Pharmacology - An Illustrated Review

1. Pharmacokinetics

Pharmacokinetics is concerned with the movement of drugs into and out of the body and includes the principles of absorption, distribution, metabolism, and elimination. Knowledge of a drug's pharmacokinetic profile allows the clinician to select the correct agent, mode of administration, and dosing regimen to achieve a timely effect.

1.1 Routes of Drug Administration

Enteral

Enteral administration is the term used to describe drugs given via the gastrointestinal (GI) tract. Oral administration (PO) is by far the most common enteral route. The predominant site of absorption for drugs given orally is the duodenum, due to its large surface area. Drugs may also be absorbed in the stomach. Several factors influence the absorption of drugs given orally:

– Stomach acid can destroy many drugs unless coated with an acid-resistant material.

– Digestive enzymes (e.g., pepsin, gelatinase, gastric amylase, and lipases) may break down drugs.

– The presence of food in the stomach may delay or decrease absorption of the drug.

Pepsin

Pepsin is an endopeptidase, formed from the proenzyme pepsinogen. Its precursor, pepsinogen, is released from chief cells in the stomach when food is ingested and is responsible for cleaving proteins into peptides. Gastrin and vagus nerve stimulation cause the release of hydrochloric acid (HCl), which converts pepsinogen to pepsin.

 

Drug absorption and food in the stomach

Certain drugs can cause irritation to the stomach unless they are taken with food. Food delays absorption until the drug (e.g., aspirin) reaches the duodenum, where it is more easily tolerated. Other drugs (e.g., ampicillin) must be taken on an empty stomach, as food may decrease their absorption.

 

Parenteral

In parenteral administration a drug is delivered by injection; therefore, the drug bypasses the GI tract. This method is used for medications that are poorly absorbed in the GI tract or when rapid onset of action or tight control of pharmacokinetic parameters (e.g., plasma concentration) is required.

Other Methods of Drug Administration

Other methods of drug administration are topical, transdermal, and by inhalation. See Table 1.1 for a comparison of the different routes of drug administration and Fig. 1.1 for the time course of plasma concentration with each route.

1.2 Absorption of Drugs

Factors that Affect Absorption

Drugs given intravenously (IV) gain direct access to the bloodstream and so their absorption is complete. Drugs given by other methods have to cross biological membranes to reach the bloodstream, leading to partial absorption. The amount and rate of absorption are critical factors in therapeutics.

Absorption of a drug from the site of administration to the bloodstream depends on both the properties of the drug and physiological variables. The factors that govern whether a drug crosses a biological membrane include size, charge, and hydrophobicity. In general, low molecular weight, nonionized, water-soluble molecules are more readily absorbed.

The mechanisms by which molecules can cross biological membranes include passive diffusion and active transport.

 Passive diffusion is the most common method of absorption and occurs when a concentration gradient exists across a membrane such that the drug will move from the side with a high concentration to that with the lower concentration. Water-soluble drugs and those with low molecular weights are able to diffuse directly through pores in cell membranes. Lipid-soluble drugs dissolve readily in the lipid bilayer of cell membranes, thus gaining entry to the cell.

 Active transport occurs when a drug is moved against a concentration gradient or when the properties of the drug do not allow it to penetrate the cell by diffusion. Transmembrane carrier proteins with high structural specificity are responsible for active transport, utilizing energy from adenosine triphosphate (ATP) hydrolysis. The rate of carrier-mediated transport may show saturation at high solute concentrations because the number of carrier proteins is finite, and the cycling of carrier proteins is limited.

  Table 1.1 image Routes of Drug Administration

Route

Advantages

Disadvantages

Enteral

Oral

Convenient

Cost-effective

Relatively safe

Desired therapeutic concentration is achieved gradually

Often low bioavailability following first-pass metabolism by liver

More difficult to adjust plasma concentration

Requires a functional GI tract

Requires compliance by patients

Rectal

Useful when patient is vomiting

Can be used in the unconscious patient

Limited first-pass metabolism

Relatively painless

Tolerated well in children

Not well accepted

Irregular absorption can compromise safety

Irritation to rectal mucosa

Sublingual (buccal)

Rapid absorption

Avoids first-pass metabolism

Only useful for small amount of drug

Requires prolonged contact with mucosa

Unpleasant taste

Parenteral

Intravenous

Allows for rapid administration of a precise amount of drug

Avoids first-pass metabolism

Dosage is easily adjusted

Suitable for large volumes

Very useful in the unconscious patient

No issues with compliance by patients

Drug cannot be recalled once administered

More complications from administration (e.g., infection and hematoma)

