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Pharmacokinetics

To produce its characteristic effects, a drug must be present in appropriate concentrations at its sites of action. Pharmacokinetics is the study of what the body does to foreign substances. It looks at how the human body absorbs, distributes and eliminates drugs. The effect of a particular drug depends upon the following:

  • Amount of drug administered
  • Extent and rate of absorption
  • Extent and rate of distribution
  • Binding and localization in tissues
  • Metabolism (bio-transformation)
  • Excretion.

The absorption, distribution, metabolism and excretion of a drug all involve its passage across cell membranes.

Factors affecting drug transfer

The following properties of the drug and the membrane will influence the transfer of a drug across cell membranes.

  • Molecular size and shape of the drug
  • Solubility at the site of absorption
  • Chemical characteristics of the drug
  • Manner of administration (oral, injection, or inhalation)

Barriers to drug movement may be a single layer of cells (intestinal epithelium) versus several layers of cells (skin). For example, aspirin would not be absorbed through the skin if you ground it up and put it on your arm, whereas it would easily be absorbed through the small intestine.

Drug absorption, bioavailability and bioequivalence

Absorption is the phenomenon of a drug leaving its site of administration and the extent to which it is absorbed by the body.

Bioavailability

Bioavailability is a term used to indicate the amount of a drug that reaches the target site. For example, a drug that is absorbed from the stomach and intestine will pass through the liver before it reaches the circulatory system. If the drug is metabolized in the liver or excreted in the bile, some of the active drug will be destroyed before it can reach the general blood circulation and be distributed to its site of action.

If the metabolic capacity of the liver for a given drug is great, bioavailability will be substantially decreased. This is called the first pass effect. The decrease in availability of the drug is a function of the anatomical site from which absorption occurs, as well as other physiological and pathological conditions. The choice of dosage and the manner of administration must be based on an understanding of these conditions.

Bioequivalence

Pharmaceutical formulations of a drug are termed "chemically equivalent" if they meet the chemical and physical standards established by scientific experts, and governmental or other regulatory agencies.

Drugs are said to be "biologically equivalent" if they yield similar concentrations of drug in blood and tissues.

Drugs are deemed "therapeutically equivalent" if they produce equal therapeutic effect at the target site.

Pharmaceutical preparations that are chemically equivalent but not biologically or therapeutically equivalent are said to differ in their bioavailablity. The reasons for differing bioavailability include:

  • Differences in crystal form of the drug
  • Particle size of the drug
  • Other physical characteristics of the drug that are not rigidly monitored and controlled in formulation or manufacture.

These factors usually affect the rate and extent of absorption, and usually only apply to oral dosages.

Factors that modify absorption

The factors that affect absorption of a drug are:

  1. Drug solubility: Drugs come in different forms, namely aqueous solutions, oils, gases, suspensions, and solids;
  2. Rate of dissolution (for solids);
  3. Local conditions at the site of absorption, particularly in the gastrointestinal tract;
  4. Stomach contents;
  5. Concentration of the drug. Generally high concentrations are absorbed more rapidly than low concentrations;
  6. Circulation to the site of absorption. For instance, increased blood flow due to massage or local application of heat enhances absorption of a drug, whereas decreased blood flow produced by vasoconstrictors (agents that narrow blood vessels), shock, or other disease factors can slow absorption;
  7. The area of the absorbing surface to which a drug is exposed helps determine the rate of drug absorption. Drugs are absorbed very rapidly in regions with large surface areas such as the lungs and the intestines. The absorbing surface is determined largely by the route of administration.

All of these factors can have considerable impact on the effectiveness of a drug and its potential to cause toxic reactions.

Routes of administration

There are several ways to administer drugs enumerated below. The method chosen is usually a function of the following considerations:

  • Convenience
  • Desired rapidity and duration of action
  • Availability of sterile preparations
  • Drug's solubility
  • Absorption characteristics of the drug
  • Onset of action

1 Oral ingestion (enteral)

This is the most common route of administration. It is also the safest, most convenient and economical. But it has disadvantages, the most signficant of which include:

  • Emesis (vomiting) as a result of irritation to the gastrointestinal tract
  • Destruction of some drugs as a result of digestive enzymes or acidic nature of the stomach
  • Irregularities in absorption or propulsion of the drug in the presence of food or other drugs
  • Necessity for cooperation by the patient
  • The enzymes of the gastrointestinal tract, the intestinal flora, or the liver may metabolize drugs before they reach the general blood circulation.

