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1

LSB384 Pharmacology for Health Professionals

PART II SYSTEMATIC PHARMACOLOGY (THERAPEUTICS)

Sheila A Doggrell PhD DSc

DRUGS AND THE CENTRAL NERVOUS SYSTEM – 1

39. Psychosis; principles of treatment

39.1 Introduction to psychoses

39.2 Introduction to pharmacological treatment

39.3 Potency as antagonists

39.4 Pharmacological effects

39.5 Side effects

39.6 Features of individual drugs

40. Depression and anti-depressants

40.1 Introduction to depression and major depression

40.2 Mechanism of action of antidepressants

40.3 Selective Serotonin Reuptake Inhibitors (SSRIs)

40.4 Inhibitors of NET and SERT

40.5 Treatment of manic-depression

41. Anxiety and sleep disorders, and their treatment

41.1 Introduction to anxiety and sleep disorders

41.2 Mechanism of action of benzodiazepines

41.3 Clinical use of benzodiazepines

41.4 Sedating antihistamines

DRUGS AND THE CENTRAL NERVOUS SYSTEM - 1

The first part of drugs and the central nervous system considers the psychotropic drugs, which are the drugs used in the

treatment of psychoses, depression, and anxiety, and drugs that have a hypnotic effect.

39. Psychosis; principles of treatment

39.1 Introduction to psychoses

Psychoses are the most severe of the psychiatric disorders. It can be divided into four types. Firstly, the mania phase of

bipolar disorder (manic depression) is a form of psychoses. People with manic depression are in a cycle between a depressive

phase and a manic phase. The depressive phase is treated with anti-depressants. The psychosis associated with manic

phase, where the subjects are overactive and can show marked agitation, is treated with anti-psychotics. The second type of

psychoses is schizophrenia, which is distinctive from the other types of psychoses (see below). Sometimes, people become

psychotic for no apparent reason, and this is known as acute idiopathic psychotic illnesses. There are a variety of other

conditions involving marked agitation, and these include the agitation seen with amphetamine intoxication and Alzheimer’s

disease.

2

Schizophrenia means “Shattered mind”. The cause is schizophrenia is unknown but genetic, neurodevelopmental (during

pregnancy), and environmental factors (stressful life) may all be involved.

Schizophrenia only directly affects 1% of population, but has a devastating effect on families and friends. The onset of

schizophrenia occurs in late adolescence or early adulthood. In men, the onset of schizophrenia tends to be late adolescence.

In women, the onset of schizophrenia is usually early adulthood.

The outlook for people with schizophrenia is not good. Typically they live 10-12 years less than their healthy counterparts,

owing to increased physical health problems and a high suicide rate. Some of the health problems can be due to the drugs

used in the treatment of schizophrenia. Schizophrenia is a major cause of disability. It is ranked 3rd behind quadriplegia and

dementia. Thus, it is difficult for people with schizophrenic to maintain a job.

The symptoms of schizophrenic have been divided into positive and negative symptoms. The positive symptoms include

delusions, which are symptoms of false beliefs. The delusions are very real to the schizophrenic, and it is almost impossible

to convince the subject that it is delusion without the help of drugs. The positive symptoms also include hallucinations, which

are false sensations, and these usually come by the auditory route (voices). The third positive symptom is thought disorder.

Subjects with schizophrenia are not very logical.

The negative symptoms of schizophrenia include blunted emotion, poverty of speech and lack of motivation.

Subjects with schizophrenia also have neurocognitive deficits. These neurocognitive deficits include reduced memory,

reduced ability to pay attention, reduced ability to undertake problem-solving, and reduced social cognition.

Subjects with schizophrenia are not all the same. Thus, there are subdivisions of schizophrenia. The paranoid-type

schizophrenia is characterized by delusions and auditory hallucination. The subject with disorganised-type schizophrenia is

characterized by speech and behaviour that are disorganised or difficult to understand, and flattening or inappropriate

emotions. The subject with catatonic-type schizophrenia is characterized by disturbances of movement. They are either

immobile (catatonic) or move all over the place. When subjects are diagnosed with undifferentiated-type schizophrenia, it

means they have a bit of the paranoid-type, disorganised-type and catatonic-type schizophrenia.

39.2 Introduction to pharmacological treatment

The 1st group of drugs that were shown to have some benefit in the treatment of schizophrenia were known as neuroleptics.

Neuroleptics are now known as conventional anti-psychotics. Chlorpromazine and haloperidol are examples of

conventional anti-psychotics. The conventional anti-psychotics have the ability to block dopamine receptors, which suggests

that overactivity of the dopaminergic system underlies schizophrenia. This is called the dopamine theory of schizophrenia.

The conventional anti-psychotic drugs also block receptors other than dopamine receptors. Some schizophrenics are not

helped by the conventional anti-psychotic drugs, which rules out overactivity of the dopaminergic system being the only

mechanism underlying schizophrenia.

