PHARMACOLOGY
CANCER PHARMCOTHERAPY
The objective of cancer pharmacotherapy is
to:
● cure cancer using cancer
pharmacotherapy, for example in the
case of testicular cancer and
lymphomas
● prevent the recurrence of cancer as a
post-operative treatment, i.e. as
adjuvant therapy, for example after
breast cancer or intestinal cancer
surgery
● Relieve symptoms caused by cancer
and extend life expectancy in the
treatment of advanced cancer.
Medication impact mechanism:  ● Hormonal therapy can be implemented
 Chemotherapy
 Hormonal therapies
 Hormonal therapies
 Targeted drugs
 Immunologic drugs
Chemotherapy
• Chemotherapy have an effect by
preventing the division of all cells,
which often leads to the death of cancer
cells.  Immunologic drugs
• Cancer cells are particularly sensitive to
cytostatics, because they divide faster
than normal cells.  body and so cause the body’s own
• Testicular cancer and lymphomas are
particularly sensitive to chemotherapy.
• Chemotherapy is usually administered
intravenously or orally as tablets. In
some cases, they can be administered
locally, for example, into the spinal
canal.
• The most common side effects include
nausea, hair loss, fatigue, problems with
bowel movement, and interferences in
the sense of taste and a decline in
overall Immunity.
HORMONAL THERAPY
The hormonal therapy of cancer aims to
prevent the production of the hormone vital to
the cancer in question and its effects on the
body.
What Is This Topic About?
Pt. receiving hormonal therapy
● i.e. female hormone among women
cause menopausal symptoms due to the
shortage of the female hormone
either as tablets or injections
● Long term therapy
Targeted drugs
● Targeted drugs are used, among other
things, in the treatment of certain blood
cancer, lung cancer, breast cancer,
lymphatic tissue cancer, renal cancer,
liver cancer and intestinal cancer types.
DISADVANTAGE
●  Aim to boost the immune system of the
immune defense system to attack the
cancer cells.
CAREFUL
● The disadvantage of treatments based
on immune defense is that, once you
interfere with the body’s defense
mechanisms, the body may also attack
its own tissue and cause autoimmune
diseases and severe inflammation
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General Principles in the Pharmacotherapy
of Cancer Anton Wellstein
THE CELL CYCLE CANCER EVOLUTION
AND DRUG DISCOVERY DRUG
RESISTANCE MOLECULAR TESTING TO
SELECT APPROPRIATE DRUGS
■ Molecular Analysis and Tumor
Heterogeneity
■ Liquid Biopsies
ACHIEVING THERAPEUTIC
INTEGRATION AND EFFICACY A
CAUTIONARY NOTE
Cancer pharmacology has changed
dramatically during the recent past with the
improved understanding of cancer biology and
an ever-expanding set of newly developed
drugs that target vulnerabilities in individual
cancers. Effective early treatments have been
developed for some fatal malignancies,
including testicular cancer, lymphomas, and
leukemia. Also, adjuvant chemotherapy and
hormonal therapy can extend over-all survival
and prevent disease recurrence following
surgical resection of localized breast,
colorectal, and lung cancers. Chemotherapy is
also employed as part of the multimodal
treatment of locally advanced head and neck,
breast, lung, and esophageal cancers; soft tissue
sarcomas; and pediatric solid tumors, thereby
allowing for surgery that is more limited with
favourable outcomes.
The Cell Cycle An understanding of the cell
cycle is essential for the rational use of anti-
cancer drugs. Many cytotoxic agents act by
damaging. DNA. Their toxicity is greatest
during S phase, the DNA synthetic phase of the
cell cycle. Other agents, such as the vinca
alkaloids and taxanes, block the formation of a
functional mitotic spindle in the M phase.
These agents are most effective on cells
entering mitosis, the most vulnerable phase of
the cell cycle.
• A phase that precedes DNA synthesis (G1)
• A DNA synthesis phase (S)
• An interval following the termination of DNA
synthesis (G2)
• The mitotic phase (M) in which the cell,
containing a double complement of DNA,
divides into two daughter G1, cells
• A probability of moving into a quiescent state
(G0) and failing to move forward for long
periods of time.
The CDK family consists of over 20
serine/threonine protein kinases that have been
amongst the first pathway targets pursued for
the treatment of cancer. However, different
tissue selectivities and distinct cell cycle
specific activity periods of the various CDKs
provide a challenge for the development of
CDK inhibitors. CDK4/6 have become
attractive targets because they control cell
cycle progression from the G1 to the S phase.
Interaction of cyclin D with CDK4/6 enhances
phosphorylation and inactivation of the
retinoblastoma (Rb) protein, followed by the
transcription of factors that control transition
into the S phase. CDK4/6 inhibition will thus
cause a G1 arrest in susceptible cells that
utilize this pathway.
The CDK4/6 inhibitor palbociclib was recently
approved for the treatment of breast cancer.
Cancer Evolution and Drug Discovery The
rapidly expanding knowledge of cancer biology
and the ability to analyse cancer genome
alterations in thousands of patient samples have
led to a better understanding of the molecular
evolution of cancer and the discovery of
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cancer-specific drug targets: growth factor
receptors, intracellular signalling pathways,
epigenetic processes, Tumor vascularity, DNA
repair defects, cell death pathways, and
immune escape mechanisms (Hanahan and
Weinberg, 2011). Human malignancies are a
highly diverse
Clinically detectable cancer lesions represent
approximately 1 g of tumor tissue or 109 cells
and can contain a multitude of subpopulations
and a wide variety of genetic alterations. The
dynamic evolution of individual cancer
genomes and the implications for the
development of therapies was established from
the analyses of specimens from diverse
cancers. This dynamic was exemplified in a
detailed analysis of a series of multiple parallel
biopsies from different sites in patients with
metastatic melanoma during treatment with
inhibitors of BRAF. The genomic analysis of
the biopsies revealed complex and distinct
evolutionary branching architectures due to the
selection of drug resistant subpopulations
during treatment
These examples emphasize that new strategies
for drug discovery and development, and
advances in patient care, will result from new
knowledge of cancer biology. One response to
the oncogene addiction paradigm has been to
group cancers by shared vulnerabilities and
include patients in so-called basket trials that
evaluate a drug based on its target rather than
particular disease entities and consider
sensitivity and resistance to treatments in that
context. However, in the foreseeable future,
targeted drugs and cytotoxics will continue to
be used in combination.
A. Treatment resistance. Cancers accumulate
mutations during their evolution. Cancer cell
subpopulations are selected based on their
growth capacity, adaptation to the tumor
microenvironment at the primary or metastatic
site, and the evasion of immune surveillance.
Drug treatment will add evolutionary pressure
and select for resistant subpopulations.
Differently colored dots indicate tumor
subpopulations of different genetic makeup.
B. Mutational load. Data are median number
of somatic mutations per million bases plus or
minus the range observed for some major
human cancers. Note that the ordinate is a
logarithmic scale. In 7042 cancer specimens
between 100 and 1,000,000 mutations were
detected per tumor specimen, with a 30 to 1000
fold range amongst individual specimens from
a single cancer type. A typical mutation burden
of 10 somatic mutations per megabase (=
30,000 per genome of 3 × 109 base pairs)
results in approximately 150 mutations in
amino acid sequences that can alter protein
function, drug sensitivity, and antigenicity.
Such data have been analysed in terms of the
likelihood of formation of specific neoantigens
that permit the immune system to distinguish
between tumor and normal cells and are
putative factors of importance in cancer
immunotherapy. (Schumacher and Schreiber,
2015). Adeno, adenocarcinoma; SCC,
squamous cell carcinoma; SCLC, small cell
lung cancer.
Drug Resistance remains the major obstacle to
successful cancer treatment. Resistance results
from a variety of molecular changes that can
defeat the best-designed treatments.
Mechanisms of drug resistance include poor
drug absorption and delivery; genetically
determined variability in drug transport,
activation, and clearance; and mutations,
amplifications, or deletions in drug targets
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(Holohan et al., 2013). The resistance process
is best understood for pathway targeted drugs.
Molecular Testing to Select Appropriate
Drugs Clinical trials and patient treatments
increasingly employ results from biomarker
analysis to identify patients likely to benefit
from particular treatments and individuals at
the greatest risk of toxicity. Some of the tests.
Have been approved by the FDA as
“companion diagnostics” in conjunction with
specific drug therapies. Pre-treatment testing of
tumor specimens is standard practice in
selecting patients for antihormonal therapy of
breast cancer and for treatment with antibodies
such as trastuzumab (anti-HER2).
Inherited differences in protein sequence
polymorphisms or levels of RNA expression
can also influence toxicity and antitumor
response. For example, tandem repeats in the
promoter region of the gene encoding
thymidylate synthase, the target of 5-
fluorouracil, determine the level of expression
of the enzyme.
Molecular Analysis and Tumor
Heterogeneity
One of the caveats to conclusions drawn from
the molecular analysis of tumor specimens is
the dynamic evolution of cancers outlined
previously. Clinically important mutations in
subclones may be missed due to geographically
inadequate sampling and may provide the
wrong guidance to treatment decisions.
Response to treatment of different
subpopulations presents a further challenge and
would require multiple-site, longitudinal
sampling (Shi et al., 2014).
Liquid Biopsies
More recent technology advances have made it
possible to measure circulating, ctDNA in
blood samples from patients with cancer
(“liquid biopsies”) and to follow changes in the
abundance of mutant KRAS during colon
cancer treatment (Diehl et al., 2008). The
analysis of ctDNA has also shown that during
antiestrogen therapy of breast cancer the
appearance of mutant estrogen receptor
coincides with subsequent resistance to
aromatase inhibitor treatment
Achieving Therapeutic Integration and
Efficacy The clinical benefit of cytotoxic drugs
has primarily been measured by radiological
assessment of drug effects on tumor size.
Pathway-targeted agents, however, may slow
or halt tumor growth, so their effects may be
measured in the assessment of time to disease
progression; however, for some immune
checkpoint inhibitors, tumor lesions may
initially increase in size due to cytotoxic
lymphocyte infiltration.
A Cautionary Note Although advances in drug
discovery and molecular profiling of tumors
offer great promise for improving the outcomes
of cancer treatment, a final word of caution
regarding all treatment regimen deserves
emphasis: The pharmacokinetics and toxicities
of cancer drugs vary amongst individual
patients. It is imperative to recognize toxicities
early, to alter doses or discontinue offending
medication to relieve symptoms and reduce
risk, and to provide vigorous supportive care.
CELL CYCLE-NON SPECIFIC AND
SPEFICIC ANTICANCER DRUGS
A cell cycle is a series of events that takes
place in a cell as it grows and divides. A cell
spends most of its time in what is called
interphase, and during this time it grows,
replicates its chromosomes, and prepares for
cell division. The cell then leaves interphase,
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undergoes mitosis, and completes its division.
The resulting cells, known as daughter cells,
each enter their own interphase and begin a
new round of the cell cycle.
Cell cycle G1 phase (post mitotic gap) -
Production of RNA, protein, and enzymes for
DNA synthesis. It lasts 15 to 18 hours
S phase (synthesis) - all components are
synthesized and the cells have doubled. It
lasted 10 to 20 hours
G2 phase (premitotic gap) - the cell continues
to grow and ensures it is not defective; lasted
approx. 3 hours
M phase (mitosis) - cell growth has stopped,
and the cell divides into 2 identical (daughter
cells); lasted approx. 1 hour
G0 phase (resting)- cells remain in the phase
and leave the cell cycle or return to the cell
cycle for cell replication. Cells in this phase are
not as sensitive to many antineoplastic drugs
Defective cells undergo apoptosis
Cell cycle-nonspecific and cell cycle specific
anticancer drugs
CCNS
 Drugs acts during any phase of the cell
cycle, including G0 phase
 Includes most alkylating drugs,
antitumor, antibiotics, and hormones
CCS
• Drugs exert their influence during a
specific phase of the cell cycle and are
most effective against rapidly growing
cancer cells
• Include antimetabolites, some
alkylating agents and vinca alkaloids
Growth fraction- the percent of actively
dividing cells, decreases as the tumor enlarges,
and double time increases
Double time- is defined as the time it takes for
a tumor to double in size
What you need to know…
 Anti-cancer drugs are more effective
against neoplastic cells that have a high
growth fraction
 Solid tumors have a large percentage of
their cell mass in the G0 phase , thus
they generally have a low growth
fraction sensitive to anticancer drugs
 High dose chemotherapy results in
better tumor-killing effects
 Adequate vascularization is needed for
the anticancer drugs to be effective
 Anticancer drugs are more effective
against small, fast-growing tumors with
sufficient blood supply
 Solid tumors can be inconsistent
 Some areas of tumor may have an
adequate blood supply, whereas other
areas are poorly perfused
CYTOTOXIC DRUGS
• (Sometimes known as antineoplastic)
describe a group of medicines that
contain chemicals which are toxic to
cells, preventing their replication or
growth, and so are used to treat cancer.
ALKYLATING DRUGS
➜ One of the largest groups of anticancer
drugs.
➜ It damage the cell’s DNA by cross-
linkage of DNA strands, abnormal base
pairing, or DNA strand breaks, thus
preventing the reproduction of cancer
cells.
➜ They are used to treat many different
types of cancer including leukemia,
lymphoma, multiple myeloma,
sarcoma, and solid tumors such as those
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 of the breast, ovary, uterus, lungs, Hodgkin disease and
bladder, and stomach. non-Hodgkin
lymphoma (NHL),
5 CLASSES OF ALKYLATING DRUGS acute and chronic
1 nitrogen mustards lymphocytic leukemia
2 nitrosoureas (CLL) and etc.
3 alkyl sulfonate
Used for immunologic
4 triazines disorders such as
5 ethylenimines lupus nephritis, and
has been shown to
NITROGEN MUSTARDS prevent progressive
➜ Were produced in 1920s and 1930s as renal scarring,
potential chemical warfare weapons. preserve renal
They are vesicants (or blister agents) function, induce renal
similar to the sulfur mustards remission and
➜ Not found naturally in the environment decrease end-stage
➜ HN-1 originally was designed to renal failure.
remove warts but later on, it was IFOSFAMIDE ADME
identified as a potential chemical Ifosfamide has a
warfare agent. plasma elimination t
1/2 is 1.5 h after doses
➜ HN-2 was designed for military agent
of 3.8–5 g/m2 and a
but was later used in cancer treatment.
somewhat shorter t 1/2
at lower doses; its
NITROGEN MUSTARDS
pharmacokinetics are
MECHLORETHA The first clinically highly variable due to
MINE used nitrogen mustard variable rates of
and is the most hepatic metabolism
reactive of the drugs
in this class. It is used Therapeutic Uses:
topically for treatment For treatment of
of CTCL as a solution patients with relapsed
that is rapidly mixed germ cell testicular
and applied to affected cancer and is
areas. It has been frequently used for
largely replaced by first-time treatment of
cyclophosphamide, pediatric or adult
melphalan, and other patients with
more stable alkylating sarcomas. It is a
agents. common component
CYCLOPHOSPHA An analogue of of high dose
MIDE nitrogen mustard and chemotherapy
has activity against regimens with bone
many neoplastic marrow or stem cell
diseases such as
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 rescue. Treatment is repeated
at 4-week intervals
Adverse Effects based on response and
Ifosfamide has a tolerance.
similar toxicity profile
as cyclophosphamide, Nausea and vomiting
although it causes are less frequent. The
greater platelet drug causes less
suppression, alopecia and, rarely,
neurotoxicity, renal or hepatic
nephrotoxicity, and dysfunction.
urothelial damage. CHLORAMBUCIL ADME:
Oral absorption of
MELPHALAN ADME: chlorambucil is
- - given as an adequate and reliable.
intravenous infusion. The drug has a t 1/2 in
The drug has a plasma plasma of about 1.5 h
t 1/2 of about 45–90 and is hydrolyzed to
min; 10%–15% of an inactive products.
administered dose is
excreted unchanged in Therapeutic Uses
the urine. Patients and Adverse Effects:
with decreased renal Chlorambucil is
function may develop almost exclusively
unexpectedly severe used in treating CLL.
myelosuppression. In treating CLL,
chlorambucil is given
Therapeutic Uses once daily and
and Adverse Effects: continued for 3–6
The alkylating agent weeks. Chlorambucil
melphalan primarily is treatment may
used to treat multiple continue for months or
myeloma and, less years, achieving its
commonly, in high- effects gradually and
dose chemotherapy often without
with marrow significant toxicity to
transplantation. a compromised bone
marrow.
Melphalan for
multiple myeloma is Marked hypoplasia of
administered orally the bone marrow may
for 4–7 days every 28 be induced with
days, with excessive doses, but
dexamethasone or the myelosuppressive
thalidomide. effects are moderate,

