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	Topical –Skin	Topical – Mucous Membrane
tablet	solution	gas	patch	powder	lozenges
capsule	suspension	aerosol	paste	lotion	sublingual tablets
suppository	depot			ointment	ophthalmic, nasal, and otic solutions
elixir				cream
suspension

II. 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	40
Digoxin	39
Gabapentin	6.5
Morphine	1.9
Paroxetine	17
Terbutaline	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

	Isoproterenol	Albuterol
Structure	Catecholamine	Saligenin
Pharmacokinetics	Peak effect: 20 minutes Duration: 1.5-2 hours	Peak effect: 30-60 min. Duration: 4-6 hours
Side Effect	Increased heart rate	Little/no change in heart rate
Class of drug	Adrenergic bronchodilator	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