The first atypical anti-psychotic drug to be useful clinically was clozapine. Clozapine was shown to be beneficial in

schizophrenics unresponsive to the conventional agents. Some of the subjects who had been catatonic became active, and

this was termed “Awakenings” by Time magazine. However, clozapine causes agranulocytosis, the breakdown of

granulocytes, and is not used as first line treatment. Several atypical antipsychotics are now available for use, and one of

these, olanzapine, is structurally related to clozapine. Other examples of atypical anti-psychotic drugs discussed in this

chapter and risperidone and amisulpride.

The present thinking is that dopamine does have a major role in schizophrenia, but it is NOT the only neurotransmitter involved.

The neurotransmitters 5-hydroxytryptamine (5-HT) and acetylcholine (Ach) may also be involved. One of the reasons for

thinking this is that the drugs used to treat schizophrenia (conventional and atypical anti-psychotics) block a range of receptors.

Drugs that only block one type of receptor are not effective in the treatment of schizophrenia.

3

The anti-psychotic drugs are effective for the treatment of schizophrenia, but there is no benefit for 2-4 weeks. Thus, people

with schizophrenia have to be convinced to take their drugs for 2-4 without any benefit, before a benefit is observed. This

finding suggests, that a long term adaptive changes due to the drug treatment, are responsible for improvements with anti-

psychotics in schizophrenia.

To get a clinical response in schizophrenia, it is necessary to block several receptors. Unfortunately, because the anti-

psychotics block a range of receptors, they also have a lot of side effects.

39.3 Potency as antagonists

Chlorpromazine and haloperidol are examples of typical anti-psychotic drugs. Olanzapine, risperidone and amisulpride

are examples of atypical anti-psychotic drugs. Table 39.1 shows the potency of anti-psychotic drugs at various receptors.

Chlorpromazine is a potent antagonist at 5-HT2 receptors, at dopamine D1, D2, and D4 receptors, and at noradrenaline (NA)

α1-adrenoceptors. Chlorpromazine is also a potent antagonist at acetylcholine muscarinic (M) receptors, and histamine H1-

receptors. Chlorpromazine is a weak antagonist at α2-adrenoceptors.

Like chlorpromazine, haloperidol is a potent antagonist at 5-HT2 receptors, at dopamine D1, D2, and D4 receptors, and at

noradrenaline (NA) α1-adrenoceptors. Like chlorpromazine, haloperidol is a weak antagonist at α2-adrenoceptors. The

difference with haloperidol compared to chlorpromazine, is that haloperidol is only a weak antagonist at acetylcholine

muscarinic (M) receptors, and histamine H1-receptors.

The atypical anti-psychotics olanzapine and risperidone are also potent antagonist at 5-HT2 receptors, at dopamine D1, D2

and D4 receptors, and at noradrenaline (NA) α1-adrenoceptors. Olanzapine and risperidone are also potent antagonists at

acetylcholine muscarinic (M) receptors, α2-adrenoceptors and histamine H1-receptors. The main difference, between

olanzapine and risperidone to chlorpromazine, is that chlorpromazine only has a weak potency at antagonising α2-

adrenoceptors.

Amisulpride is different than the other antipsychotics in that it only acts as a potent antagonist at dopamine D1 and D2-

receptors.

Table 39.1 Potency as antagonists of antipsychotic drugs (Copyright QUT, Sheila Doggrell)

39.4 Pharmacological effects

4

Many of the pharmacological effects of the anti-psychotic drugs can be linked to blocking dopamine receptors. For instance,

stimulation of dopamine receptors increases motor activity, which is a common symptom of psychoses. The anti-psychotics will

antagonise this effect of dopamine to overcome agitation/increased motility.

The dopaminergic system is involved in thought processes, which are disordered in schizophrenia. The anti-psychotics block

the dopamine receptors involved in thought processes, and this improves thought processes.

The dopaminergic system in the basal ganglia has an important role in the control of posture and aspects of movement.

Blocking these receptors underlies the side effects observed with anti-psychotics. These side effects are known as

extrapyramidal (movement) side effects. Unfortunately, presently, it is not possible to have the beneficial effects of the

conventional anti-psychotics without having the side effects.

In the limbic system, dopaminergic neurones are involved on olfaction (smell), emotion, motivation, behaviour and various

autonomic functions. Thus, the dopamine receptor blocking anti-psychotics will have effects on these parameters, which is

important as there are problems with several of these (emotion, motivation and behaviour) in psychoses.

39.5 Side effects

Some of the pharmacological effects of the anti-psychotic drugs lead to side effects. For example, dopamine acts at D2

receptors in the pituitary to inhibit prolactin production. The anti-psychotics are antagonists at D2 receptors, and this promotes

prolactin production. Prolactin promotes breast engorgement (filling with blood) and galactorrhea. Galactorrhea is the

excessive flow of milk from the breasts during lactation or spontaneous milk flow not associated with childbirth, and this can

occur in males taking anti-psychotic drugs. Breast engorgement is a characteristic of anti-psychotic drugs.

The anti-psychotic drugs are antagonists at the histamine H1 –receptor in the central nervous system, and this antagonism

mediates sedation. The anti-psychotic drugs are antagonists at α1-adrenoceptors, and this antagonism mediates hypotension.

The anti-psychotic drugs are antagonist at dopamine D2-receptors, and this leads to extrapyramidal (movement) side effects.