7
 gradual, and rapidly divided doses
reversible. GI
discomfort, Adverse Effect:
azoospermia, Gynecomastia and
amenorrhea, impotence may occur.
pulmonary fibrosis,
seizures, dermatitis, NITROSOUREAS
and hepatotoxicity ➜ an important role in the treatment of brain
rarely may be tumors and find occasional use in treating
encountered. lymphomas and in high-dose regimens with
BENDAMUSTINE ➜ Bendamustine bone marrow reconstitution
is approved for
➜ The use of nitrosoureas is presently limited
treatment of
to brain tumors due to their Lipophilicity
CLL and non-
Hodgkin
lymphoma. NITROSOUREAS
➜ Bendamustine CARMUSTIN ADME:
is given as a E (BNCU) Carmustine is unstable in
30-min aqueous solution and in
intravenous body fluids. After
infusion on intravenous infusion, it
days 1 and 2 of disappears from the
a 28-day cycle. plasma with a highly
Lower doses variable t 1/2 of 15–90
may be min or more.
indicated in Approximately 30%–80%
heavily of the drug appears in the
pretreated urine within 24 h as
patients degradation products
➜ The parent Therapeutic Uses:
drug has a Carmustine (BCNU) is
plasma t 1/2 of administered
about 30 min intravenously over 1–2 h
ESTRAMUSTINE ADME: and repeated every 6
The drug has a plasma weeks. Because of its
t 1/2 of about 20-24 h. ability to cross the blood-
brain barrier, carmustine
Therapeutic Effect: has been used in the
Estramustine is treatment of malignant
approved for gliomas. An implantable
treatment prostate carmustine wafer is
cancer. available for use as an
adjunct to surgery for
Estramustine is given
recurrent glioblastoma
as orally in 3-4
8
 multiforme.
➜ Approved for
treatment of
Hodgkin disease
and malignant
LOMUSTINE glioma.
(CCNU) ➜ given as orally for
every 6 weeks
➜ The drug has a
plasma t 1/2 of
about 16 h- 2 days.
ADME :
Streptozocin is rapidly
degraded following
intravenous
administration. The t 1/2
of the drug is about 15
min. Only 10%–20% of a
dose is recovered intact in
the urine
Therapeutic Uses:
Used in the treatment of
human pancreatic islet cell
carcinoma and carcinoid
tumors. It is administered
intravenously once daily
STREPTOZO for 5 days; this course is
CIN repeated every 6 weeks
Adverse Effects:
Nausea is frequent. Mild,
reversible renal or hepatic
toxicity occurs in
approximately two-thirds
of cases; in fewer than
10% of patients, renal
toxicity may be
cumulative with each dose
and may lead to
irreversible renal failure.
Hematological toxicities
(anemia, leukopenia, and
thrombocytopenia) occur
in 20% of patients.
ALKYL
SULFONATE
ADME
Busulfan is well
absorbed after oral
administration and has
a plasma t 1/2 of 2–3 h.
Therapeutic Uses :
In treating CML, the
initial oral dose of
busulfan varies with the
total leukocyte count
and the severity of the
disease; daily doses are
adjusted to subsequent
hematological and
clinical responses, with
the aim of reducing the
BUSULFAN
total leukocyte count to
10,000 cells/mm3 or
less.
Adverse Effects:
The toxic effects of
busulfan are related to
its myelosuppressive
properties; prolonged
thrombocytopenia may
occur. Occasionally,
patients experience
nausea, vomiting, and
diarrhea. Long-term
use leads to impotence,
sterility, amenorrhea,
and fetal malformation.
TRIAZINES
DACARBAZINE ADME :
(DTIC) Dacarbazine is
administered
intravenously. After an
initial rapid phase (t 1/2
of about 20 min),
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dacarbazine is cleared
from plasma with a
terminal t 1/2 of about 5
h. The t 1/2 is prolonged
in the presence of hepatic
or renal disease. Almost
50% of the compound is
excreted intact in the
urine by tubular secretion.
Therapeutic Uses :
The primary clinical
indication for dacarbazine
is in the chemotherapy of
Hodgkin disease. In
combination with other
drugs for Hodgkin
disease, It is given on day
1 and 15 and repeated
every 4 weeks for up to 6
cycles. It is modestly
effective against
malignant melanoma and
adult sarcomas. For
malignant melanoma is
given for a 10-day period,
repeated every 28 days;
alternatively, it can be
given daily for 5 days and
repeated every 3 weeks.
Adverse Effects:
Dacarbazine induces
nausea and vomiting in
more than 90% of
patients; vomiting usually
develops 1–3 h after
treatment and may last up
to 12 h.
Myelosuppression, with
both leukopenia and
thrombocytopenia, is mild
and readily reversible
within 1–2 weeks. A flu-
like syndrome may occur.
ADME:
Temozolomide is
administered orally and
has a bioavailability
approaching 100%.
Plasma levels of the
parent drug decline with a
t 1/2 of 1–2 h. The
primary active metabolite
MTIC reaches a
maximum plasma
concentration (150
mg/mL) 90 min after a
dose and declines with a t
1/2 of 2 h.
TEMOZOLOMI
DE
Therapeutic Uses:
Temozolomide is the
standard agent, in
combination with
radiation therapy, for
patients with malignant
glioma and astrocytoma.
Adverse Effects:
The toxicities of
temozolomide mirror
those of DTIC.
Hematological monitoring
is necessary to guide
dosing adjustments.
ETHYLENIMINES
ALTRETAM ADME:
INE Altretamine is well absorbed
from the GI tract; its
elimination t 1/2 is 4–10 h.
The drug undergoes rapid
demethylation in the liver
Adverse Effects:
The main toxicities of
altretamine are
myelosuppression and
neurotoxicity. Altretamine
10
 causes both peripheral and
central neurotoxicity (ataxia,
depression, confusion,
drowsiness, hallucinations,
dizziness, and vertigo).
ADME:
Within hours of thiotepa
administration, TEPA
becomes the predominant
form of the drug present in
plasma. The parent
compound has a plasma t 1/2
of 1.2–2 h; TEPA has a
longer t 1/2, 3–24 h. Thiotepa
pharmacokinetics essentially
are the same in children as in
adults at conventional doses
(≤80 mg/m2), and drug and
metabolite t 1/2 are
unchanged in children
THIOTEPA
receiving high-dose therapy
of 300 mg/m2 /d for 3 days.
Adverse Effects:
Toxicities include
myelosuppression and, to a
lesser extent, mucositis.
Myelosuppression tends to
develop somewhat later than
with cyclophosphamide, with
leukopenic nadirs at 2 weeks
and platelet nadirs at 3 weeks.
In high doses, thiotepa may
cause neurotoxic symptoms,
including coma and seizures
PLATINUM COORDINATION
COMPLEXES
Platinum coordination complexes have broad
antineoplastic activity and have become the
foundation for treatment of ovarian, head and
neck, bladder, esophagus, lung, and colon
cancers. Although cisplatin and other platinum
complexes do not form carbonium ion
intermediates like other alkylating agents or
formally alkylate DNA, they covalently bind to
nucleophilic sites on DNA and share many
pharmacological attributes with alkylators.
PLATINUM COORDINATION
COMPLEXES
CISPLATIN Therapeutic Uses:
Cisplatin, in combination
with bleomycin, etoposide, or
with ifosfamide and
vinblastine, cures 90% of
patients with testicular
cancer. Used with paclitaxel,
cisplatin or carboplatin
induces complete response in
the majority of patients with
carcinoma of the ovary.
Cisplatin produces responses
in cancers of the bladder,
head and neck, cervix, and
endometrium. The drug also
sensitizes cells to radiation
therapy and enhances control
of locally advanced lung,
esophageal, and head and
neck tumors when given with
irradiation.
Adverse Effects:
➜ nephrotoxicity
➜ Ototoxicity
➜ progressive peripheral
motor and sensory
neuropathy
➜ mild-to-moderate
myelosuppression
➜ Anemia may become
prominent after
multiple cycles of
treatment
➜ Electrolyte
disturbances
➜ Anaphylactic-like
11
 reactions,
characterized by facial
edema,
bronchoconstriction,
tachycardia, and
hypotension
➜ Development of
AML, usually 4 years
or more after
treatment.
CARBOPL ADME:
ATIN the majority of drug in
plasma remains in its parent
form, unbound to proteins.
Most drug is eliminated via
renal excretion, with a t 1/2 of
about 2 h
Therapeutic Uses
Carboplatin and cisplatin are
equally effective in the
treatment of patients with
suboptimally debulked
ovarian cancer, NSCLC, and
SCLC; Carboplatin, on the
other hand, may be less
effective than cisplatin in the
treatment of germ cell, head
and neck, and esophageal
cancers. Carboplatin is an
effective alternative for
patients who cannot tolerate
cisplatin due to impaired
renal function, refractory
nausea, or neuropathy, but
doses must be adjusted for
renal function. Carboplatin is
administered as an
intravenous infusion over at
least 15 min and is given
once every 21–28 days.
Adverse Effects:
Carboplatin is relatively well
tolerated clinically, causing
less nausea, neurotoxicity,
ototoxicity, and
nephrotoxicity than cisplatin.
The dose-limiting toxicity of
carboplatin is
myelosuppression, primarily
thrombocytopenia. It may
cause a hypersensitivity
reaction; in patients with a
mild reaction, premedication,
graded doses of drug, and
more prolonged infusion lead
to desensitization.
OXALIPLA ADME:
TIN Oxaliplatin has a short t 1/2
in plasma, probably as a
result of its rapid uptake by
tissues and its reactivity; the
initial t 1/2 is about 17 min.
No dose adjustment is
required for hepatic
dysfunction or for patients
with a CLCr ≥ 20 mL/min.
Therapeutic Uses:
Oxaliplatin exhibits a range
of antitumor activity
(colorectal and gastric cancer)
that differs from other
platinum agents. Oxaliplatin’s
effectiveness in colorectal
cancer is perhaps due to its
MMR- and HMG-
independent effects. In
combination with 5FU, it is
approved for treatment of
patients with colorectal
cancer.
Adverse Effects:
➜ The dose-limiting
toxicity of oxaliplatin
is peripheral
neuropathy.
➜ An acute form, often
12
 triggered by exposure N5–10 methylene FH4 and N10 formyl FH4
to cold liquids, cofactors that are required for the synthesis of
manifests as thymidylate and purines. In addition, MTX,
paresthesias or like cellular folates, undergoes addition of a
dysesthesias in the series of polyglutamates (MTX-PGs) in both
upper and lower normal and tumor cells
extremities, mouth,
and throat.
Cellular Entry and Retention
➜ Hematological
Folic acid and many of its analogues are polar,
toxicity is mild to
they cross the blood-brain barrier poorly and
moderate, except for
rare immune-mediated require specific transport mechanisms to enter
cytopenias mammalian cells.
➜ Oxaliplatin may cause 1. A folate receptor, which has high affinity for
leukemia and folic acid but much lower ability to transport
pulmonary fibrosis MTX and other analogues
months to years after 2. The reduced folate transporter, the major
administration. transit protein for MTX, raltitrexed,
➜ Oxaliplatin may cause pemetrexed, and most analogues
an acute allergic 3. A transporter that is active at low pH
response with
urticaria, hypotension, Mechanisms of Resistance to Antifolates
and • Impaired transport of MTX into cells
bronchoconstriction. • Production of altered forms of DHFR that
have decreased affinity for the inhibitor
ANTIMETABOLITES • Increased concentrations of intracellular
FOLIC ACID ANALOGUES DHFR through gene amplification or altered
Is an essential dietary factor that is converted gene regulation
by enzymatic reduction to FH4 cofactors that • Decreased ability to synthesize MTX-PGs
provide methyl groups for the synthesis of • Increased expression of a drug efflux
precursors of DNA (thymidylate and purines) transporter of the MRP class
and RNA. Folic acid analogues such as MTX
interfere with FH4 metabolism (Figure 66–5), ANTIMETABOLITES
reducing the cellular capacity for one-carbon METHOTREX ADME:
transfer and methylation reactions in the ATE Methotrexate is
synthesis of purine ribonucleotides and TMP, readily absorbed
thereby inhibiting DNA replication. from the GI tract at
doses of less than 25
Mechanism of Action mg/m2; larger doses
To function as a cofactor in one-carbon transfer are absorbed
reactions, folate must be reduced by DHFR to incompletely and are
FH4. Inhibitors such as MTX, with a high routinely
administered
affinity for DHFR, cause partial depletion of
intravenously. After
13
intravenous the intestinal
administration, the epithelium. Patients
drug disappears may be at risk for
from plasma in a spontaneous
triphasic fashion. hemorrhage or life-
threatening infection
Therapeutic Uses and may require
Methotrexate is a prophylactic
critical drug in the transfusion of
management of platelets and broad-
childhood ALL. spectrum antibiotics
High-dose MTX is if febrile.
of great value in
remission induction PYRIMIDINE ANALOGUES
and consolidation The pyrimidine antimetabolites encompass a
and in the diverse group of drugs that inhibit RNA and
maintenance of DNA function. The fluoropyrimidines and
remissions in this
certain purine analogues inhibit the synthesis of
highly curable
disease. A 6- to 24-h essential precursors of DNA.
infusion of relatively
large doses of MTX PYRIMIDINE ANALOGUES
may be employed 5- Mechanisms of Action
every 2–4 weeks but FLUOROURA 5-Fluorouracil requires
only when CIL enzymatic conversion
leucovorin rescue (ribosylation and
follows within 24 h phosphorylation) to the
of the MTX nucleotide form to exert its
infusion. cytotoxic activity. As the
Maintenance triphosphate FUTP, the drug
therapy, it is is incorporated into RNA.
administered at a Alternative reactions can
lower dose, orally produce the deoxy derivative
every week. FdUMP; FdUMP inhibits TS
Outcome of and blocks the synthesis of
treatment in children dTTP, a necessary
correlates inversely constituent of DNA
with the rate of drug
clearance. 5-Fluorouracil is
incorporated into both RNA
Adverse Effects and DNA. In 5FU-treated
The primary cells, both FdUTP and dUTP
toxicities of (which accumulates behind
antifolates are on the the blocked TS reaction)
bone marrow and incorporate into DNA in

14
place of the depleted
physiological TTP.
ADME:
5-Fluorouracil is
administered parenterally
because absorption after oral
ingestion of the drug is
unpredictable and
incomplete. 5FU is
inactivated by reduction of
the pyrimidine ring in a
reaction carried out by DPD,
which is found in liver,
intestinal mucosa, tumor
cells, and other tissues.
Inherited deficiency of this
enzyme leads to greatly
increased sensitivity to the
drug. DPD deficiency can be
detected by either enzymatic
or molecular assays using
peripheral white blood cells
or by determining the plasma
ratio of 5FU to its
metabolite, 5-fluoro-5,6-
dihydrouracil.
Plasma clearance is rapid (t
1/2 about 10–20 min). Only
5%–10% of a single
intravenous dose of 5FU is
excreted intact in the urine.
The dose does not have to be
modified in patients with
hepatic dysfunction,
presumably because of
sufficient degradation of the
drug at extrahepatic sites.
5FU enters the CSF in
minimal amounts.
Therapeutic Uses:
5-Fluorouracil. - produces
partial responses in 10%–
20% of patients with
metastatic colon carcinomas,
upper GI tract carcinomas,
and breast carcinomas but
rarely is used as a single
agent. 5FU in combination
with leucovorin and
irinotecan (FOLFOX or
FOLFIRINOX) in adjuvant
therapy is associated with a
survival advantage for
patients with colorectal
cancers.
FLOXURIDIN The drug is administered
E primarily by continuous
infusion into the hepatic
artery for treatment of
patients with metastatic
carcinoma of the colon or
following resection of
hepatic metastases; the
response rate of intrahepatic
infusion (40%–50%) is twice
of intravenous
administration. Intrahepatic
arterial infusion for 14–21
days causes minimal
systemic toxicity; however,
there is a significant risk of
biliary sclerosis if this route
is used for multiple cycles of
therapy. Treatment should be
discontinued at the earliest
manifestation of toxicity
(usually stomatitis or
diarrhea) because the
maximal effects of bone
marrow suppression and gut
toxicity will not be evident
until days 7–14.
CAPECITABI ADME:
NE The recommended dosage is
given in two divided doses
with food, for 2 weeks,
15
 followed by a rest period of
1 week. Capecitabine is well
absorbed orally.
Therapeutic Uses:
an orally administered
prodrug of 5FU, is approved
for the treatment of patients
with
(1) metastatic breast cancer,
who have not responded to a
regimen of anthracycline;
(2) metastatic breast cancer
when used in combination
with docetaxel in patients
who have had a prior
anthracycline-containing
regimen; and
(3)metastatic colorectal
cancer.
 
Adverse Effects:
The clinical manifestations
of toxicity caused by 5FU
and floxuridine are similar.
The earliest untoward
symptoms during a course of
therapy are anorexia and
nausea, followed by
stomatitis and diarrhea,
reliable warning signs that a
sufficient dose has been
administered. Mucosal
ulcerations occur throughout
the GI tract and may lead to
fulminant diarrhea, shock,
and death, particularly in
patients who are DPD
deficient.
TRIFLURIDI Therapeutic Uses:
NE It is used in eye drops for the
treatment of HSV and in a
fixed combination with
tipiracil, a thymidine
phosphorylase inhibitor, for
the treatment of patients with
metastatic colorectal cancers
who have previously
received other standard
combination treatments that
included FOLFIRINOX.
Trifluridine and tipiracil are
formulated together in a
single tablet with tipiracil
added to prevent rapid
breakdown of trifluridine.
The trifluridine mechanism
of action mimics that of 5FU
CYTIDINE ANALOGUES
CYTARABINE the most important
(CYTOSINE antimetabolite used in the
ARABINOSID therapy of AML; it is the
E; ARA-C) single most effective
agent for induction of
remission in this disease.
Mechanisms of Action:
Cytarabine is an
analogue of 2′-
deoxycytidine; the 2′-
hydroxyl in a position
trans to the 3′-hydroxyl
of the sugar hinders
rotation of the pyrimidine
base around the
nucleoside bond and
interferes with base
pairing. The drug enters
cells via ENT1 (or
SLC29A1). It is then
converted to its active
form, the 5′-
monophosphate
ribonucleotide, by dCK,
an enzyme that shows
polymorphic expression
amongst. Ara-CMP then
reacts with
deoxynucleotide kinases
16
to form diphosphate and
triphosphates (Ara-CDP
and Ara-CTP).
ADME:
Due to the presence of
high concentrations of
cytidine deaminase in the
GI mucosa and liver,
only about 20% of the
drug reaches the
circulation after oral Ara-
C administration; thus,
the drug must be given
intravenously. Peak
concentrations of 2–50
μM are measurable in
plasma after intravenous
injection of 30–300
mg/m2 but fall rapidly
 
Therapeutic Uses
The optimal interval
between bolus doses of
Ara-C is about 8–12 h, a
schedule that maintains
intracellular
concentrations of Ara-
CTP at inhibitory levels
during a multiday cycle
of treatment. children
tolerate higher doses than
adults. Ara-C is indicated
for induction and
maintenance of remission
in AML and is useful in
the treatment of patients
with other leukemias,
Because drug
concentration in plasma
rapidly falls below the
level needed to saturate
transport and
intracellular activation,
clinicians have employed
high-dose regimens
every 12 h for 3–4 days
to achieve 20–50 times
higher serum levels, with
improved results in
remission induction and
consolidation for AML.
Adverse Effects:
The onset of dyspnea,
fever, and pulmonary
infiltrates on chest
computed tomographic
scans may follow 1–2
weeks after high-dose
Ara-C and may be fatal
in 10%–20% of patients,
especially in patients
being treated for relapsed
leukemia.
Intrathecal Ara-C, may
cause arachnoiditis,
seizures, delirium,
myelopathy, or
coma,especially if given
concomitantly with
systemic high-dose MTX
or systemic Ara-C.
AZACITIDIN Mechanism of Action
E (5- The azanucleosides enter
AZACYTIDIN cells by ENT1
E); (SLC29A1). The drugs
DECITABINE incorporate into DNA,
where they become
covalently bound to the
DNA methyltransferase,
depleting intracellular
enzyme and leading to
global demethylation of
DNA that results in
tumor cell differentiation
and apoptosis. Decitabine
also induces double-
strand DNA breaks,
perhaps as a consequence
17
of the effort to repair the
protein-DNA adduct.
 
ADME
After subcutaneous
administration, 5-
azacytidine undergoes
rapid deamination by
cytidine deaminase. Due
to the formation of
intracellular nucleotides
that become incorporated
into DNA, the effects of
the azanucleosides
persist for many hours.
Therapeutic Use
are approved for
treatment of
myelodysplasia, for
which they induce
normalization of bone
marrow in 15%–20% of
patients and reduce the
transfusion requirement
in one-third of patients
The usual treatment
regimen for 5-
azacytidine in patients
with MDS is daily for 7
days every 28 days,
while decitabine is given
intravenously every day
for 5 days every 4 weeks.
Best responses may
become apparent only
after two to five courses
of treatment.
Adverse Effects
The major toxicities of
the azanucleosides
include
myelosuppression and
mild GI symptoms. 5-
Azacytidine produces
severe nausea and
vomiting when given
intravenously in large
doses.
GEMCITABIN Mechanism of Action:
E Gemcitabine enters cells
via three distinct
nucleoside transporters:
ENT1, CNT1 and a
nucleobase transporter
found in malignant
mesothelioma cells.
Intracellularly, dCK
phosphorylates
gemcitabine to the
monophosphate
(dFdCMP), which is
converted to di- and
triphosphates. Although
gemcitabine’s anabolism
and effects on DNA in
general mimic those of
cytarabine, there are
distinct differences in
kinetics of inhibition,
additional enzymatic
sites of action, different
effects of incorporation
into DNA, and a distinct
spectrum of clinical
activity. Unlike of
cytarabine, the
cytotoxicity of
gemcitabine is not
confined to the S phase
of the cell cycle.
 
ADME:
Gemcitabine is
administered as an
intravenous infusion. The
pharmacokinetics of the
parent compound are
18
largely determined by at a fixed rate of 10
deamination in liver, mg/min.
plasma, and other organs,  
and the predominant Adverse Effects:
urinary elimination The principal toxicity is
product is dFdU. In myelosuppression.
patients with significant Longer duration
renal dysfunction, dFdU infusions lead to greater
and its triphosphate myelosuppression and
accumulate to high and hepatic toxicity.
potentially toxic levels. Nonhematological
Gemcitabine has a short toxicities include a flu-
plasma t 1/2 (~15 min); like syndrome, asthenia,
women and elderly and rarely a posterior
patients clear the drug leukoencephalopathy
more slowly. syndrome. Mild,
reversible elevation in
Therapeutic Uses: liver transaminases may
a difluoro analogue of occur in 40% or more of
deoxycytidine (dFdC; see patients. Rarely, patients
Figure treated for many months
66–8), is used for may develop a slowly
patients with metastatic progressive hemolytic
pancreatic; non- uremic syndrome,
squamous, necessitating drug
non–small cell lung; discontinuation.
ovarian; and bladder Gemcitabine is a very
cancer. potent radio-sensitizer
and should not be used
The standard dosing with radiotherapy.
schedule for gemcitabine
is an intravenous infusion PURINE ANALOGUES
on days 1, 8, and 15 of Purine analogues that have valuable roles in
each 21- to 28-day cycle,
leukemia and lymphoid malignancies include
depending on the
cladribine (standard therapy of hairy cell
indication. Conversion of
gemcitabine to dFdCMP leukemia), fludarabine phosphate (standard
by dCK is saturated at treatment of CLL), nelarabine (pediatric ALL),
infusion rates of about 10 and clofarabine (T-cell leukemia/lymphoma).
mg/m2/min. To increase
dFdCTP formation, the 6-Thiopurine Analogues and 6TG
duration of infusion at Approved agents for human leukemia’s and
this maximum function as analogues of the natural purines
concentration has been hypoxanthine and guanine. The substitution of
extended to 100–150 min sulfur for oxygen on C6 of the purine ring
19
creates compounds that are readily transported URINE Absorption of oral
into cells, including activated malignant cells. mercaptopurine is
Nucleotides formed from 6MP and 6TG inhibit incomplete (10%–
de novo purine synthesis and also become 50%); the drug is
incorporated into nucleic acids subject to first-pass
metabolism by
xanthine oxidase in the
Mechanism of Action
liver. Food or oral
Hypoxanthine guanine phosphoribosyl
antibiotics decrease
transferase converts 6TG and 6MP to the absorption. Oral
ribonucleotides 6-thioGMP and 6-thioIMP (T- bioavailability is
IMP), respectively. Because T-IMP is a poor increased when
substrate for guanylyl kinase (the enzyme that mercaptopurine is
converts GMP to GDP), T-IMP accumulates combined with high-
intracellularly. T-IMP inhibits the new dose MTX. After an
formation of ribosyl-5-phosphate, as well as intravenous dose, the t
conversion of IMP to adenine and guanine 1/2 of the drug is about
nucleotides. The most important point of attack 50 min in adults due to
seems to be the reaction of glutamine and rapid metabolic
PRPP to form ribosyl-5-phosphate, the first degradation by
xanthine oxidase and
committed step in the de novo pathway. 6TG
by TPMT.
nucleotide is incorporated into DNA, where it
 
induces strand breaks and base mispairing. Therapeutic Uses:
In the maintenance
Mechanisms of Resistance therapy of ALL, an
➜ The most common mechanism of 6MP initial daily oral dose of
resistance observed in vitro is 6MP is adjusted
Deficiency or complete lack of the according to white
activating enzyme HGPRT or increased blood cell and platelet
alkaline phosphatase activity. Other counts. The
combination of MTX
mechanisms for resistance include:
and 6MP appears to be
➜ decreased drug uptake or increased synergistic. By
efflux due to active transporters; inhibiting the earliest
➜ alteration in allosteric inhibition of steps in purine
ribosyl amine 5-phosphate synthase; synthesis, MTX
and elevates the
➜ impaired recognition of DNA breaks intracellular
concentration of PRPP,
and mismatches due to loss of a
a cofactor required for
component (MSH6) of MMR system
6MP activation.
 
