The action of a drug is believed to be due to the interaction of that drug with enzymes, receptors and other molecules found in the body. When one or more drug molecules bind to the target endogenous and exogenous molecules, they cause a change in or inhibit the biological activity of these molecules. The effectiveness of a drug in bringing about these changes usually depends on the stability of the drug-target complex, whereas the medical success of the drug intervention usually depends on whether enough drug molecules bind to sufficient target molecules to have a marked effect on the course of the disease state.
The degree of drug activity is directly related to the concentration of the drug in the aqueous medium in contact with the target molecule. The factors effecting this
Quinacrine concentration in a biological system can be classified into the pharmacokinetic phase and the pharmacodynamic phase of drug action. The pharmacokinetic phase concerns the study of the parameters that control the journey of the drug from its point of administration to its point of action. The pharmacodynamic phase concerns the chemical nature of the relationship between the drug and its target, in other words, the effect of the drug on the body.
1.7.1 The pharmacokinetic phase (ADME)
The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Excretion (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Chapter 2), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution (see section 11.5.1) controls its activity when that drug is administered as a solid or suspension by enteral routes (see section 1.6)
Absorption isusually defined as the passage of the drug from its site of administration into the general circulatory system after enteral administration. The use of the term does not apply to parenteral administration discussions. The most common enteral route is by oral administration. Drugs administered in this way take ab out 24 hours to pass through the gastrointestinal tract (GI tract). Individual transit times for the stomach and small intestine are about 20 minutes and 6 hours, respectively. Compounds may be absorbed throughout the length of the GI tract but some areas will suit a drug better than others.
The absorption of drugs through membranes and tissue barriers (see Chapter 7) can occur by a number of different mechanisms (see section 7.3). However, in general, neutral molecules are more readily absorbed through membranes than charged species. For example, ionisation of orally administered aspirin is suppressed in the stomach by acids produced by the parietal cells in the stomach lining. As a result, it is absorbed in this uncharged form through the stomach lining into the blood stream in significant quantities.
The main structural properties of a drug governing its good absorption from the GI tract are its aqueous solubility (see Chapter 2) and the balance between its polar (hydrophilic) and non-polar (hydrophobic) groups (see section 1.4.2). If the drug's water solubility is too low it will pass through the GI tract without a significant amount being absorbed. Drugs that are too polar will tend to be absorbed by paracellular diffusion, which is only readily
Aspirin available in the small intestine and is usually slower than transcellular diffusion undergone by less polar and non-polar compounds (see section 11.5.2). Drugs that are absorbed by transcellular diffusion are usually absorbed along the whole length of the GI tract. If the drug is too non-polar (lipophilic) it will be absorbed into and remain within the lipid interior of the membranes of the cells forming the membrane. The Lipinski rule of fives (see section 1.4.1) is useful for assessing whether a compound is likely to be absorbed from the GI tract. However, this rule does have its limitations and the results of its use should only be used as a guide and not taken as being absolute.
The degree of absorption can also be related to the surface area of the region of tissue over which the absorption is occurring and the time the drug spends in contact with that region. For example, it can be shown by calculation using the Henderson-Hasselbalch equation (see section 2.11) that aspirin will be almost fully ionised in the small intestine. Consequently, aspirin should not be readily absorbed in this region of the GI tract. However, the very large surface area of the small intestine (300 m2) together with the time spent in this region ( ~ 6 hours) results in aspirin being absorbed in significant quantities in this region of the GI tract. Examples of some of the other factors that can effect the degree of absorption of a drug are:
• the pH of the medium from which absorption occurs (see section 2.11);
• the drug's partition coefficient (see section 3.7.2);
• the drug's particle size (see section 11.5.1); and
• for orally administered drugs, in either solid or emulsion form, their rate of dissolution (see section 11.5.1), amongst others.
It should be noted that the form of the drug that is absorbed is not necessarily the form that is responsible for its action. Benzocaine, for example, is absorbed as its neutral molecule but acts in its charged form.
