The important nursing intervention prior to administration of pre-anesthetic medication is:

Atropine Carries FDA Pregnancy Category C Rating

Atropine may be used during pregnancy as a preoperative, preanesthetic agent to reduce salivation and bronchial secretions. Atropine rapidly crosses the human placenta. In one study of 44 healthy pregnant women, a maximum umbilical to maternal vein ratio of 1.27 was observed 6 min after administration of 0.01 mg kg−1 intravenously. The corresponding umbilical and maternal vein atropine levels were 22 and 17 nmol l−1 respectively. Intramuscular injection produced lower concentrations.

Another study administered labeled atropine intravenously prior to delivery to quantify placental transfer and fetal distribution of the drug. The concentrations in the umbilical vein 1 and 5 min after injection were 12 and 93%, respectively, of the corresponding maternal value. Concentrations in the umbilical artery were approximately 50% of those in the umbilical vein during the same period.

Studies have shown that administration of atropine to a pregnant woman during the last trimester can mask the effects of vagal stimulation on the fetal heart, producing tachycardia within 5–30 min after injection. Limited data have shown that atropine can suppress fetal breathing, although fetal hypoxia has not been observed. Atropine could reduce lower esophageal sphincter pressure enough to predispose the newborn to aspiration. Uterine contractility does not appear to be significantly affected by atropine, perhaps due to a decrease in the sensitivity of muscarinic receptors on myometrial tissue during pregnancy.

Multiple prospective cohort studies have monitored tens of thousands of mother–child pairs in which the mother was exposed to atropine during pregnancy. Overall, these data do not support an association between the use of atropine and congenital defects.

Anticholinergic agents can inhibit lactation in animals, via inhibition of growth hormone and oxytocin secretion. These agents can also reduce serum prolactin in nonnursing women, but decreased prolactin levels in an established nursing mother should not affect her ability to breast-feed. In theory, long-term use of atropine may reduce milk production or milk letdown, but a single systemic or ophthalmic dose should not interfere with breast-feeding.

Historical Background of Pharmacotherapy in Schizophrenia

The serendipitous discovery of chlorpromazine, initially being investigated as a preanesthetic agent due to its sedative properties (Lopez-Munoz, Alamo, et al., 2005), to have antipsychotic effect heralded a new era in the treatment of schizophrenia. However, a decade passed before the mechanism of action of these drugs could be identified (Deniker, 1990; Weisel, 1994). The discovery of D2 receptor blockade mechanism led to synthesis of highly selective D2 antagonists, such as haloperidol and pimozide. At the same time, extrapyramidal symptoms (EPS) were noticed to be invariably associated with these agents and led to the concept of ‘neuroleptic threshold’ (Bitter, Volavka, et al., 1991). However, while the field had embraced the notion of D2 blockade as the mechanism of action of antipsychotics, the discovery of clozapine with lack of EPS (Hippius, 1989; Matz, Rick, et al., 1974) but superior clinical efficacy in treatment-resistant schizophrenia led to various nondopaminergic (e.g., serotonergic, glutamatergic, and α-adrenergic) (Meltzer, Matsubara, et al., 1989a, 1989b; Olney & Farber, 1994; Svensson, Mathe, et al., 1995) hypotheses as mechanisms of action of antipsychotics. Subsequently, the field has come a full circle with evidence demonstrating that at least some degree of D2 receptor blockade is necessary for antipsychotic activity of all medications including clozapine (Kapur & Remington, 2001a, 2001b). However, the reason for clozapine's superior efficacy in treatment-resistant schizophrenia remains enigmatic at this stage. Accordingly, understanding the mechanism of action of antipsychotics remains a key question in schizophrenia drug discovery.

Introduction

Flunitrazepam is a benzodiazepine that is marketed and licensed for use in Europe, Asia, and Latin America for the short-term treatment of insomnia, as a sedative-hypnotic and preanesthetic agent. It has pharmacological effects similar to other benzodiazepines, with a potency approximately 10 times that of diazepam. Although Flunitrazepam has not been approved by the U.S. Food and Drug Administration and is considered to be an illegal drug in the U.S., it has been available via the black market since the early 1990s. Flunitrazepam may be better known as Rohypnol or “roofie.”