PURINE ANALOGUES Adverse Effects:
MERCAPTOP ADME: The principal toxicity
20
 of 6MP is expression of RNR; or
myelosuppression. increased active
Thrombocytopenia,  
granulocytopenia, or ADME:
anemia may not Cladribine is absorbed
become apparent for orally (55%) but is
several weeks. Dose routinely administered
reduction usually intravenously. It is
results in prompt excreted by the
recovery, although kidneys, with a
myelosuppression may terminal t 1/2 in plasma
be severe and of 6.7 h. Cladribine
prolonged in patients crosses the blood-brain
with a polymorphism barrier and reaches
affecting TPMT. CSF concentrations of
Anorexia, nausea, or about 25% of those
vomiting is seen in seen in plasma. Doses
about 25% of adults, should be adjusted for
but stomatitis and renal dysfunction.
diarrhea are rare;
manifestations of GI Therapeutic Uses:
effects are less frequent Cladribine is
in children than in administered daily for 7
adults. days by continuous
CLADRIBINE Mechanisms of Action intravenous infusion. It
and Resistance: is the drug of choice in
An ADA- Cladribine enters cells hairy cell leukemia.
resistant purine via active nucleoside Eighty percent of
analogue that transport. After patients achieve a
has potent and phosphorylation by complete response after
curative activity dCK and conversion to a single course of
in hairy cell cladribine triphosphate, therapy. The drug also
leukemia, CLL, it is incorporated into is active in CLL; low-
and low-grade DNA. It produces DNA grade lymphomas;
lymphomas. strand breaks and Lang-gerhans cell his-
depletion of NAD and tiyo-sai-tosis; CTCLs,
ATP, leading to including mycosis fun-
apoptosis. It is a potent goy-des and the Sézary
inhibitor of RNR. The syndrome.
drug does not require  
cell division to be Adverse Effects:
cytotoxic. Resistance is The major dose-
associated with loss of limiting toxicity of
the activating enzyme cladribine is
dCK; increased myelosuppression.
21
 Cumulative produces
thrombocytopenia may complete
occur with repeated remissions in
courses. Opportunistic 20%–30% of
infections are common these patients.
and correlate with NELARABINE ADME:
decreased CD4+ cell (6-METHOXY- Infusion, the parent
counts. Other toxic ARABINOSYL methoxy compound is
effects include nausea, -GUANINE) rapidly activated in
infections, high fever, blood and tissues by
headache, fatigue, skin The only ADA–mediated
rashes, and tumor lysis guanine cleavage of the methyl
syndrome. nucleoside in group, yielding the
CLOFARABIN Therapeutic Uses and clinical use. It phosphorylase resistant
E (2- Adverse Effects: has selective Ara-G, which has a
CHLORO-2′- In children, clofarabine activity against plasma t 1/2 of 3 h. The
FLUORO- is administered as a 2-h acute T-cell active metabolite is
ARABINOSYL infusion daily for 5 leukemia and transported into tumor
ADENINE) days. The primary the closely cells, where it is
elimination t 1/2 in related T-cell activated by dCK to
The analogue plasma is 6.5 h. Most lymphoblastic Ara-GTP, which
clofarabine of the drug is excreted lymphoma and incorporates into DNA
incorporates the unchanged in the urine. is approved for and terminates DNA
2-chloro, Doses should be use in patients synthesis. The drug and
glycosylase- adjusted according to with its metabolite Ara-G
resistant reductions in CLCr. relapsed/refracto are primarily
substituent of The primary toxicities ry disease. Its eliminated by
cladribine and a are myelosuppression; basic metabolism to guanine,
2′-fluoro- a clinical syndrome of mechanism of and a smaller fraction
arabinosyl hypotension, action closely is eliminated by renal
substitution, tachyphemia, resembles that excretion of Ara-G.
which adds pulmonary edema, of the other Adults are given a 2-h
stability and organ dysfunction, and purine infusion on days 1, 3,
enhances uptake fever, all suggestive of nucleosides, in and 5 of a 21-day
and capillary leak that it is cycle, and children are
phosphorylation. syndrome and cytokine incorporated given a lower dose for
The resulting release that necessitate into DNA and 5 days, repeated every
compound is immediate terminates DNA 21 days.
approved for the discontinuation of the synthesis.  
treatment of drug; elevated hepatic Adverse Effects:
pediatric ALL enzymes and increased The adverse effects
after failure of bilirubin; nausea, include
two prior vomiting, and diarrhea; myelosuppression and
therapies. and hypokalemia and liver function test
Clofarabine hypophosphatemia. abnormalities, as well
22
 as infrequent serious other week and has a
neurological sequelae, mean terminal t 1/2 of
such as 5.7 h. After hydration
seizures, delirium, with 500–1000 mL of
somnolence, peripheral 5% dextrose in half-
neuropathy, or normal (0.45%) saline,
Guillain-Barré the drug is
Syndrome. administered by rapid
Neurological adverse intravenous injection or
effects may not be by infusion over a
reversible. period of 30 min or
PENTOSTATI Mechanism of Action: less, followed by an
N (2′- Inhibition of ADA by additional 500 mL of
DEOXYCOFO pentostatin leads to fluids.
RMYCIN) accumulation of  
intracellular adenosine Therapeutic Uses:
a transition-state and deoxyadenosine Pentostatin is effective
analogue of the nucleotides, which can in producing complete
intermediate in block DNA synthesis remissions (58%) and
the ADA by inhibiting RNR. partial responses (28%)
reaction, Deoxyadenosine in patients with hairy
potently inhibits (DEOXSE- cell leukemia. It largely
ADA. Its effects ADENOSIN) also has been superseded by
mimic the inactivates S-adenosyl cladribine. Toxic
phenotype of (ADENOSUL) manifestations include
genetic ADA homocysteine myelosuppression, GI
deficiency (HOMOSISTEN) symptoms, skin rashes,
hydrolase. The and abnormal liver
resulting accumulation function studies.
of S-adenosyl
homocysteine is Natural Products
particularly toxic to MICROTUBULE-DAMAGING AGENTS
lymphocytes. VINCA MECHANISM OF
Pentostatin also can ALKALOIDS ACTION
inhibit RNA synthesis, The vinca alkaloids
and its triphosphate Purified alkaloids are cell-cycle–
derivative is from the periwinkle specific agents and, in
incorporated into DNA, plant, including common with other
resulting in strand vinblastine and drugs, such as
breakage. vincristine, were colchicine,
  amongst the earliest podophyllotoxin, the
ADME: clinical agents for the taxanes, and the
Pentostatin is treatment of patients epothilones, block
administered with leukemias, cells in mitosis. The
intravenously every lymphomas, and biological activities
23
testicular cancer. A of the vincas can be vinblastine and
closely related explained by their vinorelbine are all
derivative, ability to bind potent candidates for
vinorelbine, has specifically to β- use in combination
activity against lung tubulin and to block therapy regimens for
and breast cancer. its polymerization leukemias and
with α-tubulin into lymphomas. The lack
microtubules. The of severe
Microtubules are neurotoxicity is a
found in high decided advantage in
concentration in the lymphomas and in
brain and contribute combination with
to other cellular cisplatin against
functions, such as testicular cancer.
movement, ERIBULIN
phagocytosis, and
axonal transport. Synthetic analogue of
halichondrin,
ADME originally isolated
Hepatic CYPs from the Pacific
extensively marine sponge
metabolize all three Halichondria okadai.
drugs, and the The drug binds to the
metabolites are vinca alkaloid site on
excreted in the bile. β-tubulin and inhibits
Only a small fraction micro-tubule
of a dose is found assembly. It is
unchanged in the approved for the
urine. In patients with treatment of patients
hepatic dysfunction with drug-resistant
(bilirubin > 3 mg/dL), metastatic breast
a 50%–75% reduction cancer and
in dose of any of the liposarcoma.
vinca alkaloids is
advisable. ESTRAMUSTINE ADME:
Following oral
ADVERSE Combines estradiol administration, at
EFFECT and normustine least 75% of a dose of
Adverse effects of the through a carbamate estramustine
vinca alkaloids, such link. Although the phosphate is absorbed
as their neurotoxicity, intent of the from the GI tract and
may relate to combination was to rapidly
disruption of these enhance the uptake of dephosphorylated.
functions. the alkylating agent The drug undergoes
Vincristine, into estradiol- extensive first-pass
24
sensitive prostate metabolism by impaired glucose
cancer cells, hepatic CYPs to an tolerance; and
estramustine does not active 17-keto hypersensitivity
function in vivo as an derivative, reactions, including
alkylating agent; estromustine, and to angioedema.
rather, it binds to β- multiple inactive Estramustine inhibits
tubulin and products; the active the clearance of
microtubule- drug forms taxanes.
associated proteins, accumulate in the EPOTHILONES
causing microtubule prostate. Some
disassembly and hydrolysis of the The epothilones are
antimitotic actions. carbamate linkage polyketides
occurs in the liver, discovered as
releasing estradiol, cytotoxic metabolites
estrone, and the from a strain of
normustine group. Sorangium
Estramustine and cellulosum, a
estromustine have myxobacterium
plasma half-lives of isolated from soil on
10 and 14 h, the bank of the
respectively, and are Zambezi River in
excreted as inactive southern Africa.
metabolites, mainly
in the feces.
CAMPTOTHECIN ANALOGUES
Therapeutic Use: The camptothecins are potent, cytotoxic
Estramustine is used antineoplastic agents that target the nuclear
solely for the enzyme topoisomerase I. The lead compound
treatment of patients in this class, camptothecin, was isolated from
with metastatic or
the tree Camptotheca acuminata.
locally advanced
hormone-refractory
prostate cancer. Mechanism of Action
The DNA topoisomerases are nuclear enzymes
Adverse Effects: that reduce torsional stress in supercoiled
Myelosuppression DNA, allowing selected regions of DNA to
and estramustine are become sufficiently untangled to permit
possesses estrogenic replication, repair, and transcription. Two
side effects classes of topoisomerase (I and II) mediate
(gynecomastia, DNA strand breakage and resealing.
impotence, elevated Camptothecin analogues inhibit the function of
risk of thrombosis, topoisomerase
and fluid retention);
hypercalcemia; acute
attacks of porphyria; CAMPTOTHECIN ANALOGUES
TOPOTECAN ADME:
25
Topotecan is approved small cell lung cancer
for intravenous is a 30-min infusion
administration. An for 5 consecutive days
oral dosage form in every 3 weeks.
development has a
bioavailability of Adverse Effects:
30%–40% in patients The dose-limiting
with cancer. toxicity with all
Topotecan exhibits dosing schedules is
linear neutropenia, with or
pharmacokinetics, and without
it is rapidly eliminated thrombocytopenia. In
from systemic patients with
circulation with a half hematological
life of about 3.5–4.1 malignancies, GI side
hours. Doses should effects such as
be reduced in mucositis and diarrhea
proportion to become dose limiting.
reductions in CLCr. Other less common
Hepatic metabolism and generally mild
appears to be a topotecan-related
relatively minor route toxicities include
of drug elimination. nausea and vomiting,
The Plasma protein elevated liver
binding of topotecan transaminases, fever,
is low (7%–35%), fatigue, and rash,
which may explain its Irinotecan
relatively greater CNS IRINOTECAN ADME:
penetration. The conversion of
irinotecan to its active
THERAPEUTIC metabolite SN-38 is
USES: mediated
Topotecan is indicated predominantly by
for previously treated carboxylesterases in
patients with ovarian the liver. Although
and small cell lung SN-38 can be
cancer. Significant measured in plasma
hematological toxicity shortly after beginning
limits its use in an intravenous
combination with infusion of irinotecan,
other active agents in the AUC of SN-38 is
these diseases. The only about 4% of the
recommended dosing AUC of irinotecan,
regimen of topotecan suggesting that only a
for ovarian cancer and relatively small
26
fraction of the dose is this incidence by more
ultimately converted than half. However,
to the active form of once severe diarrhea
the drug. Irinotecan occurs, standard doses
exhibits linear of antidiarrheal agents
pharmacokinetics. In tend to be ineffective.
comparison to The second most
topotecan, a relatively common irinotecan-
large fraction of both associated toxicity is
irinotecan and SN-38 myelosuppression.
are present in plasma Severe neutropenia
as the biologically occurs in 14%–47% of
active intact lactone the patients treated
form. with a schedule of
administration every 3
Therapeutic Uses: weeks and is less
Single-agent dosage frequently
of irinotecan is by encountered amongst
weekly infusion for 4 patients treated with
of 6 weeks, with a the weekly schedule. 
higher dose given ANTIBIOTICS
every 3 weeks. In DACTINOMYCIN MECHANISM OF
patients with (ACTINOMYCIN ACTION:
advanced colorectal D) The capacity of
cancer, irinotecan is actinomycins to bind
used as first-line Actinomycins are to double-helical
therapy in chromopeptides DNA is responsible
combination with isolated from for their biological
fluoropyrimidines or Streptomyces soil activity and
as a single agent or in bacteria. Most cytotoxicity. The
combination with contain the same planar phenoxazone
cetuximab following chromophore, the ring intercalates
failure of a planar phenoxazone between adjacent
5FU/oxaliplatin actinosin, which is guanine-cytosine base
regimen.  responsible for their pairs of DNA, while
yellow-red color. the polypeptide chains
Adverse Effects: The differences extend along the
The dose-limiting amongst naturally minor groove of the
toxicity with all occurring helix, resulting in a
dosing schedules is actinomycins are dactinomycin-DNA
delayed diarrhea, with confined to complex with stability
or without variations in the sufficient to block the
neutropenia. An structure of the transcription of DNA
intensive regimen of amino acids of the by RNA polymerase.
loperamide  reduces peptide side chains.
27
Actinomycin D has ADME: suppression with
beneficial effects in Dactinomycin is pancytopenia may
the treatment of solid administered by occur in the first week
tumors in children intravenous injection. after completion of
and choriocarcinoma Metabolism of the therapy. Proctitis,
in adult women. drug is minimal. The diarrhea, glossitis,
drug is excreted in cheilitis, and
both bile and urine ulcerations of the oral
and disappears from mucosa are common;
plasma with a terminal dermatological
half life of 36 hrs. manifestations include
Dactinomycin does alopecia, as well as
not cross the blood- erythema,
brain barrier. desquamation, and
increased
Therapeutic Uses: inflammation and
Dactinomycin is given pigmentation in areas
intravenously for 5 previously or
days, usually in the concomitantly
range of 10–15 μg/kg. subjected to X-ray
If no manifestations of radiation.
toxicity are ANTHRACYCLIN ADME:
encountered, ES AND Daunorubicin,
additional courses ANTHRACENEDI doxorubicin,
may be given at ONES epirubicin, and
intervals of 2–4 idarubicin are
weeks, although Anthracyclines are administered
weekly maintenance derived from the intravenously and are
doses have been used. fungus Streptomyces cleared by a complex
The main clinical use peucetius var. pattern of hepatic
of dactinomycin is in caesius. Idarubicin metabolism and
the treatment of and epirubicin are biliary excretion. Each
rhabdomyosarcoma analogues of the anthracycline is
and Wilms tumor in naturally produced converted to an active
children. anthracyclines alcohol intermediate
doxorubicin and that plays a variable
ADVERSE daunorubicin, role in the therapeutic
EFFECT: differing only activity. The plasma
Toxic manifestations slightly in chemical disappearance curves
include anorexia, structure, but having for doxorubicin and
nausea, and vomiting, somewhat distinct daunorubicin an
usually beginning a patterns of clinical multiphasic, with a
few hours after activity. terminal t 1/2 of 30 h.
administration. Daunorubicin and Idarubicin has a t 1/2
Hematopoietic idarubicin primarily of 15 h, and its active
28
 metabolite, is a biphasic pattern of
idarubicinol, has a t clearance with a terminal t
1/2 of 40 h. The drugs 1/2 of about 6–8 h in
rapidly enter the heart, patients with normal renal
kidneys, lungs, liver, function. Approximately
have been used in
and spleen; they do 40% of an administered
acute leukemias,
not cross the dose is excreted intact in
whereas doxorubicin
bloodbrain barrier. the urine.
and epirubicin
Clearance is delayed
display broader THERAPEUTIC USES:
in the presence of
activity against solid The intravenous dose of
hepatic dysfunction; at
tumors.  etoposide for testicular
least a 50% initial
reduction in dose cancer in combination
should be considered therapy (with bleomycin
in patients with and cisplatin) is 50–100
elevated serum mg/m2 for 5 days or 100
bilirubin levels. mg/m2 on alternate days
for three doses. For small
EPIPODOPHYLLOTOXINS cell carcinoma of the lung,
Podophyllotoxin Derivatives the dosage in combination
Two synthetic derivatives of podophyllotoxins therapy (with cisplatin) is
100–200 mg/m2 /d
have significant therapeutic activity in pediatric
intravenously for 3 days.
leukemia, small cell carcinomas of the lung,
The Cycles of therapy
testicular tumors, Hodgkin disease, and large usually are repeated every
cell lymphomas.  3–4 weeks. After relapse,
oral administration of 50
MECHANISMS OF ACTION AND mg/m2/d for 21 days is one
RESISTANCE treatment option. 
Etoposide and teniposide form ternary
complexes with topoisomerase ii and dna and ADVERSE EFFECTS:
prevent resealing of the break that normally The dose-limiting toxicity
follows topoisomerase binding to dna. the of etoposide is leukopenia
enzyme remains bound to the free end of the (nadir at 10–14 days,
recovery by 3 weeks).
broken dna strand, leading to an accumulation
Thrombocytopenia occurs
of dna breaks and cell death. 
less often and usually is
not severe. Nausea,
EPIPODOPHYLLOTOXINS vomiting, stomatitis, and
ETOPOSIDE ADME: diarrhea complicate
Oral administration of treatment in about 15% of
etoposide results in patients. Alopecia is
variable absorption that common but reversible. 
averages about 50%. After TENIPOSIDE
intravenous injection, there

