Distribution barbiturates

Barbiturates are usually taken orally, sometimes with alcohol to increase the intoxicating effect, or by injection. The ultrashort-acting barbiturate Pentothal produces surgical anesthesia within about one minute after intravenous administration. The onset of action of the short- and intermediateacting barbiturates taken orally for insomnia is from 10 to 60 minutes, and the effects last up to six hours. Barbiturates distribute to body fat and are found in breast milk. They may cause drowsiness, slow heartbeat, and shortness of breath in babies of nursing mothers who are taking these drugs. 

Opiates produce more discreet inhibitory effects since they bind to and activate inhibitory opioid receptors which, due to their restricted distribution, cause less widespread effects than those of the barbiturates and alcohol. Activation of the opioid receptors leads to a decrease in release of other neurotransmitters (glutamate, NA, DA, 5-HT, ACh, many peptides, etc.) and direct hyperpolarisation of cells by opening of K+ channels and decreasing Ca + channel activity via predominant actions on the mu opiate receptor (see Chapter 12). 

Bassani has reported the substrate-templated photochemical synthesis of barbituric acid receptors by irradiating a solution of olefin 104 in the presence of template 105 (see Scheme 49) [122]. In the absence of such template, the major cycloadducts formed are the head-to-head (106) and head-to-tail dimers (107) (see Scheme 49). However, in the presence of barbituric acid, the distribution of products changes and the head-to-head cycloadduct is formed in higher proportions than the rest. 

They are well absorbed from the GIT. They are widely distributed in body. Rate of entry into CNS is dependent on lipid solubility. Ultra short acting barbiturates are highly lipid soluble and quickly enter the brain. Redistribution to various tissues terminate their action and they are slowly released from the tissues and gradually metabolised in the liver. They are partly metabolised and partly excreted unchanged in urine. 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

Amobarbital is a barbituric acid derivative of intermediate duration of action. It is administered orally in doses of 15 to 200 mg as a sedative hypnotic and in ampoules of 65 to 500 mg for intravenous and intramuscular injection for the seizure control.6 Following a single oral dose of 120 mg, peak serum concentrations averaged 1.8 mg/L after 2 h.7 After an oral dose of 600 mg distributed over a 3-h period, the peak blood concentration was achieved after 30 min, averaging 8.7 mg/L, with a decline to 4.1 mg/L by 18 h.6... 

Phenobarbital is utilized as a daytime sedative and anticonvulsant. It also induces several cytochrome P450 isozymes. Compared to other barbiturates, phenobarbital has a low oil/water partition coefficient, which results in slow distribution into the brain. It is available for oral, intravenous, or intramuscular administration. Doses for epileptic patients range from 60 to 200 mg per day. After a single oral dose of 30 mg, peak serum concentrations averaged 0.7 mg/L (n = 3). Repeated doses over a period of 7 days resulted in an average peak concentration of 8.1 mg/L.6 Chronic administration of 200 mg per day as anticonvulsant medication resulted in an average blood concentration of 29 mg/L (range = 16 to 48 mg/L).8... 

Barbiturates are generally widely distributed throughout the body. The highly lipophilic barbiturates, especially those used to induce anesthesia, undergo redistribution when administered intravenously. Barbiturates enter less vascular tissues over time, such as muscle and adipose tissue, and this redistribution decreases concentrations in the blood and brain. With drugs such as thiopental, this redistribution results in patients waking up within 5 to 15 min after injection of a anesthetic dose. 

This involves considerable art, which must be learned in the clinic. It falls into two divisions (1) surface application to the mucous membranes, especially of the eye, nose, throat, and urethra and (2) injections about nerves, in different parts of their course and distribution, from their spinal roots to their ultimate fibrils. The advantages and disadvantages in comparison with general anesthesia and the selection of the local anesthetic agent also depend on clinical discrimination. Nervous, fearful, and excitable patients often suffer severely from apprehension, which also disposes toward accidents. They may be at least somewhat quieted by sedatives, morphine (0.015 g hypodermically) half an hour before the operation, or by barbiturates. The latter also tend to prevent convulsions. 

Barbiturates are absorbed orally and distributed widely throughout the body. They are metabolized in the liver by aliphatic oxygenation, aromatic oxygenation, and A-dealkylation. 

As a class, the barbiturates are very similar all are fat soluble. Once barbiturates reach the bloodstream, they distribute throughout the body and affect all body tissues. Barbiturates depress the activity of muscle tissues, including the heart, and have a great impact on the respiratory system. 

The origin of the sodium peak was controlled at first with a potassium barbiturate buffer which showed the same ionic distribution as the sodium buffer. Next, a sodium and a potassium barbiturate buffer were used simultaneously, each being fed in turn into one of the two electrode compartments or on the curtain itself, while the other buffer was used for the two remaining compartments (P6). The results of these experiments confirmed again the existence of a constant para-anodic concentration zone. 

In explaining the variance in pharmacokinetic parameters, log Poet. is not always a sufficient descriptor. The failure to correlate the kinetics of distribution and the storage of barbiturates in adipose tissue with log Poet. can serve as an example. Again, other descriptors have been investigated [90]. 

Branston NM, Hope DT, Symon L (1979) Barbiturates in focal ischemia of primate cortex effects on blood flow distribution, evoked potential and extracellular potassium. Stroke 10 647-653... 

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

The history of LSD until 1966, when curbs were placed upon further experimentation, can be seen in microcosm in Dr. Hofmann s first two experiences of the drug initially there was keen interest and optimism as the power of LSD came to be understood, there was panic. On die basis of Hofmann s light first experience, Sandoz hoped that it might be marketed generally, like barbiturates and tranquilizers. Sandoz thus distributed LSD at cost to many investigators, trying to find a standard use for it. 

Barbiturates are absorbed orally and distributed widely throughout the body. All barbiturates redistribute in the body from the brain to the splanchnic areas, to skeletal muscle, and finally to adipose tissue. This movement is important in causing the short duration of action of thiopental and similar short-acting derivatives (see p. 115). Barbiturates are metabolized in the liver, and inactive metabolites are excreted in the urine. 

The above considerations on drug partitioning mainly apply to the equilibrium of drug distribution. However, it is important to realize that it may take some time until a drug that is applied rapidly (e.g., by injection or inhalation) actually reaches equilibrium. A practically important example of non-equilibrium distribution is provided by the drug thiopental, which is a barbiturate used for short-duration narcosis (Figure 2.13). 

Figure 2.13. Kinetics of thiopental distribution. Thiopental is a very hydrophobic barbiturate that is used for transient narcosis. Duration of the narcosis is limited by redistribution of thiopental from the brain to other body compartments (which is very fast) rather than elimination of the drag (which is very slow).

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