Chapter 4 - (Pharmacokinetics)

Question 1

Absorption

Answer 1

Absorption is defined as the movement of a drug from its site of administration into the blood.

Question 2

Distribution

Answer 2

Distribution is defined as drug movement from the blood to the interstitial space of tissues and from there into cells.

Question 3

Metabolism

Answer 3

Metabolism (biotransformation) is defined as enzymatically mediated alteration of drug structure.

Question 4

Excretion & Elimination

Answer 4

Excretion is the movement of drugs and their metabolites out of the body.
The combination of metabolism plus excretion is called elimination.

Question 5

Crossing the Membrane: Channel

Answer 5

Very few drugs cross membranes via channels or pores. The channels in membranes are extremely small (approximately 4 angstroms), and are specific for certain molecules. Consequently, only the smallest of compounds (molecular weight below 200 daltons) can pass through these channels, and then only if the channel is the right one. Compounds with the ability to cross membranes via channels include small ions, such as potassium and sodium.

Question 6

Crossing the Membrane: Transport Protein

P-Glycoprotein, deserves special mention.

Answer 6

Transport systems are carriers that can move drugs from one side of the cell membrane to the other. Some transport systems require the expenditure of energy; others do not. All transport systems are selective: They will not carry just any drug. Whether a transporter will carry a particular drug depends on the drug’s structure.

P-glycoprotein is a transmembrane protein that transports a wide variety of drugs out of cells. This transporter is present in cells at many sites, including the liver, kidney, placenta, intestine, and capillaries of the brain. In the liver, P-glycoprotein transports drugs into the bile for elimination. In the kidney, it pumps drugs into the urine for excretion. In the placenta, it transports drugs back into the maternal blood, thereby reducing fetal drug exposure. In the intestine, it transports drugs into the intestinal lumen, and can thereby reduce drug absorption into the blood. And in brain capillaries, it pumps drugs into the blood, thereby limiting drug access to the brain

Question 7

Crossing the Membrane: Direct Penetration

Answer 7

For most drugs, movement throughout the body is dependent on the ability to penetrate membranes directly. Why?

(1) most drugs are too large to pass through channels or pores, and
(2) most drugs lack transport systems to help them cross all of the membranes that separate them from their sites of action, metabolism, and excretion.

A general rule in chemistry states that “like dissolves like.” Membranes are composed primarily of lipids; therefore, to directly penetrate membranes, a drug must be lipid soluble (lipophilic).

Certain kinds of molecules are not lipid soluble and therefore cannot penetrate membranes. This group consists of polar molecules and ions.

Question 8

Polar Molecule

Answer 8

Polar molecules are molecules with uneven distribution of electrical charge. That is, positive and negative charges within the molecule tend to congregate separately from one another. Water is the classic example. 
The electrons (negative charges) in the water molecule spend more time in the vicinity of the oxygen atom than in the vicinity of the two hydrogen atoms. As a result, the area around the oxygen atom tends to be negatively charged, whereas the area around the hydrogen atoms tends to be positively charged. 

Gentamicin (Fig. 4–3B), an antibiotic, is an example of a polar drug. The hydroxyl groups, which attract electrons, give gentamicin its polar nature.

Question 9

Ion

Answer 9

Ions are defined as molecules that have a net electrical charge (either positive or negative). Except for very small molecules, ions are unable to cross membranes.

Question 10

Quaternary ammonium compound

Answer 10

Quaternary ammonium compounds are molecules that contain at least one atom of nitrogen and carry a positive charge at all times. The constant charge on these compounds results from atypical bonding to the nitrogen. In most nitrogen-containing compounds, the nitrogen atom bears only three chemical bonds. In contrast, the nitrogen atoms of quaternary ammonium compounds have four chemical bonds (Fig. 4–4A). Because of the fourth bond, quaternary ammonium compounds always carry a positive charge. And because of the charge, these compounds are unable to cross most membranes.

Question 11

ph Dependent ionization

Answer 11

Unlike quaternary ammonium compounds, which always carry a charge, many drugs are either weak organic acids or weak organic bases, which can exist in charged and uncharged forms. Whether a weak acid or base carries a charge is determined by the pH of the surrounding medium.

• An acid is defined as a compound that can give up a hydrogen ion (proton). Put another way, an acid is a proton donor.
• A base is defined as a compound that can take on a hydrogen ion. That is, a base is a proton acceptor.
• -When an acid gives up its proton, which is positively charged, the acid itself becomes negatively charged. Conversely, when a base accepts a proton, the base becomes positively charged.

