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Pharm Fabs C Amaechina

SEDATIVES AND HYPNOTICS

Sedatives are drugs that cause sedation, relieve anxiety and exert calming effects, with minimal
depression of the central nervous system. Sedatives tend to remove worries and exert a temporal
calmness and reassurance on troubled mind. On the other hand, hypnotics are drugs that cause
hypnosis and enhance the onset and maintenance of state of sleep that by all standards, is similar
to natural sleep and importantly, from which the patient can easily be aroused. Hypnotics achieve
their effect by significantly depressing the central nervous system.
The sedative and hypnotic effect of a drug is usually dose dependent, and correlates with the
degree of central nervous system depression. What we are trying to say here is that sedatives
achieve a mild depression of the central nervous system with the patient still exhibiting a high
level of consciousness whereas hypnotic exhibit a pronounced depression of the central nervous
system with complete loss of consciousness.
The dividing line a sedative and hypnotic effect of a drug is the dose of that drug taken at any
point in time. At much lower clinical dose, the effect is invariably sedative, while at much higher
clinical dose, the effect tends towards hypnosis.
These classes of pharmacological agents have found immense application in other areas of
medicines. They are used to achieve amnesia before surgical procedures. They are used in the
treatment of alcohol and other sedatives/hypnotics withdrawal syndrome and also as muscle
relaxants.
Clinically, induction of sedation or hypnosis can be said to have begun in the early 1800s first
with alcohol and the opium. These were replaced with bromide salts and chloral hydrate before
the introduction of ethyl alcohol which was then described as the knock out drop. The
introduction of paraldehyde marked the beginning of deliberate search for newer synthetic
sedative-hypnotic drugs.
Consequently, the barbiturates were introduced into clinical use, first with Phenobarbital as the
prototype drug in 1930. By the mid-1900s, the benzodiazepines were introduced into clinical
practice, and since have become the sedative-hypnotics of choice.

BENZODIAZEPINES
The benzodiazepines are the most widely used sedatives and hypnotic agents clinically. Beside
their hypnotic and sedative effects, they have very potent muscle relaxation, anxiolytic and
anticonvulsant properties. On the peripheral level, they cause dilatation of the coronary artery
and are potent neuromuscular blockers at very high doses.
Γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain that functional
depresses neuronal firing. GABA binds to all its receptor subtypes (GABAA, GABAB and
GABAC receptors. The benzodiazepines bind to GABA A–receptor at an allosteric site that is
different from the site bound by GABA thereby enhancing the GABA induced ionic current
especially chloride ions. Consequence of the opening of Cl- channels, benzodiazepines potentiate
the inhibitory effect of GABA neurotransmitter.
Some of the common benzodiazepines in clinical use especially in Nigeria include:
Diazepam (Valium), Nitrazepam (Mogadon), Bromazepam (Lexotan), Lorazepam (Ativan) and
Flunitrazepam (Rohypnol).

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Pharmacology and application of Benzodiazepines

