Drug Chemistry

The physical and chemical properties of a drug will influence its ability to traverse biologic membranes and to be dissolved and transported in biologic fluids.

Molecular size and shape. Smaller molecules are absorbed more readily. Drug shape affects affinity of the drug for carrier molecules or other binding sites such as plasma proteins or tissue. Drugs of similar structure may exhibit competition for such binding sites, which can affect their pharmacokinetics.

State of ionization. The nonionized form of drugs is more lipid permeable and therefore better able to diffuse across biologic barriers. The pK_a is a characteristic of the drug and reflects the pH at which the drug will be equally partitioned between the ionized and nonionized forms.

The lipid-water partition coefficient is an index of lipid solubility. Drugs with higher lipid-water partition coefficients will cross biologic membranes more quickly.

Effect of pH

Most drugs are weak acids or bases and, as such, in solution show varying degrees of dissociation into their ionized and nonionized forms. The distribution between ionized and nonionized forms will be determined by the pK_a of the drug and the pH of the solution in which the drug is dissolved.

For drugs that are weak acids, the following equation applies, where HA = drug with proton, which is therefore nonionized. H⁺ = proton, and A⁻ is the ionized drug.

Under basic conditions, weak acids are ionized to a greater extent (because the basic environment will shift the reaction to the right).

Under acidic conditions, weak acids are nonionized to a greater extent (because the acidic environment will shift the reaction to the left).

The greater the difference between the pH and the pK_a, the greater the degree of ionization or nonionization.

The relationship between the pH of the drug’s environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation:

Henderson-Hasselbalch Equation Applied to Acidic Drugs

For drugs that are weak bases, the reverse is true compared with weak acids: HB⁺ = drug with proton, which is therefore ionized. H⁺ = proton, and B is the nonionized drug.

Under basic conditions, weak bases are nonionized to a greater extent (because the basic environment will shift the reaction to the right).

Under acidic conditions, weak bases are ionized to a greater extent (because the acidic environment will shift the reaction to the left).

Again, the greater the difference between the pH and the pK_a, the greater the degree of ionization or nonionization.

The relationship between the pH of the drug’s environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation:

Henderson-Hasselbalch Equation Applied to Basic Drugs

The practical implications are as follows: The ionized form of the drug may become stranded in certain locations. This effect, referred to as ion trapping or pH trapping, occurs when drugs accumulate in a certain body compartment because they can diffuse into this area, but then become ionized owing to the prevailing pH and are unable to diffuse out of this location. An example, shown in Figure 2-1, is the trapping of basic drugs (e.g., morphine, pK_a 7.9) in the stomach. The drug is approximately 50% nonionized in the plasma (pH approximately 7.4) because it is in an environment with a pH close to its pK_a. In the stomach (pH approximately 2), the drug is highly ionized (approximately 200,000×), it cannot diffuse across the cells lining the stomach, and the drug molecules are trapped in the stomach.

Figure 2-1 Effect of pH on drug ionization: ion trapping or pH trapping.

The concepts of acidic and basic drugs and their relative ionization at different pH values can be used clinically. For example, acidification of the urine is used to increase the elimination of amphetamine, a basic drug with pK_a approximately 9.8. Rendering the urine acidic increases the amount of amphetamine in the ionized state, preventing its reabsorption from the urine into the bloodstream. Conversely, alkalinization of the urine is used to increase the excretion of acetylsalicylic acid (aspirin), an acidic drug. Increasing the pH of urine above the pK_a of acetylsalicylic acid increases the proportion of the drug in the ionized state by about 10,000 times. The ionized form of the drug is not able to be reabsorbed across the renal tubule into the bloodstream. Moreover, the low concentration of the non-ionized form in the renal tubule compared with that in the blood favors diffusion of the non-ionized drug into the renal tubules (see Figure 2-2).

Figure 2-2 Application of pH trapping to renal drug elimination.

