Cns Pharmacology: AJAYI AM Dept of Pharm & Tox, KIU-WC 1

CNS PHARMACOLOGY
AJAYI AM Dept of Pharm & Tox, KIU-WC 1

CNS DRUGS
• SEDATIVES, HYPNOTICS
• ANXIOLYTICS
• ANTIDEPRESSANTS
• ANTIPSYCHOTICS
• ANTIEPILEPTICS
• ANALGESICS
• CNS STIMULANTS & PSYCHOTOMIMETICS

SEDATIVES – HYPNOTICS
• Sedative: A drug that subdues excitement and calms the subject
without inducing sleep, though drowsiness may be induced.
Sedation refers to the decreased responsiveness to any level of
stimulation; is associated with some decrease in motor activity and
ideation.
• Hypnotic: A drug that induces sleep and/or maintain sleep, similar
to normal arousable sleep.
• The sedatives and hypnotics are more less general CNS depressants
with somewhat differing time-action and dose-action relationships.
• Those with quicker onset, shorter duration and steeper dose
response curves are preferred as hypnotics while more slowly
acting drugs with flatter dose response curves are employed as
sedatives.
• 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.

CLASSIFICATION
• Barbiturates: classified on the basis of onset of action and

duration of action.
• Ultra -short acting e.g Thiopentone, Mephobexitone
• Short acting e.g Pentobarbitone, Secobarbitone
• Intermediate acting e. g Butabarbitone, Aprobarbitone
• Long acting e. g Phenobarbital
• Benzodiazepines: May be divided according to primary use—
• Hypnotic e. g Diazepam, flurazepam, nitrazepam,
flunitrazepam, temazepam, triazolam, midazolam.
• Antianxiety e. g Diazepam, oxazepam, lorazepam, alprazolam,
chlordiazepoxide
• Anticonvulsant e. g Diazepam, clonazepam, clobazam
• Newer non benzodiazepine hypnotics
• Zopiclone, Zolpidem

• BARBITURATES
Barbiturates - Prototype of CNS depressants.
• Barbiturates are substituted derivatives of barbituric acid (malonyl urea).
Barbituric acid as such is not a hypnotic
• Barbiturates have variable lipid solubility, the more soluble ones are more
potent and shorter acting. They are insoluble in water but their sodium
salts dissolve yielding highly alkaline solution.
• PHARMACOLOGICAL ACTIONS
Barbiturates are general depressants for all excitable cells, the CNS is most
sensitive where the effect is almost global, but certain areas are more
susceptible.
• CNS Barbiturates produce dose dependent effects:
sedation —> sleep —> anaesthesia —> coma.
 Hypnotic dose of a short acting barbiturate shortens the time taken to fall
asleep and increases sleep duration.
 Sedative dose (smaller dose of a longer acting barbiturate) given at day
time can produce drowsiness, reduction in anxiety and excitability.
However, barbiturates do not have selective antianxiety action.
 Barbiturates can impair learning, short term memory and judgment.

 They can produce euphoria in addicts.
 They have no analgesic action; small doses may even cause hyperalgesia.
An attempt to put a patient in severe pain to sleep with a barbiturate
alone may result in restlessness, mental confusion, even convulsion.
• Barbiturates depress all areas of the CNS, but the reticular activating
system is most sensitive; its depression is primarily responsible for inability
to maintain wakefullness.
Mechanism of action : Barbiturates appear to act primarily at the GABA : BZD
receptor - C1- channel complex and potentiate GABAergic inhibition by
increasing the life time of Cl- channel opening induced by GABA.
• They do not bind to the BZD receptor, but bind to another site (probably
the picrotoxin sensitive site) on the same macromolecular complex to
exert the GABA-facilitatory action.
• They also enhance BZD binding to its receptor. At high concentrations,
barbiturates directly increase Cl- conductance (GABA-mimetic action;
contrast BZDs which have only GABA-facilitatory action) and inhibit Ca2+
dependent release of neurotransmitters.
• In addition they depress glutamate induced neuronal depolarization
through AMPA receptors. At very high concentrations, barbiturates
depress Na+ and K+ channels also.

• Other Systems
• Respiration Is depressed by relatively higher doses. Neurogenic,
hypercapneic and hypoxic drives to respiratory centre are
depressed in succession.
• Barbiturates do not have selective antitussive
• CVS Hypnotic doses of barbiturates produce a slight decrease in
BP and heart rate: magnitude of change not differing from that
during normal sleep. Toxic doses produce marked fall in BP due
to ganglionic blockade, vasomotor centre depression and direct
decrease in cardiac contractility.
• Skeletal muscle Hypnotic doses have little effect but
anaesthetic doses reduce muscle contraction by depressing
excitability of neuromuscular junction.
• Smooth muscles Tone and motility of bowel is decreased
slightly by hypnotic doses; more profoundly during intoxication.
• Kidney Barbiturates tend to reduce urine flow by decreasing BP
and increasing ADH release. Oliguria attends barbiturate
intoxication.

• PHARMACOKINETICS
• Barbiturates are well absorbed from the GIT. They are widely
distributed in the body. The rate of entry into CNS is
dependent on lipid solubility: highly lipid soluble thiopentone
has practically instantaneous entry while less lipid soluble
ones (pentobarbitone, secobarbitone) take longer;
phenobarbitone enters very slowly.
• Plasma protein binding varies with the compound, e.g.
thiopentone 75%, pentobarbitone 35%, phenobarbitone 20%.
Barbiturates cross placenta and are secreted in milk; can
produce effects on the foetus and suckling infant.

• Three processes are involved in termination of action of
barbiturates: the relative importance of each varies with the
compound.
(a) Redistribution It is important in the case of highly lipid soluble
thiopentone and other ultrashort acting barbiturates. After
their i.v. injection, consciousness is regained in 8-12 mins due
to redistribution while the ultimate disposal occurs by
metabolism (t½ of elimination phase is 9 hours). Effect of
single dose of short acting barbiturate may last just 6-10
hours due to redistribution, while elimination t½ is 15-50
hours.
(b) Metabolism: drugs with intermediate lipid solubility (short
acting barbiturates) are metabolised in the liver by oxidation,
dealkylation and conjugation.
(c) Excretion: Barbiturates with low lipid solubility (long acting
agents) are significantly excreted unchanged in urine.

Barbiturates induce hepatic microsomal enzymes and
increase the rate of their own metabolism as well as that of
many other drugs.
• USES
• Except for phenobarbitone in epilepsy and thiopentone in
anaesthesia, barbiturates are seldom used now. As hypnotic
and anxiolytic they have been superseded by BZDs.
• They are occasionally employed as adjuvants in
psychosomatic disorders.
• The enzyme inducing property of phenobarbitone can be
utilized to hasten clearance of congenital non-haemolytic
jaundice and kernicterus.

• ADVERSE EFFECTS
• Side effects Hangover is common after the use of barbiturates as hypnotic,
because they have long plasma t½. On repeated nightly use they
accumulate in body—produce tolerance and dependence. Mental
confusion, impaired performance and traffic accidents may occur.
• Idiosyncrasy In an occasional patient barbiturates produce excitement.
This is more common in the elderly.
• Precipitation of porphyria in susceptible individuals.
• Hypersensitivity Rashes, swelling of eyelids, lips etc—more common in
atopic individuals.
• Tolerance and dependence: Both cellular and pharmacokinetic tolerance
develops on repeated use. However, fatal dose is not markedly increased:
addicts may present with acute barbiturate intoxication. There is partial
cross tolerance with other CNS depressants.
• Psychological as well as physical dependence occurs and barbiturates have
considerable abuse liability—one of their major disadvantages.
• Withdrawal symptoms are—excitement, hallucinations, delirium,
convulsions; deaths have occurred.

• Contraindications
• 1. Acute intermittent porphyria—barbiturates exacerbate it by
inducing microsomal enzymes (δ aminolevulinic acid synthetase)
and increasing porphyrin synthesis.
2. Liver and kidney disease.
3. Severe pulmonary insufficiency, e.g. emphysema.
4. Obstructive sleep apnoea.
• Interactions
1. Barbiturates induce the metabolism of many drugs and reduce
their effectiveness - warfarin, steroids (including contraceptives),
tolbutamide, griseofulvin, chloramphenicol, theophylline.
2. Additive action with other CNS depressants - alcohol,
antihistamines, opioids etc.
3. Sodium valproate has been found to increase plasma
concentration of phenobarbitone.
4. Phenobarbitone competitively inhibits as well as induces
phenytoin and imipramine metabollsm: complex interaction.
5. Phenobarbitone decreases absorption of griseofulvin from the
GIT

BENZODIAZEPINES
• BZDs are the most frequently prescribed sedative hypnotic
agents, this class has proliferated and has gained popularity
over barbiturates as hypnotics and sedatives.
Site and Mechanism of action: Benzodiazepines act
preferentially on midbrain ascending reticular formation
(which maintains wakefulness) and on limbic system (thought
and mental functions). Muscle relaxation is produced by a
primary medullary site of action and ataxia is due to action on
cerebellum.
• BZDs act by enhancing presynaptic/postsynaptic inhibition
through a specific BZD receptor which is an integral part of
the GABAA receptor - Cl- channel complex. The subunits of this
complex form a pentameric transmembrane anion channel
gated by the primary ligand (GABA), and modulated by
secondary ligands which include BZDs.

• The modulatory BZD receptor increases the frequency of Cl-
channel opening induced by submaximal concentrations of
GABA.
• The GABAA antagonist bicuculline antagonizes BZD action in a
non- competitive manner. It is noteworthy that the BZDs
donot themselves increase Cl- conductance; have only GABA
facilitatory but no GABA mimetic action. This probably
explains the low ceiling CNS depressant effect of BZDs.
• BZD agonists: the BZD-agonists enhance GABA induced
hyperpolarization (due to influx of Cl- ions), and decrease
firing rate of neurones,
• BZD –inverse agonists: compounds called BZD-inverse
agonists like dimethoxyethyl-carbomethoxy-13-carboline
(DMCM) inhibit GABA action and are convulsants.
• BZD antagonist: The competitive BZD-antagonist flumazenil
blocks the sedative action of BZDs as well as the convulsant
action of DMCM.