Sleep: Sleep disorders are as varied as there are many causes. Sleep disorder could be organic,
psychological, or situational. No matter the cause, sedatives like benzodiazepines have become
resolution tools of such problems. At this point, it is important to emphasize here that when the
presenting clinical situation is insomnia benzodiazepines are exceptionally effective and are the
drugs of choice. Most benzodiazepines decrease sleep latency, especially when used for the first
time. They also decrease the number of awakenings and its duration before falling asleep again.
Effect of benzodiazepines to a very large extent is dose dependent. As the dose increases, the
effect progresses from sedation to hypnosis and to a complete state of stupor. All the stages of
normal sleep are affected by benzodiazepines. In decreasing the sleep latency, they in effect
decrease the duration REM and slow wave sleep. On the other hand, the duration of the NREM
is increased and the end results is an increase in the total sleep time and induced sense of deep
and refreshing sleep.
Respiration
Respiration is not adversely affected by therapeutic dose of benzodiazepines in normal adults.
However, at higher doses like for pre-anaesthsia, benzodiazepines would cause respiratory
depression and acidosis. Benzodiazepines must be used with caution in children and adults with
compromised hepatic function.
Cardiovascular system
Effects of benzodiazepines on the CVS in normal individuals are mild. However, they would
decrease blood pressure and increase heart rate at pre-anaesthetic and toxic doses.
Gastrointestinal tract
Most benzodiazepines would decrease nocturnal acid secretion in acid-peptic ulcer patients.
Pharmacokinetic
The distribution of the lipid-water coefficient of all benzodiazepines is high in the non-ionized
form. Despite this fact, lipophilicity varies greatly among members and this is highly influenced
by the polarity and electronegativity of the substituents. They are completely and rapidly
absorbed orally. Clonazepate and indeed all benzodiazepines are however first decarboxylated in
the gastric system to N-desmethyldiazepam which is eventually absorbed. Desmethyldiazepam is
biologically active and has a half life of about 60 hrs. The pharmacokinetic profile of the
benzodiazepine to a very large extent determines half life, and hence their duration of action.
Benzodiazepines are variably bound to plasma proteins and this range from about 70% for
aprazolam to almost 99% for diazepam.
Benzodiazepines are rapidly taken up into the brain and other highly perfused tissues, and the
concentration in the cerebrospinal fluid is equal to the amount of free unbound drug in the
plasma. All benzodiazepines cross the placenta, and are secreted into the breast milk.
They are metabolized by the cytochrome-P enzyme complex of the liver and therefore are
involved greatly in drug /drug interactions. Drugs like erythromycin, ketoconazole, itraconazole,
clarithromycin and ritonavir inhibit metabolism of benzodiazepines significantly, and will
prolong the plasma half life.
Adverse effect
Side effects resulting from peak plasma concentration of benzodiazepines are light headedness,
lassitude, increased reaction time, impaired motor coordination and mental functions confusion
and antrogade amnesia.

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THE NON-BENZODIAZEPINES (The Z-Compounds)

Benzodiazepine receptor agonists
These are hypnotic and sedative drugs that have novel chemical structure that is not in any way
similar to the benzodiazepines structure, but bind to preferentially to benzodiazepine allosteric
sites as GABA receptor agonists. They are used mainly to treat insomnia. Examples of these
drugs are: Zolpidem, Zaleplon, Esizoplicone etc.
Zaleplon is a pyrazolopyrimidine class of drug that preferentially binds to benzodiazepine
receptor site on the GABAA-receptor. It is effective in relieving delayed sleep onset in insomnia,
and has sustained efficacy as a hypnotic agent without rebound insomnia on discontinuation of
use. Zaleplon is rapidly absorbed after oral administration, reaching peak plasma concentration
in 1hour. This drug is about 60% bound to plasma protein, and has a half-life of 1hour. Zaleplon
is metabolized in the liver by aldehyde oxidase enzyme. The oxidative metabolites are however
converted to glucuronides, and excreted in the urine. It is administered in doses of 5, 10 and
20mg. zaleplon is recommended for sleep at bed time when the patient has difficulty falling
asleep. This drug is more well tolerated than zolpidem, as the side effects experienced by
patients is not too different from that of placebo. This however has been attributed to it short
half.
Zolpidem: Zolpidem is an imidazopyrimidine sedative/hypnotic drug that act by stimulating
benzodiazepine receptors. Its effects are by all standards similar to the effects produced by the
benzodiazepines, except that it demonstrated a very weak anticonvulsant activity in laboratory
animals. Zolpidem does significantly affect sleep stages in normal human beings, but it
effectively shortens sleep latency and prolongs total sleep time in patients with insomnia. With a
highly reduced case of rebound insomnia, zolpidem induced improvement and prolongation of
total sleep time in insomnia has been found to persist for as long as six months after the
discontinuation of treatment.
At therapeutic doses of 5, 10 and 20mg, zolpidem produce residual daytime sedation and
amnesia especially in the elderly while other side effects are reduced.
Zolpidem is absorbed completely after oral administration. It undergoes first pass metabolism,
which reduce the bioavailability to 70% or even lower in the presence of food. The half life of
the drug can be increased in patients with liver cirrhosis and in the elderly. Zolpidem is
eliminated completely as in active metabolites.
Alternative sedative and hypnotic drugs
Certain drugs have found immense use as sedatives and hypnotic, although this effects may not
be their primary pharmacological actions and clinical usefulness. For such drugs, advantage is
usually taken of their central nervous system depression side effects. They permeate the blood
brain barrier, cause dose dependent depression of the CNS and induce drowsiness and sedation.
They are briefly discussed below.

