Central nervous system - Elsevier · 2013-12-20 · Central nervous system 5 Objectives After...

Central nervous system 5Objectives

After reading this chapter, you will:● Understand the functions of the central nervous system and the diseases that can occur● Know the drug classes used to treat these conditions, their mechanisms of action and adverse effects.

BASIC CONCEPTS

The central nervous system consists of the brain and thespinal cord, which are continuous with one another.The brain is composed of the cerebrum (which consistsof the frontal, temporal, parietal and occipital lobes),the diencephalon (which includes the thalamus andhypothalamus), thebrainstem(which consists of themid-brain, pons and medulla oblongata) and the cerebellum.The brain functions to interpret sensory informationobtained about the internal and external environmentsand send messages to effector organs in response to asituation. Different parts of the brain are associatedwith specific functions (Fig. 5.1). However, the brain is acomplex organ and is not yet completely understood.

PARKINSON’S DISEASEAND PARKINSONISM

Parkinsonism is characterized by a resting tremor, slowinitiation of movements (bradykinesia), and musclerigidity. A patient with parkinsonism will present withcharacteristic signs including:

• A shuffling gait• A blank ‘mask-like’ facial expression• Speech impairment• An inability to perform skilled tasks.

Parkinsonism is most commonly caused by Parkinson’sdisease, though other causes exist.

Parkinson’s disease is a progressive neurologicaldisorder of the basal ganglia that occurs most com-monly in elderly people.

Aetiology

The cause of Parkinson’s disease is unknown in mostcases (idiopathic) although both endogenous andenvironmental neurotoxins are known to be responsi-ble for causing parkinsonism.

Parkinson’s disease is progressive, with continuedloss of dopaminergic neurons in the substantia nigracorrelating with worsening of clinical symptoms. Thepossibility of a neurotoxic cause has been strengthe-ned by the finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a chemical contaminantof heroin, causes irreversible damage to the nigrostriataldopaminergic pathway. Thus, this damage can leadto the development of symptoms similar to those ofidiopathic Parkinson’s disease. Drugs that blockdopamine receptors can also induce parkinsonism.Neuroleptic drugs (p. 000) used in the TS1treatment ofschizophrenia can produce parkinsonian symptoms asan adverse effect. Rare causes of parkinsonism are cere-bral ischaemia (progressive atherosclerosis or stroke),viral encephalitis or other pathological damage.

HINTS AND TIPS

RATS in the parking lot! Symptoms of parkinsonism

include Rigidity, Akinesia, Tremor and Shuffling gait.

Pathogenesis

Post-mortem analysis of brains of parkinsonian pati-ents shows a substantially reduced concentration ofdopamine (less than 10% of normal) in the basalganglia. The basal ganglia exert an extrapyramidalneural influence that normally maintains smoothvoluntary movement.

The main pathology in Parkinson’s disease is a pro-gressive degeneration of the dopaminergic neurons ofthe substantia nigra, which project via the nigrostriatalpathway to the corpus striatum (Fig. 5.2). The inhibi-tory dopaminergic activity of the nigrostriatal pathwayis, therefore, considerably reduced (by 20–40%) inpeople with Parkinson’s disease.

The reduction in the inhibitory dopaminergicactivity of the nigrostriatal pathway results in unop-posed cholinergic neuron hyperactivity from the corpus

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striatum, which contributes to the pathological featuresof parkinsonism. Frank symptoms of parkinsonism ap-pear only when more than 80% of the dopaminergicneurons of the substantia nigra have degenerated.

Untreated Parkinson’s eventually results in dementiaand death.

Treatment of parkinsonism

The treatment of parkinsonism is based on correctingthe imbalance between the dopaminergic and choliner-gic systems at the basal ganglia (Fig. 5.3). Two majorgroups of drugs are used: drugs that increase dopami-nergic activity between the substantia nigra and thecorpus striatum, and anticholinergic drugs that inhibitstriatal cholinergic activity.

Drugs that increase dopaminergic activity

Dopamine precursorsAn example of a dopamine precursor is levodopa(L-dopa).

Mechanism of action—L-dopa is the immediateprecursor of dopamine and is able to penetrate theblood–brain barrier to replenish the dopamine contentof the corpus striatum. L-dopa is decarboxylated todopamine in the brain by dopa decarboxylase, and ithas beneficial effects produced through the actions ofdopamine on D2 receptors (see Fig. 5.3). Dopamineitself is not used, owing to its inability to cross theblood–brain barrier.

Fig. 5.1 Parts of the brain and their known functions.

Fig. 5.2 Basal ganglia systems involved in Parkinson’s disease.(ACh, acetylcholine; DA, dopamine; GABA, g-aminobutyricacid.)(Redrawn from Page et al. 2006.)

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Route of administration—L-dopa is administeredorally. It reaches peak plasma concentrations after1–2 hours and only 1% reaches the brain, owing toperipheral metabolism.

Indications—L-dopa is used in the treatment ofparkinsonism (excluding drug-induced extrapyramidalsymptoms).

Contraindications—Closed-angle glaucoma.Adverse effects—The extensive peripheral metabolism

of L-dopa means that large doses have to be given toproduce therapeutic effects in the brain. Large doses aremore likely to produce adverse effects. These include:

• Nausea and vomiting• Psychiatric side-effects (schizophrenia-like symptoms)• Cardiovascular effects (hypotension)• Dyskinesias.

Nausea and vomiting are caused by stimulation of do-pamine receptors in the chemoreceptor trigger zone in

the area postrema (p. 000), which lies TS1outside theblood–brain barrier.

Psychiatric side-effects are common limiting factorsin L-dopa treatment; these include vivid dreams, confu-sion and psychotic symptoms more commonly seen inschizophrenia. These effects are probably a result ofincreased dopaminergic activity in the mesolimbic areaof the brain, possibly similar to that found patho-logically in schizophrenia (dopaminergic overactivityis implicated in schizophrenia, TS1p. 000).

Hypotension is common but usually asymptomatic.Cardiac arrhythmias are due to increased catecholaminestimulation following the excessive peripheral metabo-lism of L-dopa.

Dyskinesias can often develop and tend to involvethe face and limbs. They usually reflect over-treatmentand respond to simple dose reduction.

Three strategies have been developed to optimizeL-dopa treatment, to maximize the central effects of

Fig. 5.3 Drugs used to treat parkinsonism and their site of action. (ACh, acetylcholine; DA, dopamine; L-dopa, levodopa; MAOB,monoamine oxidase B; COMT, catechol-O-methyl transferase.)

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L-dopa within the brain, and minimize its unwantedperipheral effects. These strategies involve co-adminis-tration of:

• Carbidopa (given with L-dopa as co-careldopa) orbenserazide (given with L-dopa as co-beneldopa),inhibitors of dopa decarboxylase in the periphery,that cannot penetrate the blood–brain barrier.Hence, extracerebral conversion of L-dopa to dopa-mine is inhibited.

• Domperidone, a dopamine antagonist, that doesnot penetrate the blood–brain barrier and can,therefore, block the stimulation of dopamine recep-tors in the periphery.

• Selegiline and entacapone, monoamine oxidase(MAO)B and catechol-O-methyltransferase (COMT)inhibitors, respectively, which inhibit dopaminedegradation in the central nervous system (CNS).Therapeutic notes—Initially, treatment with L-dopa is

effective in 80% of patients with possible restoration ofnear-normal motor function. Although L-dopa restoresdopamine levels in the short term, therapy has no effecton the underlying degenerative disease process.

As progressive neuronal degeneration continues, thecapacity of the corpus striatum to convert L-dopa todopamine diminishes. This affects the majority of pa-tients within 5 years and manifests itself as ‘end of dosedeterioration’ (a shortening of duration of each dose ofL-dopa), and the ‘on-off effect’ (rapid fluctuations inclinical state, varying from increased mobility and ageneral improvement to increased rigidity and hypoki-nesia). The latter effect occurs suddenly and for shortperiods from a few minutes to a few hours, tending toworsen with length of treatment.

Dopamine agonistsExamples of dopamine agonists include bromocriptine,ropinirole, cabergoline, pergolide, pramipexole, lisur-ide and apomorphine.

Mechanism of action—Bromocriptine, ropinirole,cabergoline (longer acting), pergolide, pramipexole,lisuride and apomorphine are dopamine agonistsselective for theD2 receptor (see Fig. 5.3). Apomorphinealso has agonist action at D1 receptors. Pramipexole hasa high affinity for D3 receptors.

Route of administration—Oral. Apomorphine isgiven by the subcutaneous route.

Indications—Dopamine agonists are used in com-bination with L-dopa in an attempt to reduce the lateadverse effects of L-dopa therapy (‘end of dose deterio-ration’ and ‘on-off effect’) or when L-dopa alone doesnot adequately control the symptoms.

Adverse effects—The adverse effects of dopamineagonists are similar to those of L-dopa (i.e. nausea,postural hypotension, psychiatric symptoms), but theytend to bemore commonandmore severe. Apomorphine

produces profound nausea and vomiting. Ergot-deriveddopamine agonists (bromocriptine, cabergoline, lisurideand pergolide) can cause fibrosis.

Therapeutic notes—Currently bromocriptine is themost used of the dopamine agonists in the treatmentof Parkinson’s disease.

Drugs stimulating release of dopamineAmantadine is an example of a drug that stimulates therelease of dopamine (see Fig. 5.3).

Mechanism of action—Facilitation of neuronal dopa-mine release and inhibition of its reuptake into nerves,and additional muscarinic blocking actions.

Route of administration—Oral.Indications—Amantadine has a synergistic effect

when used in conjunction with L-dopa therapy inParkinson’s disease.

Adverse effects—Anorexia, nausea, hallucinations.Therapeutic notes—Amantadine has modest antipar-

kinsonian effects, but it is only of short-term benefit,since most of its effectiveness is lost within 6 monthsof initiating treatment.

MAOB inhibitorsSelegiline is an example of a MAOB inhibitor.

Mechanism of action—Selegiline selectively inhibitsthe MAOB enzyme in the brain that is normally res-ponsible for the degradation of dopamine (seeFig. 5.3). By reducing the catabolism of dopamine,the actions of L-dopa are potentiated, thus allowingthe dose to be reduced by up to a third. There isevidence to suggest that selegiline may slow the pro-gression of the underlying neuronal degeneration inParkinson’s disease.

Route of administration—Oral.Indications—MAOB inhibitors can be used on their

own in mild cases of parkinsonism or in conjunctionwith L-dopa to reduce ‘end-of-dose’ deterioration insevere parkinsonism.

Adverse effects—The adverse effects of MAOB inhi-bitors are those that might be expected by potentiationof L-dopa.

HINTS AND TIPS

Note that with the possible exception of selegiline,

none of the drugs used in Parkinson’s disease affect

the inevitable progressive degeneration of

nigrostriatal dopaminergic neurons. The disease

process is unaffected, just compensated for by

drug therapy.


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COMMUNICATION

Mrs Patches, a 62-year-old barrister, presents to her GP

complaining of shaking arms, the right arm more

prominently so than the left. She notes that alcohol

does not help to steady the shaking and that people at

work have started complaining about her handwriting

becoming too small to read. She also mentions her

body muscles have been feeling rather stiff.

She is referred to a neurologist, who observes her

face to be expressionless, a resting tremor and

increased muscle tone. Her power, reflexes,

coordination and sensation are found to be normal.

Examination of her gait shows she is slow getting

started and has difficulty stopping and starting.

A diagnosis of Parkinson’s disease is made and the

implications discussed with Mrs Patches. She returns

3 months later and says she now wishes to commence

treatment; she has the same symptoms as before,

however, they are interfering more with her daily life.

She is given co-beneldopa and this helps to control her

symptoms.

COMT inhibitorsEntacapone and tolcapone are examples of COMTinhibitors.

Mechanism of action—Dopamine is broken downby a second pathway, in addition to that of MAOB.The enzyme COMT is responsible for the degradationof dopamine to inactivemethylatedmetabolites. COMTinhibitors specifically inhibit this enzyme.

Route of administration—Oral.Indications—As an adjunct to L-dopa preparations

when ‘end-of-dose’ is problematic.Contraindications—Phaeochromocytoma.Adverse effects—Nausea, vomiting, abdominal pain,

diarrhoea.Therapeutic notes—Due to hepatotoxicity, tolcapone

should only be prescribed under specialist supervision.

Drugs that inhibit striatal cholinergicactivity

Anticholinergic agentsBenzatropine, procyclidine and orphenadrine areexamples of anticholinergic (antimuscarinic) agents.

