Assoc. Prof. Ivan Lambeve-mail: itlambev@mail.bg

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

NeurolepticsAnxiolytics

(Abstract)

Psychotropic drugsinfluence on the psyche (mentality)and behaviour of patients.

• Neuroleptics (antipsychotics)• Anxiolytics• Mood stabilizers• Antidepressants• Psychostimulants• Nootropics (cognition enhancers), etc.

NEUROLEPTICS(Antipsychotics,

Antischizophrenic drugs)

I. Typical antipsychotics(with extrapyramidal motor symptoms)

• Phenothiazines• Thioxanthenes• Butyrophenones, etc.

II. Atypical antipsychotics (lack of extrapyramidal motor symptoms in rats)

Schizophrenia is a particular kind of psychosis (mental disorder) characterized mainly by a clearsensorium but a marked thinking disturbance.Key symptoms include hallucinations, delusions,and abnormal experiences, such as the perceptionof loss of control of one’s thoughts. Patients lose empathy with others, become withdrawn,and demonstrate inappropriate or blunted mood. Schizophrenic symptoms:Positive: can be regarded as an abnormality (incoherent speech, agitation). Negative: indicate a loss or decrease in function, such as poverty of speech or blunted affect. Negative signs are more chronic and persistent and less responsive to treatment.

The dopamine (DA) hypothesis for schizophrenia is the basis for rational drug therapy. Several linesof circumstantial evidence suggest that excessiveDA-ergic activity plays a role in this psychosis:

(1) many antipsychotic drugs strongly block post-synaptic D2-receptors in the CNS, especially in the mesolimbic-frontal system;

(2) drugs that increase DA-ergic activity, such as levodopa (a precursor), amphetamines (releasers of DA), and apomorphine (a direct DA-ergic agonist),either aggravate schizophrenia or produce psychosisde novo in some patients;

(3) DA receptor density has been found postmortemto be increased in the brains of schizophrenics whohave not been treated with antipsychotic drugs;

(4) positron emission tomography (PET) has shownincreased DA receptor density in both treated anduntreated schizophrenics when compared with suchscans of nonschizophrenic persons;

(5) successful treatment of schizophrenic patientshas been reported to increase the amount of homo-vanillic acid (HVA), a metabolite of DA, in the cerebrospinal fluid, plasma, and urine.

Neuroleptics – mechanism of actionSeveral important DA-ergic systems orpathways are now recognized in the brain:

(1) The first pathway (the one most closely relatedto behavior) is the mesocortical tract,which projects from cell bodies near the substantia nigra to the limbic system and neocortex.

(2) The second system (the nigrostriatal tract)consists of neurons that project from the substantianigra to the caudate and putamen; it is involved inthe coordination of voluntary movement.

3) The third pathway (the tuberoinfundibulartract) connects arcuate nuclei and periventricularneurons to the hypothalamus and posterior pituitary.DA released by these neurons physiologically inhibits prolactin secretion.

Five DA receptors have been described, consistingof two separate families – the D1- and D2-like groups:(1) The D1-receptor is coded by a gene on chromo-some 5, increases cAMP by activation of adenylylcyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The second member of this family is D5. It is codedby a gene on chromosome 4, also increases cAMP,and is found in the hippocampus and hypothalamus.

The therapeutic potency of the most antipsychotic drugs correlates stronglywith their D2-affinity.

(2) The D2-receptor family includes D2, D3 and D4-receptors. D2-receptors is coded on chromosome 11,decreases cAMP (by inhibition ofadenylyl cyclase), and inhibits calcium channelsbut opens potassium channels. It is found bothpre- and postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle.A second member of this family, the D3-receptor,also coded by a gene on chromosome 11, isthought to decrease cAMP and is located in thefrontal cortex, medulla, and midbrain. The D4-receptor also decreases cAMP.

Distribution and characteristics of DA receptors in the central nervous system

Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

The key steps in the synthesis and degradation of DAand the sites of action of various psychoactive substances

at the dopaminergic synapse

It has not been convincingly demonstrated thatantagonism of any DA receptors (especially D4)plays a role in the action of “atypical” antipsychotic drugs. Most of the newer “atypical” antipsychotics andsome of the traditional ones have significantaffinity for the 5-HT2A receptor, suggestingan important role for the serotonin system. Participation of glutamate, GABA, and ACh receptors in the pathophysiology of schizophreniahas also been proposed.