Question 12

Ion trapping

Answer 12

The process whereby a drug accumulates on the side of a membrane where the pH most favors its ionization is referred to as ion trapping or pH partitioning. Figure 4–6 shows the steps of ion trapping using aspirin as an example.

Because the ionization of drugs is pH dependent, when the pH of the fluid on one side of a membrane differs from the pH of the fluid on the other side, drug molecules will tend to accumulate on the side where the pH most favors their ionization. Accordingly, since acidic drugs tend to ionize in basic media, and since basic drugs tend to ionize in acidic media, when there is a pH gradient between two sides of a membrane,
• Acidic drugs will accumulate on the alkaline side.
• Basic drugs will accumulate on the acidic side.

Question 13

5 factors affecting drug absorption

Answer 13

1. Rate of Dissolution,
2. Surface Area
3. Blood Flow,
4. Lipid Solubility
5. pH Partitioning

Question 14

IV:

1. Absorption Pattern
2. Advantages
3. Disadvantages

Answer 14

1. Absorption Pattern - Instantaneous and complete
2. Advantages - Rapid onset, and hence ideal for emergencies, (Precise control over drug levels, Permits use of large fluid, Permits use of irritant drugs.)
3. Disadvantages Irreversible (Expensive, Inconvenient, Difficult to do, and hence poorly suited for self-administration; Risk of fluid overload, infection, and embolism; Drug must be water soluble.

Question 15

IM:

1. Absorption Pattern
2. Advantages
3. Disadvantages

Answer 15

1. Absorption Pattern - Rapid with water-soluble drugs; Slow with poorly soluble drugs.
2. Advantages - Permits use of poorly soluble drugs; Permits use of depot preparations.
3. Disadvantages - Possible discomfort, Inconvenient, Potential for injury.

Question 16

subQ:

1. Absorption Pattern
2. Advantages
3. Disadvantages

Answer 16

1. Absorption Pattern - Rapid with water-soluble drugs; Slow with poorly soluble drugs.
2. Advantages - Permits use of poorly soluble drugs; Permits use of depot preparations.
3. Disadvantages - Possible discomfort, Inconvenient, Potential for injury.

Same as IM

Question 17

PO:

1. Absorption Pattern
2. Advantages
3. Disadvantages

Answer 17

1. Absorption Pattern - Slow and variable
2. Advantages - Easy (Convenient, Inexpensive, Ideal for self-medication, Potentially reversible, and hence safer than parenteral routes.)
3. Disadvantages - Variability (Inactivation of some drugs by gastric acid and digestive enzymes; Possible nausea and vomiting from local irritation; Patient must be conscious and cooperative.)

Question 18

Tablet Vs. Enteric Coated Tablet

Answer 18

A tablet is a mixture of a drug plus binders and fillers, all of which have been compressed together.

Enteric-coated preparations consist of drugs that have
been covered with a material designed to dissolve in the intestine but not the stomach.

Question 19

2 Factors driving distribution

Answer 19

Blood flow to the tissues and the ability to exit the vascular system

Question 20

Blood Brain Barrier

Answer 20

Refers to the unique anatomy of capillaries in the CNS. There are tight junctions between the cells that compose the walls of most capillaries in the CNS. These junctions are so tight that they prevent drug passage. Consequently, to leave the blood and reach sites of action within the brain, a drug must be able to pass through cells of the capillary wall. Only drugs that are lipid soluble or have a transport system can cross the BBB to a significant
degree.

Question 21

Placental Drug Transfer

Answer 21

The membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs.
The same factors that determine the movement of drugs across other membranes determine the movement of drugs across the placenta.
Accordingly, lipid-soluble, nonionized compounds readily pass from the maternal bloodstream into the blood of the fetus. In contrast, compounds that are ionized, highly polar, or protein bound are largely excluded—as are drugs that are substrates for P-glycoprotein, a transporter that can pump a variety of drugs out of placental cells into the maternal blood.

Question 22

Protein Binding

Answer 22

Drugs can form reversible bonds with various proteins
in the body. Of all the proteins with which drugs can bind, plasma albumin is the most important, being the most abundant protein in plasma.
Because of its size, albumin always remains in the bloodstream. Albumin is too large to squeeze through pores in the capillary wall, and no transport system exists by which it might leave

Question 23

P450

Hepatic Drug-Metabolizing Enzymes

Answer 23

P450 refers to cytochrome P450, a key component of the hepatic microsomal enzyme system, also known as the P450 system. (Most drug metabolism that takes place in the liver is performed by this enzyme system).

It is important to appreciate that cytochrome P450 is not a single molecular entity, but rather a group of 12 closely related enzyme families. Three of the cytochrome P450 (CYP) families— designated CYP1, CYP2, and CYP3—metabolize drugs.
Each of the three P450 families that metabolize drugs is itself composed of multiple forms, each of which metabolizes only certain drugs.

