Читать книгу The Dentist's Drug and Prescription Guide - Mea A. Weinberg - Страница 8

1 Q. What is the definition of pharmacokinetics and why is it important to know?

2 A. Pharmacokinetics describes the actions of the drug as it moves through the body and how the body influences drug concentrations. It is easiest to remember pharmacokinetics by the acronym: ADME (A = absorption into the systemic circulation; D = distribution to the target tissues and organs; M = metabolism or biotransformation; E = elimination from the body). It is important to know the basics of pharmacokinetics in order to understand the basic principles of prescribing medications (Doogue and Polasek 2013). Pharmacokinetics (e.g., absorption of the drug into the blood) may be altered when certain antibiotics prescribed in dentistry are taken with food. Instructions must be verbally expressed to the patient and documented in the patient's chart on how to take medications that are prescribed by dentists (e.g., antibiotics, antimicrobial agents, analgesics, antifungal agents, antiviral agents, fluorides).

3 Q. What factors affect the rate of drug absorption?

4 A. In the gastrointestinal tract, many factors can influence the rate of drug absorption into the systemic circulation such as acidity of the stomach and food in the stomach. Some medications used in dentistry should be taken with food to reduce gastrointestinal irritation, some medications should be taken on an empty stomach because the food could delay the absorption of the drug, and some can be taken with or without food because food does not interfere with absorption. Usually, the absorption of the total amount of drug is not reduced but rather it will just take longer to be absorbed. Usually, antibiotics have the most restrictions regarding taking with meals. Nonsteroidal antiinflammatory drugs such as ibuprofen must be taken with food to avoid gastric irritation. Specific drugs will be discussed within the relevant chapters.

5 Q. What does “take on an empty stomach” mean?

6 A. “Take on an empty stomach” means to take the drug within one hour before eating or two hours after eating. Take on an empty stomach is not interpreted as not eating.

7 Q. What is the pharmacokinetics of an orally administered drug?

8 A. The pharmacokinetics of a drug administered orally such as penicillin VK is as follows (Gossel 1998a,b; Weinberg 2013).An orally administered drug is swallowed and goes down the esophagus. It is important to take a tablet/capsule with a full glass of water to facilitate its passage through the esophagus into the stomach.In the stomach, the tablet/capsule must be released or liberated from its formulation. Once a tablet is “broken up” and a capsule is “opened,” and the active ingredients are released, there is dissolution of the drug from the liberated drug particles. Some acidic drugs are enteric coated to protect the stomach lining. Dosage forms such as syrups or solutions are liquids, which are immediately available for absorption and transport. A liquid gel capsule (Aleve®, Advil®) is formulated to dissolve quickly, allowing the liquid inside the capsule to be absorbed fast.Drug goes into the upper part of the small intestine (duodenum) where most absorption into the systemic circulation occurs. This is because the small intestine has a large surface area due to microvilli, through which drugs may diffuse.From the small intestine, the drug molecules are absorbed into the bloodstream. Many factors can affect the rate and extent of drug absorption, including foods and minerals. For example, tetracycline should not be given at the same time as dairy products or minerals (e.g., iron, calcium, magnesium) because insoluble complexes form in the intestinal tract, which slows down absorption. This can be avoided by taking the tetracycline 1–2 hours before or after the dairy/mineral product. Some antibiotics (e.g., tetracycline) must be taken on an empty stomach (one hour before or two hours after meals), which increases the rate of absorption. Most antibiotics can be taken without regard to meals (with or without food) but if stomach upset occurs, these antibiotics can be taken with food (Huang et al. 2009).Absorption occurs when a drug is in a nonionized or charged form and if it is more lipid soluble. Most drugs are combined with a salt to enhance absorption (e.g., lidocaine HCl, tetracycline HCl, doxycycline hyclate, amoxicillin trihydrate).Before an orally administered drug reaches the systemic circulation, it goes to the liver via the portal vein whereby it is immediately exposed to metabolism by liver enzymes (Huang et al. 2009). This first exposure is referred to as the first‐pass effect. Some drugs such as lidocaine and morphine that undergo extensive first‐pass embolism will become inactive so they cannot be given orally. Diazepam (Valium®) has close to 100% bioavailability (low first‐pass metabolism) so it has similar oral and intravenous doses. Alternate routes of drug administration that bypass the first‐pass effect include sublingual, rectal, and parenteral (intravenous, intramuscular, subcutaneous) (Fagerholm 2007; Pond and Tozer 1984; Robertson 2017).Once it reaches systemic circulation, the drug is distributed in the blood to the various organs. Many drugs are bound to circulating proteins such as albumin (acidic drugs) and glycoproteins (basic drugs). Highly protein‐bound drugs are not active and only the free drug that is not bound to proteins is active.Once the drug has exerted its actions, it must then be eliminated from the body. The first part of drug elimination involves metabolism or biotransformation, which occurs mostly in the liver. It may take a drug several passes through the liver before it is entirely metabolized. Biotransformation converts lipid‐soluble drug molecules to metabolites or endproducts that are more water soluble and therefore easier to eliminate from the body. Most of the conversion of drugs occurs in the liver by metabolizing enzymes called microsomal enzymes. These enzymes, which are also called cytochrome P450 (CYP) enzymes, are the primary enzymes responsible for the oxidation of many drugs. There are many different isoenzymes for different drugs (e.g., CYP3A4 is involved with many dental drugs). Many drug–drug and drug–food interactions occur via the microsomal enzymes. Some prodrugs have no pharmacological activity unless they are first metabolized to the active form in the body (e.g., codeine is metabolized by the liver enzyme CYP2D6 to the active morphine) (Weinberg 2013).Drug elimination: now the more water‐soluble metabolite must be eliminated from the body. The main route of drug elimination is excretion via the kidneys so diseases of the kidney can significantly prolong the duration of drug action. Therefore, dosage adjustments may be needed from the patient's physician. Some elimination occurs through the lungs, breast milk, sweat, tears, feces, and bile. Some drugs (e.g., tetracycline) undergo biliary excretion whereby the drug is eliminated in the bile and enters the small intestine and eventually leaves the body in the feces. Most bile is then circulated back to the liver by enterohepatic recirculation and eventually metabolized by the liver and excreted via the kidneys. This route of reabsorption is helpful in prolonging the activity (increasing the half‐life) of some antibiotics (Weinberg 2013).