1. Histamine (H-1)- receptor antagonists

The first-generation H-1 receptor antagonists depress the CNS significantly in a dose dependent
manner to induce drowsiness as side effects. This is often taken advantage of to manage sleep
disorder and they are now formulated as sleep aid often with an analgesic. The have the
advantage of not cause addiction and dependence and do not induce rebound insomnia like the
benzodiazepines.
Others include:
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Paraldehyde: This is a polymer of acetaldehyde that has very strong aromatic odour and
disagreeable taste. Paraldehyde is irritating to the throat and stomach when administered orally,
and it is not administered parenterally because of injurious effect to tissues. When administered
rectally, it must be diluted with olive oil.
Paraldehyde is rapidly absorbed and widely distributed after oral administration. Sleep onset is
10 to 15minutes after administration of hypnotic dose. About 70 -80% of the administered dose
is metabolized by the liver through polymerization of acetaldehyde, and finally through
oxidation reaction to acetic acid. This is converted to carbon dioxide and water.

Look up Chloral Hydrate, Meprobamate and Flumazenil, a benzodiazepine receptor

antagonist.

ANTI-EPILEPTIC DRUGS.
Epilepsy is a neurological disorder of the central nervous system which occurs in population of
group of persons, to people of all ages, races, sex and socioeconomic group and status. It results
mainly from the malfunctioning of the brain neurons. In epileptic seizure, there is often an
impairment of consciousness which often exposes the patients to the risk of injuries resulting
from accident. For most adolescents, education is no doubt interrupted and school drop outs
increases with the population of young children that have epilepsy. For the adult, productivity at
work place is highly reduced and there is always a partial or complete withdrawal from social
activities. The most worrisome is that most epileptics have had to contend with a stigmatized
status that culminates in social isolation. This as matter of fact, arise from the erroneous believe
that epilepsy is contagious.
Seizure is referred to as temporal alteration of behaviour which results from disordered
synchronous and rhythmic firing of the brain neurons, while an epileptic fit is disorder of brain
function that is often characterized by periodic and unpredictable occurrence of seizures.
There are two main types of epileptic seizures:
There is partial seizure which refers to those originating from a focal point in the brain. Partial
seizures range from simple partial seizures to secondary clonic-tonic convulsion. The
manifestation of partial seizure is diverse and determined by the region of cortex activated by the
seizure, but it is important to point out that whichever manifestations are seen from which ever
part of the body, the key features in simple partial seizure are that there is complete preservation
of consciousness.
The second type of seizure is generalized seizures which could either be absent in nature in
which case there is abrupt impairment of consciousness associated with starring and cessation of
all ongoing activities. This lasts for about 30seconds or as it could be myo-clonic in nature. This
involves shock-like contraction of muscle. It is usually very brief and may be restricted to the
extremities. Generalized tonic-clonic seizure involves complete muscle paralysis and loss of
consciousness.

ANTI SEIZURE DRUGS

Communication in the central nervous system involves millions of neurons that generate
electrical impulses across synapses and the general postulation is that in normal healthy patients
as opposed to epileptic patients, the regulation of synaptic function is balanced whereas in an
epileptic patient, it is believed that a defective synaptic function which disorganizes the neuronal

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messaging balance triggers seizures. Communication across synapses involves neurotransmitters

in the brain especially as it relates to the discussion of epilepsy.
The neurotransmitters that mediate synaptic functions in the brain are basically:
1. Gamma amino butyric acid (GABA): This is functionally inhibitory
2. Glutamate and aspartate: These are functionally excitatory.

