PRINCIPLES OF DRUG ACTION
I.
The Drug Administration Phase
A. Definition: The method by which a drug dose is made available to
the body
B. Drug Dosage Forms
i. The physical state of the drug in association with non-drug
components such as the vehicle
ii. Examples
1. tablets
2. capsules
3. injectable solutions
iii. Factors affecting the dosage form used
1. Is a systemic or local effect desired?
2. How fast is the effect needed?
3. Is the drug stable in GI tract?
4. How can the patient take it?
5. Safety of route vs. convenience?
6. What is the amount of drug to be given?
iv. Drug formulations and additives
1. The drug is the active ingredient in a dose formulation
but it is usually not the only ingredient in the total
formulation
2. Examples of additives
a. Capsule
i. Gelatinous material
b. Aerosolized agents for inhalation
i. Nebulizer Solution
1. preservatives
ii. Metered Dose Inhaler (MDI)
1. propellants
2. dispersing agents
iii. Dry Powder Inhaler (DPI)
1. carrier agents
C. Routes of Administration
i. Enteral Route
1. absorption along the GI tract
2. oral route
a. most common
b. safest
c. most convenient
d. most economical
e. patient must be able to swallow
ii.
Parenteral Route
1. technically means “besides the intestine”
2. clinically used to mean injection through the skin
3. Options
a. Subcutaneous (SC)
i. into subcutaneous tissue below epidermis
and dermis
b. Intramuscular (IM)
i. into the muscle layer
ii. more gradual effect than IV
c. Intravenous (IV)
i. into the vein
1. most rapid access to the systemic
circulation
d. Intradermal
i. into dermis layer of skin
e. Intraspinal
i. into the vertebral interspace and CSF
f. Epidural
i. into the epideral space below the dura
g. Intraperitoneal
i. into the peritoneal space
iii. Transdermal Route
1. the drug is absorbed through the skin into the systemic
circulation
2. provides continuous drug delivery to the systemic
circulation
3. less fluctuation is plasma drug levels
iv. Inhalation Route
1. The delivery of gas or aerosol to the airways
a. systemic effect
i. anesthesia gases
b. local effect
i. aerosol for bronchodilation
2. Advantages
a. Smaller doses
b. More rapid onset
c. Decreased systemic side effects
d. Convenient and easily tolerated
3. Disadvantages
a. Some systemic absorption and side effects
b. Imprecise dose delivered
4. Delivery Devices
a. Vaporizer (anesthesia gases)
b. Atomizer
c. Small Volume Nebulizer
d. Large Volume Nebulizer
e. Metered Dose Inhaler (MDI)
f. Dry Powder Inhaler (DPI)
g. Ultrasonic Nebulizer (USN)
h. Small Particle Aerosol Generator (SPAG)
v. Topical Route
1. Mucous Membrane
a. the mucous membrane is very vascular
i. can produce a local or systemic effect
2. Skin
a. Can provide a local or systemic effect
D. Common Drug Formulations for Different Routes of Administration
Enteral
Parenteral
Inhalation
Transdermal
tablet
capsule
suppository
solution
suspension
depot
gas
aerosol
patch
paste
elixir
suspension
II.
Topical –
Skin
powder
lotion
ointment
Topical –
Mucous Membrane
lozenges
sublingual tablets
ophthalmic, nasal,
and otic solutions
cream
The Pharmacokinetic Phase
A. Definition: Describes how the body acts on a drug
B. Four components
i. Absorption
1. Oral Route
a. The tablet or capsule dissolves to liberate the
active ingredient
b. The free drug must reach the epithelial lining of
the stomach or intestine
c. The drug must diffuse across the lipid membrane
barriers of the gastric and vascular cells
d. The drug reaches the bloodstream for distribution
in the body
2. Intravenous Route
a. Injection into a vein
b. Immediate access to the bloodstream
c. 100% drug availability
3. Inhalation Route
a. Lower Respiratory Tract
i. Airway surface liquid
ii. Epithelial cells
iii. Basement membrane
iv. Interstitium
v. Capillary vascular network
vi. Smooth muscle or glands of the airway
4. Methods by which drugs move across membrane
barriers
a. Aqueous diffusion
i. Occurs in interstitial spaces and within cells
ii. Transport across epithelial linings is
restricted due to small pore size
iii. Capillaries have larger pores that allow
passage of most drug molecules
iv. Diffusion is by a concentration gradient
b. Lipid diffusion
i. A drug must be lipid-soluble in order to
diffuse across the lipid membranes of the
epithelial cells
c. Carrier-mediated transport
i. Carrier molecules can transport drugs that
are similar to the substances they normally
transport
d. Pinocytosis
i. the process of membrane engulfment and
transport of a substance (drug) into the cell
in vesicles
5. Factors Affecting Absorption
a. Route of administration
i. determines which barriers to absorption that
must be crossed by a drug
ii. determines the drug’s time to onset and
peak effect
1. IV route provides a very rapid onset
and peak effect
b. Blood flow to the site of absorption
i. Adequate flood flow is essential for optimal
absorption
ii. Distribution
1. To be effective at its desired site of action, a drug must
have a certain concentration.
