The Barbiturates

Sedatives and hypnotics may be divided into two categories barbiturates and nonbarbiturates. The Barbiturates 

The barbiturates were used extensively in the past as hypnotic sedatives, but have been replaced by the much safer benzodiazepine derivatives. They do continue to be used as anesthetics and as anticonvulsants. The primary mechanism of action of barbiturates is to increase inhibition through the GABA system. Anesthetic barbiturates also decrease excitation via a decrease in calcium conductance. 

Strycnine is a glycine receptor antagonist causing opisthotonus 

FIGURE 65.8 The actions of GABA and glycine. GABA = y-aminobutyric acid. 

Barbiturates are classified according to their duration of action these are ultrashort acting (thiopental and methohexital), short to intermediate acting (pentobarbital, secobarbital, and amobar-bital), and long acting (phenobarbital). 

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Barbituric acids as their name implies are weakly acidic and are converted to then-sodium salts (sodium barbiturates) m aqueous sodium hydroxide Sometimes the drug is dispensed m its neutral form sometimes the sodium salt is used The salt is designated by appending the word sodium to the name of the barbituric acid—pentobarbital sodium for example... 

The various barbiturates differ m the time required for the onset of sleep and m the duration of their effects All the barbiturates must be used only m strict accordance with instructions to avoid potentially lethal overdoses Drug dependence m some mdi viduals IS also a problem... 

The analysis of clinical samples is often complicated by the complexity of the sample matrix, which may contribute a significant background absorption at the desired wavelength. The determination of serum barbiturates provides one example of how this problem is overcome. The barbiturates are extracted from a sample of serum with CHCI3, and extracted from the CHCI3 into 0.45 M NaOH (pH 13). The absorbance of the aqueous extract is measured at 260 nm and includes contributions from the barbiturates as well as other components extracted from the serum sample. The pH of the sample is then lowered to approximately 10 by adding NH4CI, and the absorbance remeasured. Since the barbiturates do not absorb at this pH, the absorbance at pH 10 is used to correct the absorbance at pH 13 thus... 

The concentration of the barbiturate barbital in a blood sample was determined by extracting 3.00 mL of the blood with 15 mL of CHCI3. The chloroform, which now contains the barbital, is then extracted with 10.0 mL of 0.045 M NaOH (pH = 13). A 3.00-mL sample of the aqueous extract is placed in a 1.00-cm cell, and an absorbance of 0.115 is measured. 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Most drugs in the pyrimidine series fall into four categories the barbiturates, the sulfonamides, the antimicrobials and the antitumour agents. In addition there are innumerable pyrimidines with diverse biological activities, some of which are in use. 

The pseudo-barbiturate , 2-methyl-3-o-tolylquinazolin-4(3H)-one (methaqualone, Revonal 1017) has an even wider spectrum of activities than do the barbiturates proper it appears to be quite widely used as- a sedative, hypnotic, anticonvulsant, antispasmodic and local anaesthetic agent (63MI21301, b-75MI21301>. 

Barbituric acid is the parent of a group of compounds known as barbiturates. The barbiturates are classified as sedative-hypnotic agents, meaning that they decrease the responsiveness of the central nervous system and promote sleep. Thousands of derivatives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5,5-disubstituted derivatives. 

The continuing search for molecules that possess the sedative-hypnotic properties of the barbiturates but show a better pharmacologic ratio has, as shown above, taken many directions. To name only two variants, the ring has been contracted and even opened entirely in each case some activity of the parent was retained. Although at one time the acylurea functional array was thought necessary for activity, the work below shows that even... 

In an interesting variation on this theme, the bis acid chloride of diethylmalonate (138) is condensed with the 0-methyl ether of urea to afford the imino ether of the barbituric acid (139). Heating this ether at 200°C results in 0 to N migration of the methyl group and formation of metharbital (140). ... 

The other method used is infusion of intravenous anaesthetics such as propofol, etomidate (for induction) and the barbiturates such as thiopental and pentobarbital. Investigations into the mechanism of anaesthesia have made use of all these compounds in order to identify a common mode of action linked to likely mechanisms within the CNS. 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Discuss the uses, general drug actions, adverse reactions, contraindications, precautions, and interactions of the barbiturates and miscellaneous sedatives and hypnotics. 