However, the two mentioned above are not exclusive as there are other neurotransmitters
such as acetylcholine, norepinephrine, serotonin, aspartate etc, with their respective role in
central nervous system communication.
These neurotransmitters have respective receptors and selective agonists and antagonists
which tend to modulate their activities. The use of a selective pure GABA receptor
antagonist or by the creation of a scenario which accentuates the excitatory function of
glutamate is likely to trigger off a seizure in experimental animals. Conversely, enhancement
of GABA inhibitory function with the use of GABA receptor agonist or the inhibition of the
excitatory function of glutamate with the use of glutamate receptor antagonist will inhibit
seizure.
With the fore going, it is important to opine here that antiepileptic drugs that are currently
available do not address the pathophysiology of epilepsy but rather have shown great
specificity in treating seizure and epileptic types. These drugs were developed along basic
mechanisms of action which actually formed the underlying mechanisms for the
development of seizures.
 Potentiation of GABA:

a) Drugs like benzodiazepines, barbiturates and to a lesser extent phenytoin bind to

GABAA-receptor to enhance the inhibitory effect of GABA by activation of the
chloride gated channel.

b) Drug that inhibit GABA transaminase enzyme that actually inactivates GABA.
Example is vigabatrin.

c) Drugs that inhibit the neuronal reuptake of GABA, example is tiagabine.

 Inhibition of influx of sodium ion across the fast sodium ion channels and
propagation of action potential. Drugs like phenytoin, carbamazepine, lamotrigine
and valproate inhibit generalized seizures by this mechanism

 Inhibition of influx of calcium ions across the slow t-calcium channels, e.g.
ethosuximide.

HYDANTOINS
Phenytoin (Epanutin) – It is structurally related to the pentobarbital but was found to suppress
both the partial and tonic clonic convulsion in animals without causing sedation.

Mechanism of action

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It slows down the rate of recovery of the voltage activated sodium-ion channels, thereby limiting
the continuous firing action of potential induced by the sustained depolarization of the spinal cord
of a mouse. Phenytoin also has great impact on the other ions like K + and Ca2+, as well as the
amino acids and neurotransmitter concentrations in the brain.
Phenytoin will modify the pattern of maximal electroshock tonic- clonic convulsion, by
abolishing characteristic tonic seizure phase in laboratory animals, while prolonging or
sometimes even exaggerating the clonic phase of the maximal electroshock seizure. It is
important to note that phentyoin does not cause sedation or depress the CNS completely.
Phenytoin is completely ineffective against pentylenetetrazol induced seizure in laboratory
animal which is the clinical manifestation of petit-mal epilepsy or absence seizure.

Pharmacokinetics:
Phenytoin is extensively, about 90% bound to plasma protein and the amount of plasma protein
available determines the overall bound drug and hence the amount of free drug available in
circulation. Consequently there is more unbound drug in circulation in the neonates,
hypoalbuminamea and uremic patients. Phenytoin competes with certain drugs like valproic acid,
aspirin, coumarin anticoagulants, sulphonamide and carbamazepine for albumin binding sites.
Phenytoin is metabolized in the liver endoplasmic reticulum by the cytochrome P450 isoform
enzyme systems into an inactive parahydroxylphenyl derivative. Other substrate drugs for this
enzyme system are capable of inhibiting the metabolism of phenytoin and thereby increasing the
plasma concentration of phenytoin. On the other hand, phenytoin can inhibit the metabolism of
warfarin anticoagulant with the attendant clinical complications such as hypothrombinaemia. The
half-life of phenytoin is between 16-36 hours.
Generally, phenytoin is also an enzyme inducer and can induce the metabolism of oral
contraceptives, and other drugs that are co-substrate to the hepatic cytochrome P 450 enzyme
system.
Phenytoin is toxicologically, a teratogen and therefore should be administered with care to
pregnant mothers.
Phenytoin is indicated for the treatment of epilepsies and some forms of trigeminal neuralgias.
Patients are usually started at the dose of 300mg/day, irrespective of body weight.

Side effects
Side effects are usually dose dependent, and also depend on the route and duration of therapy.
Chronic treatment with phenytoin could result to nystagmus, diplopia and ataxia which are all
CNS side effects. Gingival hyperplasia and hirsutism are also common on long time
administration. Cardiovascular side effect usually manifests as arrhythmias and is mostly
associated with the elderly and those that already has existing cardiovascular disease.
Other members of the hydantoin group include mephenytoin, ethotoin, fesfophenytoin and
phenacemide.

