Pharmacokinetics

Oral Route

The oral (PO) route of administration is the most commonly prescribed route, as well as the route most associated with taking medications. Oral medications are beneficial for individuals taking medications on a daily basis, and medication for oral use can easily be carried along for dosing throughout the day. However, not all drugs can be given orally because of the rigorous journey from administration to site of action.

After being swallowed, a drug in a capsule, tablet, or liquid travels down the esophagus and into the stomach. Once it enters the stomach it comes in contact with various digestive enzymes and stomach fluids that are acidic in nature. The acidic environment, enzymes, and physical mixing require that the medication be formulated to withstand the conditions or it could be rendered ineffective. Most absorption of drugs occurs in the small intestine. The finger-like villi found there increase the surface area, improving the chances for drugs and nutrients to be absorbed. When the drug is absorbed it enters the gut wall, which contains drug-metabolizing enzymes and efflux pumps. If the drug makes it through the gut wall without being metabolized, it will travel via the bloodstream to the liver before finally making it to the systemic circulation. By going through the gut wall and liver before reaching the systemic circulation, some drugs are significantly metabolized before reaching the site of action. This is called the first-pass effect. Not all drugs can be given orally because they all cannot “survive” this rigorous journey.

Some drugs given orally are formulated to release their contents slowly. This may be done for many reasons. In these cases, the drug may have “sustained release” or “controlled release” in the name of the preparation. Some preparations may also have a coating (“enteric coating”), which will protect the drug from being destroyed in the journey to the absorption site. These types of medications should never be crushed or chewed or split unless the product is specifically formulated and labeled to allow this. Otherwise, the patient could be at risk for toxicity from the entire dose being available at once or lack of efficacy if the drug is destroyed.

Sublingual and Buccal

These medications are formulated to be given through the mucosa in the mouth. Sublingual (SL) administration designates administration under the tongue, and in buccal administration, the drug is placed between the gums and the cheek. This type of formulation is not chewed or swallowed but placed in the mouth to dissolve. These routes of administration provide quicker absorption and, for some drugs, greater bioavailability, because the drug is absorbed directly into the bloodstream without going to the gut and liver first, thereby avoiding the first-pass elimination. After the medication is dissolved and absorbed, it is immediately available in the bloodstream, which may lead to a quicker onset of action than would occur with an oral dose. An example of an SL product is the Nitrostat^® tablet. These are administered if a patient is experiencing chest pain due to angina. The formulation allows for an abrupt onset of action that will quickly diminish the chest pain.

Inhalation

Inhalation (INH) affords local delivery of the drug directly to the lungs or nasal passages. Following INH, an aerosolized or powdered drug can be available quickly and completely to the lungs, the nasal passages, and/or the blood vessels in these areas. This is beneficial for patients with respiratory illnesses, who can have the drug delivered to the site of action without exposing the whole body to its effects. Many drugs for the treatment of asthma or chronic obstructive pulmonary disease (COPD) come in a form to be inhaled to deliver the drug to the site of action without exposing the whole body to the drug. The INH route may also be used for the systemic delivery of drugs that cannot be given orally. Examples of this are the nasal spray of calcitonin used to deliver a bone hormone for the treatment of osteoporosis and immediate-release insulin given by oral inhalation for the treatment of type one diabetes mellitus.

Rectal

The rectal (PR) route of administration is not one most patients prefer, but it does have a place in therapy. Suppositories are solid medication dosage forms that are given rectally and may be advantageous for patients who are vomiting or for patients who are not conscious and do not have intravenous (IV) access, as well as if needed for local action. Enemas are liquid dosage forms delivered rectally; most are intended to act locally. Most medications in suppositories will not go through the liver and therefore will not have the first-pass effect.

Vaginal

While the vaginal (PV) route of administration is also not highly used, it is beneficial for local treatment of vaginal conditions. Formulations that may be used include vaginal suppositories, creams, and even some tablets. Patients who benefit from PV administration include those being treated for vaginal infections, menopause, and infertility.

Topical

Topical application includes preparations intended for use directly on the skin (dermal), into the eye (ophthalmic), into the ear (otic), and into the nose (nasal). This route is quite common and there are a variety of products available for topical administration, with subtle differences. Preparations made for direct application to the skin include creams, ointments, lotions, gels, shampoos, and solutions. Both creams and ointments have oil bases, but ointments have higher oil content than creams and provide a protective layer on top of the skin. Lotions and gels have a water base and are more easily spread on top of the skin. Solutions contain the highest liquid content and are most readily absorbed through the skin. Shampoos are soap solutions intended for use on the head and body. Both ophthalmic and otic preparations come in solutions and suspensions. A suspension is different than a solution because a suspension suspends small particles of an insoluble drug in a liquid that is usually water based. It is a good way to administer a drug that is insoluble in water. A solution, in contrast, has a soluble drug dispersed in a solvent, which is also usually water based. It is important to realize that there is a difference between them because the use of some preparations may not be appropriate for a given medical condition. For example, solutions may contain alcohol, whereas suspensions do not, and, therefore, otic drops formulated into a solution should not be used in a patient with a ruptured eardrum due to the risk of worsening the injury because of the alcohol. Ophthalmic preparations are specially formulated for comfort and safety of sensitive eye tissues and must be sterile to prevent infection.