29
Teniposide is
administered DRUGS OF DIVERSE MECHANISMS OF
intravenously. It ACTION
has a BLEOMYCIN ADME:
multiphasic Bleomycin is
pattern of The bleomycins, a administered
clearance from unusual group of intravenously,
plasma: After DNA-cleaving intramuscularly, or
distribution, a t antibiotics, are subcutaneously or
1/2 of 4 h and fermentation instilled into the bladder
another t1/2 of products of for local treatment of
10–40 h are Streptomyces bladder cancer. Having a
observed. verticillus, high molecular mass,
Approximately comprising a bleomycin crosses the
45% of the drug family of peptide blood-brain barrier
is excreted in polyketides. The poorly. The elimination t
the urine; in drug currently 1/2 is about 3 h. About
contrast to employed two-thirds of the drug is
etoposide, as clinically is a excreted intact in the
much as 80% is mixture of two urine. Concentrations in
recovered as copper-chelating plasma are greatly
metabolites. peptides, elevated in patients with
Anticonvulsants bleomycins A2 renal impairment, and
such as and B2 that differ doses of bleomycin
phenytoin only in their should be reduced in the
increase the terminal amino presence of a CLCr less
hepatic acid. Because their than 60 mL/min.
metabolism of toxicities do not
teniposide and overlap with those Therapeutic Uses:
reduce systemic of other cytotoxic Bleomycin is given
exposure. drugs and because weekly or twice weekly
Teniposide is of their unique by the intravenous,
available for mechanism of intramuscular, or
treatment of action, bleomycin subcutaneous route. A
refractory ALL maintains an test dose of 2 units or
in children and important role in less is recommended for
is synergistic treating Hodgkin patients with lymphoma.
with cytarabine. disease and Bleomycin also may be
Teniposide is testicular cancer. instilled into the pleural
administered by cavity in doses of 5–60
intravenous mg to ablate the pleural
infusion for 5 space in patients with
days or twice malignant effusions. 
weekly. MITOTANE ADME :
Approximately 40% of
30
 mitotane is absorbed ADVERSE EFFECTS:
after oral administration. Although the
Plasma concentrations of administration of
mitotane are still mitotane produces
measurable for 6–9 anorexia and nausea in
weeks following most patients,
discontinuation of somnolence and lethargy
therapy. A water-soluble in about 34%, and
metabolite of mitotane dermatitis in 15%–20%.
found in the urine These effects do not
constitutes 25% of an contraindicate the use of
oral or parenteral dose. the drug at lower doses.
About 60% of an oral Because this drug
Mitotane is a
dose is excreted damages the adrenal
compound
unchanged in the stool. cortex, administration of
chemically similar
replacement doses of
to the insecticides
THERAPEUTIC adrenocorticosteroids is
DDT and DDD, is
USES: necessary.
used in the
Mitotane initial daily TRABECTEDIN ADME:
treatment of
oral doses are 2–6 g, Trabectedin is
adrenal cortex
usually in three or four Trabectedin is administered as a 24-h
carcinoma. The
divided portions. The derived from the infusion of 1.3 mg/m2
mechanism of
maximal tolerated dose marine every 3 weeks. It is
action of mitotane
may vary from 2 to 16 invertebrate administered with
has not been
g/d. Treatment should tunicate dexamethasone, 4 mg
elucidated, but its
continue for at least 3 Ecteinascidin twice daily, starting 24 h
relatively selective
months; if beneficial turbinate. before drug infusion to
destruction of
effects are observed, Trabectedin is an diminish hepatic
adrenocortical
therapy should be alkylating drug toxicity. The drug is
cells, normal or
maintained indefinitely. that binds to the slowly cleared by
neoplastic, is well
Spironolactone should minor groove of CYP3A4, with a plasma
established.
not be administered DNA, allowing t 1/2 of about 24–40 h.
concomitantly because it the alkylation of
interferes with the the N2 position of Therapeutic Uses:
adrenal suppression guanine and Trabectedin is approved
produced by mitotane. bending the helix for the treatment of
Treatment with mitotane toward the major patients with
is indicated for the groove. unresectable or
palliation of inoperable metastatic liposarcoma
adrenocortical or leiomyosarcoma after
carcinoma, producing an anthracycline-
symptomatic benefit in containing regimen and
30%–50% of such is under study as an
patients. orphan drug for the
treatment of patients
31
 with ovarian and treatment are
pancreatic cancer. retinoids, in
particular tretinoin
Adverse Effects: (ATRA), which
Without dexamethasone induces a high rate
pretreatment, trabectedin of complete
causes significant remission in
hepatic enzyme patients with APL
elevations and fatigue in as a single agent
at least one-third of and, in
patients. With the combination with
steroid, the increases in anthracyclines,
transaminase are less cures most
pronounced and rapidly patients with this
reversible. Other disease. 
toxicities include mild ARSENIC Mechanism of Action
myelosuppression TRIOXIDE The basis for ATO’s
and,rarely, antitumor activity
rhabdomyolysis. Arsenic trioxide remains uncertain. APL
RETINOIDS (As2O3), known cells have high levels of
as ATO, is a ROS and are quite
One of the highly effective sensitive to further ROS
hallmarks of treatment of induction. ATO inhibits
malignant relapsed APL, thioredoxin reductase
transformation is a producing and thereby generates
block in complete ROS. 
differentiation. A responses in more
number of than 85% of such ADME
chemical entities patients Arsenic trioxide is well
such as vitamin D absorbed orally but in
and its analogues, cancer treatment is
retinoids, administered as a 2-h
benzamides and daily intravenous
other inhibitors of infusion in dosages of
HDAC, various 0.15 mg/kg/d for up to
cytotoxic and 60 days, until remission
biological agents, is documented. The drug
and inhibitors of enters cells via one of
DNA methylation several glucose
can induce transporters. The
differentiation in primary mechanism of
tumor cell lines. elimination is through
The most enzymatic methylation.
important of these Multiple methylated
for cancer metabolites form rapidly
32
 and are excreted in 6. Immune function, amongst other
urine. Less than 20% of advances.
administered drug is Drivers of Cancer Growth
excreted unchanged in I. Growth Factors and Receptors in
the urine. No dose Cancer Cells
reductions are indicated II. Intracellular Kinases in Cancer Cells
for hepatic or renal
III. Tumor Angiogenesis
dysfunction.
IV. Targeting the Immune System
Adverse Effects V. Other Drugs and Targets that control
Pharmacological doses Cancer Cell Behavior
of ATO are well
tolerated. Patients may 2 Classes of Pathway-Targeted Cancer
experience reversible Drugs
side effects, including Monoclonal Antibodies:
hyperglycemia, hepatic Monoclonal antibodies kill tumor cells by
enzyme elevations, blocking cell surface receptor function, by
fatigue, dysesthesias, recruiting immune cells and complement to the
and light-headedness. antigen-antibody complex, and by modulating
Fewer than 10% of
immune cell function.
patients experience a
leukocyte maturation
syndrome similar to that Small Molecules:
seen with ATRA, Small molecules may attack the same
including pulmonary targets as monoclonal antibodies but can exert
distress, effusions, and their effect by entering cells. Often inhibit
mental status changes. multiple enzymes with different selectivities

Pathway-Targeted Therapies PATHWAY-TARGETED THERAPIES

A Note on Treatment Regimens
Cancer treatment regimens change to reflect
continuous advances in basic and clinical
science:
1. New drugs, both small molecules and
biological
2. Improved methods of targeting and
timing of drug Delivery
3. Agents with altered pharmacokinetic
properties and Selectivities
4. the use of rational multidrug
combinations
5. Greater knowledge of the basic cell
biology of tumorigenesis, metastasis,
and
GROWTH FACTORS AND RECEPTORS
IN CANCER CELLS
1. Inhibitors of EGFR Function
2. HER2/NEU Inhibitors
3. Inhibitors of PDGF Receptor
4. Hedgedog Pathway Inhibitors
INHIBITORS OF EGFR FUNCTION
The EGFR belongs to the ErbB family of
transmembrane receptor tyrosine kinases also
known as ErbB1 or HER1 (human EGFR 1).
EGFR is essential for the growth and
differentiation of epithelial cells.
33
 Ligand binding to the extracellular domain of
EGFR family members causes receptor
dimerization and stimulates the protein tyrosine
kinase activity of the intracellular domain.
Two separate classes of drugs that target the
EGFR pathway:
1. PROTEIN TYR KINASE
INHIBITORS
(erlotinib, gefitinib, afatinib, osimertinib)
2. MONOCLONAL ANTIBODIES
(cetuximab, panitumumab, necitumumab)
PROTEIN TYR KINASE INHIBITORS
Mechanism of Action
Erlotinib is a reversible
inhibitor of the EGFR
tyrosine kinase, competitively
inhibiting ATP binding at the
active site of the kinase.
ADME
60% absorbed after oral
administration. PPL occur
after 4h and metabolized by
CYP3A4
AFATINIB
Therapeutic Uses Erlotinib
ERLOTINIB is used to treat certain types
of NSCLC It is also approved
for the treatment of patients
with pancreatic cancer.
Adverse Effects and Drug
Interactions
Rash, diarrhea, anorexia,
fatigue, dyspnea, nail
disorders, nausea, and
vomiting. Serious adverse
reactions include severe rash
Fatal interstitial lung disease
occurs with a frequently and
fatal hepatic failure.
GEFITINIB Mechanism of Action
Gefitinib inhibits by binding
to the intracellular enzyme
(tyrosine kinase) of the EGFR
to directly block signals
turned on by triggers outside
or inside the cell.
ADME
Oral bioavailability is about
60%; PPC are achieved
within 3–7 h. Absorption of
gefitinib is not significantly
altered by food. Metabolism
of gefitinib is predominantly
via CYP3A4,
Therapeutic Uses
Treatment of patients with
metastatic NSCLC with
EGFR mutations or lung
cancer.
Adverse Effects and Drug
Interactions.
Diarrhea and skin reactions
occur in more than 20% of
patients.
Mechanism of Action
Afatinib is a second-
generation, orally
bioavailable, irreversible
inhibitor of EGFR (HER1)
and HER2 receptor kinases
ADME
The elimination is 37h after
repeat dosing in patients with
cancer. In patients with
severe renal impairment, a
dose reduction is
recommended.
Therapeutic Uses
First-line treatment of
patients with metastatic
34
 NSCLC with EGFR
mutations and patients with
metastatic squamous NSCLC.
Adverse Effects and Drug
Interactions
Diarrhea and skin
rash/acneiform dermatitis,
stomatitis, as well as hand-
foot skin reactions. Also
observed are interstitial lung
disease, liver function
abnormalities, and left
ventricular dysfunction.
Resistance to Gefitinib, Erlotinib, and
Afatinib
Mechanism of Action
Osimertinib is a third-
generation, orally
bioavailable, irreversible
inhibitor of T790M-mutant
EGFR,
ADME
Osimertinib is a substrate
Of CYP3A. The drug is
primarily eliminated in the
feces and to a lesser extent in
the urine. Concurrent
administration of inducers of
OSIMERTINI
CYP3A4 may necessitate an
B
increase in the dose.
Therapeutic Uses.
Osimertinib is approved for
metastatic NSCLC that has
progressed after treatment
and is positive for the EGFR
T790M mutation.
Adverse Effects and Drug
Interactions
Diarrhea and skin rash. Also
observed are interstitial lung
disease, QTc prolongation,
and left ventricular
dysfunction.
Antibody Inhibitors of EGFRs
1. Cetuximab
2. Panitumumab
3. necitumumab
HER2/Neu Inhibitors
Is a recombinant, fully humanized IgG2κ
antibody that binds to the extracellular domain
III of the EGFR and prevents ligand- dependent
signaling. It is FDA approved for the treatment
of EGFR and as monotherapy after disease
progression
HER2/Neu Inhibitors
TRASTUZUMA
B
PERTUZUMAB
Lapatinib is an orally
bioavailable, small-
LAPATINIB
molecule inhibitor of the
EGFR and HER2
tyrosine kinases.
Neratinib is an orally
bioavailable, irreversible
NERATINIB inhibitor of the HER2
and EGFR protein
tyrosine kinase
INHIBITORS OF PDGF RECEPTOR
Signaling by the PDGFR plays a significant
part in mesenchymal biology, including stem
cell growth, and is involved in oncogenesis
through aberrant cancer cell signaling,
modulation of the tumor microenvironment,
and facilitation of angiogenesis and metastasis.
PDGF INHIBITORS
OLARATUM Mechanism of Action
AD Olaratumab is a human
IgG1 monoclonal antibody
that binds to PDGFRα and
35
 blocks ligand-mediated Dabrafenib is an frequency, are
receptor activation. orally hyperkeratosis,
bioavailable, headache, pyrexia,
is a first-in-class hedgehog small-molecule arthralgia, papilloma,
VISMODEGI signaling pathway inhibitor inhibitor of alopecia, and PPES. An
B approved for the treatment mutated forms of increased incidence of
of adult patients with BCC. BRAF kinases. cuSCC is expected with
a hedgehog pathway Dabrafenib can a median time of 2
inhibitor that binds to and inhibit the months to the first
SONIDEGIB inhibits SMO receptor proliferation of diagnosis.
signal transduction similar tumor cells. Is
to vismodegib used to treat a
certain types of
INTRACELLULAR PROTEIN KINASES melanoma
IN CANCER CELLS COBIMETINIB Adverse Effect
The RAS-RAF-MEK-ERK Pathway Diarrhea,
HRAS and KRAS, named after Harvey and Cobimetinib is an photosensitivity
orally reaction, nausea,
Kirsten rat sarcoma viruses and discovered in
bioavailable, pyrexia, and vomiting.
the early 1980s, were the first oncogenes
reversible Major hemorrhagic
discovered in human tumors. The first RAF inhibitor of events can occur with
gene was identified from a murine retrovirus MEK1/2 protein cobimetinib; patients
named “rapidly accelerated fibrosarcoma” kinase activity. Its should be monitored for
Due to its oncogenic effects. Following the elimination half- signs and symptoms of
discovery of the first human RAF gene, ARAF life ranges from 1 bleeding. The drug also
and BRAF were identified; their gene products to 3 days. It is increases the risk of
are ser/thre protein kinases. used to treat a cardiomyopathy.
RAS-RAF-MEK-ERK INHIBITORS certain type of
VEMURAFENIB Adverse Effects metastatic
Arthralgia, fatigue, and melanoma
Vemurafenib is an nausea are also observed INHIBITORS OF MEK KINASE
orally bioavailable but at a lower frequency. TRAMETINIB Adverse Effects
inhibitor of The median time to the Cutaneous rash,
mutated BRAF. first appearance of these Trametinib was acneiform dermatitis,
This drug is used skin lesions. Increased the first inhibitor and diarrhea. Fatigue,
to treat a type of photosensitivity of the MEK nausea, and lymphedema
skin cancer reactions can be family to be FDA also occur. Serious grade
(melanoma). prevented with sunblock. approved. It is 3–4 skin toxicity is
Vemurafenib used to treat found in 6% of patients.
works by slowing certain types of
the growth of cancer in people Drug Resistance
certain cancer who have a Activation of alternative
cells. "BRAF" gene signaling pathways
DABRAFENIB Adverse Effects mutation. signaling can bypass
In order of decreasing MEK inhibition and
36
Trametinib is an result in drug-resistant breast cancer as thrombocytopenia.
orally tumors. well as a variety
bioavailable, of other cancers.
reversible. BRUTON TYROSINE KINASE
Bioavailability of INHIBITOR
oral trametinib is Mechanism of Action
72% and is Ibrutinib is an orally
reduced if taken bioavailable, small-
with a high-calorie molecule inhibitor that
meal. inactivates BTK Use to
INHIBITORS OF JAK1 AND JAK2 treat Mantle Cell
RUXOLTINIB Adverse Effect Carcinoma.
The most common
Ruxolitinib is adverse reactions, ADME
indicated for the thrombocytopenia and Administration with
treatment of anemia, should be met food roughly doubles
IBRUTINIB
patients with with a dose reduction or absorption. The
polycythemia vera discontinuation of elimination half-life of
who have had an treatment. ibrutinib is 4 to 6 h
inadequate
response to Adverse Effect
hydroxyurea and Neutropenia, pyrexia,
for the treatment thrombocytopenia,
of myelofibrosis. hemorrhage, anemia,
CYCLIN-DEPENDENT KINASE diarrhea, nausea,
PALBOCICLIB Adverse Effect musculoskeletal pain,
The most common rash, and fatigue
Palbociclib is the adverse effects of
first CDK palbociclib are BCR-ABL Kinase Inhibitors
inhibitor approved neutropenia, leukopenia, Imatinib mesylate, originally named “sti 571”
by the FDA for infections, stomatitis, was the first protein kinase inhibitor designed
the treatment of fatigue, nausea, anemia, to target a driver mutation in a cancer and to
advanced or headache, diarrhea, and receive FDA approval.
metastatic breast thrombocytopenia. It was approved in 2001 under the name
cancer that is ER
Gleevec and is now designated as an essential
positive and
HER2 negative drug by the World Health Organization.
ABEMACICLIB Adverse Effect INHIBITORS OF THE BCR-ABL
& RIBOCICLIB The most common KINASE
adverse effects of IMATINIB
These inhibitors palbociclib are DASATINIB
are currently neutropenia, leukopenia, NILOTINIB
undergoing infections, stomatitis, INHIBITORS OF THE BCR-ABL
clinical trials in fatigue, nausea, anemia, KINASE
patients with headache, diarrhea, and BOSUTINIB Bosutinib is another

37
 second-generation. It is P13K inhibitors cause cell death, inhibit
FDA approved for the proliferation of malignant cells and interfere
treatment of patients with several signaling pathways.
with chronic, The inhibition of mTOR blocks the binding of
accelerated, or blast- the accessory protein raptor, which reduces
phase Ph+CML with protein synthesis and decrease cell mortality
resistance or intolerance
and size
to prior therapy
INHIBITOR OF P13K
Ponatinib is a third-
Therapeutic uses:
generation BCR-ABL
Approved for the
kinase inhibitor.
treatment of relapsed or
Imatinib lacks efficacy
refractory B-cell
for the more advanced
PONATINIB malignancies in
disease phases, and cells
patients who have
with mutations in the
IDELALISIB received at least two
BCR-ABL tyrosine
prior systemic therapies
kinase domain are
Adverse effect:
resistant
Liver toxicity, diarrhea,
colitis, pneumonitis,
Inhibitors of Anaplastic Lymphoma Kinase
intestinal perforations,
ALK is a substance that blocks the activity of a skin toxicity
protein, which helps control cell growth. INHIBITOR OF mTOR
Blocking the protein help keep cancer cells Therapeutic uses:
from growing and spreading. Temsirolimus and
Inhibitors of Anaplastic Lymphoma everolimus are
Kinase approved for treatmet
Therapeutic uses: of patients with
Approved for the advanced renal cancer.
treatment of Temsirolimus prolongs
patients with survival and delays
advanced or disease progression in
RAPAMYCIN
recurrent NSCLC patients with advanced
ANALOGUE
ALECTINIB and poor- or
CERITINIB Adverse effect: intermediate-risk renal
CRIZOTINIB GI toxicity and cancer
hepatotoxicity. Adverse effect:
Bradycardia, Hyperglycemia,
prolonged QT hypertriglyceridemia
intervals, fatigue, and rarely pulmonary
constipation and infiltrates and
edema interstitial lung disease
MULTIKINASE INHIBITORS
Inhibitors of the P13K/Akt/mTOR Pathway CABOZANTINI Therapeutic uses:
B Cabozantinib was also

