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Assoc. Prof. Ivan Lambev e-mail: itlambev@mail.bg Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Neuroleptics Anxiolytics (Abstract)
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Psychotropic drugs influence on the psyche (mentality) and behaviour of patients. Neuroleptics (antipsychotics) Anxiolytics Mood stabilizers Antidepressants Psychostimulants Nootropics (cognition enhancers), etc.
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NEUROLEPTICS (Antipsychotics, Antischizophrenic drugs) Typical antipsychotics (with extrapyramidal motor symptoms) Phenothiazines Thioxanthenes Butyrophenones, etc. II. Atypical antipsychotics (lack of extrapyramidal motor symptoms in rats)
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Schizophrenia is a particular kind of psychosis (mental disorder) characterized mainly by a clear sensorium but a marked thinking disturbance. Key symptoms include hallucinations, delusions, and abnormal experiences, such as the perception of 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 Patients lose empathy with others, become withdrawn, and demonstrate inappropriate or blunted mood.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.
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The dopamine (DA) hypothesis for schizophrenia is the basis for rational drug therapy. Several lines of circumstantial evidence suggest that excessive DA-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 psychosis de novo in some patients;
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(3) DA receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs; (4) positron emission tomography (PET) has shown increased DA receptor density in both treated and untreated schizophrenics when compared with such scans of nonschizophrenic persons; (5) successful treatment of schizophrenic patients has been reported to increase the amount of homo- vanillic acid (HVA), a metabolite of DA, in the cerebrospinal fluid, plasma, and urine.
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Neuroleptics – mechanism of action Several important DA-ergic systems or pathways are now recognized in the brain: (1) The first pathway (the one most closely related to 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 substantia nigra to the caudate and putamen; it is involved in the coordination of voluntary movement.
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3) The third pathway (the tuberoinfundibular tract) connects arcuate nuclei and periventricular neurons to the hypothalamus and posterior pituitary. DA released by these neurons physiologically inhibits prolactin secretion.
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Five DA receptors have been described, consisting of 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 adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The second member of this family is D5. It is coded by 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 strongly with their D2-affinity.
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(2) The D2-receptor family includes D2, D3 and D4- receptors. D2-receptors is coded on chromosome 11, decreases cAMP (by inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- 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, is thought to decrease cAMP and is located in the frontal cortex, medulla, and midbrain. The D4-receptor also decreases cAMP.
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Distribution and characteristics of DA receptors in the central nervous system Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)
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The key steps in the synthesis and degradation of DA and the sites of action of various psychoactive substances at the dopaminergic synapse
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It has not been convincingly demonstrated that antagonism of any DA receptors (especially D4) plays a role in the action of “atypical” antipsychotic drugs. Most of the newer “atypical” antipsychotics and some of the traditional ones have significant affinity for the 5-HT2A receptor, suggesting an important role for the serotonin system. Participation of glutamate, GABA, and ACh receptors in the pathophysiology of schizophrenia has also been proposed.
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The effects of DA, 5-HT and NE on the brain functions (NE) (DA) (5-HT) Schizophrenia
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Main effects (1) CNS. In normal individuals antipsychotics produce neuroleptic syndrome – indifference to surroundings, paucity of thought, psychomotor slowing, emotional quietening, reduction in initiative. In psychotic patients neuroleptics reduce irrational behaviour, agitation and aggresiveness. They control psychotic symptomatology. Disturbed thought and behaviour are gradually normalized, anxiety is relieved. Hyperactivity, hallucinations, and delusions are suppressed. The psychosedative effect is produced immediately while the antipsychotic effect takes a week to develop. Tolerance develops only to the psychosedative effect.
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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 this effect. However, they are ineffective in motor sickness. In animal antipsychotic agents produce a state of rigidity and immobility (catalepsy).
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(2) ANS. Neuroleptics have varying degrees of alpha- adrenergic blocking activity and produce hypotension (primarily postural). The hypotensive effect is more marked after parenteral administration. Anticholinergic property of neuroleptics is weak. The phenothiazines have weak H1-antihistaminic and anti-5-HT actions as well. Promethazine has strong sedative, and H1-antihistaminic action. (3) Endocrine system. Neuroleptics consistently increase prolactin release by blocking the inhibitory action of DA on pituitary gland. This may result in galactorrhea and gynecomastia. They reduce gonadotrophins, ACTH, GH and ADH secretion.