2. Concentration is partially determined by the rate of
absorption vs. the rate of elimination for a given dose
amount.
3. Affected by:
a. blood flow
b. fat or water solubility of the drug
c. protein binding
i. drugs are inactive when bound to plasma
proteins
d. blood-brain barrier
e. volume of distribution
i. The volume in which the drug is distributed
also effects drug concentration
Volumes (approximate) of major body compartments
Compartment
Volume (L)
Vascular (blood)
5
Interstitial Fluid
10
Intracellular Fluid
20
Fat (adipose tissue) 14-25
ii. Drug concentration is usually measured with
a blood sample
iii. Example
1. If 10 mg of a drug is put into the body
and the blood concentration is
measured as 2 mg/L, then the 10 mg
amount must be distributed over 5 L
2. volume of distribution (VD) = drug
amount/plasma concentration
a. VD = 10/2 = 5 L
iv. Example – Theophylline
1. If 350 mg of theophylline results in a
blood concentration of 10 mg/L, then
the volume of distribution is:
a. VD = 350/10 = 35 L
2. drug amount (loading dose) =
concentration x VD
3. To achieve a [theophylline] of 15
mg/L, with a VD of 35 L, then:
a. Dose = 15 mg/L x 35 L = 525
mg
iii. Metabolism
1. The liver is the major organ for drug metabolism
a. converts drugs to a water soluble form for
excretion by the kidney
2. the stomach has enzymes that can inactivate or destroy
the drug
3. affected by liver function and enzymes
4. First-Pass Effect
a. The amount of drug that is metabolized by the
liver before it reaches the systemic circulation
i. Drug administered orally
ii. Drug is absorbed into the blood from the
stomach or intestine
iii. The portal vein drains this blood directly
into the liver
iv. Blood from the liver leaves via the right and
left hepatic veins, enters the inferior vena
cava and into the systemic circulation
b. Drugs with a high first-pass effect may have a
significantly lower systemic blood concentration
i. Higher oral doses are needed
ii. Other route of administration
iv. Elimination
1. The kidney is the primary site of drug excretion
a. affected by renal blood flow and kidney function
2. Other sites
a. feces
b. sweat
c. respiratory tract
3. Plasma Clearance
a. A hypothetical volume of plasma that is
completely cleared of all drug over a given period
b. Expressed as liters per hour (L/hr), or liters per
hour per kilogram (L/hr/kg)
c. Used to estimate the rate at which a drug must be
replaced to maintain a steady plasma level
4. Maintenance Dose
a. to achieve a steady-state level of drug in the
body, dosing must equal the rate of elimination
5. Plasma Half-Life
a. the time required for the plasma concentration of
a drug to decrease by one half
b. Plasma half-lives of common drugs
Drug
Half-life (hr)
Acetaminophen
2
Amoxicillin
1.7
Azithromycin
Digoxin
Gabapentin
Morphine
Paroxetine
Terbutaline
40
39
6.5
1.9
17
14
6. Time-Plasma Curves
a. the concentration of a drug in the plasma over
time
b. can indicate if the dose given is sufficient to reach
and maintain a critical threshold of concentration
in the bodily fluid (usually blood) needed for
therapeutic effect in the body
C. The Pharmacokinetics of Inhaled Aerosol Drugs
i. The inhalation route together with the physical/chemical
nature of the drug will determine the absorption, distribution,
metabolism, and elimination of the aerosol drug
ii. Local effect
1. nasally inhaled vasoconstricting agents (decongestant)
a. Afrin
2. inhaled bronchodilator
a. albuterol
i. Proventil
ii. Ventolin
iii. Systemic effect
1. inhaled treatment for influenza
a. zanamivir (Relenza)
2. inhaled treatment for pain control
a. morphine
3. inhaled insulin for control of diabetes
iv. Inhaled Aerosols in Pulmonary Disease
1. intended for a local, targeted effect in the lung and
airway
2. used to maximize lung deposition while minimizing
systemic absorption and side effects
3. results in higher drug concentrations in the target organ
(lung)
v. Distribution of Inhaled Aerosols
1. Oral Portion (Stomach)
a. A portion of the aerosol impacts in the oropharynx
and is swallowed (90%)
b. Follows the same process as orally administered
drugs
c. First-pass metabolism of common inhaled aerosol
drugs
i. Albuterol: 50%
ii. Terbutaline: 90%
iii. Budesonide: 90%
2. Inhaled Portion
a. A portion of the aerosol is inhaled into the airway
b. Varies with the delivery device
i. 10-30%
vi. Lung Availability/Total Systemic Availability (L/T) Ratio
1. The proportion of aerosol drug available from the lung,
out of total systemically available drug
2. Quantifies the efficiency of aerosol drug delivery
a. The closer the L/T Ratio is to 1.0, the more
efficient the delivery system
3. Used to compare the efficiency of drug delivery systems
a. SVN vs. MDI vs. DPI
4. Factors Increasing the L/T Ratio With Inhaled Drugs
a. Efficient delivery devices
b. Inhaled drugs with a high first-pass metabolism
c. Mouth washing
d. Use of reservoir device to decrease oropharnygeal
deposition
i. Spacer
ii. Holding chamber
III.
