Lehne's Ch 4 pharmacokinetics pharmacodynamics and drug interactions

CHAPTER 4 – PHARMACOKINETICS, PHARMACODYNAMICS, AND DRUG
INTERACTIONS

PHARMACOKINETICS

 The study of drug movement throughout the body
 Four processes of pharmacokinetics: absorption, distribution, metabolism, and
excretion
 Absorption is the movement of the drug from its site of administration into the blood
 Distribution is the movement of the drug from the blood to the interstitial space of
tissues and into cells
 Metabolism (biotransformation) is the enzymatically mediated alteration of drug
structure
 Excretion is the movement of drugs and their metabolites out of the body
 These processes determine the concentration of a drug at its sites of action
 The intensity of the response to a drug is directly related to the concentration of the
drug at it site of action
 Maximum beneficial effect is achieved with a concentration high enough to elicit the
desired response while avoiding concentrations that cause harm

PASSAGE OF DRUGS ACROSS MEMBRANES

 Drugs must cross membranes to move throughout the body.
o Site of administration – bloodstream – site of action – metabolism – excretion
 Cells are very close together so drugs usually pass through cells opposed to between
 Therefore the ability of a drug to cross a biologic membrane is determined by its
ability to pass through single cells

Three ways to cross a membrane

 Through channels or pores
 Via a transport system
 Direct penetration of the membrane (most common)

Channels and pores

 Least common way for drugs to pass
 Channels and pores are very small
 Only the smallest compounds, like potassium and sodium, can pass through their
correct channels

Transport systems

 Role is to move drugs from one side to the other
 They are selective and dependent on drug structure
 P-glycoprotein (PGP) aka multidrug transporter protein is a transmembrane protein
that transport several drugs OUT of cells



Direct penetration of the membrane

 Occurs primarily

,  Most drugs are too large to pass through channels and pores, and most lack transport
systems to help them cross all the membranes separating them from the sites of
action, metabolism, and excretion
 “like dissolves like.” Membranes are mostly composed of lipids therefore a drug must
be lipid soluble (lipophilic) to directly penetrate.

POLAR MOLECULES AND IONS

 Polar molecules and ions are not lipid soluble therefore cannot penetrate membranes

Polar molecules

 Have no net charge
 Instead have an uneven distribution of electrical charge, meaning the positive and
negative charges within congregate separately
 Ex: water, the electrons (negative charges) spend more time in the vicinity of the
oxygen (-) atom than the two hydrogens (+), making the area around the oxygen
more negatively charged and the hydrogen more positively charged
 Along with “like dissolves like,” polar molecules dissolve in polar solvents (such as
water) but not in nonpolar solvents (such as lipids)

Ions

 Molecules with a positive or negative net electrical charge
 Unable to cross membranes! Unless very small.
 Must become nonionized to cross
 Many drugs are either charged or uncharged weak organic bases or weak organic
acids. The electrical charge it has is determined by the pH of the surrounding
medium
o Acids tend to ionize in basic (alkaline) media
o Bases tend to ionize in acidic media
o Therefore weak acids absorb best in acid environment (ex: gastric acid)
because they remain nonionized
o Ex: aspirin molecules pass from stomach into small intestine where it is more
alkaline, changing the molecules to ionized form, impeding absorption of
aspirin from the intestine

pH partitioning (ion trapping)

 The process of drug accumulation on the side of the membrane where the pH favors
its ionization
 When there is a difference in pH between two sides of a membrane, drug molecules
tend to accumulate on the side where pH favors their ionization
o Acidic drugs accumulate on alkaline side
o Basic drugs accumulate on acidic side

ABSORPTION

 The movement of a drug from its site of administration into the systemic circulation
 Rate of absorption determines how soon effects begin
 Amount of absorption determines how intense effects will be
 Chemical equivalence: when drug preparations contain the same amount of the drug

,  Bioavailability: preparations are considered equal in bioavailability if the drug they
contain is absorbed at the same rate and to the same extent

Factors affecting drug absorption

 Rate of dissolution
 Surface area
 Blood flow
 Lipid solubility
 pH partitioning

Rate of dissolution

 drugs must dissolve before they can be absorbed
 rate of dissolution determines rate of absorption
 Drugs formulated for rapid dissolution = faster onset compared to drugs formulated
for slow dissolution

Surface area

 Larger surface area = faster absorption
 Absorption of PO drugs is usually greater from smaller intestine than stomach
because its lined with microvilli

Blood flow

 Sites with high blood flow = more rapid absorption because blood containing a newly
absorbed drug will be replaced rapidly by drug-free blood, maintaining a large
gradient between concentration of drug outside versus inside the blood. Greater
concentration gradient = greater rate of absorption

Lipid solubility

 Highly lipid-soluble drugs are absorbed quicker than lower ones
 Lipid-soluble drugs easily pass membranes that separate them from blood



pH partitioning

 Absorption is enhanced when the difference in pH of plasma and pH at site of
administration causes drug molecules to be ionized in the plasma

Characteristics of commonly used routes of administration

 Route of administration affects rate and extent of absorption
 Major routes (see table 4.1):
o PO (enteral)
 Absorbed through epithelial lining GI tract; capillary wall
 Slow and variable
 Easy, convenient, inexpensive, potentially reversible hence safer
 Variable; possible inactivation by gastric acid or digestive enzymes,
possible n/v from irritation, pt must be conscious/cooperative
o IV