Pharmacodynamics sedative-hypnotics

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

Glutethimide (3-ethyl-3-phenyl-2,6-piperidinedione) is a sedative-hypnotic drug that is now rarely used therapeutically because of wide variation in gastrointestinal absorption, fast development of pharmacodynamic tolerance, a fairly severe discontinuation syndrome, and potential for abuse. Reports of... 

Pharmacodynamics, antipsychotics also differ in their pharmacodynamics, i.e. their pharmacological and clinical profiles of action. A rough distinction is made between highly sedative, hypnotic antipsychotics (e.g. clopenthixol, levomepromazine) and other products with weaker initial sedative action (e.g. fluphenazine and haloperidol). Sedative antipsychotics are prescribed for states of major unrest, often combined with insomnia, whereas the less sedative antipsychotics are preferred for patients suffering from delusions and hallucinations but in whom heavy sedation during daytime is undesirable. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents. 

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8—28-8—30 Table 8—4). 

A pharmacodynamic interaction involves either inhibition or enhancement of the clinical effects of the victim drug as a consequence of similar or identical end-organ actions. Examples are the increase or decrease of the sedative-hypnotic actions of benzodiazepine agonist drugs due to coadministration of ethanol or... 

A wide difference in milligram potency exists between the benzodiazepine compounds however, when dosage adjnstments are made, all agents share similar anxiolytic and sedative-hypnotic activity. The variations in lipid solubility between componnds inflnence the pharmacokinetic properties of benzodiazepines. Different pharmacokinetic and pharmacodynamic properties can assist the clinician in choosing an appropriate anxiolytic (Table 69-9). After a single dose, the onset, intensity, and duration of pharmacological effects are important factors to consider when using benzodiazepines for the short-term, intermittent, or as-needed treatment of anxiety. 

B. Toxicodynamics Toxicodynamics is a term used to denote the injurious effects of toxins, ie, their pharmacodynamics. A knowledge of toxicodynamics can be useful in the diagnosis and management of poisoning. For example, hypertension and tachycardia are typically seen in overdoses with amphetamines, cocaine, and antimuscarinic drugs. Hypotension with bradycardia occurs with overdoses of calcium channel blockers, beta-blockers, and sedative-hypnotics. Hypotension with tachycardia occurs with tricyclic antidepressants, phenothiazines, and theophylline. Hyperthermia is most frequently a result of overdose of drugs with antimuscarinic actions, the salicylates, or sympathomimetics. Hypothermia is more likely to occur with toxic doses of ethanol and other CNS depressants. Increased respiratory rate is often a feature of... 

Patients taking sodium oxybate shouid not drink aicohoiic beverages with sodium oxybate. Additive CNS depressant effects are predicted with other CNS depressant drugs, and concurrent use of sedative hypnotics shouid be avoided. No pharmacokinetic interaction occurs with omeprazoie, protriptyiine, zoipidem or mo-daflnii, but a pharmacodynamic interaction cannot be ruled out. Food markedly delays and modestly reduces the absorption of sodium oxybate. 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

Pharmacodynamic interactions. Many TCAs cause sedation and therefore co-prescription with other sedative agents such as opioid analgesics, antihistamines, anxiolytics, hypnotics and alcohol may lead to excessive drowsiness and daytime somnolence. The majority of TCAs can have undesirable cardiovascular effects, in particular prolongation of the QT interval. A similar risk of QT prolongation arises with many other cardiovascular drugs including amiodarone, disopyramide, procainamide, propa-... 

Although drug interactions may occur through a variety of mechanisms, most occur because of pharmacodynamic or pharmacokinetic interactions. Common examples of pharmacodynamic interactions resulting in enhanced effect include the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative side effects (e.g., mood stabUizers, hypnotics, alcohol, antidepressants, anxiolytics, or antihistamines). 

Except for additive effects with other sedative or hypnotic drugs, reports of clinically important pharmacodynamic interactions between benzodiazepines and other drugs have been infrequent. Ethanol increases both the rate of absorption of benzodiazepines and the associated CNS depression. Valproate and benzodiazepines in combination may cause psychotic episodes. 

Benzodiazepines are used as daytime anxiolytics, sleep inducers, anesthetics, anticonvulsants (also known as antiseizure agents), and muscle relaxants they will be discussed in depth in Chapters 20 and 22. Examination of the basic pharmacodynamic properties of the benzodiazepines (defined as receptor-specific binding activity) show that the clinically useful benzodiazepines exhibit comparable sedative activity at therapeutically comparable doses (Fig. 19.1) (13). The use of a specific benzodiazepine as a hypnotic is based primarily on... 

Diltiazem. A study in 7 healthy subjects found that diltiazem 60 mg three times daily for 3 days increased the AUC of a single 250-microgram dose of triazolam 2.3-fold and almost doubled its peak serum levels. Pharmacodynamic tests showed an increase in the sedative effects of triazolam. Another study in 10 healthy subjects found that diltiazem 60 mg three times daily for 2 days increased the AUC of a single 250-microgram dose of triazolam 3.4-fold, and approximately doubled its maximum plasma level and half-life. The pharmacodynamic changes were briefly described as profound and prolonged." In contrast, diltiazem 40 mg was found to have little or no effect on the hypnotic effects of triazolam in 16 healthy insomniacs in another study. ... 

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