Unfortunately some D2-receptor antagonism is necessary for benefit in schizophrenia. Thus, when treating with D2 receptor

antagonists, you will always end up with mix of benefits and side effects with antipsychotic drugs.

The potency of the anti-psychotics at causing the side effects of extrapyramidal side effects, hypotension and sedation is given

in Table 39.2.

Table 39.2 Potency as antagonists and side effects (Copyright QUT, Sheila Doggrell)

5

All the agents are potent antagonists at dopamine D2 receptors which leads to extrapyramidal side effects, with haloperidol

being worse than chlorpromazine, risperidone and amisulpride which in turn are worse than olanzapine.

All these antipsychotic drugs, except amisulpride, are potent antagonists at α1-adrenoceptors, and all cause hypotension.

Antagonism at histamine H1 receptors in the central nervous system causes sedation. Chlorpromazine, olanzapine and

risperidone are potent antagonists at H1 receptors and cause sedation, which is more marked with chlorpromazine than with

olanzapine or risperidone. Haloperidol is a weak antagonist at H1 receptors, and therefore causes less sedation than

chlorpromazine. Amisulpride has no effect at H1 receptors and does not cause sedation.

Unfortunately, the incidence and severity of extrapyramidal side effects increases with time that the antipsychotics are used.

These neurological side effects are listed in Table 39.3.

If the side effect of acute dystonia, which is spasm of muscles of tongue, face, next and back, is going to appear, the time it is

most likely to start is within 1 to 5 days. If akathisia, which is anxiety distress leading to motor restlessness is going to become

an adverse effect, it is apparent within 5-60 days.

There are three types of neurological side effects with the conventional anti-psychotics that resemble Parkinson’s disease.

Firstly, there can be the general symptoms of Parkinson’s disease such as bradykinesia, rigidity, variable tremor, masked

facies, and a shuffling gait, and these symptoms are called Parkinsonism. If Parkinsonism is going to appear with the anti-

psychotic drugs, it will happen between 5-30 days. Secondly, there can be neuroleptic (from the old name for the

conventional anti-psychotics) malignant syndrome. Fortunately, this side effect is rare, and consists of mimicking the serious

form of Parkinson’s disease, where there is catatonia, stupor and fever. The time of maximal risk of neuroleptic malignant

syndrome developing is weeks after the start of treatment with the anti-psychotic drug treatment. Finally, perioral (around the

mouth) tremor is another neurological side effect of the anti-psychotic drugs, but this takes months or years to appear.

Table 39.3 Neurological side effects of anti-psychotic drugs (Copyright QUT, Sheila Doggrell)

Probably the worst side effect of the anti-psychotic drugs to deal with is the tardive dyskinesia, where there is oral-facial

dyskinesis, widespread choreoatherois (flitting – rapid movement, and writhing) or dystonia (spasms).

6

Schizophrenia is a long term disease. There is no cure at present. Thus, the anti-psychotic drug treatments for schizophrenia

will continue indefinitely, as will the increased likelihood of side effects.

Thus, to continue to use the anti-psychotic drugs, it is often necessary to treat the neurological side effects.

In schizophrenia, drugs that act as antagonists at dopamine receptors are beneficial. In contrast, in Parkinson’s disease, drugs

that increase the dopaminergic system are beneficial. In Parkinson’s disease, drugs that increase the dopaminergic system are

beneficial. L-dopa increases the synthesis of dopamine and the activity of the dopaminergic system. L-dopa is useful in the

treatment of acute dystonia, akathisia, Parkinsonism, and perioral tremor.

In neuroleptic malignant syndrome, L-dopa is not an effective treatment. In neuroleptic malignant syndrome, it is necessary to

stop the treatment with neuroleptic (antipsychotic) and administer a dopamine receptor agonist (e.g. bromocriptyline).

Unfortunately, no satisfactory treatment for tardive dyskinesia has been found. It can be difficult to persuade the psychotic

subject to continue taking their anti-psychotic drugs, if they are suffering from the embarrassment associated with having

tardive dyskinesia.

39.6 Features of individual drugs

A major difference between olanzapine and chlorpromazine or haloperidol is its lesser ability to cause extrapyramidal

neurological side effects.

Chlorpromazine is active oral administration, and is used orally as a tablet or a solution. To be effective, the antipsychotic

drugs have to get into the central nervous system, so they need to be lipid soluble. Chlorpromazine is lipid soluble, and

crosses the blood brain barrier. Chlorpromazine has a weak ability to induce its own liver metabolism, thus the plasma levels

may go down with repeated administration, requiring an adjustment of the dose upwards.

Chlorpromazine causes dermatological disorders (urticaria or dermatitis) occur in about 5% of patients. When administering

chlorpromazine, you need to avoid contact, as this can give the dermatological disorders. There is often mild jaundice early in

therapy with chlorpromazine.

Haloperidol is active after oral administration, is lipid soluble, and crosses the blood brain barrier. Haloperidol can also be

administered as long-acting injections for chronic psychoses, especially in the non-compliant, which is common in subjects with

psychoses. In addition to the neurological side effects, haloperidol may cause some weight gain. This weight gain is probably

due to blocking the 5-HT2-receptors.