Absorption

In general, for a drug to reach its intended target, the drug must be present in the bloodstream (an exception is application of drug for local effects such as local anesthesia). Thus, absorption of drugs refers to the amount of drug reaching the general circulation from its site of administration. The fraction of drug reaching the systemic circulation is expressed as the bioavailability. The concept of bioavailability is important in practice because the clinician can use routes of administration that maximize bioavailability. In addition, changes in bioavailability resulting from genetic variation, disease, or drug interactions are a frequent cause of loss of drug effectiveness, because of a decrease in bioavailability, or, conversely drug toxicity, because of an increase in bioavailability.

Bioavailability will be influenced by any factors that impede the active drug from reaching the systemic circulation (Figure 2-3). These include diffusion across physiologic barriers, the effect of transporters that prevent accumulation of drug in the blood, and metabolism of the drug before it reaches the systemic circulation. For example, after oral administration, a drug may have low bioavailability if:

The drug is highly ionized at gut pH (does not readily cross lipid barrier).

The drug is actively transported from the epithelial cell cytoplasm back into the gut lumen by drug transporters such as P-glycoprotein (e.g., cyclosporine).

The drug is extensively metabolized during its passage through the liver.

Figure 2-3 Factors affecting bioavailability of drugs.

Factors that alter a drug’s ability to cross biologic membranes, its interaction with pumping mechanisms, or its metabolism will affect drug bioavailability, drug effect, and drug toxicity.

Oral bioavailability of some drugs (e.g., nitroglycerin) can be reduced so severely by these mechanisms that this route of administration is not practical, requiring the use of alternate routes of administration that bypass the major barriers to bioavailability.

Routes of Administration

Routes of administration greatly affect bioavailability by changing the number of biologic barriers a drug must cross or by changing the exposure of drug to pumping and metabolic mechanisms.

Enteral Administration

Enteral administration involves absorption of the drug via the GI tract and includes oral, gastric or duodenal (e.g., feeding tube), and rectal administration

Oral (PO) administration is the most frequently used route of administration because of its simplicity and convenience, which improve patient compliance. Bioavailability of drugs administered orally varies greatly. This route is effective for drugs with moderate to high oral bioavailability and for drugs of varying pK_a because gut pH varies considerably along the length of the GI tract. Administration via this route is less desirable for drugs that are irritating to the GI tract or when the patient is vomiting or unable to swallow. Drugs given orally must be acid stable or protected from gastric acid (e.g., by enteric coatings). Additional factors influencing absorption of orally administered drugs include the following:

Gastric emptying time. For most drugs the greatest absorption occurs in the small intestine owing to its large surface. More rapid gastric emptying facilitates their absorption because the drug is delivered to the small intestine more quickly. Conversely, factors that slow gastric emptying (e.g., food, anticholinergic drugs) generally slow absorption.

Intestinal motility. Increases in intestinal motility (e.g., diarrhea) may move drugs through the intestine too rapidly to permit effective absorption.

Food. In addition to affecting gastric emptying time, food may reduce the absorption of some drugs (e.g., tetracycline) owing to physical interactions with the drug (e.g., chelation). Alternatively, absorption of some drugs (e.g., clarithromycin) is improved by administration with food.

Intestinal metabolism and transport. The intestinal wall has extensive metabolic processes and transport mechanisms (e.g., P-glycoprotein) that affect absorption of drugs given via the oral route.

Hepatic metabolism. Orally administered drugs are absorbed into the portal circulation and carried directly to the liver. The liver has extensive metabolic processes that can affect drug bioavailability.

Rectal administration via suppositories to produce a systemic effect is useful in situations in which the patient is unable to take medication orally (e.g., is unconscious, vomiting, convulsing). Drugs are absorbed through the rectal mucosa. Because of the anatomy of the venous drainage of the rectum, approximately 50% of the dose bypasses the portal circulation, which is an advantage if the drug has low oral bioavailability. On the other hand, drug absorption via this route is incomplete and erratic, in part because of variability in drug dissociation from the suppository. Rectal administration is also used for local topical effects (e.g., antiinflammatory drugs in the treatment of colitis).