Mechanism of action—Benzatropine, procyclidineand orphenadrine are antagonists at the muscarinicreceptors that mediate striatal cholinergic excitation(see Fig. 5.3). Their major action in the treatment ofParkinson’s disease is to reduce the excessive striatalcholinergic activity that characterizes the disease.

Route of administration—Oral.Adverse effects—Typical peripheral anticholinergic

effects, such as a dry mouth and blurred vision, are lesscommon. More often, patients experience a variety ofCNS effects, ranging from mild memory loss to acuteconfusional states.

Therapeutic notes—Termination of anticholinergictreatment should be gradual, as parkinsonism canworsen when these drugs are withdrawn. Anticholiner-gic drugs are most effective in controlling tremor ratherthan other symptoms of Parkinson’s disease.

Transplantation

The transplantation of cells from the substantia nigra ofhuman fetuses into the putamen of patients withParkinson’s disease has shown some success in con-trolling parkinsonian symptoms.

Transplantation in the treatment of Parkinson’sdisease is still experimental, and its role is highlycontroversial.

DEMENTIA

Alzheimer’s disease is a specific process that results indementia and is unrelated to the dementias associatedwith stroke, brain trauma and alcohol. Its prevalenceincreases markedly with age.

Alzheimer’s disease is progressive and it is associatedwith atrophy of the brain substance, loss of neuronaltissue and deposition of amyloid plaques. The clinicalfeatures include deterioration in cognitive function,disorientation and generalized confusion.

Loss of neurons in the forebrain is most marked anda relative selective loss of cholinergic neurons mostlikely accounts for the features of this dementia.The obvious therapeutic target is, therefore, restorationof cholinergic function.

Cholinesterase inhibitorsDonepezil, galantamine and rivastigmine are cho-linesterase inhibitors, licensed for use in dementiain the UK.

Mechanism of action—The cholinesterase inhibitorsprevent the breakdown of acetylcholine within thesynaptic cleft, and they enhance endogenous cholino-genic activity within the CNS and peripheral tissues.

Route of administration—Oral.Indications—Mild to moderate dementia in Alzhei-

mer’s disease.Contraindications—Pregnancy, breastfeeding, hepatic

and renal impairment.Adverse effects—Nausea, vomiting, diarrhoea, anorexia,

agitation.

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ANXIETY AND SLEEP DISORDERS

Anxiety and anxiolytics

Anxiety is a state characterized by psychological symp-toms such as a diffuse, unpleasant and vague feelingof apprehension, often accompanied by physical symp-toms of autonomic arousal such as palpitations, light-headedness, perspiration, ‘butterflies’ and, in somepeople, restlessness.

While occasional anxiety is perfectly normal, it is acommon and disabling symptom in a variety of mentalillnesses including phobias, panic disorders andobsessive compulsive disorders. Drugs used to treatsuch anxiety disorders are called anxiolytics.

SLEEP DISORDERS ANDHYPNOTICS

Insomnia is a common and non-specific disorder thatmay be reported by 40–50%of people at any given time.

Causes of insomnia include medical illness, alcoholor drugs, periodic limb movement disorder, sleepapnoea and psychiatric illness. Without an obviousunderlying cause, it is known as primary or psycho-physiological.

Hypnotics are drugs used to treat psycho-physiological (primary) insomnia. The distinctionbetween the treatment of anxiety and that of sleepdisorders is not clear-cut, particularly if anxiety is themain impediment to sleep.

g-Aminobutyric acid receptor

The g-aminobutyric acid (GABA) receptors of theGABAA type are involved in the actions of some classesof hypnotic/anxiolytic drugs, notably:

• The benzodiazepines, which are currently the mostcommonly used clinically

• Newer non-benzodiazepine hypnotics, e.g. zopiclone• The now obsolete barbiturates.

The GABAA receptor belongs to the superfamily ofligand-gated ion channels. It consists of severalsubunits – a, b, g and d – which form the GABA/Cl–

channel complex, as well as containing benzodiazepineand barbiturate modulatory receptor sites. The GABAbinding site appears to be located on the a and bsubunits whereas the benzodiazepine modulatory siteis distinct and located on the g subunit.

GABA released from nerve terminals binds topostsynaptic GABAA receptors, the activation of whichincreases the Cl– conductance of the neuron. Occu-pation of the benzodiazepine sites by benzodiazepine

receptor agonists enhances the actions of GABA onthe Cl– conductance of the neuronal membrane. Thebarbiturates similarly enhance the action of GABA,but by occupying a distinct modulatory site (Fig. 5.4).

Anxiolytic and hypnotic drugs

The pharmacotherapy of anxiety and sleep disordersinvolves several different classes of drug, as shown inFigure 5.5, and non-pharmacological managementrelying on cognitive and behaviour psychotherapy.

Benzodiazepines

Benzodiazepines are drugs with anxiolytic, hypnotic,muscle relaxation and anticonvulsant actions that areused in the treatment of both anxiety states andinsomnia.

Benzodiazepines are marketed as either hypnotics oranxiolytics. It is mainly the duration of action that de-termines the choice of drug (see below).

Mechanism of action—Benzodiazepines potentiatethe action of GABA, the primary inhibitory neurotrans-mitter in the CNS. They do this by binding to a site onGABAA receptors, increasing their affinity for GABA.This results in an increased opening frequency of theseligand-gated Cl– channels, thus potentiating the effectof GABA release in terms of inhibitory effects on thepostsynaptic cell (Fig. 5.4).

Indications—Benzodiazepines are used clinically inthe short-term relief of severe anxiety and severe insom-nia, preoperative sedation, status epilepticus and acutealcohol withdrawal.

Route of administration—Oral is the usual route. In-travenous, intramuscular and rectal preparations areavailable.

Contraindications—Benzodiazepines should not begiven to people with bronchopulmonary disease, andthey have additive or synergistic effects with othercentral depressants such as alcohol, barbiturates andantihistamines.

Adverse effects—Benzodiazepines have several ad-verse effects:

• Drowsiness, ataxia and reduced psychomotor per-formance are common; therefore, care is necessarywhen driving or operating machinery.

• Dependence becomes apparent after 4–6 weeks,and is both physical and psychological. The with-drawal syndrome (in 30% of patients) comprisesrebound anxiety and insomnia, tremulousness andtwitching.

Although in overdose benzodiazepines alone arerelatively safe when compared with other sedatives,such as barbiturates, if benzodiazepines are taken incombination with alcohol the CNS-depressant effects


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Fig. 5.5 Drugs used to treat anxiety and sleep disorders

Anxiolytics Hypnotics

Benzodiazepines (act on GABAA receptors)e.g. diazepam, lorazepam

Benzodiazepines (act on GABAA receptors) e.g. triazolam,temazepam, lormetazepam, nitrazepam

Acting on serotonergic receptors (act on 5-HT1Aor 5-HT3 receptors) e.g. buspirone

Non-benzodiazepine hypnotics (act on GABAA receptors)e.g. zopiclone, zolpidem and zaleplon

Other drugse.g. proparnolol antidepressants

Other drugse.g. chloral hydrate clomethiazole barbiturates (obsolete)sedative antidepressants sedative antihistamines

(5-HT, 5-hydroxytryptamine; GABA, g-aminobutyric acid.)

Fig. 5.5 Drugs used to treat anxiety and sleep disorders.

Fig. 5.4 Diagrammatic representation of the GABAA receptor and how its activity is enhanced by benzodiazepines and similarly bybarbiturates. (BDZ, benzodiazepine; Cl–, chloride ion; GABA, g-aminobutyric acid.)(Redrawn from Page et al. 2006.)

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are potentiated and fatal respiratory depression can re-sult. Treatment is with the benzodiazepine antagonistflumazenil.

Therapeutic notes—Benzodiazepines are active orally,and theydiffermainly inrespectof theirdurationofaction(Fig. 5.6). Short-acting agents (e.g. lorazepam and tema-zepam) are metabolized to inactive compounds, andthese are used mainly as sleeping pills because of therelative lack of ‘hangover’ effects in the morning. Somelong-acting agents (e.g. diazepam) are converted tolong-lasting activemetaboliteswith ahalf-life longer thanthe administered parent drug. With others (e.g. nitraze-pam) it is the parent drug itself that is metabolizedslowly. Such drugs are more suitable for an anxiolyticeffect maintained all day long, or when early morningwaking is the problem.

Non-benzodiazepine hypnotics

Zopiclone, zolpidem and zaleplon are the newer-generation hypnotics that have a short duration ofaction with little or no hangover effect. Although thesedrugs are not benzodiazepines, they act in a comparablemanner to benzodiazepines on the GABAA receptor,although not at exactly the same sites.

Anxiolytic drugs acting at serotonergicreceptors

The serotonergic theory of anxiety suggests that seroto-nergic transmission is involved in anxiety as, in general,stimulation of this system causes anxiety whereasa reduction in serotonergic neuronal activity reducesanxiety.

The serotonergic theory prompted the developmentof anxiolytic drugs that act to moderate serotonergicneurotransmission while not causing sedation andincoordination.

5-HT1A agonistsBuspirone is a serotonergic (5-HT1A) agonist.

Mechanism of action—In the raphe nucleus thedendrites of serotonergic neurons possess inhibitorypresynaptic autoreceptors of the 5-HT1A subtype that,when stimulated, decrease the firing of 5-HT neurons.This class of anxiolytic agents called the azapironesare thought to reduce 5-HT transmission by acting aspartial agonists at these 5-HT1A receptors. Buspirone isthe first of this new class of anxiolytics.

Route of administration—Oral.Indications—Buspirone is indicated for the short-

term relief of generalized anxiety disorder.Contraindications—5-HT1A agonists should not be

used in people with epilepsy.Adverse effects—The adverse effects of 5-HT1A ago-

nists include nervousness, dizziness, headache andlight-headedness.

In contrast to benzodiazepines, buspirone does notcause significant sedation or cognitive impairment,and it carries only a minimal risk of dependence andwithdrawal. It does not potentiate the effects of alcohol.

Therapeutic notes—The anxiolytic effect of buspironegradually evolves over 1–3 weeks.

5-hydroxytryptamine 3 antagonistsOndansetron is a 5-HT3 receptor antagonist that is wellestablished for use as an antiemetic drug.

Ondansetron also has anxiolytic properties by virtueof its antagonism at the excitatory postsynaptic 5-HT3receptor.

b-Adrenoreceptor blockers

b-Adrenoreceptor blockers or b-blockers, e.g. proprano-lol, can be very effective in alleviating the somatic man-ifestations of anxiety caused by marked sympatheticarousal, such as palpitations, tremor, sweating anddiarrhoea.

Mechanism of action—b-Blockers act by antagonismat b-adrenoreceptors so that excessive catecholaminerelease does not produce the sympathetic responses oftachycardia, sweating, etc. b-blockers are also used incardiovascular disease (p. 000).

Route of administration—Oral.Indications—b-Blockers are indicated in patients

with predominantly somatic symptoms; this, in turn,may prevent the onset of worry and fear. Patients withpredominantly psychological symptoms may obtainno benefit. b-blockers can be useful in social phobiasand to reduce performance anxiety in musicians, forwhom fine motor control may be critical.

Contraindications—b-Blockers should not be used inpeople with asthma.

Adverse effects—b-Blockers can cause bradycardia,heart failure, bronchospasm and peripheral vasocon-striction.

Fig. 5.6 Approximate elimination half-lives of thebenzodiazepines

Benzodiazepine Approximate half-life (hours)

Midazolam 2–4

Temazepam 8–12

Lormetazepam 10

Lorazepam 12

Nitrazepam 24

Diazepam 32 (one metabolite is activefor up to 200 hours)

Fig. 5.6 Approximate elimination half-lives of thebenzodiazepines.


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Barbiturates

Barbiturates are non-selective CNS depressants thatproduce effects ranging from sedation and reductionof anxiety to unconsciousness and death from respira-tory and cardiovascular failure. Barbiturates increaseGABA-mediated inhibition by acting on the samereceptor as benzodiazepines (the GABAA receptor),though at a different site.

At low doses, barbiturates prolong the duration ofindividual Cl– channel openings triggered by a givenGABA stimulus (benzodiazepines increase the fre-quency of Cl– channel openings). At high doses, theyare far more depressant than benzodiazepines becausethey start to increase Cl– conductance directly, thusdecreasing the sensitivity of the postsynaptic membraneto excitatory transmitters.

Although very popular until the 1960s as sedative/hypnotic agents, they are now obsolete since theyreadily lead to psychological and physical dependence,and a relatively small overdose can be fatal. Conversely,benzodiazepines, which have largely replaced barbi-turates as sedative/hypnotics, have been taken in hugeoverdoses without serious long-term effects.

