06 General CNS depressants

GENERAL CNS DEPRESSANTS: neuroleptics, tranquilizers, sedatives. Lithium preparations

(Aminazinum, Triftazinum, Droperidolum, Haloperidolum, Closapinum, Chlorprotixenum, Sulpiridum, Phtorphenasinum, Chlozepidum, Sibasonum (Diasepanum), Phenazepamum, Medazepamum, Litii carbonas)

ACTIVATING CNS DRUGS: analeptics, antidepressants, metabolic cerebral protectors and adaptogens

(Imisinum, Amitriptillinum, Pyrazidolum, Fluoxetinum, Sydnocarbum Coffeinum-natrii benzoas, Piracetamum, Cavintonum, Pentoxyphylline, Natrii oxybutiras, Cinarisinum, Vinpocetinum, Nicergolin, Pentoxiphyllini, papaverini hydrochloridum, Sermionum, Tinctura Ginseng, Tinctura Schisandrae, Extract Eleuterococci, Pantocrinum, Bemetilum, Cordiaminum, Sulfocamphocainum, Camphora, Bemegridum, Aethymisolum)

 

General CNS depressants: neuroleptics, tranquilizers, sedatives. Lithium preparations

Central nervous system depressants slow down the operation of the brain. They first affect those areas of the brain that control a person’s conscious, voluntary actions. As dosage increases, depressants begin to affect the parts of the brain controlling the body’s automatic, unconscious processes, such as heartbeat and respiration.

Alcohol is the most familiar, and most widely abused depressant. With some exceptions, all depressants affect people in much the same way as does alcohol.

Most depressant users ingest these drugs orally. However, a few abusers will inject their drugs intravenously. The injection paraphernalia used by barbiturate abusers are similar to those used by heroin addicts, although a wider gauge hypodermic needle is used, because the barbiturate solution is thicker than the heroin solution. The injection sites on the skin of a barbiturate abuser exhibit large swellings, and may develop ulceration’s resembling cigarette burns.

The affects of depressants are once again compared to those of alcohol – reduced social inhibitions, impaired ability to divide attention, slow reflexes, impaired judgment and concentration, impaired vision and coordination, slurred, mumbled or incoherent speech, a wide variety of emotional effects, such as euphoria, depression, suicidal tendencies, laughing or crying for no apparent reason, etc.

Depressants vary in the amount of time it takes the user to feel the effects and also the amount of time the effects are felt. Some depressants act very quickly, and begin to affect their user within seconds. Others act more slowly, sometimes taking one-half hour or more to begin to exert an influence. The quick-acting depressants also tend to be relatively short acting: in some cases their effects wear off in a matter of minutes. The slow-acting depressants, on the other hand, tend to produce longer-acting effects.

Overdoses of depressants produce effects that are the same as alcohol overdoses. The person becomes extremely drowsy and passes out. Their heartbeat slows and respiration will become shallow. Their skin may feel cold and clammy, and death may result from respiratory failure

Hypnotic agents. Antiepileptic drugs

During sleep, the brain generates a patterned rhythmic activity that can be monitored by means of the electroencephalogram (EEG). Internal sleep cycles recur 4 to 5 times per night, each cycle being interrupted by a Rapid Eye Movement (REM) sleep phase (A). The REM stage is characterized by EEG activity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of individual muscle groups against a background of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle. Frequent interruption of sleep will, therefore, decrease the REM portion. Shortening of REM sleep (normally approx. 25% of total sleep duration) results in increased irritability and restlessness during the daytime. With undisturbed night rest, REM deficits are compensated by increased REM sleep  on subsequent nights (B).

Hypnotics fall into different categories, including the benzodiazepines (e.g., triazolam, temazepam, clotiazepam, nitrazepam), barbiturates (e.g., hexobarbital, pentobarbital), chloral hydrate,  and H1-antihistamines with sedative activity. Benzodiazepines act at specific receptors. The site and mechanism of action of barbiturates, antihistamines, and chloral hydrate are incompletely understood. All hypnotics shorten the time spent in the REM stages (B).

With repeated ingestion of a hypnotic on several successive days, the proportion of time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which tapers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unrefreshing. Thus, the attempt to discontinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence.

Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects, the former group also being anxiolytic. At higher dosage, both groups promote the onset of sleep or induce it (C).

Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action; cerebral activity is not globally inhibited (respiratory paralysis is virtually impossible) and autonomic functions, such as blood pressure, heart rate, or body temperature, are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates. Zolpidem (an imidazopyridine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, possess agonist activity at the benzodiazepine receptor.

Due to their narrower margin of safety (risk of misuse for suicide) and their potential to produce physical dependence, barbiturates are no longer or only rarely used as hypnotics. Dependence on them has all the characteristics of an addiction. Because of rapidly developing tolerance, choral hydrate is suitable only for short-term use. Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine), in which case their  sedative side effect is used as the principal effect.

 

Sleep–Wake Cycle and Hypnotics

The physiological mechanisms regulating the sleep-wake rhythm are not completely known. There is evidence that histaminergic, cholinergic, glutamatergic, and adrenergic neurons are more active during waking than during the NREM sleep stage. Via their ascending thalamopetal projections, these neurons excite thalamocortical pathways and inhibit GABA-ergic neurons. During sleep, input from the brain stem decreases,  giving rise to diminished thalamocortical activity and disinhibition of the GABA neurons (A).

The shift in balance between excitatory (red) and inhibitory (green) neuron groups underlies a circadian change in sleep propensity, causing it to remain low in the morning, to increase towards early afternoon (midday siesta), then to decline again, and finally to reach its peak before midnight (B1).

Treatment of sleep disturbances. Pharmacotherapeutic measures are indicated only when causal therapy has failed. Causes of insomnia include emotional problems (grief, anxiety, “stress”), physical complaints (cough, pain), or  the ingestion of stimulant substances (caffeine-containing beverages, sympathomimetics, theophylline, or certain  antidepressants). As illustrated for emotional stress (B2), these factors cause an imbalance in favor of excitatory influences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods. Depending on the type of insomnia, benzodiazepines with short or  intermediate duration of action are indicated,e.g., triazolam and brotizolam (t1/2 ~ 4–6 h); lormetazepam or temazepam (t1/2 ~ 10–15 h). These drugs shorten the latency of falling asleep, lengthen total sleep duration, and reduce the frequency of nocturnal awakenings. They act by augmenting inhibitory activity. Even with the longer-acting benzodiazepines, the patient awakes after about 6–8 h of sleep, because in the morning excitatory activity exceeds the sum of physiological and pharmacological inhibition (B3). The drug effect may, however, become unmasked at daytime when other sedating substances (e.g., ethanol)  are ingested and the patient shows an  unusually pronounced response due to a synergistic interaction (impaired ability to concentrate or react). As the margin between excitatory and inhibitory activity decreases with age, there is an increasing tendency towards shortened daytime sleep periods and more frequent interruption of nocturnal sleep (C).

Use of a hypnotic drug should not be extended beyond 4 wk, because tolerance may develop. The risk of a rebound decrease in sleep propensity after drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk. With any hypnotic, the risk of suicidal overdosage cannot be ignored. Since benzodiazepine intoxication may become life-threatening only when other central nervous depressants (ethanol)  are taken simultaneously and can, moreover, be treated with specific benzodiazepine antagonists, the benzodiazepines should be given preference as sleep remedies over the all but obsolete  barbiturates.

  Benzodiazepines

Benzodiazepines modify affective responses to sensory perceptions; specifically, they render a subject indifferent towards anxiogenic stimuli, i.e., anxiolytic action. Furthermore, benzodiazepines exert sedating, anticonvulsant, and muscle-relaxant (myotonolytic) effects. All these actions result from augmenting the activity of inhibitory  neurons and are mediated by specific benzodiazepine receptors that form an integral part of the GABAA receptor- chloride channel complex. The inhibitory transmitter GABA acts to open the membrane chloride channels.

Increased chloride conductance of the neuronal membrane effectively shortcircuits responses to depolarizing inputs. Benzodiazepine receptor agonists increase the affinity of GABA to its receptor. At a given concentration of GABA, binding to the receptors will, therefore, be increased, resulting in an augmented response. Excitability of the neurons is diminished. Therapeutic indications for  benzodiazepines  include anxiety states associated with neurotic, phobic, and depressive disorders, or myocardial infarction (decrease in cardiac stimulation

due to anxiety); insomnia; preanesthetic (preoperative) medication;  epileptic seizures; and hypertonia of skeletal musculature (spasticity, rigidity). Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved; for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics  by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). Since benzodiazepines depress responsivity to external stimuli, automotive driving skills and other tasks requiring precise sensorimotor coordination will be impaired. Triazolam (t1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory (anterograde amnesia) and to cause rebound anxiety or insomnia and daytime confusion. The severity of these and other adverse reactions (e.g., rage, violent hostility, hallucinations), and their increased frequency in the elderly, has led to curtailed or suspended use of triazolam in some countries (UK). Although benzodiazepines are well tolerated, the possibility of personality changes (nonchalance, paradoxical excitement) and the risk of physical dependence with chronic use must not be overlooked. Conceivably, benzodiazepine dependence results from a kind of habituation, the functional counterparts of which become manifest during abstinence as restlessness and anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of benzodiazepines. Benzodiazepine antagonists, such as flumazenil, possess affinity for benzodiazepine receptors, but they lack intrinsic activity. Flumazenil is an effective antidote in the treatment of benzodiazepine overdosage or can be used postoperatively to arouse patients sedated with a benzodiazepine. Whereas benzodiazepines possessing agonist activity indirectly augment chloride permeability, inverse agonists exert an opposite action. These substances give rise to pronounced restlessness, excitement, anxiety, and convulsive seizures. There is, as yet, no therapeutic indication for their use. Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors . The choice between different agents is dictated by their speed, intensity, and duration of  action. These, in turn, reflect physicochemical and pharmacokinetic properties. Individual benzodiazepines remain in the body for very different lengths of time and are chiefly eliminated through biotransformation. Inactivation may entail a single chemical reaction or several steps (e.g., diazepam) before an inactive metabolite suitable for renal elimination is formed. Since the intermediary products may, in part, be pharmacologically active and, in part, be excreted more slowly than the parent substance, metabolites will accumulate with continued regular dosing and contribute significantly to the final effect. Biotransformation begins either at substituents on the diazepine ring (diazepam: N-dealkylation at position 1; midazolam: hydroxylation of the methyl group on the imidazole ring) or at the diazepine ring itself. Hydroxylated midazolam is quickly eliminated following glucuronidation (t1/2 ~ 2 h).

