PharmacokineticsPharmacokinetics

DistributionDistribution

Distribution of drugsDistribution of drugs

When a drug is administered, it does not achieve an equal concentration throughout the body.

The body can be considered to be made up of aqueous and lipid compartments.

Lipid compartments include all cell membranes and adipose tissue.

Aqueous compartments include tissue fluid, cellular fluid, blood plasma and fluid in places like the central nervous system, the lymphatic system, joints and the gastrointestinal tract.

The distribution of a drug into these different compartments depends on many factors.

Factors affecting drug distributionFactors affecting drug distribution

Aqueous solubility– Water-soluble drugs have difficulty crossing cell

membranes and therefore tend to remain in the circulation.

– Thus ,water-soluble drugs are not well distributed throughout the body. They exist in large amounts in the plasma or tissue fluid.

– They are rapidly cleared by the liver or kidney.

– In practice, such drugs have little therapeutic use.

Factors affecting drug distributionFactors affecting drug distribution

Blood flow– At equilibrium, drugs are partitioned between plasma, plasma prote

ins and the different tissues.

– The rate of distribution to different tissues depends largely on the rate of blood flow through them.

– Well perfused organs receive a relatively high concentration of a drug whereas it can be difficult to get drugs into less well-perfused areas.

Although the brain has a very good blood supply, distribution of drugs into the central nervous system is restricted. This is because of the so-called ‘blood-brain barrier’.

Blood-Brain BarrierBlood-Brain Barrier

This is not an anatomical barrier as such, rather a combination of the tight junctions between endothelial cells of brain capillaries and the close association of glial cells with the outside of the capillaries.

This arrangement makes diffusion of lipid-soluble drugs into the brain difficult and diffusion of water-soluble drugs almost impossible.

Factors affecting drug distributionFactors affecting drug distribution

Plasma protein binding– A large number of drugs have a high affinity for albumin and other plasma

proteins.

– Plasma protein binding reduces active drug concentration and ultimate response to the drug.

– Drugs can compete for the same protein binding sites and this is a form of drug interaction.

Example - warfarin and aspirin. Warfarin is an anticoagulant, which binds extensively to plasma proteins, and thi

s is taken into account when dosages are worked out. Aspirin taken with warfarin competes for the same protein binding sites, which means that they each displace the other and the amount of free drug in the plasma is increased for both drugs. Patients stabilized on warfarin should never take aspirin because the effect of increased free plasma concentration of warfarin can be severe haemorrhaging. Coincidental increased activity of aspirin is not as serious.

Factors affecting drug distributionFactors affecting drug distribution

Lipid solubility– Lipid-soluble drugs enter cells readily.

– Distribution of such drugs is widespread unless plasma protein binding is extensive.

– Elimination of lipid-soluble drugs is usually slow because clearance from plasma via the kidneys removes only a small proportion of the drug in any given time.

Factors affecting drug distributionFactors affecting drug distribution

Tissue sequestration– Considerable amounts of drug may be stored in certain tissues, particularly fat and muscle.

– Sequestration in this way gives an apparent large volume of distribution but also means that only a small proportion of total drug concentration will reach its site of action. This can create difficulties with the usage of certain drugs.

For example,

– General anaesthetics are highly lipid-soluble drugs. Sequestration into adipose tissue can make anaesthetizing obese people hazardous because it is difficult to control the amount of free drug in the circulation.

– Benzodiazepines (antianxiety drugs) can be difficult to clear from the body because they are stored in large amounts in adipose tissue. This can complicate withdrawal.

– Griseofulvin has an affinity for keratin. Since this drug can be used to treat fungal infections of the skin and nails its sequestration into keratin is something of an advantage.

– Tetracycline has an affinity for bones and teeth. It should never be used in children as its accumulation can damage teeth and stunt growth.

Factors affecting drug distributionFactors affecting drug distribution

Metabolism and excretion

– The rate at which a drug is metabolized will affect its distribution.

– Similarly the rate of elimination or excretion also affects distribution and vice versa.

Factors affecting drug distributionFactors affecting drug distribution

Volume of distribution– Volume of distribution is a concept that describes the body compartments

into which a drug could be distributed.

– If a drug is water soluble it is likely to remain in the blood stream and its volume of distribution will be relatively small and equal blood volume.