3 Preanesthetic Medications

Preanesthetic drugs are not commonly used in rodents. However, the advantages of sedation, analgesia, and reduced doses of the general anesthetic agent or agents apply equally well to rodents. The principal disadvantage of using a preanesthetic agent in rodents is the need to restrain and thus stress the animals twice rather than once for the induction of anesthesia. Drugs commonly used as preanesthetic agents in other species are frequently incorporated into anesthetic combinations for rodents. However, if postprocedural analgesia is needed following very short procedures, or if preemptive analgesia is desired, then some means of preanesthetic administration must be used. Preanesthetic administration of tranquilizers, including the phenothiazine derivatives, benzodiazepines, and pote-nt analgesics will all tend to substantially reduce the required dose of the principal anesthetic agent or agents.

New Anticholinergics

There have been considerable efforts from the pharmaceutical industry to develop novel bronchodilators, and especially LABAs and LAMAs, for COPD [104,105]. Glycopyrrolate has been used extensively systemically for decades to control salivation as a pre-anesthetic agent and causes bronchodilation on isolated guinea pig trachea [106,107]. Interestingly, glycopyrrolate is a quaternary ammonium derivative which has minimal mucosal absorption and systemic toxicity when inhaled, causing prolonged bronchodilation in patients with asthma [106] and a family of anticholinergics based on glycopyrrolate have been synthesized [108]. A variant on this agent is racemically pure R,R-glycopyrrolate as a LAMA [109], while an inhaled glycopyrrolate derivative, NVA-237, is currently being developed by Novartis (license from Arakis and Ventura). An oral selective M3-selective M3-cholinergic receptor antagonist that was studied in patients with COPD (OrM3, Merck) has apparently been discontinued in clinical development [110]. However, Phase 3 studies have been successfully carried with the inhaled LAMA, aclidinium bromide (LAS-34273, Almirall), that is likely to be licensed in the near future. Recently there have been efforts to develop a combined muscarinic antagonist and beta-agonist in a single molecule: Theravance describes this as a MABA. In the future we can expect LABAs and LAMAs to be combined in single inhalers (eg. indacaterol-glycopyrrolate) and there may be the possibility of 3 agents in a single inhaler (LABA, LAMA, ICS).

10.07.4.1.1 Reflux esophagitis

Reflux esophagitis is caused by the reflux of gastric contents into the lower esophagus and is the most important cause of esophagitis in humans. Although reflux is not directly caused by toxins, a number of compounds, such as alcohol, tobacco, preanesthetic agents, and beta 3 adrenoceptor agonists (Oriowo 1998), can cause decreased tone of the lower esophageal sphincter, leading to reflux. Toxins that impair gastric emptying may also have the same result. The acidity of the refluxed material causes early mucosal damage, followed quickly by infiltration of the mucosal epithelium by eosinophils, neutrophils, and lymphocytes. In chronic cases, basal epithelial cells become hyperplastic, metaplastic (replacement with columnar epithelium, also called Barrett’s esophagus), or dysplastic. Grossly, the distal esophageal mucosa may simply appear hyperemic, and eroded or ulcerated, with or without hemorrhage. In Barrett’s esophagus, there are abrupt to patchy changes from the paler squamous mucosa to a bright red, velvety mucosa. Prolonged and/or severe cases may have strictures or may progress to become adenocarcinomas.

C Pharmacology

Even though schizophrenia as a syndrome has been present throughout recorded history, a successful pharmacological treatment has only been available since the mid-1950s. In the late 1940s, two French psychiatrists observed strong sedative properties of chlorpromazine in normal people, used as a preanesthetic agent at that time; they decided to test this drug for behavioral sedation in floridly psychotic patients.29 Delay and Deniker observed an unexpected outcome, which was a specific antipsychotic action with less sedation than in normal individuals. They directly followed up their informal observation with controlled clinical trials using chlorpromazine and documented a selective antipsychotic action.29 They documented the antipsychotic action of chlorpromazine.