N-demethyldiazepam (nordazepam) is biologically active and undergoes hydroxylation at position 3 on the diazepine ring. The hydroxylated product (oxazepam) again is pharmacologically active. By virtue of their long half-lives, diazepam (t1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t1/2 50–90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via its hydroxyl group (t1/2 = 8 h) and renal excretion (A). The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B).

Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area) because they permit maintenance of steady plasma levels with single daily dosing. Midazolam enjoys use by the i.v. route in preanesthetic medication and anesthetic combination regimens. Benzodiazepine Dependence Prolonged regular use of benzodiazepines can lead to physical dependence. With the long-acting substances marketed initially, this problem was less obvious in comparison with other dependence- producing drugs because of the delayed appearance of withdrawal symptoms. The severity of the abstinence syndrome is inversely related to the elimination t1/2, ranging from mild to moderate (restlessness, irritability,  sensitivity to sound and light, insomnia,and tremulousness) to dramatic (depression, panic, delirium, grand mal seizures). Some of these symptoms pose diagnostic difficulties, being indistinguishable from the ones originally treated. Administration of a benzodiazepine  antagonist would abruptly provoke abstinence signs. There are indications that substances with intermediate elimination  half-lives are most frequently abused (violet area in B).

Tranquilizers

Tranquilizers are depressant drugs that slow down the central nervous system (CNS), and thus are similar to such other CNS depressants as alcohol and barbituates.

The term “major tranquilizer” was formerly applied to drugs used to treat severe mental illnesses, such as schizophrenia. However, these drugs are now more commonly called neuroleptics; their action specifically relieves the symptoms of mental illness, and they are rarely misused for other purposes. This paper therefore deals with the anti-anxiety agents, or anxiolytics (formerly called “minor” tranquilizers).

Anti-anxiety agents share many similiarities with barbituates; both are classified as sedative/hypnotics. These newer agents were introduced under the term “tranquilizer” because, it was claimed, they provided a calming effect without sleepiness. Today, tranquilizers have largely replaced barbiturates in the treatment of both anxiety and insomnia because they are safer and more effective. The degree of sleepiness induced depends on the dosage. Tranquilizers are also used as sedatives before some surgical and medical procedures, and they are sometimes used medically during alcohol withdrawal.

Although tranquilizers do not exhibit the serious dependence characteristics of barbiturates, they nevertheless can produce tolerance and dependence. They may also be misused and abused.

The first drug to be labelled a tranquilizer was meprobamate – under the trade name Miltown – in 1954. Today, however, the most popular anti-anxiety agents are the benzodiazepines (e.g. Valium, Halcion, and Ativan).

The first benzodiazepine developed was chlordiazepoxide, which is sold under such trade names as Librium and Novopoxide. The next was diazepam; it is marketed, among other brand names, as Valium, E-Pam, and Vivol. In the early 1970s diazepam was the most widely prescribed drug in North America.

Now Halcion and Ativan – drugs from the same family as diazepam but eliminated more rapidly from the body – account for most benzodiazepine prescriptions. Some are prescribed as anti-anxiety drugs (e.g. Valium, Librium); others are recommended as sleeping medications (e.g. Dalmane, Somnol, Novoflupam, and Halcion).

Effects

The effects of any drug depend on several factors:

• the amount taken at one time.

• the user’s past drug experience.

• the manner in which the drug is taken.

• the circumstances under which the drug is taken (the place, the user’s psychological and emotional stability, the presence of other people, the simultaneous use of alcohol or other drugs, etc.).

With tranquilizers, a therapeutic dose (i.e. what is medically prescribed) relieves anxiety and may, in some people, induce a loss of inhibition and a feeling of well-being. Responses vary, however. Some people report lethargy, drowsiness, or dizziness. Tranquilizers, though, have very few side effects.

As the dose of a tranquilizer is increased, so is sedation and impairment of mental acuity and physical coordination. Lower doses are recommended for older people or for those with certain chronic diseases, since their bodies tend to metabolize these drugs more slowly.

Studies show that anti-anxiety agents, even at the usually recommended and prescribed doses, may disrupt the user’s ability to perform certain physical, intellectual, and perceptual functions. For these reasons, users should not operate a motor vehicle or engage in tasks calling for concentration and coordination. Such activities are particularly hazardous if tranquilizers are used together with alcohol and/or barbiturates (i.e. other sedative/hypnotics) or antihistamines (in cold, cough, and allergy remedies). These effects occur early in therapy, however, and wane over time with increased tolerance (when more of the drug is needed to produce the same effect).

Because some tranquilizers (such as diazepam) are metabolized quite slowly, residue can accumulate in body tissues with long- term use and can heighten such effects as lethargy and sluggishness.

Toxic Effects

Tranquilizer overdose, particularly with benzodiazepines, has become increasingly common since the 1960s. While these drugs are usually safe even when an overdose is taken (death rarely results from benzodiazepine use alone), they can be fatal in combination with alcohol and other drugs that depress the central nervous system.

In Canada, as elsewhere, tranquilizer-related poisonings and overdoses have kept pace with the drug’s availability. It is a fact that the drugs used in suicide attempts are those most widely prescribed and available. (The majority of these drug-related suicide attempts are by women under 30.)

Tolerance and Dependence

Because tolerance to the mood-altering effects of tranquilizers can develop with regular use, higher daily doses become necessary to maintain the desired effects. Tolerance may occur even at prescribed doses.

Chronic users may become both psychologically and physically dependent on tranquilizers.

Psychological dependence exists when a drug is so central to a person’s thoughts, emotions, and activities that the need to continue its use becomes a craving or compulsion.

With chronic use, especially at higher doses, physical dependence can also occur. The user’s body has adapted to the presence of the drug and suffers withdrawal symptoms when use is stopped. The frequency and severity of the withdrawal syndrome depends on the dose, duration of use, and whether use is stopped abruptly or tapered off. Symptoms range in intensity from progressive anxiety, restlessness, insomnia, and irritability in mild cases to delirium and convulsions in severe cases.

Dependence may also occur following long-term therapeutic use, but withdrawal symptoms in such cases are mild. Patients complain of gastrointestinal problems, loss of appetite, sleep disturbances, sweating, trembling, weakness, anxiety, and changes in perception (e.g. increased sensitivity to light, sound, and smells).

Risk of dependency increases if tranquilizers are taken regularly for more than a few months, although problems have been reported within shorter periods. The onset and severity of withdrawal differ between the benzodiazepines that are rapidly eliminated from the body (e.g. Halcion) and those that are slowly eliminated (e.g. Valium). In the former case, symptoms appear within a few hours after stopping the drug and may be more severe. In the latter case, symptoms usually take a few days to appear.

Tranquilizers and Pregnancy

If a woman uses tranquilizers regularly, the drug can affect the baby for up to 10 days after birth. Babies may exhibit the withdrawal symptoms common to such other depressant drugs as alcohol and barbituates. These symptoms include feeding difficulties, disturbed sleep, sweating, irritability, and fever. Symptoms will be more severe if the doses the mother took are higher.

Administration of diazepam during labor has been linked to decreased responsiveness and respiratory problems in some newborns.

Therapy of Schizophrenia

Schizophrenia is an endogenous psychosis of episodic character. Its chief symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical thinking; impoverished intellectual content; blockage of ideation; abrupt breaking of a train of thought: claims of being subject to outside agencies that control the patient’s thoughts), and a disturbance of affect (mood inappropriate to the situation) and of psychomotor drive. In addition, patients exhibit delusional paranoia (persecution mania) or hallucinations (fearfulness hearing of voices). Contrasting these “positive”  symptoms, the so-called “negative” symptoms, viz., poverty of thought, social withdrawal, and anhedonia, assume added importance in determining the severity of the disease. The disruption and incoherence of ideation is symbolically represented at the top left (A) and the normal psychic state is illustrated.

The term antipsychotic is applied to a group of drugs used to treat psychosis. Common conditions with which antipsychotics might be used include schizophrenia, mania and delusional disorder, although antipsychotics might be used to counter psychosis associated with a wide range of other diagnoses. Antipsychotics also have some effects as mood stabilizers, leading to their frequent use in treating mood disorder (particularly bipolar disorder) even wheo signs of psychosis are present. Some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette syndrome.

Antipsychotics are also referred to as neuroleptic drugs, or simply neuroleptics. The word neuroleptic is derived from Greek; neuro refers to the nerves and lept means “to take hold of”. Thus the word means “taking hold of one’s nerves”, which implies their role in mood stabilization.

There are currently two main types of antipsychotics in use, the typical antipsychotics and atypical antipsychotics. A new class of antipsychotic drugs has recently been discovered, known as dopamine partial agonists. Clinical development has progressed rapidly on partial dopamine agonists, and one drug in this class (aripiprazole) has already been approved by the Food and Drug Administration. Although the underlying mechanism of this new class is different from all previous typical and atypical antipsychotics, dopamine partial agonists are often categorized as atypicals.

Typical antipsychotics are sometimes referred to as major tranquilizers, because some of them can tranquilize and sedate. This term is increasingly disused because many newer antipsychotics do not have strong sedating properties and the terminology implies a connection with benzodiazepines wheone exists.

