Welcome to ePharmacology. Today our topics of discussion is "Distribution of drgus within the body". So let's get to it!
Once a drug is absorbed, it is able to gain access to varying extent to all parts of the body via the circulation. The dispersion, which begins with the escape of drug through the walls of the blood vessels and ends with the penetration of drug to the sites of action, is known as drug distribution. A drug is not usually specific for a particular tissue and therefore, will reach a number of tissues. The extent of distribution to the tissue varies widely from drug to drug.
Topics that we need to understand today:
1. Physicochemical factors
2. Plasma concentration of drug
3. Protein binding of drug
4. Volume of distribution
5. Biological half-life
6. Accumulation and storage in the body
7. Drug dilution in the body
8. Physiological barrier to distribution
- Blood-brain barrier
- Placental barrier
9. Order of kinetics
- First-order kinetics
- Zero-order kinetics
10. Steady state
11. Redistribution of drug
12. Consequences of uneven distribution
Once a drug has entered the blood stream, certain factors which tend to decrease its active concentration that comes into operation. These will be discussed under the heading of protein binding of drug, accumulation and storage in the body, and drug dilution in body water.
Drug is able to leave the circulatory space by diffusion through lipid membranes or via the large slot-like openings which allow the passage of albumin, so all but the largest of drug molecules (e.g. dextran- 70 KDa) can escape from the blood readily and rapidly. For this reason all but the very largest drug molecules are able to distribute throughout the extracellular fluid (ECF). The speed with which plasma and ECF concentrations of free drug approach equivalence depends initially on the degree of vascular perfusion of the tissue. Equilibration is rapidly achieved with heart, liver, kidneys, and brain in comparison with skin, bones and depot fat. Even after allowing sufficient time for diffusion equilibrium to be reached, differences in drug concentrations in factors like ion trapping, differences in binding affinities or capacities, and the presence of active transport mechanisms between some compartments.
The lipid-soluble, non-ionized fraction is shown as being in equilibrium between all the body compartments. However, although there is a free-bound equilibrium within each compartment, the total concentration of drug can differ widely between the compartments. There can be significant pH differences between compartments, which allow widely differing ionized:nonionized ratio. As there is an equal concentration of nonionized drug in each compartment, the pH effect produces different concentrations of ionized drug from one compartment to the next, so that the total amount of free, i.e. active drug (ionized + nonionized) can vary between the compartments.
The plasma concentration of drug actually means the concentration of free form of drug.
The concentration of drug in plasma represents the drug that is bound to the plasma protein and the drug in free form. It is the free form of drug that is distributed to the tissues and fluids and takes part in producing pharmacological effects.
The fraction of the total plasma concentration of the drug which is free is termed alpha. The factors that control the alpha are:
- The concentration of plasma protein
- The binding affinity of the plasma protein for a drug.
The alpha increases as the concentration of plasma protein decreases. This increase is more marked in case of severe hypoalbuminemia. However, the concentration of free drug always equilibrates with the tissue component.
When the concentration of plasma protein is increased, the amount of alpha will be decreased but the concentration of free remains the same due to equilibrium with larger tissue stores.
The concentration of free drug in plasma does not always remain the same level following single administration by different routes. After intravenous injection, the plasma concentration of a drug falls sharply. But in case of sublingual administration, there is sharp rise of the plasma concentration of drug and then falls gradually. The plasma concentration of drug following oral or intramuscular administration rises and falls gradually. The rising phase of drug is due to absorption and the falling phase is due to distribution, biotransformation and excretion of drug. While the drug is administered through intravenous route there is no phase because there is no absorption of drug.
Protein binding of drug
A variable and other significant portion of absorbed drug may become reversibly bound to plasma proteins. The active concentration of the drug is that part which is not bound, because it is only this fraction which is free to leave the plasma and the site of action.
There is a dynamic equilibrium between the bound and free drug fractions. In this way the bound drug can be regarded as a storage depot: a single dose of the antitrypanosomiasis drug sura min can give protection up to 3 months.
A practical consequence of binding to plasma protein is that the toxicity and activity of drugs which are normally highly bound is greatly increased in hypoproteinemia.