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Type 1 (aliphatic side chain) Chlorpromazine, Promazine, Levomepromazine, Promethazine Type 2 (piperidine side chain): Thioridazine Type 3 (piperazine side chain) Trifluoperazine, Prochlorperazine, Fluphenazine I. Typical Neuroleptics (D2-blockers) Phenothiazines
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Thioxanthenes This is a three-ring compound structurally related to phenothiazine but having the nitrogen atom at position 10 replaced by a carbon atom with a double bond. Thioxanthenes have nearly equivalent potency with phenothiazines. Chlorprothixene Flupenthixol Zuclopenthixol R
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Butyrophenones Droperidol Benperidol Haloperidol: The butyrophenones are structurally similar to GABA. They offer greater potency and fewer autonomic side effects.
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II. Atypical Neuroleptics (They block mainly 5-HT2- and D4-receptors) Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Amisulpiride Zotepine Sertindole They cause little extrapyramidal toxicity. The risperidone is representative of many of the newer agents in having a better side effect proﬁle.
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Psychiatric indications of neuroleptics Schizophrenia is the primary indication for neuroleptics. Unfortunately, many patients show little response. Antipsychotics are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproates.
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Whilst a typical antipsychotics should provide adequate treatment of positive symptoms including hallucinations and delusions in at least 60% of cases, patients are often left with unresolved negative symptoms such as apathy, flattening of affect, and alogia. Evidence suggests that clozapine and the newer atypicals have a significant advantage over typical drugs against negative symptoms.
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The manic phase in bipolar affective disorder often requires 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 of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine has been approved for this indication.
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Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines. Other indications for the use of antipsychotics include disturbed behavior in patients with Alzheimer's disease, and, with antidepressants, psychotic depression. Antipsychotics are not indicated for the treatment of various withdrawal syndromes, e.g. opioid withdrawal. In small doses antipsychotics have been promoted (wrongly) for the relief of anxiety associated with minor emotional disorders, but the anxiolytic agents are preferred.
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Nonpsychiatric indications Most older antipsychotics, with the exception of thioridazine, have a strong antiemetic effect. This action is due to D2-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazine are promoted only as antiemetics. Phenothiazines with shorter side chains have consi- derable H1-receptor-blocking action and used for relief of pruritus or, in the case of promethazine, as preoperative sedatives. The butyrophenone droperidol is used in combination with an opioid, fentanyl, in neurolept-anaesthesia (-analgesia).
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Adverse reactions – behavioral effects: The older typical antipsychotic drugs are unpleasant to take. Many patients stop taking these drugs because of the adverse effects, which may be mitigated by giving small doses during the day and the major portion at bedtime. A “pseudodepression” that may be due to drug-induced akinesia usually responds to treatment with antiparkinsonian drugs. Other pseudodepressions may be due to higher doses; the decreasing the dose may relieve the symptoms. Toxic-confusional states may occur with very high doses of drugs that have prominent antimuscarinic actions.
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Neurologic effects: Extrapyramidal reactions occurring early during treatment with older agents include typical Parkinson's syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions (spastic retrocollis or torticollis). Parkinsonism can be treated, with conventional antiparkinsonian drugs of the antimuscarinic type or, in rare cases, with amantadine. Parkinsonism may be self-limiting, so that an attempt to withdraw antiparkinsonian drugs should be made every 3–4 months. Akathisia and dystonic reactions also respond to such treatment, but many prefer to use a sedative antihistamine with anticholinergic properties, e.g. diphenhydramine.
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Tardive dyskinesia - persistent involuntary movements of mouth, tongue or face. Autonomic nervous system effects Antimuscarinic (atropine-like) adverse effects: urinary retention, dry mouth, midriasis. Alpha-blockade: Orthostatic hypotension or impaired ejaculation should be managed by switching to drugs with less marked adrenoceptor-blocking actions.