• Pharmacological actions
• Virtually all effects of the benzodiazepines result
from their actions on the CNS. The most prominent
of these effects are sedation, hypnosis, decreased
anxiety, muscle relaxation, anterograde amnesia, and
anticonvulsant activity.
• Only two effects of these drugs result from
peripheral actions: coronary vasodilation, seen after
intravenous administration of therapeutic doses of
certain benzodiazepines, and neuromuscular
blockade, seen only with very high doses.

• CNS actions: In contrast to barbiturates they are not general
depressants, but exert relatively selective anxiolytic, hypnotic,
muscle relaxant and anticonvulsant effects.
• Even when apparently anaesthetic dose of diazepam is
administered some degree of awareness is maintained,
though because of anterograde amnesia (interference with
establishment of memory trace) the patient does not clearly
recollect the events on recovery.
• The antianxiety action of BZDs is probably not dependent on
their sedative property: with chronic administration relief of
anxiety is maintained but drowsiness wanes off due to
development of tolerance.
• While there are significant differences among different BZDs,
in general, they hasten onset of sleep, reduce intermittent
awakening and increase total sleep time (specially in those
who have a short sleep span).
• Some degree of tolerance develops to the action of BZDs on
sleep after repeated nightly use.

• BZDs produce centrally mediated skeletal muscle relaxation
without impairing voluntary activity. Clonazepam and
diazepam have more marked muscle relaxant property; very
high doses depress neuromuscular transmission.
• Clonazepam, diazepam, nitrazepam and flurazepam have
more prominent anticonvulsant activity than other BZDs.
However, their utility in epilepsy is limited by development of
tolerance to the anticonvulsant action.
• Given iv., diazepam (but not others) causes analgesia. in
contrast to barbiturates, BZDs donot produce hyperalgesia.
• Other actions Diazepam decreases nocturnal gastric
secretion and prevents stress ulcers. BZDs donot significantly
affect bowel movement.

Pharmacokinetics
• Benzodiazepines are usually given orally and are well absorbed by this
route. For emergency treatment of seizures or when used in anesthesia,
the BDZ also can be given parenterally.
• Diazepam and lorazepam are available for intravenous administration.
• BDZs with greater lipid solubility tend to enter the central nervous system
more rapidly and thus tend to produce their effects more quickly.
• Tissue redistribution of benzodiazepines is an important means of
terminating the actions of selected members of this class of drugs, many
benzodiazepines do undergo extensive biotransformation.
• Clinical Uses
• Anxiety: Anxiety disorders are among the most common forms of
psychiatric illness. Anxiety often accompanies other psychiatric disease
and such medical illnesses as angina pectoris, gastrointestinal disorders,
and hypertension. Both acute and chronic anxiety can be treated with
benzodiazepines.

• Insomnia: All of the BDZs will produce sedative– hypnotic effects of
sufficient magnitude to induce sleep, provided that the dose is high
enough. However, the aim in the treatment of sleep disorders is to induce
sleep that is as close as possible to natural sleep so that the patient falls
asleep quickly, sleeps through the night, and has sleep of sufficient quality
to awake refreshed.
• Epilepsy and Seizures: Clonazepam and diazepam are two BDZs that
depress epileptiform activity and are used in the treatment of epilepsy
and seizure disorders.
• Sedation, Amnesia, and Anesthesia: Benzodiazepine- induced sedation
and amnesia are deemed useful in the preparation of patients for
anesthesia, surgery, and other frightening or unpleasant medicaland
dental procedures and diagnostic tests. Midazolam is a frequently used
anesthetic benzodiazepine.
• Muscle Relaxation : BDZs, such as diazepam, are often prescribed for
patients who have muscle spasms and pain as a result of injury. In these
circumstances, the sedative and anxiolytic properties of the drug also may
promote relaxation and relieve tension associated with the condition.

• Alcohol and Sedative–Hypnotic Withdrawal: Withdrawal from long-term
high-dose use of alcohol or sedative–hypnotic drugs can be life
threatening if physical dependence is present. BDZs, such as
chlordiazepoxide and diazepam, are sometimes used to lessen the
intensity of the withdrawal symptoms when alcohol or sedative–hypnotic
drug use is discontinued. Benzodiazepines are also employed to help
relieve the anxiety and other behavioral symptoms that may occur during
rehabilitation.
ADVERSE EFFECTS
• These include drowsiness, excessive sedation, impaired motor
coordination, confusion, and memory loss.
• Less common adverse effects include blurred vision, hallucinations, and
paradoxical reactions consisting of excitement, stimulation, and
hyperactivity.

TOLERANCE & DEPENDENCE
• Tolerance and dependence do occur with the use of benzodiazepines.
• Discontinuation of drug administration, particularly abrupt withdrawal,
can be associated with a variety of symptoms, including rebound insomnia
and rebound anxiety. The level of insomnia or anxiety may even exceed
that which preceded the treatment.
• Usually, a gradual tapering of the dose until it is eventually discontinued
lessens the likelihood of a withdrawal reaction, although in some
individuals even this method of drug removal can result in anxiety,
apprehension, tension, insomnia, and loss of appetite.
• More severe symptoms may occur when an individual withdraws from a
supratherapeutic dose, particularly if the drug has been taken for months
or years. These symptoms can include, in addition to those already
mentioned, muscle weakness, tremor, hyperalgesia, nausea, vomiting,
weight loss, and possibly convulsions.

• Zolpidem
• The hypnotic zolpidem is not a benzodiazepine in structure, but it acts
on a subset of the benzodiazepine receptor family, BZ1.
• Zolpidem has no anticonvulsant or muscle-relaxing properties. It shows
few withdrawal effects, and exhibits minimal rebound insomnia, and
little or no tolerance occurs with prolonged use.
• Zolpidem is rapidly absorbed from the gastrointestinal tract, and it has
a rapid onset of action and short elimination half-life (about 2 to 3
hours).
• Zolpidem undergoes hepatic oxidation by the cytochrome P450 system
to inactive products. Thus, drugs such as rifampin, which induce this
enzyme system, shorten the half-life of zolpidem, and drugs that
inhibit the CYP3A4 isoenzyme may increase the half-life this drug.
• Adverse effects of zolpidem include nightmares, agitation, headache,
gastrointestinal upset, dizziness, and daytime drowsiness.

ANXIOLYTICS
• Anxiety disorders as recognised clinically include:
• Generalised anxiety disorder (an ongoing state of excessive
anxiety lacking any clear reason or focus)
• Panic disorder (sudden attacks of overwhelming fear occur in
association with marked somatic symptoms, such as sweating,
tachycardia, chest pains, trembling and choking). Such attacks can
be induced even in normal individuals by infusion of sodium
lactate, and the condition appears to have a genetic component).
• Phobias (strong fears of specific objects or situations, e.g. snakes,
open spaces, flying, social interactions)
• Post-traumatic stress disorder (anxiety triggered by recall of past
stressful experiences)
• Obsessive compulsive disorder (compulsive ritualistic behaviour
driven by irrational anxiety, e.g. fear of contamination).

• CLASSIFICATION OF ANXIOLYTIC DRUGS
• Benzodiazepines. This is the most important
group, used as anxiolytic drugs.
• Buspirone. This 5-HT1A receptor agonist is
anxiolytic but not appreciably sedative.
• β-Adrenoceptor antagonists (e.g.
propranolol).
• Antidepressants e. g paroxetine

• BUSPIRONE
• The first example of a class of anxiolytic agents that can relieve some
symptoms of anxiety in doses that do not cause sedation. Buspirone is
structurally unrelated to existing psychotropic drugs.
• Mechanism of Action: it appears that its clinically relevant effects are
mediated through interactions at the serotonin (5-hydroxytryptamine, 5-
HT) 5-HT1A receptor, where it acts as a partial agonist.
• Pharmacokinetics: Buspirone is well absorbed from the gastrointestinal
tract, and peak blood levels are achieved in 1 to 1.5 hours; the drug is
more than 95% bound to plasma proteins. Buspirone is extensively
metabolized, with less than 1% of the parent drug excreted into the urine
unchanged. At least one of the metabolic products of buspirone is
biologically active.
• Clinical Uses: Buspirone is effective in general anxiety and in anxiety with
depression.
• Adverse Effects: The most common side effects are dizziness, light-
headedness, and headache. Abuse, dependence, and withdrawal have not
been reported,

• β -Adrenoceptor Blocking Agents
• Propranol have been widely used in the treatment of cardiovascular
diseases. These blockers also are useful in some forms of anxiety,
particularly those that are characterized by somatic symptoms or by
performance anxiety (stage fright). There is general agreement that
-blockers can lessen the severity and perhaps prevent the appearance of
many of the autonomic responses associated with anxiety. These
symptoms include tremors, sweating, tachycardia, and palpitations.
• Antidepressants
• Antidepressant drugs, such as the tricyclic antidepressants and the
selective serotonin reuptake inhibitors (SSRIs), are very important for the
treatment of psychotic depression. They have been shown to be effective
when used in the treatment of several anxiety disorders, including general
anxiety, obsessive- compulsive disorder, and several phobias, including
agoraphobia. Because the SSRIs are less toxic than the tricyclic
antidepressants, their use in the treatment of anxiety is safer and less
likely to produce serious side effects.