Adverse reactions more likely, so monitoring by clinician is vital

IV access often difficult to establish

Intramuscular

Relatively easy to administer

Fairly rapid absorption under normal circumstances

May be used to deliver depot injections, where the active compound of a drug is released consistently over time

Painful

Can cause nerve damage

Can cause bleeding, so contraindicated in bleeding disorders

Can only be used for relatively small injection volumes

Subcutaneous

Easy to administer

Slow and constant absorption

Minimal pain involved

May be used to deliver depot injections, where the active compound of a drug is released consistently over time

Can only be used for very small volumes of drug

Potential tissue irritation

Other Methods

Topical

Applied to various surfaces, commonly the skin, eyes, nose, and vagina, to produce a local effect

May cause irritation

Transdermal

Controlled release preparations may be used via this mode of application

Can achieve systemic effects

Rate of absorption variable

May cause irritation

Inhalation

Rapid absorption

Ideal for drugs that can be administered as an aerosol

Ideal for treating lung disease, as drug is essentially exerting a local effect

Variable systemic distribution (not considered a disadvantage for the current drugs administered by this route)

May cause irritation of the respiratory tract

Abbreviations: GI, gastrointestinal; IV, intravenous.

Effect of Ionization on Drug Absorption

Most drugs exist as weak acids or weak bases; however, un-ionized forms will be absorbed more readily. The fraction of drug in the un-ionized form depends on the pH of the environment. This can be determined using the Henderson-Hasselbalch equation.

For a weak acid, A, the equation is as follows:

image

Fig. 1.1 image Mode of administration and time course of plasma drug concentration.

Drugs given intravenously (red) reach their peak plasma drug concentration almost immediately, but this declines rapidly as the drug is distributed and eliminated. Drugs given intramuscularly (green) take longer to reach their peak plasma concentration, followed by drugs given subcutaneously (blue). Drugs taken orally (purple) are the slowest to reach their peak plasma concentration, the value of which is determined by bioavailability following first-pass metabolism.

image

where

pH = –log10 [H+] (pH units)

pKa = –log10 equilibrium constant (pH units)

[A-] = concentration of the unprotonated, or ionized, form of the acid

[HA] = concentration of the protonated, or un-ionized, form of the acid

For a weak base, B, the equation is as follows:

image

where

pH = –log10 [H+] (pH units)

pKa = –log10 equilibrium constant (pH units)

[B] = concentration of the unprotonated, or un-ionized, form of the base

[BH+] = concentration of the protonated, or ionized, form of the base

When the pH equals the pKa, the drug is 50% ionized and 50% un-ionized. When the pH is less than the pKa the protonated forms HA and BH+ predominate; conversely, when the pH is greater than the pKa, the unprotonated forms A- and B predominate. At gastric pH, acidic drugs will tend to be un-ionized and are absorbed well through the stomach, whereas basic drugs will tend to be ionized in the stomach and be absorbed only when they reach the duodenum, where they will exist in their more un-ionized form.

Bioavailability (F)

Bioavailability (F) is the fraction of the administered dose of a drug that reaches the systemic circulation in an unchanged form. It is calculated by comparing the plasma concentration over time achieved by giving an IV dose (where all of the drug reaches the plasma) with the plasma concentration over time following administration of the same dose of a drug given by another route (e.g., orally). Absorption and first-pass metabolism are the main influences on bioavailability. First-pass metabolism is the metabolism of a drug that occurs during its first pass through the liver immediately following its absorption in the GI tract. It principally affects drugs that are taken orally, but can also affect drugs that are administered rectally to a lesser extent. The parenteral administration of drugs avoids first-pass metabolism.

Portal circulation

A portal system is one in which veins from one capillary bed drain into another capillary bed, instead of emptying into the heart. The hepatic portal system is one such example of this. In this system, the hepatic portal vein, formed from the superior mesenteric and splenic veins, drains blood from the stomach, intestines, pancreas, and spleen. This nutrient-rich blood drains into the hepatic sinusoids, and the substrates it contains are then metabolized by hepatocytes. Blood leaves the liver via the hepatic vein, which empties into the inferior vena cava, then into the right atrium of the heart. This system ensures that ingested substances are metabolized before entering the systemic circulation.