Olanzapine is effective in some people schizophrenia and related psychoses. It is active after oral administration, is lipid

soluble, and crosses the blood brain barrier. Olanzapine can also be used in long-acting preparation that is administered

intramuscularly. Despite not causing extrapyramidal neurological side effects to the same extent as the conventional anti-

psychotics, olanzapine is still an unpleasant drug to use. For instance, weight gain is prominent, probably due to blocking 5-

HT2-receptors. This weight gain is pronounced and gives an increased risk of type 2 diabetes and hyperlipidemia.

Risperidone is used in the treatment of schizophrenia and related psychoses. It can be administered orally, as a tablet or

liquid. Risperidone can also be used in a long-acting preparation administered intramuscularly. Risperidone requires dose

reduction in renal and/or liver impairment, as it undergoes liver metabolism and kidney excretion. The common side effects

with risperidone are insomnia, akathisia, and headache

Amisulpiride is used to treat schizophrenia. It is used orally, either as a tablet or in liquid form. With amisulpride, it is

necessary to reduce the dose in mild-to-moderate renal impairment, and it is not used in severe renal impairment. The

common side effects with amisulpiride are insomnia and hypersalivation.

7

40. Depression and anti-depressants

40.1 Introduction to depression and major depression

As treatment is required for major depression not normal depression, it is necessary to know the difference. Depression is

normal grief, sadness, and disappointment. Major depression, at its worst, leads to contemplation of suicide or even suicide.

Major depression is depression out of proportion with the cause of the depression. Major depression is classically

characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, lack of

pleasure, self-deprecation, and agitation or hostility. Major depression is characterised by physical changes, such as insomnia

or hypersomnia (sleeping too much), altered eating patterns, decreased energy and libido, and disruptions of normal circadian

rhythms (e.g. hormonal secretion times are altered).

The incidence of major depression is high. 10% of Australian men and 20% of Australian women will have major depression at

some point of their lives.

Adolescents can also get major depression. In addition to the classical symptoms (e.g feelings of intense sadness and

despair etc), major depression is adolescents is characterised by poor school performance, persistent boredom, and

complaints of physical problems (headache, stomach aches).

The elderly also can get major depression. As well as the classical symptoms, major depression in the elderly is characterised

by diminished ability to think or concentrate, and by unexplained physical complaints.

The baby blues, depression after childbirth, or as it is correctly called post-partum depression is common. Post-partum

depression occurs in10-20% of women after childbirth.

Risk factors for depression in adults include being female, advanced age, lower socioeconomic status, recent stressful life

experience, and chronic medical conditions

Major depression is not identical in all depressed people. One way we can identify this is that some subjects respond to one

antidepressant while others respond to another.

Depression is linked to neurotransmitters in the brain. The neurotransmitters that are most commonly implicated in major

depression are 5-hydroxytryptamine (5-HT; serotonin) and noradrenaline (NA). Drugs that inhibit the transport of these

amines into their neurones, increase the levels in the synapse, and are useful in the treatment of depression. However, the

antidepressant effect is not apparent for days or weeks, so there is not a simple relationship whereby inhibiting the transporters

leads to increased levels of the neurotransmitters leads to an antidepressant effect. The time lapse before anti-depressant

work, suggests that it is a long term adaptive change to increased levels of 5-HT and/or NA in the synapses, which underlies

the antidepressant effect with these drugs.

40.2 Mechanism of action of antidepressants

The antidepressants inhibit either the serotonin transporter (SERT), the noradrenaline transporter (NET), or both.

On activation of the tryptaminergic nerve terminal, 5-HT is released and stimulates 5-HT receptors on the postjunctional

membrane to have an effect. 5-hydroxytryptamine (5-HT) is inactivated by transport back into the neurone on the serotonin

transporter (SERT), and this leads to the termination of action of 5-HT.

The short term effect of fluoxetine (Prozac) is to selectively inhibit the SERT transporter, which inhibits the inactivation of 5-

HT (Figure 7.9). Consequently, there are increased levels of 5-HT in the synapse, which leads to an increased stimulation of

receptor, and an increased effect. However, this short term effect does not directly underlie the antidepressant effect, as the

antidepressant effect is long term. Rather it is a long term adaptive change to the increase concentrations of 5-HT in the

synapse that underlies the antidepressant effect. Fluoxetine is selective for the SERT transporter, and has little effect on the

8

transport of noradrenaline. Fluoxetine is one example of a group of drugs known as the selective serotonin reuptake inhibitors

(SSRIs).

The SSRIs do not work in all depressed people, which illustrates that depression is not a homologous disease. Depressed

people unresponsive to fluoxetine, may respond to an inhibitor of both the SERT and NET transporters e.g. venlafaxine. The

physiological processed whereby 5-HT and NA are inactivated are similar, both involve the transporter for the neurotransmitter.

The SERT transporter has binding sites for 5-HT and not for NA, whereas the NET (noradrenaline transporter) has binding sites

for NA but not for 5-HT.

On activation of the noradrenergic nerve terminal, NA is released and stimulates adrenoceptors to have an effect. NA is

inactivated by transport back into the neurone on the noradrenaline transporter (NET), and this leads to the termination of the

actions of NA.