– Similarly, acidic drugs tend to bind to plasma albumin and therefore also remain in the blood stream and have a small volume of distribution.

– If a drug is highly lipid soluble, then it will be distributed to many parts of the body and have a large volume of distribution.

– In addition, basic drugs tend to bind to tissue proteins and as a result have a large volume of distribution.

Drug metabolism

On entering the body, drugs are treated as if they are toxic substances, which need to be detoxified, if a mechanism exists, and eliminated as soon as possible.

This means that most drugs are subjected to some kind of metabolism and then excreted.

Metabolism involves changes to the molecular structure of a substance and these changes are produced by the action of enzymes.

Drug metabolism

This has two important effects on drug molecules:

1. The drug is made more water soluble and therefore more easily excreted by the kidneys;

2. The metabolites are usually less pharmacologically active than the parent drug.

This is not always the case. A drug metabolite may have a new and completely different pharmacological activity, or it may be as active as or more active than the original drug.

Drug metabolism

Some drugs have to be metabolized in order to become active.

Prodrugs are drugs that have been designed to remain inactive until they have been metabolized by the body.

They may be formulated in this way because the active drug is difficult to administer, whereas the inactive prodrug does not cause the same complications, or because the active drug is not absorbed or distributed to its intended site of action easily.

Drug metabolism

Most tissues in the body have the enzymes capable of metabolizing a variety of substances.

However, as one of the main functions of the liver is the metabolism of toxic substances produced during normal metabolic processes, it is not surprising that the majority of drug metabolism takes place in the liver.

Some drugs are almost completely inactivated by first pass metabolism in the liver.

The extent of first pass metabolism varies from individual to individual and can lead to unpredictable effects for some drugs administered orally.

Other tissues where significant metabolism of drugs can occur include the intestinal mucosa, the lungs and plasma.

Drug metabolism (Metabolic reactions)

There are two general types of metabolic reactions, which are

– Phase 1 reaction

– Phase 2 reaction

Some drugs undergo both Phase 1 and Phase 2 reactions, but, depending on its chemical nature, it is possible for a drug to be metabolized by either type of reaction only.

Drug metabolism (Metabolic reactions)

Phase 1 reactions

Phase 1 reactions involve the biotransformation of a drug by reactions to a more water-soluble metabolite, which is more likely to be excreted by the kidney or go on to Phase 2.

This may increase the toxicity of some drugs.

Phase 1 reactions

Oxidation Oxidation

Oxidation is the most important and commonest type of metabolic reaction, which involves the addition of oxygen to the drug molecule.

In the liver, oxidation reactions are catalysed by a group of enzymes known as the microsomal mixed function oxidase system or the cytochrome P450 enzyme family.

Oxidative reactions take place in many other tissues as well.

Phase 1 reactions

Reduction Reduction

Reduction reactions involve the removal of oxygen or the addition of hydrogen to the drug molecule.

Enzymes capable of catalysing reduction reactions are found in many body tissues, including the liver and in the intestinal bacteria.

Phase 1 reactions

Hydrolysis Hydrolysis

Hydrolysis involves the splitting of a drug molecule by the addition of water.

Enzymes capable of catalysing hydrolysis are found in many body tissues but particularly in the small intestine.

Phase 2 reactions

Phase 2 reactions make drugs or Phase 1 metabolites into more hydrophilic, less toxic substances by conjugation with endogenous compounds in the liver.This too encourages renal excretion.

The most important conjugation reaction is with glucuronic acid to form a glucuronide.

Other conjugations occur with sulfate, acetyl, methyl and glycine groups.

Many drugs are metabolized by a combination of routes and this can vary from individual to individual and depends on the dose of drug, the presence of interacting drugs and the state of the liver.

Inhibition of drug metabolism

Metabolism of one drug can be completely inhibited by the other drug if it utilizes the same enzyme or co-factors.

Not common because different drugs are substrates for different cytochrome P-450isoenzymes.A drug may inhibit one one isoenzyme while being itself a substrate for another isoenzymes.

E.g.quinidine is metabolized by CYP3A4 but inhibits CYP2D6 Limited blood flow limits metabolism. E.g.propanolol reduces rate of lidocaine metabolism by reducin

g blood flow.