The Pharmacodynamic Phase
A. Definition: Describes the mechanism of drug action, by which a
drug molecule causes its effect on the body
B. Structure-Activity Relations
i. The ability of a drug to bind to a receptor or enzyme
1. determined by the structure of the drug molecule
ii. The structure of the drug molecule will determine the effects
on the body
iii. Example of structure-activity relations (SAR) for two drugs in
the same class of bronchodilator
Structure
Pharmacokinetics
Side Effect
Class of drug
Isoproterenol
Catecholamine
Peak effect: 20 minutes
Duration: 1.5-2 hours
Increased heart rate
Adrenergic bronchodilator
Albuterol
Saligenin
Peak effect: 30-60 min.
Duration: 4-6 hours
Little/no change in heart rate
Adrenergic bronchodilator
Therapeutic effect
Relax airway smooth muscle
Relax airway smooth muscle
1. minor structural differences lead to significantly
different clinical effects
C. Nature and Type of Drug Receptors
i. Drug Receptors
1. proteins whose shape and electric charge provide a
match to a drug’s chemical shape or charge
a. receptors on cell surfaces
b. receptors within the cell
ii. Lipid-Soluble Drugs and Intracellular Receptor Activation
1. lipid-soluble drugs cross the cell membrane and act on
intracellular receptors
a. corticosteroids
b. vitamin D
c. thyroid hormone
iii. Drug-Regulated Ion Channels
1. The drug attaches to a surface receptor, which
regulates the opening of an ion channel
a. acetylcholine receptors on skeletal muscle
iv. Receptors Linked to G Proteins
1. The drug attaches to a transmembrane receptor that is
coupled to an intracellular enzyme by a G protein
a. Mediate both bronchodilation and
bronchoconstriction in the airways
b. Beta adrenergic bronchodilators
D. Dose-Response Relations
i. Response to a drug is proportional to the drug concentration
1. As drug concentration increases, the number of
receptors occupied increases, and the drug effect
increases
ii. Graphed as a dose-response curve
iii. ED50 - the dose that produces 50% of the maximal effect
iv. Potency Versus Maximal Effect
1. Potency
a. Refers to the dose (ED50) of a drug producing
50% of that drug’s maximal response
b. The potency of two drugs can be compared using
the ED50 values
2. Maximal Effect
a. The greatest response that can be produced by a
drug
b. A dose above which no further response can be
elicited
3. The lower the ED50 for a given drug, the more potent
the drug is
v. Therapeutic Index
1. Calculation
a. LD50
i. The dose of a drug lethal to 50% of the test
population (animal)
b. ED50
i. The dose of a drug effective for 50% of the
test population
c. TI = LD50/ED50
2. Represents the safety margin of a drug
3. The smaller the TI, the greater the risk of going from a
therapeutic effect to a toxic effect
4. Example of drugs with narrow TI
a. Theophylline
b. Digitalis
5. Example of drug with wide TI
a. Penicillin
vi. Terms related to pharmacodynamics
1. drug affinity
a. the tendency of a drug to combine with a receptor
b. may be on cell surface, in cell or with enzyme
2. drug efficacy
a. the tendency of a drug-receptor complex to cause
a specific response
3. agonist
a. a drug that binds to a receptor (has affinity) and
initiates a response (has efficacy)
4. antagonist
a. a drug that binds to a receptor (has affinity) but
causes no response (has no efficacy)
vii. Drug Interactions
1. antagonism
a. two drugs with opposing effects
b. one drug counteracts the other drug by:
i. inactivating the drug
ii. the two effects of the drugs cancel each
other
iii. one drug blocks another from binding to
and activating the receptor
2. synergism
a. occurs when two drugs act on a target organ by
different mechanisms of action, and the effect of
the drug pair is greater than the sum of the
separate effects of the drug (1+1=3)
3. additivity
a. occurs when two drugs act on the same receptors
and the combined effect is the simple linear sum
of the two drugs’ effects, up to a maximum effect
(1+1=2
4. potentiation
a. A special case of synergism in which one drug has
no effect but can increase the activity of the other
drug (1+0=2)
viii. Terms for Drug Responsiveness
1. Idiosyncratic effect
a. An effect that is opposite to or unusual or no
effect, compared with the usual predicted effect
2. Hypersensitivity
a. An allergic or immune-mediated reaction to a
drug
3. Tolerance
a. A decreasing intensity of response to a drug over
time
4. Tachyphylaxis
a. A rapid decrease in responsiveness to a drug
IV.
Pharmacogenetics
A. Definition: The study of heredity or genetic differences in an
individuals response to a drug
B. Genetic differences affecting drug metabolism have been most
extensively studied
C. Example: succinylcholine
i. A paralyzing agent used during surgery and endotracheal
intubation
ii. Duration of action is usually minutes
iii. In approximately 1 in 3000 individuals, it may take several
hours to recover from the drug and begin to breathe
spontaneously
1. mechanical ventilation will be required until
spontaneous breathing is adequate