 Neuroleptics After administration of a neuroleptic, there is at first only psychomotor dampening. Tormenting paranoid ideas and hallucinations lose their subjective importance  dimming of flashy colors); however, the psychotic processes still persist. In the course of weeks, psychicprocesses gradually normalize; the psychotic episode wanes, although complete normalization often cannot be achieved because of the persistence of negative symptoms. Nonetheless, these changes are significant because the patient experiences relief from the torment of psychotic personality changes; care of the atient is made easier and return to a familiar community environment is accelerated.

The range of interactions can produce different adverse effects including extrapyramidal reactions, including acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, and hyperprolactinaemia.

The atypical antipsychotics (especially olanzapine) seem to cause weight gain more commonly than the typical antipsychotics. The well documented metabolic side effects associated with weight gain include diabetes that, not infrequently, can be life threatening.

Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is io danger.

One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements often of the lips, face, legs or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder. It is believed by some that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benztropine, though this has not been established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

A potentially serious side effect of many antipsychotics is that they tend to lower an individuals seizure threshold. Chlorpromazine and clozapine particularly, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions (such as epilepsy, or brain damage).

Another serious side effect is neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency as the patient’s temperature suddenly increases to dangerous levels.

Another problematic side effect of antipsychotics is dysphoria, meaning that it just makes the patient feel bad. This side-effect is a major problem for patients with schizophrenia in that it causes them to discontinue medication, and this produces a relapse of psychotic symptoms.

Whilst this may seem a daunting list, it must be noted that some people suffer few of the obvious side effects from taking antipsychotic medication. Some side effects, such as subtle cognitive problems, may go unnoticed.

Other symptoms of akinesia of antipsychotics include deterioration of teeth due to a lack of saliva. The link between such symptoms and the use of antipsychotics is often overlooked.

While the atypical, second-generation medications were marketed as offering greater efficacy in reducing psychotic symptoms while reducting side effects (and extra-pyramidal symptoms in particular) than typical medications, these results showing these effects often lack robustness. To remediate this problem, the NIMH conducted a recent multi-site, double-blind, study (the CATIE project), which was published in 2005. A phase 2 part of this study roughly replicated these findings.

The conventional (or classical) neuroleptics comprise two classes of compounds with  distinctive chemical structures: 1. the phenothiazines derived  from the antihistamine promethazine(prototype: chlorpromazine), including their analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype: haloperidol). According to the chemical structure of the side chain, phenothiazines and thioxanthenes can be subdivided into aliphatic (chlorpromazine, triflupromazine,  and piperazine congeners (trifluperazine, fluphenazine, flupentixol). The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at – muscarinic acetylcholine receptors _ atropine-like effects; – б-adrenoceptors for norepinephrine _ disturbances of blood pressure regulation; – dopamine receptors in the nigrostriatal system _ extrapyramidal motordisturbances; in the area postrema _ antiemetic action, and in the pituitary gland _increased secretion of prolactin; – histamine receptors in the cerebral  cortex _ possible cause of sedation. These ancillary effects are also elicited in healthy subjects and vary in intensity among individual substances. Other indications. Acutely, there is sedation with anxiolysis after neuroleptization has been started. This effect can be utilized for: “psychosomatic uncoupling” in disorders with a prominent psychogenic component; neuroleptanalgesia by means of the butyrophenone droperidol in combination with an opioid; tranquilization of overexcited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania. It should be pointed out that neuroleptics do not exert an anticonvulsant action, on the contrary, they may  lower seizure thershold.

Because they inhibit the thermoregulatory center, neuroleptics can be employed for controlled hypothermia.

Adverse Effects. Clinically most important and therapy-limiting are extrapyramidal disturbances; these result from dopamine receptor blockade. Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinsonian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkinson drugs of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neuroleptization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics.  Chronic use of neuroleptics can, on occasion, give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of intensive countermeasures (including treatment with dantrolene).

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include: antipsychotic efficacy (symbolized by the arrow); the extent of sedation; and the ability to induce extrapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively. Thus, the butyrophenones carry an increased risk of adverse motor reactions because they lack anticholinergic activity and, hence, are prone to upset the balance between striatal cholinergic and dopaminergic activity.

Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphenazine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflupromazine). However, their antipsychotic effects are qualitatively indistinguishable. As structural analogues of the phenothiazines, thioxanthenes (e.g., chlorprothixene, flupentixol) possess a central nucleus in which the N atom is replaced by a carbon linked via a double bond to the side chain. Unlike the phenothiazines, they display an added thymoleptic activity. Clozapine is the prototype of the so-called atypical neuroleptics, a group that combines a relative lack of extrapyramidal adverse effects with superior efficacy in alleviating negative symptoms. Newer members of this class include risperidone, olanzapine, and sertindole. Two distinguishing features of these atypical agents are a higher affinity for 5-HT2 (or 5-HT6) receptors than for dopamine D2 receptors and relative selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons. Clozapine also exhibits high affinity for dopamine receptors of the D4 subtype, in addition to H1 histamine and muscarinic acetylcholine receptors. Clozapine may cause dose–dependent seizures and agranulocytosis, necessitating close hematological monitoring. It is strongly sedating. When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations.

Lithium ions

Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

Activating CNS drugs: analeptics, antidepressants, metabolic cerebral protectors and adaptogens

The central nervous system (CNS) represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. The CNS is contained within the dorsal cavity, with the brain within the cranial subcavity, and the spinal cord in the spinal cavity.

Since the strong theoretical influence of cybernetics in the fifties, the CNS is conceived as a system devoted to information processing, where an appropriate motor output is computed as a response to a sensory input. Yet, many threads of research suggest that motor activity exists well before the maturation of the sensory systems and then, that the senses only influence behavior without dictating it. This has brought the conception of the CNS as an autonomous system.
See main article on Brain Function

In the developing fetus, the CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral/cephalic). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon.See main article on Neural development

The CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon give rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles.

See main article on Neuroanatomy

The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

 Therapy of Manic-Depressive Illness

Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition. Patients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disorder, mood swings may alternate between the two directions (bipolar depression, cyclothymia) or occur in only one direction (unipolar depression)

I. Endogenous Depression

In this condition, the patient experiences profound misery (beyond the observer’s empathy) and feelings of severe guilt because of imaginary misconduct. The drive to act or move is inhibited. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpitations, loss of libido, impotence, etc.). Although the patient may have suicidal thoughts, psychomotor retardation prevents suicidal impulses from being carried out. In A, endogenous depression is illustrated by the layers of somber colors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups:

_ Thymoleptics, possessing a pronounced ability to re-elevate depressed mood e.g., the tricyclic antidepressants;

_ Thymeretics, having a predominant  activating effect on psychomotor drive, e g., monoamine oxidase inhibitors.

It would be wrong to administer  drive-enhancing drugs, such as amphetamines,to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomotor inhibition (A), the danger of suicide increases.

History: Imipramine is considered the prototype tricyclic antidepressant. The tricyclic antidepressants are chemically derived from a three-ring aromatic nucleus that has three forms: dibenzazepine (imipramine), dibenzocycloheptene (amitriptyline), or dibenzoxepin (doxepin).

 

 

Imipramine was first synthesized in the late 1940s and was approved for use for depression in 1959 and for enuresis in 1973. Recently, clomipramine was introduced, but it is indicated for treatment of obsessive-compulsive disorder, not depression. Since the introduction of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (see Heterocyclic Antidepressants Overview), the use of tricyclic antidepressants has decreased. The SSRIs have a more well-tolerated adverse effect profile than the tricyclic type antidepressants in depression and obsessive-compulsive disorder. Fluoxetine, and presumably other serotonin-specific agents, appear to be inferior, however, to desipramine and other norepinephrine-active drugs in the treatment of diabetic neuropathy.

Tricyclic antidepressants (TCA; prototype: imipramine) have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibitors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics. The side chaiitrogen is predominantly protonated at physiological pH. The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine  and serotonin is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, б-adrenoceptors, and certain 5-HT and histamine (H1) receptors are blocked. Interference  with the dopamine system is relatively minor. How interference with these transmitter/ modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and в-adrenoceptors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria). Apart from the antidepressant effect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differentiated clinical use, based upon the divergent patterns of interference with amine transmitters/modulators.

Mechanism of action antidepressants

The precise mechanism of action of tricyclic antidepressants is not fully understood. It is believed that these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. This results in a potentiation of the neurotransmitter at the post-synaptic receptor. Imipramine, a tertiary amine, inhibits the reuptake of serotonin more than do secondary amines, which inhibit primarily norepinephrine. Because imipramine is metabolized to a secondary amine (desipramine), however, classification of tricyclic antidepressants according to type of neurotransmitter affected is problematic.

The mechanism of action of tricyclic antidepressants (adverse effects)

Mood elevation secondary to antidepressant therapy occurs only in depressed individuals and may require 2-3 weeks of therapy. Adverse effects, however, can be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory because blockade of neurotransmitter reuptake occurs much more rapidly than the clinical antidepressant effect. Improvement in the depressive state might result from the correction of an abnormal neurotransmitter-receptor relationship.

Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated.

Effect of Amitriptyline

In contrast, desipramine produces psychomotor activation. Imipramine occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipramine). Likewise, the desmethyl derivative of amitriptyline (nortriptyline) is less dampening. Iondepressive patients whose complaints are of predominantly psychogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic uncoupling.” In this connection, clinical use as “co-analgesics”  may be noted. The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances.

The serotonin pathways in panic disorder

These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropinelike effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. Changes in adrenergic function are complex. Inhibition of neuronal catecholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of б1-receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasynaptic concentrations of norepinephrine by blocking presynaptic б2-receptors, rather than reuptake.

