabolism involves;
a) Oxidation
The products of oxidation of C5 substituents include carboxylic acids, alcohols and phenols.
Oxidation is the most common pathway and is followed by conjugation with glucoronic acid or
sulphate radicals.
Other metabolic pathways include;
I. N-dealkylation
II. Ring hydrolysis to form acetamyl and urea derivatives.
III. Desulfuration to those having S

Thiobarbiturates undergo oxidative desulfuration to their barbiturate analogs. Long chains of

barbiturates must first be metabolized before the compound can be eliminated.
3. PIPERIDINE DIONES AND QUINAZOLINES

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Older agents, less commonly used.
They are cyclic amides or imides structurally similar to barbiturates, e.g. glutethimide,
methaquolone (mandrax). It is a quinazoline derivative.
Thalidomide was used in pregnancy but was realized to cause deformities in pediatrics-
phocomelia.

4. ALCOHOLS AND ETHERS

Older agents, less commonly used.
Alcohols include the monohydric and polyhydric alcohols.
Monohydric alcohols
Hypnotic activity- a straight chain alcohol increases with molecular weight because the lipid
solubility increases with molecular weight up to a maximum of eight carbons. Tertiary >
secondary > primary shows decreasing activity.
Replacement of hydrogen by halogens doesn’t affect hypnotic activity.

Chlorate hydrate
It causes vomiting, nausea and local irritation.
It’s administered as a drought in plenty of water. It’s used as a sedative hypnotic in paediatric
bitter.

Ethychlorovynol
Rarely used.
It is a colourless to yellow liquid with pungent odour.
It darkens on exposure to air due to free radical formation.
Paraldehyde
It’s a colourless liquid with disagreeable taste and smell hence given rectally. If left exposed, it
hydrolyzes to acetic acid.
O-paraldehyde should be stored under refrigeration.
Drugs exposed for more than 24 hours should not be administered. Its now obsolete but can be
used in status epilepticus.
It has irritation on the GIT mucosa.
Polyhydric alcohols
They include mephenism, glyceryl guiacolate – used as cough suppressant.

Propane diol derivatives/propane diol Carbamates/carbamic acid ester

Meprobamate- older agent. No longer in use.

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 5. ANTIHISTAMINES
 Promethazine
 Hydroxyzine
 Diphenhydramine

These drugs are used to treat allergies but have strong sedative effects.
6. INORGANIC SALTS
Na and K bromides were once used as hypnotics.

7. Antiepileptic drugs: Gabapentin, Pregabalin, Tiagabine and Valproate, are also effective
in the Rx of generalised anxiety disorder.
8. Some atypical antipsychotic agents s.a. Olanzepine and Risperidone may be effective in
generalised anxiety disorder and post- traumatic stress disorder
 However, their incidence of SEs may be greater than with other anxiolytic drugs
9. Antidepressants
o The following are effective in the Rx of generalised anxiety disorder, phobias, social
anxiety disorder & post- traumatic stress disorders
i) SSRIs e.g. Fluoxetine, Paroxetine and Sertraline
ii) 5-HT/ noradrenaline reuptake inhibitors (SNRIs) e.g. Venlafaxine
o Older antidepressants are also effective, e.g.
i) TCAs &
ii) MAOIs
o However, SSRIs are preferred because they have less SEs
o These drugs have the additional advantage of reducing any depression that may be
associated with anxiety

ATYPICAL HYPNOTICS
a. Azaspirodecanediones/pyrimidinylbutylpiperazines/Azaspirones.
Example is buspirone (buspar) – serotonin agonists.

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It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A receptors, but it
also has affinity for brain dopamine. In marked contrast to the BZs, it has a slow- onset of action
and its anxiolytic effects may take > 1/52 to become established

It has been used as an anxiolytic.

It has no euphoric effect.
It has minimal abuse potential
b. Imidazopyridines, e.g. zolpidem (stilnox), albidem.
Selectively binds to BDZ receptors to facilitate GABA mediated metabolism.
It has no rebound phenomena on withdrawal.
It has minimal anti-convulsant activity……
It is used in shirt term insomnia

c. Pyrazolopyrimidines, e.g. zaleplon, ocinaplon, indiplon.

Effects are similar to that of zolpidem but have short duration of action.

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 d. Cyclopyrrolones(zopiclone, eszopiclone)
They also bind to BDZ receptors. It has a minimal CNS depression effect. it has a short DOA.
Decreases sleep latency and number of waking. Increases sleep duration and efficacy.

e. RAMELTEON
Melatonin receptors are thought to be involved in maintaining circadian rhythms
undelying the sleep- wake cycle
Ramelteon, is a hypnotic drug used specifically for patients who have difficulty in
falling asleep
It is an agonist at MT1 and MT2 melatonin receptor located in the suprachiasmatic nuclei
of the brain
In patients with chronic insomnia, it reduces the latency to persistent sleep with no
rebound insomnia or withdrawal symptoms

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 ANTICONVULSANTS/ANTISEIZURE DRUGS
Epilepsies- These are a group of disorders of the CNS characterized by paroxysmal cerebral
dysrhythmia, manifesting as brief episodes (seizures) of loss or disturbance of consciousness,
with or without characteristic body movements (convulsions), sensory or psychiatric
phenomena. These episodes are unpredictable and their frequency is highly variable. Epilepsy
has a focal origin in the brain, manifestations depend on the site of the focus, regions into
which the discharges spread and postictal depression of these regions. In summary, epilepsy is a
disorder of the CNS characterized by excessive electronic discharge with or without loss of
consciousness.
Anticonvulsants act on the brain to reduce the frequency and severity of seizures. They may
prevent the speed of the seizure activity and or suppress the normal discharge of epileptogenic
zone.
Monotherapy is usually preferred starting with a low dose and raising it gradually.
Certain cones require polytherapy, e.g. in multiple seizures types. The choice of drug will
depend on the type of seizure, age and any pathological or physiological condition, e.g.
pregnancy.

Type of seizures(classification)
I. Generalised seizures
1. Generalized tonic-clonic seizures (GTCS, major epilepsy, grand mal): commonest, lasts 1–2 min.
The usual sequence is aura—cry—unconsciousness—tonic spasm of all body muscles—clonic
jerking followed by prolonged sleep and depression of all CNS functions.
2. Absence seizures (minor epilepsy, petit mal): prevalent in children, lasts about 1/2 min.
Momentary loss of consciousness, patient apparently freezes and stares in one direction, no
muscular component or little bilateral jerking. EEG shows characteristic 3 cycles per second spike
and wave pattern.
3. Atonic seizures (Akinetic epilepsy): Unconsciousness with relaxation of all muscles due to excessive
inhibitory discharges. Patient may fall.
4. Myoclonic seizures Shock-like momentary contraction of muscles of a limb or the whole body.
5. Infantile spasms (Hypsarrhythmia) Seen in infants. Probably not a form of epilepsy. Intermittent
muscle spasm and progressive mental deterioration. Diffuse changes in the interseizure EEG are
noted.