 

1.3 Drug Distribution

Factors that Affect Distribution

Following its absorption, a drug is distributed in the bloodstream before it leaves this compartment and enters the extracellular fluid and/or the cells of tissues (Fig. 1.2). This process is primarily affected by the blood flow to a particular tissue, the permeability of capillaries to the drug, and the degree of drug binding to proteins in plasma and tissues. A drug will tend to move from the bloodstream to tissues along a concentration gradient until equilibrium is established. When blood levels of a drug fall, the process reverses, and the drug is eliminated from the tissues.

Blood Flow

Initial distribution will tend toward those tissues with a higher blood flow (brain or central nervous system [CNS], liver, and kidneys), then gradually be redistributed to those that are less vascular (skin, bone, and adipose tissue).

Permeability of Capillaries

Capillary endothelial cells that line blood vessels are, in general, separated by junctions that allow drugs to pass between them quite readily (Fig. 1.3). In the liver, these junctions are larger than usual, allowing drugs to pass even more readily. This is useful as the liver is the major site of drug metabolism. Conversely, the capillary endothelial cells of the brain have very tight junctions between them, which, along with glial cells, form the blood–brain barrier. For drugs to enter the brain, they must diffuse through the endothelial cells (i.e., lipophilic drugs), or they may be transported across the endothelial cell membrane via a carrier molecule.

Plasma Protein Binding

Drugs that are bound to plasma proteins (usually albumin but also α1 acid glycoprotein) cannot be distributed into tissues or eliminated and so are pharmacologically inactive. However, they act as a reservoir such that when the concentration of free drug in plasma falls (due to redistribution, metabolism, or elimination), the bound drug proportionally dissociates from albumin to maintain a constant free-drug concentration.

Drugs bind with vastly different affinities for albumin. Competition for binding occurs when two drugs with a high affinity for albumin are given at the same time. This will increase plasma free-drug concentration, which could lead to increased side effects or toxicity. This is a common cause of drug interactions.

Table 1.2 lists the drug types that bind to albumin and α1 acid glycoprotein and gives examples of such drugs.

  Table 1.2 image Plasma Protein Binding

Plasma Protein

Drug Type

Examples

Albumin

Acidic

drugs

Neutral drugs Warfarin, naproxen, phenytoin, sulfamethoxazole

α1 acid glycoprotein

Basic drugs

Alprenolol, amitryptyline, imipramine, lidocaine

Note: Plasma protein binding is reversible.

Albumin

Serum albumin is the most abundant plasma protein in the body. It is synthesized by the liver and is an important transport molecule for endogenous substances, such as steroid hormones, bilirubin, bile salts, free fatty acids, and calcium. It also acts as a transporter of many drugs. Albumin plays a critical role in regulating blood volume by maintaining the oncotic pressure of blood, which allows fluid to be retained in the vascular compartment. The concentration of albumin falls in liver disease, kidney disease (e.g., nephrotic syndrome, where kidney damage causes proteins to leak into urine), in inflammatory states, and in malnutrition.

 

α1 acid glycoprotein

α1 acid glycoprotein (AAG) is an acute-phase protein whose levels are increased in acute inflammatory states and tissue injury. Like albumin, AAG is synthesized in the liver and acts as a transport protein for endogenous substances, such as steroid hormones, and for many drugs.

 

Reflection coefficient

Reflection coefficient is a number between 0 and 1 that describes the ability of a membrane to prevent diffusion of a solute relative to water. If the reflection coefficient is 1, the solute is completely impermeable. Serum albumin has a reflection coefficient through endothelium that is close to 1. This explains why albumin is retained in the vascular compartment and exerts an oncotic effect. If it is 0, the solute is equally as permeable as water and will not exert any oncotic effect, i.e., it will not cause water to flow.

 

Hypoalbuminemia

Lower than normal levels of albumin in the blood (hypoalbuminemia), and hence decreased plasma protein binding, may occur in the following conditions: liver disease (e.g., hepatitis, cirrhosis, or hepatocellular necrosis), ascites, nephrotic syndrome, malabsorption syndromes (e.g., Crohn disease), extensive burns, and pregnancy.