Sedatives and hypnotics may be divided into two classes barbiturates and miscellaneous sedatives and hypnotics. The barbiturates are divided into several groups, depending on tiieir duration of action ... 

Miscellaneous or nonbarbiturate sedatives and hypnotics have essentially the same mode of action as the barbiturates, that is, they depress the CNS. However,... 

Like the barbiturates, the miscellaneous drugp sedative or hypnotic effects diminish after approximately 2 weeks. Ffersons taking these dragp for periods longer than 2 weeks may have a tendency to increase the dose to produce the desired effects (eg, sleep, sedation). Physical and psychological dependence may occur, especially after prolonged use of high doses. However, their addictive potential appears to be less than that of the... 

MONITORING AND MANAGING RESPIRATORY DEPRESSION These drugs depress the CNS and can cause respiratory depression. The nurse carefully assesses respiratory function (rate, depth, and quality) before administering a sedative, Vs, to 1 hour after administering the drug, and frequently thereafter. Toxic reaction of the barbiturates can cause severe respiratory depression, hypoventilation, and circulatory collapse. 

As with the barbiturates, the most common adverse reaction seen with the use of clonazepam (Klonopin), clorazepate (Tranxene), and diazepam (Valium) is sedation in varying degrees. Additional adverse effects may include anorexia, constipation, or diarrhea. Some adverse reactions are dose dependent, whereas others may diminish in intensity or cause few problems after several weeks of therapy. 

The barbiturates are contraindicated in patients with known hypersensitivity to the drugs. The barbiturates are used cautiously in patients with liver or kidney disease and those with neurological disorders. The barbiturates (eg, phenobarbital) are used with caution in patients with pulmonary disease and in hyperactive children. When barbiturates are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. See Chapter 26 for additional information on the barbiturates. 

Phenytoin interacts widi many different drugp. For example isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, die analgesic effect of meperidine is decreased. 

BARBITURATES. The barbiturate phenobarbital (Luminal) is commonly used to treat convulsive disorders. When administering the barbiturates by the intravenous (IV) route, it is important not to exceed a rate of 60 mg/min and to administer the drug within 30 minutes of preparation. The nurse monitors the patient carefully during administration of a barbiturate. The blood pressure and respirations are taken frequently. Resuscitation equipment and artificial ventilation equipment are kept nearby. 

BARBITURATES The barbiturates can produce a hypersensitivity rash. Should a skin rash occur, the nurse must notify the primary health care provider immediately because the primary health care provider may discontinue the drug. The nurse carefully examines all affected areas and provides an accurate description. If pruritus is present, the nurse keeps the patient s nails short, applies an antiseptic cream (if prescribed), and tells the patient to avoid the use of soap until the rash subsides. 

The barbiturates may produce marked excitement, depression, and confusion in the elderly. In some individualsthe barbiturates produce excitement rather than depression. The nurse should monitor the older adult carefully during therapy with the barbiturates and report any unusual effects to the primary health care provider. 

When two antiarrhythmic dragp are administered concurrently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis, tiie risk of digitalis toxicity is increased. Hiarmacologic effects of procainamide may be increased when procainamide is administered with quinidine When quinidine is administered with the barbiturates or cimetidine, quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. 

When amphotericin B or diuretics are administered with ACTH, the potential for hypokalemia is increased. There may be an increased need for insulin or oral antidiabetic drag s in the patient with diabetes who is taking ACTH. There is a decreased effect of ACTH when the agent is administered with the barbiturates. Profound muscular depression is possible when ACTH is administered with the anticholinesterase drugp. Live virus vaccines taken while taking ACTH may potentiate virus replication, increase vaccine adverse reaction, and decrease the patient s antibody response to the vaccine... 

Fludrocortisone is contraindicated in patients with hypersensitivity to fludrocortisone and those with systemic fungal infections. Fludrocortisone is used cautiously in patients with Addison s disease infection, and during pregnancy (Pregnancy Category C) and lactation. Fludrocortisone decreases the effects of the barbiturates, hydantoins, and rifampin. There is a decrease in serum levels of the salicylates when those agents are administered with fludrocortisone... 

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