Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
DRUG DISTRIBUTION When a drug gets into the systemic circulation; it needs to be distributed throughout the whole body. This depends on the blood circulation. If, for example the person is in shock where there is reduced blood flow, it will take longer for the drug to distribute itself throughout the body. Distribution of drugs is rarely uniform. Drugs are simultaneously being eliminated and distributed, but distribution is usually faster. Steps of drug distribution 1. Dilution in blood The drug has to reach equilibrium with itself in the blood. You can’t have an area of high concentration and low concentration. The concentration needs to be uniform. 2. Movement into extracellular fluid surrounding cells Drugs need to be able to get out of the vascular system, either between endothelial cells or through them. 3. Uptake into cells The drug must be able to cross the cell membrane Factors affecting drug distribution Is the drug bound to proteins or not? (Ability of the drug to cross vascular endothelium) Most of the vascular endothelium is porous to drugs; however some drugs are bound to plasma proteins. These drugs will be unable to get out since the proteins are so large. Ability of the drug to cross cell membranes Is the drug lipid soluble? Extent of blood perfusion If a tissue is well perfused, the drug is able to get there faster. e.g. Adipose tissue has a low blood perfusion and so drugs will not be able to reach these places very quickly. Sequestration in lipid Determine if the drug is lipid soluble pH differences across membrane barriers A drug will pass through the membrane better if it is unionized. The pH is important regarding whether the drug is an acid or a base. An acid drug will be unionized in an acid environment; a basic drug will be unionized in a basic environment. Binding of drugs to other tissue components The blood brain barrier Most endothelial cells of the body are leaky except for the brain capillaries. These capillaries are special in that they have tight junctions between the endothelial cells, so it is not easy for substances to pass between the cells. The only way a drug can pass from a brain capillary into the brain is if it is sufficiently lipid soluble to pass through the endothelium, rather than between them. Thus, water soluble drugs are immediately excluded as being used as a CNS acting drug. Also are highly polar compounds and proteins. All this is a protective mechanism which effectively shields the brain from all the ups and downs of the peripheral circulation. The brain wants to live in a constant environment, not a hectic one. The blood brain barrier also protects to a certain extent against some toxins. Drug reservoirs Drugs do not distribute themselves in an even manner, which leads to pooling of drugs in some places. A drug reservoir is a site in the body where drugs accumulate. The reservoir is will be like a storage depot – as drug is cleared from the system, the reservoir keeps on releasing drugs back into the plasma. This is able to prolong the action of the drug because not the entire drug is cleared from the plasma at once. Examples of drug reservoirs are: Plasma proteins Acidic drugs are preferentially bound Only the unbound drug is able to get out of the circulation and into the tissues. The binding is non selective The bound drug may become displaced by a similar drug with similar properties Cells Accumulation of drugs in cells occurs due to the active transport of drugs into cells or due to the binding of the drug to cell membrane receptors. e.g. long term treatment of quinacrine (an antimalarial drug) leads to it being concentrated in the liver. Hence, when the concentration of the drug in the circulation decreases, the liver is able to release the drug to keep the circulating levels high. Fat Highly lipid soluble drugs are able to make their way to adipocytes and become stored there. However, they are slow to get there because fat has low blood perfusion. When the drug is stored there, it is generally stable because of the low perfusion – the drug is slow to get out into the circulation. Sometime lead can be stored in fat. If people go on crash diets, all the fat goes, releasing a whole heap of Pb – you get lead poisoning. Bone Some drugs bind to the bone crystal surface and become incorporated into the crystal lattice. Example of the principles of drug distribution e.g. Thiopental This drug is a highly lipid soluble general anesthetic. Because it is lipid soluble, it is able to get through the blood brain barrier and gets there quickly due to the high brain perfusion. It is administered intravenously because we want it to act quickly to put a person to sleep. It has a short duration of action because it redistributes quickly to muscle. Muscle is acting as the reservoir, hence decreasing the concentration of the drug in the body. 3 If repeated doses are given; we can greatly lengthen the action by saturating the “sponge” (the muscle). Because the muscle can no longer absorb any more circulating drug, the drug is able to circulate. Only when the muscle starts to break the drug down, will it be able to soak up more drugs from the circulation. Volume of distribution “Volume of body water in which a drug appears to be dissolved in after it has distributed throughout the body” Vd = amount of the drug in whole body / concentration in plasma Vd = X / C We then divide the result (which is in litres) by the mass of the person (in kg) to give a value in L/kg Often, it is very difficult to measure X, unless you are given an IV infusion. In that case, X can be approximated as being the amount of drug given (the dose) at time = 0. Vd = Xo / Co Only applies to an IV infusion The factors determining the volume of distribution are: Binding to plasma proteins If a drug binds to plasma proteins; Vd will be small and approach plasma volume. This is because most of the drug is found in the plasma (hence a high C, low X). Vd will approach plasma volume (0.06 L/kg) The amount of drug in the whole body is considered to be the amount of free, unbound drug. Binding to tissues If a drug passes through the capillaries, but does not enter cell membranes, the drug will end up in the Extra Cellular Fluid . Hence the Vd will be close to ECF volume (0.2L/kg) A drug will can pass through the cell membrane but is not bound to tissue will have a Vd close to total body water (0.6 L/kg). e.g. Morphine has a Vd = 2.8L/kg because it is bound to sites outside the circulation (X is large, C is small). What does a pharmacokineticist sees: amount of drug administered Kabs amount of drug in the body Kelim amount of drug eliminated A pharmacokineticist only sees the amount of drugs. (i.e. what they can measure) The rate constants determine the speed of movement of the drug between the different amounts (e.g. from amount administered to the amount in your body).