Far Eastern University

Institute of Nursing

MODULE 6A: Drug Action: Pharmaceutic and Pharmacokinetic Phase

I. INTRODUCTION:

A tablet or capsule taken by mouth goes through three phases: pharmaceutic phase
(dissolution), when the drug becomes a solution so that it can cross the biologic
membrane. When the drug is administered parenterally by subcutaneous (SQ),
intramuscular (IM), or intravenous (IV) routes there is no pharmaceutic phase. The
pharmacokinetic phase is composed of four processes: absorption, distribution,
and metabolism (biotransformation), and excretion (elimination).

II. OBJECTIVES

Upon completion of this module, the student is expected to:

1. Differentiate the three phases of drug action.
2. Discuss the two processes that occur before tablets are absorbed into the body.
3. Describe the four processes of pharmacokinetics.
4. Define the terms protein-bound drugs, half-life, therapeutic index, therapeutic
drug range, side effects, adverse reaction, and drug toxicity.
5. Check drugs for half-life, percentage of protein-binding effect, therapeutic range,
and side effects in a drug reference book.
6. Describe the nursing implications of pharmacokinetics.
7. Differentiate the four pharmacokinetic processes related to drug interaction.

III. DISCUSSION

Three Phases of Drug Action

The basic phases associated with all drugs and their actions are pharmaceutics,
pharmacokinetics, and pharmacodynamics.

1. Pharmaceutic Phase
Approximately 80% of drugs are taken by mouth. The pharmaceutic phase
dissolution is the first phase of drug action. In the gastrointestinal (GI) tract,
drugs need to be in a solution so they can be absorbed.

A drug in solid form (tablet or capsule) must disintegrate into smaller particles
to be dissolved into a liquid, a process known as dissolution. Drugs in liquid
form are already in solution.

The figure below displays the two pharmaceutic phases of a tablet –

disintegration and dissolution:

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1.1. Use of Excipients to Promote Drug Absorption
Tablets are not 100% drug. Fillers and inert substances. Generally
called excipients, are used in drug preparation to allow the drug to take
a particular size and shape and to enhance drug dissolution. Some
additives in drugs, such as the ions potassium (K) and sodium (Na) in
penicillin potassium and penicillin sodium, increase the absorbability of
the drug. Penicillin is poorly absorbed in the GI tract because of gastric
acid. However, by making a drug a potassium or sodium salt, penicillin
can then be absorbed. Disintegration is the breakdown of a tablet into
smaller particles while dissolution as dissolving of the smaller particles
in the GI fluid before absorption.

Rate of dissolution is the time it takes the drug to disintegrate and

dissolve to become available for the body to absorb it. Drugs in liquid
form are more rapidly available for GI absorption than are solids

1.2. The Effect of Gastric Ph.

pH stands for 'potential of Hydrogen; a scale used to specify how acidic
or basic a water-based solution is. Acidic solutions have a lower pH,
while basic solutions have a higher pH. Generally, drugs are both
disintegrated and absorbed faster in acidic fluids with a pH of 1 to 2
rather than alkaline fluids. Alkaline drugs would become ionized and
have difficulty crossing cell membrane barriers. Both the very young
children and older adults have less gastric acidity; therefore, drug
absorption is generally slower for those drugs absorbed primarily in the
stomach for individuals in these age groups.

1.3. Use of Enteric-Coated Drugs and Proper Administration

Enteric-coated drugs resist disintegration in the gastric acid of the

stomach, so disintegration does not occur until the drug reaches the
alkaline environment of the small intestine. Enteric-coated tablets can
remain in the stomach for a long time therefore, their effect may be
delayed in onset. Enteric-coated tablets or capsules and sustained-
release (beaded) capsules should not be crushed. Crushing would alter
the time and place of absorption of the drug. Some drugs are taken on
an empty stomach because food in the GI tract may interfere with the
dissolution of certain drugs. There are some drugs that are on the other
hand taken with food or fluids to dilute drug concentration and to act as
protectant from drugs that irritate the gastric mucosa.

