copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 4 pharmacokinetics

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 4

Pharmacokinetics

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Pharmacokinetics

Application of pharmacokinetics in therapeutics

Passage of drugs across membranes Three ways to cross a cell membrane Polar molecules Ions


Pharmacokinetics

Absorption Distribution Metabolism Excretion Time course of drug responses


Fig. 4-1. The four basic pharmacokinetic processes.Dotted lines represent membranes that must be crossed as drugs move throughout the body.


Application of Pharmacokinetics in Therapeutics By applying knowledge of pharmacokinetics

to drug therapy, we can help maximize beneficial effects and minimize harm.


A Note to Chemophobes

Chemophobes are students who fear chemistry.

This chapter contains some of the most difficult material in the book.

This chapter lays an important foundation for the rest of the chapters.


Passage of Drugs Across Membranes

Three ways to cross a cell membrane

•Channels and pores•Transport systems•P-glycoprotein•Direct penetration of the membrane


Membrane Structure

Fig. 4-2. Structure of the cell membrane.The cell membrane consists primarily of a double layer of phospholipid molecules. The large globular structures represent protein molecules imbedded in the lipid bilayer.


Passage of Drugs Across Membranes

Polar molecules Uneven distribution of a charge No net charge

Ions Molecules that have a net electrical charge


Fig. 4-3. Polar molecules. A, Stippling shows the distribution of electrons within the water molecule. As indicated, water’s electrons spend more time near the oxygen atom than near the hydrogen atoms, making the area near the oxygen atom somewhat negative and the area near the hydrogen atoms more positive. B, Kanamycin is a polar drug. The —OH groups of kanamycin attract electrons, thereby causing the area around these groups to be more negative than the rest of the molecule.


Ions

Quaternary ammonium compounds Molecules that contain at least one atom of

nitrogen and carry a positive charge at all times pH-dependent ionization

Acid is a proton donor – tends to ionize in basic (alkaline) media

Base is a proton acceptor – tends to ionize in acidic media

Ion trapping (pH partitioning) Acidic drugs accumulate on the alkaline side. Basic drugs accumulate on the acidic side.


Fig. 4-4. Quaternary ammonium compounds. A, The basic structure of quaternary ammonium compounds. Because the nitrogen atom has bonds to four organic radicals, quaternary ammonium compounds always carry a positive charge. Because of this charge, quaternary ammonium compounds are not lipid soluble and cannot cross most membranes. B, Tubocurarine is a representative quaternary ammonium compound. Note that tubocurarine contains two “quaternized” nitrogen atoms.


Fig. 4-5. Ionization of weak acids and weak bases. The extent of ionization of weak acids (A) and weak bases (B) depends on the pH of their surroundings. The ionized (charged) forms of acids and bases are not lipid soluble and hence do not readily cross membranes. Note that acids ionize by giving up a proton and that bases ionize by taking on a proton.


Fig. 4-6. Ion trapping of drugs.


Absorption

Movement of a drug from its site of administration into the blood Rate of absorption determines how soon effects

will begin. Amount of absorption helps determine how

intense the effects will be.


Absorption

Factors affecting drug absorption Characteristics of commonly used routes of

administration Pharmaceutical preparations for oral

administration Additional routes of administration


Factors Affecting Drug Absorption

Rate of dissolution Surface area Blood flow Lipid solubility pH partitioning


Characteristics of Commonly Used Routes of Administration

Intravenous Barriers to absorption Absorption pattern Advantages Disadvantages

Intramuscular Barriers to absorption Absorption pattern Advantages Disadvantages


Fig. 4-7. Drug movement at typical capillary beds. In most capillary beds, “large” gaps exist between the cells that compose the capillary wall. Drugs and other molecules can pass freely into and out of the bloodstream through these gaps. As illustrated, lipid-soluble compounds can also pass directly through the cells of the capillary wall.


Characteristics of Commonly Used Routes of Administration

Subcutaneous No significant barriers to absorption

Oral Barriers to absorption Absorption pattern Drug movement following absorption Advantages Disadvantages


Fig. 4-8. Movement of drugs following GI absorption. All drugs absorbed from sites along the GI tract—stomach, small intestine, and large intestine (but not the oral mucosa or distal rectum)—must go through the liver, via the portal vein, on their way toward the heart and the general circulation. For some drugs, passage is uneventful. Others undergo extensive metabolism. Still others undergo excretion into the bile, after which they re-enter the small intestine (via the bile duct), and then either (1) undergo reabsorption into the portal blood, thereby creating a cycle known as enterohepatic recirculation, or (2) exit the body in the stool (not shown).


Pharmaceutical Preparations for Oral Administration

Tablets Enteric-coated preparations Sustained-release preparations


Additional Routes of Administration

Topical Transdermal Inhaled Rectal Vaginal Direct injection to a specific site (eg, heart,

joints, nerves, CNS)


Distribution

Movement of drugs throughout the body


Distribution

Drug distribution is determined by

these three factors

•Blood flow to tissues•Exiting the vascular system•Entering cells


Blood Flow to Tissues

Drugs are carried by the blood to tissues and organs of the body.