Barbiturates, however, still have a place in anaes-thesia (p. 000) and to a lesserTS1 extent in the treatmentof epilepsyTS1 (p. 000).

HINTS AND TIPS

An understanding of the GABAA/Cl– channel complex

is central to the mechanism of action of several classes

of hypnotic/anxiolytic drugs. You should be aware

what these are.

Miscellaneous agents

A number of miscellaneous hypnotic agents have beenused historically and are still prescribed under certaincircumstances.

Chloral hydrate and derivativesChloral hydrate is metabolized to trichloroethanol,which is an effective hypnotic. It is cheap, but causesgastric irritation and there is no convincing evidence thatit has any advantage over the newer benzodiazepines.

Chloral hydrate and its derivatives were previouslypopular hypnotics for children. Current thinking doesnot justify the use of hypnotics in children, and thesedrugs now have very limited uses.

Clomethiazole (chlormethiazole)Clomethiazole may be a useful hypnotic in elderlypeople because of the relative freedom from hangovereffects. It has no advantage over benzodiazepines inyounger adults.

Clomethiazole was once indicated to attenuatethe symptoms of acute alcohol withdrawal, though ithas been largely replaced by the benzodiazepine,chlordiazepoxide.

AntidepressantsIf the underlying cause of insomnia is associated withdepression, or particularly in depressed patients exhibit-ing anxiety and agitation, then tricyclic antidepressants(TCAs) with sedative actions (p. 000), e.g. amitriptyline,may be useful, as they act as hypnotics when given atbedtime. Alternatively, selective serotonin reuptake in-hibitors (SSRIs, p. 000) may correct the mood TS1disorderand lessen the symptoms of anxiety or insomnia.

Sedative antihistaminesThe older antihistamine drugs, e.g. diphenhydramine,have antimuscarinic actions and pass the blood–brainbarrier, commonly causing drowsiness and psychomo-tor impairment.

Proprietary brands of diphenhydramine are on saleto the public to relieve temporary sleep disturbances,as these drugs are relatively safe.

AFFECTIVE DISORDERS

Affective disorders involve a disturbance of mood(cognitive/emotional symptoms) associated with chan-ges in behaviour, energy, appetite and sleep (biologicalsymptoms). Affective disorders can be thought of aspathological extremes of the normal continuum ofhuman moods, from extreme excitement and elation(mania) to severe depressive states.

There are two types of affective disorder: unipolaraffective disorders and bipolar affective disorders.

Monoamine theory of depression

The aetiology of major depressive disorders is not clear.Genetic, environmental and neurochemical influenceshave all been examined as possible aetiological factors.

The most widely accepted neurochemical explana-tion of endogenous depression involves the mono-amines (noradrenaline; serotonin (5-HT); dopamine).The original hypothesis of depression, ‘the monoaminetheory’, stated that depression resulted from a func-tional deficit of these transmitter amines, whereasconversely mania was caused by an excess.

The monoamine theory explains why:

• Drugs that deplete monoamines are depressant,e.g. reserpine and methyldopa.

• A wide range of drugs that increase the functionalavailability of monoamine neurotransmittersimprove mood in depressed patients, e.g. tricyclicantidepressants (TCAs) and MAO inhibitors.

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• The concentration of monoamines and their metab-olites is reduced in the cerebrospinal fluid (CSF) ofdepressed patients.

• In some post-mortem studies the most consistentfinding is an elevation in cortical 5-HT2 binding.

The monoamine theory cannot explain why:

• A number of compounds that increase the func-tional availability of monoamines, e.g. amphet-amines, cocaine and L-dopa, have no effect on themood of depressed patients.

• Someolder,atypicalantidepressantse.g. iprindole,wor-ked without manipulating monoaminergic systems.

• There is a ‘therapeutic delay’ of 2 weeks between thefull neurochemical effects of antidepressants andthe start of their therapeutic effect.

It is unlikely, therefore, that monoamine mechanismsalone are responsible for the symptoms of depression.Other systems that may be involved in depressioninclude:

• The GABA system• The neuropeptide systems, particularly vasopressin

and the endogenous opiates• Secondary-messenger systems also appear to have a

crucial role in some treatments.

Unipolar affective disorders

A common unipolar affective disorder is depression,which is characterized bymisery, malaise, despair, guilt,apathy, indecisiveness, low energy and fatigue, changesin sleeping pattern, loss of appetite and suicidal

thoughts. Attempts have been made to classify types ofdepression as either ‘reactive’ or ‘endogenous’ in origin.

Reactive depression is where there is a clear psycho-logical cause, e.g. bereavement. It involves less-severesymptoms and less likelihood of biological disturbance.It affects 3–10% of the population, with the incidenceincreasing with age, and it is more common in females.

Endogenousdepression iswhere there is noclear causeand more severe symptoms, e.g. suicidal thoughts, and agreater likelihood of biological disturbance, e.g. insom-nia, anorexia. It affects1%of thepopulation,usually start-ing in early adulthood, and affecting both sexes equally.

The distinction between reactive and endogenousdepression is of importance since there is some evidencethat depressions with endogenous features tend torespond better to drug therapy.

Treatment of unipolar depressivedisorders

The major classes of drug that are used to treat depres-sion, and their mechanisms of action, are summarizedin Figure 5.7.

HINTS AND TIPS

Although almost certainly flawed and incomplete,

the monoamine theory is probably the best way to

rationalize your thinking about affective disorders, and

to understand the mechanism of action of the drugs

used in their treatment.

Fig. 5.7 Major classes of antidepressant drugs and their mechanisms of action

Class of antidepressant drug Examples Mode of action

Tricyclic antidepressants (TCAs) Amitriptyline ImipramineLofepramine

Non-specific blockers of monoamine uptake

Selective serotonin reuptakeinhibitors (SSRIs)

Fluoxetine ParoxetineSertraline

Selective blockers of 5-HT reuptake

Serotonin-noradrenaline reuptakeinhibitors (SNRIs)

Venlafaxine Selective blockers of 5-HT and noradrenallineuptake

Monoamine oxidase inhibitors(MAOIs)

PhenelzineTranylcrpromine

Non-competitive, non-selective irreversibleblockers of MAOA and MAOB

Reversible inhibitors of MAOA

(RIMAs)Moclobemide Reversibly inhibit MAOA selectively

Atypical ReboxetineMirtazapine

Act by various mechanisms that are poorlyunderstood

(5-HT, 5-hydroxytryptamine; MAO, monoamine oxidase.)

Fig. 5.7 Major classes of antidepressant drugs and their mechanisms of action.


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TCAs and related drugsExamples of TCAs and related drugs include amitrip-tyline, imipramine, dosulepin (dothiepin) andlofepramine.

Mechanism of action—TCAs act by blocking 5-HTand noradrenaline uptake into the presynaptic terminalfrom the synaptic cleft (Fig. 5.8). They also have acertain affinity for H1 and muscarinic receptors, andfor a1- and a2-receptors.

Contraindications—TCAs and related drugs shouldnot be used in:

• Recent myocardial infarction or arrhythmias(especially heart block) since TCAs increase the riskof conduction abnormalities

• Manic phase• Severe liver disease• Epilepsy, where TCAs lower the seizure threshold• Patients taking other anticholinergic drugs, alcohol

andadrenaline as TCAspotentiate the effects of these.

Lidocaine is contraindicated in combination withTCAs, owing to a potentially fatal drug interaction.

Adverse effects—Although TCAs are an effectivetherapy for depression, their adverse effects can reducepatient compliance and acceptability. Side-effectsinclude:

• Muscarinic blocking effects such as a dry mouth,blurred vision, constipation

• a-Adrenergic blocking effects causing postural hypo-tension

• Noradrenaline uptake block in the heart, increasingthe risk of arrhythmias

• Histamine-blocking effects leading to sedation• Weight gain.

TCAs are relatively dangerous in overdose. Patientspresent with confusion, mania, and potentiallyfatal arrhythmias due to the cardiotoxic nature ofthe drug.

Fig. 5.8 Site of action of the major classes of drug used to treat unipolar depression. (5-HT, 5-hydroxytryptamine (serotonin);MAO, monoamine oxidase; NA, noradrenaline.)

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Therapeutic notes—No individual TCA has superiorantidepressant activity, and the choice of drug is usuallydetermined by the most acceptable or desired side-effects. For example, drugs with sedative actions, suchas amitriptyline or trimipramine, are the TCAs of choicefor patients in agitated or anxious states. The mostrecent TCA is lofepramine, which causes fewer antimus-carinic side-effects, and is less dangerous if taken inoverdose.

Therapeutic effects take 2–3 weeks to develop. TCA-related antidepressants should be withdrawn slowly.

Tricyclic antidepressentsþ lidocaine¼ toxicity

Selective serotonin reuptake inhibitors (SSRIs)SSRIs are the most recently introduced class of antide-pressant agent. Fluoxetine (ProzacW) is an SSRI. Otherexamples include citalopram, fluvoxamine, paroxetineand sertraline.

Mechanism of action—SSRIs act with a high specific-ity for potent inhibition of serotonin reuptake intonerve terminals from the synaptic cleft, while havingonly minimal effects on noradrenaline uptake (seeFig. 5.8). They block serotonin transporters, which be-long to a class of Naþ/Cl–-coupled transporters.

Contraindications—SSRIs should not be used withMAO inhibitors as the combination can cause a poten-tially fatal serotonergic syndrome of hyperthermia andcardiovascular collapse.

Adverse effects—The side-effect profile of SSRIs ismuch better than that of TCAs and MAO inhibitors asthere are no amine interactions, anticholinergic actions,adrenergic blockade or toxic effects in overdose. Adverseeffects, however, caused by their effect on serotonergicnerves throughout the body, include nausea, diarrhoea,insomnia, anxiety and agitation. Sexual dysfunction issometimes a problem.

Therapeutic notes—SSRIs have a similar efficacyto that of TCAs. It is their clinical advantages andlack of side-effects that have led to their popu-larity. SSRIs are now the most widely prescribedantidepressants.

Serotonin-noradrenaline reuptake inhibitorsVenlafaxine is the most commonly used serotonin-noradrenaline reuptake inhibitor (SNRI)-type anti-depressant.

Mechanism of action—SNRIs cause potentiation ofneurotransmitter activity in the CNS, by blocking thenorepinephrine and serotonin reuptake transporter(see Fig. 5.8).

Contraindications—The drug interactions of SNRIsare much like those of SSRIs; however, extra care mustbe taken with hypertensive patients as venlafaxineraises blood pressure.

Adverse effects—The adverse effects of SNRIs aresimilar to those of SSRIs, but they occur with lowerfrequency.

Therapeutic notes—The pharmacological effects ofvenlafaxine are similar to those of the TCAs, butadverse effects are reduced because it has little affinityfor cholinergic and histaminergic receptors ora-adrenoreceptors.

MAO inhibitorsExamples of irreversible MAO inhibitors includephenelzine, tranylcypromine and isocarboxazid, andan example of reversible inhibitors of MAOA (RIMAs)is moclobemide.

Mechanism of action—MAO inhibitors block theaction of MAOA and MAOB, which are neuron enzymesthat metabolize the monoamines (noradrenaline, 5-HTand dopamine) (see Fig. 5.8). MAO has two main iso-forms, MAOA and MAOB. Inhibition of the MAOA formcorrelates best with antidepressant efficacy. Both non-selective irreversible blockers of MAOA and MAOB,and drugs that reversibly inhibit MAOA are available.

Adverse effects—Dietary interactions may occur, suchas the ‘cheese reaction’. MAO in the gut wall and livernormally breaks down ingested tyramine. When the en-zyme is inhibited, tyramine reaches the circulation andthis causes the release of noradrenaline from sympa-thetic nerve terminals; this can lead to a severe and po-tentially fatal rise in blood pressure. Patients on MAOinhibitors must, therefore, avoid foods rich in tyramine,which include cheese, game and alcoholic drinks. Prep-arations containing sympathomimetic amines (e.g.cough mixtures and nasal decongestants) should alsobe avoided. MAO inhibitors are not specific, and theyreduce the metabolism of barbiturates, opioids and al-cohol. Side-effects include CNS stimulation causing ex-citement and tremor, sympathetic blockade causingpostural hypotension, andmuscarinic blockade causinga dry mouth and blurred vision. Phenelzine can behepatotoxic.

Therapeutic notes—Response to treatment may bedelayed for 3 weeks or more. Phobic and depressedpatients with atypical, hypochondriacal or hystericalfeatures are said to respond best to MAO inhibitors.Because of the dietary and drug restrictions outlinedabove, MAO inhibitors are largely reserved for depres-sion refractory to other antidepressants and treatment.