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BARBITURATES
Barbiturates are a class of drug with wide spread application in the central nervous system. They
are clinically useful as sedatives and hypnotics and phenobarbital was the first to show
effectiveaess in the management of seizures.
It is important to point out here that most barbiturates that must qualify for use as antiseizure
drugs should be able to inhibit seizures at doses very well below that required to invoke hypnosis.
The prototype barbiturate and perhaps the most widely used in the management of seizure is
Phenobarbital. Phenobarbital is non-selective as it inhibits seizures of all types including maximal
electro and pentyltetrazol induced seizures in laboratory animals.
Mechanism of action
Barbiturates exhibit anti-seizures effect mostly by acting on GABA A-receptor to potentiate
synaptic inhibition. It increases the GABA receptor mediated chloride ion current at therapeutic
concentration while at concentration beyond the therapeutic concentration, barbiturates will
inhibit the receptive firing of mouse cortical or spinal cord neurons by reducing the frequency of
action potential generation, through the prolongation of refractory period. This underlines the
mechanism by which barbiturates arrest status epilepticus.

Pharmacokinetics
Phenobarbital has excellent PCK. Absorption after oral administration is slow but complete. It is
widely distributed throughout the body and moderately bound to plasma protein, tissue and the
brain. The elimination of Phenobarbital is PH dependent, and about ¼ of administered dose of
barbital is excreted unchanged in the urine. Phenobarbital is metabolized in the liver by the
cytochrome P450 enzyme system which it also induces.

Side effects
Sedation occurs almost in all patients at the beginning of treatment. Nystagmus and ataxia will
occur at excessively high dose of barbiturate. Hypothrombinaemia has been observed in new born
whose mothers were on barbiturates while pregnant. This condition can be ameliorated by
administering vitamin K. Megaloblastic anaemia and osteomalacia are induced by Phenobarbital
during chronic therapy and can be corrected with supplementation with folate and high dose of
vitamin D.

Clinical uses
Barbiturates are indicated for the treatment of partial and generalized seizure, and for use as
hypnotic and sedatives.

DEOXYBARBITURATE (PRIMIDONE)
Primidone share some pharmacological similarities with Phenobarbital. Like Phenobarbital it is
effective against the tonic clonic and partial seizures, but less effective against pentylenetetrazol
induced seizure in seizures in laboratory animals. Pirimidine inhibits seizure directly on its own
and also by the utilization of the potent anti-seizure activity of its active metabolites, one of
which is Phenobarbital

Pharmacokinetic

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It is rapidly absorbed after oral administration while peak plasma concentration is reached 3hours
after administration. Plasma half life ranges from 5-15 hours. Pirimidone is converted to both
Phenobarbital and phenylethyl malonamide(PEMA) which are active metabolites. A large portion
of the plasma protein is bound by the metabolite Phenobarbital while the remaining is bound by
both primidone and PEMA. Both metabolites of primidone have long plasma half-lives. PEMA
has half life of 15hours while that of Phenobarbital ranges between 5-15hours. Only 40% of the
administrative drug in excreted unchanged in the urine.
Side Effects
Sedation, vertigo, dizziness, nausea, vomiting,ataxia,diplopia and nystagmus. Some patients may
experience some feeling of intoxication which may occur at the initiation of treatments, before
significant metabolism of primidone occurs.

Drug interactions
Enzyme inducers will enhance the metabolism of pirimidone to its active metabolites especially
Phenobarbital.
Clinical Uses
Primidone is useful against generalised tonic-clonic and all forms of partial seizures.

IMINOSTILIBENES
The popular drug here is carbamazephine. It is manufactured by Norvatis as Tegretol 200mg
plain 200mgCR and 400mgCR. Also Carzepin marketed by Pharmatex.
Carbamazepine has immense use in other areas of CNS disorder apart from seizures. It is a
constant feature in the prescription of almost all patients that leave psychiatric hospital for manic
and manic depression illness. It is a drug of primary consideration for the treatment of trigeminal
neuralgia. Carbamazepine is also effective in the treatment of tonic-clonic and partial seizures.

Mechanism of action
Carbamazepine shares the same Mechanism of action with phenytoin. Both drugs
1. Inhibit the repetitive firing of action potentials evoked by the sustained depolarisation of
mouse spinal cord or cortical neurones in-vitro.
2. They slow down the rate of recovery of voltage activated sodium channel from inactivation.