Distinguishing Features: The tricyclic antidepressants can be differentiated by several features. The most important clinical distinction is based on the number of ligands bonded to the nitrogen on the “tail” attached to the tricyclic ring system: tertiary or secondary amines. The tertiary-amine tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) tend to be more sedating and have greater anticholinergic effects. The secondary amines (desipramine and nortriptyline) are metabolites of the tertiary amines (imipramine and amitriptyline, respectively). The secondary-amine tricyclic antidepressants are generally better tolerated.

Besides major depression, the tricyclic antidepressants are useful in a number of other clinical conditions. Imipramine has been used for childhood enuresis, amitriptyline has been successful for short-term treatment of fibromyalgia, and protriptyline has been used as a respiratory stimulant in patients with chronic obstructive pulmonary disease. Amitriptyline, desipramine, doxepin and presumably other tricyclic antidepressants with activity oorepinephrine are effective agents for diabetic neuropathy. Tricyclic antidepressants have also been used in the management of neurogenic pain, attention-deficit hyperactivity disorder (ADHD) in children over age 6 (usually only after therapy with methylphenidate and pemoline fail), eating disorders, and panic or phobic disorder, although these are not FDA-approved uses.

The tricyclic antidepressants can also be differentiated based on the dosing and plasma concentration range: amitriptyline (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 60-200 ng/mL); clomipramine (starting dose 25 mg TID, dosage range 50-300 mg/day); desipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 125-250 ng/mL); doxepin (starting dose 25 mg TID, dosage range 75-300 mg/day, therapeutic Cp range 110-250 ng/mL); imipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range >180 ng/mL); nortriptyline (starting dose 25 mg TID, dosage range 50-200 mg/day, therapeutic Cp range 50-150 ng/mL); protriptyline (starting dose 5 mg TID, dosage range 15-60 mg/day, therapeutic Cp range 100-200 ng/mL); and trimipramine (starting dose 25 mg TID, dosage range 15-90 mg/day). Of all the tricyclic antidepressants, nortriptyline has the most well-studied relationship between response and plasma concentration. Tricyclic antidepressant plasma concentrations are always measured 12 hours after the evening dose and before any morning dose. If the drug has active metabolites, they are measured as well and added together.

Adverse Reactions: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants because they exert a direct quinidine-like action, possess strong anticholinergic activity, and potentiate norepinephrine. Drowsiness is the most frequent central nervous system (CNS) adverse effect. The adverse effect of sedation may be used therapeutically by administering the tricyclic antidepressant at bedtime. Tremors can result from norepinephrine-reuptake blockade. Seizures and alterations in EEG patterns have been observed more commonly in children than in adults.

Ocular manifestations of the high anticholinergic activity of the tricyclic antidepressants can result in blurred vision due to loss of accommodation, mydriasis, and increased intraocular pressure. Increased intraocular pressure can precipitate a crisis in patients with angle-closure glaucoma. Gastrointestinal manifestations of these drugs’ high anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, paralytic ileus, abdominal cramps, nausea, vomiting, anorexia, diarrhea, and jaundice.

The effects of tricyclics on the endocrine system can cause sexual dysfunction including libido changes, impotence, testicular swelling, painful ejaculation, breast engorgement and galactorrhea in females, and gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.

Photosensitivity, rash, erythema, urticaria, fever, and pruritus are generally indicative of allergic reactions.

Heterocyclic antidepressants

History: The heterocyclic antidepressants are a chemically and pharmacologically diverse group of drugs. Many of the antidepressants in this category (e.g., amoxapine, maprotiline, and trazodone) are now considered third or fourth line agents. At this time, the most important subgroup of the heterocyclic antidepressants are the serotonin specific reuptake inhibitors (SSRIs) which have revolutionized the treatment of depression. Fluoxetine, released in 1987, is the prototype of the SSRIs. Fluoxetine has been used in the treatment of major depression, alcohol dependence, anorexia nervosa, borderline personality disorder, bulemia nervosa, eating disorders, obesity, obsessive-compulsive disorder, and panic disorder. Since then, sertraline (1991), paroxetine (1992), and fluvoxamine (1994) have been approved for use.

Mechanism of Action: The precise mechanism of action of antidepressants is not fully understood. It is thought these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. The SSRIs are very specific in their ability to inhibit the reuptake of serotonin resulting in potentiation of the neurotransmitter at the post-synaptic receptor.

Mood-elevation occurs only in depressed individuals and may require 2-3 weeksof therapy. Adverse effects, however, may be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory, since blockade of neurotransmitter reuptake occurs much more rapidly the a clinical antidepressant action. Improvement in the depressive state may result from the correction of an abnormal neurotransmitter-receptor relationship.

 Distinguishing Features: All of the antidepressants have clinically indistinguishable efficacy, with the possible exception of trazodone. Trazodone may have significantly lower efficacy than other antidepressants, based on meta-analysis of double blind clinical trials.

The most important clinical distinction of the SSRIs from all other antidepressants is their very high specificity for blocking the reuptake of serotonin compared to their

effects on other knoweurotransmitters such as norepinephrine, acetylcholine, histamine, or dopamine. Fluoxetine has the longest half-life of all the SSRIs. Half-life values for paroxetine, sertraline, and newly-released fluvoxamine range 15-26 hours in patients without hepatic disease. None of these 3 antidepressants have active metabolites. Fluoxetine has an elimination T1/2 of 2-3 days and an active metabolite with an elimination T1/2 of 7-9 days.

Adverse Reactions: Nausea, vomiting, diarrhea, dyspepsia, and anorexia are the most commonly experienced adverse reactions. Nausea usually subsides after a few weeks therapy, but occasionally is severe enough to necessitate discontinuation of the drug, and occurs more frequently with SSRIs than with tricyclic antidepressant drugs or the other heterocyclic antidepressants. Fluvoxamine has been associated with a higher incidence of nausea (37%) than the other SSRI antidepressants, but this may have been due, in part, to excessively high initial dosages. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common and may require medical attention if severe. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine treated patients, mostly at higher doses. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.

CNS side effects occur in a number of patients and include, anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Among the SSRI antidepressants, fluvoxamine and paroxetine are more sedating while fluoxetine and sertraline are more excitatory. Headache is a commonly reported ADR. All effective antidepressants can cause a switch from depression to mania in predisposed individuals. Overdose or a pre-existing seizure disorder may cause a drug-induced seizure, particularly with bupropion. Extrapyramidal symptoms (dystonia, torticollis, and akathisia) have occurred in some patients, particularly with amoxapine. The possibility of tardive dyskinesia from amoxapine, limits its use to patients with psychotic depression. All antidepressants should be used with caution because of the possibility of suicidal ideation. Despite the widespread attention that fluoxetine has received, there is no evidence that one antidepressant has a higher potential for inducing patients to attempt suicide.

Hypoglycemia has been observed rarely in patients treated with SSRIs. Hyperglycemia has been observed following discontinuation of SSRIs. . Patients experience visual disturbance, including blurred vision in ~3% of cases. Sexual dysfunction (including delayed ejaculation or impotence in men, anorgasmia in women) have been reported in a significant number of patients, most commonly when sertraline is used. Rash and other dermatologic reactions can occur with any drug, however, this is most common with maprotiline.

Pruritus and rash occur during the first few weeks of therapy in a small number of patients receiving heterocyclic antidepressants.

Overdoses of amoxapine are characterized by severe neurotoxicity, with seizures that are difficult to control. Overdoses of maprotiline also have a tendency to cause seizures as well as cardiotoxicity.

Overdoses of the other heterocyclic drugs appear to create only minor problems and can usually be managed with purely supportive measures. For example, in one recorded case even 11 g of nefazodone failed to cause serious injury.

Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include: overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function.

Moclobemide is a new representative of the group of MAO inhibitors. Inhibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels.

A psychomotor stimulant thymeretic action is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irreversible inhibition of the two isozymes MAOA and MAOB.

Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, which are ingested in food (e.g., aged cheese and Chianti), will be impaired.

To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonselective MAO inhibitors calls for stringent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAOA and does so in a reversible manner.

Mania

The manic phase is characterized by exaggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggressive color tones. The patients are overconfident, continuously active, show  progressive incoherence of thought and loosening of associations, and act irresponsibly (financially, sexually etc.).

Lithium ions

Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

Alternate treatments. Mood-stabilization and control of manic or hypomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively.

 III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the recurrence of either manic or depressive states, effectively stabilizing mood at a

normal level.

Amitriptyline

How does it work?

Amitriptyline is a type of medicine called a tricyclic antidepressant (TCA). This type of medicine acts oerve cells in the brain.

In the brain there are numerous different chemical compounds called neurotransmitters. These act as chemical messengers between the nerve cells. Serotonin and noradrenaline are neurotransmitters and they have various functions that we know of.

When serotonin and noradrenaline are released from nerve cells in the brain they act to lighten mood. When they are reabsorbed into the nerve cells, they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and noradrenaline released from nerve cells in the brain.

Amitriptyline works by preventing serotonin and noradrenaline from being reabsorbed back into the nerve cells in the brain. This helps prolong the mood lightening effect of any released noradrenaline and serotonin. In this way, amitriptyline helps relieve depression.

Amitriptyline can cause side effects such as drowsiness. This means it may be useful in treating depression in people who are also anxious and agitated, or who are suffering from disturbances in sleep.

It may take between two to four weeks for the benefits of this medicine to appear, so it is very important that you keep taking it, even if it doesn’t seem to make much difference at first. If you feel your depression has got worse, or if you have any distressing thoughts or feelings in these first few weeks, then you should talk to your doctor.