 

Volume of Distribution (Vd)

Volume of distribution is a pharmacological term that is defined as the volume in which a drug would need to be uniformly distributed to produce the same concentration throughout the body as found in plasma. It is an arbitrary value that is useful as a guide when comparing the relative concentration of the drug in plasma with the rest of the body and should not be thought of as an actual physical volume of fluid. A low Vd (e.g. 4 L) indicates that the drug is mainly distributed in plasma, whereas a larger Vd (> 10 L) means that the drug has been distributed to additional compartments (e.g. interstitial or intracellular fluid). In reality, a drug will not be exclusively contained within one fluid compartment but distributed unevenly throughout one or more of them. Figure 1.4 illustrates the compartments for drug distribution. Table 1.3 lists the physiochemical features of drugs that cause them to predominate in a certain compartment and provides examples.

Fig. 1.2 image Distribution following different modes of administration.

Drugs given intravenously, transdermally, intramuscularly, sublingually, and buccally enter the venous circulation following administration and reach the general circulation after passing through the heart and lungs. Oral drugs are absorbed from the stomach or duodenum into the portal circulation, where they undergo first-pass metabolism in the liver before reaching the venous and then general circulation. Drugs given rectally are mainly transported directly to the venous circulation, but some of the drug enters the portal circulation to the liver. Drugs given by inhalation have a local effect on the lungs and may also reach the general circulation (e.g. general anesthetics).

image

Fig. 1.3 image Blood–tissue barriers.

The penetrability of the capillary wall depends on the tissue. In cardiac muscle (top right), there is endocytotic and transcytotic activity (arrowheads in micrographs) that transports fluid and macromolecules into and out of the interstitium. Drugs that are in the fluid will also be transported, regardless of their physiochemical properties. In the endocrine glands (e.g., the pancreas, lower right) and the gut, the endothelial cells have fenestrations (arrowheads) that are closed by diaphragms. These diaphragms, along with the basement membrane, can readily be penetrated by low-molecular-weight substances (i.e., most drugs), but macromolecule penetration will depend on molecular weight and ionization. The liver (lower left) has large fenestrations that are not closed by diaphragms or basement membranes, so drugs are able to move freely into the interstitium. Finally, the central nervous system (CNS, top left) has no pores, fenestrations, or transcytotic activity, so drugs must either diffuse or be transported through the endothelial cells to gain access. (AM, actomyosin; D, Disse space; E, erythrocyte; G, insulin storage granule; Z, tight junction. Solid black line in schematic drawings are basement membranes.)

image

Fig. 1.4 image Fluid compartments for drug distribution.

Drugs may be distributed to different body compartments depending on their physiochemical properties. See Table 1.3 for examples of drugs in each compartment.

image

image

The apparent volume of distribution of a drug relates to the amount of drug administered to the plasma concentration according to the equation

image

Calculating the Amount of Drug to Administer from Vd

The Vd is used to calculate the amount of drug needed to achieve a desired plasma concentration by rearrangement of the above equation:

image

This assumes, for simplicity, that the bioavailability of the drug is complete, distribution is instantaneous, and the drug is not being eliminated.

Effect of Vd on the Half-life of a Drug

For a drug to be eliminated, it must be present in its free form in plasma so that it may pass through the liver or kidney for excretion in bile or urine. The higher the volume of distribution, the less a drug is contained in the plasma compartment, so its half-life is prolonged.

1.4 Metabolism of Drugs

Drug metabolism usually inactivates therapeutic agents, transforming them into derivatives that are more readily excreted. However, metabolism can also produce active agents from inactive prodrugs, or can produce toxic metabolites.

The liver and intestinal wall are the main sites of metabolism, but drug metabolism can also occur in the kidneys, lungs, and gonads.

Phase 1 Metabolism

Metabolism generally consists of a phase 1 reaction that converts a drug to a less active form, followed by a phase 2 conjugation reaction (Fig. 1.5). Phase 1 metabolism involves the oxidation, reduction, or hydrolysis of a drug, making it more polar by adding or exposing a functional group (-OH, -NH2,-SH, -COO-). These functional groups can then act as the site of conjugation in phase 2 metabolism.

Oxidation Reactions

In the liver, the most important site of metabolism is the microsomal enzyme system. This includes the mixed function oxidases located in the smooth endoplasmic reticulum. Pharmacologically, the most important of these is the cytochrome P-450 family of enzymes (Fig. 1.6).