Distribution is the transport of the drug from its initial point of administration or absorption to its site of action. The main route is through the circulation of the blood although some distribution does occur via the lymphatic system. Once the drug is absorbed it is rapidly distributed throughout all the areas of the body reached by the blood. This means that the
Inactive form transported through membranes
Inactive form transported through membranes
Benzocaine chemical and physical properties of blood will have a considerable effect on the concentration of the drug reaching its target site.
Drugs are transported in the blood stream as either a solution of drug molecules or bound to the serum proteins, usually albumins. The binding of drugs to the serum proteins is usually reversible.
Drug molecules bound to serum proteins have no pharmacological effect until they are released from those proteins. Consequently, this equilibrium can be an important factorin controlling a drug's pharmacological activity (see section 11.4.1). However, it is possible for one drug to displace another from a protein if it forms a more stable complex, that is, has a stronger affinity for that protein. This aspect of protein binding can be of considerable importance when designing drug regimens involving more than one drug. For instance, the displacement of antidiabetic agents by aspirin can trigger hypoglycaemic shock and so aspirin should not be used by patients taking these drugs. Protein binding also allows drugs with poor water solubility to reach their target site. The drug-protein complex acts as a depot maintaining the drug in sufficient concentration at the target site to bring about a response. However, a low plasma protein concentration can also affect the distribution of a drug in some diseases such as rheumatoid arthritis as the 'reduced transport system' is unable to deliver a sufficient concentration of the drug to its target site. Protein binding can also increase the duration of action if the drug-protein complex is too large to be excreted through the kidney by glomerular filtration.
Major factors that influence distribution are the solubility and stability of drugs in the biological environment of the blood. Sparingly water-soluble compounds may be deposited in the blood vessels, leading to restriction in blood flow. This deposition may be influenced by the commonion effect (see section 2.4.1). Drug stability is of particular importance in that serum proteins can act as enzymes that catalyse the breakdown of the drug. Decompositions such as these can result in a higher dose of the drug being needed in order to achieve the desired pharmacological effect. This increased dose increases the risk of toxic side effects in the patient. However, the active form of some drugs is produced by the decomposition of the administered form of the drug. Drugs that function in this manner are known as prodrugs (see section 12.9). The first to be discovered, in 1935, was the bactericide prontosil. Prontosil itself is not active but is metabolised in situ to the antibacterial sulphanilamide. Its discovery paved the way to the devolvement of a wide range of antibacterial sulphonamide (sulfa) drugs. These were the only effective antibiotics available until the general introduction of penicillin in the late 1940s.
Drug ^ Drug—Serum Protein complex
The distribution pattern of a drug through the tissues forming the blood vessels will depend largely on the nature of the tissue (see section 7.2.9) and on the drug's lipid solubility. For example, in general, the pH of the tissues (~ pH 7.0) forming blood vessels is less basic than that of the plasma (~ pH 7.4). Acidic drugs such as aspirin, which ionise in aqueous solution, exist largely in the form of their anions in the slightly basic plasma. Since uncharged molecules are transferred more readily than charged ions these acidic anions tend to remain in the plasma and not move out of the plasma into the tissues surrounding the blood vessel. Consequently, acids have a tendency to stay in the plasma rather than pass into the surrounding tissue. Conversely, a significant quantity of a basic drug tends to exist as neutral molecules in the plasma. As a result, bases are more likely to pass into the tissues surrounding the plasma. Furthermore, once the base has passed into the tissue the charged form of the base is likely to predominate and so the drug will tend to remain in the tissue. This means that the base is effectively removed from the plasma, which disturbs its equilibrium in the plasma to favour the formation of the free base, which results in further absorption of the base into the tissue (Fig. 1.12). As a result, basic drugs, unlike acidic drugs, are likely to be more widely distributed in tissues.