The effects of DA, 5-HT and NE on the brain functions

(NE)

(DA)

(5-HT)

Schizophrenia

Main effects(1) CNS. In normal individuals antipsychotics produceneuroleptic syndrome – indifference to surroundings,paucity of thought, psychomotor slowing, emotionalquietening, reduction in initiative.In psychotic patients neuroleptics reduceirrational behaviour, agitation and aggresiveness.They control psychotic symptomatology. Disturbedthought and behaviour are gradually normalized,anxiety is relieved. Hyperactivity, hallucinations,and delusions are suppressed.

The psychosedative effect is produced immediatelywhile the antipsychotic effect takes a week to develop.Tolerance develops only to the psychosedative effect.

The thermoregulatory centre is turned off, rendering the patient poikilothermic (body tem-perature falls if surroundings are cold and the contrary).

The medullary, respiratory and other vital centres are not affected, except of very high doses. It is very difficult to produce coma with neuroleptics.Antiemetic effect is exerted through the CTZ. Almost all neuroleptics, except thioridazine, have thiseffect. However, they are ineffective in motor sickness.

In animal antipsychotic agents produce a state of rigidity and immobility (catalepsy).

(2) ANS. Neuroleptics have varying degrees of alpha-adrenergic blocking activity and produce hypotension (primarily postural). The hypotensiveeffect is more marked after parenteral administration. Anticholinergic property of neuroleptics is weak.The phenothiazines have weak H1-antihistaminic andanti-5-HT actions as well. Promethazine has strongsedative, and H1-antihistaminic action.

(3) Endocrine system. Neuroleptics consistentlyincrease prolactin release by blocking the inhibitoryaction of DA on pituitary gland. This may resultin galactorrhea and gynecomastia. They reducegonadotrophins, ACTH, GH and ADH secretion.

Type 1 (aliphatic side chain) Chlorpromazine, Promazine, Levomepromazine, PromethazineType 2 (piperidine side chain): ThioridazineType 3 (piperazine side chain) Trifluoperazine, Prochlorperazine, Fluphenazine

I. Typical Neuroleptics (D2-blockers)

Phenothiazines

Thioxanthenes

This is a three-ring compound structurally relatedto phenothiazine but having the nitrogen atom atposition 10 replaced by a carbon atom with a double bond. Thioxanthenes have nearly equivalent potency with phenothiazines.

•Chlorprothixene•Flupenthixol•Zuclopenthixol

R

Butyrophenones

•Droperidol•Benperidol•Haloperidol:

The butyrophenones are structurally similar to GABA. They offer greater potency

and fewer autonomic side effects.

II. Atypical Neuroleptics(They block mainly 5-HT2- and D4-receptors)

•Clozapine•Olanzapine•Quetiapine•Risperidone•Ziprasidone•Amisulpiride•Zotepine•Sertindole

They causelittle extrapyramidal toxicity.The risperidone isrepresentative of many of the newer agents in having a betterside effect profile.

Psychiatric indications of neuroleptics

Schizophrenia is the primaryindication for neuroleptics.Unfortunately, many patientsshow little response.

Antipsychotics are also indicated for schizoaffectivedisorders, which share characteristics of bothschizophrenia and affective disorders. The psychotic aspects of the illness require treatmentwith antipsychotic drugs, which may be used with otherdrugs such as antidepressants, lithium, or valproates.

Whilst a typical antipsychotics shouldprovide adequate treatment of positive symptomsincluding hallucinations and delusions in at least60% of cases, patients are often left with unresolved negative symptoms such asapathy, flattening of affect, and alogia. Evidencesuggests that clozapine and the newer atypicalshave a significant advantage over typical drugsagainst negative symptoms.

The manic phase in bipolar affective disorder oftenrequires treatment with neuroleptics (chlorpromazine,haloperidol), though lithium or valproic acid supplemented with high-potency benzodiazepines (e.g. lorazepam or clonazepam) may suffice in milder cases.

Recent controlled trials support the efficacy ofmonotherapy with atypical antipsychotics in theacute phase (up to 4 weeks) of mania, andolanzapine has been approved for this indication.

Nonmanic excited states may also be managedby antipsychotics, often in combination withbenzodiazepines.Other indications for the use of antipsychotics include disturbed behavior in patients withAlzheimer's disease, and, with antidepressants,psychotic depression. Antipsychotics are not indicated for the treatmentof various withdrawal syndromes, e.g. opioidwithdrawal. In small doses antipsychotics havebeen promoted (wrongly) for the relief of anxietyassociated with minor emotional disorders, but the anxiolytic agents are preferred.