Amitriptyline is also occasionally used for a completely different purpose – for the treatment of bedwetting in children. It works in this situation by blocking receptors called cholinergic or muscarinic receptors that are found on the surface of muscle cells in the wall of the bladder. This prevents a chemical called acetylcholine from acting on these receptors. Acetylcholine acting on these receptors normally causes the muscle in the bladder wall to contract, and the bladder to empty. By reducing this, amitriptyline helps the muscle in the bladder wall to relax. This reduces unstable, involuntary contractions of the bladder, and thereby increases the capacity of the bladder to hold urine. This in turn reduces the need to pass urine. When used for this purpose, amitriptyline should generally only be used for a maximum of three months, unless a full physical examination is given and the child is fully re-assessed.

What is it used for?

• Depressive illness.

• Bedwetting (nocturnal enuresis) in children aged six years and over.

• Nerve pain (unlicensed use).

• Preventing migraine (unlicensed use).

Warning!

• Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide. You should be aware that this medicine may not start to make you feel better for at least two to four weeks. However, it is important that you keep taking it in order for it to work properly and for you to feel better. If you feel your depression has got worse, or if you have any distressing thoughts or feelings, particularly about suicide or harming yourself in these first few weeks, or indeed at any point during treatment or after stopping treatment, then it is very important to talk to your doctor.

• This medicine may cause drowsiness and could reduce your ability to drive or operate machinery safely. Do not drive or operate machinery until you know how this medicine affects you and you are sure it won’t affect your performance.

• It is recommended that you avoid drinking alcohol while taking this medicine because it may enhance drowsiness.

• This medicine can occasionally cause your blood pressure to drop when you move from a lying down or sitting position to sitting or standing, especially when you first start taking the medicine. This may make you feel dizzy or unsteady. To avoid this try getting up slowly. If you do feel dizzy, sit or lie down until the symptoms pass.

• Antidepressants may cause the amount of sodium in the blood to drop – a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching or convulsions. Elderly people may be particularly susceptible to this effect. You should consult your doctor if you develop any of these symptoms while taking this medicine so that your blood sodium level can be checked if necessary.

• This medicine can cause a dry mouth, which may increase the risk of tooth decay with long-term use of the medicine. It is therefore important to visit your dentist regularly for check-ups.

• You should not suddenly stop taking this medicine, as this can cause withdrawal symptoms such as nausea, vomiting, loss of appetite, headache, giddiness, chills, insomnia, restlessness or anxiety. Withdrawal symptoms are temporary and are not due to addiction or dependence on the medicine. They can usually be avoided by stopping the medicine gradually, usually over a period of weeks or months, depending on your individual situation. Follow the instructions given by your doctor when it is time to stop treatment with this medicine.

• During long-term treatment with this medicine your doctor may want to monitor your heart and liver function and take blood tests to monitor the levels of blood cells in your blood. You should let your doctor know if you experience symptoms such as a fever or sore throat while you are taking this medicine.

• Changes in behaviour have been seen in children taking this medicine to treat bedwetting. For further information talk to your doctor or pharmacist.

Use with caution in

• Children.

• Young adults.

• Elderly people.

• Decreased liver function.

• Heart disease.

• History of difficulty passing urine (urinary retention).

• Enlarged prostate gland (prostatic hypertrophy).

• History of increased pressure within the eye, eg glaucoma.

• History of epilepsy.

• People at risk of seizures (fits), eg due to alcohol/drug withdrawal, brain damage, other medicines.

• Overactive thyroid gland (hyperthyroidism).

• People taking thyroid medication for an underactive thyroid gland (hypothyroidism).

• Tumour of the adrenal gland (phaeochromocytoma).

• Psychotic illness, eg schizophrenia.

• Bipolar affective disorder (manic depression).

• People receiving electroconvulsive therapy (ECT).

• People with a history of suicidal behaviour or thoughts.

Not to be used in

• Severe liver disease.

• People who have recently had a heart attack.

• Defect of the heart’s electrical message pathways resulting in decreased function of the heart (heart block).

• Irregular heart beats (arrhythmias).

• Closed angle glaucoma.

• Manic phase of manic depression.

• People who have taken a monoamine oxidase inhibitor antidepressant (MAOI) in the last two weeks.

• Hereditary blood disorders called porphyrias.

• This medicine is not recommended for treating depression in children under 16 years of age, or for treating bedwetting in children under six years of age.

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and breastfeeding

Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

• The safety of this medicine for use during pregnancy has not been established. It is not recommended for pregnant women, particularly in the first and third trimesters, unless considered essential by your doctor and the benefits to the mother outweigh the potential risks to the unborn baby. Seek medical advice from your doctor.

• This medicine passes into breast milk. It should be used with caution in mothers who are breastfeeding, and only if the potential benefits outweigh any risks to the nursing infant. Seek medical advice from your doctor.

Label warnings

• This medication may cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.

• Dry mouth.

• Drowsiness.

• Blurred vision.

• Constipation.

• Nausea.

• Difficulty in passing urine.

• Drop in blood pressure when moving from a lying or sitting position to sitting or standing, causing dizziness and lightheadedness (postural hypotension).

• Sweating.

• Involuntary muscle movements such as tremors or twitching.

• Rashes.

• Confusion or delirium.

• Headache.

• Sexual problems.

• Changes in behaviour.

• Increased appetite and weight gain.

• Taste disturbances.

• Low blood pressure (hypotension).

• Disturbances in the normal numbers of blood cells in the blood.

• Abnormal heart beats.

• Faster thaormal heart beat (tachycardia).

• Convulsions (fits).

The side effects listed above may not include all of the side effects reported by the drug’s manufacturer For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

How can this medicine affect other medicines?

It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to ensure that the combination is safe.

Amitriptyline should not be taken in combination with a monoamine oxidase inhibitor antidepressant (MAOI), eg phenelzine, tranylcypromine, isocarboxazid, or moclobemide. Treatment with amitriptyline should not be started until at least two weeks after stopping an MAOI. Conversely, an MAOI should not be started until two weeks after stopping amitriptyline. Moclobemide should not be started until at least a week after stopping amitriptyline.

If amitriptyline is taken with other medicines that enhance serotonin activity in the brain, there may be an increased risk of side effects such as agitation, tremor, shivering, increased heart rate and diarrhoea, known collectively as the ‘serotonin syndrome’. Other medicines that increase serotonin activity include the following:

• lithium

• rasagiline

• selegiline

• sibutramine

• SSRI antidepressants, eg fluoxetine, paroxetine

• SNRI antidepressants, eg duloxetine, venlafaxine

• other tricyclic antidepressants.

There may be an increased risk of drowsiness if other medicines that can cause drowsiness, such as the following, are taken in combination with amitriptyline:

• sedating antihistamines, eg chlorphenamine, promethazine

• benzodiazepines, eg diazepam, temazepam

• sleeping tablets, eg zopiclone

• strong opioid painkillers, such as morphine, codeine.

There may be an increased risk of side effects such as dry mouth, constipation, difficulty passing urine and blurred vision if amitriptyline is taken with other medicines that have anticholinergic effects, such as the following:

• anticholinergics for urinary incontinence, eg tolterodine, oxybutynin

• anticholinergics for Parkinson’s disease, eg procyclidine, trihexyphenidyl

• antihistamines, eg promethazine, chlorphenamine

• antispasmodics, eg hyoscine, atropine

• antipsychotics, eg chlorpromazine, clozapine (some antipsychotics may also increase the blood level of amitriptyline)

• antiarrhythmics, eg disopyramide, propafenone

• certain other antidepressants

• muscle relaxants, eg baclofen

• antisickness medicines, eg meclozine, cyclizine.

There may be an increased risk of side effects on the heart if amitriptyline is taken in combination with the following medicines; these medicines should be avoided in people taking amitriptyline:

• atomoxetine

• medicines to treat abnormal heart rhythms (antiarrhythmics), eg amiodarone, procainamide, quinidine, disopyramide, sotalol

• the antihistamines astemizole, terfenadine or mizolastine

• the antimalarials halofantrine, chloroquine or quinine

• certain antipsychotics, eg thioridazine, haloperidol, pimozide

• moxifloxacin

• pentamidine.

Amitriptyline may alter the anti-blood-clotting effect of anticoagulant medicines such as warfarin. Your blood clotting time (INR) should be carefully monitored if you are taking these two medicines together.

Amitriptyline may oppose the blood pressure lowering effects of clonidine and guanethidine.

There may be a sudden and marked increase in blood pressure and heart rate if adrenaline, noradrenaline or phenylephrine are given by injection to people taking amitriptyline. These medicines should be avoided in people taking amitriptyline.

The following medicines may increase the blood level of amitriptyline and could increase the risk of its side effects:

• calcium channel blockers such as diltiazem or verapamil

• cimetidine

• methylphenidate

• oestrogen-containing contraceptives (these may also decrease the antidepressant effect of amitriptyline)

• ritonavir

• SSRI antidepressants such as fluvoxamine and fluoxetine.

The level of amitriptyline in the blood may be decreased by the following medicines, and these could make it less effective:

• barbiturates such as phenobarbital

• rifampicin

• the herbal remedy St John’s wort (Hypericum perforatum).

If you experience a dry mouth as a side effect of this medicine you may find that medicines that are designed to dissolve and be absorbed from under the tongue, eg sublingual glyceryl trinitrate (GTN) tablets for angina, become less effective. This is because the tablets do not dissolve properly in a dry mouth. To resolve this, drink a mouthful of water before taking sublingual tablets.

Sibazon (sibazonum)

SIBAZON (Sibazonum). 7-Chloro-2, 3-digidro-1- metil-5- phenyl-1 H-1, 4-benzodiazepin-2- it.

      Synonyms: Apaurin, Bensedin, Diazepam, Relanium, Seduksen, Ansiolin, Apaurin, Apozepam, Atilen, Bensedin, Diapam, Diazepam, Eridan, Lembrol, Pacitrian, Quetinil, Relanium, Saromet, Seduxen, Serenamin, Serensin, Sonacon, Stesolin, Ushamir, Valitran, Valium, Vatran, Vival, etc.