Blood flow determines the rate of delivery. Abscesses and tumors

Low regional blood flow impacts therapy. Pus-filled pockets, not internal blood vessels Solid tumors have limited blood supply.


Exiting the Vascular System

Typical capillary beds Drugs pass between capillary cells rather than

through them.


Blood-Brain Barrier (BBB)

Tight junctions between the cells that compose the walls of most capillaries in the CNS

Drugs 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.


Fig. 4-9. Drug movement across the blood-brain barrier. Tight junctions between cells that compose the walls of capillaries in the CNS prevent drugs from passing between cells to exit the vascular system. Consequently, to reach sites of action within the brain, a drug must pass directly through cells of the capillary wall. To do this, the drug must be lipid soluble or must be able to use an existing transport system.


Placental Drug Transfer

Membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs. Movement determined in the same way as other

membranes Risks with drug transfer

Birth defects: mental retardation, gross malformations, low birth weight

Mother’s use of habitual opioids: birth of drug-dependent baby


Fig. 4-10. Placental drug transfer. To enter the fetal circulation, drugs must cross membranes of the maternal and fetal vascular systems. Lipid-soluble drugs can readily cross these membranes and enter the fetal blood, whereas ions and polar molecules are prevented from reaching the fetal blood.


Protein Binding

Drugs can form reversible bonds with various proteins.

Plasma albumin is the most abundant and important. Large molecule that always remains in the

bloodstream Impacts drug distribution


Fig. 4-11. Protein binding of drugs. A, Albumin is the most prevalent protein in plasma and the most important of the proteins to which drugs bind. B, Only unbound (free) drug molecules can leave the vascular system. Bound molecules are too large to fit through the pores in the capillary wall.


Entering Cells

Some drugs must enter cells to reach the site of action.

Most drugs must enter cells to undergo metabolism and excretion.

Many drugs produce their effects by binding with receptors on the external surface of the cell membrane. Do not need to cross the cell membrane to act


Drug Metabolism

Also known as biotransformation Defined as the enzymatic alteration of drug

structure Most often takes place in the liver


Drug Metabolism

Hepatic drug-metabolizing enzymes Therapeutic consequences of drug

metabolism Special considerations in drug metabolism


Hepatic Drug-Metabolizing Enzymes

Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as the P450 system.

Metabolism doesn’t always result in a smaller molecule.


Therapeutic Consequences of Drug Metabolism

Accelerated renal drug excretion Drug inactivation Increased therapeutic action Activation of prodrugs Increased or decreased toxicity


Fig. 4-12. Therapeutic consequences of drug metabolism.(See text for details.)


Enterohepatic Recirculation

Repeating cycle in which drug is transported From the liver into the duodenum (via bile duct) Then back to the liver via the portal blood

Limited to drugs that have undergone glucuronidation


Special Considerations in Drug Metabolism

Age Induction of drug-metabolizing enzymes First-pass effect Nutritional status Competition between drugs


Excretion

Defined as the removal of drugs from the body

Drugs and their metabolites can exit the body through Urine, sweat, saliva, breast milk, or expired air


Renal Routes of Drug Excretion

Steps in renal drug excretion Glomerular filtration Passive tubular reabsorption Active tubular secretion

Factors that modify renal drug excretion pH-dependent ionization Competition for active tubular transport Age


Fig. 4-13. Renal drug excretion.


Nonrenal Routes of Drug Excretion

Breast milk Other nonrenal routes of excretion

Bile• Enterohepatic recirculation

Lungs (especially anesthesia) Sweat/saliva (small amounts)


Time Course of Drug Responses

Plasma drug levels Single-dose time course Drug half-life Drug levels produced with repeated doses


Fig. 4-14. Single-dose time course.


Plasma Drug Levels

Clinical significance of plasma drug levels Two plasma drug levels defined

Minimum effective concentration Toxic concentration

Therapeutic range


Therapeutic Range

The objective of drug dosing is to maintain plasma drug levels within the therapeutic range.


Single-Dose Time Course

The duration of effects is determined largely by the combination of metabolism and excretion.

Drug levels above minimum effective dose – therapeutic response will be maintained


Half-Life

Defined as the time required for the amount of drug in the body to decrease by 50%

Percentage vs. amount Determines the dosing interval


Drug Levels Produced with Repeated Doses

Process by which plateau drug levels are achieved

Time to plateau Techniques for reducing fluctuations in drug

levels Loading doses vs. maintenance doses Decline from plateau


Fig. 4-15. Drug accumulation with repeated administration. This figure illustrates the accumulation of a hypothetical drug during repeated administration. The drug has a half-life of 1 day. The dosing schedule is 2 gm given once a day on days 1 through 9. Note that plateau is reached at about the beginning of day 5 (ie, after four half-lives). Note also that, when administration is discontinued, it takes about 4 days (four half-lives) for most (94%) of the drug to leave the body.

copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 4 pharmacokinetics

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