Each cytochrome P-450 enzyme is denoted by the abbreviation CYP followed by a number related to the family, then an upper case letter related to its subfamily, followed by a number to specify the particular enzyme. Each enzyme has the capacity to catalyze the metabolism of many drugs with some overlap between them for substrates. More than 50% of drugs are catalyzed by the CYP3A family, with ~30% by CYP2D6 and 15% by CYP2C. This system can be induced or inhibited by drugs, which creates a huge potential for drug interactions (Fig. 1.7).

Fig. 1.5 image Process of metabolism.

Drugs and other endogenous and exogenous substances undergo biotransformations that ultimately allow them to be excreted in urine or bile. (UDP-GlcUA = urinidine diphosphate glucuronate; UDP = uridine diphosphate.)

image

Fig. 1.6 image Cytochrome P-450 synthesis in the liver.

Inducer substances activate transcription factors in the CYP gene, producing more cytochrome P-450. Cytochrome P-450 enzymes are then able to metabolize substrates unless they are acted upon by an inhibitor. Inhibitors bind to cytochrome P-450 enzymes with high affinity and cause the substrates of cytochrome P-450 enzymes to be metabolized more slowly. (mRNA, messenger RNA).

image

Fig. 1.7 image Substrates, inducers, and inhibitors of cytochrome P-450 enzymes.

Inducer substances can be environmental, endogenous substances, or they may be drugs themselves. The cytochrome enzyme that they induce is then able to metabolize specific substrates (drugs) more rapidly, so these drugs may not reach their effective therapeutic concentration. Inhibitors interfere with substrate metabolism and may cause toxic accumulation of a drug in the body. (HIV, human immunodeficiency virus; SSRIs, selective serotonin reuptake inhibitors.)

image

The cytochrome P450-dependent oxidation reactions include:

– aromatic and aliphatic hydroxylation

– alkyl oxidations and desulfuration

– oxidative deamination

– N-dealkylation from nitrogen, oxygen, and sulfur

– sulfoxidation

– epoxidation

When a drug is oxidized, oxygen is reduced to water as a byproduct. This type of reaction requires energy in the form of NADPH to drive the conversion the enzyme cytochrome P-450 reductase.

Some drugs are metabolized by noninducible, nonmicrosomal enzymes. Examples include monoamine oxidase (in mitochondria) in the metabolism of sympathomimetic amines, e.g., epinephrine, norepinephrine, dopamine; alcohol dehydrogenase (in cytosol) in the metabolism of ethanol; and xanthidine oxidase (in cytosol) in the catabolism of purines and xanthines.

Reduction Reactions

Reduction reactions generally require anaerobic conditions and may be catalyzed by bacteria in the gut or urinary tract. Microsomal enzymes can also reduce drugs under appropriate conditions. Examples of reduction reactions include the formation of nitrites from organic nitrates and amine formation from the reduction of nitro (-NO2) containing compounds.

Hydrolysis Reactions

Drug hydrolysis predominantly occurs in plasma and cellular cytosol as a result of chemical or enzymatic reactions. Examples of enzymes that catalyze these reactions include esterases, which metabolize acetylcholine, atropine, and procaine; amidases, which metabolize procain-amide and lidocaine; and peptidases, which metabolize insulin and vasopressin. Metabolites produced by these reactions are usually more water soluble than the parent compound and may be excreted in this form or processed further by conjugation.

Phase 2 Metabolism

Drug conjugations are referred to as phase 2 reactions because they often occur after initial drug oxidation, reduction, or hydrolysis; however, drugs can bypass phase 1 metabolism and go straight to phase 2. Conjugated compounds are generally inactive, especially glucuronide, sulfate, and glutathione conjugates, which are highly water soluble and readily excreted in urine.

Drug–Grapefruit Interactions

Grapefruit juice is a powerful inhibitor of CYP3A4-mediated drug metabolism. This can lead to elevated plasma concentrations of many drugs, including benzodiazepines, codeine, and amiodarone (a potent antiarrhythmic drug), and the possible toxicity of these drugs.

 

Table 1.4 lists the types of phase 2 conjugation reactions and gives examples of drugs that undergo each type of conjugation.

image

1.5 Elimination of Drugs

Elimination of drugs and their metabolites mainly occurs in urine and feces, although many other minor routes of elimination exist, such as saliva, sweat, tears, breast milk, and expired air (from the lungs).

Renal Elimination

To undergo renal elimination, a drug must be filtered or actively transported into the urine and must resist reabsorption back into plasma and subsequent reentry into the systemic circulation.