The short term effect of venlafaxine includes inhibiting the NET transporter, which inhibits the inactivation of NA.

Consequently, there is an increased level of NA in the synapse. With more NA in the synapse, there is an increased

stimulation of adrenoceptors, and increased effects. However, this short term effect does not directly underlie the

antidepressant effect with venlafaxine, as the antidepressant effect does not start for days or weeks. Rather it is a long term

adaptive change to the increase concentrations of the neurotransmitters NA and 5-HT in synapseS that underlies the

antidepressant effect of venlafaxine.

40.3 Selective Serotonin Reuptake Inhibitors (SSRIs)

The SSRIs (e.g. fluoxetine) are considered to be efficacious in depression in adults. A variety of SSRIs including fluoxetine are

used in adults, and in adults, they all seem to be similarly effective. Thus, in adults, the choice of SSRI is often a preference of

the doctor, or may be the cheapest SSRI.

In contrast, in adolescents, efficacy has only been demonstrated with fluoxetine, NOT the other SSRIs. Thus, only fluoxetine

should be used in adolescents. The best results are when fluoxetine is combined with some cognitive-behavioural therapy.

The SSRIs, e.g fluoxetine, are efficacious in depression in pregnancy. The SSRIs do cross the placenta and will reach the

unborn baby. In depression in pregnancy, the use of SSRIs in the late stages is associated with an increased risk of persistent

pulmonary hypertension of the newborn. The use of SSRIs prior to the 20th week of pregnancy does not alter the incidence

of persistent pulmonary hypertension. Thus, SSRIs can be used in depression in pregnancy up to the 20th week, and then they

have to be stopped.

The SSRIs are efficacious in postpartum depression, the baby blues. The SSRIs are excreted into breast milk, and the infant

receives 0.5-10% of maternal daily dose of SSRI. This may sound high, but there is no evidence of adverse effects in the

newborn. Consequently, the SSRIs are used in the treatment of postpartum depression and the new mum can continue to

breast feed.

Fluoxetine has an active metabolite norfluoxetine, which probably contributes to the antidepressant effect. Fluoxetine is very

selective for the SERT over the NET, with 300 times the concentration of fluoxetine that inhibits the uptake of 5-HT being

required to inhibit the uptake of NA. Fluoxetine has a long half-life (elimination half-life is 50 hours) and consequently,

fluoxetine only has to be administered once a day. Fluoxetine is inhibits CYP2D6, which inhibits the metabolism of drugs

metabolised by CYP2DC such as haloperidol. This causes the plasma levels of haloperidol to rise to potentially toxic levels.

Norfluoxetine inhibits CYP3A4, which inhibits the metabolism of all the drugs metabolised by CYP3A4, which included

phenytoin. This causes the plasma levels of phenytoin to rise to potentially toxic levels.

Adverse effects are not a major problem with the SSRIs. The adverse effects that are considered common with the SSRIs are

gastrointestinal (dry mouth, nausea, constipation), neuropsychiatric (anxiety, dizziness, headache, insomnia and tremor) and

sexual dysfunction. However, these usually occur in less than 5% of patients, which means that the SSRIs give no adverse

effects in the majority of people treated with them.

9

When a person, especially if it is an adolescents takes an antidepressant and then commits suicide, there are often news

headlines such as “Prozac killed my kid”. However, there is no good evidence for this with the fluoxetine. Suicide occurs in up

to 15% of subjects with depression each year. Thus, it is the depression that usually kills not the fluoxetine. Huge studies have

shown that there is no increased risk of suicide in adults with fluoxetine or the otherSSRIs. There is also no increased risk of

suicide with fluoxetine in adolescents. However, there is a slight increased risk with the other SSRIs in adolescents,

probably because they don’t have any benefit! As mentioned previously, the only SSRI that should be used in adolescents in

fluoxetine, as it is the only SSRI that has been shown to be effective in adolescent depression.

The SSRIs can interact with St John’s Wort. St John’s Wort is a well known over-the-counter medicine for the treatment of

depression. Only recently has the mechanism of action of St John’s Wort been determine. It has been shown that hypericin

and hyperforin are active ingredients of St John’s Wort. Hypericin and hyperforin inhibits SERT, and to a lesser extent NET.

Thus, St John’s Wort has a similar mechanism to the SSRIs. Inhibiting the SERT will increase the levels of 5-

hydroxytryptamine (also known as serotonin).

St John’s Wort is absorbed after oral administration, and has a half-life of elimination of 14-48 hours. It is quite a safe drug, and

the side effect rate is 2.4%. St John’s Wort is superior to placebo and as effective as fluoxetine or the tricyclic antidepressants

in the treatment of mild-to-moderate depression. There are conflicting results with St John’s Wort in subjects with major

depression with trials either showing no effect or some benefit.

St John’s Wort should not be combined with antidepressants that inhibit SERT or NET, as they have same mechanism of

action, and an additive effect on levels of 5-hydroxytryptamine (serotonin) or noradrenaline, and the increased levels may be

toxic. In combination with SSRIs, St John’s Wort may trigger the serotonin syndrome. The serotonin syndrome is due to high

levels of serotonin in the brain.