II.Partial seizures
1. Simple partial seizures (SPS, cortical focal epilepsy): lasts 1/2–1 min. Often secondary. Convulsions
are confined to a group of muscles or localized sensory disturbance depending on the area of
cortex involved in the seizure, without loss of consciousness.
2. Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor): attacks of bizarre and
confused behaviour and purposeless movements, emotional changes lasting 1–2 min along with
impairment of consciousness. An aura often precedes. The seizure focus is located in the temporal
lobe.

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3. Simple partial or complex partial seizures secondarily generalized The partial seizure occurs first
and evolves into generalized tonic-clonic seizures with loss of consciousness. Most of the cases of
epilepsy are primary (idiopathic), some may be secondary to trauma/ surgery on the head,
intracranial tumour, tuberculoma, cysticercosis, cerebral ischaemia, etc. Treatment is symptomatic
and the same whether epilepsy is primary or secondary

CLASSES OF ANTICONVULSANTS
Ureidal agents
They have a common moiety which is the ureidal(ureide) moiety plus its derivatives. (formed
by bi isosteric replacement of one N of the ureide)
1. Barbiturates an deoxybarbiturate
2. Hydantoins
3. Oxazolidinediones
4. Succinimides
5. Acyl ureas

Other anticonvulsants (non uredidal and misc. agents:

1. Iminostibenes(dibenzazepine derivatives)- carbamazepine, oxcarbazepine
2. Branched chains carboxylic acids, e.g. valproic acid(sodium valproate)
3. Benzodiazepines, e.g. diazepam, clonazepam, clorazepate, midazolam and lorazepam

Misc. agents
1. Phenyl triazines, e.g. lamotrigine

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 2. Cyclic GABA analogs, e.g. gabapentin, vigabatrin, pregabalin
3. Amides, e.g. progabide
4. Sulphonamides and sulphonamide derivatives e.g. acetazolamide, zonisamide
5. Biscarbamates/dicarbamate e.g felbamate
6. Amino acid related- lacosamide
7. Pyrrolidine derivative – levetiracetam
8. Triazole derivative- rufinamide
9. Sulfamate-substituted monosaccharide derived from fructose - topiramate
10. Nipecotic acid derivative- tiagabine

BARBITURATES AND DEOXYBARBITURATE

The ones used for epilepsy are: phenobarbitone, mephobarbitone, pirimidone(primidone).
Phenobarbital was the first clinically useful anticonvulsant and is still the drug of choice for
epilepsy in infants.
Pirimidone is 2 deoxo derivative of phenobarbitone with similar properties. It is metabolized to
the active products: phenobarbitone and phenylethylmalonamide (PEMA). Barbiturates and
deoxobarbiturates induce hypnosis which is undesirable in treating epilepsy.
Barbiturates act by GABAA receptor mediated synaptic inhibition.They act in all parts of CNS.
They depress the excitability of both pre and post synaptic membranes. This reduces the
number of nerve impulses ascending to the cerebral cortex via the reticular activating system.
At high doses, they inhibit Na and K channels. Phenorbarbtone is a broad spectrum
anticonvulsant, cheap and less toxic than many antiepileptics.
Chemical structures

SAR
- Phenyl group at position 5 gives maximum anticonvulsant activity.

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- The other substituent at position 5 should be an alkyl with the ethyl, propyl, isopropyl giving
maximum activity. Longer chains diminish activity. Unsaturated groups/unsaturation of the
aliphatic group reduce activity
- A second phenyl group i.e. 5,5 diphenyl reduces activity but have almost no hypnosis
- Ironically, 5,5 dibenzyl derivatives induce convulsions.
- Non substitution in the phenyl substituent gives maximum activity. Substitution in the
phenyl diminishes or abolishes activity.
- Methylation of N-1 of phenobarbitone gives mephobarbitone(methyl phenobarbitone)
which is metabolised to phenobarbitone and offers no advantage over phenobarbitone.
- 2 deoxy analog of phenobarbitone – pirimidone has the same pharmacological activity as
phenobarbitone, even as a sedative hypnotic.
HYDANTOINS
Hydantoins are 5 member cyclic ureides. Like Barbiturates, they are weakly acidic with pKa 8.1
through keto enol tautomerism and may form salts with strong bases, e.g. phenytoin sodium.
Phenytoin(diphenyl hydantoin) shows the least hypnotic activity but highest anticonvulsant
activity. Phaneytoin may be synthesized by diacylation of urea.
Phenytoin is a widely used antiepileptic, also used in trigeminal neuralgia and cardiac
arrhythmias.
Physicochemical properties: Hydantoins have poor water solubility, oral bioavailability and
narrow therapeutic index. The Na ions salts are soluble in water.
They are formulated as salts of strong bases e.g phenytoin sodium to improve water solubility.
Phenytoin is a white crystalline product insoluble in water but slightly soluble in ethanol.

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SAR
- A phenyl group at position 5 is essential for activity. Essential for tonic clonic seizures.
- The second substituent at the same position may be an alkyl, e.g. methyl or ethyl or thienyl
but having another phenyl group gives maximum activity.
- The alkyl substituents contribute to drowsiness.
- Alkylation at position 3 reduces activity if C5 are two ph groups.
- Alkylation at position 3 increases activity if the substituents at position 5 are a phenyl and a
small aliphatic group, e.g. in mephenytoin.
- When the groups at C5 are different, the stereoisomers that arise are equipotent.
- Replacement of the carbonyl group (keto group) at position 2 and 4 with C=5 where O is
replaced by S produces thiohydantoins which have less activity.
- Reduction of the carbonyl group at position 2 leads to an active compound.
MOA
It inhibits spread of seizures from focus to the neurons not initially involved.
In excitable tissue, it has a membrane stabilizing effect. (Action potential inhibition). Acts by
prolongation of Na channel inactivation. Phenytoin is effective in all types of partial and tonic
clonic seizures.
Metabolism
1. Parahydroxylation/aromatic hydroxylation of the phenyl group at position 5. It can be
eliminated in this form or may undergo conjugation by glucuronide or suphate.
2. Phenytoin is an inducer of Cyp P 450 and thus levels of drugs metabolized by the same iso
form because of the increasing metabolism. Examples of those drugs that it interacts with:
other anticonvulsants, warfarin, theophylline and oral contraceptives.
3. N-demethylation, e.g. mephenytoin.

OXAZOLIDINE DIONES
They are iso esters of hydantoins by replacement of posn 1- N.