ANTIDEPRESSANTS
• Depression is the most common of the affective disorders (defined as
disorders of mood rather than disturbances of thought or cognition); it
may range from a very mild condition, bordering on normality, to severe
(psychotic) depression accompanied by hallucinations and delusions.
• Worldwide, depression is a major cause of disability and premature death.
In addition to the significant suicide risk, depressed individuals are more
likely to die from other causes, such as heart disease or cancer.
• The symptoms of depression include emotional and biological
components.
• Emotional symptoms:
– misery, apathy and pessimism
– low self-esteem: feelings of guilt, inadequacy and ugliness
– indecisiveness, loss of motivation.
• Biological symptoms:
– retardation of thought and action
– loss of libido
– sleep disturbance and loss of appetite.
• There are two distinct types of depressive syndrome, namely
• Unipolar depression, in which the mood swings are always in the same
direction. Unipolar depression is commonly (about 75% of cases) non-
familial, clearly associated with stressful life events, and accompanied
by symptoms of anxiety and agitation; this type is sometimes termed
reactive depression. . Other cases (about 25%, sometimes termed
endogenous depression) show a familial pattern, unrelated to external
stresses, and with a somewhat different symptomatology.
• Bipolar affective disorder, in which depression alternates with mania.
Bipolar depression, which usually appears in early adult life, is less
common and results in oscillating depression and mania over a period
of a few weeks.
• Mania is in most respects exactly the opposite, with excessive
exuberance, enthusiasm and self-confidence, accompanied by
impulsive actions, these signs often being combined with irritability,
impatience and aggression, and sometimes with grandiose delusions of
the Napoleonic kind

• THE MONOAMINE THEORY OF DEPRESSION
• The main biochemical theory of depression is the
monoamine hypothesis, proposed by Schildkraut in
1965, which states that depression is caused by a
functional deficit of monoamine transmitters at
certain sites in the brain, while mania results from
a functional excess.
• The monoamine hypothesis grew originally out of
associations between the clinical effects of various
drugs that cause or alleviate symptoms of
depression and their known neurochemical effects
on monoaminergic transmission in the brain.

• TYPES OF ANTIDEPRESSANT DRUG
• Inhibitors of monoamine uptake:
– tricyclic antidepressants (TCAs) (non-selective noradrenaline/serotonin uptake
inhibitors); these include (e.g. imipramine, amitriptyline)
– selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine, fluvoxamine,
paroxetine and sertraline).
– selective noradrenaline uptake inhibitors (e.g. maprotiline, reboxetine).
• Monoamine oxidase (MAO) inhibitors (MAOIs):
– irreversible, non-competitive inhibitors (e.g. phenelzine, tranylcypromine),
which are non-selective with respect to the MAO-A and -B subtypes
– reversible, MAO-A-selective inhibitors (e.g. moclobemide).
• Miscellaneous (atypical) receptor-blocking compounds whose
antidepressant actions are poorly understood (e.g. bupropion,
mianserin, trazodone, mirtazapine, venlafaxine and duloxetine).
• The herbal preparation St John's wort, whose main active ingredient is
hyperforin, has similar clinical efficacy to most of the prescribed
antidepressants.

• TRICYCLIC ANTIDEPRESSANTS (TCAs)
• They are generally categorized as tertiary or secondary amines.
• Tertiary amines include imipramine, amitriptyline, trimipramine, and
doxepin.
• Desipramine, nortriptyline,and protriptyline are secondary amines.
• Maprotiline and amoxapine are heterocyclic antidepressant agents.
• Mechanism of action
• Inhibition of neurotransmitter reuptake: TCAs and amoxapine are potent
inhibitors of the neuronal reuptake of norepinephrine and serotonin into
presynaptic nerve terminals. the TCAs cause increased concentrations of
monoamines in the synaptic cleft, ultimately resulting in antidepressant
effects.
• Maprotiline and desipramine are selective inhibitors of norepinephrine
reuptake.
• Pharmacokinetics
• Tricyclic antidepressants are well absorbed upon oral dministration.
Because of their lipophilic nature, they are widely distributed and readily
penetrate into the CNS.
• Therapeutic uses
• The TCAs are effective in treating moderate to severe major depression. Some
patients with panic disorder also respond to TCAs.
• Imipramine has been used to control bed-wetting in children (older than 6 years)
by causing contraction of the internal sphincter of the bladder. At present, it is
used cautiously because of the inducement of cardiac arrhythmias and other
serious cardiovascular problems.
• The TCAs, particularly amitriptyline, have been used to treat migraine headache
and chronic pain syndromes (for example, neuropathic pain) in a number of
conditions for which the cause of the pain is unclear.
• Adverse effects
• Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth),
urinary retention, constipation, and aggravation of narrow-angle glaucoma.
• The TCAs also block adrenergic receptors, causing orthostatic hypotension,
dizziness, and reflex tachycardia. In clinical practice, this is the most serious
problem in the elderly.
• Weight gain is a common adverse effect of the TCAs. Sexual dysfunction, as
evidenced by erectile dysfunction in men and anorgasmia in women, occurs in a
significant minority of patients

• SELECTIVE SEROTONIN REUPTAKE INHIBITORS
• Fluoxetine, fluvoxamine, paroxetine, citalopram and sertraline.
• They are the most commonly prescribed group of antidepressants. As well
as showing selectivity with respect to 5-HT over noradrenaline uptake,
they are less likely than TCAs to cause anticholinergic side effects and are
less dangerous in overdose. In contrast to MAOIs (see below), they do not
cause 'cheese reactions'.
• They are as effective as TCAs and MAOIs in treating depression of
moderate degree, but probably less effective than TCAs in treating severe
depression. They are also used to treat a particular type of anxiety
disorder known as obsessive compulsive disorder.
• Pharmacokinetic
• The SSRIs are well absorbed, and most have plasma half-lives of 15-24
hours (fluoxetine is longer acting: 24-96 hours). The delay of 2-4 weeks
before the therapeutic effect develops is similar to that seen with other
antidepressants. Paroxetine and fluoxetine are not used in combination
with TCAs, whose hepatic metabolism they inhibit, for fear of increasing
TCA toxicity.

• Therapeutic uses: 5-HT uptake inhibitors are used in a variety of
psychiatric disorders, as well as in depression, including anxiety disorders,
panic attacks and obsessive compulsive disorder.
• Adverse effects: Common side effects are nausea, anorexia, insomnia, loss
of libido and failure of orgasm.
• In combination with MAOIs, SSRIs can cause a 'serotonin syndrome'
characterised by tremor, hyperthermia and cardiovascular collapse, from
which deaths have occurred. The use of SSRIs is not recommended for
treating depression in children under 18, in whom efficacy is doubtful and
adverse effects, including excitement, insomnia and aggression in the first
few weeks of treatment, may occur. The possibility of increased suicidal
ideation is a concern in this age group.
• Fluoxetine: Fluoxetine (Prozac) is given in the morning because of its
potential for being activating and causing insomnia. Food does not affect
its systemic bioavailability and may actually lessen the nausea reported by
some patients. Fluoxetine is highly bound to serum proteins and may
interact with other highly protein bound drugs. It is demethylated in the
liver to form an active metabolite, norfluoxetine. Inactive metabolites are
excreted by the kidney.
• MONOAMINE OXIDASE INHIBITORS
• Monoamine oxidase (MAO) inhibitors (MAOIs):
– irreversible, non-competitive inhibitors (e.g. phenelzine, tranylcypromine),
which are non-selective with respect to the MAO-A and -B subtypes
– reversible, MAO-A-selective inhibitors (e.g. moclobemide).
• Most MAO inhibitors, such as phenelzine, form stable complexes with the
enzyme, causing irreversible inactivation. This results in increased stores of
norepinephrine, serotonin, and dopamine within the neuron and subsequent
diffusion of excess neurotransmitter into the synaptic space.
• These drugs inhibit not only MAO in the brain but also MAO in the liver and gut
that catalyze oxidative deamination of drugs and potentially toxic substances,
such as tyramine, which is found in certain foods. The MAO inhibitors therefore
show a high incidence of drug-drug and drug-food interactions.
• These drugs are well absorbed after oral administration, but antidepressant
effects require at least 2 to 4 weeks of treatment. MAO inhibitors are
metabolized and excreted rapidly in the urine.

• Therapeutic uses: The MAO inhibitors are indicated for depressed patients
who are unresponsive or allergic to TCAs or who experience strong
anxiety. Patients with low psychomotor activity may benefit from the
stimulant properties of the MAO inhibitors. These drugs are also useful in
the treatment of phobic states.
• Adverse effects: Severe and often unpredictable side effects due to drug-
food and drug-drug interactions limit the widespread use of MAO
inhibitors.
• For example, tyramine, which is contained in certain foods, such as aged
cheeses and meats, chicken liver, pickled or smoked fish such as anchovies
or herring, and red wines, is normally inactivated by MAO in the gut.
Individuals receiving an MAO inhibitor are unable to degrade tyramine
obtained from the diet. Tyramine causes the release of large amounts of
stored catecholamines from nerve terminals, resulting in occipital
headache, stiff neck, tachycardia, nausea, hypertension, cardiac
arrhythmias, seizures, and possibly, stroke.
• Other possible side effects of treatment with MAO inhibitors include
drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria,
and constipation.
• The MAO inhibitors and SSRIs should not be coadministered due to the
risk of the life-threatening serotonin
AJAYI AM syndrome.
Dept of Pharm & Tox, KIU-WC 36
• Bupropion
• This drug acts as a weak dopamine and norepinephrine reuptake inhibitor
to alleviate the symptoms of depression.
• Its short half-life may require more than once-a-day dosing or the
administration of an extended-release formulation. Bupropion is unique in
that it assists in decreasing the craving and attenuating the withdrawal
symptoms for nicotine in tobacco users trying to quit smoking.
• Side effects may include dry mouth, sweating, nervousness, tremor, a very
low incidence of sexual dysfunction, and an increased risk for seizures at
high doses.
• Mirtazapine
• This drug enhances serotonin and norepinephrine neurotransmission via
mechanisms related to its ability to block presynaptic α- receptors.
Additionally, it may owe at least some of its antidepressant activity to its
ability to block 5-HT2 receptors.
• It is a sedative because of its potent antihistaminic activity, but it does not
cause the antimuscarinic side effects of the tricyclic antidepressants, or
interfere with sexual functioning, as do the SSRIs. Increased appetite and
weight gain frequently occur.
• Mirtazapine is markedly sedating, which may be used to advantage in
depressed patients having difficulty
AJAYI AM sleeping.
Dept of Pharm & Tox, KIU-WC 37
• Trazodone
• Trazodone is a second-generation antidepressant.
• It blocks the neuronal reuptake of serotonin and is an antagonist at
• the 5HT2-receptor. Also, its major metabolite, mchlorophenylpiperazine (mCPP),
is a postsynaptic serotonin receptor agonist. When compared to the TCAs,
trazodone is relatively free of antimuscarinic side effects, but it does block the α
-adrenoceptor.
• Common side effects include marked sedation, dizziness, orthostatic
hypotension, and nausea.
• Because of trazodone’s sedating quality, it is often used in low doses to counter
the insomnia associated with the newer antidepressants, such as the SSRIs.
• Venlafaxine
• Venlafaxine inhibits the reuptake of both serotonin and norepinephrine at their
respective presynaptic sites. This drug does not have significant effects at
muscarinic, histamine, or -adrenergic receptors and therefore is devoid of many
of the side effects associated with the TCAs.
• Venlafaxine has a side effect profile similar to that of the SSRIs. Higher doses of
venlafaxine result in modest increases in blood pressure in approximately 5% of
patients.