The serotonin syndrome is a life threatening condition characterized by behavioural changes (euphoria, drowsiness, loss of

consciousness), autonomic nervous system function changes (sweating, diarrhoea), and abnormal muscle movements.

There are other problems with the use of St John’s Wort. St John’s Wort induces CYP3A4, the enzyme responsible for

metabolising about half the available medicines. By inducing CYP3A4, St John’s Wort reduces the levels of drugs metabolised

by this enzyme, and they may become ineffective. For instance, St John’s Wort reduces the effectiveness of oral

contraceptives. It shortens the half-life of estrogen and can cause increased breakthrough bleeding, and unwanted pregnancy.

Thus, women using oral contraceptives, who also want to use St John’s Wort, need to swap from oral to barrier contraceptives.

There are lots of other possible interactions of St John’s Wort with drugs that are metabolised by CYP3A4. For instance,

decreased levels of several drugs (digoxin, theophylline, simvastatin) have been reported, but it is not known whether this is

clinically meaningful.

40.4 Inhibitors of NET and SERT

Venlafaxine is an inhibitor of the noradrenaline transporter (NET) and the serotonin transporter (SERT). Venlafaxine is

effective in about the same percentage of people with major depression as the SSRIs. Venlafaxine is efficacious in some of the

subjects who do not respond to SSRIs. This illustrates that major depression is not the same disease in all people, as some

respond to increases in serotonin levels only, whereas other require an increase in noradrenaline levels as well.

Venlafaxine is active after oral administration. It has a half-life of elimination of 5 h. Venlafaxine has a longer lasting active

metabolite (desmethylvenlafaxine). Nevertheless, venlafaxine has to be administered twice daily to be effective as an

antidepressant.

Selective SSRIs and venlafaxine are preferred over the older tricyclic antidepressants. The tricylic antidepressants are so

named, as their structure have 3 rings/cycles in it.

The tricyclic antidepressants do inhibit SERT and/or NET and this underlies their efficacy in the treatment of depression. Thus,

they have similarities to the SSRIs.

10

An example of a tricyclic antidepressant is amitriptyline. Amitriptyline inhibits both SERT and NET to increase the levels of

serotonin and noradrenaline in the synapses. The difference between the SSRIs and venlafaxine and the tricyclic

antidepressants is that the tricyclic antidepressants have additional effects that lead to side effects. Consequently, the tricyclic

antidepressants are used when depression is refractory to SSRIs.

In addition to inhibiting SERT and NET the tricyclic antidepressants inhibit muscarinic receptors. Thus, the adverse effects

are equivalent to blocking the parasympathetic nervous system. The anti-muscarinic side effects observed with the tricyclic

antidepressants are dry mouth with a sour or metallic taste, epigastric distress, constipation, dizziness, tachycardia,

palpitations, and blurred vision (with an increased risk of glaucoma).

Tricyclic antidepressants also inhibit α1-adrenoceptors. This removes the vasoconstrictor effect of noradrenaline at the α1-

adrenoceptors, to maintain venous return when standing up, and this causes postural hypotension (hypotension, when standing

up).

Tricyclic antidepressants inhibit cardiac Na+ channels. Thus, tricyclic antidepressants should be avoided after myocardial

infarction, in conduction defects of the heart, or use with other cardiac depressants, as further cardiac conduction inhibition with

these agents may be harmful.

Tricyclic antidepressants are antihistaminic, and by inhibiting H1-receptors in the central nervous system. This can lead to a

centrally mediated weakness and fatigue.

Thus, in the treatment of major depression, the SSRIs are much preferred to the tricyclic antidepressant, as they have few side

effects. However, if the depression is resistant to the SSRIs, tricyclic antidepressants may be effective.

40.5 Treatment of manic-depression

Manic-depression is also known as bipolar disease. In manic-depression/bipolar disease, subjects alternate between major

depression and mania, and this can occur within the same day. 1-2% of the population has bipolar disease. It is characterised

by the recurrences of severe depression and manic excitement, often with psychotic features.

The primary treatment to prevent mania occurring is the mood stabilising drugs. Examples of these are lithium and

valproate. Valproate is also used as an anti-epileptic, and is discussed in that section.

The depression in manic-depression is usually treated with SSRIs such as fluoxetine.

The psychosis associated with the manic phase of bipolar disease is treated with antipsychotic drugs. The antipsychotic drug

olanzapine is quite effective and often used in the treatment of psychosis associated with the manic phase. Olanzapine is an

atypical antipsychotic agent, similar in structure to clozapine. The use of antipsychotics in the treatment of schizophrenia was

discussed in Chapter 39.

The mechanism underlying mood stabilising effect of lithium is unknown. Lithium is readily absorbed from the gut. It has a

long elimination half-life of 20-24h, which may suggest it is suitable for once daily dosing. However, lithium is used in divided

doses, twice a day to prevent plasma levels reaching toxic levels.