9 Q. What is the definition of drug absorption?

10 A. Drug absorption is the movement of a drug from the site of administration to the systemic circulation.

11 Q. What does it mean when a drug has 100% bioavailability?

12 A. Bioavailability describes the portion of an administered drug that reaches the systemic circulation. It is the rate and extent of absorption and how fast and how much of the drug is absorbed. It indicates that the drug is 100% absorbed into the blood. Only intravenously administered drugs have 100% bioavailability because 100% of the drug enters directly into the blood. A drug administered orally that undergoes extensive first‐pass metabolism (or first‐pass effect) by traveling first to the liver, where it is metabolized, and can become almost inactive by the time it reaches the systemic circulation, is a drug with low bioavailability.

13 Q. What is the first step involved in drug absorption?

14 A. The first step before a drug can be absorbed in the small intestine is disintegration of the dosage formulation into a formulation that can easily be absorbed. The stomach might be expected to be the first site of absorption but in reality, very little absorption occurs in the stomach because the surface area is very small. A tablet must break up to expose the active ingredient, which takes some time. A capsule must open up, which takes less time than a tablet. A solution is already in a liquid, easily absorbed form and takes the least time for disintegration and absorption. The order of bioavailability is oral solution > oral suspension > capsule > tablet (Lloyd et al. 1978).

15 Q. Is there any systemic absorption of a topical anesthetic applied on the surface of the gingiva?

16 A. Yes. The purpose of topical agents is to maximize the concentration of the drug at the target site while minimizing potential systemic adverse effects. Although drug absorption is not desired, there could be some systemic absorption, especially if the agent is applied on abraded gingiva or skin. Because of its lipophilic nature, the stratum corneum of the skin may act as a reservoir for many drugs. Consequently, the local effects of the drug may persist long enough to allow once‐daily application. For example, once‐daily application of corticosteroid preparations is as effective as multiple applications in most circumstances. Direct access to the skin may predispose the patient to frequent topical applications, increasing the risk of systemic adverse effects.

17 Q. How does a drug get absorbed into the systemic circulation?

18 A. A drug must pass through many cell membranes to get into the blood. A drug must have some water solubility to go through aqueous fluids and some lipid solubility to get through the cell membrane, which is composed of two layers of phospholipids.

19 Q. What is the purpose of epinephrine added to local anesthetics?

20 A. Epinephrine is a vasoconstrictor that acts to constrict blood vessels to decrease blood flow in the submucosal area via activating alpha‐1 receptors (Becker and Reed 2012). This allows the anesthetic solution to stay at the site of action longer, which slows absorption of the anesthetic solution.

21 Q. What is drug distribution and what factors affect distribution?

22 A. Drug distribution is the movement of an agent through the blood or lymph to various sites of action in the body. An important factor affecting drug distribution is protein binding. Many drugs in the blood are bound to circulating proteins such as albumin for acidic drugs (e.g., penicillin, barbiturates, aspirin, vitamin C) and acid glycoproteins and lipoproteins for basic drugs (e.g., narcotic analgesics, erythromycin). When drugs are bound to plasma proteins, they are inactive while circulating in the blood. This binding to proteins is temporary, reversible, and can convert to free drug. Only drugs that are not bound to plasma proteins are “freely active” and bind to specific receptors on the target tissue/organ. Another factor that affects drug distribution is blood flow to the target organs.