It took another 10 years for Carlsson and Lindquist to discover that chlorpromazine blocks dopamine and other catecholamine receptors.30 Dopamine receptor blockade was put forth as the mechanism of action of chlorpromazine, providing pharmaceutical companies a molecular target for drug development. Over the next 50 years, many dopamine receptor antagonists have been developed and successfully tested in the illness.31 Among antipsychotics, the clinical potency in reducing psychotic symptoms was shown to be directly proportional to dopamine receptor affinity, supporting dopamine receptor blockade as the mechanism of antipsychotic action. Currently, there is a strong push to indentify novel antipsychotics to improve the manifestations of psychosis.32

Several candidates have presented themselves but with only preliminary efficacy data. LY404039 (a prodrug for LY2140023) is an mGluR2/3 agonist which has already shown some preliminary evidence of antipsychotic action.33 Postmortem tissue evidence in schizophrenia of a reduction in mGluR3 receptors in PFC provides a molecular basis for drug efficacy.34 Also, xanomeline is a muscarinic cholinergic agonist which is being tested for cognitive enhancement in schizophrenia.35 However, there is one small published study testing xanomeline in Alzheimer's dementia, showing positive outcomes on cognition despite limiting peripheral gastrointestinal side effects; the single study in schizophrenia is interesting in that it shows positive outcomes on both psychosis and cognition.36 Other novel candidates are modifications of dopamine antagonism and not altogether novel.

The dopamine hypothesis of schizophrenia proposed that the molecular pathophysiology of the illness is based on increased dopamine transmission at some critical CNS neuronal populations and was a popular explanation of schizophrenia for several decades. However, the evidence of alterations in dopamine transmission never materialized from studies done in the past 60 years, with the exception of some isolated dopamine release data,37 leading scientists to propose that the dopamine hypothesis of schizophrenia has been falsified.38 This negation of the dopamine-based disease concept does not falsify the firm knowledge that dopamine blockade is involved in the antipsychotic action of these psychotropic drugs.

1. Anticholinergics

Atropine and glycopyrrolate are usually used in anesthesia to prevent or treat bradycardia, and to minimize salivation and respiratory secretions. Olsen et al. 1993 compared atropine at 0.05 mg/kg and glycopyrrolate at 0.5 mg/kg in the rat and found glycopyrrolate to be superior as a preanesthetic agent in terms of maintaining heart rate during ketamine/xylazine or ketamine/detomidine anesthesia. Anticholinergics are also used treat or prevent the oculocardiac and similar vagal reflexes in surgery of the head and neck (Hall et al., 2001a; Naff et al., 2004). Anticholinergic drugs are invaluable when indications for their use are present or reasonably predictable, but they are not wholly benign, and their indiscriminate use is not warranted. Unlike diethyl ether, modern inhalation agents are not respiratory irritants, so airway drying may be a greater concern than secretions. Further, the use of anticholinergics to prevent the bradycardia associated with α2-adrenergic administration has also been questioned (Savola, 1989; Alibhai et al., 1996).

Pre-Anaesthetic Medication

Dogs respond positively to human contact, and if the animal’s regular handler is present then restraint will rarely be a problem. It is often preferable, however, to administer pre-anaesthetic medication to dogs, to ease handling, to ensure a smooth and stress-free induction of anaesthesia and to provide a quiet and gradual recovery. Dogs should be fasted for 12 h prior to induction of anaesthesia. Intravenous injection for induction of anaesthesia is easy to carry out; particularly if the skin has been anaesthetized by prior application of EMLA cream (see “Pre-anaesthetic agents” in Chapter 1) and a sedative or tranquillizer has been administered.

The following drugs can be used for pre-anaesthetic medication and are listed in order of preference (see also Table 5.16).

Table 5.16. Sedatives, Tranquillizers and Other Pre-Anaesthetic Medication for Use in the Dog

Medetomidine (10–80 µg/kg i.m., sc or i.v.) or dexmedetomidine (5–40 µg/kg i.m., sc or i.v.) produces light to deep sedation, and at higher dose rates, the dog is completely immobilized enabling minor procedures to be carried out. The degree of analgesia is insufficient for anything other than superficial surgical procedures. Sedation can be reversed completely and rapidly by administration of atipamezole (50–400 µg/kg i.m.).

Buprenorphine (0.009 mg/kg i.m.) and acepromazine (0.07 mg/kg i.m.) produce moderate or deep sedation, enabling minor procedures such as radiography to be undertaken easily.

Acepromazine (0.2 mg/kg i.m.) alone produces sedation, but has no analgesic action.

