Book Cover for Pharmacotherapeutics for Advanced Practice Nurse

Prescribers, Sixth Edition.

Chapter 2
Review of Basic Principles
of Pharmacology

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 Objectives

1. Identify the factors influencing drug

responses
2. Describe drug-receptor binding
3. Explain the 4 processes of pharmacokinetics:
absorption, distribution, metabolism, and
excretion

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 Overview
 Pharmacology—the study of drugs
 How new drugs are developed
 Drug responses
 Receptors
 Pharmacokinetics
 Summary

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 Pharmacology
 Study of drugs and their actions
 Ideal drug properties:
• Convenient administration and duration of action
• Established dosage
• Immediate onset of action
• Produces a single desired biological action
• Dosage unaffected by disease state
• Improves longevity and quality of life

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 How New Drugs Are Developed
 Preclinical stage—animal studies
 Clinical stage
• Phase I: establish safety and biological effects
• Phase II: establish efficacy
• Phase III: randomized clinical trial comparing new
drug to standard therapy or placebo
 Postmarketing surveillance
• Pharmacogenomic studies to identify biological
factors of benefits or adverse effects

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 Drug Responses
 Dose–response curves
 Types of drug responses
 Expressing drug responses
 Drug selectivity
 Drug responses in the real world
 Brand versus generic drugs

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 Dose–Response Curves
 Dose–response curve depicts the
relationship between drug dose and the
magnitude of effect
 Doses below the curve do not produce a
pharmacological response
 Doses above the curve do not produce much
additional pharmacological response
• May have unwanted effects → toxicity

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 Types of Drug Responses
 Graded: biological effects can be measured
continually up to the maximum responding
capacity
• Blood pressure
• Heart rate
 Quantal: biological effects are present or
absent
• Seizures
• Rash

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 Expressing Drug Responses
 Potency: how much drug is needed to
produce a biological effect
 Efficacy: the maximum effect of a drug
 Intrinsic activity: ability of drug to produce
maximum stimulation of occupied receptors

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 Drug Selectivity
 Ratio of the dose producing undesired
effects to the dose producing the desired
effects
 Minimum effective concentration (MEC):
level below which therapeutic effects will
not occur
 Minimum toxic concentration (MTC): level
above which toxic effects begin
 Therapeutic index: ratio of MTC to MEC

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 Drug Response in the Real World
 Placebo effect
 Dose–effect relationship in real world

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 Brand Versus Generic Drugs
 Both brand-name and generic drugs contain
same active ingredient
 Differences in inactive ingredients may result
in different rate of absorption
 U.S. Food and Drug Administration (FDA)
Orange Book rates generic substitutions for
brand-name products

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 Receptors
 Ion channel receptors  Enzymes
 Receptors coupled to G  Drug action at receptors
proteins  Disease states and
 Transmembrane receptors
receptors  Nonreceptor
 Intracellular receptors mechanisms
regulating gene
expression

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 Receptors (continued)
 Most drugs work by binding and interacting
with receptors (usually proteins)
 Receptors determine dose–effect
relationship, selectivity of drugs, and actions
of antagonists
 Structure–activity relationship (SAR):
association between chemical structure with
pharmacological activity

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 Ion Channel Receptors
 Transmit signals across cell membranes by
increasing flow of ions and altering electrical
potential across membrane
• Include receptors for nicotinic (ACh), gamma-
aminobutyric acid (GABA), and excitatory amino
acids (e.g., glycine)

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 Receptors Coupled to G Proteins
 G-protein receptors have general structure
but different binding site
• Receptor activation through second messengers
(e.g., adenosine monophosphate)

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 Transmembrane Receptors
 Consist of an extracellular hormone-binding
domain and an intracellular enzyme domain
that phosphorylates the amino acid tyrosine
• Tyrosine includes receptors for insulin

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 Receptors Regulating Gene Expression
 Lipid-soluble hormones
pass through cell
membrane and bind to
intracellular receptors
• Receptor moves to
nucleus; controls gene
transcription by binding to
specific DNA sequences

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 Enzymes
 Biological molecules that encourage specific
chemical reactions in the body
• Drugs can stimulate or inhibit specific enzymes
• Antibiotics inhibit enzymes essential for bacteria

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 Drug Action at Receptors
 Agonists: drugs that produce receptor
stimulation every time they bind
 Partial agonists: drugs stimulate only some
of the receptors
 Antagonist: drugs occupy receptors without
simulating them; prevent agonists from
occupying same site (e.g., atenolol)

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 Disease States and Receptors
 Disease states or drugs can selectively alter
the number of receptors in various tissues
• Examples: nutrition, cachexia, liver disease
 Not all drugs act through receptors

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 Pharmacokinetics
 Absorption
 Distribution
 Metabolism
 Excretion

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 Absorption
 Parenteral administration
 Oral administration
 Site of administration
 Bioavailability
 Peak blood levels

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 Distribution
 Movement of absorbed drug in bodily fluids
throughout body to target tissues
• Drugs can be distributed by:
‒ Passive diffusion
‒ Facilitated passive diffusion
‒ Active transport
• Drug distributed to areas of high blood flow
followed by low blood flow

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 Properties Affecting Distribution
 Water or lipid solubility
 Molecular size
 pH environment
 Henderson-Hasselbalch relationship
 Protein binding
 Transporters
 Volume of distribution

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 Distribution: Protein Binding
 Drugs passively diffuse when unbound to
plasma proteins and uncharged
 Drugs bound to plasma proteins circulate in
bloodstream rather than being distributed
by passive diffusion
• Protected from metabolism and excretion
• Helps normalize drug concentrations in body
• Low plasma proteins (e.g., albumen) will result in
more unbound drug in the circulation