Lithium has a low therapeutic index i.e. the dose that causes toxicity is only slightly above the concentrations that cause a

therapeutic effect. Thus, it is necessary to monitor levels of lithium, especially at the start of treatment or when there is break

through mania, to determine whether the levels are sufficient for a therapeutic effects

Eighty percent of lithium is reabsorbed by proximal tubule, and the other 20% is cleared by the kidney. In kidney disease, the

clearance of lithium is inhibited, and plasma concentrations may reach toxic levels. Thus, it may be necessary to reduce the

dose of lithium in mild renal dysfunction.

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41. Anxiety and sleep disorders, and their treatment

41.1 Introduction to anxiety and sleep disorders

Anxiety, stress and tension are all names for the same thing: a feeling of apprehension or fear that lingers. Stress is good for

you in small quantities, as it makes us more productive. Students would not learn about pharmacology without the stress of

examination. The stress makes us revise and learn about pharmacology.

However, too much stress is unhealthy and counterproductive. The physical symptoms of excessive stress are twitching or

trembling, muscle tension, headaches, sweating, dry mouth, and difficulty in swallowing. These symptoms will not help us learn

about pharmacology.

What is the cause of anxiety? Sometimes it is genetic predisposition, sometimes early childhood exposure to stress, and

sometimes a current stressful environment.

Some types of anxiety require behavioural change e.g. social phobia (public speaking). Thus, those who have a fear of public

speaking may be helped by behavioural changes such as relaxation techniques, or learning how to do public speaking in role

playing.

However, some types of anxiety require a combination of psychiatric and pharmacotherapy (sedative) help. For example, post-

traumatic stress disorder cannot be overcome by behavioural changes, and requires the use of medicines.

Often anxiety and depression occur together in the same person. We do not have single drugs that are good for both anxiety

and depression, so we treat the anxiety and depression separately.

To treat anxiety, sedative or anxiolytic drugs are used. Sedative drugs are used prior to an operation. Both sedative and

anxiolytic drugs decrease activity, moderate excitement and calms the recipient. The main class of drugs used as sedative and

anxiolytics are the benzodiazepines. The benzodiazepines are also used in the treatment of insomnia.

Insomnia is one of the most common complaints in general practice. Ten percent of people of people who visit their GP do so,

because they have insomnia. There are three types of insomnia. Probably the most common is initial insomnia, where the

person has difficulty in falling asleep. But other types of insomnia include middle insomnia, when the person has difficulty in

staying asleep, and terminal insomnia, when the person wakes up too early.

There are numerous causes of insomnia. Some have obvious reasons such as jet lag and shift work, where there is an upset

in your circadian rhythms, so the body confuses day and night, and you can’t sleep when you want to. Other causes of

insomnia include grief, depression, and anxiety/stress. Excitements, central stimulation with caffeine or nicotine, excessive

physical or intellectual stimulation at bedtime are all other causes of insomnia.

Why do we need to treat insomnia? Firstly, it is unpleasant for the sufferer. We also treat insomnia, because chronic insomnia

increases the risks of having accidents of all types. There are a range of non-pharmacological things you can do to prevent

insomnia, such as not having intellectual stimulation at bedtime. Exercise promotes sleep, but not just before you want to do to

sleep.

When insomnia accompanies depression or anxiety or other medical condition, we do not treat the insomnia first. First, we treat

the underlying medical condition. When the underlying medical condition is treated, the insomnia often goes away, and we do

not need to treat the insomnia.

The drugs used to treat insomnia are the hypnotics. The hypnotic drugs produce drowsiness, facilitate the onset and

maintenance of state of sleep that resembles natural sleep and from which the recipient is easily aroused.

Benzodiazepines are the main drugs used to treat anxiety and insomnia, and to cause sedation. The anxiety prior to an

operation is treated with pre-anaesthetic medication. Thus, the benzodiazepines are used for anxiolysis, amnesia and

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sedation prior to general anaesthesia. Alternatively sedatives (benzodiazepines) are used for sedation during procedures

not requiring general anaesthesia e.g. endoscopy.

In addition to the benzodiazepines, sedating anti-histamines are used in the treatment of insomnia. These are the histamine

H1-receptor antagonists that cross the blood brain barrier to have a sedative effect.

41.2 Mechanism of action of benzodiazepines

The benzodiazepines potentiate the effects on an inhibitory neurotransmitter in the central nervous system. This inhibitory

neurotransmitter is gamma (γ)-aminobutyric acid (GABA). There are cell surface receptors for GABA and there are two main

types GABAA and GABAB. The GABAA receptor is the one the benzodiazepines interact with. The GABAA receptor has 5

subunits that form a Cl- channel (Figure 41.1). Benzodiazepines bind to a distinct binding site, the benzodiazepine binding site

on the GABAA receptor to potentiate the effect of GABA, which is to open the chloride channel, and the more chloride that goes

through the channel, the bigger the inhibitory effect. Benzodiazepines have no effect alone, and are only effective when GABA

is present.

