Basic Principles of Clinical Pharmacology

TRANSFER OF DRUGS ACROSS MEMBRANES

Transport Processes
Passive diffusion
Simple diffusion
Facilitated diffusion
Active transport

Reduced by:
Incomplete absorption
First-pass effect
Pulmonary uptake of drugs
DRUG DISTRIBUTION
Redistribution
Rapid entry & equally rapid egress of
lipophilic drugs from richly perfused
organs
Placental Transfer
Simple diffusion
Highly polar, water-soluble compounds
does not significantly cross the placenta
DRUG ELIMINATION

Effects of Molecular Properties

Drugs are either weak acids or weak bases
Present in ionized and nonionized forms
pKa
Ion trapping phenomenon
DRUG ABSORPTION
Routes of Administration

Bioavailability
Fraction of the total dose that reaches the
systemic circulation
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Drug Clearance
Elimination clearance - Theoretical volume of
blood from which drug is completely and
irreversibly removed in a given time interval
Total Drug Clearance- equal to the sum of the
clearances of all the elimination pathways
Hepatic Drug Clearance
3 biologic factors:
Hepatic blood flow
Intrinsic ability of the liver to irreversibly
eliminate the drug from the blood
Extent of drug binding to plasma
proteins or other blood constituent
Venous Equilibration Model
The unbound concentration of drug in
hepatic
venous blood is in equilibrium with the
unbound concentration in hepatocytes
Limited by deliver of drug to the liver
Elimination is a first-order process
Factors that Alter Hepatic Drug Clearance
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Basic Principles of Clinical Pharmacology

Heat stress
Hypovolemia
Congestive cardiac failure
Liver diseases
Drugs that alter splanchnic
hemodynamics

Renal Drug Clearance

Phase I Reactions
Oxidation
Reduction
Hydrolysis
Cytochrome P450 system
catalyzes most oxidative and some
reductive biotransformations
Phase II Reactions
Also known as conjugation or synthetic
reactions
Occurs only after a Phase I reaction
Produce conjugates that are polar,
water-soluble compounds
Factors Affecting Biotransformation
Polymorphism
Age
Exposure to various foreign compounds
Liver disease
Congestive heart failure
Effects of anesthesia and surgery

DRUG METABOLISM
Drug Redistribution
primary mechanism for reducing drug
concentrations in the blood
Metabolism
Biotransformation of drugs to more
polar, water soluble compounds
Facilitates the ultimate excretion of
metabolites
Biotransformation Reactions

BINDING OF DRUGS TO PLASMA PROTEINS

Binding Proteins
Albumin
Most important drug-binding protein
binds to barbiturates, benzodiazepines,
penicillins and bilirubin
1-acid glycoprotein (AAG)
Primary binding protein for many basic
drugs
Factors Affecting Drug Binding
Maternal and neonatal drug binding
Age and sex
Hepatic disease
Renal disease
Other disease, surgery and trauma

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Basic Principles of Clinical Pharmacology

Compartmental Pharmacokinetic Models

PHARMACOKINETIC PRINCIPLES
Pharmacokinetics is the study of what the
body does to a drug
Quantitative analysis of the relationship
between the dose of a drug and the ensuing
changes in drug concentration in the blood and
other tissues
RATE CONSTANTS AND HALF-TIMES
First-order kinetics
a constant fraction of drug is removed
during a finite period of time.
Rate constant
Half-lives
time required for the concentration to
change by a factor of 2
Volume of Distribution
Quantifies the extent of drug
distribution
Overall capacity of tissues vs capacity of
blood
Apparent volume or compartment

Total Drug Clearance

Elimination clearance
Portion of the volume of distribution
from which drug is completely and
irreversibly removed during a given time
interval
Analogous to creatinine clearance

Effects of Hepatic or Renal Disease

An increase in the free-fraction will
produce the greatest increase in the Vd
of drugs that are highly bound to
plasma proteins
Non-linear Pharmacokinetics
Dose-dependent
A constant amt of drug is excreted per
unit time

PHARMACODYNAMIC PRINCIPLES
Pharmacodynamics - is the study of what
a drug does to the body.
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Basic Principles of Clinical Pharmacology

Dose-Response Curves- Dose of a drug and its
pharmacologic effects
4 aspects of the relationship of dose and
pharmacologic effect
Potency
Slope of the curve
Efficacy
Variability
Concentration-Response Relationships Relationship between drug concentration in the
blood and pharmacologic effects
Cp50
steady state plasma concentration
producing 50% of the maximal response
Drug-Receptor Interactions
DRUG INTERACTIONS
Physiochemical properties can occur in vitro
Alter each others absorption,
distribution and elimination
Drugs that inhibit or induce the enzymes
that catalyze biotransformation
reactions can affect clearance of other
concomitantly administered drugs
CLINICAL APPLICATIONS
Systems for Administration of Intravenous
Agents
Infusion pumps
Target-Controlled Infusions (TCI)
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