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 Distribution: Competition for Binding Sites
 Finite number of plasma proteins
 Several drugs can bind to the same plasma
protein
• Compete and displace each other → greater free
drug circulating
• Higher risk for toxicity
• More drug may be eliminated

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 Distribution: Transport Systems
 Membrane proteins that facilitate
movement of molecules across cell
membranes
 Can transport drugs into (influx) and out of
(efflux) cells
 The basis for controlling the distribution into
protected tissues (e.g., brain)

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 Volume of Distribution (Vd)
 Vd is the amount of drug administered
divided by plasma concentration
• Important for understanding where the drug is
distributed once absorbed
• A large Vd reflects low drug plasma
concentration, little protein binding, and
extensive distribution to body tissues
• Water-soluble drugs have a Vd similar to plasma
volume; lipophilic drugs have a large Vd
• Vd affected by dehydration, obesity, edema

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 Metabolism: Introduction
 Biotransformation involving chemical
alterations of drugs into metabolites
• Increases or decreases onset, duration, and
toxicity of drug
• Occurs primarily in liver but also kidneys, lungs,
skin, and gastrointestinal (GI) tract
• First-pass metabolism: metabolism by liver
following oral administration

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 Metabolism: Phases
 Phase I (nonsynthetic or preconjugation):
drugs become more water soluble through
oxidation, reduction, or hydrolysis for easier
excretion
 Phase II (synthetic or conjugation):
attachment of drug to a polar molecule,
making it highly water-soluble with little or
no pharmacologic activity

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 Metabolism: Cytochrome P450
 Enzyme system part of phase I metabolism
• Organized into numbered families based on
function: CYP1, CYP2, CYP3, CYP4
• Subfamilies organized by chemical structure: A, B, C
‒ Examples: CYP3A, CYP2C, CYP1A, CYP2E, CYP2D
• Genetic polymorphisms can change drug metabolic
activity and explain why individuals react
differently to medications

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 Metabolism and Half-Life
 Half-life of a drug is the amount of time
required for the amount of drug in the body
to decrease by one-half
• Dependent on volume of distribution and
clearance
• Half-life useful for estimating the amount of time
it takes to reach the steady state of a drug

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 Patterns of Metabolism
 Prodrug: Biologically inactive drug precursor
that is biotransformed following
administration to improve the
pharmacokinetic properties of the original
compound
• The inactive oral prodrug can be stable in the GI
tract and only biotransformed by CYP450 in the
liver or plasma

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 Metabolism and Drug Interactions
 A drug can cause alterations in enzyme
metabolism of another drug by being an
inhibitor or an inducer
• Inhibition occurs through competition of two
drugs metabolized by the same enzyme
• In inhibition, the drug decreases the production
of the enzyme needed for metabolism
• Drugs causing enzyme induction make the
metabolic pathway work quickly, causing the
drug to be deactivated more rapidly

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 Excretion
 Removal of the drug from the body by the
organs of elimination
 Drugs are excreted by:
• Kidneys (primarily)
• Gastrointestinal tract
• Lungs
• Sweat and saliva
• Mammary glands (via breast milk)

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 Renal Excretion
 Passive glomerular
filtration
 Active tubular secretion
 Tubular reabsorption

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 Glomerular Filtration
 Preserves plasma proteins while removing
free drugs from plasma
 Large-sized drugs have slower filtration rate
 Uncharged forms of drug diffuse more
readily
 Acidification of urine creates “ion trapping,”
favoring excretion of drugs and metabolites

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 Renal Excretion of Drugs
 Affected by:
• Kidney function—renal blood flow
• Molecular size, charge, and degree of protein
binding of the drug
• Tubular acidity
• Height and weight
• Age
• Sex

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 Gastrointestinal (GI) Tract Excretion
 Biliary excretion
• After being metabolized in the liver, the
metabolite is excreted into the bile
• Some drugs may then be reabsorbed in the
intestine
• Enterohepatic cycling decreases the amount of
drug excreted
 Fecal excretion

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 Lung Excretion
 Gases
 General anesthetics and volatile liquids
 After alcohol consumption
 Rate of excretion based on respiratory rate
and pulmonary blood flow

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 Skin and Salivary Excretion
 Skin is a minor route of excretion
• Can be used to noninvasively detect drugs in the
body
• Excretion in sweat may cause adverse effects,
such as a rash (dermatitis)
 Salivary excretion
• Some drugs produce changes in taste

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 Mammary Excretion
 Many drugs are excreted in breast milk
• Smaller molecular weight and unionized
passively diffuse
• Lipid soluble
 Breast milk is acidic; accumulates basic drugs

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 Summary
 Drug responses
 Receptors
 Pharmacokinetics
• Absorption
• Distribution
• Metabolism
• Excretion

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 Knowledge Check

Which of the following describe the

processes of pharmacokinetics?
A. Absorption, transporter, receptors
B. Absorption, distribution, metabolism,
excretion
C. Absorption, receptors, filtration
D. Absorption, selectivity, enzymes, proteins

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 Answer

Correct Answer: B
Pharmacokinetics is the analysis of the
processes of absorption, distribution,
metabolism, and excretion of medication. It is
used to determine the dose and frequency of
medication prescribed to the patient.

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 Knowledge Check (continued)
Which of the following statements are true
about cytochrome (CYP) 450?
A. They are a family of enzymes important for
drug metabolism
B. They are concentrated primarily in the
kidneys
C. They include only 2 major numbered groups
D. Genetic polymorphisms have no effect on
CYP450
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 Answer (continued)

Correct Answer: A
The most extensively studied pathway in
medication metabolism is the family of
enzymes known as cytochrome (CYP) 450.
CYP450 operates throughout the body but is
concentrated in the liver, intestines, and lungs.
Genetic polymorphisms can result in changes
in the metabolic activity of medications in
individuals and populations.

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