Glomerular Filtration

Drugs are filtered into the urine from plasma depending on their molecular weight, ionization, and degree of protein binding.

 Low-molecular-weight and/or ionized drugs are more readily filtered.

 Drugs that are highly bound to plasma proteins are too large to be filtered.

Drugs that are filtered in the glomerulus and not reabsorbed are eliminated at a rate that equals creatinine clearance (125 mL/min).

Creatinine

Creatinine is formed in a nonenzymatic reaction from creatine phosphate in skeletal muscle. It is excreted with minimal reabsorption in the kidneys, and its clearance rate is an excellent indication of glomerular filtration and therefore renal function.

 

Active Transport in the Proximal Tubule

Drugs that are acids or bases in plasma can be actively secreted into the tubular lumen against a concentration gradient by anionic and cationic transport systems. This process requires energy.

Reabsorption in the Distal Tubule

Un-ionized drugs are able to passively diffuse back into plasma, especially if they are lipid soluble and there is a favorable concentration gradient. The ionization of a drug is affected by changes in urinary pH. For example, if urine is made more alkaline by administration of bicarbonate, weak acids will become more ionized, thereby slowing their reabsorption and increasing their elimination (see Henderson-Hasselbalch equation page 3).

Hepatic Elimination

Conjugated drugs (mainly glucuronic acid derivatives) are actively secreted into bile. Unconjugated drugs are liberated in the small intestine by bacterial enzyme hydrolysis and reabsorbed into the portal circulation. This is the enterohepatic cycle. Some of the drug escapes reabsorption and appears in feces. Antibiotic-induced decreases in intestinal bacterial flora will decrease the hydrolysis of conjugated drugs thus interfering with enterohepatic cycling and decreasing the drug concentration below its therapeutic range (e.g., steroids used for contraception).

1.6 Drug Interactions

Drug interactions may occur at any stage between absorption and elimination, but competition for plasma albumin binding and induction/inhibition of the CYP-450 enzymes (Fig. 1.8) are by far the most common interactions. Table 1.5 lists some common mechanisms of interactions and gives examples of drugs that can cause them.

Fig. 1.8 image Drug interactions involving cytochrome P-450 enzymes.

In patients taking cyclosporine (an immunosuppressant drug used to prevent organ rejection), concomitant use of rifampicin (an antibiotic) or St. John's wort (a herbal drug, used to treat depression) will induce CYP3A4, increasing cyclosporine metabolism and elimination. In this case, plasma levels of cyclosporine are not maintained at the therapeutic level, leading to transplant rejection. Conversely, if itraconazole (an antifungal agent) is taken with cyclosporine, CYP3A4 is inhibited, and cyclosporine metabolism and elimination are slowed, leading to toxic accumulation in the kidneys.

image

image

1.7 Determinants of Plasma Concentration and Dosing

The rate of drug dosing depends primarily on its rate of elimination. Most drugs are removed from plasma by processes that are concentration-dependent (i.e., metabolism, secretion, and filtration) and result in “first-order” kinetics of elimination.

First-Order Elimination

With first-order kinetics,

 A constant percentage of the drug is eliminated per unit of time. This is known as the elimination rate constant (Ke).

– The elimination half-life (t½) is the time it takes for the plasma concentration to be reduced by 50%. It is constant and is independent of the dose.

– Half-life is related to Ke by the following:

image

– Clearance (CL) is the volume of fluid from which the drug is eliminated per unit of time.

image

Substituting 0.693/t½ for Ke gives

image

– A plot of log plasma concentration against time is a straight line (Fig. 1.9). The y-intercept is an extrapolated value and would be the plasma concentration of drug at time 0 assuming instantaneous distribution.

– Most drugs exhibit first-order kinetics unless they are given in very high doses.

Fig. 1.9 image First-order elimination.

With first-order kinetics, a constant percentage of the drug is eliminated per unit of time. Note that plasma concentration is plotted on a logarithmic scale.

image

Zero-Order Elimination

With zero-order kinetics,

– A constant amount of drug is eliminated per unit of time regardless of its concentration. This usually occurs because the route of elimination has become saturated.

– The half-life is not constant but depends on the concentration, i.e., the higher the concentration, the longer the half-life.

– Drugs in this category will demonstrate first-order kinetics whenever the drug concentration falls substantially below the saturation level of the elimination process.