      White or white with a yellowish sheen weak melkokristallichesky powder. Almost nerastvorim in water, soluble in alcohol difficult.

      Sibazon (diazepam) is a major benzodiazapine tranquilizers, widely used in medical practice.

      The drug has a sedative effect, removes the emotional stress, reduce anxiety, fear, anxiety. Has miorelaksantny and protivosudorozhny effect. To enhance hypnotics, narcotics, neyrolepticheskih, analgeticheskih drugs, alcohol.

      The drug and its major metabolites derived mainly from urine.

      Sibazon appointed in various diseases neuro-psychiatric: nervousness, Psychopathy as well as TV and psihopatopodobnyh state with schizophrenia, organic brain damage, including cerebrovascular diseases, with somatic disease, accompanied by signs of emotional stress, anxiety, fear, increased irritability, senestoipohondricheskimi, obsessions and anxiety disorders, and sleep disorders. Used also for edema psychomotor stimulation and disturbing azhitatsii with these diseases.

      In child mental practice sibazon appointed to neurotic and client states, along with the above-mentioned phenomena, as well as headaches, minor, mood and behavior disorders.

      Sibazon used in the treatment of epilepsy for epileptic convulsions, mental equivalents for edema epileptic status. In connection with miorelaksiruyuschim of drug use when different spastic state.

      In combination with other drugs to treat designate sibazon abstinence syndrome in alcoholism.

      In practice anaesthetics used for the preparation of pre patients.

      In DERMA practice in zudyaschih Medicine.

      The drug reduces the secretion of gastric juice night, which may play an important role in his appointment as a means of calming and sleeping pills to patients with stomach ulcers; Also antiaritmicheskoe effect.

      Applied sibazon inside, intravenously or intramuscularly.

      When administered to designate drug adults from the dose-0, 0025 0.005 g (2, 5, 5 mg), 1 to 2 times a day and then gradually increase it. Usually single dose for adults is 0,005 – 0,01 g (5 – 10 mg). In some instances (the increased anxiety, fear, anxiety), a single dose can be increased to 0.02 g (20 mg). When treating a patient and careful clinical observation of daily intake of up to 0,045 g (45 mg). If outpatient treatment is not advisable to appoint more than 0,025 g (25 mg) a day.

      The maximum daily doses of 0.06 g (60 mg). Daily dose treatment given in 2 – 3 admission.

      Weakened and the elderly to take medication in small doses (0.0025 g = 1 / 2 g 2 – 1 pill twice a day).

      In sleep disorders adults appoint one-two tablets at night.

      Children sibazon appointed interior in the following single dose: aged 1 to 3 years – 0,001 grams (1 mg), from 3 to 7 years – 0,002 grams (2 mg), 7 years and older-0003 – 0, 005 grams (3 to 5 mg). DSA doses up to 0,002 g (2 mg), 0,006 g (6 mg) and 0,008 – 0,01 g (8-10 mg).

      Older children may need to increase the daily dose of up to 0,014-0,016 grams (14 – 16 mg).

      Cancel sibazona should be held by gradually lowering doses. Because of the possible development of psychological dependence continuous duration of treatment should not exceed two months. Before reconnecting course of treatment interruption of at least three weeks.

      Intravenous (drip or struyno) and intramuscular injection drug introduce adults mostly in cases involving mental institution, convulsions, and edema epileptic status, the treatment of acute anxiety-anxiety, depression, anxiety, including alcoholic psychosis and abstinence. The average single dose is 10 mg (2 ml solution of 0,5%), average daily mg- 30. Maximum dose: single 30 mg, 70 mg daily.

      Sedate effects within minutes after intravenous and after 30 to 40 minutes after intramuscular introduction sibazona, therapeutic effect through 3-10 days. After withdrawing severity of the disease sibazon appointed interior.

      When epileptic status sibazon slowly injected dose of 10 to 40 mg. You can, if necessary, repeated intravenous or intramuscular introduction of a 3 to 4 hour (3 to 4 times). The best effects observed in early sibazona appointment in the first three hours after a status report submitted in the form of dwarfism.

      Sibazon (diazepam) is used for sedation and ataralgezii with analgetikami and other neurotropic medications.

      Possible complications, contraindications and precautions are basically the same as for hlozepida. When intravenous solution sibazona could experience a local inflammatory processes, and therefore advised to change their place of the drug.

      Solution sibazona there should be a syringe with other drugs to avoid falling sludge.

      Method of issuance: pills to 0,005 grams (5 mg) white or white with weak yellowish sheen colors in a package of 20 pieces, as well as tablets for children to 0,001 and 0,002 grams (T abulettae Sibazoni obductae 0 , 001 aut 0, 002 pro infantibus) orange or yellow in a package of 20 pieces in orange glass banks: 0.5% solution in ampoules (Solutio Sibazoni pro injectionibus 0.5%) and 2 ml pack of 10 vials.

      Storage: List B. In the dark spot (capsules stored at a temperature not exceeding 5 + S).

      Some foreign firms diazepam (under various names), not only in the form of tablets and solutions for injection, but in the form Suppositories (5 mg of the drug) and solutions for the reception inside (2 mg in 1 ml in 100 ml bottles ).

      Diazepam is part of the preparation reladorm sleeping pills (see Tsiklobarbital).

 Phenazepam is a benzodiazepine with anxiolytic, euphoric, anticonvulsant, amnestic, muscle relaxant, and hypnotic (sleep-inducing) effects.

 Sulpiride

Sulpiride is a selective dopamine D2 antagonist with antipsychotic and antidepressant activity.

Dosing Information: Oral doses of sulpiride in schizophrenia have varied considerably, ranging from 200 to 3200 mg daily; higher doses have been required in chronic, severely ill schizophrenics. Dose reductions are recommended in patients with renal impairment.

Pharmacokinetics: Sulpiride is slowly and poorly absorbed from the gastrointestinal tract, with peak serum levels occurring in 2 to 6 hours; its bioavailability is approximately 30%. Sulpiride does not appear to be metabolized; 70% to 90% of an intravenous dose and 15% to 25% of an oral dose is excreted unchanged in the urine. A high percentage of an oral dose of sulpiride has been recovered in feces; the elimination half-life of sulpiride is 6 to 8 hours.

Cautions: Despite its relative selectivity for dopamine D2 receptors, adverse effects of sulpiride have not differed significantly from those of other neuroleptic agents in most studies; predominant adverse effects have been extrapyramidal reactions and sedation. Tardive dyskinesia has been reported; similar to other neuroleptics, sulpiride has been associated with neuroleptic malignant syndrome and cholestatic jaundice.

Clinical Applications: Sulpiride is effective in the treatment of acute and chronic schizophrenia but does not appear to offer a significant advantage over other antipsychotic agents; it has also been investigated in Huntington’s disease, duodenal ulcer, poor lactation, contraception, depression, and for the treatment of tardive dyskinesia. Further studies are needed to determine its ultimate role in these conditions.

Dosing Information

Adult Dosage: Intramuscular: Intramuscular doses of 600 to 800 mg daily have been administered in acute schizophrenia.

Oral: The recommended oral dose of sulpiride in the treatment of schizophrenia is 200 to 400 mg twice daily with gradual increases based on clinical response to a maximum of 1200 mg daily. However, effective doses have varied considerably in clinical studies, ranging from 200 to 3200 mg daily in 2 or 3 divided doses. Lower doses may be adequate in acute, untreated patients, whereas higher doses may be required for chronic, severely ill schizophrenic patients. Further studies are needed to define optimal doses of sulpiride in specific patient subgroups.

Dosage in Renal Failure: Sulpiride is primarily excreted renally, and dose adjustments have been suggested in renal insufficiency. Bressolle et al (1989) recommended the following modifications during long-term sulpiride therapy: creatinine clearance 30 to 60 mL/minute – 70% of normal dose; creatinine clearance 10 to 30 mL/minute – 50% of normal dose; Dreatinine clearance of less than 10 mL/minute – 34% of normal dose. Alternatively the dosage interval can be prolonged by a factor of 1.5, 2, and 3, respectively.

Pharmacokinetics

Onset and Duration

Onset: Serum Level: Sulpiride is slowly absorbed following oral administration of tablets or capsules, with peak plasma levels occurring in 2 to 6 hours. Following an oral 100 mg dose, peak plasma concentrations of sulpiride have varied considerably, ranging from 0.05 to 0.2 mcg/mL. After 200 mg oral doses, peak levels of 0.2 to 2 mcg/mL have been observed.

Therapeutic Effect: Significant improvement in schizophrenic symptoms has been reported after 8 to 12 weeks of oral sulpiride therapy.

Drug Concentration Levels

Therapeutic: Gerlach et al (1985) reported no correlation between plasma levels and clinical effects of sulpiride in chronic schizophrenic patients.

Absorption: Oral: Sulpiride is absorbed poorly and slowly from the gastrointestinal tract. The bioavailability of sulpiride is reportedly 27% to 34%. The low bioavailability of sulpiride appears related to incomplete absorption as opposed to presystemic metabolism.

Food Effects: Based on urinary excretion data, Shinkuma et al (1990) reported that concurrent administration of oral sulpiride with food reduced sulpiride absorption by 30%.

Distribution: Distribution Kinetics: Volume of Distribution: The volume of distribution of sulpiride ranges from 1 to 2.7 L/kg following intravenous administration.

Metabolism Sites and Kinetics: Sulpiride does not appear to be metabolized to a significant extent, if at all. Metabolites of the drug have not been identified.

Excretion: Breast Milk: Concentrations of sulpiride in breast milk have been low (about 1ng/mL) with maternal oral administration of 100 mg daily, suggesting a low propensity for prolactin release or other adverse effects in the infant. However, further investigations are needed before sulpiride can be recommended for use during lactation.