38
 shown to produce
superior efficacy to
sunitinib in patients
with treatment-naïve
intermediate- or poor-
risk metastatic renal
cancer
Adverse effect:
Diarrhea, fatigue,
nausea, decreased
appetite, PPES,
hypertension, vomiting,
weight loss,
constipation
Tumor Angiogenesis
Cancer cells secrete angiogenic factors that
induce the formation of new blood vessels and
guarantee the flow of nutrients to the tumor
cells to permit growth and metastasis
Angiogenesis plays a critical role in the growth
of cancer because solid tumors need a blood
supply.
INHIBITION VEGF and VEGFR
PATHWAY
BEVACIZUM Therapeutic Uses:
AB Use to treat ovarian cancer
RAMUCIRUM combined with
AB chemotherapy and renal
AFLIBERCEP cell carcinoma combined
T with interferon
Metastatic colorectal
cancer in combination of
chemotherapy
It is indicated for patients
with mCRC that is
resistant to or has
progressed following an
oxaliplatin containing
regimen
Adverse effect:
Hypertension, related
congestive, heart failure,
impaired wound healing,
spontaneous GI perforation
The most common adverse
effects are hypertension
and diarrhea
ANTIANGIOGENIC SMALL-
MOLECULE KINASE INHIBITOR
Therapeutic Uses:
Approved for the treatment
of pancreatic NETs and of
GISt in patients who have
developed resistance to
imatinib
Sofafenib is the only drug
currently approved for
treatment of patients with
hepatocellular-carcinoma
and for the patients with
metastatic renal cell cancer
SUNITINIB
SORAFENID Adverse Effect:
Bleeding, hypertension,
proteinuria and
uncommonly arterial
thromboembolic events
and intestinal perforation
Fatigue, nausea, diarrhea,
anorexia, rash and palmar-
plantar erthrodysesthesias;
uncommonly, bone
marrow suppression, GI
perforation and
cardiomyopathy occur
OTHER RECEPTOR KINASE
INHIBITOR WITH ANTIANGIOGENIC
EFFECTS
Axitinib is approved for
the treatment of patients
AXITINIB with advanced RCC after
failure of one prior
systemic therapy
LENVATINIB Lenvatinib is approved for
the treatment of patients
39
 with recurrent or metastatic Mechanism of Action
differentiated thyroid Ipilimumab blocks the
cancer and in combination interaction of CTLA-4
with everolimus for with B7 ligands on
patients with advanced APCs and thereby
renal cell cancer. augments T-cell
activation.
TARGETING THE IMMUNE SYSTEM ADME
AND OTHER TARGETS Ipilimumab is
IMMUNE CHECKPOINT INHIBITORS administered
The conceptual breakthrough is based on the intravenously.
discovery of inhibitory signals that limit T-cell
Therapeutic Uses
activation, so called immune activation. The Current recommended
discovery of receptors, ligands, and their IPILIMUMAB dosing of iplimumab is
function in the control of immune cell activity 3 mg/kg intravenously
during the past two decades led to the a fully human
over 90 min every 3
development of clinically effective monoclonal lgG1 monoclonal
weeks for a total of four
antibody that
antibodies that enable T cells to recognize and doses for patients with
binds to CTLA-4
eradicate cancer cells with acceptable adverse metastatic disease and
and is approved
effects. 10 mg/kg followed by
for the treatment
Mechanism of T-Cell Activation 10 mg/kg every 12
of late stage
Antigen-mediated activation of T cells is weeks for up to 3 years
melanoma and
initiated by engagement of the TCR with or until documented
under study for
disease recurrence or
antigen presented on MHC protein on the other cancers.
unacceptable toxicity for
surface of an APC, “signal 1.”
patients treated in the
This “signal 2” is provided by B7 surface adjuvant setting.
proteins on APCs, for example, CD80 or Adverse Effect
CD86. T-cell activation is tightly controlled by Blockade of CTLA-4
immune-suppressive cells and cytokines as compromises immune
well as by coinhibitory molecules present on T tolerance to some
cells, such as CTLA-4 or PD-1. normal tissue antigens
and provokes
INHIBITORS OF CYTOTOXIC T inflammatory toxicities,
LYMPHOCYTE–ASSOCIATED PROTEIN mostly in the skin,
4 (CTLA4) pituitary gland,
The CTLA-4 is upregulated during the antigen intestine, and liver.
Other Drugs in This
priming of T cells and binds B7 on APCs to
Class
attenuate the T-cell response and thus reduce
TREMELIMU
the risk for chronic autoimmune-dependent MAB
inflammation.
CYTOTOXIC LYMPHOCYTE- (formerly
ASSOCIATED PROTEIN 4 (CTLA4) ticilimumab) is a
40
 fully human
IgG2 monoclonal
antibody that
targets CTLA-4;
it is under
investigation in
several clinical
trials.
Inhibitors of Programmed Cell Death 1 (PD-
1)
Activation of the PD-1 checkpoint pathway in
T cells by PD-L1 or PD-L2 evokes a negative
regulatory immune response and inactivates T
cells.
PROGRAMMED CELL DEATH 1 (PD-1)
INHIBITOR
Nivolumab Mechanism of Action
Nivolumab is a fully human
monoclonal IgG4 antibody
that blocks the interaction
between PD-1 and its
ligands.
ADME; Clinical Use
Nivolumab is administered
as an intravenous infusion
every 2 weeks until the time
of disease progression or of
unacceptable toxicity.
Adverse Effects
In patient with Melanoma,
Rash (>20%)
In patient with advance
squamous NSCLC
Fatigue, dyspnea,
musculoskeletal pain,
decreased appetite, cough,
nausea, and constipation.
Immune-mediated adverse
reactions are much less
common than with CTLA-4
antibodies; corticosteroids
are recommended based on
the severity of the reaction.
ADME; Clinical Use
The recommended treatment
schedule for pembrolizumab
is 2 mg/kg (or a 200-mg flat
dose) as an intravenous
infusion over 30 min every
Pembrolizuma 3 weeks. The elimination
b half-life is 26 days.
Pembrolizumab
Adverse Effect
(formerly called
The most common adverse
lambrolizumab
effects, experienced by
or MK-3475) is
more than 20% of patients,
a humanized
are fatigue, cough, nausea,
monoclonal
pruritus, rash, decreased
IgG4-κ isotype
appetite, constipation,
antibody that
arthralgia, and diarrhea. An
blocks
additional 10% of patients
interaction
may experience
between PD-1
complications with
and its ligands.
infections. Serious adverse
events include immune-
mediated inflammation,
specifically pneumonitis,
colitis, hepatitis, and
hypophysitis and both
hyper- and hypothyroidism.
Antagonist of PD-1 Ligand 1
Programmed cell death 1 has two ligands, PD-
L1 and PD-L2, each with distinct expression
profile. The PD-L1 ligand is expressed on
APCs, T cells, B cells, and nonhematopoietic
cells, which can include cancer cells.
ATEZOLIMU Mechanism of Action
MAB Atezolizumab, also known
as MPDL3280A, is a fully
human IgG1 monoclonal
antibody that blocks the
41
interaction of PD-L1 with
PD-1 and B7-H1.
ADME
Atezolimumab is
administered as an
intravenous infusion over
60 min every 3 weeks. The
terminal half-life is 27
days.
Clinical Use
Atezolimumab is indicated
for conventional treatment-
resistant metastatic NSCLC
as well as locally advanced
or metastatic urothelial
cancer.
Adverse Effect:
Patient with metastatic
NSCLC; fatigue, decreased
appetite, dyspnea, cough,
nausea,musculoskeletal
pain, constipation
Patient with urothelial
carcinoma may have
urinary infection
Immune-related adverse
effect; hepatitis, colitis,
hypophysitis, thyroid
disorders, adrenal
insufficiency, type 1
diabetes mellitus,
pancreatitis, myasthenia
gravis, Guillain-barre
syndrome, ocular
inflammation, these may
require discontinuation of
treatment.
Female should be advised
accordingly due to potential
embryo-fetal toxicity.
Therapeutic Uses:
DURVALUMA Evaluated for efficacy
B AND toward cancers of the head
AVELUMAB and neck, stomach, lung
and ovary, as well as
hepatocellular cancer
COMBINATION OF ANTI- PD-1 AND
ANTI-CTLA4
Anti-CTLA-4 and anti-PD-1 target distinct
immune checkpoints during T-cell activation,
preclinical studies have shown that concurrent
targeting of CTLA-4 and PD-1 significantly
improves therapeutic efficacy when compared
to effects of single agents.
CYTOKINES TO STIMULATE
IMMUNE RESPONSE
INTERLEUKIN 2 Mechanism of
Action:
70 or so proteins It stimulates the
and glycoproteins proliferation of
that are classified activated T cells and
as cytokines, only secretion of cytokines
IFN and IL-2 are from NK cells and
routine clinical use, monocytes. IL-2
often for actions stimulations increases
against cancer cytotoxic killing by T
cells and NK cells
ADME:
Administered
intravenously. The
serum t1/2 of IL-2
after intravenous
administration has an α
phase of about 13 min
and a β phase of about
90 mins. Il-2 is
excreted in the urine as
an inactive metabolite.
Therapeutic uses:
Aldesleukin possesses
42
 the biological activities laherparepvec) is an
of native human IL-2. oncolytic herpesvirus that
The drug us approved replicates within tumors
for use in patients with and expresses GM-CSF.
metastatic renal cancer Tumor antigens are
and metastatic released after virally
melanoma. induced cell death, and
the presense of GM-CSF
Adverse effect: can promote an antitumor
Dominated by the immune response
capillary leak
syndrome, in which Chimeric Antigen Receptor T Cells
intravascular fluid CARS contain the antigen-binding domain of a
leaks into the monoclonal antibody to confer recognition of
extravascular space, the targeted tumor antigen coupled to
producing
intracellular domains capable of activating T
hypotension, edema,
respiratory difficulties, cells.
confusion, tachycardia,
oliguric renal failure,
electrolyte problems.
Symptoms include
fever, chills, malaise,
nausea, vomiting,
diarrhea

CANCER VACCINES
Future challenges of immunotherapy
Vaccination against cancer antigens has shown
The potential for immunotherapies to augment
little efficacy with the exception of two
conventional chemotherapy pathway- targeted
approaches that were approved by the FDA in
treatment, and radiotherapy will require
2010 (sipuleucel-T) and in 2015 (T-VEC)
detailed exploration and will be a common
theme in the design of future clinical trials
CANCER VACCINES
A cell-based approach
INHIBITORS OF POLY (ADP-RIBOSE)
designed to induce an
immune response against POLYMERASE
PAP, which is expressed DNA damage-repair genes are frequently
in most prostate cancers. inactivated in human cancer. PARP1 is the
SIPULEUCEL- product of one such gene. PARP1 is a nuclear
This autologous cellular
T protein that transfers ADP-ribose from NAD to
immunotherapy is
generated from a patients target proteins, and this poly (ADP-ribosyl)
peripheral blood cells, ation (or PARylation) of nuclear proteins by
which are isolated by PARP1 plays a significant role in the DNA
leukapheresis damage response. Inactive PARP1 associates
T-VEC T-VEC (talimogene
43
with chromatin and helps to create a compact with
chromatin structure in the nucleosome. Germline BRCA-
The mechanisms of relaxation are the mutated, advanced,
PARylation of PARP1 itself, and of histones ovarian cancer who
and other chromatin associated proteins. have been treated with
Resulting in their dissociation from DNA. three or more prior lines
of chemotherapy.
The synthesis and degradation of PAR chains
in vivo is tightly regulated, with the chains Adverse effects:
having half-lives measured in minutes (Wei GI upset (nausea and
and Yu, 2016). vomiting) and loss of
Deficient PARP1 activity leads to defective appetite; fatigue; muscle
DNA repair. However, PARP-deficient cells and joint pain; low
are still able to carry out DNA repair through a blood cell counts and
different mechanism homologous anemia; and
recombination. The protein machinery for occasionally leukemia.
homologous recombination repair includes the Potentially fatal MDS
breast cancer susceptibility genes BRCA1 and and pneumonitis have
BRCA2, suggesting that cells with diminished been observed.
Clinical use:
or absent BRCA1/2 function could be
The drug is
unusually susceptible to the inhibition of PARP
administered orally but
activity. should not be given until
Olaparib and rucaparib are approved for the RUCAPARIB
the patient has
treatment of patients with advanced ovarian recovered from any
cancer. Is a
benzimidazole hematological toxicity
INHIBITORS OF POLY (ADP-RIBOSE) caused by previous
derivative that
POLYMERASE chemotherapy. WP2D6
inhibits PARP1.
OLAPARIB ADME: Rucaparib is FDA metabolizes Rucaparib,
Rapidly absorbed after approved for yielding a half-like of
An orally oral administration and about 18 h.
treatment of
bioavailable metabolized primarily advanced ovarian
inhibitor of PARP by CYP3A4, yielding a Adverse effect:
cancer in patients
enzyme t1/2 of about 12 h. Drug GI upset and abdominal
exhibiting
exposure is increased or pain, fatigue, and
deleterious
reduced when decreased appetite.
BRCA mutations
administered in MDS and AML rare but
who have been
combination with serious adverse effects
treated with at
CYP3A4 inhibitor or (<1%). This
least two prior
inducer, respectively agent may cause fetal
chemotherapies.
harm and should not be
Therapeutic uses: administered to pregnant
Olaparib is EMA and females or used by
FDA approved as nursing mothers.
monotherapy in patients BCL2 INHIBITORS
44
The BCL2 protein family comprises moFe
than 20 proteins that goveFn mitochondrial
outeF membrane peFmeabilization
and control pFogFammed cell death
apoptosis).
VENETOCLAX Mechanism of Action:
A first-in-class, orally
bioavailable, small-
molecule inhibitor of
BCL2. It was designed
as a BH3 mimetic that
inhibits BCL2
interaction with the
proapoptotic BH3-only
family members, such as
BIM, BID, and BAD.
ADME:
Oral absorption is
significantly improved
3- to 5-hold by
administration with a
meal. Venetoclax, a Pgp
substrate, is metabolized
by CYP3A4/5;
concomitant use of
CYP3A inhibitors or
inducers and Pgp
inhibitors should be
avoided. The
elimination half-life is
18—26 h.
Therapeutic use:
Approved for the
treatment of patients
with CLL with a 17p
deletion.
Adverse effect:
Neutropenia, diarrhea,
nausea, anemia, upper
respiratory tract
infection,
thrombocytopenia,
fatigue. Venetoclax
should not be
administered during
pregnancy or
breastfeeding until
further data are
available.
Thalidomide and Lenalidomide
Thalidomide originally was used for the
treatment of pregnancy-associated morning
sickness but was withdrawn from the market
due to teratogenicity and dysmelia (stunted
limb growth).
Further research revealed its antiangiogenic
and immunomodulatory effects. At least four
distinct mechanisms have been proposed to
explain its antitumor activity.
Both thalidomide and lenalidomide possess
potent
Activity in patients with newly diagnosed and
heavily pre-treated relapsed/refractory MM.
Lenalidomide also is approved for its activity
in the 5q — subset [or del (5q) subset] of
MDS. A specific gene array profile identifies
patients with MDS who lack the 5q —
abnormality but respond to Ienalidomide. A
more recently added derivative of thalidomide
is porn Lenalidomide, approved for treatment
of patients with MM resistant to Lenalidomide.
LENALIDOMIDE ADME:
Lenalidomide The standard dosage
constitutes the lead of lenalidomide is 25
compound of mg/d for 21 days or a
immunomodulatory 28-day cycle.
thalidomide The drug is rapidly
derivatives. absorbed following
Lenalidomide oraI administration,
induces the teaching peak plasma
ubiquitination and levels within 1.5 h.
45
degradation of involvement, and carpal tunnel syndrome
target proteins by Therapeutic Uses: POMALIDOMID
the E3 ubiquitin Lenalidomide exhibits E Adverse effects are
ligase CRL4CRBN. potent antitumor similar to those of
Target proteins in activity in MM, MDS, A thalidomide thalidomide.
MM cells are and CLL; this agent congener, is
IKZF1/3, which are causes fewer adverse indicated for the
crucial for cell effects and lacks the treatment of
survival. In MDS, teratogenicity of patients with MM
casein kinase 1A1 is thalidomide. who have received
the target protein at least two prior
Adverse effect: therapies including
Are less severe; it lenalidomide.
causes little sedation, PROTEASOME INHIBITORS (FIRST
constipation, or GENERATION)
neuropathy. BORTEZOMIB Mechanism of
Lenalidomide Action:
depresses bone First generation Bortezomib binds to
marrow function and inhibitor of the β5 subunit of the
is associated with proteasome- 205 core of the 26S
significant leukopenia mediated protein proteasome and
(20% of patients). degradation that has reversibly inhibits its
Hepatotoxicityand a central role in the chymotrypsin-like
renal dysfunction are treatment of MM activity. This event
rare. In some patients disrupts multiple
with CLL, intracellular signalling
lenalidomide causes cascades, leading to
dramatic lymph node apoptosis. An
swelling and tumor important
lysis (tumor flare consequence of
reaction). proteasome inhibition
Adverse effect of Thalidomide and is its effect on NP-
lenalidomide: KB, a transcription
Thalidomide is well tolerated at doses less factor that promotes
than 200 mg daily. Common adverse effects cell damage response
are sedation and constipation. The most and cell survival.
serious adverse effect is peripheral sensor Most cellular NF-kB
neuropathy, which occurs in 10%—30% of is cytosolic and bound
patients with MM or other malignancies in a to ITB; in this form,
dose- and time-dependent manner. NP-<B is restricted to
Thalidomide-related neuropathy is an the cytosol and cannot
asymmetrical, painful, peripheral paresthesia enter the nucleus to
with sensor loss, commonly presenting with regulate transcription.
numbness of toes and feet, muscle cramps, In response to stress
weakness, signs of pyramidal tract signals resulting from
46
hypoxia, chronic of the
chemotherapy, and toxicities, develops
DNA damage, ITB most frequently in
becomes ubiquitinated patients with a prior
and then degraded via history of neuropathy
the proteasome secondary to prior
drug treatment (e.g.,
ADME: thalidomide) or
The recommended diabetes or with
starting dose of prolonged use.
bortezomib is 1.3
mg/m 2 given as an SECOND GENERATION
intravenous bolus on A second-generation
days 1, 4, B, and 11 of selective proteasome
every 21 -day cycle CARFILZOMIB inhibitor based on
{with a 10-day rest tetrapeptide
period per cycle). At epoxyketone
Ieast 72 h should an orally bioavailable
elapse between doses. second-generation
peptide analogue
Therapeutic Uses: proteasome inhibitor
Bortezomib is used as IXAZOMIB
that interacts with
initial therapy for subunit beta type 5
patients with MM and (PSMB5) of the 20S
as therapy for patients proteasome complex
with MM after relapse This agents
from other drugs. It is mechanisms of action
also approved for include inhibition of
treatment of patients protein translation by
with relapsed or preventing the initial
refractory MCL. OMACETAXINE
elongation step of
protein synthesis,
Adverse effect: thereby depleting the
Bortezomib toxicities cell of short-lived
include proteins
thrombocytopenia
(28%), fatigue (12%), CD20 INHIBITORS
peripheral neuropathy
A cell surface antigen expressed on the surface
(12%), neutropenia,
anemia, vomiting, of all B cells beginning with the pro—B cell
diarrhea, limb pain, stage through its terminal differentiation to
dehydration, nausea, plasma cells and is expressed on about 90% of
and weakness. B-cell neoplasms.
Peripheral
neuropathy, the most CD20 INHIBITORS