Atypical antidepressantsExamples of atypical antidepressants include reboxe-tine, mirtazapine and tryptophan.

Mechanism of action—Reboxetine is a selectiveinhibitor of noradrenaline reuptake, increasing theconcentration of this mediator in the synaptic cleft.Mirtazapine has a2-adrenoreceptor-blocking activity,which, by acting on inhibitory a2-autoreceptors on


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central noradrenergic nerve endings, may increase theamount of noradrenaline in the synaptic cleft. Trypto-phan is an amino acid precursor for serotonin.

Contraindications—The contraindications for atypi-cal antidepressants are similar to those for TCAs.

Adverse effects—Atypical antidepressants generallycause less autonomic side-effects and are less dangerousin overdose, owing to their lower cardiotoxicity com-pared with TCAs. Mirtazapine may cause agranulocyto-sis. Tryptophan is associated with eosinophilmyalgiasyndrome.

Therapeutic notes—Mirtazapine is sedative, and it is,therefore, used in depression when a degree of sedationis desirable. Neither reboxetine nor mirtazapine arecurrently first-line drugs for the treatment of depression.Tryptophan requires specialist supervision due to thestated adverse affect.

Bipolar affective disorder

Bipolar affective disorder presents with mood and be-haviour oscillating between depression and mania,and it is, therefore, also known as manic-depressivedisorder.

Bipolar affective disorder develops earlier in life thanunipolar depressive disorders, and it tends to be inher-ited. It affects 1% of the population, and it can have as-sociated elements of psychotic phenomena.

HINTS AND TIPS

Mania hardly ever exists in isolation from depression,

which is why it is referred to as bipolar affective

disorder, as it has two faces.

Treatment of bipolar affectivedisorders

Bipolar affective disorder is treated with a combinationofmood stabilizers and antidepressants, and sometimesantipsychotics (p. 000). MoodTS1 stabilizers includelithium and carbamazepine.

LithiumLithium is administered as lithium carbonate, and it isthe most widely used mood stabilizer, with antimanicand antidepressant activity.

Mechanism of action—The mechanism of action oflithium is unclear, but it probably involves modulationof secondary-messenger pathways of cAMP and inositoltriphosphate (IP3). It is known that lithium inhibits thepathway for recapturing inositol for the resynthesis ofpolyphosphoinositides. It may exert its effect by reduc-ing the concentrations of lipids important in secondarysignal transduction in the brain.

Indications—Lithium salts are mainly used in theprophylaxis and treatment of bipolar affective disorder,but also in the prophylaxis and treatment of acutemania and in the prophylaxis of resistant recurrentdepression.

Contraindications—Some drugs may interact, caus-ing a rise in plasma lithium concentration and soshould be avoided. Such drugs include antipsychotics,non-steroidal anti-inflammatory drugs (NSAIDs),diuretics and cardioactive drugs. Lithium is excretedvia the kidney, and caution should be employed inpatients with renal impairment.

Adverse effects—Lithium has a long plasma half-lifeand a narrow therapeutic window; therefore, side-effects are common and plasma concentrationmonitor-ing is essential. Early side-effects include thirst, nausea,diarrhoea, tremor and polyuria; late side-effects in-clude weight gain, oedema, acne, nephrogenic diabetesinsipidus and hypothyroidism. Toxicity/overdose(serum level >2–3 mmol/L) effects include vomiting,diarrhoea, tremor, ataxia, confusion and coma.

Therapeutic notes—Careful monitoring after initia-tion of treatment is essential.

CarbamazepineCarbamazepine is as effective as lithium in the prophy-laxis of bipolar affective disorder and acute mania, par-ticularly in rapidly alternating bipolar affective disorder.

Mechanism of action—Carbamazepine is a GABAagonist, and this may be the basis of its antimanic prop-erties. The relevance of its effect in stabilizing neuronalsodium, and on calcium channels, is unclear.

Adverse effects—Drowsiness, diplopia, nausea, ataxia,rashes and headache; blood disorders such as agranu-locytosis and leucopenia; and drug interactions withlithium, antipsychotics, TCAs and MAO inhibitors.Many other drugs can be affected by the effect of carba-mazepine on inducing hepatic enzymes. Diplopia,ataxia, clonus, tremor and sedation are associated withacute carbamazepine toxicity.

Therapeutic notes—At the start of treatment withcarbamazepine, plasma concentrations should bemonitored to establish a maintenance dose.

PSYCHOTIC DISORDERS

Psychotic disorders are characterized by a mental statethat is out of touch with reality, involving a variety ofabnormalities of perception, thought and ideas.

Psychotic illnesses include:

• Schizophrenia• Schizoaffective disorder• Delusional disorders• Some depressive and manic illnesses.

5Psychotic disorders

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Neuroleptics, or antipsychotics, are drugs used in thetreatment of psychotic disorders.

Schizophrenia

Epidemiology

Schizophrenia characteristically develops in peopleaged 15–45 years; it has a relatively stable cross-culturalincidence affecting 1% of the population; with a greaterproportion being male.

Symptoms and signs

Schizophrenia is a psychotic illness characterized bymultiple symptoms affecting thought, perceptions,emotion and volition.

Symptoms fall into two groups (positive and nega-tive) that may have different underlying causes.

Positive symptoms include:

• Delusions – false personal beliefs held with absoluteconviction.

• Hallucinations – false perceptions in the absence ofa real external stimulus; most commonly, these areauditory (hearing voices) and occur in 60–70%of schizophrenics, but they can be visual, tactile orolfactory.

• Thought alienation and disordered thought – beliefthat one’s thoughts are under the control of anoutside agency (e.g. aliens, MI5). This type of beliefis common, and thought processes are oftenincomprehensible.

Negative symptoms include:

• Poverty of speech – restriction in the amount ofspontaneous speech.

• Flattening of affect – loss of normal experience andexpression of emotion.

• Social withdrawal.• Anhedonia – inability to experience pleasure.• Apathy – reduced drive, energy, and interest.• Attention deficit – inattentiveness at work or on

interview.

The distinction between the positive and negativesymptoms found in schizophrenia is of importance asneuroleptic drugs tend to have most effect on positivesymptoms, whereas negative symptoms are fairly refrac-tory to treatment and carry a worse prognosis.

Theories of schizophrenia

The cause of schizophrenia remains mysterious. Anytheory of the cause of schizophrenia must take into ac-count the strong, though not invariable, hereditary ten-dency (50% concurrence inmonozygotic twins), as wellas the environmental factors known to predispose to-wards its development.

Many hypotheses have been suggested to explain themanifestations of schizophrenia at the level of neuro-transmitters in the brain. The potential role of excessivedopaminergic activity, in particular, has attracted con-siderable attention. Evidence for this theory includesthe following:

• Most antipsychotic drugs block dopamine receptors,the clinical dose being proportional to the ability toblock D2 receptors.

• Single photon emission computed tomography(SPECT) ligand scans show that there are increasedD2 receptors in the nucleus accumbens of schizo-phrenic patients.

• Psychotic symptoms can be induced by drugs thatincrease dopaminergic activity, such as some of theantiparkinsonian agents.

However, there is much evidence that the dopaminergictheory fails to explain. Current research indicates alikely role for other neurotransmitters in schizophrenia,including 5-HT, GABA and glutamate. Although the do-pamine theory cannot explain many of the features andfindings in schizophrenia, most current pharmacologi-cal treatment (typical neuroleptics) is aimed at dopami-nergic transmission (Fig. 5.9).

COMMUNICATION

Mr Sarhan is a 28-year-old postman who was found

at 5 am standing on the edge of Tower Bridge

and shouting ‘Freedom is through flying’. He was

previously seen erratically throwing his mailbag into

the River Thames. The police manage to grab him

just before he jumped and took him to accident

and emergency. The on-call psychiatrist sees him.

Mr Sarhan is very agitated and shouting ‘They gave me

powers to fly! Let me prove it! I can prove it! Don’t

try to steal my powers, go away!’. A mental state

examination supports a diagnosis of schizophrenia. A

collateral history is obtained from his parents, who say

that he has been acting more and more bizarrely over

the past year but they just thought it was due to stress.

Shortly after admission, he began shouting abuse

and pushing past staff with the intention of leaving

despite their discouragement. He was, thus, rapidly

tranquillized using haloperidol and sectioned

under section 2 of the Mental Health Act.

Treatment of schizophrenia

The treatment of schizophrenia and all other psychoticillnesses involves the use of antipsychotic medication,the neuroleptic drugs. Neuroleptic drugs produce a gen-eral improvement in all the acute positive symptoms of


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schizophrenia, but it is less clear how effective they arein the treatment of chronic schizophrenia and negativesymptoms.

Mechanism of action—Antipsychotic drugs have a va-riety of structures and fall into various classes (Fig. 5.9and 5.10). There is a strong correlation between clinicalpotency and affinity for D2 receptors among the typicalneuroleptics.

Neuroleptics take days or weeks to work, suggestingthat secondary effects (e.g. increase in number of D2 re-ceptors in limbic structure) may be more importantthan a direct effect of D2 receptor block.

Most neuroleptics also block other monoaminereceptors, and this is often the cause of some of theside-effects of these drugs.

The distinction between typical and atypical groupsis not clearly defined, but it rests partly on the incidence

of extrapyramidal motor side-effects and partly on re-ceptor specificity. Atypical neuroleptics are less proneto producing motor disorders than other drugs, andthey tend to have different pharmacological profileswith respect to dopamine and other receptor specificity.

Route of administration—All the neuroleptic drugscan be given orally, though some of the typical drugscan be given by the intramuscular route, which prolongstheir release and aids drug compliance.

Typical neuroleptics

PhenothiazinesThis class of compounds is subdivided into three groupsby the type of side chain attached to the motherstructure (phenothiazine ring) (Fig. 5.10). Side-effectpatterns vary with the different side chains:

Fig. 5.9 Classes of dopamine receptor

Type 2nd messenger+cellular effects Location in CNS and postulated function

D1 cAMP increase Mainly postsynaptic inhibitionFunctions unclear

D2 cAMP decrease Kþ

conductance up Ca2þ

conductance down

Mainly presynaptic inhibition of dopamine synthesis/release innigrostriatal, mesolimbic and tuberoinfundibular systemsAffinity of neuroleptics for D2 receptors correlates with antipsychoticpotency

D3 Unknown Localized mainly in limbic and cortical structures concerned withcognitive functions and emotional behaviourNot clear whether antipsychotic effects of neuroleptics are mediatedby the D3 type

D4 Unknown Similar to D3 type; clozapine has particular affinity for D4 receptors

(cAMP, cyclic adenosine monophosphate; CNS, central nervous system.)

Fig. 5.9 Classes of dopamine receptor.

Fig. 5.10 Classes of neuroleptic drugs

Class Chemical classification Examples

Typical anti-psychotics Phenothiazines:propylamine side chainspiperidine side chainspiperazine side chains

ButyrophenonesThioxanthines

ChlorpromazineThioridazineFluphenazineHaloperidolFlupentixol

Atypical anti-spsychotics DibenzodiazepinesDopamine/5-HT blockers:diphenylbutylpiperidinessubstituted benzamidesbenzixasoles

Clozapine, olanzapinePimozideSulpirideRisperidone

(5-HT, 5-hydroxytryptamine.)

Fig. 5.10 Classes of neuroleptic drugs.


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• Propylamine side chains – e.g. in chlorpromazine,produce strong sedation, a moderate muscarinicblock, and moderate motor disturbance. Indicatedfor violent patients, owing to their sedative effect.

• Piperidine side chains – e.g. in thioridazine, producemoderate sedation, strong muscarinic block andlow motor disturbance. Favoured for use in elderlypatients.

• Piperazine side chains – e.g. in fluphenazine, pro-duce low sedation, low muscarinic block and strongmotor disturbance. Contraindicated for use in el-derly patients, owing to the motor effects.

Butyrophenones and thioxanthenesThe butyrophenone and thioxanthene groups ofcompounds have the same profile of low sedation,low muscarinic block and high incidence of motordisturbance.

An example of a butyrophenone compound is halo-peridol; flupentixol is an example of the thioxanthenes.

Atypical neuroleptics

DibenzodiazepinesDibenzodiazepines such as clozapine and olanzapinehave a low affinity for the D2 receptor and a higheraffinity for D1 and D4 receptors.

Indications—In the UK and US, atypical neurolepticsare indicated only in chronic cases refractory to otherdrugs, or with severe motor disturbance. This is becauseof a 1% risk of potentially fatal neutropenia in those pa-tients on these agents.