Pharmacokinetic
Carbamazepine is not well soluble in water. It is slowly and erractically absorbed after oral
administration. Peak plasma concentration is achieved within 4hours, but may sometimes be
delayed for up to 24hours. The drug is extensively distributed to all tissues and is about 75%
bound to plasma protein. Carbamazepine is metabolized by cP-450 enzyme system to a
potent active metabolite, 10, 11-epoxycarbamazepine.
The active metabolite is further metabolized to inactive glucuronide which is excreted in the
urine. It is an enzyme inducer and will therefore increase the metabolism of other drugs.
Adverse effects

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Acute intoxication of Carbamazepine can result to stupor and coma, hyper-irritability,

convulsion and even respiratory depression. Drowsiness, impetigo, diplopia, ataxia and
blurred vision have been associated with chronic treatment with carbamazepine. This drug
has the tendency to increase seizure frequencies during incidence of overdose. There may be
nausea, vomiting, aplastic anaemia, dermatitis, lymphadenopathy and encephalopenia.
Clinical Uses
Carbamazepine is indicated primarily for the treatment of tonic-clonic convulsion, partial
seizures, trigeminal neuralgia and for maniac depression in psychiatric disorders.

SUCCINIMIDES
The prototype of this group is ethosuximide. This is the first group of antiseizure drugs to
show effectiveness in the protection of laboratory animal against pentylenetetrazol induced
seizure. At therapeutic doses ethosuximide protects against the tonic motor seizure induced
by pentylenetetrazol, but is completely ineffective against maximal electroshock induced
seizure. This in essence implies that clinically, ethosuximide will be effective in the treatment
of absence seizure in human beings.
Mechanism of action:
Ethosuximide decrease the low threshold calcium (T-current) in the thalamic neurons,
without modifying the voltage dependent stage of inactivation. However, this drug does not
inhibit the sustained repetitive firing of action potential in mouse cortical neuron, neither does
it enhance GABA responses in clinically relevant doses.
Pharmacokinetic:
Ethosuximide is smoothly and completely absorbed after oral administration, and peak
plasma concentration is achieved 3hours after a single oral dose. It is moderately bound to
plasma protein and 25% of the administered dose is excreted unchanged while the remaining
75% is excreted by the hepatic microsomal enzyme. The plasma half life is averagely 14-
16hours in adults, and approximately 30hours in children.

Valproic acid
This is available as Epilim by Sanofi Aventis and as generics by other companies. Valproic
acid is effective against partial, absence and generalized seizures.

Mechanisms of action
Valproic acid like phenytoin will inhibit repetitive firing of mouse cortical neuron by
prolonging the recovery of sodium channel after the propagation of action potential. Valproic
acid also inhibits the slow T-current of calcium ions, but does not in any way modulate
GABA transmission directly. However, valproic acid has been found to prevent GABA
degradative enzymes, stimulate the activity of GABA synthetic enzymes and the activity of
glutamate decarboxylase enzymes. All this contribute to the antiseizure activity of valproic
acid.

Pharmacokinetics
Valproic acid is well absorbed after oral administration and peak plasma concentration is
attained between 1-2hrs however bio-pharmaceutic of dosage formulation and presence of

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food may delay the attainment of peak plasma concentration to several hours and also
decrease the toxicity of valproic acid. The drug is extensively (90%) bound to plasma protein.
The clearance of valproic acid is very slow and about 20% is cleared as conjugate drug. Half-
life varies from 9-18 hours. It is strictly distributed to extracellular fluids in the body.

Clinical uses and toxicity

Valproic acid is administered at the initial dose of 15mg/kg, which may be increased weekly
by 5-10mg/kg/d up to a maximum of 60mg/kg. valproic acid should be administered in
divided doses once the daily administered dose exceeds 250mg.
Dose related toxicity include nausea, vomiting and other gastrointestinal tract disorder such
as abdominal pain and heart burn. Hepatotoxicity may manifest as idiosyncratic toxicity. This
is most severe I patients under 2years old and those on multidrug therapy.

Look up Gabapentin, Lamotrigine and pregabalin

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