Kidney: Between 70% and 90% of an intravenous dose of sulpiride is excreted unchanged in the urine. With oral doses, the amount of unchanged drug is substantially lower (15% to 30%) due to poor absorption. No metabolites of sulpiride have been detected in the urine.

Feces: A high percentage of an oral dose of sulpiride is recovered in feces, related to incomplete absorption.

Half-life: Parent Compound: the elimination half-life of sulpiride is 6 to 8 hours. It is prolonged significantly in patients with moderate-to-severe renal insufficiency (20 to 26 hours after intravenous doses).

Cautions

Contraindications

Hypersensitivity to sulpiride, pheochromocytoma, Parkinson’s disease.

Precautions

Cardiovascular disease; manic or hypomanic patients (may exacerbate symptoms); renal insufficiency (dose reductions); patients with epilepsy, hyperthyroidism, pulmonary disease, or urinary retention; previous hypersensitivity to other benzamide derivatives (metoclopramine, tiapride, sultopride); elderly patients (increased risk of adverse effects; reduced renal function may be present requiring dose adjustments).

Adverse Reactions

Cardiovascular: Palpitations have been observed in some sulpiride-treated patients. Worsening of hypertension has been reported.

Central Nervous System: Adverse central nervous system (CNS) effects of sulpiride have been similar to those of other neuroleptic agents, and include sedation or drowsiness, dizziness, depression, sleep disturbances, headache, restlessness, and impaired concentration. Sedation is the predominant effect, and has occurred in approximately 25% of patients in open and controlled studies. The incidence of sedation and other CNS effects has not differed significantly from that of other neuroleptics in comparative studies.

Extrapyramidal Effects: despite its selective action at dopamine D2 receptors, a relatively high incidence of extrapyramidal reactions has been reported with the clinical use of sulpiride including Parkinsonian symptoms, acute dystonias, akathisia, tardive dyskinesia and tardive dystonia. In controlled studies the incidence of extrapyramidal effects has been as high as 30% and was not significantly different from that of other neuroleptics.

Neuromuscular Effects: Sulpiride was associated with the Neuroleptic Malignant Syndrome in one patient.

Endocrine/Metabolic: Galactorrhea, Breast engorgement and galactorrhea have occurred occasionally during sulpiride therapy.

Gastrointestinal: Xerostomia, nausea, vomiting, constipation and anorexia have been reported with sulpiride. The incidence of dry mouth and constipation, related to anticholinergic activity, was less with sulpiride as compared to amitriptyline in one study.

Kidney/Geritourinary: Menstrual disorders: Amenorrhea has been reported during sulpiride therapy.

Liver: Hepatotoxicity: Cholestatic jaundice was described in one patient following 3 months of therapy with sulpiride 150 mg daily for the treatment of hiccups. Serum bilirubine levels declined gradually following withdrawal of the drug. Cholestasis was considered to be an idiosyncratic reaction to sulpiride in this patient.

Ocular: Blurred vision, attributed to anticholinergic activity, has been reported with sulpiride.

Skin: Diaphoresis has been reported occasionally during sulpiride therapy.

Drug Intereactions

Drug-Drug Combinations:Antacids: Administration of sulpiride with (or 2 hours after) a dose of aluminum-magnesium hydroxide antacid has been reported to significantly reduce the absorption of sulpiride.

Sucralfate: Administration of sulpiride with (or 2 hours after) a therapeutic dose of sucralfate has been reported too significantly reduce the absorption of sulpiride.

Drug-Food Combinations:Food: Based on urinary excretion data, Shinkuma et al (1990) reported that concurrent administration of oral sulpiride with food reduced sulpiride absorption by 30%. More studies are required to confirm these findings.

Clinical Applications

Place in Therapy: Data are insufficient at present to evaluate the place in therapy of sulpiride in other neurological disorders, depression, neurosis, inadequate lactation, or peptic ulcer disease. All studies with sulpiride have involved relatively small patient populations. Larger, long-term comparative studies are suggested to more clearly assess the efficacy and safety of this agent, particularly with regard to certain patient subgroups or specific target symptoms of schizophrenia. Studies evaluating its potential role in patients refractory to other neuroleptics would also appear warranted. The selective dopemine D2 receptor blocking action of sulpiride does not appear to have significantly reduced its propensity to induce extrapyramidal effects or other adverse effects. Recent reports of tardive dyskinesia have emerged. Sulpiride has not offered a clinical advantage over other neuroleptics in the treatment of schizophrenia in studies to date. At present, it is not recommended for hospital formularies.

Mechanism of Action/Pharmacology

Mechanism of Action: Sulpiride is a substituted benzamide derivative with antipsychotic and antidepressant activity. Other benzamide derivatives include metoclopramide, tiapride, and sultopride. In contrast to most other neuroleptics which block both dopamine D1 and D2 receptors, sulpiride is more selective and acts primarily as a dopamine D2 antagonist. Sulpiride appears to lack effects on norepinephrine, acetylcholine, serotonin, histamine, or gamma-aminobutyric acid (GABA) receptors. The relatively low incidence of extrapyramidal and possibly other adverse effects observed with sulpiride in some studies have been attributed to its specific D2 blocking activity. This selectivity has led to its investigation in the treatment of patients with tardive dyskinesia. There is some evidence that low doses of sulpiride (50 to 150 mg daily) exert antidepressant activity, whereas higher doses (800 to 1000 mg daily) are effective for positive symptoms of schizophrenia. It is speculated that antidepressant effects of sulpiride at lower doses are attributed to preferential blockage of dopamine autoreceptors, with activation of dopamine transmission. Sulpiride also stimulates secretion of prolactin and has been investigated in the treatment of inadequate lactation and to improve progestin-only contraception. As sulpiride has been shown to improve blood flow and mucus secretion in the gastroduodenal mucosa, its use in duodenal ulcer has also been evaluated. Sulpiride reportedly has antiemetic actions. It has also been used for the treatment of vertigo and migraine headache.

Therapeutic Uses

Contraception: A combination of sulpiride and norethindrone was reported more effective thaorethindrone alone in suppressing urinary excretion of estrone and pregnanediol in one small study. It was suggested that the combination may improve contraception by virtue of mimicking lactation secondary to sulpiride-induced increases in prolactin secretion. The use of sulpiride in this manner has been criticized due to its potential to produce tardive dyskinesia and because combination oral contraceptives are highly effective. Other investigators suggest that increasing the dose of progestogen alone would achieve the same effect as combined sulpiride therapy.

 

Depression: Several small studies have reported the efficacy of sulpiride 200 to 1000 mg daily in the treatment of patients with depressive disorders. Further well-controlled trials are needed to evaluate the potential role of sulpiride in depression.

Duodenal Ulcer: Oral sulpiride 50 to 100 mg 3 times daily was reported to enhance the efficacy of antacids (aluminum-magnesium hydroxide) on duodenal ulcer healing in a controlled study. In another study, duodenal ulcer recurrence rates were healed with a combination of sulpiride (200 mg daily) plus cimetidine (800 mg daily) as compared with cimetidine alone. Further studies are required to assess the potential role of sulpiride in Peptic Ulcer disease, including comparisons with bismuth subsalicylate or colloidal bismuth subcitrate regimens.

Huntington’s Disease: Oral sulpiride has reduced abnormal movements in patients with Huntington’s disease. However, no functional improvement was observed.

Inadequate Lactation: Oral sulpiride 50 mg two or three times daily for 4 days to 4 weeks has increased serum prolactin levels and enhanced breast milk yield in puerperal women with inadequate lactation. In one study, efficacy was observed in primiparous but not multiparous mothers; this was attributed to spontaneous increases in milk secretion in the multiparous group without medication. Further investigations are needed before sulpiride can be recommended for improving lactation, including potential neonatal endocrinogical effects. Some investigators suggest that simply increasing the frequency of nursing is the best stimulus to inadequate lactation.

Neuroses: Sulpiride 150 to 300 mg daily has been reported effective in the treatment of neurotic disorders, with symptoms of anxiety, mixed anxiety-depression, tension, obsessions, and hypochondriasis, in limited double-blind studies. In these studies, however, sulpiride offered no apparent advantage over chlordiazepoxide or diazepam. Diazepam was superior to sulpiride with regard to alleviation of psychic anxiety in one trial.

Schizophrenia: Summary – Numerous double-blind studies employing a placebo or other neuroleptics have reported the efficacy of oral sulpiride in the treatment of schizophrenia. Effective doses have ranged from 300 to 3200 mg daily. Lower dose ranges are usually effective in acute, untreated patients, whereas higher doses may be required for chronic, severely-ill schizophrenic patients. Sulpiride has been comparable in efficacy to other antipsychotic agents (e.g., chlorpromazine, trifluoperazine, haloperidol, perphenazine). Although uncontrolled studies have reported a relatively low incidence of extrapyramidal symptoms with sulpiride, the incidence of these complications has not been significantly different with sulpiride and other neuroleptics in most double-blind studies. Other adverse effects have also not differed significantly. There is some evidence that low doses of sulpiride may be superior to higher doses in schizophrenic patients with primary negative features. Other studies have suggested potentially greater benefits of sulpiride over other neuroleptics in improving thought content and mood state (compared to haloperidol) and aggressiveness and hyperactivity (compared to chlorpromazine). However, all studies investigating sulpiride have involved small numbers of patients. In addition, specific diagnostic criteria were frequently unclear or not provided; methods of objectively measuring clinical response also varied. Larger controlled trials are needed to fully assess the comparative efficacy of sulpiride with other neuroleptic agents, and to determine optimal doses and which patients may be most likely to respond to therapy.