Question 24

Prodrug (activation) Vs. Drug (inactivation)

Answer 24

A prodrug is a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form via metabolism. Activation of a prodrug is illustrated by the metabolic conversion of fosphenytoin to phenytoin.

Drug metabolism can convert pharmacologically active compounds to inactive forms. This process is illustrated by the conversion of procaine (a local anesthetic) into para-aminobenzoic acid (PABA), an inactive metabolite

Question 25

6 consequences of drug metabolism

Answer 25

1. Accelerated renal excretion of drugs
2. Drug inactivation
3. Increased therapeutic action
4. Activation of “prodrugs”
5. Increased toxicity
6. Decreased toxicity

Question 26

5 factors that alter metabolism

Answer 26

1. Age
2. Induction and inhibition of drug-metabolizing enzymes
3. First-pass effect
4. Nutritional status
5. Competition between drugs

Question 27

3 steps in renal drug excretion

Answer 27

(1) glomerular filtration, (2) passive tubular reabsorption, and (3) active tubular secretion

Question 28

3 factors that modify renal drug excretion

Answer 28

1. pH-Dependent Ionization - can be used to accelerate renal excretion
2. Competition for Active Tubular Transport - can deley renal excretion, thereby prolonging its effects
3. Age - newborns and infants have limited capacity to excrete drugs due to immature kidneys. As we get age, renal excretion of drugs decreases.

Question 29

Enterohepatic Recirculation

Answer 29

Is a repeating cycle in which a drug is transported from the liver into the duodenum (via the bile duct) and
then back to the liver (via the portal blood). It is important to note, however, that only certain drugs are affected. Specifically, the process is limited to drugs that have undergone glucuronidation.

Question 30

Excretion in new mothers that could impact the infant

Answer 30

Drugs taken by breast-feeding women can undergo excretion into milk. As a result, breast-feeding can expose the nursing infant to drugs.
The factors that influence the appearance of drugs in breast milk are the same factors that determine the passage of drugs across membranes.
Accordingly, lipid-soluble drugs have ready access to breast milk, whereas drugs that are polar, ionized, or protein bound cannot enter in significant amounts. Because infants may be harmed by drugs excreted in breast milk, nursing mothers should avoid all unnecessary
drugs. If a woman must take medication, she should consult with her prescriber to ensure that the drug will not reach concentrations in her milk high enough to harm her baby.

Question 31

Minimum Effective Concentration

Answer 31

The plasma drug level below which therapeutic effects will not occur. Hence, to be of benefit, a drug must be present in concentrations at or above the MEC.

Question 32

Minimum Toxic Concentration

Answer 32

Toxicity occurs when plasma drug levels climb too high. The plasma level at which toxic effects begin is termed the toxic concentration. Doses must be kept small enough so that the toxic concentration is not reached.

Question 33

Half-Life

Answer 33

It is the time required for the amount of drug in the body
to decrease by 50%. A few drugs have half-lives that are extremely short—on the order of minutes. In contrast, the half-lives of some drugs exceed 1 week. Drugs with short half-lives leave the body quickly. Drugs with long half-lives leave slowly.

Question 34

Plateau Drug Level

Answer 34

When a drug is administered repeatedly in the same dose, plateau will be reached in approximately four half-lives. Administering repeated doses will cause a drug to build up in the body until a plateau (steady level) has been achieved.
What causes drug levels to reach plateau? If a second dose of a drug is administered before all of the prior dose has been eliminated, total body stores of that drug will be higher after the second dose than after the initial dose. As succeeding doses are administered, drug levels will climb
even higher. The drug will continue to accumulate until a state has been achieved in which the amount of drug eliminated between doses equals the amount administered. When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached.

Question 35

Peak Concentration

Answer 35

When a drug is administered repeatedly, its

level will fluctuate between doses; the highest level is referred to as the peak concentration

Question 36

Trough Concentration

Answer 36

When a drug is administered repeatedly, its level will fluctuate between doses; the lowest level is referred to as the trough concentration.

Question 37

Loading dose Vs. Maintenance dose

Answer 37

When plateau must be achieved more quickly, a large initial dose can be administered. This large initial dose is called a loading dose. After high drug levels have been
established with a loading dose, plateau can be maintained by giving smaller doses. These smaller doses are referred to as maintenance doses.

Question 38

Decline from plateau

Answer 38

When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval
equal to about four half-lives.

Question 39

Why ethanol is an oddball “drug”

Answer 39

It is important to note that the concept of half-life does not apply to the elimination of all drugs. A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of how much is present.