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2. Pharmacokinetic Phase

Pharmacokinetics is the process of drug movement to achieve drug action.

The four processes are absorption, distribution, metabolism (or
biotransformation), and excretion (or elimination). The nurse applies
knowledge of pharmacokinetics when assessing the patient for possible
adverse drug effects. The nurse communicates assessment findings to
members of the healthcare team in a timely manner to promote safe and
effective drug therapy for the patient.

2.1. Absorption
Absorption is the movement of drug particles from the GI tract to body
fluids by passive absorption, active absorption, and pinocytosis.

Most oral drugs are absorbed into the surface area of the small intestine
through the action of the extensive mucosal villi. Absorption is reduced
if the villi are decreased in number because of disease, drug effect, or
the removal of small intestine. Protein based drugs such as insulin and
growth hormones re destroyed in the small intestine by digestive
enzymes.

Passive absorption occurs mostly by diffusion (movement from higher

concentration to lower concentration). With the process of diffusion, the
drug does not require energy to move across the membrane. Active
absorption requires a carrier such as an enzyme or protein to move
the drug against a concentrated gradient. Energy is required for active
absorption. Pinocytosis is a process by which cells carry a drug across
their membrane by engulfing the drug particles.

The Effect of Lipid Solubility and Drug Absorption.

The GI membrane is composed mostly of lipid (fat) and protein, so

drugs that are lipid-soluble pass rapidly through the GI membrane.
Water soluble drugs need a carrier, either enzyme or protein, to pass
through the cell membrane. Large particles pass through the cell
membrane if they are non-ionized (Have no positive or negative

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charge). Weak acid drugs such as aspirin are less ionized in the
stomach, and they pass through the stomach lining easily and rapidly

Some drugs cannot be administered by mouth. Protein-based drugs

such as insulin and growth hormones are destroyed in the small
intestine by digestive enzymes, so they are not administered by mouth
but rather parenterally.

In the illustration above, a lipid, non-ionized and a less ionized weak acid like
aspirin undergo passive absorption. While water soluble and ionized drugs like
atenolol needs a carrier to cross the membrane and undergo active absorption.

First-Pass Effect or Hepatic First Pass

Some drugs do not go directly into the systemic circulation following
oral absorption but pass from the intestinal lumen to the liver via the
portal vein. The process in which the drug passes to the liver first is
called the first-pass effect, or hepatic first pass.

Most drugs given orally are affected by first-pass metabolism. Lidocaine

and some nitroglycerines are not given orally because they have
extensive first-pass metabolism and therefore, most of the dose would
be destroyed. Examples of drugs with first-pass metabolism, are
warfarin (Coumadin) and morphine.

Bioavailability is a sub-category of absorption. It is the percentage of

the administered dose that reaches the systemic circulation. For the
oral route of drug administration, bioavailability occurs after absorption
and first pass metabolism. The percentage of bioavailability for the oral
route is always less than 100%, but for the IV route it is usually 100%
owing to the high first-pass hepatic metabolism of oral drugs. Oral
medication that has a high first-pass hepatic metabolism may have a
bioavailabilty of only 20% to 40% on entering systemic circulation. To
obtain the desired drug effect, the oral dose could be higher than the
drug dose for the IV use.