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For best activity, at least two methyl groups , at posn 5 and at posn 3 are required.
Longer alkyl groups at posn 5 reduce activity. Thus trimethadione is more active than
paramethadione. Metabolism: N- demethylation
They are effective in treatment of petit mal epilepsy/absence seizures as 2 nd line drugs or
reserved drugs due to their side effects i.e. bone marrow suppression etc

SUCCINIMIDES
Developed to overcome oxazolidine dione toxicity.

SAR
Unsubstituted succinamide is inactive.
N- substitution (R2) increases activity but also hypnotics effects.
Ethosuximide is the most selective for absence seizures and the least toxic of the compounds,
preferred to trimethadioine because of safety and effectiveness. However, valproic acid is
preferred to ethosuximide for absence seizures.
Substitution at position with a phenyl group increases activity.
Succinimides are metabolized through N-demethylation, aromatic and aliphatic hydroxylation
to hydroxyl methyl derivatives (major pathway)
BENZODIAZEPINES
The anticonvulsants have ureidal moiety.
Clonazepam, clobazam and clorazepate are used as anti epileptics.
I.M and I.V diazepam or lorazepam are used in status epilepticus as drugs of choice.

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SAR
- C3 of the ureidal structure is substituted in some BDZ anticonvulsants but in most other
BDZs it is not substituted.
- Substitution at C3induces anticonvulsant activity, e.g. clorazepate, lorazepam.
- Substitution at N1 is not essential for activity, e.g. clorazepam is 200 times active as an
anticonvulsant than diazepam.
- A keto group at position 2 is essential for activity hence chlordiazepoxide has the least
anticonvulsant activity because it has no keto group.
- Electron withdrawing group at C7 is essential for activity.
- Substitution at C7 varies depending on the same pattern as for sedative hypnotics where CF3
> NO2 > Cl > F > NH2 (reducing activity comparison).
- Another halogen substitution in ring C at para position of the ph group substitute abolishes
activity.
- A 2nd halogen in an ortho position enhances activity, e.g. in lorazepam.
MOA
It potentiates GABA mediated inhibition, sustain high frequency firing of neurons. This activity is
also in phenytoin, valproic acid and carbamazepine.
I.V or I.M diazepam is the drug of choice for status epilepticus since it controls rapid control of
seizures due to high lipid solubility which leads to high penetration hence high CNS distribution.
It also has faster elimination from the CNS.
If there is no recovery, use phenobarbitone.
Oral diazepam is not used as an anticonvulsant because it is less effective and may cause
tolerance.
Clonazepam – petit mal seizures 2nd to ethosuximides. Rated 2nd to diazepam in status
epilepticus.
Clorazepate is used as an adjunct for partial seizures especially in children.

21
Triazo BDZs can be used as anticonvulsants especially in chemically induced seizures, e.g.
triazolam.

DIBENZAZEPINES/ IMINOSTILBENES
Examples: carbamazepine (Tegretol®), oxcarbazepine (Trileptal ®)
They are dibenzazepine derivatives structurally related to tricyclic antidepressants.
They have a carbamyl group at position 5. This is the group responsible/essential for the
activity.
MOA: Prolongation of Na+ channel inactivation.

Carbamazepine is a 1° drug for the management of partial tonic seizures.

It has equivalent potency as phenytoin and it’s relatively safe. It is the drug of choice for
epilepsy in pregnancy.
It also has an antidiuretic activity. It is used in manic depression and trigeminal neuralgia.
Metabolism of Carbamazepine
It is metabolized mainly to its C10 – C11 epoxide which is active.
The epoxide is converted to the inactive dihydroxy compound by epoxide hydroxylase.

Carbamazepine exhibits hepatic enzyme induction. It is an enzyme inducer. Induces metabolism

of phenobarbitone, valproate, phenytoin and viceversa. Reduces efficacy of oral contraceptives
and haloperidol. Erythromycin inhibits its metabolism.
Oxcarbazepine is metabolized by rapid reduction of the keto group to give an active alcohol
product which is then conjugated with glucoronide.
Carbamazepine is also used in trigeminal and related neuralgias, manic depressive illness and
acute mania.

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BRANCHED CHAIN ALIPHATIC CARBOXYLIC ACID
Valproic acid(Sodium valproate).Broad spectrum anticonvulsant.

It is colourless liquid with a characteristic odour.

It is slightly water soluble.
The salt formed is odourless, soluble both in water and ethanol.
Drugs unlike most anticonvulsants/it is not an enzyme inducer.
It’s used in absence and partial seizures. Drug of choice for absence seizures.Also uused in
mania and bipolardisorder.
Metabolism
Metabolism is through glucoronidation and beta- oxidation to an alcohol.
SAR
Other branched chain carboxylic acids have similar potency to valproic acid but increasing the
chain link to alpha carbon decreases the potency.
Straight chain carboxylic acids have little or no activity.
The 10 amide of valproic acid is twice as active as the acid.

CYCLIC GABA ANALOGS

Examples are;
Gabapentin (Neurontin®)
Vigabatrin (Sabril®)

The drugs are gabamimetics that are able to cross the BBB to alleviate or prevent seizures by
compensating for a perceived GABA deficiency.
Actions are similar to phenytoin, valproic acid and BDZs.

23
Vigabatrin selectively and irreversibly inhibit GABA transaminases from metabolically
hydrolyzing inactive GABA.
It’s effective in complex partial seizures as an adjunct. It is well tolerated.
They are adjuvant medication. Added to other drugs.

AMIDES
Example is felbamate, progabide,
Felbamate is a dicarbamate structurally related to meprabamate. It is useful in complex partial
seizures.
Progabide is a derivative of gamma amino butyramide.

It directly stimulates the GABA receptors. It has a similar activity to Na valproate but slightly less
than phenytoin.
It’s very expensive.
PHENYL TRIAZINES (Lamotrigine®)

Although the anticonvulsant activity is not related to antifolate effect, convulsions disappear
when it is used.
MOA
It stabilizes presynaptic neural membranes by breaking Na+ channels.
Uses
It is used in partial and tonic-clonic seizures which cannot be controlled by other
anticonvulsants.
ACYL UREAS/ ARYL UREAS
They are product of cleavage of barbiturates rings, e.g. phenacemide.

24
Their use is limited because of severe liver and agranulocylosis.
NB: cleavage of hydrantoin ring gives inactive product.
SULPHONAMIDES
E.g. acetazolamide

Acetazolamide – carbonic anhydrase inhibitor. It is used as an antihypertensive/diuretic.

Carbonic anhydrase is an enzyme that catalyzes the reverse hydration of CO 2.
H2O+CO2→H2CO3
An accumulation of CO2 in the brain and spinal cord gives anticonvulsant activity.
It’s used as an adjunct to other anticonvulsants.
Tolerance develops rapidly with the continuous treatment.

Chemical structures of misc. agents.

Use of anti epileptics

1. Partial seizures with or without 20 generalization.
Drugs include;
Carbamazepine, lamotrigine, Na valproate, phenytoin, oxycarbazapine. They can be used as
monotherapy.