TREATMENT OF MANIC-DEPRESSIVE
ILLNESS
• Mood Stabilising drugs: These drugs are used to control the mood
swings characteristic of manic-depressive (bipolar) illness.
• Lithium is most commonly used, but antiepileptic drugs such as
carbamazepine, valproate and gabapentin, which have fewer side
effects than lithium, have also proved efficacious.
• Mood -stabilising drugs are used prophylactically in bipolar
depression, they prevent the swings of mood and thus reduce both
the depressive and the manic phases of the illness.
• They are given over long periods, and their beneficial effects take 3-
4 weeks to develop. Given in an acute attack, they are effective only
in reducing mania, not during the depressive phase (although
lithium is sometimes used as an adjunct to antidepressants in severe
cases of unipolar depression).

• LITHIUM
• Pharmacological effects and mechanism of action
• Lithium is clinically effective at a plasma concentration of 0.5-1 mmol/l,
and above 1.5 mmol/l it produces a variety of toxic effects, so the
therapeutic window is narrow.
• Lithium is a monovalent cation that can mimic the role of Na+ in excitable
tissues, being able to permeate the voltage-gated Na+ channels that are
responsible for action potential generation. It is, however, not pumped out
by the Na+/K+ ATPase, and therefore tends to accumulate inside excitable
cells, leading to a partial loss of intracellular K+, and depolarisation of the
cell.
• The biochemical effects of lithium are complex, and it inhibits many
enzymes that participate in signal transduction pathways.
• Lithium is believed to attenuate signaling via receptors coupled to the
phosphatidylinositol bisphosphate (PIP2) second-messenger system.
Lithium interferes with the resynthesis (recycling) of PIP2, leading to its
relative depletion in neuronal membranes of the CNS. PIP2 levels in
peripheral membranes are unaffected by lithium.

• Pharmacokinetic aspects and toxicity
• Lithium is given by mouth as the carbonate salt and is excreted by the
kidney.
• The narrow therapeutic window (approximately 0.5- 1.5 mmol/l) means
that monitoring of the plasma concentration is essential.
• Na+ depletion reduces the rate of excretion by increasing the reabsorption
of lithium by the proximal tubule, and thus increases the likelihood of
toxicity. Diuretics that act distal to the proximal tubule also have this
effect, and renal disease also predisposes to lithium toxicity.
• The main toxic effects that may occur during treatment are as follows.
• Nausea, vomiting and diarrhoea andTremor.
• Renal effects: polyuria (with resulting thirst) resulting from inhibition of
the action of antidiuretic hormone. At the same time, there is some Na+
retention associated with increased aldosterone secretion. With
prolonged treatment, serious renal tubular damage may occur, making it
essential to monitor renal function regularly in lithium-treated patients.
• Thyroid enlargement, sometimes associated with hypothyroidism.
• Weight gain.

ANTIPSYCHOTIC DRUGS
• THE NATURE OF SCHIZOPHRENIA
• Schizophrenia is a debilitating psychiatric illness that affects about 1% of the
population. It affects young people, is often chronic and is usually highly
disabling. There is a strong hereditary factor in its aetiology, and evidence
suggestive of a fundamental biological disorder (see below). The main clinical
features of the disease are as follow.
– delusions (often paranoid in nature)
– hallucinations, usually in the form of voices which are often exhortatory in their message
– thought disorder, comprising wild trains of thought, garbled sentences and irrational
conclusions, sometimes associated with the feeling that thoughts are inserted or
withdrawn by an outside agency
– abnormal behaviours, such as stereotyped movements and occasionally aggressive
behaviours.
• Negative symptoms:
– withdrawal from social contacts
– flattening of emotional responses.

• AETIOLOGY AND PATHOGENESIS OF SCHIZOPHRENIA
• Genetic and Environmental Factors The cause of schizophrenia remains unclear but
involves a combination of genetic and environmental factors .
• The Dopamine Hypothesis of Schizophrenia
• The dopamine hypothesis for schizophrenia is the most fully developed of several
hypotheses and is the basis for much of the rationale for drug therapy. Several lines of
circumstantial evidence suggest that excessive dopaminergic activity plays a role in the
disorder:
(1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous
system, especially in the mesolimbic-frontal system;
(2) drugs that increase dopaminergic activity, such as levodopa (a precursor), amphetamines
(releasers of dopamine), and apomorphine (a direct dopamine receptor agonist), either
aggravate schizophrenia or produce psychosis de novo in some patients;
(3) dopamine receptor density has been found postmortem to be increased in the brains of
schizophrenics who have not been treated with antipsychotic drugs;
(4) positron emission tomography (PET) has shown increased dopamine receptor density in
both treated and untreated schizophrenics when compared with such scans of
nonschizophrenic persons; and
(5) successful treatment of schizophrenic patients has been reported to change the amount
of homovanillic acid (HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma,
and urine.

• Glutamate theory
• Another transmitter implicated in the pathophysiology of schizophrenia is glutamate.
• NMDA receptor antagonists such as phencyclidine, ketamine and dizocilpine
produce psychotic symptoms (e.g. hallucinations, thought disorder) in humans, and
reduced glutamate concentrations and glutamate receptor densities have been
reported in post-mortem schizophrenic brains.
• Other theories
• Other transmitters that may be important include 5-HT and noradrenaline
(norepinephrine). The idea that 5-HT dysfunction could be involved in schizophrenia
was based on the fact that LSD produces schizophrenia-like symptoms, and has
drifted in and out of favour many times.
• Many effective antipsychotic drugs, in addition to blocking dopamine receptors (see
below), also act as 5-HT-receptor antagonists. 5-HT modulates dopamine pathways,
so the two theories are not incompatible.
• Many 'atypical' antipsychotic drugs produce fewer extrapyramidal side effects than
dopamine-selective compounds, and combine with 5-HT 2A-receptors. Whether 5-
HT2A-receptor blockade accounts directly for their antipsychotic effects, or merely
reduces undesirable side effects associated with D2-receptor antagonists, remains
controversial.

• Classification of antipsychotic drugs
• The antipsychotic drugs (also called neuroleptic drugs, or major tranquilizers)
are used primarily to treat schizophrenia, but they are also effective in other
psychotic states, such as manic states with psychotic symptoms such as
grandiosity or paranoia and hallucinations, and delirium.
• Main categories are:
– first-generation ('typical') antipsychotics (e.g. chlorpromazine,
haloperidol, fluphenazine, flupenthixol, clopenthixol)
– second-generation ('atypical') antipsychotics (e.g. clozapine, olanzapine,
risperidone, sertindole, quetiapine, amisulpride, aripiprazole, zotepine).
• Distinction between typical and atypical groups is not clearly defined but rests
on:
– receptor profile
– incidence of extrapyramidal side effects (less in atypical group)
– efficacy (specifically of clozapine) in 'treatment-resistant' group of
patients
– efficacy against negative symptoms.

• Dopamine receptor blocking activity in the brain: All of the older and
most of the newer neuroleptic drugs block dopamine receptors in the
brain and the periphery. Five types of dopamine receptors have been
identified.
• D1 and D5 receptors activate adenylyl cyclase, often exciting neurons,
whereas D2, D3 and D4 receptors inhibit adenylyl cyclase, or mediate
membrane K+ channel opening leading to neuronal hyperpolarization. The
neuroleptic drugs bind to these receptors to varying degrees.
• The clinical efficacy of the typical neuroleptic drugs correlates closely with
their relative ability to block D2 receptors in the mesolimbic system of the
brain. On the other hand, the atypical drug clozapine has higher affinity
for the D4 receptor and lower affinity for the D2 receptor, which may
partially explain its minimal ability to cause extrapyramidal side effects
(EPS).
• Serotonin receptor blocking activity in the brain: Most of the newer
atypical agents appear to exert part of their unique action through
inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors.
Thus, clozapine has high affinity for D1, D4, 5-HT2, muscarinic, and α-
adrenergic receptors, but it is also a dopamine D2-receptor antagonist.
• ACTIONS
• Antipsychotic actions: All of the neuroleptic drugs can reduce the
hallucinations and delusions associated with schizophrenia (the so-called
positive symptoms) by blocking dopamine receptors in the mesolimbic
system of the brain. The negative symptoms, such as blunted affect,
anhedonia (not getting pleasure from normally pleasurable stimuli),
apathy, and impaired attention, as well as cognitive impairment are not
as responsive to therapy, particularly with the typical neuroleptics.
• Extrapyramidal effects:
• Dystonias (sustained contraction of muscles leading to twisting distorted
postures),
• Parkinson -like symptoms, akathisia (motor restlessness), and
• Tardive dyskinesia (involuntary movements of the tongue, lips, neck,
trunk, and limbs) occur with chronic treatment.
• Blocking of dopamine receptors in the nigrostriatal pathway probably
causes these unwanted movement symptoms. The atypical neuroleptics
exhibit a lower incidence of these symptoms.