Similarly, the free concentration of a highly bound drug can be increased by administering a second drug which has a greater affinity for the same binding sites. This is one mechanism by which drug interaction toxicity can and does occur, especially when the displaced drug is extensively protein bound (e.g. the displacement of warfarin by phenylbutazone).
Drug binding in the circulation is usually but not exclusively to plasma albumin, for example, binding to blood cells and glycoproteins does also occur. The bond is usually freely reversible and is of the ionic, hydrogen, van der Waal's or hydrophobic type. The amount of drug bound can exceed 99%, e.g. with phenylbutazone, or can be virtually nil, as with amino-antipyrine. Albumin is capable of both high affinity-low capacity and high capacity-low affinity binding.
Volume of distribution
To be effective, drug must attain and maintain an adequate therapeutic concentration at its site of action. A knowledge of its volume of distribution (Vd) enables one to calculate the dose to be administered initially and subsequently to achieve these ends.
The volume of distribution is measured by injecting intravenously a known amount of drug, and the determining its total concentration in the plasma (both free and combined) after a period of time, adequate to allow its dilution into the, part of total body water into which it can gain access. Ideally, in this connection, substances are divisible into three categories as shown in the table.
|Fluid compartment||Mean Volume Vd (/kg)||Average value for 70 kg adult (L)||Approx. time for equilibration (t)||Type of substance with example|
High plasma protein bound (e.g. warfarin) or molecular weight > 15000 (e.g. heparin, dextran)
Highly ionized (e.g. + tubocurarine, gentamicin)
Total body water
lipid soluble(e.g. ethanol)
Vd= Amount of drug injected intravenously / Total concentration in plasma at time t
In practice however, when a drug in given therapeutically the equilibrium is commonly not attained because, before absorption is complete, the opposing processes of metabolism or excretion have come into play.
The drug is distributed into the body fluid and delivered to the tissues in different extents. Thus, the concentration in the plasma may not represent the concentration of drug in other parts of the body. The apparent volume of distribution in an artificial but convenient mathematical concept relating to the amount of drug administered and its apparent dilution in the body fluids as evidenced by its concentration in the blood. So, Vd generally refers to the size of the total amount of drug within the body if it presents throughout the body in the same concentration found in the plasma.
Biological half-life (t l/2) is the time taken for the concentration of drug in the blood or plasma to decline to half of its original volume or the amount of drug in the body to be reduced by 50%. It has two phases- half-life of distribution (alpha half-life) and half-life of elimination (beta half-life).
A half-life value can be readily determined for most drugs by administering a dose of drug to a subject, taking blood samples at various time interval and then assaying the samples for drug content. For example, the blood content of drug N is 8.6 mg/ml at 10 min and 4.3 mg/ml at 60 min. So, the half-life of that drug is 50 min. The drug A at the dose of 1 mg is injected intravenously, and blood samples are taken at specific time interval. Each sample is analyzed for its plasma concentration. If these concentrations are plotted against time on linear graph paper, then an exponential curve is obtained. A straight curve is obtained for the same data if the blood concentrations are plotted against time on semi logarithmic graph paper. This is the characteristic of first-order process meaning that the drug disappearance rate at any time is proportional to its concentration at any time.
If the elimination of a drug follows an exponential process, the period during which the drug falls from one concentration to one half this concentration is called the half-life. If the straight line is extrapolated back by Y-axis, the concentration of drug in plasma immediately after injection can be determined (approximately 10 mg/ml). One half of the initial concentration is 5 mg/ml and the time it takes for the plasma concentration to fall to this level is approximately 50 min. This is the half-life for this drug.
The knowledge of half-life is clinically useful for drugs such as morphine, theophylline, and phenytoin whose, concentrations are closely related to their pharmacological effects. The half-life can be used to predict the time active minimum effect, when such a drug is discontinued, the fall in response can be anticipated.
Learn more about half life of a drug:
Accumulation and storage of drugs in the body
Certain drugs tend to accumulate at subcellular structures: for example, the acridine dyes are known to enter nucleoprotein, while many drugs exert their action on the mitochondria. While some drugs, either fortuitously or by design, become concentrated at their site of action, e.g. the mercurial diuretics in the kidney and iodine in the thyroid, this is not always the case. On occasions the body is unable
to distinguish between normal and undesirable agents, e.g. the sequestration of strontium-90 and lead in bones in place of calcium. Chelation by calcium is one mechanism by which drugs can become stored in teeth and bone, e.g. the tetracyclines.