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Ocular complications Deposits in the anterior portions of the eye (cornea and lens) are a common complication of Chlorpromazine therapy. They may accentuate the normal processes of aging of the lens. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with “browning” of vision. The maximum daily dose of thioridazine has been limited to 800 mg to reduce the possibility of this complication.
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Metabolic and endocrine side effects Weight gain is very common, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates. Hyperglycemia may develop. Hyperprolactinemia in women results in the amenorrhea – galactorrhea syndrome and infertility; in men loss of libido, impotence, and infertility may result. Toxic or allergic reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used.
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Neuroleptic malignant syndrome This life-threatening ADR occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotics. The initial symptom is marked muscle rigidity. If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. The stress leukocytosis and high fever associated with this syndrome suggest an infectious process. Autonomic instability, with altered blood pressure and pulse rate, is often present. Creatine kinase isoenzymes are usually elevated, reflecting muscle damage.
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This syndrome is believed to result from an excessively rapid blockade of postsynaptic DA receptors. A severe form of extrapyramidal syndrome follows. Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonian drugs is worthwhile. Muscle relaxants, particularly diazepam, are often useful. Other muscle relaxants, such as dantrolene, or DA agonists, such as bromocriptine, have been reported to be helpful. If fever is present, cooling by physical measures should be tried.
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ANXIOLYTICS (antianxiety drugs) Benzodiazepines Azapirones (buspirone) Benzoxazines (etifoxine) Sedative H1-blockers (hydroxyzine) Nonselective beta-blockers SSRIs Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Gamma aminobutyric acid (GABA) is probably the most important inhibitory transmitter in the CNS. GABA-ergic neurones are distributed widely 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 balance swings in favour of GABA, then sedation, amnesia, muscle relaxation and ataxia appear and nervous- ness and anxiety are reduced. The mildest reduction of GABA-ergic activity elicits arousal, anxiety, rest- lessness, insomnia and exaggerated reactivity.
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Most drugs used in insomnia act as agonists at the GABAA-receptor and have effects other than their direct sedating action, including muscle relaxation, memory impairment, and ataxia, which can impair performance of skills such as driving. Clearly those drugs with onset and duration of action confined to the night period will be most effective in insomnia and less prone to unwanted effects during the day. Those with longer duration of action are likely to affect psychomotor performance, memory and concentration; they will also have enduring anxiolytic and muscle-relaxing effects.
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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
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When GABA binds with the GABAA-receptor, the permeability of the central pore of the receptor to chloride ions increases (hyperpolarization) and decreasis excitability. Benzodiazepines (BDZs) enhance the effectiveness of GABA by increasing the frequency of the opening of the chloride ions. BDZs are agonists at the receptor and the flumazenil (antagonist) prevents agonists from binding at the receptor site.
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A model of the GABAA receptor-chloride ion channel macromole- cular complex Basic & Clinical Pharmacology – 10th Ed. (2007)
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Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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BDZs enhance GABA-ergic inhibition. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Advantages of BDZs BDZs have a high therapeutic index. In hypnotic doses they do not affect respiration and cardiovascuar functions. Only in i.v. injection the blood pressure may fall. BDZs cause less distortion of sleep architecture. They do not alter disposition of other drugs by microsomal enzyme induction. They have lower abuse liability: tolerance is mild, psycholgical and physical dependence and withdrawal syndrome are less marked. A selectve BDZs antagonist flumazenil (partial agonist of benzodiazepinic receptor) can be used in case of poisoning.
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Chlordiazepoxide Flumazenil
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CNS action and classification of BDZs The action of all BDZs is qualitatively similar, but there are prominent differences in selectivity and time course of effect: different members of BDZs are used for different therapeutic purposes. In contrast to barbiturates BDZs exert relatively selective anxiolytic (antianxiety), hypnotic (euhypnotic), muscle relaxant, and anticonvulsant (antiepileptic) effects. Anxiolytic effect have all BDZs: Alprazolam, Bromazepam (Lexotan – tab. 3 mg), Chlordiazepoxide, Diazepam, Lorazepam, Мedazepam (daily tranquillisant), Nordiazepam, etc.