Discuss factors that alter bioavailability:

1. Drug form
2. Route of administration
3. GI mucosa and motility
4. Food and other drugs
5. Changes in liver metabolism

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 Pharmacokinetic interactions during Absorption. When a patient
takes two drugs at the same time, the rate of absorption of one or both
drugs can change by one of three ways:
1. By decreasing or increasing gastric emptying time
2. By changing the gastric pH
3. By forming drug complexes
Laxatives and metoclopramide (Reglan) increase gastric and intestinal
motility and cause a decrease in drug absorption. Narcotics and
anticholinergic drugs (atropine) decrease gastric emptying time and GI
motility, thus causing an increase in absorption rate. Alteration of
bacteria normally found in the GI tract may affect the pharmacokinetics
of a medication, too. Digoxin is a digitalis preparation that is used to
treat heart failures and arrythmias. Metabolism of this drug by gut
bacteria decreases its bioavailability. Another example is the concurrent
administration of antibiotic with contraceptives. The antibiotic may alter
intestinal bacteria, preventing the optimal absorption and effectiveness
of oral antibiotics. Tetracycline should not be administered with dairy
products, multivitamins, and antacids. Tetracycline and the heavy-metal
ions found in antacids or iron may lead to the formation of a drug
complex and thereby prevent the absorption of tetracycline.

2.2. Distribution

Distribution is the process by which the drug becomes available to

body fluids and body tissues. Drug distribution is influenced by blood
flow, the drug’s affinity to the tissue, and the protein-binding effect.

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Protein-binding
As drugs are distributed to plasma, many are bound to varying degrees
(percentages) to protein (primarily albumin). The portion of the drug that is
bound to protein is inactive because it is not available to receptors. The
portion that remains unbound is free, active drug.

Only free drugs (drugs not bound to protein) are active and can cause a
pharmacologic response. As the free drugs in the circulation decreases,
more bound drugs are released from protein to maintain the balance of free
drugs. Drugs bound to proteins cannot leave the systemic circulation to get to
the site of action. This is why only free drugs are active.

Pharmacokinetic interactions during Distribution. A drug’s distribution to

tissues can be affected by its binding to plasma/serum protein and is affected
by
1. The drug concentration in the blood
2.Protein-binding power of the drugs
3.Volume of distribution (Vd)
When two highly protein-bound drugs are given concurrently, they
compete for the protein-binding sites, thus releasing more free drugs into the
systemic circulation. In this situation drug accumulation and possible drug
toxicity can result. In the same way, low protein levels decrease the number
of protein-binding sites and can cause an increase in the amount of free drug
in the plasma, drug toxicity may then result. Patients with low protein levels
include those with liver or kidney disease, those who are malnourished, and
those with advanced age. These patients are at risk for possible drug toxicity.

To avoid possible drug toxicity, checking the protein-binding percentage of all

drugs administered to a patient is important. Check patient’s plasma protein
and albumin levels (decrease in plasma protein/albumin decreases protein-
binding sites permitting freer drug in the circulation). Depending on the drug,
the result could be life threatening. Drug dose is prescribed according to the
percentage in which the drug binds to the protein.

The Blood-Brain Barrier (BBB)

The BBB is a semi-permeable membrane in the central nervous system (CNS)
that protects the brain from foreign substances. Highly lipid-soluble drugs can
cross the BBB. Unbound (to protein) and are not lipid soluble drugs cannot
cross the BBB, which make it difficult to distribute the drug.

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The Placental Barrier
During pregnancy, both lipid-soluble and lipid-insoluble drugs can cross the
placental barrier, which can affect the fetus & the mother. The risk-benefit ratio
should be considered before drugs are given during pregnancy. During
lactation, drugs can be secreted into breast milk, which could affect the nursing
infant. The nurse needs to check which drugs may cross into the breastmilk
before administering to a lactating patient.

2.3. Metabolism or Biotransformation

Metabolism or biotransformation is process by which the body
inactivates, or bio transforms drugs.
Drugs can be metabolized in several organs; however, the liver is the
primary site for metabolism. Most drugs are inactivated by liver
enzymes & are then converted or transformed by hepatic enzymes to
inactive metabolites or water-soluble substances for excretion. Most
drugs are lipid soluble; the liver metabolizes them to water soluble
substance for renal excretion. However, some drugs are transformed
into active metabolites, causing an increased pharmacologic
response. Liver diseases such as cirrhosis and hepatitis inhibit drug
metabolizing enzymes in the liver. When the drug metabolism rate is
decreased, excess drug accumulation can occur and lead to toxicity.