Absorption from the gastrointestinal tract is governed by the following factors:

  • Surface area at the site of absorption
  • Blood flow to the site of absorption
  • Physical state of the drug at the site of absorption
  • Concentration of the drug at the site of absorption

Drugs that are destroyed by gastric juices or that cause gastric irritation are sometimes administered in a dosage form with a coating that prevents dissolution in the acidic gastric contents.

Some enteric-coated preparations of a drug may also resist being dissolved in the intestine. This too would limit the amount of a drug that is absorbed.

The rate of absorption of a drug administered as a tablet or other solid dosage form is partly dependent on the location of absorption and the rate at which it is dissolved in gastrointestinal fluids.

Controlled release

This factor is the basis for the so-called controlled release, time-release or sustained release preparations. They are designed to produce slow, uniform absorption of a drug for 8-12 hours or longer. Potential advantages include:

  • Reduction in the frequency of administration
  • Maintenance of the therapeutic effect overnight
  • Decreased incidence of undesired effects by the elimination of peaks in drug concentration that often occur in other dosage forms.

Not all controlled release preparations work reliably. For example:

  • The dissolution rate may be irregular due to technical manufacturing problems
  • There may be variations in gastric acidity and emptying, intestinal motility and other physiological factors that modify drug absorption
  • Slow absorption from the gastro-intestinal (GI) tract is often incomplete and erratic

Drugs required for a brief therapeutic effect should not be in the controlled release form. Also, controlled release forms would not be used for drugs with a long duration of effect. In controlled release preparations the total dose may be several times the dose of the conventional form and faulty release of the entire amount at once could lead to toxic reactions, even death.

2 Injection (parenteral)

Parenteral administration has advantages over oral administration. For example:

  • Necessary for certain drugs to be absorbed in an active form
  • Absorption is usually faster and more predictable than for oral administration
  • Effective dose can be more readily determined
  • For emergency therapy, if patient is unconscious, uncooperative or unable to retain anything given orally

However, injection of drugs also has disadvantages:

  • Possibility for infection
  • Pain may accompany the injection
  • Difficult to perform self-injection for self-medication
  • Expense (injectable form is usually costlier)

Here are the different ways to inject a drug:

2.1 Intravenous - direct injection into a vein

  • Absorption via the gastro-intestinal tract is bypassed with potentially immediate effects
  • Valuable for emergency use
  • Permits titration of dosage (dosage can be accurately predicted because there is no loss of drug through absorption in gastro-intestinal tract)
  • Suitable for large volumes and can be used for diluting irritating substances (eg. morphine and other analgesics administered in a saline solution in an intravenous drip)
  • Increased risk of adverse effects
  • Solutions must be injected slowly
  • This method is unsuitable for oily solutions or insoluble substances

2.2 Subcutaneous - injection beneath the skin

  • Slow and sustained release over a few hours into the surrounding blood vessels
  • Insulin is given this way
  • Can only be used for drugs that are not irritating to tissue

2.3 Intramuscular - direct injection into a muscle

  • Can provide prompt absorption, from aqueous solution
  • Slow and sustained absorption from repository preparations
  • Suitable for moderate volumes, oily solutions, and some irritating substances.

2.4 Intra-arterial - direct injection into an artery

  • Localizes effect in a particular tissue or organ
  • Very dangerous
  • Can be used to administer diagnostic agents

2.5 Intrathecal - direct injection into the spinal subarachnoid space (membrane covering the brain and spinal cord).

2.6 Intraperitoneal - direct injection into the peritoneal cavity

  • Large surface area for absorption.
  • First pass hepatic losses are possible.
  • Danger of infection; this type of injection is usually performed in the laboratory

3 Topical application

Drugs are applied to mucous membranes in the eyes, colon, vagina, nose and skin. Absorption occurs rapidly. Few drugs readily penetrate skin. Absorption through skin can be enhanced by suspending the drug in an oily solution and rubbing the resulting preparation into the skin (inunction).