25
Phenobarbitone and pirimidone are 2nd line alternatives.
2. General seizures
a. Absence seizures
Drugs include; ethosuximide and Na valproate
b. Tonic-clonic seizures
Carbamazepine, lamotrigine, phenytoin and Na valproate.
c. Status epilepticus
Drazepam, clonazepam, lorazepam, paraldehyde and phenytoin.
d. Monoclonic seizures
Na valproate, clonazepam, ethosuccimide andlamotrigine.
e. Atypical absence, atonic and tonic seizures
Phenytoin, Na valproate, lamotrigine, ethosuximide and phenobarbitone

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ANAESTHETIC AGENTS
Local anaesthetics are drugs which upon topical application or local injection cause reversible loss of
sensory perception of pain, in a restricted area of the body. They block generation and conduction of
nerve impulse to the brain without loss of consciousness or impairment of vital cardiorespiratory
functions. They are used in dentistry and minor surgical procedures to prevent or reduce pain and
administered via different routes: topical, infiltration, field or nerve block, regional i.v, spinal and
epidural.
MOA: Local anesthetics block nerve conductance by binding to selective sites on the Na + channels in the
excitable membranes, thus reducing passage of Na + ions and consequently interfering with generation of
action potential.

Chemically, they consist of a hydrophilic group (usually a tertiary amine) and a hydrophobic group
separated by an ester or amide linkage. Generally, lipophillicity increases potency, duration of action
and toxicity.
Chemical classification:
1. Ester groups
2. Amide group
3. Miscellaneous agents

GENERAL ANAESTHETICS
These are drugs which produce reversible loss of all sensation and consciousness. The cardinal
features of general anesthetics include: loss of sensation, sleep (unconsciousness), muscle
relaxation and abolition of reflexes. Anasthetics are CNS depressants. Anasthesia is usually
produced in combination of drugs. They are structurally non specific, relatively inert organic
compounds and chemically unrelated.
A wide variety of unrelated chemical compounds produce GA. The action of general anesthetics
is primarily related to physicochemical properties, notably high partition coefficient.
They exert their effect non specifically on cell membrane of the mid brain reticular activating
systems of the cortex.

Stepwise action of CNS depressants: Graphical illustration.

STAGES OF ANAESTHESIA
Stage 1 (analgesia) – Induction stage. Patient is conscious, normal reflexes, pain abolished
progressively.

27
Stage 2 (delirium) – loss of consciousness to beginning of regular respiration. Apparent
excitement (patient may shout, struggle, hold breath) and involuntary movement may
occur(muscle tone, jerky breathing, micturition, defacation).
Stage 3 (surgical anaesthesia) – Extends from onset of regular respiration to cessation of
spontaneous brerathing. There is sleep, analgesia and muscle relaxation.
Stage 4 (medullary paralysis) – indicates overdose of the anaesthetic. Cessation of breathing to
circulatory failure and death.

General anaesthetics are divided into;

 Intravenous agents
 Inhalational agents

I. Inhalational anaesthetics
Gases or vapours that diffuse rapidly across pulmonary alveoli and tissue barriers.
Gases: cyclopropane(obsolete), nitrous oxide
Volatile liquids (vapours): ethers (diethyl ether, vinyl ether) and halogenated hydrocarbons
(enflurane, halothane, desflurane, isoflurane, sevoflurane)

- Cyclopropane and diethyl ether are powerful anaesthetics with good muscle relaxing effect.
- Diethyl ether is effective, safe to handle and with reduce toxicity as compared to other
inhalational drugs. However, it is highly inflammable and explosive in air, O 2 or N2O.It is also
irritating. No longer used.
- Chloroform is highly toxic.
- Because of influence of halogens on hydrocarbons as seen in chloroform, most inhalational
anaesthetics used today are halogenated hydrocarbons. The halogens reduce flammability.
- Bromine and fluorine contribute to potency. Fluorine adds to chemical stability and
volatility as well.
- Newer drugs developed from enflurane retain the ether structure with their hydrogens
substituted with halogens to reduce flammability.
- These agents(enflurane, isoflurane etc are non irritating, non inflammable)

Isoflurane CF3-CHCl – CF2H, Desflurane CF3CHF-O-CF2H, Enflurane CHClF – CF2-O-CF3

Halothane
It is most commonly used. It auto oxidizes to HBr, HCl and phosgene thus stored in ambered
glass with thymol to prevent auto oxidation.
CF3 – CBrClH
Halothane is a highly volatile liquid with sweet odour like chloroform, colourless, non
flammable, non irritant with rapid action. Slightly soluble in water but miscible with alcohols,
ethers.

28
It has a better safety record than chloroform despite their similar physical and anaesthetic
properties. Has low analgesic and muscle relaxing properties. Its deficiencies in terms of poor
analgesia and muscle relaxation are compensated by concomitant use of N 2O, or opioids and
NMJ blockers. Administration with N2O also helps avoid use of high doses that can depress the
CNS.
Nitrous oxide: N2O is the least potent of the agents used today. It is a colourless, odourless,non
flammable gas, non irritating, non toxic & a good analgesic. Its an adjuvant to other agents.

II. Intravenous anaethetics

Generally used to induce anaesthsia which is then maintained by inhalational agents. Loss of
conciousness is within seconds. They can be used alone with analgesics and muscle relaxants.
They include;
Inducing agents:
a) Barbiturates, e.g. thiopental Na. It is an ultrashort acting thiobarbiturate. Has a thioketo
groups at C2 to make it ultra-short acting. Highly soluble in water yielding a very alkaline
solution. Which must be prepared freshly before injection.
Others barbiturates: methohexital(more potent than thiopentone, briefer and action) and
thiamylal.
Barbiturates produce a rapid and smooth induction of anaesthesia but with no analgesic effect.
They are highly lipophilic.
Methohexital has no sulfur group but has a longer unsaturated C side chain at C 5.
They are easy to control dose.
b) Propofol –Unconsciousness occurs in 15-45 sec, lasts 15 min.
c) Etomidate- Briefer duration of action(5-10 min) than thiopentone.