Half-life (T1/2)
Half-life is the time it takes for the amount of drug in the body to be
reduced in half. Metabolism & elimination affect the half-life of a drug.
For example, with kidney & liver dysfunction, drug’s half-life is
prolonged, and less drug is metabolized & eliminated. When a drug is
taken continually, drug accumulation may occur.

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A drug goes through several half-lives before more than 90% of the
drug is eliminated. Drug half-life is used to determine dosing interval.

It takes 3 hours for the first half-life to eliminate 325 mg, 6 hours for the
2nd half-life to eliminate an additional 162 mg, and so on until the 6th
half-life (or 18 hours), when 10mg of aspirin is left in the body.
By knowing the half-life, the time it takes for a drug to reach a steady
state of serum concentration can be computed. Administration of the
drug for three to five half-lives saturates the biologic system to the
extent that the intake of the drug equals the amount metabolized and
excreted. An example is digoxin, which has a half-life of 36 hours with
normal renal function. It would take approximately 5 days to one week
(three to five half-lives) to reach a steady state for renal concentration.
Half-life is a useful pharmacokinetic parameter as it provides an
accurate indication of the length of time that the effect of the drug
persists in an individual. It can also show if accumulation of the
drug is likely to occur with a multiple dosing regimen. This is helpful
when it comes to deciding the appropriate dose amount and
frequency. From this information, appropriate decisions to promote
patient health outcomes can be made.

Pharmacokinetic interactions during Metabolism or

Biotransformation
Many drug interactions of metabolism occur with the induction or
inhibition of the hepatic microsomal system. A drug can increase the
metabolism of another drug by stimulating liver enzymes. Drugs that
promote induction of enzymes are called enzyme inducers. For this
section on pharmacokinetic interactions during absorption, we will use
the drug theophylline, a drug used to treat lung diseases such as
asthma and COPD (bronchitis, emphysema), as an example to explain
and differentiate the interactions.

Barbiturates like phenobarbital are drug inducers. Phenobarbital

increases the metabolism of most antipsychotics and methylxanthine

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 (theophylline). Increased metabolism promotes drug elimination and
decreases plasma concentration of a drug. The result is a decrease in
drug action.

Some drugs are enzyme inhibitors. The antiulcer drug cimetidine

(Tagamet) is an enzyme inhibitor that decreases metabolism of certain
drugs such as theophylline, causing an increase in the plasma
concentration of theophylline. The theophylline dose must be
decreased to avoid toxicity. If cimetidine or any enzyme drug inhibitor
is discontinued, the theophylline dosage should be adjusted. Other well-
known drug inhibitors are erythromycin (an antibacterial) and
itraconazole (an antifungal).

The use of tobacco and alcohol have variable effects on drug

biotransformation. Chronic cigarette smoking leads to an increase in
hepatic enzyme activity and can increase theophylline clearance.
Asthmatics who smoke and take theophylline to manage their disease
may require an increase in theophylline dosage. With chronic alcohol
use, hepatic enzyme activities are increased; with acute alcohol use,
metabolism is inhibited.

2.4. Elimination or Excretion

Elimination or excretion is the process of eliminating drugs
from the body. The main route of drug elimination is through the
kidneys. Other routes include hepatic metabolism, bile, feces, lungs,
saliva, sweat, and breast milk.

Kidneys filter free drugs (in healthy kidneys, drugs bound to protein are
not filtered), water-soluble drugs, and drugs that are unchanged. The
lungs eliminate volatile drug substances & products metabolized to
CO2 and water

Urine pH influences drug excretion. Normal urine pH varies from 6.0 to

8.0. Acidic urine promotes elimination of weak base drugs. Alkaline
urine eliminates weak acid drugs. Aspirin, a weak acid is excreted
rapidly in alkaline urine. If a person takes an overdose of aspirin, sodium
bicarbonate may be given to change the urine pH to alkaline to promote
excretion of the drug. Large quantities of cranberry juice can decrease
urine pH, causing acidic urine and thus inhibiting the elimination of
aspirin.