4 Sublingual administration (oral mucosa)

Absorption from the oral mucosa (under the tongue) has special importance for certain drugs, even though the surface area in this location is small. Nitroglycerine is effectively administered in this fashion.

5 Rectal administration

The rectal route is often used when vomiting precludes oral ingestion or when the subject is unconscious. It should be noted, however, that rectal absorption is often irregular and incomplete and many drugs cause irritation of the rectal mucosa.

6 Pulmonary administration

Drugs administered as gases penetrate the cell linings of the respiratory tract easily and rapidly. Anaesthetic gases have small molecular sizes and high fat solubility. They are absorbed almost as fast as they are inhaled, because contact between blood and the lung membrane is close. This process is almost as efficient as intravenous injection.

Despite this knowledge about the rapid absorption of gases through the lungs, very little information is available about the pulmonary absorption of drugs other than those administered as gases.

Cigarettes and marijuana are examples of such administration, since nicotine and tars in cigarettes and cannabinoids in marijuana are not gases but particles carried in smoke.

Although many drugs appear to be absorbed readily when inhaled as sprays, aerosols, smokes, or dusts, knowledge of the extent and rate of absorption is incomplete.

Because of the ultrasensitivity of the lung tissue to foreign substances, administration of drugs by inhalation should probably not be widely adopted.

Distribution of Drugs

Once absorbed, a drug is distributed throughout the body by means of the circulation of the blood. The distribution of most drugs in the body is far from even. This complicates the efforts to correlate blood levels and the pharmacological effects of the drugs used.

  • Some drugs tend to bind to blood elements
  • Some drugs dissolve more readily in body fat depots
  • A few drugs have a strong tendency to locate in bone

Drugs must be very fat soluble to enter the brain. It is generally true that high blood drug levels yield correspondingly greater pharmacological effects.

Even though a drug is in the bloodstream it must pass across various barriers to reach its site of action. Only a very small proportion of the total amount of drug in a body at any one time is in direct contact with the specific cells that produce the pharmacological effect. Most of the drug is to be found in areas of the body remote from the drug's site of action. In the case of psychoactive drugs, most of the drug is to be found outside the brain and is therefore not directly contributing to the pharmacological effect.

Drug that has accumulated in a given tissue may serve as a reservoir that prolongs drug action in that same tissue or at a distant site reached through circulation.

Distribution by the heart and blood

The heart pumps approximately 6 litres of blood per minute. With only 6 litres of blood in the circulatory system, the entire blood volume circulates in the body about once every minute.

Once a drug is absorbed into the blood, it is quite rapidly (usually within this 1 minute circulation time) distributed throughout the circulatory system. The following cycle of events describes the circulation of a drug within the human body.

The drug is taken orally passing through the mouth, throat and esophagus into the stomach. Once in the stomach it is subjected to the acidic conditions of the stomach and eventually allowed to pass into the small intestine after the pyloric sphincter (valve at the base of the stomach) opens.

The drug in the intestine comes in contact with the intestinal mucosa (lining of the intestine) and is absorbed into the blood stream via the portal vein. This vein carries the recently absorbed drug to the liver and empties into the vena cava which carries the blood returning to the heart from the rest of the body.

This blood, containing carbon dioxide returns to the right side of the heart and is circulated to the lungs by the pulmonary artery, where it is purified by exchanging the carbon dioxide for oxygen. The purified blood returns to the left side of the heart by the pulmonary vein. After leaving the heart, the purified blood is circulated to the remainder of the body by large arteries. About one-third of the blood goes to the brain; the remainder goes to the rest of the body.

The aorta is the largest artery in the body and supplies blood to the lower extremities and all of the organs in the abdomen. The carotid artery is the major artery supplying blood to the brain.

10 billion capillaries

Once the blood is in the major arteries it flows to smaller and smaller arteries eventually arriving at the capillaries. There are about 10 billion capillaries in the body.

Drug circulation in capillary blood can now diffuse into the interstitial fluid surrounding the cells. If the drug is able to penetrate the cell wall, it can enter the cell and start its effect.

After some time, the drug can leave the cell, passing through the cell wall, enter the interstitial fluid, and pass into the capillary blood leaving the cell area.