In the plasma (pH ~7.4, slightly basic) In the tissue (pH ~7.0, neutral)
Exists as HA Exists mainly as
Figure 1.12 The species involved in the transfer of acidic and basic drugs from the plasma to the surrounding tissues
In the plasma (pH ~7.4, slightly basic) In the tissue (pH ~7.0, neutral)
Figure 1.12 The species involved in the transfer of acidic and basic drugs from the plasma to the surrounding tissues u nch arged B:
u nch arged B:
A drug's lipophilicity (see sections 1.4.2 and 3.7.2) will also influence its distribution. Highly lipophilic drugs can readily enter and accumulate in the fatty deposits of humans. These fatty deposits, which form up to 15 per cent in the body weight of normal individuals and 50 per cent in obese persons, can act as pharmacologically inert depots for drugs, which could terminate their action. For example, the concentration of the ultra-short-acting anaesthetic thiopental rapidly falls after administration to an ineffective level because it accumulates in the fatty tissue deposits of the body. It is slowly released from these deposits in concentrations that are too low to cause a pharmacological response.
The distribution of drugs to the brain entails having to cross the blood-brain barrier (BBB) (see section 7.2.9). This barrier protects the brain from both exogenous and
Figure 1.13 The structures of some of the drugs that are able to cross the blood-brain barrier
endogenous compounds. The extent to which lipophilic drugs are able to cross this barrier varies: highly lipophilic drugs, such as diazepam, midazolam and clobazopam (Fig. 1.13), are rapidly absorbed while less lipophilic drugs are absorbed more slowly. Polar drugs are either unable to cross the BBB or only do so to a very limited extent. For example, calculations using the Henderson-Hasselbalch equation (see section 2.11) show that at blood pH, 99.6 per cent of amphetamine and 98.4 per cent of chlorpromazine exist in their charged forms (Fig. 1.13). However, these polar drugs are still sufficiently lipid soluble to cross the BBB. Some polar drugs may cross by an active transport mechanism (see section 7.3.5). Other polar endogenous compounds such as amino acids, sugars, nucleosides and small ions (Na +, Li+, Ca2 + and K+) are also able to cross the BBB.
Drug metabolism (see Chapter 12) is the biotransformation of the drug into other compounds (metabolites) that are usually more water soluble than their parent drug and are usually excreted in the urine. It usually involves more than one route and results in the formation of a succession of metabolites (Fig. 1.14). These biotransformations occur mainly in the liver but they can also occur in blood and other organs such as the brain, lungs and kidneys. Drugs that are administered orally usually pass through the liver before reaching the general circulatory system. Consequently, some of the drug will be metabolised before it reaches the systemic circulation. This loss is generally referred to as either the first-pass effect or first-pass metabolism (see section 11.4.1). Further metabolic losses will also be encountered before the drug reaches its target site, which means it is
Figure 1.14 An outline of the known metabolic pathways of the local anaesthetic lignocaine
Figure 1.14 An outline of the known metabolic pathways of the local anaesthetic lignocaine important to administer a dose large enough for sufficient of the drug to reach its target site.
Drug metabolism may produce metabolites that are pharmacologically inert, have the same or different action to the parent drug or are toxic (see section 12.2). Exceptions are prodrugs (see sections 1.8.4 and 12.9) where metabolism is responsible for producing an active drug, for example the non-steroidal anti-inflammatory agent sulindac is metabolised to the active sulphide (Fig. 1.15). In addition, the metabolic products of a drug may be used as leads for the development of a new drug.
Inactive administered form of the drug Active sulphide metabolite of the drug
Figure 1.15 An outline of the metabolic pathway for the formation of the active form of sulindac
Excretion is the process by which unwanted substances are removed from the body. The main excretion route for drugs and their metabolites is through the kidney in solution in the urine. However, a significant number of drugs and their metabolic products are also excreted via the bowel in the faeces. Other forms of drug excretion, such as exhalation, sweating and breast feeding, are not usually significant except in specific circumstances. Pregnant women and nursing mothers are recommended to avoid taking drugs because of the possibility of biological damage to the foetus and neonate. For example, the use of thalidomide by pregnant mothers in the 1960s resulted in the formation of drug-induced malformed foetuses (teratogenesis). It has been estimated that the use of thalidomide led to the birth of 10,000 severely malformed children.