Slower acting agents:

Benzodiazepines e.g. diazepam, midazolam, lorazepam. In addition to use as preanaesthetic
medication, they can be used for induction, maintenance and supplementing anaesthesia.
Ketamine
It is usually presented as HCl salt.
It has potent analgesic activity. Can be given by IM.
It has CNS stimulation activity/hallucinogenic, thus advantageous to elderly patients and
patients in shock, e.g. burned patients.
Uses
Head an d neck operations, patients who have bled, burned,thoise who do not want to lopse
consciousness and short operations. Good for repeated anaesthesia e.g. in burn dressing.
It’s given to sedate uncontrollable patients.
Well tolerated and in children, it’s used in minor surgery in children.
Fentanyl-droperidol combination- Fentanyl is a short acting(30-50min) opioid analgesic.
Droperidol is related to haloperidol. Alfentanil and sufentanil can substitute fentanyl.
Steroids, e.g. alfaxalone

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Cyclohexanone derivatives, e.g. ketones
Clonidine
Questions
Discuss preanaesthetic medication as follows:
- Aims
- Classes and examples of drugs and their roles

LOCAL ANAESTHETICS
Are used for minor surgery.
They reversibly block generation and conduction of action potential/impulses along the axon by
preventing entry and exit of Na+ ions and K+ ions respectively; hence there is no generation of
action potential.
They are used in minor surgical procedures, e.g. dental operations.
Can be administered through various routes: topical, infiltration, field or nerve block, regional
i.v, spinal and epidural.
Chemistry: Consists of hydrophobic and hydrophilic moieties, separated by an ester or an
amide linkage. The hydrophilic group is usually a 30 amine.
Classification
 Esters
 Amides
 Miscellaneous
a) Esters
st
The 1 to be discovered was cocaine.
Cocaine;

Cocaine is an ester of benzoic acid, methanol and ecgonine.

It has undesirable properties: addiction, poor aqueous solubility, irritant, allergic properties
It is hydrolysed to benzoic, methanol and ergonine in solution leading to loss of activity.
Newer agents; benzoyl esters with less addictive properties were developed.
Others; amylocaine, benzoyltropine, butacaine, tetracaine(most potent), benzocaine.
All compounds are hydrolysed in aqueous solution to benzoic acid or its derivatives.
SAR
a. There must be an N atom in an ester either as part of the acid, alcohol or both.
b. The acid must be aromatic. Esters of p-aminobenzoic acid are more active than those of
benzoic or p-hydroxybenzoic acid.
c. The alcohol should be aliphatic.
d. Presence of an alkyl on the aromatic nitrogen increases potency, e.g. tetracaine.
e. The amino group should be at the para position.
b) Amides

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They are less prone to hydrolysis unlike the esters hence they have long DOA although they are
less potent than esters, e.g. Lidocaine/lignocaine

Advantages of lidocaine
-has a good analgesic activity, stable in solution, does not cause allergic reactions.
It is only given by injection because it is prone to 1st pass effect
Others amides include;
-mepivacaine , bupivacaine, prilocaine, etidocaine,

Other local anaesthetics include;

-eugenol
-promoxine (topically) – in pruritus associated with eczema. it’s an aminoether.

DRUGS USED FOR MOOD DISORDERS

Affective disorders refer to a pathological change in mood. The two extremes include mania
and depression. Bipolar disorder is characterized by cylces of mood swings from mania to
depression. The drugs used in mood disorders include:
a) Antidepressants
b) Antimanic agents (mood stabilizers)

ANTIDEPRESSANTS
Describe depression…..Depression may be endogenous/idiopathic or due to external factors.
Antidepressants are drugs that elevate the mood in depressive illness. They act by increasing
the availability of biogenic amines; catecholamines (i.e. noradrenaline) and indole amines (i.e
serotonin) at the receptor sites of the brain. This may be either by inhibiting the reuptake of the
amines or by inhibiting degradation/breakdown of the amines by inhibiting the activity of
enzymes that catalyze this degradation, e.g. monoamine oxidase.
Classes of antidepressants
 Tricyclic antidepressants, TCAs
 Heterocyclic antidepressants.
 Monoamine Oxidase inhibitors, MAOIs
 Selective serotonin reuptake inhibitors, SSRIs
 Miscellaneous agents

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 1. TRICYCLIC AND HETEROCYCLIC ANTIDEPRESSANTS.
They are mixed noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors at their neurons
thus potentiating their activity. Some agents have more NA reuptake than 5-HT reuptake
inhibitors. This group of antidepressants and the SSRIs are more used than MAOIs.
Structurally, they are related to phenothiazines, dibenzazepines and benzapines because of
their tricyclic nature. Structurally they are divided into;
a. Analogs of diphenyl methane
b. Analogs of diphenyl amines

a. Analogs of diphenyl methane

b. Analogs of diphenyl amine

Differences of the ring of tricyclic from those of antipsychotics

- The central ring of tricyclic antidepressants has 7 and 8 members hence it is more twisted
than antipsychotics.
- Tricyclic antidepressant is more out of plane compared to antipsychotics.
- With a side chain of two carbons, tricyclic antidepressants activities are still retained.
- The amino group for tricyclic antidepressant is 20 compared to 30 in antipsychotics.
SAR of tricyclic antidepressant (TCAs)
 Ring structure
 Side chain
 Substitution on the ring
 Terminal N
1. Ring structure – for only analogs of diphenyl methane.

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- For activity, the double bond can be exocyclic at C5 or endocyclic at C10 and C11, e.g.
protryptyline has endocyclic bond at C10 and C11.

- Compounds with exocyclic double bond are more potent and their metabolites more toxic
than those with endocyclic double bonds.
- Heteroatoms can be incorporated into the central ring without loss of activity, e.g. in the
doxepin.

- Two heteroatoms cannot be used in the same structure as this will interfere with the shape
resulting in tranquilizing/antipsychotic effect .
- Activity is maximum with a 6, 7, 6 ring structure arrangement,
Atypical antidepressants - Tricyclic related compounds/heterocyclic antidepressants
- Activity is maximum with a 6, 7, 6 ring structure arrangement, however, other
arrangements exist that have antidepressant activity. These are varying compounds some
with heterocyclic structures, varying numbers of rings and arrangements different from the
TCAs. They are referred to as atypical antidepressants.
a. 6, 5, 8 arrangement iprindone,

b. Tetracyclic compounds which have 4 rings.

These compounds are modifications of tricyclic antidepressants and are classified as 2nd
generation TCA related cpds. Their activity is midway between antidepressants and

33
tranquilizers and they have fewer antimuscarinic effect. They include; maprotiline, traxodone,
miariserin, amoxapine.
c. Monocyclics, e.g. bupropion, vioxazine.
d. Bicyclics, e.g. tofenacine.
rd
3 generation tricyclic related antidepressants are well tolerated especially for patients who
cannot tolerate SSRI (selective serotonin reuptake inhibitors). They include; nefazodone,
mirtrazapine, venlafaxine (SNRI - selective noradrenaline reuptake inhibitor)
2. Side chain
- For antidepressant activity, the side chain should have 2 or 3 carbon atoms separating the
terminal nitrogen and the position 5 carbon or nitrogen.
- A 3 carbon chain gives optimal activity. Longer chains/unbranched chains give inactive
compounds. However, butripytline though branched has activity.
3. Terminal nitrogen
- A terminal N is necessary for activity. It is substituted with methyl groups making it 2 0 or 30.
Tertiary amines undergo demethylation to give primary and secondary amines hence have
slow onset of action. However, some primary and secondary amines have unreliable and
distribution pattern hence tertiary amines are reliable in terms of absorption and
distribution.
4. Substituents on the ring structure
Substitution can be at position 3, 10 or 11. Compounds without substituents are active just like
those with substituents. Substituents have to be small groups like halogens, methoxy groups.