The capillary blood flows into larger and larger veins, terminating in the vena cava. At this point, the cycle begins anew.

A normal, lean 150 pound man contains approximately 41 litres of water (58% of total body weight). Therefore, if 41 litres represents the total body water and 6 litres of this represent the volume of the circulating blood, the remaining 35 litres of water must be in the body tissues.

This water is not isolated from the blood, for fluids and drugs are transferred between the blood and body fluids, in and around the cells of the body. Therefore, drugs are diluted not only by the blood, but also by body tissues, since virtually all drugs can move out of the bloodstream and into the fluid that closely surrounds the cells of the body tissues. If the drug is capable of penetrating the cells, it will be further diluted by the intracellular fluids.

Protein-bound drugs

Another factor that can limit distribution is that many drugs may actually become bound firmly to proteins contained in the blood. Since blood proteins can be very large, they are unable to leave the bloodstream and are confined to the blood vessels. Such a protein bound drug is prevented from reaching the cells of the body tissue. This might appear to render it useless. If the drug's site of action is outside the blood vessels (in the brain for example), its binding would decrease its effectiveness. However if the drug's site of action is directly on blood cells, such a binding might augment its action.

Warfarin is used to prevent blood clots. This drug is almost completely bound and is therefore confined inside the blood vessels. Since the drug acts directly on blood cells to stop clots from forming, this confinement is useful. The more common situation is that only small amounts of a drug are bound to blood proteins and the distribution of a drug may be more general.

There may be unequal distribution among different parts of the body. Protein bound drug is confined to the blood stream. Drugs not bound to protein but soluble in water and insoluble in fat easily pass out of the bloodstream into the extracellular fluid but not into the intracellular fluid. An unbound drug which is soluble in both water and fat will move easily through to the intracellular fluid.

Thiopental, a commonly used anesthetic, will cause a person to pass out within seconds when injected intravenously because it is extremely soluble in fat, so it can rapidly leave the bloodstream and pass into the cells of the brain, where it quickly depresses the brain and causes unconsciousness. LSD is another example of a drug that readily penetrates brain cells.

Many drugs are distributed throughout the body in an unequal manner and the concentration of a drug may be higher in one organ than in another. It is also important to note, however, that the organ with the highest concentration of the drug is not necessarily the organ most affected by that drug. With respect to thiopental, most of this drug, in the body of a patient awakened from anesthesia, will be found in body fat and muscle. The effect of this drug is not on muscle or body fat. Any drug that remains in the body, but elsewhere than its site of action is considered to be inactive until it is redistributed.

Blood capillaries

Drug molecules are distributed throughout the body by means of the circulation of blood and are distributed fairly evenly within a minute or so after they enter the blood stream.

Most drugs, however, are not confined to the bloodstream, because they can be exchanged back and forth across the capillaries.

Capillaries are tiny cylindrical tubes with walls formed by a thin layer of cells tightly packed together and surrounded (for structural rigidity) by a thin membrane.

Each cell is separated from the others by minute passageways, called pores, which connect the interior of the tube, the capillary, with the body tissues around it. The pores have a very small diameter but are larger than most drugs. Since it is only in the capillaries that drugs are exchanged between blood and body cells, the capillaries must be small, to bring water and essential nutrients into close contact with the surrounding cells.

The capillaries are so small that only one red blood cell at a time can squeeze through a given capillary and fluid readily diffuses through both the ceiling lining and the water filled pores.

Since most drugs are smaller than the pores, even the least fat soluble drug is able to pass out of the capillaries into the surrounding tissue.

The rate at which drug molecules enter specific tissues of the body depends on two factors:

  • The rate of blood flow through the tissue
  • The ease with which drug molecules pass through the capillary membranes

Blood flow is greatest to the brain and much poorer to the bones, joints and fat deposits. Drug distribution, all else being equal, would follow a similar pattern.

Some capillaries have special properties that may further limit the rapid and free diffusion of a drug into the brain.

Blood-brain barrier

The passage of drugs into the central nervous system (CNS) is a special aspect of cellular penetration and is a unique example of the unequal distribution of drugs.