– Examples of drug that exhibit zero-order kinetics include ethanol and heparin, plus other drugs at high doses (e.g., salicylates such as aspirin).

1.8 Pharmacokinetics of Drug Administration in Practice

It is important that clinicians understand the factors that affect the total amount of drug in the body, how much drug is in plasma, and how this changes over time so that an appropriate therapeutic regimen can be devised. To illustrate these concepts, we will discuss the two different types of drug administration: continuous IV infusion and repeated dosing.

Kinetics of Continuous IV Infusion

If a drug is given by IV infusion, a constant amount of the drug enters plasma, and a constant percentage is eliminated (cleared from the blood) per unit of time (if elimination is first-order); that is, plasma concentration and elimination are proportional such that any increase in plasma concentration of a drug will lead to an increase in its elimination. At the start of an IV infusion, plasma drug concentration will rise until it reaches the point where elimination exactly matches administration. At this point, the plasma concentration will remain constant and is referred to as the steady-state concentration (Css) (Fig. 1.10). For drugs that are given by continuous IV infusion, the equation for calculating Css is

image

where

Ro = the infusion rate

CL = clearance (mL/min)

– Note that the time to reach steady-state concentration is solely determined by the half-life. It takes roughly four half-lifes for a drug to be eliminated from the body, and because steady-state concentration and elimination are proportional, it takes about four half-lifes to reach steady-state concentration.

– Increasing the rate of infusion does not increase the rate at which the steady-state concentration is reached; rather, it will increase the rate at which any given concentration of drug in the plasma is achieved.

Fig. 1.10 image Time for drug to reach plasma steady-state concentration and be eliminated.

When a drug is given by IV infusion, 50% of plasma steady-state concentration (Css) is achieved after one half-life and 75% after two half-lifes; Css is complete after approximately four half-lifes. If the infusion is stopped, the drug is eliminated in these same proportions (i.e., 50% is eliminated after one half-life and so on until it is almost completely eliminated after four half-lifes).

image

Kinetics of Repeated Dosing

Fixed-Dose/Fixed-Time-Interval Regimens

The most common drug-dosing regimen is to take a drug orally one or more times per day; however, such a repeated dosing regimen introduces issues related to fluctuations in plasma drug concentration. With any fixed-dose/fixed-time-interval regimen, a steady-state concentration is ultimately reached as before, but it is not achieved in a smooth, exponential way as for the IV infusion, but rather by way of fluctuating around a mean (Fig. 1.11). This is because most intermittent doses of drugs are given in fewer than four half-lifes (i.e., before the preceding dose has been completely eliminated), so the drug will accumulate until the steady state is achieved. The magnitude of the peaks and troughs around the mean will depend on the dosing interval (see Table 1.6). Smaller doses at shorter intervals will minimize these fluctuations but will not alter the steady-state concentration or the rate at which it is attained.

Table 1.6 image Effect of Dosing Interval on Time To Reach Steady-State Concentration, the Degree of Fluctuation of Plasma Drug Concentration, and the Most Useful Mode of Administration to Combat These Variables

Half-life (Hours)/Dosing Interval

Time to Reach Css

Plasma Concentration Fluctuation

Mode of Administration

< 4

Short

Large

IV infusion

Sustained-release preparation

6–24

Medium

Medium

Usually oral fixed dose at interval equal to t½

> 24

Long

Small

Sustained-release preparation ± loading dose

Abbreviation: Css, steady-state concentration; IV, intravenous.

Fig. 1.11 image Accumulation: dose, dose interval, and fluctuation of plasma level.

When a large dose of a drug is given once per day, the plasma concentration shows a large fluctuation. Toxic levels are obtained (pink area) at peak plasma concentrations and subtherapeutic levels (green area) are obtained at the trough. If the drug is given in smaller, more frequent doses, the peaks and troughs are smaller. The mean steady-state concentration will be obtained in four half-lifes, independent of the frequency of dosing.

image

For drugs that are taken orally on a fixed-dose/fixed-time-interval regimen, the equation for calculating the steady-state concentration is

image

where

Css = Steady-state concentration (mg/mL)

F = Bioavailability

D = Dose (mg)

T = Dosing interval (min)

CL = clearance (mL/min)

Note:

– To change the steady-state concentration, it is generally better to increase the frequency of dosing rather than the amount of drug given to avoid toxic effects related to larger excursions around the mean concentration (i.e., larger peak and trough values).