Adverse effects—Clozapine has a low incidence of ad-verse motor effects because of its low affinity for the D2

receptor. Side-effects of dibenzodiazepines includehypersalivation, sedation, weight gain, tachycardiaand hypotension.

Therapeutic notes—Olanzapine is similar to cloza-pine, though carries less risk of agranulocytosis.

Dopamine/5-HT blockersExamples of dopamine/5-HT blockers include thediphenylbutylpiperidines (e.g. pimozide and sulpiride)and the benzixasoles (e.g. risperidone).

Sulpiride, and the newer agent pimozide, show highselectivity for D2 receptors compared with D1 or otherneurotransmitter receptors. Both drugs are effective intreating schizophrenia but, sulpiride is claimed to haveless tendency to cause adverse motor effects. Pimozideappears to be similar to conventional neurolepticagents, but it has a longer duration of action, allowingonce-daily medication.

Benzixasoles such as risperidone show a high affinityfor 5-HT receptors and a lower affinity for D2 receptors.With this class of drugs, extrapyramidal motor side-effects occur with less frequency than with ‘classic’neuroleptics.

Quetiapine fumarate is a dibenzothiazepine deriva-tive and acts an as antagonist at the D1, D2, 5-HT1Aand 5-HT2 receptors.

Aripiprazole appears to mediate its antipsychoticeffects primarily by partial agonism at the D2 receptor.It is also a partial agonist at the 5-HT1A receptor, and likethe other atypical antipsychotics, aripiprazole displaysan antagonist profile at the 5-HT2A receptor, as wellas moderate affinity for histamine and a-adrenergicreceptors.

Zotepine has good efficacy against negative symp-toms of schizophrenia. This is thought to be due to itsnoradrenaline reuptake inhibition. It also has a highaffinity for the dopamine D1 and D2 receptors. It alsoaffects the 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 receptors.

Adverse effects of neuroleptics

Neuroleptic drugs cause a variety of adverse effects(Fig. 5.11). The majority of the unwanted effects ofneuroleptics can be inferred from their pharmacologicalactions, such as the disruptionof dopaminergic pathways(themajor action ofmost neuroleptics) and the blockadeofmonoamine andother receptors, includingmuscarinicreceptors, a-adrenoreceptors and histamine receptors.

In addition, individual drugs may cause immuno-logical reactions or have their own characteristic side-effect profile.

Adverse effects on the dopaminergicpathways

There are three main dopaminergic pathways in thebrain (Fig. 5.12):

• Mesolimbic and/or mesocortical dopamine path-ways running from groups of cells in the midbrainto the nucleus accumbens and amygdala. Thispathway affects thoughts and motivation.

Fig. 5.11 Adverse effects of the neuroleptics

Acute neurological effects: acute dystonia, akathisia,parkinsonismChronic neurological effects: tardive dyskinesia, tardivedystoniaNeuroendocrine effects: amenorrhoea, galactorrhoea,infertilityIdiosyncratic: neuroleptic malignant syndromeAnticholinergic: dry mouth, blurred vision, constipation,urinary retention, ejaculatory failureAntihistaminergic: sedationAntiadrenergic: hypotension, arrhythmiaMiscellaneous: photosensitivity, heat sensitivity,cholestatic jaundice, retinal pigmentation

Fig. 5.11 Adverse effects of the neuroleptics.Redrawn from Page et al. 2006.


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• Nigrostriatal dopamine pathways running from themidbrain to the caudate nuclei. This pathway isimportant in smooth motor control.

• Tuberoinfundibular neurons running from thehypothalamus to the pituitary gland, the secretionsof which they regulate.

Antagonism of dopamine receptors leads to interferencewith the normal functioning of these pathways, bring-ing about unwanted side-effects as well as the desiredantipsychotic effect. This antagonism is the cause ofthe most serious side-effects associated with neuro-leptic use, which include:

• Psychological effects – due to D2 receptor blockadeof the mesolimbic/mesocortical pathway.

• Movement disorders – due to D2 receptor blockadeof the nigrostriatal pathways.

• Neuroendocrine disorders – due to D2 receptorblockade of the tuberoinfundibular pathway.

It is by dopaminergic antagonism of the mesolimbicmesocortical pathway that it is thought that typicalneuroleptics exert their antipsychotic effects. However,as a side-effect ofmesolimbic andmesocortical dopami-nergic inhibition, sedation and impaired performanceare common.

Blocking of dopamine receptors in the basal ganglia(corpus striatum) frequently results in distressing anddisabling movement disorders. Twomain types of move-ment disorder occur. Acute reversible parkinsonian-likesymptoms (tremor, rigidity and akinesia) are treated bydose reduction, anticholinergic drugs or switching to anatypicalneuroleptic.Slowlydevelopingtardivedyskinesia,often irreversible, and manifesting as involuntary move-ments of the face, trunk and limbs, appears months oryears after the start of neuroleptic treatment. It may bea result of proliferation or sensitization of dopaminereceptors. Incidence is unpredictable, and it affects ap-proximately 20% of long-term users of neuroleptics.Treatment is generally unsuccessful. The newer atypicalneuroleptics may be less likely to induce tardivedyskinesia.

By reducing the negative feedback on the anteriorpituitary, over-secretion of prolactin can result (hyper-prolactinaemia). This can lead to gynaecomastia,galactorrhoea, menstrual irregularities, impotence andweight gain in some patients (Fig. 5.12).

Adverse effects from non-selective receptorblockadeThe adverse effects of neuroleptics from non-selectivereceptor blockade include:

• Anticholinergic effects due to muscarinic-receptorblockade, such as dry mouth, urinary retention,constipation, blurred vision, etc.

• Adverse effects due to a-adrenoreceptor blockade.Many neuroleptics have the capacity to blocka-adrenoreceptors and cause postural hypotension.

• Adverse effects due to histamine-receptor blockade.Antagonism of central histamine H1 receptors maycontribute to sedation.

Adverse effects due to individual drugs

or immune reactionsThe neuroleptic drug clozapine can cause neutropeniadue to toxic bone marrow suppression, while pimozidecan cause sudden death secondary to cardiac arrhythmia.

Immune reactions to neuroleptic drugs can includedermatitis, rashes, photosensitivity and urticaria. Such

Fig. 5.12 Effect of D2 dopamine receptor blockade on thedopaminergic pathways in the brain.


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reactions are more common with the phenothiazines,which can also cause deposits in the cornea and lens.

Neuroleptic malignant syndrome—This is the most le-thal adverse effect of neuroleptic use. It is an idio-syncratic reaction of unknown pathophysiology.Symptoms include fever, extrapyramidal motor dis-turbance, muscle rigidity and coma. Urgent treatmentis indicated.

HINTS AND TIPS

Neuroleptics have many side-effects, some related

to their principal mechanism of action (dopamine

receptor antagonism) and some unrelated to this.

Learn these well as they are a popular examination

topic.

DRUG MISUSE

Definitions

Drug misuse

Drug misuse is defined as the use of drugs that causesactual physical ormental harm to an individual or to so-ciety, or that is illegal. Therefore, drug misuse includesalcohol, nicotine, and the damaging overprescriptionof tranquillizers, as well as themore obvious illicit drugssuch as ecstasy or amphetamines.

Drug dependence

Drug dependence is defined as the compulsion to take adrug repeatedly, with distress being caused if this is pre-vented. Drugs of dependence all have rewarding effects(this is why they are taken), but they also have un-pleasant effects, often as the drug is metabolized andexcreted.

Dependence involves psychological factors as well asphysical aspects. These are not exclusive and there is amixture of both in most people who are dependenton drugs. Psychological dependence is when the re-warding effects (positive reinforcement) predominateto cause a compulsion to continue taking the drug.Physical dependence is when the distress on stoppingthe drug (negative reinforcement) is the main reasonfor continuing to take it, i.e. avoidance of the ‘with-drawal syndrome’.

Drug tolerance

Drug tolerance is the necessity to increase the dose of anadministered drug progressively to maintain the effectthat was produced by the (smaller) original doses. Drug

tolerance is a phenomenon that develops with chronicadministration of a drug.

Many different mechanisms can give rise to drugtolerance, though they are rather poorly understood.They include:

• Down-regulation of receptors• Changes in receptors• Exhaustion of biological mediators or transmitters• Increasedmetabolic degradation (enzyme induction)• Physiological adaptation.

Withdrawal

Withdrawal is the term used to describe the syndromeof effects caused by stopping administration of a drug.It results from the change of (neuro) physiologicalequilibrium induced by the presence of the drug.

Drugs of misuse

Drugs with a high potential for misuse fall into manydistinct pharmacological categories. They may or maynot be used therapeutically and they may be illegal orlegal (Fig. 5.13). Controlled drugs are categorized intothree clases (Fig. 5.14).

Fig. 5.13 Drugs with high potential for misuse

Drug class Examples

Central stimulants CocaineAmphetaminesMDMA (ecstasy)Nicotine

Central depressants AlcoholBenzodiazepinesBarbiturates

Opioid analgesics MorphineHeroin (diamorphine)Methadone

Cannabinoids CannabisTetrahydrocannabinoids(THCs)

Hallucinogens LSDMescalinePsilocybin

Dissociativeanaesthetics

KetaminePhencyclidine

(LSD, lysergic acid diethylamide; MDMA,

methylenedioxymethamfetamine.)

Fig. 5.13 Drugs with high potential for misuse.


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Central stimulants

HINTS AND TIPS

Always use the correct chemical name when describing

drugs of misuse, e.g. amphetamines rather than whizz

or speed.

Amphetamines

Other names—Speed, whizz, billy, base.Mechanism of action—Amphetamines cause the re-

lease of monoamines and the inhibition of monoaminereuptake, especially of dopamine and noradrenaline inneurons.

Route of administration—Amphetamines are admin-istered orally, or ‘snorted’ as a powder nasally; some-times used intravenously.

Effects—Increased motor activity; euphoria andexcitement; anorexia and insomnia; peripheral sympa-thomimetic effects, such as hypertension and inhibitionof gut motility; and stereotyped behaviour and psycho-sis, which develop with prolonged usage.

Clinical uses—The clinical uses of amphetamines arefor narcolepsy and for hyper-kinesis in children. Theyare no longer recommended as appetite suppressants,owing to their adverse effects.

Tolerance, dependence and withdrawal—Tolerance tothe peripheral sympathomimetic stimulant effects ofamphetamines develops rapidly, but it develops muchmore slowly to other effects such as locomotor stimula-tion. Amphetamines cause strong psychological depen-dence but no real physical dependence. After stoppingchronic use, the individual will usually enter a deep,

long sleep (‘REM rebound’) and awake feeling tired, de-pressed and hungry. This state may reflect the depletionof the normal monoamine stores.

Adverse effects—Acute amphetamine toxicity causescardiac arrhythmias, hypertension and stroke. Chronictoxicity causes paranoid psychosis, vasoconstriction,tissue anoxia at sites of injection or snorting, anddamage to the fetal brain in utero.

Cocaine

Other names—Coke, charlie, snow, crack.Mechanism of action—Cocaine strongly inhibits the

reuptake of catecholamines at noradrenergic neurons,and thus strongly enhances sympathetic activity.

Route of administration—Cocaine hydrochloride isusually snorted nasally. ‘Crack’ is the free base, whichis more volatile and which does not decompose onheating. It can, therefore, be smoked, producing a briefintense ‘rush’.

Effects—The behavioural effects produced by cocaineare similar to those produced by amphetamines, such aseuphoria. The euphoric effects may be greater, and thereis less of a tendency for stereotypical behaviour andparanoid delusions.

The effects of cocaine hydrochloride (lastingabout an hour) are not as long lasting as those ofamfetamine, while those obtained from crack are brief(minutes).

Clinical uses—Cocaine is occasionally used asa topical anaesthetic by ear, nose and throat specialists.

Tolerance, dependence and withdrawal—Cocainecauses strong psychological dependence but no realphysical dependence. Withdrawal causes a markeddeterioration in motor performance, which is restorableon provision of the drug.

Adverse effects—Acute cocaine toxicity causestoxic psychosis, cardiac arrhythmias, hypertensionand stroke. Chronic toxicity causes paranoid psychosis,vasoconstriction, tissue anoxia at sites of injection orsnorting and damage to the fetal brain.

Methylenedioxymethamfetamine (MDMA)

Other names—Ecstasy, E, disco biscuits, pills.Mechanism of action—MDMA is an amphetamine

derivative that has amechanism of action similar to thatof amphetamines (release of monoamines, inhibitionof monoamine reuptake). MDMA acts on serotonergicneurons, potentiating 5-HT.