• Endocrine Effects: Older antipsychotic drugs produce striking adverse
effects on the reproductive system. Amenorrhea-galactorrhea, false-
positive pregnancy tests, and increased libido have been reported in
women, whereas men have experienced decreased libido and
gynecomastia.
• Antiemetic effects: With the exceptions of aripiprazole and thioridazine,
most of the neuroleptic drugs have antiemetic effects that are mediated by
blocking D2-dopaminergic receptors of the chemoreceptor trigger zone of
the medulla.
• Antimuscarinic effects: Some of the neuroleptics, particularly thioridazine,
chlorpromazine, clozapine, and olanzapine, produce anticholinergic effects,
including blurred vision, dry mouth (exception: clozapine increase
salivation), confusion, and inhibition of gastrointestinal and urinary tract
smooth muscle, leading to constipation and urinary retention.
• Cardiovascular Effects: Orthostatic hypotension and high resting heart
rates frequently result from use of the low-potency phenothiazines. Mean
arterial pressure, peripheral resistance, and stroke volume are decreased,
and heart rate is increased.

• After oral administration, the neuroleptics show variable absorption
that is unaffected by food. These agents readily pass into the brain,
have a large volume of distribution, bind well to plasma proteins, and
are metabolized to many different substances, usually by the
cytochrome P450 system in the liver, particularly the CYP2D6, CYP1A2,
and CYP3A4 isoenzymes.
• Fluphenazine decanoate, haloperidol decanoate, and risperidone
microspheres are slow-release (up to 2 to 4 weeks) injectable
formulations of neuroleptics that are administered via deep gluteal
intramuscular injection. These drugs are often used to treat outpatients
and individuals who are noncompliant with oral medications. However,
patients may still develop extrapyramidal symptoms (EPS), but the risk
of EPS is lower with these long-acting, injectable formulations
compared to their respective oral formulations.
• The neuroleptic drugs produce some tolerance but little physical
dependence.

• Therapeutic Uses
• Treatment of schizophrenia: The neuroleptics are considered to be
the only efficacious treatment for schizophrenia. The traditional
neuroleptics are most effective in treating positive symptoms of
schizophrenia (delusions, hallucinations, thought processing, and
agitation).
• Clozapine is reserved for the treatment of individuals who are
unresponsive to other neuroleptics, because its use is associated with
blood dyscrasias and other severe adverse effects.
• Prevention of severe nausea and vomiting: The older neuroleptics
(most commonly prochlorperazine) are useful in the treatment of
drug-induced nausea.
• Other uses: The neuroleptic drugs can be used as tranquilizers to
manage agitated and disruptive behavior secondary to other
disorders. Neuroleptics are used in combination with narcotic
analgesics for treatment of chronic pain with severe anxiety.
Chlorpromazine is used to treat intractable hiccups.

• Adverse Effects
• Extrapyramidal side effects: The inhibitory effects of dopaminergic neurons are
normally balanced by the excitatory actions of cholinergic neurons in the striatum.
Blocking dopamine receptors alters this balance, causing a relative excess of
cholinergic influence, which results in extrapyramidal motor effects.
• The maximal risk of appearance of the movement disorders is time and dose
dependent, with dystonias occurring within a few hours to days of treatment,
followed by akathisias (the inability to remain seated due to motor restlessness)
occurring within days to weeks.
• Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually occur within
weeks to months of initiating treatment.
• Atypical antipsychotics (clozapine and risperidone): These drugs exhibit a lower
potential for causing extrapyramidal symptoms and lower risk of tardive dyskinesia,
• Tardive dyskinesia: Long-term treatment (months or years) with neuroleptics can
cause this motor disorder. Patients display involuntary movements, including lateral
jaw movements and fly-catching motions of the tongue. A prolonged holiday from
neuroleptics may cause the symptoms to diminish or disappear within a few months.
• Weight gain: The development of gynaecomastia (breast development in men) and
male impotence.

• Neuroleptic malignant syndrome: This potentially fatal reaction to neuroleptic drugs is
characterized by muscle rigidity, fever, altered mental status and stupor, unstable blood
pressure, and myoglobinemia. Treatment necessitates discontinuation of the neuroleptic
and supportive therapy. Administration of dantrolene or bromocriptine may be helpful.
• Other effects: Drowsiness occurs due to CNS depression and antihistaminic effects,
usually during the first few weeks of treatment. Confusion is sometimes encountered.
Those neuroleptics with potent antimuscarinic activity often produce dry mouth, urinary
retention, constipation, and loss of accommodation.
• Cautions and contraindications:
• Acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated
by the neuroleptics. Stabilization with a simple sedative, such as a benzodiazepine, is the
preferred treatment.
• All antipsychotics may lower the seizure threshold, and chlorpromazine and clozapine are
contraindicated in patients with seizure disorders. Therefore, the neuroleptics can also
aggravate preexisting epilepsy, and they should be used with caution in patients with
epilepsy.
• The high incidence of agranulocytosis with clozapine may limit its use to patients who are
resistant to other drugs.
• All of the atypical antipsychotics also carry the warning of increased risk for mortality
when used in elderly patients with dementia-related behavioral disturbances and
psychosis.

ANTIEPILEPTIC DRUGS
• EPILEPSY
• Epilepsy is a chronic, usually life-long disorder characterized by recurrent
seizures or convulsions and usually, episodes of unconsciousness and/or
amnesia.
• It is a common neurological abnormality affecting about 1% of the human
population.
• The term seizure refers to a transient alteration of behavior due to the
disordered, synchronous, and rhythmic firing of populations of brain neurons.
• The term epilepsy refers to a disorder of brain function characterized by the
periodic and unpredictable occurrence of seizures.
• The characteristic event in epilepsy is the seizure, which is associated with the
episodic high-frequency discharge of impulses by a group of neurons in the
brain.

• The cause of the seizure disorder is not known (idiopathic epilepsy), although
trauma during birth is suspected of being one cause.
• Head trauma, meningitis, childhood fevers, brain tumors, and degenerative
diseases of the cerebral circulation are conditions often associated with the
appearance of recurrent seizures.
• Seizures also may be a toxic manifestation of the action of central nervous
system (CNS) stimulants and certain other drugs.
• Seizures often occur in hyperthermia (febrile seizures are very common in
infants); sometimes in eclampsia, uremia, hypoglycemia, or pyridoxine
deficiency; and frequently as a part of the abstinence syndrome of individuals
physically dependent on CNS depressants.
• Abnormal electrical activity during and following a seizure can be detected by
electroencephalography (EEG) recording from electrodes distributed over the
surface of the scalp.
• The particular symptoms produced depend on the function of the region of the
brain that is affected. The involvement of the motor cortex causes convulsions;
involvement of the hypothalamus causes peripheral autonomic discharge, and
involvement of the reticular formation in the upper brain stem leads to loss of
consciousness.

EPILEPTIC SEIZURE CLASSIFICATION
• Various types of seizure can be recognized on the basis of the nature and
distribution of the abnormal discharge.
• Seizures have been classified into two broad groups: partial (or focal), and
generalized.
• Partial Seizures
• Partial seizures are those in which the discharge begins locally and often remains
localised.
• The symptoms depend on the brain region or regions involved, and include
involuntary muscle contractions, abnormal sensory experiences or autonomic
discharge, or effects on mood and behaviour, often termed psychomotor
epilepsy.
• Simple partial: The electrical discharge does not spread, and the patient does
not lose consciousness. The patient often exhibits abnormal activity of a single
limb or muscle group that is controlled by the region of the brain experiencing
the disturbance.
• The patient may also show sensory distortions. This activity may spread. Simple
partial seizures may occur at any age.

• Complex partial: In complex partial seizures, loss of consciousness
may occur at the outset of the attack, or somewhat later, when the
discharge has spread from its site of origin to regions of the brain
stem reticular formation.
• These seizures exhibit complex sensory hallucinations, mental
distortion, and loss of consciousness. Motor dysfunction may
involve chewing movements, diarrhea, and/or urination.
Consciousness is altered.
• Simple partial seizure activity may spread and become complex and
then spread to a secondarily generalized convulsion.
• GENERALISED SEIZURES
• Generalised seizures involve the whole brain, including the reticular
system, thus producing abnormal electrical activity throughout both
hemispheres. Immediate loss of consciousness is characteristic of
generalised seizures.
• Two important categories are tonic-clonic seizures (grand mal) and
absence seizures (petit mal) .
• Tonic-clonic seizure:
• A tonic-clonic seizure consists of an initial strong contraction of the whole
musculature, causing a rigid extensor spasm and an involuntary cry.
• Respiration stops, and defecation, micturition and salivation often occur. This tonic
phase lasts for about 1 minute, and is followed by a series of violent, synchronous
jerks that gradually die out in 2-4 minutes.
• The patient stays unconscious for a few more minutes and then gradually recovers,
feeling ill and confused. Injury may occur during the convulsive episode.
• The EEG shows generalised continuous high-frequency activity in the tonic phase and
an intermittent discharge in the clonic phase.
• Absence Seizure
• Absence seizures occur in children; they are much less dramatic but may occur more
frequently (many seizures each day) than tonic-clonic seizures. The patient abruptly
ceases whatever he or she was doing, sometimes stopping speaking in mid-sentence,
and stares vacantly for a few seconds, with little or no motor disturbance. Patients are
unaware of their surroundings and recover abruptly with no after-effects.
• The EEG pattern shows a characteristic rhythmic discharge during the period of the
seizure
• Status epilepticus: refers to continuous uninterrupted seizures, requiring emergency
medical treatment