Stability of TCAs
Due to the excess electron from aromatic rings and heteroatoms, these compounds undergo
auto oxidation in light and air. However, they are more stable than phenothiazines since they
have only one heteroatom.
They should be protected from air and light and formulated as sugar coated and salt forms for
stability.
Metabolism
N demethylation followed by oxidative deamination to the primary amine to their respective
acid.
Oxidation/hydroxylation at C2 and or C10 followed by glucoronic acid conjugation.
Demethylation may produce active compounds, e.g. amitriptyline to nortriptyline.
Pharmacology and Uses
MOA- They prevent reuptake of biogenic amines NA and 5HT at the synaptic cleft.
TCAs are associated with:
- anticholinegric effects(dry mouth, blurring of vision, constipation, urinary retention)
- sedation in some agents(e.g. amitryptiline),
- increased appetite and weight gain(not in SSRIs)
Uses:
- Are used for moderate to severe endogenous(major) depression.

34
- Obsessive compulsive and phobic states
- Attention deficit hyperasctive disorders in children
- Nocturnal enuresis e.g. Imipramine
- Migraine
- Pruritus, peptic ulcers…
Those with sedation, e.g. amitriptyline are preferred for agitated patients

2. MONAOAMINE OXIDASE INHIBITORS (MAOIS)

They irreversibly inhibit the oxidative deamination of the naturally occurring biogenic amines
e.g. catecholamines, notably noradrenaline and 5- HT.
Their action is non selective of enzymes metabolizing other amine drugs, e.g. indirect acting
sympathomimetics found in cough expectorants and decongestants and food containing
amines, e.g. tyramine, hence their use is limited because of this non selectivity that leads to
undesirable effects, e.g. increased blood pressure which is a major side effect of MAOIs.
They have high liver toxicity/hepatotoxicity potential because of accumulation in the liver.
They have high drug and food interactions with drugs/foods containing amines, e.g.
barbiturates, sympathomimetics containing cough mixtures, antihistamines, local anaesthetics,
pethidine,levodopa,TCAs, antiparkinsonaian anticholinergics, cold and cough remedies
containing sympathomimetics(e.g. ephedrine,phenylephrine) etc.
Cheese reaction describes the interaction of MAOIs with foods containing tyramine e.g.
cheese, wine, beer, pickled meat and fish, yeast extracts, caffeine, alcohol, chocolate and
chicken liver etc .This results in a hypertensive crisis.

Their use is limited to atypical depression and social phobia that are not responsive to other
drugs.
Classification:

Non selective MAO inhibitors Selective inhibitors

Hydrazines Amphetamine MAO- A MAO- B
derivatives derivatives
phenelzine, Tranylcypromine Clorgiline, Selegiline
isocarboxazid Methyl phenidate moclobemide(reversible
isoniazid, pargyline inhibitor)
iproniazid,nialamide

MAO inhibitors non-competitively and irreversibly inhibit MAO, allowing accumulation of NA,
dopamine and 5-HT in neurons in the brain and periphery.
Moclobemide is a reversible inhibitor(RIMA).Safer than most others, less tyramine interaction.
Effective like TCAs with no anticholinergic, sedative and CVS effects of typical TCAs. Thus, a
good alternative to TCAs in major depression and social phobias.
Chemistry:

35
Hydrazine derivatives:

R1 – is a small group
R2 - is a bulky group, e.g. phenyl, pyridine or other heteroromatic gruop.
R3 – is an intermediate between R1 and R2, not a bulky or small but the smaller the group the
higher the potency but hepatotoxity is increased e.g phenelzine.
Amphetamine derivatives

Amphetamine itself is not used as antidepressant because of its short DOA because of being
prone to metabolism.
Modification to increase its DOA and effectiveness was done which included;
a. To produce compounds which are not easily metabolized by MAO by incorporating
nitrogen in heterocyclic ring which sterically protects it from attack by MAO.
e.g. methyl phenidate

b. Cyclizing the hydrocarbon chain, e.g. in tranylcypromine.

c. By making the terminal hydrogen tertiary. E.g in pargyline

SAR of MAOIs
- For maximum activity, the terminal amine with a bulky group should be separated from
bulky group by two carbons.

36
- Increasing the chain branching or changing polarity decreases potency. However, branching
gives less toxic compounds and usually the substituents are usually at α and β position.
- Disubstitution of N leads to loss of activity except in pargyline.
- Presence of OH on the bulky group/ring removes activity.
NB: MAOIs are very stable.
Metabolism
- Oxidative deamination
- Aromatic hydroxylation and aliphatic hydroxylation
- N dealkylation

3. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

They enhance the effect of serotonin by inhibiting or preventing reuptake into the presynaptic
nerve endings without affecting other neurotransmitters. They exhibit better safety than and
are less sedating than other antidepressants.
They don’t produce anticholinergic, sedative, hypotensive and cognitive side effects observed in
TCAs. Preferred in patients with conditions like e.g. diabetes.
Disadvantage: they exhibit many drug-drug interactions which include inhibition of
metabolizing enzymes. The interaction may include interactions with other antidepressants.
Structurally, they are aryl alkyl amines or aryl oxy alkyl amines.
They are unrelated structurally to TCAs and also among themselves.
Their activities are not also related.

They include;
Fluoxetine, fluvoxamine, sertraline and citalopram.Fluoxetine and citalpram are marketed as
racemic mixtures. The levo isomer of paroxetine is more active than the dextro. In sertraline,
the dextro isomer is more active.
Fluoxetine has an active metabolite called norfluoxetine. It has along half life (days – one week)
hence the dose is minimized and drug given in minimum frequency.
Paroxetine is the most potent SSRIs.
Citalopram is the most specific SSRIs.
The most recent SSRIs are; atomoxetine and duloxetine.

Some SSRIs have anxiolytic activity notably flouxetine and paroxetine. They are used in panic
disorders, obsessive, compulsive disorders and general social phobias.
Other antidepressants:
Flupenthixol- used in endogenous depression.

ANTIMANIC (MOOD STABILIZING) DRUGS

Lithium salts, e.g. Li2CO3 used for manic depressive illness(antimanic).