Route of administration—MDMA is usually taken as apill containing other psychoactive drugs, such asamfetamine or ketamine.

Effects—MDMA has mixed stimulant and hallu-cinogenic properties, especially in its pure form. Eupho-ria, arousal and perceptual disturbances are common.Uniquely, MDMA has the effect of creating a feeling ofeuphoric empathy, so that social barriers are reduced.

Fig. 5.14 Classes of controlled drugs

Class A drugs Class B drugs Class C drugs

CocaineMDMA(ecstasy)Diamorphine(heroin) andother strongopioidsLysergic aciddiethylamide(LSD) class Bsubstancewhen preparedfor injectionOthers

AmphetaminesBarbituratesSome weakopioidsOthers

BenzodiazepinesCannabisAndrogenic andanabolic steroidsHuman chorionicgonadotrophinOthers

(MDMA, methylenedioxymethamfetamine.)

Fig. 5.14 Classes of controlled drugs.

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Clinical uses—MDMA has no clinical use. Trials havebeen licensed in the USA for its evaluation as a treat-ment for people with social avoidant personalitydisorders.

Tolerance, dependence and withdrawal—It is not cur-rently known to what extent tolerance and dependenceoccur with MDMA. The withdrawal syndrome is similarto that with amphetamines.

Adverse effects—The most serious acute con-sequences of acute MDMA toxicity appear to be hyper-thermia, exhaustion and dehydration caused indirectlyby the hyperexcitability that is induced.

NicotineNicotine is found in cigarettes, cigars, pipes andchewing tobacco.

Mechanism of action—Nicotine exerts its effects bycausing nicotinic acetylcholine receptor (nicAChR)excitation leading to neurotransmitter release andnicAChR desensitization.

Route of administration—Nicotine is usually inhaled,although it can be chewed.

Effects—Nicotine has both stimulant and relaxantproperties. Physiologically, nicotine increases alertness,decreases irritability and relaxes skeletal muscle tone.Peripheral effects due to ganglionic stimulation includetachycardia, increased blood pressure and decreasedgastrointestinal motility

Clinical uses—Nicotine has no clinical use.Tolerance, dependence and withdrawal—Tolerance to

nicotine occurs rapidly, first to peripheral effects butlater to central effects.

Nicotine is highly addictive, causing both physicaland psychological dependence. Withdrawal from to-bacco often leads to a syndrome of craving, irritability,anxiety and increased appetite for approximately 2–3 weeks.

Adverse effects—Acute nicotine toxicity causes nauseaand vomiting. Chronic toxicity caused by smoking leadsto more morbidity in the UK than all other drugs com-bined, predisposing to all of the following diseases, of-ten greatly so:

• Cardiovascular diseases, including atherosclerosis,hypertension and coronary heart disease.

• Cancer of the lung, bladder and mouth.• Respiratory diseases such as bronchitis, emphysema

and asthma.• Fetal growth retardation.

Smoking cessation

The most successful smoking cures combine psycho-logical and pharmacological treatments.

Pharmacological options largely rely on nicotinereplacement, once the patient has stopped smoking,with gradual reduction in nicotine. The latest drug to

be used to help cigarette smokers is bupropion(ZybanW), which is derived from an antidepressant.

Nicotine products

Mechanism of action—Measured doses of nicotine areused to replace nicotine derived from cigarettes once thepatient has stopped smoking, meeting the physical nic-otine needs. The dose of nicotine is gradually reducedover 10–12 weeks.

Route of administration—Oral (chewing gum, sub-lingual tablets), transdermal (patches), nasal (spray),inhalation.

Indications—Adjunct to smoking cessation.Contraindications—Severe cardiovascular disease, re-

cent cerebrovascular accident, pregnancy, breastfeeding.Adverse effects—Nausea, dizziness, headache and

cold, influenza-like symptoms, palpitations.Therapeutic notes—Nicotine products are available

over the counter or GPs can prescribe them for patientsintending to stop smoking.

Bupropion (ZybanW)

Mechanism of action—Bupropion is a selectiveinhibitor of the neuronal uptake of noradrenaline anddopamine. This is believed to reduce nicotine cravingand withdrawal symptoms.

Route of administration—Oral.Indications—Adjunct to smoking cessation.Contraindications—History of epilepsy and eating

disorders, pregnancy, breastfeeding.Adverse effects—Dry mouth, gastrointestinal distur-

bances, insomnia, tremor, impaired concentration.Therapeutic notes—BupropionisavailableontheNHS.

Central depressants

Ethanol

Mechanism of action—Ethanol, or alcohol, acts in asimilar way to volatile anaesthetic agents, as a generalCNS depressant. The cellular mechanisms involvedmay include inhibition of calcium entry, hencereduction in transmitter release, as well as potentiationof inhibitory GABA transmission.

Route of administration—Ethanol is administeredorally.

Effects—The familiar effects of ethanol intoxicationrange from increased self-confidence and motor inco-ordination through to unconsciousness and coma.Peripheral effects include a self-limiting diuresis andvasodilatation.

Clinical uses—Ethanol is used as an antidote tomethanol poisoning.

Tolerance, dependence and withdrawal—Tolerance,and physical and psychological dependence all occurwith ethanol, such that 15 000 people a year are admit-ted to psychiatric hospital for alcohol dependence and


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psychosis, and up to 20% of males on a medical wardhave alcohol-related disabilities.

The alcohol withdrawal syndrome is a rebound ofthe nervous system after adaptation to the depressioncaused by alcohol. This syndrome occurs in two stages:

• Early stage (‘hangover’) – which is common andstarts6–8hoursafter cessationofdrinking. It involvestremulousness, nausea, retching and sweating.

• Late stage (delirium tremens) – which is much lesscommon and starts 48–72 hours after cessation ofdrinking. It involves delirium, tremor, hallucina-tions and confusion.

Management of these late withdrawal symptoms in-volves sedation with clomethiazole or benzodiazepines(such as chlordiazepoxide); clonidine may be useful.

Adverse effects—Acute ethanol toxicity causes ataxia,nystagmus, coma, respiratory depression and death.Chronic ethanol toxicity causes neurodegeneration(potentiated by vitamin deficiency), dementia, liverdamage, pancreatitis, etc., and accompanying psychiat-ric illness-depression/psychosis is common.

BenzodiazepinesMechanism of action—Benzodiazepines exert their ef-

fects by potentiation of inhibitory GABA transmission(p. 000).

Route of administration—Benzodiazepines areadministered orally.

Effects—The effects of benzodiazepines includesedation, agitation and ataxia.

Clinical uses—Benzodiazepines are heavily pre-scribed as anxiolytics and hypnotics.

Tolerance, dependence and withdrawal—Benzodia-zepines have a potential for misuse – tolerance anddependence are common.

A physical withdrawal syndrome can occur inpatients given benzodiazepines, even for short periods.Symptoms include rebound anxiety and insomniawith depression, nausea and perceptual changes thatmay last from weeks to months.

Adverse effects—The adverse effects of acute benzodi-azepine toxicity include hypotension and confusion.Cognitive impairment occurs in chronic benzodiaze-pine toxicity.

COMMUNICATION

Mr Alrum is a 45-year-old banker who lives by himself.

He presents to accident and emergency following a fall

in the road. The examining doctor sees someminor cuts

and bruises on his right arm and leg but also notices the

patient smells strongly of alcohol. On talking to the

patient, the doctor discovers Mr Alrum has recently

lost his job due to poor performance, elicits some

feelings of low mood, hopelessness and helplessness

and that at the time of the fall he was on his way to buy

some bottles of rum since he had run out. The AUDIT

questionnaire is used and supports a diagnosis

of alcohol dependence. Mr Alrum is admitted for

assistance. Blood tests are done and show a macrocytic

anaemia, elevated g-glutamyl transferase and alanine

aminotransferase (liver transaminases). A couple of

hours after the blood was taken, he is found at the

wrong end of the ward, disorientated, sweating and

trembling. He is given chlordiazepoxide, the dose of

which is gradually reduced over 10 days to help

manage his withdrawal symptoms.

Opioid analgesics

HINTS AND TIPS

Heroin addicts are able to tolerate 300–600-mg doses

several times per day. This is 30–60 times the normal

dose needed to produce an analgesic effect. A non-

addict given this would die of respiratory depression.

Diamorphine (heroin) and other opioidsOther names—Smack, H, gear, junk, jack, brown.Mechanism of action—Opioids show agonist action

at opioid receptors (p. 000).Note that the sense of euphoria and well-being pro-

duced by strong opioids undoubtedly contributes totheir analgesic activity by helping to reduce the anxietyand stress associated with pain. This effect also accountsfor the illicit use of these drugs by addicts.

Route of administration—Opioids are generally takenintravenously by misusers as this produces the most in-tense sense of euphoria (‘rush’).

Effects—Opioids produce feelings of euphoria andwell-being. Other effects are mentioned on p. 000.

Clinical uses—Opioids are used in analgesia formod-erate to severe pain.

Tolerance, dependence and withdrawal—Tolerance toopioid analgesics develops quickly in addicts and resultsin larger and larger doses of the drug being needed toachieve the same effect.

Dependence involves both psychological factors andphysical factors. Psychological dependence is based onthe positive reinforcement provided by euphoria.

There is a definite physical withdrawal syndromein addicts following cessation of drug treatment withopioids. This syndrome comprises a complex mixtureof irritable and sometimes aggressive behaviour,

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combined with autonomic symptoms such as fever,sweating, yawning, pupillary dilatation, and piloerec-tion that gives the state its colloquial name of ‘cold tur-key. Patients are extremely distressed and restless andstrongly crave the drug. Symptoms are maximal at2 days and largely disappear in 7–10 days.

Treatment of withdrawal—Methadone is a long-acting opiate, active orally, that is used to wean addictsfrom their addiction. The withdrawal symptoms fromthis longer-acting compound are more prolonged,but less intense than, for example, those of heroin.Treatment usually involves substitution of methadonefollowed by a slow reduction in dose over time.

Clonidine, an a2-adrenoreceptor agonist, inhibitsfiring of locus ceruleus neurons, and it is effective insuppressing some components of the opioid withdrawalsyndrome, especially thenausea, vomitinganddiarrhoea.

Adverse effects—Acute opioid toxicity causes thefollowing:

• Confusion, drowsiness and sedation. Initial excite-ment is followed by sedation and finally coma onoverdose.

• Shallow and slow respiration – due to reduction ofsensitivity of the respiratory centre to CO2.

• Vomiting – due to stimulation of the chemoreceptortrigger zone.

• Autonomic effects such as tremor and pupillaryconstriction.

• Bronchospasm, flushing and arteriolar dilatationdue to histamine release.

Acute toxicity may be countered by use of an opioidantagonist such as naloxone. The adverse effects ofdirect chronic toxicity are minor (p. 000).

Cannabinoids

CannabisThere are two forms of cannabis: marijuana is the driedleaves and flowers of the cannabis plant, and hashish isthe extracted resin of the cannabis plant.

Other names—Hashish, weed, skunk, pot, dope,gear, grass, ganja, blow.

Mechanism of action—How cannabis exerts its effectsis not clearly defined, but it includes both depressant,stimulant and psychomimetic effects. The active cons-tituent of cannabis is D9-tetrahydrocannabinol(THC), though metabolites that also have activity maybe important.

Route of administration—Cannabis is usuallysmoked, although it may be eaten.

Effects—Cannabis has several effects:

• Subjectively, users feel relaxed and mildly euphoric.• Perception is altered, with apparent sharpening of

sensory experience.• Appetite is enhanced.

• Peripheral actions include vasodilatation and bron-chodilatation, and a reduction in intraocular pressure.Clinical uses—Cannabis is not currently licensed for

use in the UK. It is being evaluated for palliative orsymptomatic relief use in certain conditions in theUSA, e.g. for the antiemetic effect of THC, and a possi-ble role in treatment ofmultiple sclerosis and glaucoma.

Tolerance, dependence and withdrawal—Tolerance tocannabis occurs to a minor degree. It is not dangerou-sly addictive, with only moderate physical andpsychological withdrawal effects noted, such as mildanxiety/dysphoria and sleep disturbances.

Adverse effects—Acute cannabis toxicity causesconfusion and hallucinations. Chronic toxicity maycause flashbacks, memory loss and ‘de-motivationalsyndrome’. There is a clear correlation between canna-bis use and schizophrenia.

Psychotomimetic drugs or hallucinogens

Examples of psychotomimetic drugs include LSD,mescaline and psilocybin.