The antimalarial drug mepacrine leaves the plasma in a matter of minutes and accumulates within cells to reach concentrations up to several hundred times that of the plasma. In recent years attention has been focused on agents which can persist in body fat depots, as periods of starvation could result in their release and consequently cause toxicity problems.
Dissolution, in fact is a common occurrence with highly lipid soluble compounds, e.g. the volatile anesthetics but long-term persistence requires in addition the non-volatility and chemical stability, e.g. the organochlorine pesticides. The fact that griseofulvin is deposited in keratinizing epithelium is the basis for its value in the treatment of ring worm infection.
Drug dilution in the body
By no means all drugs diffuse throughout the total body water. The volume of distribution of a particular drug refers to that portion of total body water which is capable of entering.
Large molecules are almost unable to leave the plasma (e.g. the plasma volume expander dextran sulfate). The lipophilic agents distribute throughout the total body water, some so rapidly and evenly that they can be used to estimate its volume by dilution after intravenous injection (e.g. aminoantipyrine). Approximately 70% of body weight (fat excluded) is water. The contribution of depot fat to total body weight varies considerably from individual to individual. About two-thirds of body water is intracellular. Extracellular water exists in three compartments: plasma, interstitial and transcellular fluids.
Physiological barriers to distribution of drugs in body
There are some specialized physiological barriers in the body because of which the drug will not be distributed uniformly in all the tissues. The blood-brain barrier is one example, but further barriers occur in the placenta and in the secretory epithelia (intestinal barrier, serous membranes, milk). The effect of the barrier can be the total exclusion of certain drugs.
This barrier exists between the plasma and the extracellular space of the brain while the blood-cerebrospinal fluid (CSF) barrier occurs in the choroid plexus.
Most of the drugs cannot enter into the brain while some drugs can enter and produce either stimulatory or inhibitory effect. From these observations the concept of blood-brain barrier has been established. The endothelial cells of brain capillaries differ from those of most other capillaries in that they appear to be highly joined together and there are no intercellular pores and pinocytotic vesicles.
Whether a drug can easily pass through the blood-brain barrier depends on the following factors:
- Low ionization at plasma pH
- High lipid/water partition coefficient
- Minimal plasma protein binding
An example of a drug which crosses the blood-brain barrier is the thiopentone sodium. It easily enters into the brain and produces its depressive effect immediately after administration. On the contrary, the highly ionized drugs such as benzylpenicillin cannot cross the blood-brain barrier. But in case of meningitis, the permeability of this drug through blood-brain barrier is increased and is useful for the treatment of disease.
Dopamine cannot enter into the brain due to its inability to cross the blood-brain barrier. So, it is not used for the treatment of Parkinson’s disease. But its precursor levodopa can easily cross the blood-brain barrier and is then decarboxylated to dopamine within the brain.
The placental barrier has the general properties of a lipid membrane and allows the transfer of nonionized drugs with high lipid/water partition coefficient by a process of sample diffusion. This means that most drugs that are well absorbed from the alimentary tract, and drugs which are able to cross the blood-brain barrier can easily enter the fetal circulation through placental membrane.
The transfer of drug from maternal circulation to fetal circulation through placenta is responsible for many adverse effects. Alcohol, morphine or other CNS depressants should not be administered during pregnancy. The administration of drugs such as cortisone, streptomycin, antineoplastic drugs during the first trimester of pregnancy produce malformation of the fetus.
The drugs in ionized form in the maternal circulation do not cross the placental barrier. Drugs with high molecular weight rapidly metabolized by placental enzymes and highly bound to placenta do not readily cross the placental barrier.
When antibiotics are given orally, many of them are not absorbed into the system in therapeutic concentrations. Streptomycin and neomycin are examples. The reverse may also hold.
Some antibiotics such as penicillin will not readily pass either way across the pleural or peritoneal membrane.