47
RITUXIMAB ADME: infusion rates and
The drug is antihistamines.
Chimeric administered by Uncommonly, patients
murine/human intravenous infusion may develop severe
monoclonal IgG1 both as a single agent mucocutaneous skin
antibody that and in combination with reactions including
targets the CD20 chemotherapy. Drug 5tevens-Johnson
B-cell surface half-life is about 22 syndrome. Rituximab
antigen days. may cause reactivation
of hepatitis B virus or
Therapeutic Uses: rarely, JC virus (with
Rituximab is approved progressive multifocal
as a single agent for leukoencephalopathy)
relapsed indolent a second monoclonal
lymphomas and antibody that binds to
significantly enhances CD20 at sites on the
response and survival in OFATUMUMA major and minor
combination with B extracellular loops of
chemotherapy for the CD20, distinct from the
initial treatment of site targeted by
diffuse large BCL. rituximab
Rituximab improves A humanized
response Fates when monoclonal IgG1
added to combination OBINUTUZUM antibody that recognizes
chemotherapy for other AB the CD20 antigen
indolent B-cell NHLs, expressed on the surface
including ALL, MCL, of B-cells
WM, and marginal zone OTHER CELL SURFACE TARGETS
lymphomas. FOR MONOCLONAL ANTIBODIES
ALEMTUZUM Therapeutic Uses:
Resistance and AB Approved as a single
Adverse effect: agent for the treatment
Resistance to rituximab A humanized of B-cell CLL. Clinical
may emerge through IgG-K activity had been
down regulation of monoclonal demonstrated in both B-
CD20, impaired antibody that and T-cell lowgrade
antibody- dependent binds to CD52 lymphomas and CLL,
cellular cytotoxicity antigen. CD52 is including patients with
decreased complement found on the disease refractory to
activation limited effects surface of a purine analogues.
on signalling and subset of normal
induction of apoptosis neutrophils and Adverse effects:
and inadequate blood on all B and T Serious toxicities
levels. lymphocytes, on include acute infusion
All respond to decreased testicular reactions and depletion
48
 of normal neutrophils
and T cells.
Myelosuppression with
depletion of all blood
lineages, occurs in the
majority of MAB
Patients and may
elements and
represent either direct
sperm, and on
marrow toxicity or
most BCLs and
autoimmune responses.
T-cell
Immunosuppression
lymphomas.
leads to a significant
risk of fungal, viral, and
other opportunistic
infections, particularly
in patients who have
previously received
purine analogues.
a monoclonal antibody
that targets glycolipid
GD2, expressed on
DINUTUXIMA neuroblastoma cells and
B on normal cells of
neuroectodermal origin,
including the CNS and
GEMTUZUMA
peripheral nerves
B
A human IgG1
OZOGAMICIN
monoclonal antibody
that binds to CD38 and
inhibits the growth of
DARATUMUM
CD38- expressing tumor
AB
cells by inducing
immune-mediated tumor
cell lysis through CDC
and ADCC
A humanized
monoclonal IgG1
antibody that targets
SLAMF7 (CD319). It is
ELOTUZUMAB approved for the BRENTUXIMA
treatment of patients B VEDOTIN
with MM who have
received one to three
prior therapies
BILINATUMO A bispecific antibody
that recognizes sites on
the surfaces of B cells
and T cells, thereby
enabling a patients T
cells to recognize
malignant B cells.
Bilitumomab binds
simultaneously to CD3
(part of the TCR) on T
cells and to CD19 on B
cells.
MONOCLONAL ANTIBODY-
CYTOTOXIN CONJUGATES
Mechanism of Action:
A humanized
monoclonal antibody
against CD33 covalently
linked to a
semisynthetic derivative
of calicheamicin, a
potent antitumor
antibiotic.
ADME:
The antibody conjugate
produces a 30%
complete response rate
in relapsed AML when
administered at a dose 9
mg/m2 for up to three
doses at 2-week
intervals
Therapeutic Uses:
The drug was initially
approved for use in
patients more than 60
years of age with AML
in first relapse.
An anti-Cd30 IgG1
monoclonal antibody
linked with the
microtubule-disrupting
agent MMAE. CD30 is
expressed on a number
49
 of malignant cells and is in combination with
especially prevalent in G-CSF to mobilize
Hodgkin and anaplastic HSC to the
lymphoma peripheral blood for
Ado-trastuzumab-DM1 collection and
combines the HER2- subsequent
targeted properties of autologous
trastuzumab with the transplantation in
ADO- antimicrotubule agent patients with NHL
TRASTUZUMA DM1 (derived from and MM.
B EMTANSINE maytansine), allowing
preferential intracellular INHIBITORS OF HISTONE
rug delivery to HER2+ DEACETYLASE
cells in the treatment of Histone deacetylases are a class of enzymes
HER+ breast cancer that catalyse the removal of acetyl groups from
ADME: acetylated lysine amino acids in histones,
Administered by
thereby altering the transcriptional activation of
intravenous infusion
cellular genes
DENILEUKIN over 30-60 min for 5
DIFTITOX consecutive days every ADME:
21 days for 8 cycles. The oral bioavailability
An immunotoxin The drug is quickly is about 21%.
made from the distributed and has Panobinostat is
genetic terminal t ½ of about 70 PANOBINOSTA metabolised through
recombination of min. T CYP3A. it is
IL-2 and the recommended to avoid
catalytically Therapeutic Uses: An orally concomitant use with
active fragment of Approved for the bioavailable, strong CYP3A4
diphtheria toxin treatment of nonselective pan- inducers or inhibitors.
recurrent/refractory HDAC inhibitor. Otherwise, dose
cutaneous T-cell The inhibitory adjustments will be
lymphomas. activity leads to necessary. The
CYTOKINES AND GROWTH FACTORS apoptosis of elimination half-life is
malignant cells approximately 37 h
Colony-Stimulating Factors
via multiple
Many agents used for cancer chemotherapy
pathways Adverse effect:
suppress the production of multiple types of Diarrhea,fatigue,nausea,
hematopoietic cells, and bone marrow peripheral edema,
suppression can limit the delivery of decreased appetite,
chemotherapy on schedule and at prescribed pyrexia, vomiting
doses ROMIDEPSIN ADME:
PLERIXAFOR a small-molecule After intravenous
inhibitor of the An HDAC administration, the
CXCr4 chemokine inhibitor used in major metabolism is
receptor and is used the treatment of through CYP3A4
cutaneous and
50
 Adverse effects: thrombocytopenia,
Nausea and vomiting, anorexia, and dysgeusia.
anemia, Patients with severe
peripheral T-cell
thrombocytopenia, hepatic impairment
lymphoma
leukopenia as well as should be excluded from
abnormal electrolyte treatment. Vorinostat is
levels and ECG changes classified as pregnancy
VORINOSTAT Mechanism of Action category D: evidence of
Vorinostat binds to the risk.
A small- active site of HDACs
molecule, orally and chelates zinc ions in Hormones and Related Agents in the
bioavailable the active site. The Therapy of Cancer
HDAC inhibitor; resulting inhibition of DRUGS THAT TARGET THE
it is also known HDACs causes the GLUCOCORTICOID RECEPTOR
as SAHA based accumulation of Glucocorticoids act by binding to a specific
on its chemical acetylated histones and
GR that is a member of the nuclear receptor
name other acetylated
suberanilohydrox family of transcription factors. The GR
proteins, amongst which
amic acid are transcription factors translocates to the nucleus and induces
crucial for cell complex gene expression changes that lead to
differentiation. anti-proliferative and apoptotic responses in
sensitive cells. In acute lymphoblastic or
ADME undifferentiated leukemia of childhood,
The absorption of glucocorticoids may produce prompt clinical
vorinostat is slightly improvement and objective hematological
improved when taken remissions in 30% of children.
with a meal. Metabolism
is mostly through ESTROGENS AND ANDROGENS IN
glucuronidation and
CANCER
hydrolysis. The
elimination t1/2 is about
2 h. ■ Hormone Therapy of Breast Cancer
High doses of estrogen have been recognized
Therapeutic Use; as effective treatment of breast cancer. More
Adverse Effects recent studies have suggested lower doses of
Vorinostat is approved estrogen can be effective in the management of
for the treatment of endocrine-resistant disease.
patient with cutaneous However, interruption of estrogen-induced
T-cell lymphoma with signaling with anti-estrogens such as tamoxifen
persistent or recurrent and drugs that reduce estrogen production have
disease after two
been found to be more effective and better
systemic therapies. The
tolerated. These drugs have largely replaced
most comma n adverse
reactions are diarrhea, estrogens or androgens for the treatment of
fatigue, nausea, breast cancer.

51
 (hot flashes), atrophy
■ Hormone Therapy of Prostate Cancer of the lining of the
Drugs That Target the Estrogen Receptor vagina, menstrual
TAMOXIFEN Mechanism of irregularities, vaginal
Action: bleeding and
The most widely Tamoxifen is a discharge, and
studied anti- competitive inhibitor pruritus vulvae and
estrogenic drug used of Estrogens binding occur with increasing
in the treatment of to the ER, and severity in
breast cancer. These antagonizes postmenopausal
novel anti-estrogens estrogen-induced women years.
can be divided into proliferation of Tamoxifen slightly
tamoxifen analogues; human breast cancer. increases the risk of
fixed ring compunds; Binding of estrogen thromboembolic
and the SERDs, the and SERMs to the events, which
latter also termed estrogen-binding increase with the age
“pure antiestrogen” sites of the ERs of a patient and also
initiates a change in in the perioperative
was developed as an conformation of the period. Hence, it
oral contraceptive ER, dissociation of often is advisable to
the ER from heat- temporarily halt
Tamoxifen is shock proteins, and tamoxifen prior to
prescribed for the ER dimerization. elective surgery.
adjuvant therapy of Therapeutic Uses:
early-stage breast TOREMIFENE Toremifene is used
Therapeutic Uses:
cancer and for the Tamoxifen is used occasionally in the
therapy of advanced for the treatment of a triphenylethylene
metastatic setting for
breast. derivative of
women with ER+ the treatment of
tamoxifen and has a
metastatic breast breast cancer in
Tamoxifen is also similar
cancer or following women with tumors
used for the pharmacological
primary excision of that are ER+ or of
prevention of breast profile, clinical
an ER+ tumor as an unknown receptor
cancer in high-risk efficacy, and safety
adjuvant treatment to status.
patients such as those prevent recurrence pharmacological
with a strong family and extend overall profile, clinical Adverse Effect:
history or prior efficacy, and safety In rare case it can
survival. For the
nonmalignant breast adjuvant treatment of cause heart rhythm
pathology. premenopausal problems through
.
women, prolongation of the
QT interval
Adverse effect:
The common adverse SELECTIVE ESTROGEN RECEPTOR
reactions to DOWNREGULATORS (SERDs)
tamoxifen include
vasomotor symptoms
52
The SERDS, also termed pure antiestrogens, setting as the third-
include fulvestrant and a number of agents in generation AI
experimental trials. SERDs, unlike SERMs, are anastrozole.
devoid of any estrogen agonist activity.
FULVESTRANT Mechanism of
Action: Adverse Effect:
is currently the  Fulvestrant is a Most common adverse
only FDA- steroidal effects includes
approved SERD, antiestrogen nausea, asthenia, pain,
either as a single that binds to hot flashes, arthralgias,
agent or in the ER with an and headache. The risk
combination with affinity more of injection site
palbociclib, a than 100 times reactions, seen in
CDK4/6 inhibitor that of almost 10% patients, is
for postmenopausal tamoxifen. reduced by giving the
women with HR+  The drug not injection slowly.
metastatic breast only inhibits
cancer that has the binding of
progressed on anti- AROMATASE INHIBITORS
estrogen but
estrogen therapy.  Aromatase converts androgens to estrogens.
also alters the
receptor  AIs Aromatase (CYP19A1) is responsible
structure such for the conversion of adrenal androgens and
that the gonadal androstenedione and testosterone
receptor is to the estrogens estrone (E1) and estradiol
targeted for (E2), In postmenopausal women, this
proteasomal conversion occurs in non-ovarian tissues
degradation and is the primary source of circulating
 fulvestrant also estrogens. Therapy or after tamoxifen block
may inhibit this enzymatic activity, thereby reducing
receptor estrogen production .
dimerization.
 AIs are now considered the standard of care
Therapeutic Uses: for adjuvant treatment of postmenopausal
Fulvestrant is used in women with ER+ breast cancer, either as
postmenopausal initial.
women as antiestrogen
therapy of HR+ First- and second-generation
metastatic breast  AIs are no longer used for breast cancer
cancer after treatment because of their side effects.
progression on first-  Third-generation inhibitors include the type
line antiestrogen 1 steroidal agent exemestane and the type 2
therapy such as
nonsteroid imidazoles anastrozole and
tamoxifen or an AI.
letrozole
Fulvestrant is at least
as effective in this
53
 they are approved for use in post- EXEMESTANE
menopausal women
 Third-generation AIs are Used as part of a more potent, orally
the treatment of early-stage and advanced administered
analogue of the
breast cancer in postmenopausal women Therapeutic Uses:
natural aromatase
and for chemoprevention. The use of the mTOR
substrate
inhibitor everolimus
androstenedione and
Therapeutic Uses: with exemestane has
ANASTROZOLE lowers estrogen
AIs are approved for been approved for
levels more
up-front adjuvant treatment of
Is absorbed rapidly effectively than does
hormonal therapy for advanced-stage breast
after oral its predecessor,
5–10 years or cancer that has
administration formestane.
following prior progressed on
Steady state is Exemestane
tamoxifen in nonsteroidal type 2
attained after 7 days irreversibly
postmenopausal Ais GnRH Agonists
of repeated dosing. inactivates aromatase
women with early- and is a “suicide
Anastrozole is
stage breast cancer substrate” type 1
metabolized by N-
and as treatment of inhibitor of
dealkylation,
advanced and aromatase.
hydroxylation, and
metastatic breast
glucuronidation.
cancer. In early-stage Drugs That Target the Progesterone
breast cancer, anastro- Receptor
The main metabolite
zole is significantly
of anastrozole is a  Progestational agents are mainly used as
more effective than
triazole. Less than secondary agents in hormonal therapy for
tamoxifen in delaying
10% of the drug is metastatic hormone-dependent breast
time totumor
excreted as the cancer and are also used in the management
recurrence and
unmetabolized parent
decreasing the odds of of endometrial carcinoma previously
compound.
a primary treated by surgery and radiotherapy.
contralateral tumor.  Medroxyprogesterone acetate is available
Therapeutic Uses: for oral administration; an alternative oral
The clinical progestational agent is megestrol acetate.
LETROZOLE indications for use of Beneficial effects have been observed in
letrozole in breast one-third of patients with endometrial
The clinical uses and cancer treatment are
cancer. The response of breast cancer to
side-effect profile of the same as for
the type 2 AI megestrol is predicted by both the presence
anastrozole In
letrozole are similar addition, improved of HRs (ER and PR) and the evidence of
to that detailed in the progression-free response to a prior hormonal treatment
previous section for survival is observed
anastrozole. when HR+ advanced Hormone Therapy of Prostate Cancer
stage breast cancer is  Androgens stimulate the growth of normal
treated. and cancerous prostate cells. These findings
established androgen deprivation therapy
54
 (ADT) as the mainstay of treatment for decrease LH production; therefore, testosterone
patients with advanced prostate cancer. levels are normal or increased. Men treated
 ADT is also given in conjunction with with antiandrogen maintain some degree of
radiation therapy or following surgery for potency and libido and do not have the same
some men with regionally localized spectrum of side effects seen with castration.
intermediate- to high-risk disease. However, antiandrogen therapy is typically
 In patients with metastasis, ADT is given in combination with ADT.
typically the standard first-line treatment. Antiandrogens are classified as steroidal,
including cyproterone or nonsteroidal,
Androgen Deprivation Therapy including enzalutamide, flutamide,
GnRH Agonists and Antagonists bicalutamide, and nilutamide.
The most common form of ADT involves
chemical suppression of the pituitary gland is the most recently
with GnRH agonists (see previous section). FDA-approved second-
GnRH agonists in common use for prostate generation antiandrogen.
cancer include leuprolide, goserelin, triptorelin, It prolongs survival in
histrelin, and nafarelin Long-acting patients with metastatic
CRPC when given to
preparations are available in doses that are
chemotherapy naïve
approved for 3-, 4-, and 6-month patients or after
administrations. ENZALUTAMI
docetaxel therapy.
Toxicity DE
During the transient rise in LH, the resultant Enzalutamide is a
testosterone surge may induce acute synthetic nonsteroidal
stimulation of prostate cancer growth and a antiandrogen that has 5-
“flare” of symptoms from metastatic deposits. to 8-fold higher binding
Patients may experience an increase in bone affinity for the AR
pain, spinal cord compression, or obstructive compared to
bladder symptoms lasting for 2–3 weeks. bicalutamide.
The flare phenomenon can be effectively BICALUTAMID The agent bicalutamide
E is given once daily in
counteracted with concurrent administration of
conjunction with a
2–4 weeks of oral anti-androgen therapy, which GnRH agonist.
may inhibit the action of the increased serum Bicalutamide has a 1/2
testosterone levels. of 5–6 days.
Bicalutamide undergoes
Drugs That Target the Androgen Receptor glucuronidation to
Antiandrogens bind to Ars and competitively inactive metabolites,
inhibit the binding of testosterone and and the parentcompound
dihydrotestosterone, thereby preventing AR and metabolites are
nuclear translocation and inhibiting eliminated in bile and
transcription of downstream androgen- urine. The 1/2 of
responsive genes. Unlike castration, bicalutamide is
increased in severe
antiandrogen therapy by itself does not
55
 hepatic insufficiency that also inhibits both
and is unchanged in testicular and adrenal
renal insufficiency. steroidogenesis by
given orally once daily. blocking CYP 11A and
It has an elimination 1/2 primarily
of 45 h and is Ketoconazole is
metabolized to five administered off label
products that are all as secondary hormone
LE
excreted in the urine. therapy to reduce
Common side effects adrenal androgen
NILUTAMIDE include mild nausea, synthesis in CRPC.
alcohol intolerance Diarrhea and hepatic
(5%–20%), and enzyme elevations
diminished ocular limit its use as initial
adaptation to darkness hormone therapy.
(25%–40%); rarely,
interstitial pneumonitis ABIRATERONE Mechanism of Action
occurs. Abiraterone inhibition
is given orally three used with of CYP17A1 reduces
times per day. It has a t prednisone for the the conversion of
1/2 of 5 h; its major treatment of CRPC pregnenelone and
metabolite, in patients who are progesterone to their
hydroxyflutamide, is chemotherapy 17α-hydroxy
biologically active. naïve or in those derivatives and
FLUTAMIDE Common side effects who have received reduces the synthesis
include diarrhea, breast previous docetaxel. of DHEA and
tenderness, and nipple In both settings, it androstenedione. Thus,
tenderness. Less prolongs survival. circulating levels of
commonly, nausea, testosterone drop to
vomiting, and almost-undetectable
hepatotoxicity occur. levels after abiraterone
administration.
Drugs That Inhibit Androgen Synthesis
 In the castrate state, AR signaling, despite
low steroid levels, supports continued Estrogens
prostate cancer growth. AR signaling may High estrogen levels can reduce testosterone to
occur due to androgens produced from non- castrate levels in 1–2 weeks via negative
gonadal sources, AR gene mutations, or AR feedback on the hypothalamic-pituitary axis.
gene amplification. Estrogen also may compete with androgens for
steroid HRs and may thereby exert a cytotoxic
 Androstenedione, produced by the adrenal
effect on prostate cancer cells. Although
glands, is converted to testosterone in
estrogens reduce bone loss and are as effective
peripheral tissues and tumors.
as orchiectomy for metastatic prostate cancer,
KETOCONAZO is an antifungal agent
56
They are no longer used clinically because of  Prepare the lining of the uterus
their risk for serious and potentially fatal side for a fertilized egg
effects as well as impotence and lethargy.  Support pregnancy
 Suppress estrogen production
DRUGS AFFECTING THE FEMALE after ovulation
REPRODUCTIVE SYSTEM
Phase Range
FEMALE SEX HORMONES
Hormones are natural substances produced in before puberty 0.1–0.3 ng/mL
the body. They help to relay messages between
cells and organs and affect many bodily during first
functions. Everyone has what are considered (follicular) stage of 0.1–0.7 ng/mL
“male” and “female” sex hormones. menstrual cycle