Topical nasal preparations are commonly drops or gels that are applied directly into the nose. The nasal route is beneficial for patients suffering from allergies as the drug is delivered directly to the site of the symptoms.

Intravenous/Intramuscular/Subcutaneous Injections

Injection routes of administration deliver the medication directly into the vein (IV), muscle (IM), or subcutaneous (SUBQ) tissue of the patient. Injection methods require delivery by a needle. Because the drugs bypass the gastrointestinal (GI) tract, lack of absorption and destruction in the journey to the systemic circulation is not an issue for IV medications, and is less problematic for IM formulations than for those administered PO.

Transdermal

The application of patches is considered transdermal drug delivery. After a patch is applied to unbroken skin, the drug travels across the layers of skin and is absorbed by the body. This route is beneficial because of the ease of administration of the drug. Also, while most oral medications require everyday dosing, patches allow for multiple-day and longer dosing. For a patient who is unable to take pain medications due to effects on the GI system, the transdermal application allows the administration of an effective analgesic without many of the adverse effects associated with the oral form. Transdermal dosage forms are described in more detail in Chapter 32.

Absorption

If a drug is given by any route other than intravenously, it must first be absorbed. For the drug, the trip from the site of administration to the systemic circulation can be difficult. Medications taken orally must pass through and withstand the conditions of the stomach and then travel to the small intestine for absorption. There are enzymes found in the wall of the small intestine that can metabolize (break down or change) the drug. Also, in the wall of the small intestine, there are pumps that can transport the drug back into the GI tract. After absorption, the drug must travel to the liver, where it again may be metabolized. With routes of administration other than IV, it is possible that not all of the drug given will be available to the body. The percent of medication available to the body from a given dose is known as the drug’s bioavailability. This is a property specific to each drug and depends on many factors, including dosage form and route of administration. If the drug is able to bypass the absorption step, as with those given intravenously, drug absorption is not an issue and the bioavailability of the drug is 100%. Some drugs are so highly affected before reaching the systemic circulation that it is not useful to give them by the oral route. In most cases, however, a larger dose can be given when administered orally to overcome any decrease in bioavailability related to poor absorption or the first-pass effect (described in the section on Metabolism that follows). Drug-drug and drug-food interactions can occur at many points in the absorption process (details are described later on in the section on Drug and Disease Interactions).

Distribution

Distribution describes the process by which the drug is spread throughout the body and to what extent it is concentrated in various tissues. This property is also unique to each drug, as some drugs distribute widely throughout the body and have large distributions and others do not travel much beyond the bloodstream and therefore have small distributions. Common sites of distribution are the blood, muscles, fat tissue, bones, and organs. These may become important when treating certain conditions that require the drug to penetrate tissues to be effective. Besides this, the volume of distribution of a drug also helps pharmacists determine the rate at which the drug is removed from the body. Drugs having a larger volume of distribution will take longer to be eliminated from the body, whereas drugs with smaller volumes of distribution will take less time to be removed.

Metabolism

As soon as drugs enter the body, elimination begins. Some drugs need to be changed into a new compound to enhance their elimination. Metabolism is the process by which the drug is broken down or changed by various enzyme systems. The compounds formed as a result of the interaction between the drug and enzymes are known as metabolites. Metabolites may be active (with a therapeutic effect) or inactive (with little or no therapeutic effect) when compared to their precursors (the original drug compounds) and some may even be responsible for toxic side effects. Some drugs are inactive until they are activated by being metabolized. These are called prodrugs. Recall that drugs taken orally are absorbed and transported to the liver before reaching the rest of the body. This is an important safeguard built into our bodies, to ensure than anything eaten must go through the liver for possible metabolism before being utilized by the body. This, however, may result in significant metabolism of drugs before reaching the site of action. This is called the first-pass effect because drugs taken orally must “first pass” through the liver before reaching the systemic circulation. If a drug intended for systemic effect is highly eliminated by the first pass, (ie, nitroglycerin, lidocaine), it may be ineffective when given orally and, therefore, should be given via a “non-first-pass route” such as SL or IV.