• MECHANISTIC APPROACH TO THE TREATMENT OF EPILEPSY
1. ENHANCEMENT OF GABA ACTION
• Several antiepileptic drugs (e.g. phenobarbital and benzodiazepines) enhance
the activation of GABAA receptors, thus facilitating the GABA-mediated
opening of chloride channels.
• Vigabatrin acts by inhibiting the enzyme GABA transaminase, which is
responsible for inactivating GABA,
• Tiagabine inhibits GABA uptake; both thereby enhance the action of GABA as
an inhibitory transmitter.
• Gabapentin was designed as an agonist at GABAA receptors.
2. INHIBITION OF SODIUM CHANNEL FUNCTION
• Several of the most important antiepileptic drugs (e.g. phenytoin,
carbamazepine, valproate, lamotrigine) affect membrane excitability by an
action on voltage-dependent sodium channels, which carry the inward
membrane current necessary for the generation of an action potential.
3. INHIBITION OF CALCIUM CHANNELS
• Several antiepileptic drugs have minor effects on calcium channels, but only
ethosuximide specifically blocks the T-type calcium channel, activation of
which is believed to play a role in the rhythmic discharge associated with
absence seizures.
4. Other mechanisms include inhibition of glutamate release and block of
glutamate receptors. AJAYI AM Dept of Pharm & Tox, KIU-WC 59
Therapeutic strategies for managing newly diagnosed epilepsy
• Newly diagnosed epilepsy
- Consider starting therapy after the second seizure.
• First choice drug:
- Choose drug appropriate for the patient’s type of siezure
- Consider toxicities of the agent
- Consider characteristics of the patient
- Gradually titrate the dosage to that which is maximally tolerated and/or
producers optimal seizure control.
• If seizure persist, choose a second drug
- The second drug is titrated to a therapeutic level that controls seizures
before tapering and discontinuing the original antiseizure drug.
- If the first drug is associated with significant adverse effects, it should be
tapered while the second drug is added.
• If the seizure persists, give rational combination of two drugs
• If the seizure persists, consider vagal nerve stimulation

Classification of antiepileptic drugs
1. Drugs Used in Partial Seizures & Generalized Tonic-Clonic Seizures
- Well established drugs (first generation): phenytoin, carbamazepine,
valproate, and the phenobarbitone.
- Newer drugs (Second generation): lamotrigine, levetiracetam, gabapentin,
oxcarbazepine, pregabalin, topiramate, vigabatrin, and zonisamide.
2. Drugs Used in Absence Seizures
- Ethosuximide, valproic acid, Trimethadione,
3. Other Drugs Used in Management of Epilepsy
- Benzodiazepine, acetazolamide.
• The antiseizure drugs exhibit many similar pharmacokinetic properties
because most have been selected for oral activity and all must enter the
central nervous system. absorption is usually good, with 80–100% of the
dose reaching the circulation. Most antiseizure drugs are not highly bound
to plasma proteins. Antiseizure drugs are cleared chiefly by hepatic
mechanisms, although they have low extraction ratios. Plasma clearance is
relatively slow; many anticonvulsants are therefore considered to be
medium- to long-acting. Some have half-lives longer than 12 hours. Many
of the older antiseizure drugs are potent inducers of hepatic microsomal
enzyme activity.
• PHENYTOIN AND FOSPHENYTOIN
• MOA: Phenytoin blocks voltage-gated sodium channels by selectively
binding to the channel in the inactive state and slowing its rate of
recovery. At very high concentrations, phenytoin can block voltage-
dependent calcium channels and interfere with the release of
monoaminergic neurotransmitters.
• Phenytoin is effective for treatment of partial seizures and generalized
tonic-clonic seizures and in the treatment of status epilepticus.
• It is well absorbed when given orally, and about 80-90% of the plasma
content is bound to albumin. Other drugs, such as salicylates,
phenylbutazone and valproate, inhibit this binding competitively. This
increases the free phenytoin concentration but also increases hepatic
clearance of phenytoin, so may enhance or reduce the effect of the
phenytoin in an unpredictable way.
• Phenytoin is an inducer of drugs metabolized by the CYP2C, and CYP3A
families and the UGT enzyme system.

• Adverse effects
• The milder side effects include vertigo, ataxia, headache and
nystagmus, but not sedation. At higher plasma concentrations, marked
confusion with intellectual deterioration occurs.
• Hyperplasia of the gums often develops gradually, as does hirsutism
and coarsening of the features, which probably result from increased
androgen secretion.
• Megaloblastic anaemia, associated with a disorder of folate
metabolism, sometimes occurs, and can be corrected by giving folic
acid. Hypersensitivity reactions, mainly rashes, are quite common.
• Phenytoin has also been implicated as a cause of the increased
incidence of fetal malformations in children born to epileptic mothers,
particularly the occurrence of cleft palate, associated with the
formation of an epoxide metabolite.
• Severe idiosyncratic reactions, including hepatitis, skin reactions and
neoplastic lymphocyte disorders, occur in a small proportion of
patients.

• CARBAMAZEPINE
• Carbamazepine, one of the most widely used antiepileptic drugs, is
chemically derived from the tricyclic antidepressant drugs .
• Pharmacologically and clinically, its actions resemble those of phenytoin,
although it appears to be particularly effective in treating complex partial
seizures (e.g. psychomotor epilepsy). It is also used to treat other
conditions, such as neuropathic pain and manic-depressive illness.
• Pharmacokinetic aspects: Carbamazepine is well absorbed. Its plasma
half-life is about 30 hours when it is given as a single dose, but it is a
strong inducing agent, and the plasma half-life shortens to about 15 hours
when it is given repeatedly.
• Adverse effects: Carbamazepine produces a variety of unwanted effects
ranging from drowsiness, dizziness and ataxia to more severe mental and
motor disturbances. It can also cause water retention (and hence
hyponatraemia) and a variety of gastrointestinal and cardiovascular side
effects.
• Severe bone marrow depression, causing neutropenia, and other severe
forms of hypersensitivity reaction can occur but are very rare.

• Drug Interactions
• Drug interactions involving carbamazepine are almost exclusively related to
the drug's enzyme-inducing properties. Carbamazepine is a powerful
inducer of hepatic microsomal enzymes, and thus may cause a reduction
in steady-state carbamazepine concentrations as well as accelerates the
metabolism of many other drugs, eg, primidone, phenytoin, ethosuximide,
valproic acid, clonazepam, oral contraceptives, warfarin and
corticosteroids.
• Other drugs such as propoxyphene, troleandomycin, and valproic acid may
inhibit carbamazepine clearance and increase steady-state carbamazepine
blood levels.
• Other anticonvulsants, however, such as phenytoin and phenobarbital, may
decrease steady-state concentrations of carbamazepine through enzyme
induction.
• In general, it is inadvisable to combine it with other antiepileptic drugs.
• Ozcarbazepine, introduced recently, is a prodrug that is metabolised to a
compound closely resembling carbamazepine, with similar actions but less
tendency to induce drug-metabolising enzymes.

• VALPROIC ACID & SODIUM VALPROATE
• Valproate is a simple monocarboxylic acid, which is fully ionized at body pH, and
for that reason the active form of the drug may be assumed to be the valproate
ion regardless of whether valproic acid or a salt of the acid is administered.
• MOA: Valproate works by several mechanisms, It causes a significant increase in
the GABA content of the brain and is a weak inhibitor of two enzyme systems
that inactivate GABA, namely GABA transaminase and succinic semialdehyde
dehydrogenase, it enhances the action of GABA by a postsynaptic action, It may
also inhibits sodium channels.
• Pharmacokinetics: Valproate is well absorbed following an oral dose, with
bioavailability greater than 80%. Peak blood levels are observed within 2 hours.
Food may delay absorption, and decreased toxicity may result if the drug is given
after meals. Valproic acid is 90% bound to plasma proteins, and excreted, mainly
as the glucuronide, in the urine.
• Clinical Use: Valproate is very effective against absence seizures. Although
ethosuximide is the drug of choice when absence seizures occur alone, valproate
is preferred when the patient has concomitant generalized tonic-clonic attacks.
• Adverse effects: The most serious side effect is hepatotoxicity.

• PHENOBARBITAL
• Phenobarbital was one of the first barbiturates to be developed, and its
antiepileptic properties were recognised in 1912. In its action against
experimentally induced convulsions and clinical forms of epilepsy, it
closely resembles phenytoin; it affects the duration and intensity of
artificially induced seizures, rather than the seizure threshold, and is (like
phenytoin) ineffective in treating absence seizures.
• The clinical uses of phenobarbital are virtually the same as those of
phenytoin, although phenytoin is preferred because of the absence of
sedation.
• Pharmacokinetic aspects: Phenobarbital is well absorbed, and about 50%
of the drug in the blood is bound to plasma albumin. It is eliminated
slowly from the plasma (half-life, 50-140 hours). About 25% is excreted
unchanged in the urine. Because phenobarbital is a weak acid, its
ionisation and hence renal elimination are increased if the urine is made
alkaline. The remaining 75% is metabolised, mainly by oxidation and
conjugation, by the hepatic microsomal enzymes.