Excretion of drugs

Drugs are potentially toxic substances and must be eliminated by the body as quickly as possible. The main route of excretion of drugs and drug metabolites is via the kidneys.

Elimination varies amongst individuals and depends on the rate of metabolism of a particular drug, the rate of production of urine and the pH of urine.

There are three processes to the production of urine .Drugs, like waste products from normal metabolism, can be subjected to all structures of the kidney.

Glomerular filtration

The glomerulus is adapted for the filtration of water and substances dissolved in it from plasma. Pressure in the capillaries of the glomerulus forces fluid and dissolved substances into the Bowman’s capsule. Most drugs are small enough to be filtered, although if they are lipid soluble they are readily reabsorbed from other parts of the kidney tubule.

Proteins are generally too large to be filtered at the glomerulus and do not appear in the urine. Therefore, drugs that are extensively bound to plasma proteins pass through the glomerulus slowly.

Tubular secretion

Tubular secretion of drugs occurs in the proximal convoluted tubule by active transport mechanisms normally used for the removal of waste products. Transport systems exist for the secretion of acidic substances, for example uric acid and basic substances, for example creatinine. Many drugs can be actively secreted by this mechanism, which increases their rate of removal from the body.

Active transport does not depend on concentration gradients and can overcome plasma protein binding. As the free drug is transported, more of the drug dissociates from the protein binding site and can be eliminated.

Substances transported by the same transport system compete with each other and the more slowly a drug is transported the more effective it is at inhibiting the transport of another.

A well-documented historical example of this is the competition between penicillin and probenecid. Penicillin is a drug that is approximately 80% protein bound, but is rapidly

A well-documented historical example of this is the competition between penicillin and probenecid. Penicillin is a drug that is approximately 80% protein bound, but is rapidlyeliminated by a kidney transport system. This was a disadvantage in the days whenpenicillin was expensive and difficult to produce, because its action was prematurely terminated unless high doses were given.Penicillin used to be administered together with probenecid. Probenecid is slowly transported by the same system and therefore considerably reduces the elimination of penicillin.

Probenecid is used to treat gout because it also inhibits the reabsorption of uric acid by a similar mechanism.

Tubular reabsorption

Useful substances are reabsorbed from the kidney tubules back into plasma by diffusion or active transport. Much of this occurs early on in the nephron at the proximal convoluted tubule but also at the distal convoluted tubule where tubular filtrate concentration is high.

Lipid-soluble drugs may be reabsorbed in this way and as a result, they are eliminated slowly from the body.

Metabolism of drugs tends to make them less lipid soluble, more water soluble and therefore more likely to ionize.

Tubular filtrate is normally slightly acid and this favours the excretion of basic drugs.

Change in pH of the tubular filtrate can affect drug ionization. Manipulation of pH to increase the rate of elimination of a drug has a practical use in cases of overdose as shown by the following examples.

Administration of sodium bicarbonate increases the alkalinity of the tubular filtrate therefore acidic drugs, for example aspirin and barbiturates become ionized and cannot diffuse back from the tubules to the plasma. Hence their rate of elimination is increased.

This may be useful in the event of an overdose.

Conversely, the elimination of basic drugs such as amphetamine, antihistamines, morphine and tricyclic antidepressants can be increased by making tubular filtrate more acidic by administration of ammonium chloride.

Other routes of excretion

It is possible for drugs to move back across the intestinal wall by diffusion or active transport and be lost in faeces. Some drugs, particularly hormones, can also be excreted into the intestine via bile. Such drugs are conjugated in the liver and passed into bile before they reach the systemic circulation. Often bacteria in the large intestine digest the conjugate releasing free drug, which can then be reabsorbed and recycled by the processof enterohepatic shunting.

Prolonged use of antibiotics can sterilize the large intestine and interrupt this cycle and increase drug elimination in faeces. Unexpected loss of a drug in this way can reduce its therapeutic action. Diarrhoea can have a similar effect.

Certain drugs are excreted via expiration; the rate of excretion depends on plasma concentration, alveolar air concentration and blood-gas partition. Anaesthetic gases are the only group of drugs that are significantly excreted in expired air.

A small amount of alcohol is excreted in this way but this accounts for only a small proportion of the overall elimination.

Loss of drugs in sweat and breast milk occurs, but is of minor importance although the appearance of drugs in breast milk can have serious consequences for the nursing baby