Order of kinetics
Drugs are used for the treatment of disease but the modes of administration of drugs are different. As for example, atenolol is administered once daily, whereas paracetamol needs to be given 3 times daily. Morphine is more effective in intramuscular route and insulin in subcutaneous route.
The mode of administration is devised on the basis of absorption, distribution, biotransformation, and excretion of a drug.
Drugs usually follow two processes for their pharmacokinetic behavior in the body. These are first order process and zero-order process.
First-order kinetics is the most common for both drug absorption and elimination. This process depends on the concentration at any given point. From pharmacokinetic point of view, the rates at which absorption, distribution, biotransformation and excretion occur are proportional to the concentration of the drugs. This is because these processes follow the law of mass action, which states that the rate of reaction is directly proportional to the active masses of reacting substances.
Zero-order kinetics is one which occurs at a constant rate and is independent of the amount of drug present at the particular site(s) of drug absorption or removal. Few drugs follow this process, e.g. ethanol, phenytoin. This is due to the enzyme system responsible for the reaction. In this circumstance, the rate of reaction is not proportional to the dose.
When a drug dose is given repeatedly over a period, a steady state is eventually reached, at which point the amount of drug absorbed is in equilibrium with that eliminated from the body. Steady state is usually achieved within 4 to 5 half-life for most of the drugs governed by first-order kinetics. For example, a drug with half-life of 4 hours will be expected to be at steady state after more than 24 hours of infusion.
The pattern of drug accumulation during repeated administration of a drug at intervals equal to its elimination half-life. When drug absorption is ten times as rapid as elimination, as the relative rate of absorption increases, the concentration maximally approach 2 and the minimally approach 1 during the steady state.
Redistribution of drugs
This phenomenon is well illustrated by the consideration of the pharmacokinetics of thiopentone. When this lipophilic agent is given intravenously, it diffuses rapidly into the highly vascular, lipid-rich CNS and brings about immediate anesthesia. However, this initial blood-brain equilibrium becomes disturbed as the drug equilibrate more slowly with other tissues and so some drugs diffuse back from the CNS to the blood to create a new blood-brain equilibrium. A continuation of this process results in recovery as anesthetic is transferred from brain vascular tissues and eventually to body fat, the least vascular tissue.
Redistribution is, therefore, one way in which a drug action in the body may be terminated: it is unusual in that the drug is still present, and chemically unchanged, in the body. It is rather a dramatic example of a consequence of the different rates at which drug concentrations in compartments of the body come to equilibrium with the plasma concentration.
Try to answer the following questions
- What do you mean by drug distribution?
- What factors affect drug distribution?
- Which drugs tend to accumulate in the body?
- What is meant by redistribution of drugs
- Briefly mention one mechanism of drug distribution
- Briefly describe protein binding of drugs
- What is biological half life? Explain it
- What is the importance of physiological barriers in drug distribution?
- Name the drugs that can cross the placenta
Consequences of uneven distribution
The mechanisms described in the preceding sections contribute to variations in the concentration of drug between different locations in the body at equilibrium. Such differences can be revealed in living animals which undergo whole-body scanning after administration of radiolabelled drug. Alternatively, tissue samples from dosed animals killed at various intervals after dosing can be analyzed for drug content. In the case of an antimicrobial agent, tissue studies reveal whether or not adequate therapeutic concentrations arc achieved in all organs.
The concentrations of drug present in tissues at known time intervals since their last dosing, established by so called residue studies, is essential to the setting of withdrawal periods, i.e. the time which must elapse before slaughter of food animals for human consumption. The withdrawal period does not define the time between last dosing and the total elimination of the drug or other substance. It defines the time to achieve a concentration which, if extrapolated to the basis of toxicological studies, would have a high probability of being without adverse effect for the consumer. If the capacity to bind or sequester drug at sites other than the site of action (so-called sites of loss, drug acceptors or silent receptors) is considerable, then it may be necessary to give an initial large dose satisfy this need. After this loading dose, smaller maintenance doses may be all that is needed to continue a constant level of response.
Finally, it is possible that a local, high concentration of drug might be disfiguring (e.g. nitrofurantoin stains developing-teeth yellow, chloroquine causes retinal damage), or even of forensic value (e.g. arsenic and heavy metals in hair).
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