– For orally administered drugs, bioavailability must be taken into account in the calculation of steady-state concentration.

– No simple prediction of steady-state concentration can be made for drugs eliminated by zero-order kinetics. In this case toxic concentrations can accumulate more quickly and be eliminated more slowly than drugs that follow first-order kinetics.

Use of a Loading Dose

It is often desirable to achieve the steady-state coxncentration more quickly than four half-lifes, especially if the half-life of the drug is long. In these cases, a loading dose (LD) can be used. Loading doses can be given as a single bolus injection, but the high initial plasma concentrations achieved can sometimes lead to adverse effects. These adverse effects may be avoided by staggering the loading dose over a short period, which allows time for some redistribution of the drug to occur. Loading dose (mg) is calculated as follows:

image

For an orally administered loading dose, bioavailability must be considered.

Irregular Dosing Regimens

Irregular dosing occurs to an extent during fixed-dose/fixed-time-interval regimens because patients do not take a drug dose during the night. It also commonly occurs when patients do not adhere strictly to the prescribed dosing interval. As a consequence of irregular dosing, plasma drug concentrations often fall below the therapeutic level (Fig. 1.12).

Table 1.7 summarizes the factors that should be considered when choosing a dosing regimen.

  Table 1.7 image Summary of Factors to Consider When Choosing a Dosing Regimen

Factor

Comments

Steady-state plasma concentration (Css)

This will be the desired therapeutic plasma concentration and will lie within the therapeutic index.

Clearance (CL

This is the same as creatinine clearance in a healthy adult patient (125 mL/min).

Half-life (t½)

This dictates the time taken to reach the steady-state concentration and therefore the dosing interval.

Therapeutic index (TI)

The therapeutic index is a means of comparing the amount of a drug required to attain the therapeutic level in 50% of patients to the amount that is lethal to 50% of patients.

A large TI allows for a variety of dosing regimens.

A small TI often necessitates that a drug is given intravenously (IV), by IV infusion, or as a sustained-release preparation.

Bioavailability (F)

This must be factored in when considering all methods of administration of drugs except for IV (100% bioavailability). It is especially important in determining oral dosing regimens.

Volume of distribution (Vd)

This will affect the concentration of free drug in plasma, which, in turn, determines how much is available for elimination.

Vd is usually constant and can be largely ignored when calculating a dosing regimen, but it gains in significance in disease states.

Route of administration

This is determined by patient factors and the biochemical properties of the drug.

Drug interactions

Clinicians should always consider drug interactions, especially the most serious and clinically relevant ones.

Fig. 1.12 image Plasma concentration of drugs with irregular dosing.

Irregular dosing, such as occurs with the increased nocturnal dosing interval with fixed-dose/fixed-time-interval regimens or due to missed doses (poor patient compliance), results in the plasma drug concentration falling below the desired therapeutic level (pink areas). It then takes several doses to reach the desired therapeutic level once again. Note that the arrows signify when each dose of drug is taken and the question mark (?) represents a missed dose.

image

Drug Dosage in Renal Disease

Renal disease must be taken into consideration when drugs are excreted primarily (> 50%) unchanged by the kidney.

– The initial dose is the same as for any patient, but because clearance is decreased, the maintenance dose is decreased or the dosing interval is increased in proportion to the decrease in renal clearance of creatinine. In doing this, the percentage of drug eliminated by the kidney remains unchanged.

Nephrotoxic drugs

An example of a nephrotoxic drug is gentamicin, an aminoglycoside antibiotic used to treat severe bacterial infections. It is excreted in unchanged form, mostly by glomerular filtration, in the kidney. In renal impairment, gentamicin will accumulate in the kidney causing destruction of kidney cells (nephrotoxicity). When gentamicin is prescribed, the dosage and treatment period should be minimal, and plasma concentration should be closely monitored.

 

Drug Dosage in Hepatic Disease

Hepatic disease has the potential to affect the pharmacokinetics of many drugs; however, because hepatic reserves are large, disease has to be severe for changes in drug metabolism to occur. The mechanisms by which the pharmacokinetics may be altered include the following:

– Reduced hepatic blood flow reduces first-pass metabolism of drugs taken orally.

– Reduced plasma protein binding may affect both distribution and elimination.

– Plasma clearance of a drug is reduced if it is eliminated following metabolism and/or following excretion into bile.

A dose reduction will be necessary in hepatic disease, but it should be calculated for each individual patient.