In the kidneys drugs are excreted by either glomerular filtration or tubular secretion. However, some of the species lost by these processes are reabsorbed by a recycling process known as tubular reabsorption. In the kidney, the glomeruli act as a filter allowing the passage of water, small molecules and ions but preventing the passage of large molecules and cells. Consequently, glomerular filtration excrets small unbound drug molecules but not the larger drug-protein complexes. Tubular secretion on the other hand is an active transfer process (see section 7.3.5) and so both bound and unbound drug molecules can be excreted. However, both of these excretion systems have a limited capacity and not all the drug may be eliminated. In addition, renal disease can considerably increase or decrease the rate of drug excretion by the kidney.
Tubular reabsorption is a process normally employed in returning compounds such as water, amino acids, salts and glucose that are important to the well-being of the body from the urine to the circulatory system, but it will also return drug molecules. The mechanism of reabsorption is mainly passive diffusion (see section 7.3.3), but active transport (see section 7.3.5) is also involved, especially for glucose and lithium ions. The reabsorption of acidic and basic compounds is dependent on the pH of the urine. For example, making the urine alkaline in cases of poisoning by acidic drugs, such as aspirin, will cause these drugs to form ionic salts, which will result in a significantly lower tubular reabsorption since the passage of the charged form of a drug across a lipid membrane is more difficult than the passage of the uncharged form of that drug. Similarly, in cases of poisoning by basic drugs such as amphetamines, acidification of the urine can, for a similar reason, reduce reabsorption.
Control of urinary pH is also required for drugs whose concentration reaches a level in the urine that results in crystallisation (crystalluria) in the urinary tract and kidney with subsequent tissue damage. For example, it is recommended that the urine is maintained at an alkaline pH and has a minimum flow of 190 ml hwhen sulphonamides are administered.
Excretion also occurs via the intestines and bowel through biliary clearance from the liver. The liver is linked to the intestine by the bile duct and some compounds are excreted by this route. However, very large molecules are metabolised to smaller compounds before being excreted. However, a fraction of some of the excreted drugs are reabsorbed through the enterohepatic cycle. This reabsorption can be reduced by the use of suitable substances in the dosage form, for example the ion exchange resin cholestyramine is used to reduce cholesterol levels by preventing its reabsorption.
A drug must reach its site of action in sufficient quantity to be effective. One of the tasks of the medicinal chemist is to take an active compound and modify the structure to achieve the desired ADME properties. However, having satisfactory ADME properties is not the only requirement for a new drug. A drug candidate must also be:
• potentially effective in treating a patient;
• free of existing patents;
• produced in sufficient quantities;
• capable of being dispensed in a dosage form acceptable to the patient;
• must not exhibit teratogenicity or mutagenicity;
• and commercial development must be cost effective.
Failure to comply with these additional aspects of drug discovery and design will mean that work on the candidate is discontinued before the project proceeds past its preliminary stages.
Pharmacodynamics is concerned with the result of the interaction of drug and body at its site of action, that is, what the drug does to the body. It is now known that a drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary with the stereoelectronic structure of the target site.
The role of the medicinal chemist is to design and synthesise a drug structure that has the maximum beneficial effects with a minimum of toxic side effects. This design has to take into account the stereoelectronic characteristics of the target site and also such factors as the drug's stability in situ, its polarity and its relative solubilities in aqueous media and lipids. The stereochemistry of the drug is particularly important as stereoisomers often have different biological effects which range from inactive to highly toxic (see section 1.4.3 and Table 1.1).
Drugs act at their target site by either inhibiting or stimulating a biological process with, hopefully, beneficial results to the patient. To bring about these changes the drug must bind to the target site, that is, its potency will depend on its ability to bind to that site. This binding is either reversible or permanent. In the former case, the bonding is due to weak electrostatic bonds such as hydrogen bond and van der Waals' forces. The binding takes the form of a dynamic equilibrium with the drug molecules repeatedly binding to and being released from their target site (see section 8.6). Consequently, in this instance, a drug's duration of action will depend on how long it remains at the target site. Permanent binding usually requires the formation of strong covalent bonds between the drug andits target. In this case, the duration of action will depend on the strength of the bond. However, in both cases, the drug structure must contain appropriate functional groups in positions that correspond to the appropriate structures in the target site.
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