When the patient has decreased glomerular filtration rate (GFR) or

decreased renal tubular secretion, drug excretion is slowed or impaired.

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 Drug accumulation with possible severe adverse drug reactions can
result. A decrease in drug flow to the kidneys can also alter drug
excretion.

Common tests used to determine renal function are creatinine

clearance (CLcr) and blood urea nitrogen (BUN). Creatinine is a
metabolic by-product of muscle that is excreted by the kidneys.
Creatinine clearance test compares the level of creatinine in the urine
and the level of creatinine in the blood. Creatinine clearance varies with
age and gender. Lower values are expected in patients with decreased
muscle mass, such as older adult patients and some female patients.
A decrease in GFR results in an increase in serum creatinine level and
a decrease in urine creatinine clearance.

Drug dose usually needs to be decreased with renal dysfunction in

either older adults or those with kidney disorders. It is important for
nurses to know the patient's kidney function to ensure correct drug
dosage. Creatinine clearance (CLcr) is the most accurate test to
determine renal function.

Pharmacokinetic Interactions during Elimination. Most drugs are filtered

through the glomeruli and excreted in the urine. With some drugs, excretion
occurs in the bile, which passes into the intestinal tract.

The following are the factors that affect drug excretion:

1. Drugs that affect renal excretion - Drugs can increase or decrease
renal excretion and have an effect on the excretion of other drugs.
2. Drugs that decrease cardiac output - Drugs that decrease cardiac
output, decrease blood flow to the kidneys, and decrease glomerular
filtration rate can also decrease or delay drug excretion. The
antiarrhythmic drug quinidine decreases the excretion of digoxin;
therefore, the plasma concentration of digoxin is increased, and digitalis
toxicity can occur.
3. Use of diuretics - diuretics promote water and sodium excretion from
the renal tubules. Furosemide (Lasix) acts on the loop of Henle, and
hydrochlorothiazide (HydroDIURIL) acts on the distal tubules. Both
diuretics decrease reabsorption of water, sodium, and potassium. A
renal loss of potassium, which may lead to a condition known as
hypokalemia, can enhance the action of digoxin, and digitalis toxicity
may occur.
4. Competition of drugs that undergo the same route of excretion -
two or more drugs that undergo the same route of excretion may
compete with another for elimination from the body. Probenecid, a drug
for gout, decreases penicillin excretion by inhibiting the secretion of
penicillin in the renal tubules of the kidneys. In some cases, this is an
effect may be desirable to maintain the plasma concentration of
penicillin (which has a short-life) for a prolonged period of time.
5. Change of urine pH - The antacid sodium bicarbonate causes the
urine to be alkaline. Alkaline urine promotes the excretion of drugs that
are weak acids (e.g., aspirin, barbiturates). Alkaline urine also promotes

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 reabsorption of weak base drugs. Acid urine promotes the excretion of
weak base drugs such as quinidine.
6. Patients with decreased renal or hepatic function - With decreased
renal or hepatic function, there is usually an increase in free drug
concentration. It is essential to monitor patients for drug toxicity when
they take multiple drugs. Checking serum drug levels, a practice known
as therapeutic drug monitoring (TDM), is especially important for drugs
that have a narrow therapeutic range and are highly protein bound.
Digoxin and phenytoin are two drugs that require TDM.

Additional reference:

DG Lambert, BSc (Hons) PhD, Drugs and receptors, Continuing Education in Anaesthesia Critical Care
& Pain, Volume 4, Issue 6, December 2004, Pages 181–184, https://doi.org/10.1093/bjaceaccp/mkh049

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