Several liver enzymes are responsible for the metabolism of drugs. They are categorized into two groups: phase I and phase II enzyme systems. The most common phase I drug-metabolizing enzymes are known collectively as the cytochrome P450 enzymes, sometimes abbreviated CYP P450 (pronounced “sip P four-fifty”). The CYP P450 family of enzymes includes a large number of individual enzymes. Other enzyme systems that can metabolize drugs include phase II enzymes, which act by conjugating (chemically combining) drugs with glucuronic acid or glutathione, or modifying the drug by the transfer of methyl, acetyl, or sulfa groups from donor compounds. Most enzymes can be upregulated and downregulated by inducing or inhibiting the enzymes. There are drugs and diseases that can induce and inhibit enzymes. This is a major source of drug and disease interactions (as described later in the section on Drug and Disease Interactions).

There are also some enzymes that are genetically controlled and could exist in greater or lesser amounts in individual patients. For example, if a patient has a large amount of enzymes available to metabolize a drug, he or she will be a fast metabolizer and will have a more rapid clearance of the drug. In this case, the patient may suffer from a lack of efficacy because of this genetically determined increase in the enzyme. This patient would possibly need a higher dose of the drug compared to patients without this genetic trait. On the other hand, slow metabolizers would have genetically less enzyme available and would need lower doses of drugs metabolized by that enzyme. Pharmacogenomics is a relatively new and exciting field of study that examines how to accurately predict and react to such potential over- or under-dosing of drugs based upon the genetic make-up of the patient. Tests are available to predict the genetic types for some critical metabolizing enzymes. This information can be utilized to determine if some drugs can or should be used, and to help tailor the proper dosages of drugs to ensure that they are safe and effective. Chapter 3 examines this field in detail.

Excretion

Excretion is the process by which the drug and its metabolites are eliminated from the body. The main routes of excretion are through the urine and feces. Drugs may also exit the body through exhalation and sweating but to a much lesser extent. How readily drugs and metabolites are excreted in the urine or feces is dependent on their physiochemical properties and the function of the excreting organ. A drug excreted primarily by the kidneys will likely require dose adjustment for a patient with kidney failure. If the dose is not adjusted, the concentration of the drug may increase to a range that is toxic to the patient. Similarly, if two drugs are cleared by the same mechanism, one drug may be preferentially eliminated over another, resulting in hindering the elimination of the other drug. This may result in an increased concentration of the drug that had its elimination reduced. There are even drug interactions that can occur in the kidneys (as described in the section on Drug and Disease Interactions).

Determination of the Dosing Rate

The average concentration over a dosing interval at steady state (C_ss,avg) is determined by the clearance (CL), bioavailability (F), and dose rate (DR) of the drug given. While bioavailability is important in most routes of administration, it is not necessary to consider it when determining a dosing rate for a drug given intravenously. (Recall that the bioavailability of these drugs is 100%.)

Once the drug is at steady state and assuming that the F and CL remain constant, the average concentration at steady state will be proportional to the amount of drug given per unit of time (dose rate). Therefore, if the concentration is too low, the dose rate can be increased proportionally to raise the concentration to the target range. If the concentration is too high, the dose rate should be proportionally lowered to ensure that the patient doesn’t suffer from toxicity. This is only true for drugs that exhibit linear clearance. This is when a given fraction of the drug is removed per unit of time.

There are some drugs that are eliminated in a nonlinear fashion. In this case, an amount of drug is removed per unit of time, not a fraction of the drug per unit of time. Drugs that are eliminated this way will have a clearance that is concentration dependent. The C_ss,avg will not be proportional to the dose rate in this case. Phenytoin (Dilantin^®), a drug used for seizures, is cleared this way. If the dose rate of phenytoin is doubled, the resulting concentration would be much more than double. This is a concern as it could result in toxicity.

Determination of the Dose Interval

The dose interval is how often the drug is given (ie, daily, twice a day, etc.). The longer the dosing interval, the more variation there will be in the concentrations over the dosing interval. For most drugs, the goal is to minimize the difference between the maximum concentration (C_max) achieved, usually at or near the beginning of the dosing interval, and the minimum concentration (C_min) achieved at the end of the dosing interval. The longer the dosing interval, the larger the difference between C_max and C_min. Figure 2-2 demonstrates the difference when giving 150 mg every 12 hours (blue line) compared to giving 75 mg every 6 hours (red line). The amounts given per time are the same (12.5 mg/hr), so the patient will get the same amount of drug per time (same dose rate) but the C_max and C_min will differ.

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Concentration time curves when giving the same dose rate but differing dose intervals. Half-life is 6 hours.