Tardive Dyskinesia: Due to a potential lower tendency to induce extrapyramidal disorders by virtue of selective dopamine D2 receptor antagonism, oral sulpiride has been used as an alternative to phenothiazines and butyrophenones to suppress tardive dyskinesia symptoms. In limited studies, sulpiride 200 to 1200 mg daily has been effective in reducing movement abnormalities in patients which tardive dyskinesia. However, parkinsonian symptoms (which were intended to be avoided) occurred in 30% to 75% of these patients; an increase in tardive dyskinesia symptoms was also observed occasionally with institution of sulpiride therapy. Recently, several reports of tardive dyskinesia and tardive dystonia attributed to sulpiride therapy of anxiety, depression, and gastrointestinal symptoms have been described. Until further is known regarding the propensity of the drug to induce tardive dyskinesia, its use for the treatment of this disorder is not recommended.

Tourette’s Disorder: Oral sulpiride 200 to 1000 mg daily was reported beneficial in the treatment of Gilles de la Tourette syndrome in a retrospective study. Reductions in the frequency or severity of vocal or motor tics, obsessional behavior, and aggression were observed. A controlled study comparing sulpiride with haloperidol is needed to determine if sulpiride will have a role in this disorder.

Comparative Efficacy and Evaluation with Other Similar Therapeutic Agents

Amitriptyline: Depression: Sulpiride 4400 to 1000 mg orally daily was comparable in efficacy to amitriptyline 75 to 200 mg daily in the treatment of mixed neurotic/psychotic depression in one single-blind study. In a subsequent double-blind trial amitriptyine (50 to 150 mg daily) and sulpiride 200 to 400 mg daily) were similarly effective in major depressive disorder for the first 12 weeks of treatment, but amitriptyline was superior at 24 weeks. Anxiolytic effects of each agent were similar.

Chlorpromazine: Schizophrenia: Alfredsson et al (1985) compared the effects of sulpiride 800 mg/day and chlorpromazine 800 mg/day during a period of 8 weeks in a double-blind trial in 50 schizophrenic patients. Both drugs reduced positive psychotic symptoms to the same degree, but sulpiride was superior to chlorpromazine in decreasing autistic symptoms in schizophrenic patients. Low concentrations of sulpiride in serum produced the best results, since high concentrations seemed to counteract the beneficial effects on autistic symptoms.

Diazepam: Anxiety Neurosis: Sulpiride has offered no significant advantage over diazepam for the management of neurotic disorders, including anxiety, mixed anxiety-depression, and tension. In one trial, diazepam was superior to sulpiride with regard to alleviation of anxiety, whereas sulpiride was more effective with regard to depressive symptoms and somatic complaints.

Haloperidol: Schizophrenia: Sulpiride in doses of 300 to 1200 mg daily has been comparable in efficacy to chlorpromazine 150 to 675 mg daily, trifluoperazine 15 to 45 mg daily, haloperidol 0.5 to 10.5 mg daily, and perphenazine 4 to 80 mg daily in patients with acute or chronic schizophrenia. One study reported the superiority of sulpiride 200 to 800 mg/day over haloperidol 1 to 4 mg/day with regard to overall global improvement, as well as improvement of thought content and mood state; however, the doses of haloperidol in this study may have been too low to enable a fair comparison. In patient with severe chronic schizophrenia, higher doses of sulpiride (800 to 3200 mg daily) were as effective as haloperidol 6 to 24 mg daily in controlling symptoms. Median doses in these studies were 1600 to 2000 mg sulpiride and 12 mg haloperidol daily. In some studies greater benefits of sulpiride have been observed on certain target symptoms, including more improvement in thought content and mood state as compared to haloperidol and greater reductions in aggressiveness and hyperactivity as compared to chlorpromazine. However, haloperidol tended to be more effective than sulpiride in a subgroup of chronic, disturbed patients who had received long-term neuroleptic therapy in one study and perphenazine had a greater effect on hallucinations in another.

Adverse Reactions: McClelland et al (1990) compared haloperidol, chlorpromazine, and sulpiride iormal volunteers to test mood state. The twelve volunteers were assessed using sixteen visual analog scales such as elapsed time estimation, tapping rate, body sway and tremor, etc. The volunteers were divided into four groups: haloperidol (3 mg per day), chlorpromazine (50 mg per day), sulpiride (400 mg per day) and a placebo group. The results showed chlorpromazine and haloperidol users experienced reduced alertness and well-being. Haloperidol reduced feelings of “calmness” in the volunteers. Sulpiride did not significantly alter vision in the volunteers. Haloperidol affected the information processing function, but did not affect motor ability and speed in the group taking this drug.

Paroxetine: Headache was significantly reduced compared to baseline in patients receiving paroxetine 20 to 30 mg per day for 8 weeks during a randomized, double-blind, cross-over study with sulpiride. Fifty patients with chronic tension headache received either sulpiride 200 to 400 mg/day or paroxetine for 8 weeks. Headache was recorded by the patients on a 5-point verbal score. Comparison between the 2 treatment groups after the first 8 weeks demonstrated no statistical differences in headache scores; however, both treatments did reduce headaches when compared to baseline. Following crossover, patients switched to sulpiride demonstrated a reduction in headache scores, while those switched to paroxetine did not. It should be noted that there was no washout period between the crossover and paroxetine is known to have a relatively long half-life. More controlled, large scale clinical trials are necessary to determine paroxetine’s role in the treatment of chronic tension headache.

Perphenazine: Schizophrenia: Sulpiride in doses of 300 to 1200 mg daily has been comparable in efficacy to chlorpromazine 150 to 675 mg daily, trifluoperazine 15 to 45 mg daily, haloperidol 0.5 to 10.5 mg daily, and perphenazine 4 to 80 mg daily in patients with acute or chronic schizophrenia. One study reported the superiority of sulpiride 200 to 800 mg/day over haloperidol 1 to 4 mg/day with regard to overall global improvement, as well as improvement of thought content and mood state; however, the doses of haloperidol in this study may have been too low to enable a fair comparison

Trifluoperazine: Schizophrenia: Sulpiride in doses of 300 to 1200 mg daily has been comparable in efficacy to chlorpromazine 150 to 675 mg daily, trifluoperazine 15 to 45 mg daily, haloperidol 0.5 to 10.5 mg daily, and perphenazine 4 to 80 mg daily in patient with acute or chronic schizophrenia. One study reported the superiority of sulpiride 200 to 800 mg/day over haloperidol 1 to 4 mg/day with regard to overall global improvement of thought content and mood state: however, the doses of haloperidol in this study may have been too low to enable a fair comparison.

Preparations Available

Tricyclics

Amitriptyline (generic, Elavil, others)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Parenteral: 10 mg/mL for IM injection

Clomipramine (generic, Anafranil; labeled only for obsessive-compulsive disorder)

Oral: 25, 50, 75 mg capsules

Desipramine (generic, Norpramin, Pertofrane)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Doxepin (generic, Sinequan, others)

Oral: 10, 25, 50, 75, 100, 150 mg capsules; 10 mg/mL concentrate

Imipramine (generic, Tofranil, others)

Oral: 10, 25, 50 mg tablets (as hydrochloride); 75, 100, 125, 150 mg capsules (as pamoate)

Parenteral: 25 mg/2 mL for IM injection

Nortriptyline (generic, Aventyl, Pamelor)

Oral: 10, 25, 50, 75 mg capsules; 10 mg/5 mL solution

Protriptyline (generic, Vivactil)

Oral: 5, 10 mg tablets

Trimipramine (Surmontil)

Oral: 25, 50, 100 mg capsules

Second- & Third-Generation Drugs

Amoxapine (generic, Asendin)

Oral: 25, 50, 100, 150 mg tablets

Bupropion (generic, Wellbutrin)

Oral: 75, 100 mg tablets; 100, 150 mg sustained-release tablets

Maprotiline (generic, Ludiomil)

Oral: 25, 50, 75 mg tablets

Mirtazapine (Remeron)

Oral: 15, 30, 45 mg tablets

Nefazodone (Serzone)

Oral: 50, 100, 150, 200, 250 mg tablets

Trazodone (generic, Desyrel)

Oral: 50, 100, 150, 300 mg tablets

Venlafaxine (Effexor)

Oral: 25, 37.5, 50, 75, 100 mg tablets; 37.5, 75, 150 mg extended-release tablets

Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa)

Oral: 20, 40 mg tablets

Escitalopram (Lexapro)

Oral: 5, 10, 20 mg tablets

Fluoxetine (generic, Prozac)

Oral: 10, 20 mg pulvules; 10 mg tablets; 20 mg/5 mL liquid

Oral delayed release (Prozac Weekly): 90 mg capsules

Fluvoxamine (Luvox, labeled only for obsessive- compulsive disorder)

Oral: 25, 50, 100 mg tablets

Paroxetine (Paxil)

Oral: 10, 20, 30, 40 mg tablets; 10 mg/5 mL suspension; 12.5, 25, 37.5 mg controlled-release tablets

Sertraline (Zoloft)

Oral: 25, 50, 100 mg tablets

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Oral: 15 mg tablets

Tranylcypromine (Parnate)

Oral: 10 mg tablets

Other

Atomoxetine (Strattera)

Oral: 10, 18, 25, 40, 60 mg capsules

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8.      http://www.youtube.com/watch?v=ITkBMqwb-0Q&feature=related

9.      http://www.youtube.com/watch?v=uaESK4ohM-I&feature=related

10. http://www.youtube.com/watch?v=KIjOZq_AUeE&feature=fvw

11. http://www.youtube.com/watch?v=AqJhWG1aSVQ&feature=channel

12. http://www.youtube.com/watch?v=rg3KgRXDB3k&feature=related

13. http://www.youtube.com/watch?v=cWx6RbBVTnA&feature=related

14. http://www.youtube.com/watch?v=ocSptPUBbuo&feature=related

15. http://www.youtube.com/watch?v=HryOhK4E7aU&feature=related

16. http://www.youtube.com/watch?v=pziYmeEM9Zg&feature=related

17. http://www.netdoctor.co.uk/depression/medicines/amitriptyline.html#ixzz2NJinGkQo