Nonpsychiatric indicationsMost older antipsychotics, with the exception ofthioridazine, have a strong antiemetic effect. This action is due to D2-receptor blockade, both centrally (in the chemoreceptor trigger zoneof the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazineare promoted only as antiemetics.Phenothiazines with shorter side chains have consi-derable H1-receptor-blocking action and used forrelief of pruritus or, in the case of promethazine, as preoperative sedatives. The butyrophenonedroperidol is used in combination with an opioid,fentanyl, in neurolept-anaesthesia (-analgesia).

Adverse reactions – behavioral effects:The older typical antipsychotic drugs are unpleasantto take. Many patients stop taking these drugsbecause of the adverse effects, which may be mitigated by giving small doses during the day andthe major portion at bedtime. A “pseudodepression” that may be due to drug-induced akinesia usuallyresponds to treatment with antiparkinsonian drugs.Other pseudodepressions may be due to higher doses; the decreasing the dose may relieve thesymptoms. Toxic-confusional states may occurwith very high doses of drugs that have prominent antimuscarinic actions.

Neurologic effects:Extrapyramidal reactions occurring early during treatment with older agents include typicalParkinson's syndrome, akathisia (uncontrollablerestlessness), and acute dystonic reactions(spastic retrocollis or torticollis). Parkinsonism canbe treated, with conventional antiparkinsoniandrugs of the antimuscarinic type or, in rare cases,with amantadine. Parkinsonism may be self-limiting,so that an attempt to withdraw antiparkinsoniandrugs should be made every 3–4 months.Akathisia and dystonic reactions also respond tosuch treatment, but many prefer to use a sedativeantihistamine with anticholinergic properties,e.g. diphenhydramine.

Tardive dyskinesia- persistent involuntary movements of mouth,tongue or face.

Autonomic nervous system effectsAntimuscarinic (atropine-like) adverse effects:urinary retention, dry mouth, midriasis. Alpha-blockade: Orthostatic hypotension or impairedejaculation should be managed by switching to drugswith less marked adrenoceptor-blocking actions.

Ocular complicationsDeposits in the anterior portions of the eye (cornea and lens) are a common complication ofChlorpromazine therapy. They may accentuate the normal processes of aging of the lens. Thioridazine is the only antipsychoticdrug that causes retinal deposits,which in advanced cases may resemble retinitispigmentosa. The deposits are usually associatedwith “browning” of vision. The maximum dailydose of thioridazine has been limited to 800 mgto reduce the possibility of this complication.

Metabolic and endocrine side effectsWeight gain is very common, especially with clozapine and olanzapine, and requires monitoringof food intake, especially carbohydrates. Hyperglycemia may develop.Hyperprolactinemia in women results in theamenorrhea – galactorrhea syndrome and infertility;in men loss of libido, impotence, and infertilitymay result.Toxic or allergic reactionsAgranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potencyantipsychotic drugs currently used.

Neuroleptic malignant syndromeThis life-threatening ADR occurs in patients whoare extremely sensitive to the extrapyramidal effectsof antipsychotics. The initial symptom is markedmuscle rigidity. If sweating is impaired, as it oftenis during treatment with anticholinergic drugs,fever may ensue, often reaching dangerous levels.The stress leukocytosis and high fever associatedwith this syndrome suggest an infectious process.Autonomic instability, with altered blood pressureand pulse rate, is often present. Creatine kinaseisoenzymes are usually elevated, reflecting muscle damage.

This syndrome is believed to result from an excessivelyrapid blockade of postsynaptic DA receptors. A severeform of extrapyramidal syndrome follows. Early in the course, vigorous treatment of the extrapyramidalsyndrome with antiparkinsonian drugs is worthwhile.Muscle relaxants, particularly diazepam, are oftenuseful. Other muscle relaxants, such as dantrolene,or DA agonists, such as bromocriptine, have beenreported to be helpful. If fever is present, coolingby physical measures should be tried.

ANXIOLYTICS(antianxiety drugs)

•Benzodiazepines•Azapirones (buspirone)•Benzoxazines (etifoxine)•Sedative H1-blockers

(hydroxyzine)•Nonselective beta-blockers•SSRIs

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Gamma aminobutyric acid (GABA) is probablythe most important inhibitory transmitter in the CNS. GABA-ergic neurones are distributedwidely in the CNS. GABA controls the state of excitability in all brain areas and the balance between excitatory inputs (mostly glutamatergic)and the inhibitory GABA-ergic activity. If the balanceswings in favour of GABA, then sedation, amnesia,muscle relaxation and ataxia appear and nervous-ness and anxiety are reduced. The mildest reductionof GABA-ergic activity elicits arousal, anxiety, rest-lessness, insomnia and exaggerated reactivity.