Sublingual (under the tongue) or buccal (between gum and cheek) administration is advantageous for drugs that have low oral availability because venous drainage from the mouth bypasses the liver. Drugs must be lipophilic and are absorbed rapidly. Buccal formulations can provide extended-release options to provide long-lasting effects.

Parenteral Administration

Parenteral administration refers to any routes of administration that do not involve drug absorption via the GI tract (par = around, enteral = gastrointestinal), including the IV, intramuscular (IM), subcutaneous (SC or SQ), and transdermal routes. Reasons for choosing a parenteral route over the oral route include drugs with low oral bioavailability, patients who are unable to take the drug by mouth (e.g., it irritates the GI tract), the need for immediate effect (e.g., emergency situations), or the desire to control the rate of absorption and duration of effect.

IV administration is the most reliable method for delivering drug to the systemic circulation because it bypasses many of the absorption barriers, efflux pumps, and metabolic mechanisms. In fact, by definition, bioavailability of drugs is 100% by IV injection because the drug is administered directly into the vascular space. It is also one of the preferred routes of administration to rapidly achieve therapeutically effective drug concentrations. IV infusions may be used to achieve a constant level of drug in the bloodstream. Drugs must be in aqueous solution or very fine suspensions to avoid the possibility of embolism. Caution must be used with drugs or drug combinations with the propensity to form precipitates.

IM administration of drugs in aqueous solution results in rapid absorption of drug in most cases. Drug absorption is dependent on muscle blood flow and thus is influenced by factors that alter blood flow to the muscle (e.g., exercise). It is also possible to achieve a slower, more constant absorption and effect of drug by altering the drug vehicle. Depot IM injections use drug formulation to slowly release drug at the site of injection.

SC administration is used for drugs that have low oral bioavailability (e.g., insulin). In addition, the rate of absorption can be manipulated by using different formulations of the drug (e.g., fast-acting versus slow-acting insulin preparations). This route is not appropriate for solutions that are irritating to tissue because these may produce necrosis and sloughing of the skin.

Transdermal administration is administration through the skin. The drug must be highly lipophilic. Drugs may be applied as ointments or in special matrices (e.g., transdermal patches). Absorption via this route is slow but conducive to producing long-lasting effects. Special slow-release matrices in some transdermal patches can maintain steady drug concentrations that approach those of constant IV infusion.

Inhalational administration can be used. The lungs serve as an effective route of administration of drugs. The pulmonary alveoli represent a large surface and a minimal barrier to diffusion. The lungs also receive the total cardiac output as blood flow. Thus, absorption from the lungs can be very rapid and complete. Drugs must be nonirritating and gaseous or very fine aerosols. The intended effects may be systemic (e.g., inhaled general anesthetics) or local (e.g., bronchodilators in the treatment of asthma).

Topical administration involves application of the drug primarily to elicit local effects at the site of application and to avoid systemic effects. Examples include drugs administered to the eye, the nasal mucosa, or the skin. Generally drugs are formulated to be less lipophilic to reduce systemic absorption.

Intrathecal administration penetrates the subarachnoid space to allow access of the drug to the cerebrospinal fluid of the spinal cord. This approach is used to circumvent the blood-brain barrier. Intrathecal administration is used to produce spinal anesthesia and in pain management and, in select cases, to administer cancer therapy.

Drug Distribution

After absorption into the bloodstream, drugs are distributed to the tissues via blood flow and diffusion and/or filtration across the capillary membranes of various tissues. Because the circulatory system is the main distribution mechanism and it is a readily accessible body compartment, plasma concentrations are used as an index of tissue concentrations in determining pharmacokinetics of drugs and in clinical management of drug therapy.