Lipid-soluble drugs

Another type of therapeutically active molecule is one designed primarily with pharmacokinetics in mind (designed to be well absorbed and to enter the central compartment readily), which can then be converted to the therapeutically active molecule in the body. These are referred to as pro-drugs. This process, called latentiation, consists of the conversion of hydrophilic drugs into lipid-soluble drugs (usually by masking hydroxyl, carboxyl, and... 

Filtered drug Absorbed (lipid-soluble) drug... 

A discussion of all the reasons for this phenomenon is beyond the scope of this chapter, but a simple example will illustrate the concept. Highly lipid-soluble drugs, such as pentobarbital, are preferentially distributed into adipose tissue. The result is that plasma concentrations are extremely low after distribution is complete. When the apparent volumes of distribution are calculated, they are frequently found to exceed total body volume, occasionally by a factor of 2 or more. This would be impossible if the concentration in the entire body compartment were equal to the plasma concentration. Thus, Vd is an empirically fabricated number relating the... 

Fat/lean body mass T Vd lipid-soluble drugs... 

K Umezawa, A Karino, M Hayashi, K Tahara, A Kimura, S Awaza. Hepatic uptake of lipid-soluble drugs from fat emulsion. J Pharmacobio-Dynam 14 591-598, 1991. 

I. Lipid-soluble drugs cross the membrane at a rate proportional to the concentration gradient across the membrane and the lipid water partition coefficient of the drug... 

Since the volume of distribution is increased, the elimination half-life of lipid-soluble drugs is increased. This affects for example medium- and long-acting benzodiazepines as well as i.e. verapamil that can accumulate in the body. 

When the percent fat is greater, the extracellular fluid is less. Therefore, there is less distribution of polar drugs. As a result, the plasma concentration of polar drugs will be higher and there may be a need to lower the dose of such drugs. In the case of nonpolar or lipid soluble drugs, their distribution in cellular tissues will be more and there may be a need to increase the dose... 

A third type of interaction is due to hydrophobic effects. These are the result of nonelectrostatic domains interacting. This type of interaction occurs mainly with the highly lipid-soluble drugs in the lipid part within the cytoplasm of the cell. 

Placental Barrier The placental barrier consists of several layers of cells between the maternal and fetal circulatory systems. Diffusion of polar drugs is limited. However, lipid-soluble drugs can pass through the barrier. Fetuses are rich in lipids and may form a reservoir for sequestering lipid-soluble drugs. 

Vi is a hypothetical volume and Cb is the concentration of drug in blood. When Cb is low, Vi may turn out to be a large value, many times more than the volume of a person of around 60-70 liters. Highly lipid-soluble drugs have a very high volume of distribution. Lipid-insoluble drugs, which remain in the blood, have a low Vi. 

For example, obesity affects Vi because lipid-soluble drugs diffuse into the adipose tissues of the obese person. Vi is a useful parameter for determining the loading dose for a drug to attain equilibrium after the drug is administered. 

When levels of the drug decline in plasma, usually due to biotransformation and excretion, the drug then redistributes away from its site of action into other tissues (e.g., drugs may distribute across the placenta during pregnancy). This is a passive process, but lipid-soluble drugs penetrate the most. 

Lactation It is not known whether tizanidine is excreted in human milk although, as a lipid-soluble drug, it might be expected to pass into breast milk. 

As examples of the range of oral bioavailability a very lipid-soluble drug such as the anticonvulsant phenytoin, or the steroidal anti-inflammatory compound prednisolone, would normally have an oral bioavailability greater than 90%, whereas a very lipid-insoluble drug such as the antibiotic, neomycin, has an oral bioavailability of less than 1%. 

It is therefore important not to lose sight of the fact that many lipid-soluble drugs are metabolized to water-soluble products, which may be pharmacologically active in their own right. 

Topical administration It is employed for local action in the form of ointments, creams, jellies etc. for its antiseptic and local anaesthetic action. The lipid soluble drugs penetrate the skin easily and rapidly. 

Other drug reservoirs are cellular and fat reservoir. The accumulation of drug in the cells may be the result of active transport or binding. Many drugs are accumulated in muscle and other cells in higher concentration than in the extracellular fluids. Many lipid soluble drugs are stored in the neutral fat, and act as the important reservoir. 

The ability of a drug to penetrate cell membranes is determined by its chemical structure and its physicochemical properties, in particular the degree of ionisation, protein binding and lipid affinity. Lipid-soluble drugs diffuse easily across membranes, whereas water-soluble ones pass through at slower rates. 

Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets."... 

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of -amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs. 

Preterm infants have much less fat than full-term infants. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full-term neonates. Therefore, organs that generally accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in less mature infants. 

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