TYPES OF FEMALE SEX HORMONES while ovulating

2–25 ng/mL
ESTROGEN (luteal stage of cycle)
Estrogen is the major female hormone. These
first trimester of
share comes from the ovaries, but small 10–44 ng/mL
pregnancy
amounts are produced in the adrenal glands and
fat cells. During pregnancy, the placenta also second trimester 19.5–82.5 ng/mL
makes estrogen.
third trimester 65–290 ng/mL
The roles of estrogen:
 Puberty
TESTOSTERONE
 Menstruation Testosterone is a hormone that is responsible
 Pregnancy for many of the physical characteristics specific
 Menopause to adult males. It plays a key role in
Normal ranges in picograms per milliliter reproduction and the maintenance of bone and
(pg/mL): muscle strength.
 Adult female, The role of testosterone:
 premenopausal: 15-350 pg/mL  Sexual desire
 Adult female, postmenopausal: <10  Regulation of the menstrual cycle
pg/mL  Bone and muscle strength
 Adult male: 10-40 pg/mL  The normal range for females is 15 to 70
nanograms per deciliter (ng/dL).
PROGESTERONE
The ovaries produce the female sex hormone CHANGES IN THE ROLES THAT THE
progesterone after ovulation. During HORMONES PLAY OVER TIME
pregnancy, the placenta also produces some. ● Puberty
The role of progesterone: ● Menstruation
● Sexual desire and contraception
57
 ● Pregnancy
● After childbirth and breastfeeding
● Perimenopause and menopause
PUBERTY
★ Between ages of 8 and 13.
★ The luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) are produced in
the pituitary gland.
★ Production increases at puberty, which in
turn stimulates the sex hormones —
especially estrogen.
This increase in female sex hormones results
in:
1. Development of the breast
2. Growth of pubic and armpit hair
3. An overall growth spurt
4. Increase in body fat, especially in the
hips and thighs
5. Maturation of the ovaries, uterus, and
vagina
6. Start of menstrual cycle
MENSTRUATION
★ The first menstrual period (menarche)
happens about two to three years after the
breasts begin to develop.
★ Most females get their first period between
the ages of 10 and 16.
SEXUAL DESIRE AND
CONTRACEPTION
★ Estrogen, progesterone, and testosterone all
play a role in female sexual desire — also
called libido — and sexual functioning.
★ There’s generally less fluctuation in libido
if you’re using hormonal birth control
methods, which affect hormone levels.
PREGNANCY
★ During the luteal phase of your cycle, the
rise in progesterone prepares your uterus to
receive a fertilized egg.
★ Progesterone thickens the cervix to protect
the uterus from bacteria and sperm.
Estrogen levels are also higher,
contributing to the thickening of the lining
of the uterus.
★ As soon as conception takes place, you start
to produce human chorionic gonadotropin
hormone (hCG).
★ Human placental lactogen (hPL) is a
hormone made by the placenta.
★ Levels of another hormone called relaxin
also rise during pregnancy.
AFTER CHILDBIRTH AND
BREASTFEEDING
★ Once pregnancy ends, hormone levels
start to fall immediately.
★ Breastfeeding lowers estrogen levels
and can prevent ovulation.
PERIMENOPAUSE & MENOPAUSE
★ During perimenopause — the period
leading up to menopause — hormone
production in the ovaries slows down.
Estrogen levels begin to fluctuate while
progesterone levels start a steady
decline.
HORMONAL IMBALANCE
DUE TO:
★ Puberty
★ Pregnancy
★ Breastfeeding
★ Perimenopause and menopause
★ Use of hormonal contraception or
hormone therapy
Hormonal imbalance can sometimes be a
sign of:
58
 • Polycystic ovarian syndrome
(PCOS). This is the most common
endocrine disorder among young
females. PCOS can cause irregular
menstrual cycle and interfere with
fertility.
• Androgen excess. This is an
overproduction of male hormones. This
can cause menstrual irregularities,
infertility, acne and male pattern
baldness.
• Hirsutism. This is an increase in hair
growth on the face, chest, abdomen, and
back. It’s caused by excessive male
hormones and can sometimes be a
symptom of PCOS.
Underlying conditions include:
★ Hypogonadism, which is a shortage of
female hormones
★ Miscarriage or abnormal pregnancy
★ Multiple pregnancy (having twins,
triplets, or more)
★ Ovarian Tumor
See your doctor as soon as you can if you’re
experiencing:
★ Morning sickness or other signs of
pregnancy
★ Decreased sexual desire
★ Vaginal dryness or pain during sex
★ Skipped periods or
increasingly irregular cycles
★ Difficulty conceiving
★ Pelvic pain
★ Hair loss or hair growth on your face or
trunk
★ Depression after giving birth
★ Prolonged menopause symptoms that
interfere with your life
SELECTIVE ESTROGEN RECEPTOR
MODULATORS
Selective estrogen receptor modulators, called
SERMs for short, block the effects of estrogen
in the breast tissue. SERMs work by sitting in
the estrogen receptors in breast cells. If a
SERM is in the estrogen receptor, there is no
room for estrogen and it can't attach to the cell.
Cells in other tissues in the body, such as bones
and the uterus, also have estrogen receptors.
But each estrogen receptor has a slightly
different structure, depending on the kind of
cell it is in. So breast cell estrogen receptors are
different from bone cell estrogen receptors and
both of those estrogen receptors are different
from uterine estrogen receptors.
TAMOXIFEN Mechanism of Action:
Tamoxifen competitively
Tamoxifen in inhibits estrogen binding
pill form (also to its receptor, which is
called tamoxifen critical for it's activity in
citrate; brand breast cancer cells.
name: Tamoxifen leads to a
Nolvadex) and decrease in tumor growth
in liquid form factor α and insulin-like
(brand name: growth factor 1, and an
Soltamox) increase in sex hormone
binding globulin. The
increase in sex hormone
binding globulin limits
the amount of freely
available estradiol. These
changes reduce levels of
factors that stimulate
tumor growth.
Therapeutic Uses:
Indicated to treat estrogen
receptor positive
metastatic breast cancer
in adults, as an adjuvant
in the treatment of early
59
 stage estrogen receptor
positive breast cancer in
adults, to reduce the risk
of invasive breast cancer
after surgery and
radiation in adult women
with ductal carcinoma in
situ.
Adverse Effect:
• Menopause-like
symptoms, including
hot flashes, night
sweats and vaginal
dryness.
• Weight gain (more
common) or fluid
retention (edema).
• Irregular or loss of
menstrual periods.
• Leg swelling.
• Nausea.
• Vaginal discharge.
• Skin rash.
• Erectile dysfunction.
• Fatigue.
• Headaches.
Mechanism of Action:
Acts as both an estrogen
agonist and antagonist via
differential effects on the
tissue-specific estrogen
receptors. Based on the
findings of competitive
EVISTA
binding assays, evista
displays binding affinity
Chemical name:
that is similar to that of
raloxifene
estradiol, the predominant
circulating estrogen.
Estrogens play variable
roles at different tissues
in females, including the
bone, breasts, uterus and
liver, by binding to the
steroid nuclear hormone
receptors, Estrogen
Receptor alpha (ERα) or
Estrogen Receptor beta
(ERβ).
Therapeutic Uses:
Indicated for the
prevention and treatment
of osteoporosis in
postmenopausal women,
as well as prevention and
treatment of
corticosteroid-induced
bone loss.
Indicated for the
reduction in the risk of
invasive breast cancer in
postmenopausal women
with osteoporosis or
postmenopausal women
with a high risk for
invasive breast cancer.
Adverse Effect:
• hot flashes,
• increased
sweating,
• headache,
• dizziness,
• spinning
sensation,
• leg cramps or leg
pain,
• joint pain,
• nausea,
• vomiting,
• stomach pain, or
• Runny or stuffy
nose.
• Evista may
infrequently cause
stroke or serious
60
 blood clots to • bone pain
form in the legs, • skin redness or
lungs, or eyes. rash
FARESTON Mechanism of Action: • dry skin
Fareston is a nonsteroidal • hot flashes
Chemical name: triphenylethylene • sweating
Toremifene derivative. Fareston binds • nausea
to estrogen receptors and • mood swings
may exert estrogenic, • vaginal discharge
antiestrogenic, or both or bleeding
activities, depending upon • vision problems
the duration of treatment, • dry eyes
animal species, gender, • dizziness
target organ, or endpoint • swelling of the
selected hands, feet,
ankles, or lower
Therapeutic Uses: legs
For the treatment of • endometrial
metastatic breast cancer cancer
in postmenopausal
women with estrogen BENEFITS OF SERMS
receptor-positive or Because tamoxifen is the most commonly used
receptor-unknown SERM, most of the studies comparing SERMs
tumors. Fareston is
to aromatase inhibitors have looked at
currently under
tamoxifen versus aromatase inhibitors. Several
investigation as a
preventative agent for studies have compared tamoxifen with
prostate cancer in men aromatase inhibitors to see which type of
with high-grade prostatic medicine was more effective in treating early-
intraepithelial neoplasia stage, hormone-receptor-positive breast cancer
and no evidence of in postmenopausal women.
prostate cancer.
BASED ON THE RESULTS, MOST
Adverse Effect: DOCTORS GO BY THE FOLLOWING
• tumor flare RECOMMENDATIONS:
(sudden increase • An aromatase inhibitor is the best type of
in tumor-related
hormonal therapy to start with for
symptoms, such as
postmenopausal women.
bone pain, lymph
node swelling, or • Switching to an aromatase inhibitor after
skin rash) taking tamoxifen for 2 to 3 years (for a total
• hypercalcemia of 5 years of hormonal therapy) offers more
(increased calcium benefits than 5 years of tamoxifen.
levels in the • Taking an aromatase inhibitor for 5 years
blood) after taking tamoxifen for 5 years continues
61
 to reduce the risk of the cancer coming CONTRAINDICATIO
back, compared to no treatment after NS & CAUTIONS:
tamoxifen. • Presence of
• You should not take a SERM if you are primary ovarian
breastfeeding, pregnant, trying to get Failure
pregnant, or if there is any chance that you • Thyroid and
adrenal
could be pregnant. These medicines may
dysfunction
cause damage to developing embryos. You
• Ovarian cysts
should use an effective non-hormonal type • Pregnancy
of birth control — such as condoms, a • Breastfeeding
diaphragm along with spermicide, or a non- • Idiopathic uterine
hormonal I.U.D. — while you are taking a bleeding
SERM. • Known allergies
• Thromboembolic
FERTILITY DRUGS diseases
Some women may have difficulty getting • Respiratory
pregnant because their ovaries do not release N diseases
(ovulate) eggs. Fertility specialists may use
Adverse Effect:
medications that work on ovulation to help
• Vasomotor
these women get pregnant. There are two
flushing
common ways these medicines are used: 1) to • Visual changes
cause ovulation in a woman who does not • Abdominal
ovulate regularly, and 2) to cause multiple eggs discomfort
to develop and be released at one time. • Distention &
About 25% of infertile women have problems Bloating
with ovulation. These women may ovulate less • Nausea
often or not at all (anovulation). Ovulation • VomitinG
induction medications can help a woman to • Ovarian
ovulate more regularly, increasing her chance enlargement
of getting pregnant. These medicines, • Breast tenderness
sometimes called “fertility drugs,” may also • Ovarian
overstimulation
improve the lining of the womb or uterus
• Multiple
(endometrium).
pregnancies
CETROTIDE Therapeutic Uses:
(CETRORELI Work either directly to
INDUCTION OF OVULATION
X) stimulate follicles and
Clomiphene citrate (CC) is a selective estrogen
HUMAN ovulation or stimulate the
CHORIONIC hypothalamus to receptor modulator (SERM) that competes for
GONADOTRO inCrease Follicle estrogen receptors within the hypothalamus.
PIN stimulating hormone With the binding of CC to the estrogen
CLOMIPHENE (Fsh) and luteinizing receptors, the hypothalamus receives a signal
MENOTROPI hormone (Lh) levels that circulating estrogen levels are low. This

62
sets the hypothalamus in motion to secrete LH. The results are
more GnRH, thus stimulating the HPO axis. ovarian stimulation,
The GnRH instructs the anterior pituitary gland maturation of the
to release FSH and LH to initiate a response ovarian follicle,
from the ovarian follicles. Estrogen levels ovulation, and
increase in response to FSH and LH, and a development of the
corpus luteum.
follicle becomes dominant, producing the level
of estrogen needed for the LH surge. The LH
surge causes release of an ovum from the Uterine Motility Drugs
dominant follicle. It is important for LH to Uterine motility drugs stimulate uterine
reach a level high enough to produce an contractions to assist labor (oxytocics) or
ovulatory cycle and that the timing of the LH
induce abortion (abortifacients). Tocolytics are
surge be at the height of follicle formation, drugs used to slow uterine activity. Terbutaline,
which is mid-cycle. a beta2 -selective adrenergic agonist, was
widely used off-label as a tocolytic agent to
CLOMIPHENE Pharmacokinetics relax the gravid uterus to prolong pregnancy.
CITRATE (CC)
In 2011 the U.S. Food and Drug
Clomiphene citrate is
Administration (FDA) required a black box
readily absorbed from
the GI tract. It is warning on this drug alerting prescribers to
partially metabolized significant risks in using the drug for this
in the liver and is purpose and stressing that this was not an
primarily excreted in approved indication for the drug. That same
the feces via biliary year, hydroxyprogesterone caproate (Makena)
elimination. CC has a was approved to reduce the risk of preterm
half-life of about 5 birth in women with a single-fetus pregnancy
days. and a history of singleton spontaneous preterm
birth.
Pharmacodynamics It is not approved for use in multiple-fetus
pregnancies. It is a synthetic progestin and has
The mechanism of
the effects and adverse effects of the
action of CC is
unknown, but it is progestins. It is given by IM injection by a
hypothesized that it health care provider once a week, starting
competes with between 16 and 20 weeks of gestation and
estrogen at receptor continuing until the 37th week.
sites. The perception
of decreased OXYTOCICS ADME:
circulating estrogen by 0.2 mg IM or IV, may
the hypothalamus and Methylergonovine repeat q2-4 h; 0.2 mg PO
pituitary gland triggers (methergine) t.i.d. during the
the negative feedback Oxytocin (Pitocin) peurperium for up to 1
response that increases wk
secretion of FSH and
63
 1-2 mU/min IV through
infusion pump, increase
as needed, do not exceed
20 mU/min; 10 units IM
after delivery of the
placenta;
One spray in each nostril
2-3 min before
breastfeeding
Therapeutic uses:
Promotion of postpartum
uterine involution;
stimulation of last stage
of labor, induction of
labor; promotion of
uterine contractions
postpartum; used nasally
to stimulate milk “let
down” in lactating
women; also being
evaluated as a diagnostic
agent to test abnormal
fetal heart rates (oxytocin
challenge) and to treat
breast engorgement
ADME:
250 mcg IM at intervals
of 1.5-3.5 h, not to
exceed 12 mg total dose;
250 mcg IM to control
postpartum bleeding, not
to exceed 2 mg total dose
CARBOPROST Therapeutic Uses:
(hemabate) Stimulates uterine muscle
contraction (similar to
labor contractions) for
termination of early
pregnancy; evacuation of
missed abortion; control
of postpartum
hemorrhage and uterine
atony that does not
respond to other therapy
A prostaglandin used for
evacuation of the uterus;
stimulation of cervical
ripening before labor
ADME:
20 mg vaginal
suppository, may repeat
q3-5 h as needed for
termination of
pregnancy; 0.5 mg gel
via cervical catheter,
DINOPROSTON
repeated in 6 h if needed
E
for cervical ripening,
(cervidil, propedil,
then wait 6-12 h before
gel, prostin E2)
using oxytocin
Therapeutic Uses:
A prostaglandin used for
evacuation of the uterus;
stimulation of cervical
ripening before labor
ADME:
600 mg PO as a single
dose; if pregnancy not
terminated by day 3, 400-
mcg misoprostol PO; If
not terminated by day 14,
surgical intervention is
suggested.
MIFEPRISTONE Therapeutic uses:
(mifeprex, RU- Approved for use in
486) terminating early
pregnancy durinf the first
49 d by acting as an
antagonist of
progesterone to stimulate
uterine activity by sites in
the endometrium to
dislodge or prevent the
implantation of any
fertilized eggs
64
ABORTIFACIENTS dilation of the cervix
ABORTION Expulsion of some
• Abortion is defined as the spontaneous INCOMPLETE products of
or induced termination of pregnancy conception
before fetal viability. Expulsion of all
• In medical practice, abortion occurs in COMPLETE products of
1st trimester, miscarriage in 2nd conception
trimester, and premature labor in 3rd ≥ 2 to 3 consecutive
RECURRENT OR
spontaneous
trimester HABITUAL
abortions
Undetected death of
TYPES OF ABORTION an embryo or a fetus
TYPES DEFINITION MISSED that is not expelled
Abortion before 12 and that causes no
EARLY
weeks gestation bleeding
Abortion between 12 Serious infection of
LATE and 20 weeks the uterine contents
gestation SEPTIC during or shortly
Non induced before or after an
SPONTANEOUS
abortion abortion
Termination of
pregnancy for CRIMINAL ABORTION
INDUCED
medical or elective
reasons Criminal abortion is the induced destruction or
Termination of
expulsion of the fetus from the womb of the
pregnancy because
mother unlawfully that is where there is no
the woman’s life or
health is endangered therapeutic indication for operation
THERAPEUTIC or because the fetus
is dead or has METHODS TO INDUCE CRIMINAL
malformation ABORTION
incompatible with 1. Mechanical violence (general and local)
life 2. Abortifacient drugs
Vaginal bleeding 3. Instruments
occurring before 20
weeks gestation MECHANICAL VIOLENCE
without cervical GENERAL MECHANICAL VIOLENCE
THREATENED
dilation and These methods may act directly on the uterus
indicating that
or act indirectly by promoting congestion of
spontaneous abortion
pelvic organs and causing hemorrhage between
may occur
INEVITABLE vaginal bleeding or uterus and pelvic membranes.
rupture of the
membrane These methods are:
accompanied by 1. Severe pressure over abdomen
65
2. Violent exercise cellular metabolism, and bone and muscle
3. Cupping growth
4. Very hot and cold baths alternatively
TESTOSTERONE
Local mechanical violence  It is the prototype of the androgen
While correcting the retroverted uterus hormones
bimanualy  Testes
 Adrenal Cortex
ABORTIFACIENT DRUGS  In women
 In adult males
Abortifacient, any drug or chemical
preparation that induces abortion Testosterone Levels by Age

THE ABORTIFACIENT DRUGS ARE:

1. ECBOLICS
2. EMMENAGOGUES
3. IRRITANTS OF GENITOURINARY
TRACT
4. IRRITANTS OF THE
GASTROINTESTINAL TRACT
5. DRUGS HAVING POISONOUS EFFECT
ON THE BODY
 Inorganic irritants
 Organic irritants
 Abortion pill f-6103
INSTRUMENTS
The instruments are used for the purpose of:
PHARMACOKINETICS
1. RUPTURE OF MEMBRANES
● 98% of circulating testosterone
2. ABORTION STICK
● 2% unbound
3. AIR INSUFFLATION
● excreted in the urine as glucuronic and
4. ELECTRICITY
sulfuric acid conjugates and its metabolites
5. PASTE
6. SYRINGING
PHARMACODYNAMICS
● Testosterone and dihydrotestosterone act as
Drugs Affecting the Male Reproductive
androgens by way of a single androgen
System
receptor officially designated NR3A
● The manufacture of protein within the
ANDROGEN
target cells results in the buildup of cellular
tissue (anabolism)
Control the development and maintenance of
● As men age, the number of Leydig cells
sexual processes, accessory sexual organs,
decreases, sperm production declines, and
66
 luteinizing hormone (LH) and follicle- Skeletal maturation must be monitored every 6
stimulating hormone (FSH) levels rise. months by radiography of the hand and wrist.
Levels of unbound testosterone are reduced Artificial induction of puberty is undertaken
in older men to one third to one fifth the only after boys reach age 15 to 17 years and
peak value. after hypothalamic and pituitary function has
been assessed. A 4- to 6-month trial of
SECONDARY SEX CHARACTERISTICS androgen therapy is implemented, followed by
• pubic hair growth a similar period of rest for reevaluation. If
• beard and body hair growth prolonged therapy is required, testosterone
• Baldness cypionate is used, 50 to 400 mg IM every 2 to
• deepening of the male voice 4 weeks
• thickening of the skin
• sebaceous gland activity ● Testosterone may be administered buccally,
• increased musculature nasally, transdermally, or parenterally.
• bone development ● A buccal mucoadhesive system is available
• Red blood cell formation. that provides a 30-mg dose every 12 hours.
● Transdermal testosterone (TT) patches
INDICATIONS FOR ANDROGEN achieve adequate serum concentrations
THERAPY when applied to the arm, back, or upper
buttocks
Hypogonadism ● Testosterone gel is applied to clean dry skin
of shoulders or upper arms. It should not be
Male hypogonadism is a defect of the applied to the genitals
reproductive system that results in failure of the ANDROGEN Side effect:
testes to produce testosterone, sperm, or both. • frequent erections or
priapism
2 BASIC TYPE • gynecomastia
PRIMARY HYPOGONADISM • urinary urgency
• Spermatogenesis
 Low testosterone with elevated LH
• abdominal pain
 Impaired testicular function • Nausea
• Insomnia
SECONDARY HYPOGONADISM • diarrhea or
 Low testosterone with low-normal LH constipation
 Impaired hypothalamic or pituatary • hives or redness at the
failure injection site
• increased salivation
Adult men may experience testicular atrophy, • mouth soreness
impotence, decreased libido, decreased bone • increased or decreased
density, loss of muscle mass, hair loss, sexual desire
gynecomastia, fatigue, difficulty concentrating, Adverse effect:
or vasomotor flushing. • Androgen therapy may

67
 cause hypercalcemia include increased
by stimulating bone hematocrit, altered
resorption in thyroid and liver
immobilized patients function tests, and
and those with breast elevated urine 17-
cancer. The drug ketosteroids (a by-
should be discontinued product of the
and appropriate breakdown of
measures instituted if androgens). Rare
signs of hypercalcemia complications of long-
occur; signs include term therapy include
nausea and vomiting, hepatic necrosis,
lethargy, decreased hepatic peliosis
muscle tone, polyuria, (blood-filled cysts),
and increased urine hepatic tumors, and
and serum calcium. leukopenia.