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As a rule of thumb, dosing every one or two half-lives works well for most drugs. Since it takes one half-life to eliminate half the drug, this means that there will be half (one half-life) or a quarter (two half-lives) of the drug at the end of the dosing interval when compared to the beginning of the dosing interval. Therefore, drugs with longer half-lives can be given less often. This is usually desirable to improve patient adherence to the dosage regimen.

Drug Interactions in Absorption

Absorption can be increased or decreased depending on disease states, the drugs, or the foods that are administered at the same time. This can pose a problem for individuals who have multiple disease states requiring the use of multiple medications. Absorption drug interactions may result in either more or less drug being absorbed and, therefore, leave some therapies possibly toxic and some possibly ineffective. It is important to understand that drug, food, and disease interactions do not just happen when an interfering drug or food is added but the reverse effect will often happen when the drug or food is stopped.

One such interaction occurs when drugs given orally bind with other compounds, decreasing their ability to be absorbed. An example of this is ciprofloxacin (Cipro^®), an antibiotic. When calcium is given with oral ciprofloxacin, it will decrease the amount of ciprofloxacin available for absorption. This could result in suboptimal concentrations of this antibiotic, possibly resulting in therapeutic failure. If you add the auxiliary label that says do not take with antacids, this is likely the reason why.

When grapefruit or grapefruit juice comes into contact with the intestinal tract, it can decrease the effectiveness of some of the enzymes in the intestinal wall. By decreasing the enzyme activity, drugs that are subject to this enzyme can have an increase in the amount of drug that is bioavailable or the amount that makes it to the systemic circulation. This increase in bioavailability will increase the concentration of drug in the body, possibly putting the patient at risk for toxicity. An example of this drug-food interaction happens with grapefruit juice and a group of cholesterol-lowering medications called statins, as well as with cyclosporine, an immunosuppressant used to block the rejection of transplanted organs.

These are only a few examples of many types of interactions that can occur in the process of absorption. There are many others. These are most significant for drugs with small therapeutic ranges (Table 2-1).

Drug Interactions in Metabolism

Metabolism may also be the source of drug-disease, drug-drug, and drug-food interactions. Recall from earlier discussion, the importance of the CYP P450 system of enzymes. Many, but not all, drugs require metabolism by these enzymes to become active or inactive. There are many drugs that can induce or inhibit CYP P450 enzymes. If an enzyme inhibitor of the CYP P450 3A4 enzyme, such as fluconazole (Diflucan^®), is added to the regimen of a patient who is already taking a drug like phenytoin (Dilantin^®) that is metabolized by this system, the phenytoin will not be metabolized as quickly and will increase the concentration of the phenytoin, putting the patient at risk for toxicity. Conversely, if erythromycin, a CYP P450 3A4 inducer is added to the regimen of a patient on phenytoin, the clearance of phenytoin will increase, causing a decrease in the concentration of phenytoin. This could result in therapeutic failure.

Enzymes that metabolize drugs can be induced or inhibited by other drugs and diseases. Recall that genetic predispositions for being fast and slow metabolizers will also enter into the determination of the dosing regimen for metabolized drugs. A more detailed discussion can be found in chapter 3.

Drug Interactions in Excretion

When a patient who has kidney disease is taking a drug for which the body relies on the kidneys for elimination, it would be expected that the clearance would decrease. This would result in an increase in the amount of drug in the body, possibly putting the patient at risk for toxicity unless the dose rate is decreased.

There are drug interactions that can occur as well. Some drugs are eliminated by utilizing transport systems or “carriers” that move them from the blood into the nephron and out of the body in the urine. Drugs may compete with each other for the carrier taking them from the blood into the nephron. If two drugs are competing for the same carrier, one may be preferentially carried into the nephron and one left behind. The one left behind will not be cleared, thereby decreasing drug clearance and increasing concentrations and half-life. This drug interaction is utilized for a beneficial therapeutic effect when probenecid is added to the regimen of a patient who is already on penicillin. The probenecid will be preferentially carried into the nephron leaving the penicillin behind, purposefully increasing the concentrations and duration (t½) of the antibiotic penicillin. There are other similar drug interactions that are not always considered to be beneficial.

There are also drug interactions associated with changes in the pH of the urine that could increase or decrease the clearance of a drug eliminated in the urine. If a patient with renal impairment is taking a drug that is cleared by the kidneys, the patient is at risk for toxicity. Adding or stopping a drug that affects the carrier of another drug for secretion into the nephron could alter the clearance of drugs susceptible to these interactions.

Knowing about all these interactions will be helpful to ensure that patients are properly warned or advised by the pharmacist. However, it is ultimately the pharmacist’s role to evaluate the situation and confer with the prescriber for suggested changes in the dosing regimen or warn the patient about potential problems.