• Phenobarbital is a powerful inducer of liver P450 enzymes, and it lowers the
plasma concentration of several other drugs (e.g. steroids, oral
contraceptive, warfarin, tricyclic antidepressants) to an extent that is
clinically important.
• Adverse effects
• The main unwanted effect of phenobarbital is sedation, objective tests of
cognition and motor performance show impairment even after long-term
treatment.
• Other unwanted effects that may occur with clinical dosage include
megaloblastic anaemia (similar to that caused by phenytoin), mild
hypersensitivity reactions and osteomalacia. Like other barbiturates, it must
not be given to patients with porphyria.
• Primidone
• Primidone has two active metabolites, phenobarbital and
phenylethylmalonamide, which have longer half-lives than the parent drug.
• Due to the nature of the long term adverse effects associated with
phenobarbital, this drug should be considered for use only in those patients
with refractory epilepsy.

• ETHOSUXIMIDE
• Ethosuximide, Phensuximide and Methsuximide belongs to the succinimide

class.
• Ethosuximide is used clinically for its selective effect on absence seizures.
• Methsuximide is generally considered more toxic, and phensuximide less
effective, than ethosuximide, both were used as anti-absence seizure.
• MOA: Ethosuximide reduces propagation of abnormal electrical activity in the
brain, most likely by inhibiting T-type calcium channels.
• Pharmacokinetics: Ethosuximide is well absorbed, and metabolised and
excreted much like phenobarbital, with a plasma half-life of about 50 hours.
• Adverse effects: Its main side effects are nausea and anorexia, sometimes
lethargy and dizziness, and it is said to precipitate tonic-clonic seizures in
susceptible patients. Very rarely, it can cause severe hypersensitivity
reactions.
• Drug Interactions: Administration of ethosuximide with valproic acid results
in a decrease in ethosuximide clearance and higher steady-state
concentrations owing to inhibition of metabolism.

• VIGABATRIN
• Vigabatrin, the first 'designer drug' in the epilepsy field, is a vinyl-substituted analogue of
GABA that was designed as an inhibitor of the GABA-metabolising enzyme GABA
transaminase.
• Vigabatrin is extremely specific for this enzyme and works by forming an irreversible
covalent bond. In humans, vigabatrin increases the content of GABA in the cerebrospinal
fluid. Although its plasma half-life is short, it produces a long-lasting effect because the
enzyme is blocked irreversibly, and the drug can be given by mouth once daily.
• The main drawback of vigabatrin is the occurrence of depression, and occasionally
psychotic disturbances, in a minority of patients;
• Vigabatrin has been reported to be effective in a substantial proportion of patients
resistant to the established drugs, and may represent an important therapeutic advance.
• TIAGABINE
• Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be
available for receptor binding, thus, there is thought to be enhanced inhibitory activity.
• Tiagabine is effective in decreasing the number of seizures in patients with partial onset
epilepsy.
• Binding to albumin and a1-acid glycoprotein is greater than 95 percent, and metabolism is
mainly completed by the CYP3A family of enzymes.
• Adverse effects include tiredness, dizziness, and gastrointestinal upset.

• GABAPENTIN
• Gabapentin was designed as a simple analogue of GABA that would
be sufficiently lipid-soluble to penetrate the blood-brain barrier.
• Its main site of action appears to be on T-type calcium channel
function, by binding to a particular channel subunit (α2δ), and it
inhibits the release of various neurotransmitters and modulators,
but the details remain unclear.
• A recently introduced follow-up drug, pregabalin, is more potent
than gabapentin but otherwise very similar.
• The side effects of gabapentin (mainly sedation and ataxia) are less
severe than with many antiepileptic drugs.
• These drugs are excreted unchanged in the urine, and so must be
used with care in patients whose renal function is impaired.
• Gabapentin has limited efficacy when used on its own, so is used
mainly as add-on therapy. It is also used as an analgesic to treat
neuropathic pain.

• BENZODIAZEPINES
• Diazepam, given intravenously or rectally, is used to treat status epilepticus,
a life-threatening condition in which epileptic seizures occur almost without
a break.
• Its advantage in this situation is that it acts very rapidly compared with other
antiepileptic drugs.
• A rectal gel is available for refractory patients who need acute control of
bouts of seizure activity.
• Lorazepam appears in some studies to be more effective and longer-acting
than diazepam in the treatment of status epilepticus and is preferred by
some experts.
• With most benzodiazepines, the sedative effect is too pronounced for them
to be used for maintenance therapy.
• Clonazepam and the related compound clobazam are claimed to be
relatively selective as antiepileptic drugs.
• Sedation is the main side effect of these compounds, and an added problem
may be the withdrawal syndrome, which results in an exacerbation of
seizures if the drug is stopped abruptly.

OPIOID ANALGESICS
• Morphine, the prototypical opioid agonist, has long been known to relieve
severe pain with remarkable efficacy.
• The opium poppy is the source of crude opium from which Sertürner in
1803 isolated morphine, the pure alkaloid.
• Opium is an extract of the juice of the poppy Papaver somniferum, which
has been used for social and medicinal purposes for thousands of years as
an agent to produce euphoria, analgesia and sleep, and to prevent
diarrhoea.
• These drugs are collectively known as opioid analgesics and include not
only the natural and semisynthetic alkaloid derivatives from opium but also
include synthetic surrogates, other opioid-like drugs whose actions are
blocked by the nonselective antagonist naloxone, plus several endogenous
peptides that interact with the several subtypes of opioid receptors.

• Endogenous Opioids
• The endogenous opioids are naturally occurring peptides. The
enkephalins, and endorphins.
• Three families of endogenous opioid peptides have been described in
detail: the endorphins, the pentapeptides methionine-enkephalin (met-
enkephalin) and leucine-enkephalin (leu-enkephalin), and the
dynorphins. The three families of opioid receptors have overlapping
affinities for these endogenous peptides
• The endogenous opioids have been implicated in the modulation of most
of the critical functions of the body, including hormonal fluctuations,
thermoregulation, mediation of stress and anxiety, production of
analgesia, and development of opioid tolerance and dependence.
• The endogenous opioids maintain homeostasis, amplify signals from the
periphery to the brain, and serve as neuromodulators of the body’s
response to external stimuli.
• As such, the endogenous opioids are critical to the maintenance of
health and a sense of well-being.

• Opioid Receptors
• Opioids interact stereospecifically with protein receptors on the
membranes of certain cells in the CNS, on nerve terminals in the periphery,
and on cells of the gastrointestinal tract and other anatomic regions.
• The major effects of the opioids are mediated by three major receptor
families. These are designated by the Greek letters μ (mu), κ (kappa), and δ
(delta).
• Each receptor family exhibits a different specificity for the drug(s) it binds.
• The analgesic properties of the opioids are primarily mediated by the μ
receptors; however, the κ receptors in the dorsal horn also contribute. For
example, butorphanol and nalbuphine primarily owe their analgesic effect
to K-receptor activation.
• The enkephalins interact more selectively with the δ receptors in the
periphery.
• It has been shown that μ1-receptors mediate the analgesic and euphoric
effects of the opioids and physical dependence on them, whereas μ2-
receptors mediate the bradycardiac and respiratory depressant effects.

• δ -Receptors, of which at least two subtypes have been identified pharmacologically,
mediate spinal analgesic effects and have been implicated in the modulation of
tolerance to μ-opioids.
• Three κ-opioid receptors have been identified and are thought to mediate spinal
analgesia, miosis, sedation, and diuresis.
• Cellular Mechanisms of Action
• All three opioid receptors are members of the G protein coupled receptor family and
inhibit adenylyl cyclase.1
• They are also associated with ion channels, increasing postsynaptic K+ efflux
(hyperpolarization) or reducing presynaptic Ca2+ influx, thus impeding neuronal firing
and transmitter release.
• The net result of the cellular decrease in calcium is a decrease in the release of
dopamine, serotonin, and nociceptive peptides, such as substance P, resulting in
blockage of nociceptive transmission.
• Pure agonists: They all have high affinity for μ receptors and generally lower affinity for
δ and κ sites.
• Partial agonists and mixed agonist-antagonists: These drugs, typified by nalorphine and
pentazocine, combine a degree of agonist and antagonist activity on different receptors.
• Antagonists. These drugs produce very little effect when given on their own but block
the effects of opiates. The most important examples are naloxone and naltrexone.

• Opioid Anagelsics classification
1. Morphine analogues. These are compounds closely related
in structure to morphine and often synthesised from it.
- Agonists (e.g. morphine, diamorphine [heroin] and
codeine).
- Partial agonists (e.g. nalorphine and levallorphan)
- Antagonists (e.g. naloxone).
2. Synthetic derivatives with structures unrelated to morphine:
– phenylpiperidine series (e.g. pethidine and fentanyl)
– methadone series (e.g. methadone and dextropropoxyphene)
– benzomorphan series (e.g. pentazocine and cyclazocine)
– semisynthetic thebaine derivatives (e.g. etorphine and
buprenorphine).
– Antidiarrheal opiates (e.g loperamide)

PHARMACOLOGICAL ACTIONS
• Morphine is typical of many opiate analgesics and will be taken as the
reference compound.
• Effects on the central nervous system
• Analgesia: Morphine is effective in most kinds of acute and chronic pain.
Morphine reduces the affective component of pain, patients treated with
morphine are still aware of the presence of pain, but the sensation is not
unpleasant.
• Although opiates in general are less useful in neuropathic pain syndromes
(such as phantom limb and other types of deafferentation pain, and
trigeminal neuralgia) than in pain associated with tissue injury, inflammation
or tumour growth.
• Euphoria: Morphine causes a powerful sense of contentment and well-being.
This is an important component of its analgesic effect, because the agitation
and anxiety associated with a painful illness or injury are thereby reduced.
• Different opiate drugs vary greatly in the amount of euphoria that they
produce. It does not occur with codeine or with pentazocine to any marked
extent, and nalorphine, in doses sufficient to cause analgesia, produces
dysphoria.