37
Other alterbatives to lithium include:
- Carbamazepine
- Sodium valproate

ANTIPSYCHOTIC DRUGS
Psychoses/psychotic disorders are severe mental conditions with serious distortion of thought,
behavior, capacity to recognize reality and of perception (delusions and hallucinations).
positive symptoms: hallucinations, delusions, disorganized thought, restlessness,insomnia,
anxiety, aggression.
Negative symptoms: apathy, loss of insight and volition, affective flattening, poverty of speech,
social withdrawal.
Psychoses include;
 Schizophrenia
 Mania
 Bipolar disorders Describe them?
 Major paranoid states
 Organic mental states
Chemical Classification of antipsychotic drugs
1. Phenothiazines
2. Thioxanthenes and xanthenes
3. Butyrophenones
4. Diphenylbutylpiperidines
5. Benzamides
6. Benzazepines
7. Rauwolfia alkaloids
The drugs also referred to as neuroleptics and previously as major tranquillizers.
MOA: All antipsychotics (except clozapine like) antagonize dopamine (especially D 2) receptors in
the limbic system of the brain. They are associated with extrapyramidal effects (EPEs): tremors,
dystonia, dyskinesia, akathisia, tardive dyskinesia, occulogyral crisis etc). Other receptors in the
CNS may be involved i.e. Acetylcholine, noradrenaline, histamine and serotonin. Centrally
acting antimuscarinics may be administered with antipsychotics to counter the EPEs. E.g.
benzhexol, benztropine
Pharmacologically, they can be classified as:

38
 i) Typical agents - Improve only the +ve effects of schizophrenia. Associated with
extrapyramidal effects. Include butyrophenones, phenothiazines,
diphenybutylpiperidines
ii) Atypical agents – Improve both +ve and – ve symptoms of schizophrenia. Higher
efficacy, are better tolerated and have less extrapyramidal effects (EPEs). Examples:
benzamides, benzazepines, indole derivatives.
Antipsychotics reduce irrational behavior, agitation and aggressiveness and control
psychomotor symptomatology. Hallucinations and delusions are suppressed.

1. PHENOTHIAZINES
General structure

The prototype drug, chlorpromazine, was the 1st to be used as an antipsychotic but was
accompanied by extra-pyramidal side effects (EPEs).
Other Phenothiazines and related compounds were derived from chlorpromazine e.g.
thioxanthines. The phenothiazine structure is composed of:
a. Propyl chain at position 10
b. The phenothiazine nucleus
c. Position 2 substituents or modification (R1)
d. A terminal nitrogen on the propyl side chain.

SAR AND DERIVATIVES

a) The propyl side chain
- A propyl side chain separating the nucleus from the terminal nitrogen is essential for
antipsychotic activity only.
- Shortening the chain length abolishes antipsychotic effect while increasing antihistaminic
activity e.g. promethazine with a two carbon side chain has antihistamine activity but no
antipsychotic activity and Ethopropazine has no antipsychotic activity but has
anticholinergic and antiparkinsonian activity.

39
- Unbranched propyl side chain has good antipsychotic activity while branching increases
antihistaminic activity/reduces antipsychotic activity.
- Branching of the propyl side chain (Substituents on the propyl chain) e.g. with a methyl
group, decreases activity.
- The methyl group creates a chiral activity in which the L isomer is more potent than the D
isomer.
- The bulkiness of the substituent also restricts rotation around the propyl chain hence
decreasing activity, e.g. Trimeprazine. It has antihistaminergic activity with good antipruritic
activity but has lost antipsychotic activity.
- Elongating propyl chain decreases activity.
- Aliphatic side chains have lowest activity, pronounced sedative and antimuscarinic effects,
and moderate extrapyramidal effects (EPEs). Compare with the other groups below.
Depending on the substituent at position 10, phenothiazines are classified into three classes.
a. Aliphatic phenothiazines, e.g. chlorpromazine.
b. Piperidines e.g thioridazine
c. Piperazines e.g fluphenazine

a. Aliphatic phenothiazines
Include: chlorpromazine, triflupromazine
- This group is the least potent (lowest activity) with marked sedation and relative
antihistamic activity and anticholinergic/antimuscarinic activity.
- When R2 is CF3, it gives the highest potency in aliphatic phenothiazenes.
- They have a high tendency for extra-pyramidal side effects (EPEs): tremors, rigidity,
bradykinesia, occulogical crisis.

b. Piperidines

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 Include: thioridazine, mesoridazine.
- A piperidine group confers moderate activity and reduced extra-pyramidal effects.
- This class has the least extra-pyramidal side effects probably due to their increased
antimuscarinic effects.
- They have little antiemetic activity among phenothiazines and have the least toxicity (EPEs)
among phenothiazines.

c. Piperazines

Include: Fluphenazine, acetophenazine, perphenazine, prochlorperazine, trifluoperazine.

- They have an alkyl piperazine side chain which makes them the most potent phenothiazines
but also with the most extra-pyramidal side effects.
- They have least sedation and antimuscarinic effects and most effective antiemetic activity.
- The larger the alkyl group, the more the activity.
NB: the degree of activity in phenothiazines is determined by the various groups attached to
the terminal nitrogen.
Larger alkyl piperazines >methyl piperazines>piperidines>aliphatic side chains.
→ decreasing antipsychotic effectiveness/activity →
b) Phenothiazine nucleus
- Compounds with activity have 3 closed rings each being six membered with a hetero atom
in the central ring. This configuration gives the structure a twist that makes the compound
not rigid or non coplanar. The hetero atom in the central ring gives the compound the twist
making it have antipsychotic activity rather than antidepressant activity. This hetero atom is
sulphur at C5 and is responsible for tranquilizing effect.
- An open chain has no activity, e.g. diphenyl amine….Sketch??
- A 5 membered ring in the structure leads to loss of activity…Sketch??
- If there is no hetero atom, there is no activity, e.g. in anthracenes…Sketch??
- Quarternization of the posn 10 nitrogen makes the compound polar hence cannot cross the
BBB thus reducing activity.

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- Absence of the nitrogen at position 10 of the central ring does not lead to loss of activity as
seen in xanthenes and thioxanthines which have activity. See later
- Any substitution on the ring nucleus other than position 2 destroys activity.

c) Position 2 substituent
- Phenothiazines have a substitution at position 2 which makes the compound asymmetric, a
feature that is necessary for activity.
- The substituent is an electron withdrawing group. The more the electron withdrawing the
group, the better the activty.
CF3>Cl>OCH3
→decreasing activity →
d) The terminal nitrogen
- The terminal nitrogen in the side chain is essential for activity. Removal of the terminal
nitrogen leads to loses activity.
- The nitrogen may be part of a simple heterocyclic structure e.g. in piperazines and
piperidines.
- The terminal nitrogen must be tertiary. Secondary and primary nitrogen have less activity.
- The substituents on the nitrogen have dimethyl substituents giving the best therapeutic
index. Diethyl have less activity and more anticholinergic side effects. Chain longer than
ethyl has no activity.