Fentanyl/fluanisone (Hypnorm, Janssen) (0.1–0.2 ml/kg) or fentanyl/droperidol (Innovar-Vet, Janssen) (0.1–0.15 ml/kg i.m.) produces good analgesia, sufficient for minor surgical procedures and heavy sedation. A moderate bradycardia is often produced, but this can be prevented by administration of atropine. Partial reversal of these agents is possible using nalbuphine or other mixed agonist/antagonist opioids (Tables 5.1 and 5.2).

Xylazine (2.0 mg/kg i.m.) produces good sedation and mild analgesia. Vomiting often occurs after administration and animals may be easily roused by loud noises. Other side-effects include production of bradycardia, occasional heart-block and hyperglycaemia, although the cardiac effects can be prevented by pre-treatment with atropine.

Atropine (0.05 mg/kg sc) or glycopyrrolate (0.01 mg/kg) should be administered prior to the use of fentanyl/fluanisone, fentanyl/droperidol or xylazine. It may also be included as pre-medication prior to use of the anaesthetic regimens described below.

The dose rates of anaesthetic drugs listed below and in Table 5.17 can be reduced by 30–50% if one of the drugs (1–6) listed above has been administered.

Table 5.17. Anaesthetic Dose Rates in the Dog

Duration of anaesthesia and sleep time (loss of righting reflex) are provided only as a general guide, since considerable between-animal variation occurs. For recommended techniques, see text.

Barbiturates

Barbiturates have the basic structure of barbituric acid.53 These drugs act as CNS depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. Barbiturates are a family of compounds that have sedative and hypnotic activities and act as nonselective CNS depressants.54 The GABA receptor is one of barbiturates’ main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates.55 The most common use for barbiturates currently is as anesthesia for surgery. Current indications for the barbiturates include short-term treatment of insomnia and as a preanesthetic agent. Amobarbital (Amytal) and butabarbital (Soneryl, Butisol) are currently available short-acting barbiturates for parenteral administration, being used largely as preanesthetic agents.56 Other short-acting agents in use include secobarbital, which is available as a 100-mg capsule generically and under the brand name Seconal; it is also classified as a schedule II substance because there is the potential for physical and psychological dependence and abuse.57 Very-short-acting drugs in use include pentobarbital (Nembutal), methohexital (Brevital), and thiopental (Pentothal).58–60 Further medium-acting agents, such as butalbital (Fiorinal, Fioricet), Talbutal (Lotusate) and long-acting mephobarbital (Mebaral) and methylphenobarbital (Prominal), are available.61,62

Barbiturates induce several hepatic cytochrome P (CYP) enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs that are metabolized by these enzymes to inactive metabolites. This property can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolized by CYP enzymes.63 Although all known members of the class possess relevant enzyme induction capabilities, the degree of inhibition overall, as well as the impact on each specific enzyme, span a broad range, with secobarbital being the most potent enzyme inducer and butalbital and talbutal being among the weakest enzyme inducers in the class.

In addition to their sedative-hypnotic properties, this class also has anxiolytic and anticonvulsant properties. Barbiturates also have analgesic effects; however, these effects are weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have addiction potential, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical use, mainly because benzodiazepines are significantly less dangerous in overdose because there is no specific reversal agent for barbiturate overdose.64,65 The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic use of long-acting barbiturates wears off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic/prescribed dose) despite the user feeling little or no effect from the plasma-bound concentrations of the drug.66 Individuals who consume alcohol or who are given sedatives after the drug effects have worn off, but before it has cleared the system, could experience an exaggerated effect from the sedatives, which can be incapacitating or even fatal.

There are special risks to consider for older adults, women who are pregnant, and babies. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people more than 65 years of age are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose.67 A rare adverse reaction to barbiturates is Stevens-Johnson syndrome, which primarily affects the mucous membranes.68,69

Barbiturates in overdose with other CNS depressants (eg, alcohol, opiates, benzodiazepines) are even more dangerous because of additive CNS and respiratory depressant effects.70 In the case of benzodiazepines, not only do they have additive effects but barbiturates also increase the affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects.71,72 Frequent side effects include drowsiness, sedation, hypotension, nausea, headache, and skin rash.