Most drugs used in insomnia act as agonists at the GABAA-receptor and have effects other than their directsedating action, including muscle relaxation,memory impairment, and ataxia, which can impairperformance of skills such as driving. Clearly thosedrugs with onset and duration of action confined tothe night period will be most effective in insomniaand less prone to unwanted effects during the day.Those with longer duration of action are likely toaffect psychomotor performance, memory and concentration; they will also have enduringanxiolytic and muscle-relaxing effects.

Bromazepam (t1/2 20 h)•Chlordiazepoxide•Cinolazepam•Clorazepate•Diazepam (t1/2 40 h)•Flurazepam •Flunitrazepam•Lorazepam•Nitrazepam: tab. 5 mg•Medazepam•Midazolam (t1/2 2 h)•Triazolam (t1/2 3 h)•Tetrazepam etc.

Benzodiazepines

When GABA binds withthe GABAA-receptor, the permeability of the centralpore of the receptor tochloride ions increases(hyperpolarization) and decreasis excitability.Benzodiazepines (BDZs) enhance the effectivenessof GABA by increasing the frequency of the openingof the chloride ions. BDZs are agonists at the receptor and the flumazenil (antagonist) prevents agonistsfrom binding at the receptor site.

A model of the GABAA

receptor-chloride ion channel macromole-cular complex

Basic & ClinicalPharmacology –10th Ed. (2007)

Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

BDZs enhance GABA-ergic inhibition.Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Advantages of BDZsBDZs have a high therapeutic index. In hypnotic dosesthey do not affect respiration and cardiovascuarfunctions. Only in i.v. injection the blood pressuremay fall. BDZs cause less distortion of sleep architecture. They do not alter disposition of otherdrugs by microsomal enzyme induction.They have lower abuse liability: tolerance ismild, psycholgical and physical dependence andwithdrawal syndrome are less marked.A selectve BDZs antagonist flumazenil (partial agonist of benzodiazepinic receptor)can be used in case of poisoning.

Chlordiazepoxide Flumazenil

CNS action and classification of BDZsThe action of all BDZs is qualitatively similar, but thereare prominent differences in selectivity and time course of effect: different members of BDZs areused for different therapeutic purposes. In contrastto barbiturates BDZs exert relatively selectiveanxiolytic (antianxiety), hypnotic (euhypnotic), musclerelaxant, and anticonvulsant (antiepileptic) effects.

Anxiolytic effect have all BDZs:Alprazolam, Bromazepam (Lexotan – tab. 3 mg),Chlordiazepoxide, Diazepam, Lorazepam, Мedazepam (daily tranquillisant), Nordiazepam, etc.

Hypnotic (euhypnotic) effect:Bromazepam, Flurazepam, FlunitrazepamNitrazepam, Midazolam, Triazolam, etc.

Anticonvulsive (antiepileptic) BDZs:Clonazepam, Clorazepate, Diazepam, Lorazepam, Nitrazepam

Central muscle relaxants:Diazepam, Tetrazepam

Pharmacokinetics

BDZs are effective after administrationby mouth but enter the circulation at very differentrates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow.The liver metabolizes them, usually to inactive metabolites, but some compounds produceactive metabolites with long t1/2 which greatlyextends drug action, e.g. chlordiazepoxide, clorazepate, and diazepam.

Biotransformation of benzodiazepines Biotransformation of benzodiazepines Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)

Clorazepate

Uses•Benzodiazepines are used for: insomnia; anxiety; alcohol withdrawal states; muscle spasm (tetrazepam, diazepam) due to a variety of causes, including tetanus and cerebral spasticity; epilepsy (clonazepam, lorazepam, diazepam); anaesthesia and sedation (diazepam, midazolam,triazolam) for endoscopies and cardioversion.•Potent BDZs alprazolam and lorazepam injected i.m. have an adjuvant role in the management of acutely psychotic and manic patients.•The choice of drug as hypnotic and anxiolytic is determined by their pharmacokinetic properties.

Adverse effects of BDZs•Common reactions: Fatigue, drowsiness, ataxia.

•Infrequently reactions:Constipation, incontinence, •urinary retention, •dysarthria, blurred vision, •diplopia, hypotension, •nausea, dry mouth, skin rash, tremor.

Tolerance to the anxiolytic effects doesnot seem to be a problem. Studies of subjective sleep quality show enduring efficacy but about half of the objective (EEG) studies indicatedecreased effects after 4–8 weeks,implying that some tolerance develops.The necessity for dose escalation in sleep disorders is rare.