Figure 41.1 Benzodiazepine binding site, GABAA receptor and chloride channel (Copyright QUT, Sheila Doggrell)

41.3 Clinical use of benzodiazepines

Firstly, the general properties of all the benzodiazepines are discussed and then the properties of some of the specific drugs

are discussed. Central nervous system effects of the benzodiazepine are prominent. They cause sedation, hypnosis, and

decreased anxiety, with differences between individual drugs and doses. They also cause muscle relaxation, and anterograde

amnesia, which is a deficit in ability to learn new information. Anterograde amnesia is good when the benzodiazepines are

being used as sedatives in an operation, but not so good when taken for anxiety. The benzodiazepines are not anaesthetics,

as awareness usually persists. Thus, with benzodiazepines the subject is not unconscious but has enough relaxation to

undergo surgery without becoming distressed.

The hypnotic effects of benzodiazepines are without effects on respiration in normal subjects. However, pre-anaesthetic doses

do depress alveolar ventilation. Therefore, care has to be taken with people with impaired respiration e.g. people with chronic

obstructive pulmonary disease. Severe respiratory depression can occur when the benzodiazepines are used/abused with

another respiratory depressant (e.g. opioids, alcohol).

The benzodiazepines are active after oral administration. The benzodiazepines are very lipid soluble, and almost completely

absorbed. They have rapid uptake into brain and undergo liver metabolism.

The benzodiazepines are also used as anti-convulsants, and that use is discussed briefly in Chapter 43.

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There are lots of untoward (unwanted) effects with the benzodiazepines. They cause lightheadedness, lassitude, increased

reaction time, motor incoordination, impairment of mental and motor functions, and confusion. These actions are additive with

alcohol. They cause residual day-time sleepiness.

Addiction to benzodiazepines is a commonly mentioned in the media. However, there is actually only a low incidence of abuse

and physical dependence with benzodiazepine, if the benzodiazepines are used as prescribed. There is no major withdrawal

syndrome, and any withdrawal syndromes can be avoided by tapering off the benzodiazepines i.e. stabilising on one dose of

the long-acting benzodiazepine, diazepam, and then gradually decreasing the dose. Mild psychological dependence can

develop to the benzodiazepines, and this can be difficult to break.

The benzodiazepines are relatively safe. An overdosage of any of the benzodiazepines can be overcome with flumazenil the

antagonist at the benzodiazepine binding site. Flumazenil reduces the ability of the benzodiazepines to promote the inhibitory

effect of GABA.

There are lots of different benzodiazepines, but only one example for each use is discussed here. Probably, the best known

benzodiazepine is diazepam. Diazepam is used in the treatment of anxiety. It has a long half-life (43 hours), which makes

diazepam long acting. Diazepam also has active metabolites. The active metabolites nordiazepam and oxazepam are used as

benzodiazepines in their own right.

As there are different types of insomnia, different benzodiazepines have been developed to treat it. Lorazepam is particular

good for insomnia associated with anxiety. Thus, it has prominent hypnotic and anxiolytic properties.

Temazepam is used for the short term treatment of insomnia. It is a very good hypnotic. However, of all the benzodiazepines,

temazepam is probably the one with the most potential for abuse and psychological dependent. Thus, its medicinal use is

restricted to short term.

Flunitrazepam was developed to treat severe insomnia. It is very effective in severe insomnia, it has a quick onset of action,

and short durations of action, which makes it ideal for people who have great difficulty going to sleep, but then sleep okay.

Unfortunately, these properties of flunitrazepam have led to serious abuse of the drug. It is known as the date-rape drug, and

sedates after drink spiking.

Midazolam is the benzodiazepine commonly used as an anaesthetic adjunct. It is used in two different ways. It is used as a

sedative prior to general anaesthesia. Also, it is used for sedation during procedures not requiring general anaesthesia. Thus,

sedation with midazolam is used in endoscopy, or in minor interventions and regional anaesthesia with local anaesthetic

lignocaine. Midazolam is also used as a sedating agent in very anxious people. Thus, the paramedics use midazolam to calm

people who have been involved in an accident.

Midazolam is commonly use intravenously for a fast effect, but it is active after oral administration. With intravenous

administration there is rapid onset of the sedation with midazolam. The peak effect after intravenous administration is in 2

minutes. Midazolam has a short duration of action causing sedation for 30 minutes.

Midazolam undergoes liver metabolism. Midazolam decreases blood pressure and respiratory rate, and these need to be

monitored when it is being used.

41.4 Sedating antihistamines

The antihistamines were originally developed as anti-allergy drugs, and they are effective against mild allergy. The

antihistamines are antagonists at the H1-receptors, the receptor that mediates the allergy effects of histamine. The older

agents (e.g. diphenhydramine) cross the blood brain barrier and antagonism at H1-receptors produces sedation. This

indicates that there a H1-receptor in the central nervous system that mediates alertness, and when this is antagonised, there is

sedation. Diphenhydramine and all the other older antihistamines that caused sedation have been replaced in the treatment of

allergy by less sedating anti-histamines e.g. fexofenadine, which do not get into the brain to any great extent.

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Diphenhydramine has been re-invented as a sedative. It is available on prescription, but is not commonly prescribed for

insomnia as the benzodiazepines are preferred. Low dose preparations of diphenhydramine are available over the counter,

and are used for insomnia. Tolerance tends to develop to the sedating effect of diphenhydramine, and thus, it is only effective

short term.