The brain constitutes only 2% of the body weight and yet under resting conditions it receives 16% of the blood pumped by the heart. The brain is the organ most richly supplied with blood. The average rate of blood flow to the brain is approximately 10 times that to the resting muscles.

Since the distribution of drugs to the various areas of the body is largely dependent upon the blood flow to the tissue, one might expect that drugs would pass very rapidly from the blood to the brain.

Indeed, some compounds (thiopental) do reach the brain very quickly, but many enter brain tissue only slowly, if at all. The decreased permeability of the capillaries of the brain has a structural basis and is frequently called the blood-brain barrier.

The blood-brain barrier can be bypassed if the drug is injected into the cerebrospinal fluid.

Placental barrier

Among all the membrane systems in the body, the placenta is unique. It separates two human beings with different genetic compositions, physiological responses, and sensitivities to drugs. The fetus receives essential nutrients and eliminates metabolic waste products through the placenta without depending on its own organs, many of which are not yet functioning.

This dependence of the fetus on the mother places the fetus at the mercy of the placenta when foreign substances, such as drugs, appear in the mother's blood. Pregnant women can present dangers to their fetus by taking drugs, or exposing themselves to toxic substances in food, cosmetics, household chemicals and in the environment.

The effects of drugs on the fetus are of two major types:

Early in pregnancy, when the limbs and organs are being formed, drugs may induce structural abnormalities: teratogenesis. The best example of this was thalidomide. Later in pregnancy and during delivery, drugs may induce respiratory problems in the newborn.

In general, the mature placenta consists of a network of vessels and pools of maternal blood into which protrude treelike or fingerlike villi containing the blood capillaries of the fetus.

Oxygen and nutrients move from the mother's blood to that of the fetus while carbon dioxide and other waste products move from the fetal to the maternal blood.

The membranes separating fetal blood from maternal blood in the intervillous space resemble cell membranes found elsewhere in the body.

Fat-soluble substances move across readily while fat-insoluble substances don't transfer as smoothly. This is of interest, since late in pregnancy and at the time of delivery, most anesthetic liquids and gases and most pain relieving agents penetrate both the blood-brain barrier and the placental barrier very well.

Anesthetic agents and narcotic analgesics may be found in fairly high concentrations in the newborn infant. We are all aware of stories about withdrawal symptoms in infants born to addicted mothers.

Biotransformation - metabolism

Once it enters the body, a drug divides into two parts, the part that remains unchanged and the part that changes. It can be eliminated from the body in both of these states -- as the drug administered and as the new chemical entities.

The amount of drug eliminated in a particular state depends on the nature of the drug, the dose, the route of administration, and the physiological characteristics of the user.

The process by which drugs are changed into different chemical compounds is called metabolism. The new substances that are produced are called metabolites.

Drugs are metabolized by compounds called enzymes. These are sophisticated proteins which act as catalysts in a chemical reaction. Most drug metabolism occurs in the liver, but enzymes in the gastrointestinal tract, lung and blood also assist in this breakdown process.

Conversion

The conversion of fat-soluble drugs to water soluble substances may involve several chemical steps, each step yielding a slightly more soluble substance, for eventual excretion by the kidneys. One drug can therefore yield many different metabolites.

As the drug becomes progressively less fat-soluble, it simultaneously loses its ability to cross the blood-brain barrier, and loses its strength in the brain.

Many intermediate metabolites are less potent than the parent drug, while others are completely devoid of pharmacological activity. Some drugs are pharmacologically more active than the parent drug. Metabolites are also capable of producing a completely different activity from the parent drug.

Repeated drug exposure can cause enzyme systems to increase in number, resulting in a faster metabolic rate. A more rapid rate of conversion can lead to increased intensity and speedier effect if the original substance was inactive and the metabolites active. It can also result in decreased intensity and duration of effect if the original drug was active and the metabolites inactive.

Many drugs are fat (lipid) soluble, or weak organic acids or bases and are not readily eliminated from the body.

Advantage may sometimes be taken of drug-metabolizing enzymes by administering an agent in an inactive form as a prodrug. In this case the metabolism creates the active species.

If drug metabolites are active, termination of action takes place by further biotransformation or by excretion of the active metabolite in the urine.

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