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Hypnotic (euhypnotic) effect: Bromazepam, Flurazepam, Flunitrazepam Nitrazepam, Midazolam, Triazolam, etc. Anticonvulsive (antiepileptic) BDZs: Clonazepam, Clorazepate, Diazepam, Lorazepam, Nitrazepam Central muscle relaxants: Diazepam, Tetrazepam
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Pharmacokinetics BDZs are effective after administration by mouth but enter the circulation at very different rates 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 produce active metabolites with long t1/2 which greatly extends drug action, e.g. chlordiazepoxide, clorazepate, and diazepam.
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Biotransformation of benzodiazepines Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) Clorazepate
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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.
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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.
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Tolerance to the anxiolytic effects does not seem to be a problem. Studies of subjective sleep quality show enduring efficacy but about half of the objective (EEG) studies indicate decreased effects after 4–8 weeks, implying that some tolerance develops. The necessity for dose escalation in sleep disorders is rare.
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Withdrawal of BDZs should be gradual after as little as 3 weeks’ use but for long-term users it should be very slow, e.g. about 6–12 weeks. With- drawal should be slowed if marked symptoms occur and it may be useful to substitute a long t1/2 drug (e.g. diazepam) to minimize rapid fluctuations in plasma concentrations. In difficult cases withdrawal may be assisted by concomitant use of an antidepressant. Commonly there is a kind of psychological depend- ence based on the fact that the treatment works to reduce patients’ anxiety or sleep disturbance and therefore they are unwilling to stop. If they do stop, there can be relapse, where original symptoms return.
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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 administration occurs with i.v. high doses, for endoscopy, dental surgery (with local anaesthetic), cardioversion, and in these situations it can be regarded as a blessing. Women (1 in 200), may experience sexual fantasies, including sexual assault, after large doses of BDZs as used in some dental surgery, and have brought charges in lawsuits against male staff.
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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 and can cause fetal cardiac arrhythmia and muscular hypotonia, suckling hypothermia and respiratory depression in the newborn.
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Interactions All BDZs potentiate the effects of alcohol and other central depressants, and all are likely to exacerbate breathing difficulties where this is already compromised, e.g. in obstructive sleep apnoea. BDZs potentiate the action of analgetics too. The fluoroquinolones block GABAA-receptors and decrease the action of BDZs. Overdose. Flumazenil (Anexate®) selectively reverses benzodiazepine effects and is useful in diagnosis and in treatment of intoxication with them. Flumazenil is a competitive partial agonist.
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Fluoroquinolones Adapted from Bennett and Brown (2003)
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Azapirones Buspirone is a selective partial agonsist of presynaptic 5-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 (panic reactions and obsessive compulsive disorder). Sedative H1-blockers Hydroxyzine is an H1-blocker with sedative, antiemetic, antimuscarinic, and spasmolytic effects. It is effective in pruritus, and urticaria.
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Etifoxine (Stresam®) produces its anxiolytic effects by binding to β2 and β3 subunits of the GABAA-receptor. It is used in anxiety disorders.
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Nonselective beta-blockers Many symptoms of anxiety (palpitations, rise in blood pressure, shaking, tremor, GI hurrying) are due to sympathetic overactivty and these symptoms reinforce anxiety. Propranolol and other nonselective beta-blockers cut the vicious cycle and provide the symptomatic relief. They do not affect psychologycal symptoms, such as fear, tension and worry, 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 generalized anxiety disorders.
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Treatment of anxiety Anxiety is a universal phenomenon, but if it is frequent and persists in a severe form, it may cause distress and markedly impair performance. The established drugs for treatment of excessive anxiety are BDZs, which must be used in the smallest possible dose. The usual practice is to give ½ to 2/3 of DD 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 are required to avoid high plasma peaks.
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Buspirone is a nonsedating alternative to BDZs for a less severe form of generalized anxiety. The SSRI antidepressants are now being increasingly used in many forms of severe anxiety disorders. They produce a delayed but often gratifying response and combined with BDZs. The SSRIs are now drugs of choice for treatment of social anxiety in which BDZs 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 low doses of BDZs intermittently in addition to specific therapy, though anxiety may not be a prominent manifestation.