23 Q. What is the minimum effective concentration (MEC) of a drug?

24 A. The minimum effective concentration (MEC) is the amount of drug required to produce a therapeutic effect. This is important to know because a drug should not be given above the MEC as this will produce toxic concentrations. The ideal concentration of a drug should be between the MEC and the toxic concentration. This is referred to as the therapeutic range. For example, after periodontal surgery, it is recommended that the patient take ibuprofen (Motrin®, Nuprin®). If the patient decides to take only one 200 mg tablet during the day, they will still experience pain because the therapeutic range was not reached. The patient should take two or three tablets which will increase the plasma level of ibuprofen into the therapeutic range. If the patient takes five or more tablets at one time, then adverse effects may occur because the plasma level of ibuprofen is outside the therapeutic range and the maximum dose has been exceeded. Beyond the maximum dose, the analgesic effect does not increase.

25 Q. What does the term “dose” mean?

26 A. The dose of a drug is the amount of drug taken at any one time. Dose is expressed as the weight of drug (e.g., 500 mg), the number of dosage forms (e.g., one capsule), or the volume of liquid (e.g. two drops).

27 Q. What is the elimination half‐life of a drug?

28 A. The elimination half‐life (t½) of a drug is essentially the duration of action of a drug. Also, it is used to determine the dosing of a drug. The elimination half‐life of a drug is the amount of time required for a drug to decrease its original concentration by 50%. The second half‐life is when it removes another 50%, leaving 25% in the blood. The third half‐life is when it removes another 50%, leaving 12.5% in the blood. Drugs have different predetermined half‐lives. As repeated doses of a drug are administered, the plasma concentration builds up and reaches “steady state.” Steady state occurs when the amount of drug in the plasma builds up to a level considered therapeutically effective. In order to achieve steady state, the amount of drug administered must balance the amount being cleared from the body. It usually takes about between four and five half‐lives to reach clinical steady state and about six half‐lives before 98% of the drug is eliminated from the body (Ito 2011). For example, if a drug has a t½ of 2 hours, it will take about 8–10 hours to reach clinical steady state (Ito 2011).Drugs with a short t½ are eliminated faster than drugs with a long t½. For example, tetracycline HCl has a t½ of 6–12 hours and doxycycline hyclate has a t½ of 14–24 hours. Thus, tetracycline dosing is one capsule every four hours while doxycycline is dosed 100 mg every 12 hours on day 1, then 100 mg every day. On average, doxycycline's half‐life is around 19 hours. By multiplying 19 hours by six hours (average t½ to be 98% eliminated from the body) (19 × 6 = 114 hours), it takes 114 hours, or about five days, before 98% of the doxycycline has been removed from the body. Penicillin VK has a t½ of 30 minutes and amoxicillin's t½ is 1–1.3 hours. Thus, penicillin is given every six hours and amoxicillin is dosed every eight hours (Thomson 2004a,b).Ibuprofen has a short t½ and is cleared from the body more rapidly than a drug with a longer t½. Ibuprofen requires a more frequent, regular dosing regimen of 200–400 mg (OTC strength) q4–6h or prescription ibuprofen 600–800 q6–8h in order to build up and maintain a high enough concentration in the plasma to be therapeutically effective.

29 Q. What is the volume of distribution (VD)?

30 A. Apparent volume of distribution (VD) refers to the amount of drug in the various tissues of the body. Volume of distribution is a calculated value referring to the volume of fluid (e.g., plasma, interstitial fluid [fluid between the cells], and lymph) in which a drug is able to distribute to the organs. The volume of distribution can be used to calculate the LD, MD, and clearance of a drug (Aki et al. 2010; Thomson 2004a, b; Wesolowski et al. 2016).

31 Q. What is drug biotransformation?

32 A. Drug biotransformation (or metabolism, as it is sometimes called) terminates the action of a drug. It is a process by which a substance changes from one chemical form to another via a reaction in the body. Usually, biotransformation occurs in the liver but can also occur in the plasma and kidney.

33 Q. What is the importance of drug clearance?

34 A. Clearance refers to the volume of fluid (e.g., plasma) that would be completely cleared of drug if the entire drug being excreted were removed from that volume of fluid. Essentially, clearance is the removal of a drug from the plasma. It is a calculated value and measured in liters/hour. Clearance indicates the ability of the liver and kidney to eliminate a drug from the body (Doogue and Polasek 2013). Clearance may be reduced in the elderly. Both clearance and VD are important values in determining the half‐life of a drug (Gossel 1998a,b).

35 Q. What must happen to a drug in the body in order for a drug effect to occur?

36 A. The rate of absorption must be greater than the rate of elimination for the drug to have an effect on the body. Usually, the rate of elimination is slower than the rate of absorption so that the rate of elimination is the controlling factor in the presence of the drug in the body (Fujimoto 1979).