Withdrawal of BDZs should be gradual afteras little as 3 weeks’ use but for long-term usersit should be very slow, e.g. about 6–12 weeks. With-drawal should be slowed if marked symptoms occurand it may be useful to substitute a long t1/2 drug (e.g.diazepam) to minimize rapid fluctuations in plasmaconcentrations. In difficult cases withdrawal may beassisted by concomitant use of an antidepressant.Commonly there is a kind of psychological depend-ence based on the fact that the treatment works toreduce patients’ anxiety or sleep disturbance andtherefore they are unwilling to stop. If they do stop,there can be relapse, where original symptoms return.

BDZs can affect memory and balance.Hazards with car driving or operating any machinery can arise from amnesia and impaired psychomotor function, in addition to sleepiness (warn the patient).Amnesia for events subsequent to administrationoccurs with i.v. high doses, for endoscopy, dentalsurgery (with local anaesthetic), cardioversion, andin these situations it can be regarded as a blessing.Women (1 in 200), may experience sexual fantasies,including sexual assault, after large doses of BDZsas used in some dental surgery, and have brought charges in lawsuits against male staff.

Plainly a court of law has, in the absence of a witness,great difficulty in deciding whom to believe.Paradoxical behavior effects and perceptual disorders,e.g. hallucinations, can occur. Headache, giddiness, GI upset, skin rashes and reduced libido can occur too.

The PRC of BDZs is D. BDZs cross the placenta andcan cause fetal cardiac arrhythmia and muscular hypotonia, suckling hypothermia and respiratorydepression in the newborn.

InteractionsAll BDZs potentiate the effects of alcoholand other central depressants, and all are likelyto exacerbate breathing difficulties where this isalready compromised, e.g. in obstructive sleepapnoea. BDZs potentiate the action of analgetics too.The fluoroquinolones block GABAA-receptors anddecrease the action of BDZs.

Overdose. Flumazenil (Anexate®) selectivelyreverses benzodiazepine effects and is useful indiagnosis and in treatment of intoxication with them.Flumazenil is a competitive partial agonist.

Fluoroquinolones

Adapted from Bennett and Brown (2003)

AzapironesBuspirone is a selective partial agonsist of presynaptic5-HT1A-receptors. By stimulating these receptors it reduces activity of dorsal raphe 5-HT-ergic neurons.Buspirone relieves mild to moderate generalized anxiety, but is ineffective in severe cases (panicreactions and obsessive compulsive disorder).

Sedative H1-blockersHydroxyzine is an H1-blockerwith sedative, antiemetic,antimuscarinic, and spasmolyticeffects. It is effectivein pruritus, and urticaria.

Etifoxine (Stresam®) produces its anxiolytic effects by binding to β2 andβ3 subunits of the GABAA-receptor. It is used in anxiety disorders.

Nonselective beta-blockersMany symptoms of anxiety (palpitations, rise in bloodpressure, shaking, tremor, GI hurrying)are due to sympathetic overactivty and thesesymptoms reinforce anxiety. Propranolol and othernonselective beta-blockers cut the vicious cycle andprovide the symptomatic relief. They do not affectpsychologycal symptoms, such as fear, tension andworry, but are valuable in acutely stessful situations(examination fear, unaccustomed public appearance).SSRIs (selective serotonin reuptake inhibitors)are effective in obsessive compulsive disorder (OCD),phobias, panic and many types of sever generalizedanxiety disorders.

Treatment of anxietyAnxiety is a universal phenomenon, but if it isfrequent and persists in a severe form, it maycause distress and markedly impair performance.The established drugs for treatment of excessiveanxiety are BDZs, which must be used in the smallestpossible dose. The usual practice is to give ½ to 2/3 ofDD at bed time to ensure good night’s rest; the remain-ing part is divided in 2 to 3 doses, given at day time. Though the plasma half-life of many BDZs, used in anxiety are longer, divided daytime doses arerequired to avoid high plasma peaks.

Buspirone is a nonsedating alternative to BDZs for aless severe form of generalized anxiety. The SSRI antidepressantsare now being increasingly used in many forms of severeanxiety disorders. They produce a delayed but often gratifyingresponse and combined with BDZs. The SSRIs are nowdrugs of choice for treatment of social anxiety in whichBDZs though effective, carry abuse potential on long term use.Patients with arterial hypertension, angina pectoris, peptic ulcer, ulcerative colitis, irritable bowel,gastroesophageal reflux, thyrotoxicosis are often given lowdoses of BDZs intermittently in addition to specifictherapy, though anxiety may not be a prominent manifestation.