2. XANTHINES AND THIOXANTHINES

- Thioxanthines and xanthenes do not have nitrogen at position 10 but instead they have a
side chain joined to the nucleus by C = C double bond. xanthenes have O heteroatom in
posn 5 while thioxanthenes have S heteroatom. Sketch??
- The double bond at position 10 introduces geometric isomerism in xanthenes and
thioxanthines in which the trans isomer is more active than cis isomer.
- Saturation of the double bond decreases activity.

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- Flupenthixol exist in both cis (alpha) and trans (beta) form where the cis is more potent. The
two isomers have same physico-chemical properties but they in vary pharmacological
activity.

SAR
- Have isomers where the trans is more active than cis.
- Saturation at posn 10 C=C side chain leads to loss/reduction of activity.

Stability of phenothiazines
They are readily auto-oxidized when exposed to air and light forming coloured, toxic and inert
compounds. Auto-oxidation is due to the lone pair of electrons from the hetero atoms and the
π electrons in the rings.
To avoid this autoxidation, they are;
a. Sugar coated
b. Stored in nitrogen and with antioxidants
c. Stored in dry conditions and away from light
Formulations of phenothiazines and thioxanthenes
- As free bases, they are basic in nature and they are water insoluble. They are formulated as
salts of strong acids to improve aqueous solubility, e.g. chlorpromazine hydrochloride which
exists as a white crystalline powder.
- Esterification of phenothiazines that have a free OH with long chain fatty acids gives esters
that have a long DOA. This esters may be given as long acting depot drugs that can be
administered as IM injection, e.g. once in 2-4 weeks e.g. fluphenazine decanoate
- The IM depot formulations give stable sustained activity improving patient’s compliance.

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Metabolism of phenothiazines and thioxanthenes/xanthenes
They are highly lipophilic hence bind to proteins and membranes hence they cross the placenta
barrier and therefore can reach the foetus.

Pathways
Illustrate metabolic pathways of chlorpromazine!!
1. N-dealkylation at position 10 N terminal
2. Sulfoxidation (sulfoxide formation)
3. Oxidative deamination of the amino propyl side chain to give aldehyde, alcohol and
ammonia
4. Aromatic ring hydroxylation at position 3 and 7 followed by N-glucorination
5. N oxidation
6. Direct N glucorination

Uses of phenothiazines
 Schizophrenia and other psychotic disorders
 Mania and psychomotor agitation

3. BUTYROPHENONES

Others: Droperidol, bromperidol, trifluperidol, spiperone, fluanisone, fenaperone

They were discovered during the SAR studies of the narcotic analgesic normeperidine which is
related to pethidine.
They are non tricyclic antipsychotics in which the flourophenone is considered to be equivalent
to the tricyclic nucleus of antipsychotics.

SAR
a. The benzene/aromatic ring
- It is necessary for activity.
- Its replacement by saturated groups or five or six membered heterocyclic groups leads to
loss of activity.
- A flouro or methoxy substituent at the para position of the benzene ring is essential for
activity. Flouro gives better activity and only compounds with F are used clinically.
- Substitution at ortho or meta position diminishes activity.
- Other halogens, chloro, bromo and iodo, have lower activity.

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- The keto group must be para to the halogen to attain activity. Ortho or meta keto group
have no activity.
b. Propyl chain
- It is necessary for activity.
- Lengthening, branching or shortening it diminishes activity but does not result in
antihistaminic activity like in phenothiazines.
c. Keto group
- It cannot be replaced by a thioketo or olefinic group.
- Reduction of the keto group abolishes activity.
d. Terminal amino group
- It must be a tertiary nitrogen. It is usually attached to the 4th carbon of the butyrophenone.
- The nitrogen may be part of a ring that is para or meta substituted(piperidine, or
piperazine)

Stability of butyrophenones
The compounds have excess electron contributed by the π electrons and lone pair of electrons
and are therefore prone to auto-oxidation in light to give dark coloured compounds that are
toxic and inactive. They are therefore stored in air tight amber coloured containers.
Formulations as capsules or sugars coated tabs, also injectable forms especially long acting
formulations e.g. haloperidol is esterified by long chain fatty acids like decanoate which is given
IM once in 2-3 weeks.
Metabolism
- N-dealkylation
- Reduction of the keto group

4. DIPHENYLBUTYL PIPERIDINES
All derivatives of butyrophenones where the keto group is replaced by a 4 fluorophenyl group.
They have a shorter duration of action compared to butyrophenones. Those in clinical use
include: Pimozide, fluspirilene, penfluridol –long acting (once weekly admn)

5. BENZAMIDES
They were derived by observing that metoclopromide antagonizes D2 Receptors.
They include: Tiapride, cisapride, sulpiride, metoclopromide(plasil ®)

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Metoclopromide and cisapride are used for nausea and vomiting.Though they have
antipsychotic activity.
Sulpiride, tiapride - atypical antipsychotic in clinical use with minimal extrapyrimidal side
effects.

6. BENZAZEPINES/ DIBENZAZEPINES
They are atypical antipsychotic agents with minimal extrapyrimidal side effects.
a. Dibenzodiazepines – N, N (at position 1 and 4) – clozapine, olanzapine
b. Dibenzoxazepines – N, O (1 and 4) - loxapine
c. Dibenzothiazepines N, S (1 and 4) - Quatiapine

Clozapine – Weak D2 receptor antagonism, few EPEs. Supresses both +ve and –ve signs of
schizophrenia. Relative selectivity for D4 receptors, 5-HT2 and α1 blockade. Modest
antimuscarinic and H1 blocking activity. It’s used as a reserve drug in resistant schizophrenia.

7. INDOLE DERIVATIVES
Examples: Sertindole, molindole, ziprasidone, risperidone. They have an indole structure.

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Risperidone – Has D2 and 5-HT2 receptor antagonism. Also H1 and α1,α2 blockade.

8. RAUWOLFIA ALKALOIDS
- Reserpine
- deserpidine
- Rescannamine
Are alkaloids Isolated from Rauwolfia serpentine. Reserpine has both antipsychotic and
antihypertensive activity. They are amides depleting
The drugs are obsolete due to the side effects including marked depression leading to suicidal
tendency, hypertension and emergence of better drugs. They are metabolized by ester
hydrolysis.

Adverse effects of antipsychotics:

- Extrapyramida disturbances- Describe them!
- CNS- drowsiness, mental confusion, ↑appetite & weight gain, aggravation of seizures in
epileptics
- α adrenergic blockade; postural hypotension, inhibition of ejaculation, (esp. thioridazone)
- Anticholinergic :Dry mouth etc
- Endocrinal; gynaecomastia, amenorrhoea, infertility
Uses of antipyschotics:
- Psychoses, Mania, Organic brain syndrome
- Anxiety - Anxiety with a psychiatric basis
- As antiemetics – Not effective in motion sickness
- Other uses: Preanaesthesia –
To potentaite hypnotics, analgesics, anesthetics in anesthesia
- Intractable hiccup
- Tetanus
- Alcoholic hallucinosis, etc

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