Street names—Acid, trips, magic mushrooms.Mechanism of action—How LSD, mescaline and

psilocybin produce changes in perception is not wellunderstood, but it seems to involve serotonin. LSDappears to affect serotonergic systems by acting on5-HT2 inhibitory autoreceptors on serotonergicneurons to reduce their firing. Whether LSD is an ago-nist, an antagonist or both is not clear.

Route of administration—Psychotomimetic drugs areadministered orally as a liquid, pills or paper stamps.

Effects—Psychotomimetic drugs cause a dramaticallyaltered state of perception-vivid and unusual sensory ex-periences combined with euphoric sensations. Halluci-nations, delusions and panic can occur; this is known asa ‘bad trip’ and it can be terrifying.

Clinical uses—Psychotomimetic drugs have noclinical uses.

Tolerance, dependence and withdrawal—Toleranceto, dependence on, and withdrawal from psychotomi-metic drugs are not significant.

Adverse effects—Acute toxicity from psychotomi-metic drugs causes frightening delusions or hallucina-tions that can lead to accidents or violence. In chronictoxicity, ‘flashbacks’ (a recurrence of hallucination)may occur long after the ‘trip’. Other psychotic symp-toms may also occur.

EPILEPSY

Epilepsy is a chronic disease, in which seizures resultfrom the abnormal high-frequency discharge of a groupof neurons, starting focally and spreading to a varyingextent to affect other parts of the brain. According to


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the focus and spread of discharges, seizures may beclassified as:

• Partial (focal) – which originate at a specific focusand do not spread to involve other cortical areas.

• Generalized – which usually have a focus (often inthe temporal lobe) and then spread to other areas.

Different epileptic syndromes can be classified on thebasis of seizure type and pattern, with other clinicalfeatures (such as age of onset), anatomical location offocus, and aetiology taken into account.

Common types of epilepticsyndrome

Epileptic syndromes result from either generalizedseizures or focal seizures (Fig. 5.15).

Generalized seizure involves loss of consciousness,and it may be convulsive or non-convulsive:

• Tonic-clonic (grand-mal seizures) – convulsive gen-eralized seizure characterized by periods of tonicmuscle rigidity followed later by jerking of the body(clonus).

• Absence (petit-mal seizures) – generalized seizurescharacterized by changes in consciousness lastingless than 10 seconds. They occur most commonlyin children, where they can be confused with day-dreaming.

The effect on the body of focal seizures depends on thelocation of the abnormal signal focus: e.g. involvementof the motor cortex will produce convulsions whereasinvolvement of the brainstem can produce uncon-sciousness. Psychomotor or temporal lobe epilepsy re-sults from a partial seizure with cortical activitylocalized to the temporal lobe. Such seizures are charac-terized by features including impaired consciousnessor confusion, amnesia, emotional instability, atypicalbehaviour and outbursts.

Partial motor seizures have their focus in corticalmotor regions and they present with convulsive ortonic activity corresponding to the neurons involved,e.g. the left arm.

Another type of epileptic syndrome is status epilepti-cus. This is a state in which fits follow each other with-out consciousness being regained. Status epilepticusconstitutes a medical emergency because of possibleexhaustion of vital centres.

Causes of epilepsy

The aetiology of epilepsy is unknown in 60–70% ofcases, but heredity is an important factor. Damage tothe brain – for example, by tumours, head injury, infec-tions or cerebrovascular accident – may subsequentlycause epilepsy.

The neurochemical basis of the abnormal dischargesin epilepsy are not known, but it may involve alteredGABA metabolism.

Treatment of epilepsy

HINTS AND TIPS

Remember that epilepsy is simply aberrant electrical

activity spreading throughout anareaof, or thewholeof,

thebrain.Antiepilepticmedications limit thepropagation

of this spread and inhibit development of symptoms.

Drugs used to treat epilepsy are termed antiepileptics;the term anticonvulsant is also used.

The aim of pharmacological treatment of epilepsy istominimize seizure activity/frequency, without produc-ing adverse drug effects.

Mechanisms of action of antiepileptics

Antiepileptic drugs act generically to inhibit the rapid,repetitive neuronal firing that characterizes seizures.There are three established mechanisms of action bywhich the antiepileptic drugs achieve this (Fig. 5.16).

Inhibition of ionic channels involved in neuronal

excitabilityDrugs such as phenytoin, carbamazepine and valproateinhibit the ‘fast’ sodium current. These drugs bind pref-erentially to inactivated (closed) sodium channels, pre-venting them from opening. The high-frequencyrepetitive depolarization of neurons during a seizure in-creases the proportion of sodium channels in the inac-tivated state susceptible to blockade. Eventually,sufficient sodium channels become blocked so thatthe ‘fast’ neuronal sodium current is insufficient tocause a depolarization. Note that neuronal transmis-sion at normal frequencies is relatively unaffected be-cause a much smaller proportion of the sodiumchannels are in the inactivated state.

Fig. 5.15 Classification of common epileptic syndromes

Partial (local, focal)seizures

Generalized seizures

Psychomotor (temporallobe) epilepsyPartial motor epilepsy

Tonic-clonic seizure orgrand-mal epilepsyAbsence seizure or petit-mal epilepsy

Fig. 5.15 Classification of common epileptic syndromes.

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Fig. 5.16 Mechanism and site of action of antiepileptic drugs. (GABA, g-aminobutyric acid; GAD, glutamic acid decarboxylase;Glu, glutamate.)


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Ethosuximide inhibits ‘T-type’ low-threshold, fast-nactivating calcium. Absence seizures involve oscilla-tory neuronal activity between the thalamus and thecerebral cortex. The oscillation involves ‘T-type’ calciumchannels, which produce low-threshold spikes, thusallowing groups of cells to fire in bursts. It appears thatthe anti-absence drug ethosuximide reduces this fast-inactivating calcium current, dampening the thalamo-cortical oscillations that are critical in the generationof such absence seizures.

Inhibition of excitatory transmissionDrugs that block excitatory amino acid receptors(N-methyl-D-aspartate (NMDA) antagonists) havebeen shown to be antiepileptic in animal models. Suchdrugs may prove useful in the clinical treatment ofepilepsy in the future. Lamotrigine, one of the newerantiepileptic agents, inhibits the release of glutamateas one of its actions, and this may contribute to itsantiepileptic activity.

Enhancement of GABA-mediated inhibitionThis can take any of the following forms:

• Enhancement by direct GABA agonist properties,e.g. by gabapentin, another of the newer antiepilep-tics, agent which has been designed to mimic GABAin the CNS.

• Potentiation of chloride currents through theGABAA/Cl

– channel complex, e.g. by benzodiaze-pines and barbiturates. The increased postsynapticinhibitory chloride current at GABAA receptors,hyperpolarizes neurons and makes them refractoryto excitation (see Fig. 5.5).

• Inhibition of GABA degradation in the CNS, e.g. byvigabatrin, which is an irreversible inhibitor ofGABA transaminase (GABAT), the enzyme normallyresponsible for metabolism of GABA in the neuron.Inhibition of GABAT, therefore, leads to an increasein synaptic levels of GABA and so enhances GABA-mediated inhibition.

Antiepileptic drugs (anticonvulsants)

Antiepileptic drugs can be classified according to theirmechanism of action (Fig. 5.16), but in clinical practiceit is useful to think of the drugs according to their use(Fig. 5.17).

Phenytoin

Mechanism of action—This involves use-dependentblock of voltage-gated sodium channels. Phenytoinreduces the spread of a seizure. It does not preventthe ignition of an epileptic discharge, but it does stopit spreading and causing overt clinical symptoms.

Route of administration—Oral, intravenous.Indications—Phenytoin is indicated in all forms of

epilepsyS1 except absence seizures; neuralgic pain (p. 000).

Contraindications—Phenytoin has many contraindi-cations, mainly because it induces the hepaticcytochrome P450 oxidase system, increasing the meta-bolism of oral contraceptives, anticoagulants, dexa-methasone and pethidine.

Adverse effects—The adverse effects of phenytoin maybe dosage- or non-dosage-related. The dosage-relatedeffects of phenytoin affect the cere-bellovestibular system,leading to ataxia, blurred vision and hyperactivityAcute toxicity causes sedation and confusion. The non-dosage-related effects include collagen effects such asgum hypertrophy and coarsening of facial features;allergic reactions, e.g. rash, hepatitis and lymphadenopa-thy; haematological effects, e.g. megaloblastic anaemia;endocrine effects, e.g. hirsutism (hair growth); and terato-genic effects (it may cause congenital malformations).

Therapeutic notes—The use of phenytoin is compli-cated by its zero-order pharmacokinetics, characteristictoxicities, and necessity for long-term administration.Phenytoin has a narrow therapeutic index, and therelationship between dose and plasma concentrationis non-linear. This is because phenytoin is metabolizedby a hepatic enzyme system that is saturated at thera-peutic levels. Small dosage increases may, therefore,produce large rises in plasma concentrations with acuteside-effects. Monitoring of plasma concentration greatlyassists dosage adjustment. Because of its adverse effectsand narrow therapeutic window, phenytoin is no longera first-line treatment for any of the seizure syndromes.

Sodium valproate

Mechanism of action—Sodium valproate has twomechanisms of action: like phenytoin, it causes use-dependent block of voltage-gated sodium channels; italso increases the GABA content of the brain when givenover a prolonged period.

Route of administration—Oral, intravenous.

Fig. 5.17 Drugs used for epilepsy classified by clinical use

Seizure type Primary drugs Secondarydrugs

Partial and/orgeneralized tonic-clonic seizures

SodiumvalproateCarbamazepine

PhenytoisnVigabatrinGabapentinLamotriginePhenobarbital

Absence seizures EthosuximideSodiumvalproateLamotrigine

Phenobarbital

Status epilepticus Lorazepam DiazepamClonazepamss

Fig. 5.17 Drugs used for epilepsy classified by clinical use.

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Indications—Sodium valproate is useful in all formsof epilepsy.

Contraindications—Sodium valproate should notbe given to people with acute liver disease or a historyof hepatic dysfunction.

Adverse effects—Sodium valproate has fewer side-effects than other antiepileptics; the main problemsare gastrointestinal upset and, more importantly, liverfailure. Hepatic toxicity appears to be more commonwhen sodium valproate is used in combination withother antiepileptics.

Therapeutic notes—Sodium valproate is wellabsorbed orally and has a half-life of 10–15 hours.Sodium valproate is now the first-line drug for mosttypes of seizure syndromes.

CarbamazepineMechanism of action—Like phenytoin, carbamaze-

pine causes use-dependent block of voltage-gatedsodium channels. Oxcarbazepine, another antiepileptic,is structurallyaderivativeofcarbamazepine. Ithasanextraoxygen atom on the dibenzazepine ring, which helpsreduce the impact on the liver of metabolizing thedrug, and also prevents the serious forms of anaemiaoccasionally associatedwith carbamazepine. It is thoughtto have the samemechanismof action as carbamazepine.

Route of administration—Oral, rectal.Indications—Carbamazepinecanbeusedinall formsof

epilepsy except absence seizures; neuralgic pain (p. 000).Contraindications—Like phenytoin, carbamazepine

is a strong enzyme inducer and so causes similar druginteractions.

Adverse effects—Ataxia, nystagmus, dysarthria, ver-tigo, sedation.

Therapeutic notes—Carbamazepine is well absorbedorallywitha longhalf-life (25–60hours)when first given.Enzyme induction subsequently reduces this half-life.

Ethosuximide

Mechanism of action—Ethosuximide exerts its effectsby inhibition of low-threshold calcium currents(T-currents).

Route of administration—Oral.Indications—Ethosuximide is the drug of choice in

simple absence seizures and is particularly well toleratedin children.

Contraindications—Ethosuximide may make tonic-clonic attacks worse.

Adverse effects—The adverse effects of ethosuximideinclude gastrointestinal upset, drowsiness, moodswings and skin rashes. Rarely, it causes serious bonemarrow depression.

VigabatrinMechanism of action—Vigabatrin exerts its effects

by irreversible inhibition of GABA transaminase.Route of administration—Oral.

Indications—Vigabatrin is indicated in epilepsy notsatisfactorily controlled by other drugs.

Contraindications—Vigabatrin should not be usedin people with a history of psychosis because of theside-effect of hallucinations.

Adverse effects—Drowsiness, dizziness, depression,visual hallucinations.

Therapeutic notes—Vigabatrin is a new drug, used asan adjunct to other therapies.

Lamotrigine

Mechanism of action—Lamotrigine appears to act viaan effect on sodium channels, and inhibiting the releaseof excitatory amino acids.