• Respiration: Morphine causes respiratory depression by reduction of
the sensitivity of respiratory center neurons to carbon dioxide. This
occurs with ordinary doses of morphine and is accentuated as the dose
increases until, ultimately, respiration ceases. Respiratory depression
is the most common cause of death in acute opioid overdose.
• Depression of cough reflex: Both morphine and codeine have
antitussive properties. In general, cough suppression does not
correlate closely with analgesic and respiratory depressant properties
of opioid drugs. The receptors involved in the antitussive action
appear to be different from those involved in analgesia.
• Pupillary constriction (miosis): Pupillary constriction is caused by μ
and κ receptor-mediated stimulation of the oculomotor nucleus.
Pinpoint pupils are an important diagnostic feature in opiate
poisoning, because most other causes of coma and respiratory
depression produce pupillary dilatation.
• Emesis: Morphine directly stimulates the chemoreceptor trigger zone
in the area postrema that causes vomiting.

• Peripheral Effects
• Gastrointestinal tract: Morphine relieves diarrhea and dysentery by
decreasing the motility and increasing the tone of the intestinal circular
smooth muscle.
• Morphine also increases the tone of the anal sphincter. Overall, morphine
produces constipation, with little tolerance developing.
• It can also increase biliary tract pressure due to contraction of the gallbladder
and constriction of the biliary sphincter.
• Cardiovascular: Morphine has no major effects on the blood pressure or
heart rate except at large doses, when hypotension and bradycardia may
occur.
• Histamine release: Morphine releases histamine from mast cells, causing
urticaria, sweating, and vasodilation. Because it can cause
bronchoconstriction, asthmatics should not receive the drug.
• Labor: Morphine may prolong the second stage of labor by transiently
decreasing the strength, duration, and frequency of uterine contractions.
• Neuroendocrine: Opioid analgesics stimulate the release of ADH, prolactin,
and somatotropin but inhibit the release of luteinizing hormone.

• Clinical Use of Opioid Analgesics
• Analgesia: Severe, constant pain is usually relieved with opioid analgesics with
high intrinsic activity. Opioids induce sleep, and in clinical situations when pain
is present and sleep is necessary, opiates may be used to supplement the
sleep-inducing properties of benzodiazepines, such as temazepam.
• The pain associated with cancer and other terminal illnesses, obstetric labor,
and acute, severe pain of renal and biliary colic.
• Acute Pulmonary Edema: The relief produced by intravenous morphine in
dyspnea from pulmonary edema associated with left ventricular failure is
remarkable. Proposed mechanisms include reduced anxiety (perception of
shortness of breath), and reduced cardiac preload (reduced venous tone) and
afterload (decreased peripheral resistance). Morphine can be particularly
useful when treating painful myocardial ischemia with pulmonary edema.
• Cough: Suppression of cough can be obtained at doses lower than those
needed for analgesia. Codeine or dextromethorphan are more widely used for
this purpose. Codeine has greater antitussive action than morphine.
• Diarrhea: Diarrhea from almost any cause can be controlled with the opioid
analgesics, but if diarrhea is associated with infection such use must not
substitute for appropriate chemotherapy.

• Adverse effects: Severe respiratory depression occurs and can result in
death from acute opioid poisoning. A serious effect of the drug is stoppage
of respiratory exchange in patients with emphysema or cor pulmonale.
• Other effects include vomiting, dysphoria, and allergy-enhanced hypotensive
effects. The elevation of intracranial pressure, particularly in head injury, can
be serious.
• Morphine enhances cerebral and spinal ischemia. In benign prostatic
hyperplasia, morphine may cause acute urinary retention. Patients with
adrenal insufficiency or myxedema may experience extended and increased
effects from the opioids.
• Morphine should be used with cautiously in patients with bronchial asthma
or liver failure.
• Drug interactions: The depressant actions of morphine are enhanced by

phenothiazines, monoamine oxidase inhibitors, and tricyclic
antidepressants. Low doses of amphetamine inexplicably enhance analgesia,
as does hydroxyzine.

Tolerance and Dependence
• Tolerance to opiates (i.e. an increase in the dose needed to produce a given
pharmacological effect) develops within a few days and is readily demonstrated.
• Repeated use produces tolerance to the respiratory depressant, analgesic,
euphoric, and sedative effects of morphine. However, tolerance usually does not
develop to the pupil-constricting and constipating effects of the drug.
• Physical and psychological dependence readily occur with morphine and with
some of the other agonists.
• Physical dependence refers to a state in which withdrawal of the drug causes
adverse physiological effects, i.e. the abstinence syndrome
• Withdrawal produces a series of autonomic, motor, and psychological responses
that incapacitate the individual and cause serious almost unbearable symptoms,
anxiety, insomnia, GI upset, rhnorrhea, diarrhea, mydriasis, tachycardia, fever,
hypertension, chills, tremor, seizure.
• However, it is very rare that the effects are so profound as to cause death.
• Addiction is rare in patients receiving opiates to control pain.
• Detoxification of heroin- or morphine-dependent individuals is usually
accomplished through the oral administration of methadone, buprenorphine, or
clonidine.

OTHER OPIATE ANALGESICS
• Diamorphine (heroin) is the diacetyl derivative of morphine. In the body, it is
rapidly deacetylated to morphine, and its effects are indistinguishable following oral
administration.
• However, because of its greater lipid solubility, it crosses the blood-brain barrier more
rapidly than morphine and gives a greater rush when injected intravenously Its only
advantage over morphine is its greater solubility, which allows smaller volumes to be
given orally, subcutaneously or intrathecally. It exerts the same respiratory depressant
effect as morphine, and if given intravenously is more likely to cause dependence.
• Codeine (3-methylmorphine) is more reliably absorbed by mouth than morphine,
but has only 20% or less of the analgesic potency. It is used mainly as an oral analgesic
for mild types of pain (headache, backache, etc.).
• Unlike morphine, it causes little or no euphoria and is rarely addictive, so is available
freely without prescription.
• It is often combined with paracetamol in proprietary analgesic preparations. It does,
however, cause constipation.
• Codeine has marked antitussive activity and is often used in cough mixtures.
Dihydrocodeine is pharmacologically very similar, having no substantial advantages or
disadvantages over codeine.

• Pethidine (meperidine): Very similar to morphine in its pharmacological effects,
except that it tends to cause restlessness rather than sedation, and it has an additional
antimuscarinic action that may cause dry mouth and blurring of vision as side effects.
• It produces a very similar euphoric effect and is equally liable to cause dependence.
• Pethidine is partly N-demethylated in the liver to norpethidine, which has a
hallucinogenic and convulsant effect. This becomes significant with large oral doses of
pethidine, producing an overdose syndrome rather different from that of morphine.
• Pethidine is preferred to morphine for analgesia during labour, because it does not
reduce the force of uterine contraction.
• Severe reactions, consisting of excitement, hyperthermia and convulsions, have been
reported when pethidine is given to patients receiving monoamine oxidase inhibitors.
• Fentanyl and sufentanil: Highly potent phenylpiperidine derivatives, with actions
similar to those of morphine but with a more rapid onset and shorter duration of
action, particularly sufentanil.
• Their main use is in anaesthesia, and they may be given intrathecally. They are also
used in patient-controlled infusion systems, where a short duration of action is
advantageous, and in severe chronic pain, when they are administered via patches
applied to the skin.

• Pentazocine: Is a mixed agonist-antagonist with analgesic properties similar to those
of morphine. Promotes analgesia by activating receptors in the spinal cord, and it is
used to relieve moderate pain.
• However, it causes marked dysphoria, with nightmares and hallucinations, rather than
euphoria, and is now rarely used.
• Methadone: Is pharmacologically similar to morphine, the main difference being that
its duration of action is considerably longer (plasma half-life > 24 hours), and it is
claimed to have less sedative action.
• Methadone is used as an analgesic as well as in the controlled withdrawal of dependent
abusers from heroin and morphine.
• Orally administered, methadone is substituted for the injected opioid. The patient is
then slowly weaned from methadone.
• Tramadol: a metabolite of the antidepressant trazodone, is widely used as an
analgesic for postoperative pain.
• It is a weak agonist at μ-opioid receptors, and also a weak inhibitor of noradrenaline
reuptake.
• It is effective as an analgesic and appears to have a better side effect profile than most
opiates, although psychiatric reactions have been reported.
• It is given by mouth or by intramuscular or intravenous injection for moderate to severe
pain.

OPIOID ANTAGONISTS
• Naloxone: It rapidly displaces all receptor-bound opioid molecules and,
therefore, is able to reverse the effect of a heroin overdose.
• The main clinical uses of naloxone are to treat respiratory depression caused by
opiate overdosage, and occasionally to reverse the effect of opiate analgesics,
used during labour, on the respiration of the newborn baby.
• Within 30 seconds of IV injection of naloxone, the respiratory depression and
coma characteristic of high doses of heroin are reversed, causing the patient to be
revived and alert.
• Naloxone has no important unwanted effects of its own but precipitates
withdrawal symptoms in addicts. It can be used to detect opiate addiction.
• Naltrexone: It has actions similar to those of naloxone. It has a longer duration
of action than naloxone, and a single oral dose of naltrexone blocks the effect of
injected heroin for up to 48 hours.
• Naltrexone in combination with clonidine and, sometimes, with buprenorphine is
employed for rapid opioid detoxification.
• It may also be beneficial in treating chronic alcoholism by an unknown
mechanism; however, benzodiazepines and clonidine are preferred.
• Naltrexone is hepatotoxic.
REFERENCES AND FURTHER READINGS
• Katzung Bertram G: Basic & Clinical
Pharmacology, 10th International Edition
2007.
• Rang H.P., Dale M.M., Ritter J.M., Moore P.K:
Pharmacology. Fifth Edition, International
Edition 2003.
• Goodman G: The Pharmacological basis of
therapeutics. Tenth Edition.
• Craig Stitzel. Modern Pharmacology with
Clinical applications. Fifth Edition.

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CNS PHARMACOLOGY

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