Route of administration—Oral.Indications—Monotherapy and adjunctive treatment

of partial seizures and generalized tonic-clonic seizures;neuralgic pain (p. 000).

Contraindications—Hepatic impairment.Adverse effects—Rashes, fever, malaise, drowsiness

and, rarely, hepatic dysfunction.

Gabapentin

Mechanism of action—Gabapentin is a lipophilicdrug that was designed to act like GABA in the CNS(agonist), though it does not appear to have GABA-mimetic actions. Its mechanism of action remainselusive, but its antiepileptic action almost certainlyinvolves voltage-gated calcium-channel blockade.

Route of administration—Oral.Indications—As an adjunct to therapy in partial

epilepsy with or without secondary generalization.Contraindications—Avoid sudden withdrawal, in

elderly patients and in those with renal impairment.Adverse effects—Somnolence,dizziness, ataxia, fatigue

and, rarely, cerebellar signs.

BarbituratesExamples of barbiturates include phenobarbital andprimidone (which itself, is largely converted tophenobarbital).

Mechanism of action—Barbiturates cause potentia-tion of chloride currents through the GABAA/Cl

–

channel complex.Route of administration—Oral, intravenous.Indications—Barbiturates are used in all forms of

epilepsy, including status epilepticus.Contraindications—Barbiturates should not be used

in children, elderly people, and people with respiratorydepression.

Adverse effects—The main side-effect of barbituratesis sedation, which limits their use clinically, alongwith the danger of potentially fatal CNS depressionin overdose. Phenobarbital is a good inducer ofcytochrome P450, and so it can be involved in druginteractions.


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Therapeutic notes—Only the long-acting barbitu-rates are antiepileptic. Phenobarbital has a plasmahalf-life of 10 hours. The strong sedating nature of thesedrugs now limits their use in the management ofepilepsy.

BenzodiazepinesExamples of benzodiazepines include clonazepam andclobazam.

Mechanism of action—Benzodiazepines causepotentiation of chloride currents through the GABAA/Cl– channel complex (see Fig. 5.5).

Route of administration—Oral, intravenously.Indications—Clonazepam is occasionally used for

tonic-clonic and partial seizures. Lorazepam anddiazepam are effective in the management of statusepilepticus.

Contraindications—Benzodiazepines should not beused in people with respiratory depression.

Adverse effects—The most common adverse effect ofthe benzodiazepines is sedation. Intravenous loraze-pam and diazepam can depress respiration.

Therapeutic notes—The repeated seizures of statusepilepticus can damage the brain and be potentiallylife-threatening, so they should be controlled byadministration of intravenous diazepam. Lorazepamhas a longer half-life than diazepam.

Other anticonvulsantsOther agents used as antiepileptics include levetirace-tam, tiagabine, topiramate, acetazolamide and pirace-tam. Their indications and side-effect profiles can beobtained from the British National Formulary (BNF).

COMMUNICATION

Emmett Hezz, a 19-year-old student car mechanic

is brought to accident and emergency following a

collapsewhilewaiting for a taxi. His fianceewaswith him

at the time and tells staff that he fell to the ground all of a

suddenand thathis breathing appeared to stop for about

30 seconds. He then developed jerking movements of

his arms and legs and by this time his face had turned

blue. He was incontinent of urine and on regaining

consciousnesswas drowsy, confusedand complainingof

aching muscles. In hospital he was able to explain that

8 monthsago,heexperiencedasimilar episodewhen ina

park, but was too embarrassed to tell anybody.

On examination, his pulse is 76 beats per minute and

regular. No abnormalities are found, other than a

bleeding tongue. The history is very indicative of a

tonic-clonic (grand mal) seizure. He is admitted for 24

hours and sent for blood investigations, ECG, head CT

and EEG. EEG reveals generalized spike-and-wave

activity, but no other abnormality. He is warned not to

drive or operate heavy machinery until he has been

seizure-free for a year. Emmett agrees to start taking

the anticonvulsant sodium valproate and return for a

follow-up appointment.

Status epilepticus

Intravenous benzodiazepines (lorazepam or diazepam)are first-line drugs in status epilepticus. If these fail tobring an end to seizure activity, intravenous sodiumvalproate or phenytoin, or carbamazepine via a naso-gastric tube should be attempted, ideally in an intensivecare setting. Alternatively intravenous fosphenytoin, aprodrug of phenytoin, can be given more rapidly but re-quires ECG monitoring. Thiopental (p. 000) can beused as a final option.

THE EYE

The eyeball is a 25 mm sphere made up of two fluid-filled compartments (the aqueous humour and thevitreous humour) separated by an translucent lens, allencased within four layers of supporting tissue(Fig. 5.18). These four layers consist of:

• The cornea and sclera• The uveal tract, comprising the iris, ciliary body and

choroid• The pigment epithelium• The retina (neural tissue containing photoreceptors).

Light entering the eye is focused by the lens onto theretina, and the signal reaches the brain via the opticnerve.

Glaucoma

Glaucoma describes a group of disorders characterisedby a loss in visual field associated with cupping of theoptic disc and optic nerve damage. The glaucomas arethe second commonest cause of blindness in the worldand the commonest cause of irreversible blindness.Glaucoma is generally associated with raised intraocularpressure (IOP), but can occur when the IOP is withinnormal limits.

There are two types of glaucoma: open-angle andclosed-angle.

Open-angle glaucoma is the most common type ofglaucoma and it may be congenital. It is caused by patho-logy of the trabecular meshwork that reduces thedrainage of the aqueous humour into the canal of Sch-lemm. Treatment involves either reducing the amountof aqueous humour produced or increasing its drainage.

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In closed-angle glaucoma, the angle between the irisand the cornea is very small, and this results in forwardballooning of the iris against the back of the cornea.

Chronic open-angle glaucoma is of insidious onsetand often picked up at routine check up, whereas acuteclosed-angle glaucoma symptoms include painful, redeyes and blurred vision. Acute closed-angle glaucomais a medical emergency and requires admission to savesight. It is difficult for patient to notice gradual loss ofvisual fields associated with chronic open-angleglaucoma and so regular check ups are vital for at-riskgroups, such as elderly people.

Treatment of open-angle glaucoma

The most effective way of preventing this damage to theeye is by lowering the IOP. Most drugs used to treat eyedisease can be given topically in the form of drops andointments. To enable these drugs to penetrate thecornea, they must be lipophilic or uncharged.

Drugs used to inhibit aqueous production

b-Adrenoceptor antagonists and prostaglandin ana-logues are the current choice for first-line treatment.

b-Adrenoceptor antagonistsTimolol and betaxolol are examples of b-adrenoceptorantagonists used in glaucoma.

Mechanism of action—b-Adrenoceptor antagonistsblock b2-receptors on the ciliary body and on ciliaryblood vessels, resulting in vasoconstriction and reducedaqueous production (Fig. 5.19).

Route of administration—Topical.Indications—Open-angle glaucoma. b-adrenoceptor

antagonistsarealsousedincardiovasculardisease(Ch.2).Contraindications—b-Adrenoceptor antagonists

should not be given to patients with asthma, bradycar-dia, heart block or heart failure.

Adverse effects—Systemic side-effects includebronchospasm in asthmatic patients, and potentiallybradycardia owing to their non-selective action onb-receptors. Other side-effects include transitory dryeyes and allergic blepharoconjunctivitis.

Prostaglandin analoguesExamples include latanoprost and travoprost.

Mechanism of action—Promote outflow of aqueousfrom the anterior chamber via an alternative drainageroute, called the uveoscleral pathway.

Fig. 5.18 Anatomy of the eye.(Redrawn from Page et al. 2006.)


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Indications—Open angle glaucoma, ocular hyper-tension.

Contraindication—Pregnancy.Adverse effects—Brown pigmentation of the iris may

occur.

Sympathomimetics (adrenoceptor agonists)Adrenaline, dipivefrine and brimonidine are commonlyused sympathomimetics.

Mechanism of action—Agonism at a-adrenoceptors isthought to be the principal means by which these agentsreduce aqueous production from the ciliary body.Adrenaline may also increase drainage of aqueous(see Fig. 5.19).

Route of administration—Topical.Indications—Open-angle glaucoma. Sympathomi-

metics are also used in the management of cardiac(Ch. 2) and anaphylactic emergencies and in reversibleairways disease (Ch. 3).

Contraindications—Closed-angle glaucoma, hyper-tension, heart disease.

Adverse effects—Pain and redness of the eye.

Therapeutic notes—Adrenaline is not very lipophilicand, therefore, it doesnot penetrate the cornea effectively.This can be overcome by administering dipivefrinehydrochloride, a prodrug that crosses the cornea andthat is metabolized to adrenaline once inside the eye.

Carbonic anhydrase inhibitors (CAIs)Acetazolamide and dorzolamide are CAIs.

Mechanism of action—CAIs inhibit the enzymecarbonic anhydrase, which catalyses the conversion ofcarbondioxide andwater to carbonic acid, which dissoci-ates into bicarbonate and Hþ. Bicarbonate is requiredby the cells of the ciliary body, and underproduction ofbicarbonate limits aqueous secretion (Fig. 5.19). CAIsgiven systemically have a weak diuretic effect (Ch. 7).

Route of administration—Oral, topical, intravenous.Indications—Open-angle glaucoma.Contraindications—Hypokalaemia, hyponatraemia,

renal impairment. These effects can be reduced if thedrug is given in a slow-release form.

Adverse effects—Irritation of the eye, nausea, vomit-ing, diarrhoea, diuresis.

Fig. 5.19 Production and drainage of the aqueous humour.(Redrawn from Page et al. 2006.)

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Drugs used to increase the drainageof aqueous humour

Miotics–muscarinic agonistsPilocarpine is a muscarinic agonist.

Mechanism of action—Pilocarpine causes contractionof theconstrictorpupillaemusclesof the iris, constrictingthe pupil, and allowing aqueous to drain from the ante-rior chamber into the trabecular meshwork (Fig. 5.19).

Route of administration—Topical.Indications—Open-angle glaucoma.Contraindications—Acute iritis, anterior uveitis.Adverse effects—Eyeirritation,headacheandbrowache,

blurred vision, hypersalivation. May exacerbate asthma.

Treatment of closed-angleglaucoma

Drugs to treat closed-angle glaucoma are used in emer-gencies as a temporary measure to lower IOP.

Pilocarpine and a carbonic anhydrase inhibitor areoften first-line treatments, with mannitol and glycerolbeing administered systemically and reduce IOP forresistant or more serious cases.

YAG (yttrium-aluminium-garnet) laser surgery pro-vides a permanent cure for closed-angle glaucoma. Ahole is made in the iris (iridectomy) to allow increasedflow of aqueous humour.

HINTS AND TIPS

Stimuli that cause the pupils to dilate, such as sitting

awake in a dark room, increase the tightness of the

angle between the iris and the cornea and can thus

precipitate an attack of acute closed-angle glaucoma.

Examining the eye

Mydriatic drugs dilate the pupil, i.e. cause mydriasis,while cycloplegic drugs cause paralysis of the ciliarymuscle, i.e. cycloplegia. Mydriatic and cycloplegic drugsare used in ophthalmoscopy to allow a better view of theinterior of the eye.

Mydriasis and cycloplegia reduce the drainage of theaqueous humour, and they should, therefore, beavoided in patients with closed-angle glaucoma.

Muscarinic antagonistsThe most effective mydriatics are the muscarinic antag-onists. These block the parasympathetic control of theiris sphincter muscle.

The type of muscarinic antagonist chosen will de-pend on the length of the procedure and on whetheror not cycloplegia is required.

The most commonly used muscarinic antagonists,their duration of action, and their mydriatic and cyclo-plegic effects are summarized in Fig. 5.20.

a-Adrenoceptor agonistsa-Adrenoceptor agonists can cause mydriasis by stimu-lating the sympathetic control of the iris dilator muscle.The sympathetic system does not control the ciliarymuscle, however, and, therefore, these drugs do not pro-duce cycloplegia. The a-agonist most commonly used toproduce mydriasis is phenylephrine.

Muscarinic agonists and a-antagonistsA muscarinic agonist such as pilocarpine, or an a-antagonist such as moxisylyte may be used to reversemydriasis at the end of an ophthalmic examination.This is not usually necessary.

Fig. 5.20 Mydriatic and cycloplegic effects of the commonly used muscarinic antagonists

Drug Duration (h) Mydriatic effect Cycloplegic effect

Tropicamide 1–3 þþ þCyclopentolate 12–24 þþþ þþþAtropine 168–240 þþþ þþþ

Fig. 5.20 Mydriatic and cycloplegic effects of the commonly used muscarinic antagonists.


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