• Virilization refers to Contraindications:

the development of • Androgen therapy is
male secondary sex contraindicated during
characteristics in pregnancy and in
women or individuals with
hypogonadal males. nephrosis or those in
the nephrotic phase of
• Less frequent adverse nephritis; it is also
effects include contraindicated in
dizziness, weakness, patients with
changes in skin color, hypercalcemia,
frequent headaches, pituitary insufficiency,
confusion, respiratory hepatic dysfunction,
distress, depression, benign prostatic
pruritus, allergic skin hyperplasia (BPH),
rash, edema of the prostate cancer, or
lower extremities, history of myocardial
jaundice, bleeding, infarction. Men with
paresthesias, chills, breast cancer are not
polycythemia, muscle treated with
cramps, and sodium androgens, nor are
and water retention women whose breast
• Serum cholesterol may cancer is not estrogen
become elevated dependent.
during androgen • Caution must be
therapy. Other exercised when using
alterations in androgen therapy in
laboratory tests individuals with
68
 hypertension, GONADOTROPIN-REALISING hormone
hypercholesterolemia, (GnRH) or a synthetic analogue such as
coronary artery leuprolide, most effective inhibitor of
disease, renal disease, testosterone synthesis.
or seizure disorder. Ketoconazole an anti fungal drug, has
testosterone-suppressing effects similar to
Drug interactions: those of GnRH analogues.
• Androgens potentiate Flutamide is an oral nonsteroidal
the effects of oral antiandrogen drug used as an anti-hormonal
anticoagulants, agent in the treatment of metastatic prostate
necessitating a cancer.
decrease in
Finasteride a synthetic compound inhibits
anticoagulant dosage.
conversion of testosterone to DHT.
Androgens antagonize
calcitonin and
parathyroid hormones
ANTIANDROGENS
• Concurrent use of
corticosteroids GOSERELIN
Inhibits gonadotropin
exacerbates the edema ACETATE
release, suppressing
that can occur with LEUPROLIDE
levels of testosterone
androgen therapy. ACETATE
Barbiturates, Inhibits testosterone
KETOCONAZOLE
phenytoin, and synthesis
phenylbutazone Blocks conversion of
decrease the effects of FINASTERIDE testosterone to
androgens. dihydotestosterone
FLUTAMIDE Androgen receptor
BICALITAMIDE inhibitors
Anabolic steroids
• anabolic steroids, or anabolic- androgenic
Drugs for Treating Penile Erectile
steroids (aass), are a class of steroid
Dysfunction
hormones related to the hormone
testerones.
Sexual Dysfunction
• it has androgenic and virilizing properties
Sexual dysfunction is the inability to
• two steroids that have gained popularity are
experience sexual desire, erection, ejaculation,
human chorionic gonadotropin (hcg) and
and/or detumescence.
tetrahydrogestrinone (thg)
 Androgen deficiency
 Affective disorders
ANTIANDROGENS  Discord in the sexual relationship
 Certain drugs
Antiandrogens or androgen antagonist block
the synthesis or action of androgens. Ejaculatory dysfunction
Impaired ejection of seminal fluid from the
male urethra, can be psychogenic or a result of
69
drug therapy, androgen deficiency, or
sympathetic degeneration. CONTRAINDICATIONS

Erectile dysfunction o Nitroglycerin and other nitrate drugs

Is the inability to achieve or maintain an o Patients with significant
erection satisfactory for sexual performance. cardiovascular
ED happens when not enough blood flows to o Individuals who have anatomic
the penis during sexual stimulation. deformities
 Papaverine FACTS
 Phentolamine  Grapefruit
 prostaglandin E  Amyl nitrate
 nitroglycerin.  Cantharides

A class of drugs called phosphodiesterase Complementary and Alternative Medicine

inhibitors facilitate erection by enhancing
blood flow to the penis. To self-treat sexual problems or to enhance
sexual performance, consumers use a wide
PDE-5 inhibitors currently approved by the variety of herbs and plant-derived compounds
FDA
 Sildenafil  Pausinystalia yohimbine
 Tadalafil  Muira puama
 Vardenafil  Panax quinquefolius
 Avanafil  Lepidium meyenii
 Ginkgo biloba
Phosphodiesterase-5 Inhibitors for Erectile  Mandia whitei
Dysfunction  Saw palmetto
 Tribulus terrestris

70
 PHARMACOLOGY
DRUGS AFFECTING BLOOD PRESSURE (ANTIHYPERTENSIVES)
HYPERTENSION – the most common
condition leading to myocardial infarction
(MI), stroke, renal failure and death
ESSENTIAL HYPERTENSION – The most
common type of hypertension and affects 95%
of persons with high BP. Contributing factors
may include hyperlipidemia, African American
race, diabetes, aging, stress, excessive alcohol
ingestion, smoking, obesity, and family history
of hypertension
SECONDARY HYPERTENSION - 30% of
hypertension cases are attributable to obesity.
5% of hypertension cases are related to renal
and endocrine disorders.
PHYSIOLOGIC RISK FACTORS
 Diet in high saturated fat and simple
carbohydrates
 Carbohydrates intake can sympathetic
nervous activity.
 Alcohol increases renin secretion,
causing the production of angiotensin II
 Obesity
 Normal weight loss can decrease
hypertension, but mild to moderate
sodium restriction
INITIAL DRUG - First prescribed for
hypertension.
6 CATEGORIES OF
ANTIHYPERTENSIVE DRUGS
 Diuretics
 Sympatholytic (Sympathetic
depressants)
 Direct-acting arteriolar vasodilators
 ACE inhibitors
 Angiotensin II-receptor blockers
(ARB’s)
 Direct renin inhibitors
 Calcium channel blockers
DIURETICS
 Promote sodium depletion, which
decreases extracellular fluid volume
(ECFV).
 First line drug for treating mild
hypertension
HYDROCHLOROTHIAZIDE
 Most frequently prescribed diuretic for
controlling mild hypertension by
decreasing excess fluid volume.
 Can be used alone for recently
diagnosed mild hypertension or can be
used with antihypertensive drugs.
THIAZIDE DIURETICS
 Not recommended for patient with renal
insufficiency (creatinine clearance <30
mL/min)
 Single thiazide drug, a combination of
potassium wasting and potassium-
sparing diuretics may be useful; less
potassium excretion would occur.
 Can combined to antihypertensive drug
to increase their effectiveness
LOOP DIURETICS (high ceiling)
 Furosemide, recommended because
they do not depress renal blood flow.
 Not used in if hypertension is the result
of RAAS involvement because they
tend to immediately elevate serum renin
level.
SYMPATHOLYTICS (sympathetic
depressants)
 Beta adrenergic blockers
 Centrally acting alpha 2 agonist
 Alpha-adrenergic blockers
71
  Adrenergic neuron blockers constipation/diarrhea,
(peripherally acting sympatholytic) dyspnea, visual
 alpha 1−¿∧beta blockers¿
impairment
1−adrenergic

BETA ADRENERGIC BLOCKERS ATENOLOL Uses: hypertension,

CARDIOSELEC angina, prophylaxis,
 Called beta blockers
TIVE BETA 1 treatment of AMI
 Used as antihypertensive drugs or in SE: hypotension, heart
combination with diuretics. failure, bradycardia,
 Used in antianginals and fatigue, dizziness, nausea,
antidysrhythmics diarrhea, cool extremities,
 Beta (β+ and β-) adrenergic blockers edema
reduce cardiac output by diminishing BETAXOLOL Uses: hyperternsion,
the sympathetic nervous system HYDROCHLORI glaucoma
response to decrease basal sympathetic DE SE: headache, dizziness,
tone. With continued use, vascular CARDIOSELEC bradycardia, fatigue,
TIVE BETA1 insomnia, arthralgia,
resistance is diminished, and renin
nausea, chest pain
release
BISOPROLOL Uses: hypertension
 More effective in lowering BP in FUMARATE SE: dizziness, headache,
patients who have elevated serum renin BETA1 fatigue, bradycardia,
level. BLOCKER peripheral edema,
NONSELECTIVE BETA BLOCKERS orthostatic hypotension,
 Ex. Propranolol and carvedilol, inhibit diarrhea, arthralgia
beta1 (heart) and beta2 (bronchial) CARVEDILOL Uses: hypertension, AMI,
receptor ALPHA heart failure
 Heart rate slows, BP decreases BREAKER, SE: dizziness,
secondary to the decreases in heart rate, NONSELECTIV drowsiness, weakness,
E Β1 AND Β2 orthostatic hypotension,
and bronchoconstriction occurs because
headache, weight gain,
of unopposed parasympathetic tone. diarrhea, bradycardia,
CARDIOSELECTIVE BETA BLOCKERS fatigue, dyspnea,
 They act mainly as beta1- rather than peripheral edema,
the beta2- receptors, and hyperglycemia
bronchoconstriction is less likely occur. METROPROLO Uses: hypertension, acute
 Ex. Acebutolol, atenolol, betaxolol, L myocardial infarction,
bisoprolol and metoprolol. CARDIOSELEC angina, HF
 Partially effective TIVE Β1 SE: bradycardia,
DRUG Uses and consider. hypotension, stroke,
thrombocytopenia,
ACEBUTOLOL Uses: Hypertension and
diabetes mellitus
HYDROCHLORI dysrhythmias
DE SE: dizziness, NADOLOL Uses: hypertension and
CARDIOSELEC headache,fatigue, NONSELECTIV angina
TIVE BETA1 hypotension, bradycardia, E Β1 & Β2 SE: dizziness,
nausea, drowsiness, fatigue,
bradycardia, hypotension,
72
 palpitations, cold provides a 7-day bradycardia, orthostatic
extremities, erectile duration of action. hypotension, pruritus
dysfunction
PINDOLOL Uses: hypertension GUANFACINE Uses: hypertension
NONSELECTIV SE: dizziness, fatigue, HYDROCHLORI SE: drowsiness, dry
E Β1 &Β2 visual impairment, DE mouth, headache,
myalgia, edema, dizziness, fatigue,
bradycardia, dyspnea, Similar effects to weakness, anorexia,
hypotension, weakness clonidine. abdominal pain,
PROPRANOLOL Uses: hypertension, AMI, constipation, diarrhea,
NONSELECTIV angina, HF, has long half-life erectile dysfunction,
E Β1 & Β2 dysrhythmias, migraine and usually is taken orthostatic hypotension,
prophylaxis once a day bradycardia
SE: dizziness, visual
impairment, fatigue, METHYLDOPA Uses: hypertension,
bradycardia, cool hypertensive urgency,
extremities, erectile first drug widely emergency
dysfunction, used to control SE: orthostatic
hyperkalemia, seizures, hypertension. hypotension, drowsiness,
agitation in high dose, bradycardia, depression,
methyldopa and dizziness, angina,
clonidine can cause peripheral edema,
CENTRALLY ACTING ALPHA2 sodium and water erectile dysfunction,
AGONIST retention constipation
 Decrease the sympathetic response methyldopa and
from the brainstem to the peripheral clonidine are
vessels. They stimulate the alpha 2 administered with
receptor, which in turn decreases diuretics
sympathetic activity; increases vagus
activity; decreases cardiac output; and
decreases serum epinephrine, ALPHA-ADRENERGIC BLOCKERS
norepinephrine, and renin release.  Alpha blockers resulting in vasodilation
 Has minimal effect on cardiac output and decreases BP.
and blood flow to the kidney.  They help maintain the renal blood
 Ex. Methyldopa, clonidine and flow.
guanfacine.  Useful in treating hypertension in
DRUG Uses and SE patients with lipid abnormalities. They
CLONIDINE Uses: hypertension decrease the VLDL and LDL
HYDROCHLORI SE: fatigue, responsible for the build-up of fatty
DE drowsiness,dizziness, plaques in the arteries (atherosclerosis)
confusion, edema, dry and they also increase HDL levels
Available in mouth, anxiety, nausea,  Safe for patients with diabetes because
transdermal vomiting, constipation, they do not affect glucose metabolism.
preparation that abdominal pain,

73
  Can cause sodium and water retention palpitations, tachycardia,
with edema; therefore diuretics are pancreatitis, elevated
frequently given concomitantly to liver enzymes
decrease fluid accumulation in the TERAZOSIN Uses: hypertension,
extremities. HYDROCHLORI BPH
NONSELECTIVE ALPHA ADRENERGIC DE SE: dizziness,
drowsiness, nasal
BLOCKERS
congestion, headache,
 Should not be given to patients with weakness, nausea,
coronary heart disease because of their orthostatic hypotension,
stimulating effects and resultant palpations, peripheral
increase in myocardial oxygen demand edema, erectile
 Ex. Phenoxybenzamine and dysfunction
phentolamine SELECTIVE ALPHA-ADRENERGIC
SELECTIVE ALPHA ADRENERGIC BLOCKERS
BLOCKERS PHENOXYBENZ Uses: hypertension
 Used mainly to reduce BP and can be AMINE associated with
used to treat benign prostatic HYDROCHLORI pheochromocytoma
DE SE: dizziness,
hypertrophy (BPH).
drowsiness, fatigue,
 Ex. Prazosin, terazosin, doxazosin orthostatic hypotension,
PRAZOSIN tachycardia, weakness,
 Commonly prescribed drug gastritis, ejaculatory
 When taken with alcohol or other dysfunction, nasal
antihypertensive drug, the hypotensive congestion
state can be intensified. PHENTOLAMINE Uses: hypertension
TERAZOSIN AND DOXAZOSIN before and after
 Have longer half-lives than prazosin pheochromocytomectom
and they are normally given at bedtime. y, pheochromocytoma
diagnosis, prevention
DRUG Uses and SE
and treatment of IV drug
NONSELECTIVE ALPHA-ADRENERGIC extravasation
BLOCKERS SE: dental pain,
DOXAZOSIN Uses: hypertension and tachycardia, headache,
MESYLATE BPH vomiting, diarrhea,
SE: orthostatic abdominal pain,
hypotension, headache, paresthesias
dizziness, fatigue,
edema, weakness,
ADRENERGIC NEURON BLOCKERS
palpitations, visual
impairment, erectile (peripherally acting sympatholytic)
dysfunction  Potent antihypertensive drugs that block
PRAZOSIN Uses: hypertension norepinephrine release from the
HYDROCHLORI SE: orthostatic sympathetic nerve endings, causing
DE hypotension,

74
 decrease in norepinephrine release that
results in lowering BP.
 A decrease occurs in both cardiac
output and peripheral vascular
resistance.
 Considered as last choices for treatment
of chronic hypertension because these
drugs can cause orthostatic
hypotension.
 Can cause sodium and water retention
and can be taken alone or with a
diuretic to decrease peripheral edema.
RESERPINE
 Most potent drug, used to control severe
hypertension.
 Orthostatic hypotension, common side
effect, the patient is advised to rise
slowly from reclining or sitting
position.
 Cause vivid dreams, nightmares, and
suicidal ideation
DRUG Uses and SE
RESERPINE Uses: hypertension
SE: dizziness, drowsiness,
depression, dyspnea,
hearing loss, hypotension,
bradycardia,
erectile/ejaculatory
dysfunction,
pseudoparkinsonism
ALPHA1−¿∧BETA 1−¿ ADRENERGIC BLOCKERS ¿
 Both have the alpha1 and beta1
receptor.
 Labetalol, example of alpha/beta
blocker
 Blocking the alpha1 receptor causes
vasodilation, which decreases resistance
blood flow.
 The effect of alpha receptor is stronger
than the effect on the beta receptor;
therefore BP is lowered, and pulse rate
is moderately decreased.
 By blocking the cardiac beta1 receptor,
both heart rate and AV contractility are
decreased.
 Large dose of alpha/beta blockers could
block beta2-adrenergic receptors, thus
increasing airway resistance.
 Large dose of labetalol can cause
atrioventicular (AV) heat block.
 Common side effects: orthostatic
hypotension, GI disturbances,
nervousness, dry mouth, and fatigue.
DRUG Uses and SE
LABETALO Uses: hypertension,
L hypertensive emergency,
preeclampsia, eclampsia
SE: orthostatic hypotension,
dizziness, hyperhidrosis,
erectile/ejaculatory
dysfunction, fatigue, nasal
congestion, paresthesia,
nausea, depression
DIRECT-ACTING ARTERIOLAR
VASODILATORS
 Act by relaxing the smooth muscles of
blood vessels, mainly the arteries,
causing vasodilation.
 Promote an increase in blood flow to
the brain and kidney.
¿  With vasodilation, the BP decreases and
sodium and water are retained, resulting
in peripheral edema.
 Diuretics can be given with direct-
acting vasodilator to decrease the
edema.
HYDRALAZINE AND MINOXIDIL
 Used for moderate to severe (dose-
related) hypertension
 Cause little orthostatic hypotension
because of minimum dilation of the
75
 arterioles. However, reflex tachycardia acts on both headache, palpitations
and release of renin can occur arterial and
secondary to vasodilation and decrease venous vessel.
BP.
Hydralazine side effects ANGIOTENSIN-CONVERTING ENZYME
 numerous and include reflex INHIBITORS (ACE)
tachycardia  ACE is inhibited, it in turns inhibits the
 palpitations formation of angiotensin II
 edema (vasoconstrictor) and blocks the release
 nasal congestion of aldosterone. When aldosterone is
block, sodium is excreted along with
 headache
water, and potassium is retained.
 dizziness
 ACE inhibitors can cause little change
 GI bleeding
in cardiac output or heart rate and lower
 lupus-like symptoms
peripheral resistance.
 neurologic symptoms (tingling,
 Used primarily to treat hypertension;
numbness)
also effective in treating heart failure
 Ex. Benazepril, captopril, quinapril,
DRUGS Uses and SE
ramipril, and trandolapril. These drugs
HYDRALAZIN Uses: hypertension,
are used for first-line antihypertensive
E hypertensive urgency and
HYDROCHLOR emergency, preeclampsia, therapy, but thiazide diuretics are
IDE eclampsia recommended by JNC 8.
SE: headache, anorexia,  African American and older adults do
nausea, vomiting, not respond to ACE inhibitors with
diarrhea, tachycardia, desired reduction in BP, but when taken
hypotension, angina, with diuretics, BP will usually be
palpitations lowered.
MINOXIDIL Uses: hypertension and  ACE inhibitors should not be given
alopecia during pregnancy because they reduce
SE: headache,
placental blood flow.
hypotension, tachycardia,
angina, peripheral edema,  For patients with renal insufficiency,
erythema, pericardial reduction of the drug dose.
effusion, excess hair  ACE inhibitors can be administered
growth, precipitate angina with food but except for moexipril,
attack which should be taken on an empty
NITROPRUSSI Uses: hypertensive stomach for maximum effectiveness.
DE urgency and emergency, Side effects
very potent HF  Constant, irritated cough (ACE cough,
vasodilator that SE: confusion, may be relieved upon discontinuance of
rapidly decreases hypotension, bradycardia, drug)
bp tachycardia, restlessness,
 Nausea
flushing, dizziness,
76
  Vomiting LISINOPRIL Uses: hypertension, AMI,
 Diarrhea HF
 Headache SE: orthostatic
hypotension, blurred
 Dizziness
vision, weakness, ,
 Fatigue dizziness, headache,
 Insomnia syncope, cough,
 Serum potassium excess(hyperkalemia) hyperkalemia
 Tachycardia MOEXIPRIL Uses: hypertension
DRUG USES AND SE SE: serum lithium levels
ACE INHIBITORS causing toxicity.
BENAZEPRIL Uses: hypertension Dizziness, diarrhea,
HYDROCHLOR SE: headache, dizziness, fatigue, chest pain,
IDE hypotension, fatigue, palpitations, constipation,
palpitations, peripheral cough, hyperkalemia,
edema, erectile hyponatremia, flushing,
dysfunction, rash, orthostatic
hyperkalemia, nausea, hypotension
constipation, flushing, PERINDOPRIL Uses: hypertension and to
angina ERBUMINE prevent MI
CAPTOPRIL Uses: hypertension, post SE: dizziness, cough,
MI, diabetic neuropathy, headache, weakness, back
HF pain, elevated hepatic
SE: cough, , dizziness, enzymes, orthostatic
hypotension, tachycardia, hypotension,
syncope, anorexia, hyperkalemia
constipation, dyspnea, QUINAPRIL Uses: hypertension, HF
hyperkalemia, HYDROCHLOR SE: dizziness, cough,
hyponatremia, rash, IDE headache, orthostatic
fatigue hypotension, tachycardia,
ENALAPRIL Uses: hypertension, HF hyperkalemia, nausea,
MALEATE SE: orthostatic vomiting, chest pain,
hypotension, dizziness, dyspnea, edema
headache, weakness, RAMIPRIL Uses: hypertension, AMI,
syncope, cough, anorexia, HF, prevention of stroke
hyperkalemia, SE: dizziness, cough,
hyponatremia, rash, headache, orthostatic
tachycardia, palpitations hypotension, palpitations,
FOSINOPRIL Uses: hypertension, HF angina, syncope,
SE: dizziness, cough, weakness, nausea,
headache, weakness, vomiting, hyperkalemia
peripheral edema, rash, TRANDOLAPRI Uses: hypertension, AMI,
hyperkalemia, L HF
palpitations, flushing, SE: dizziness, cough,
orthostatic hypotension syncope, dyspepsia,
77
 bradycardia, hypotension,  ARBs may be used as first-line
hyperkalemia, treatment for hypertension
hypocalcemia, myalgia,  Ex. Losartan, valsartan, irbesartan,
weakness, hyperuricemia candesartan, eprosartan, olmesartan,
COMBINATION OF ACE INHIBITORS azilsartan and telmisartan.
WITH CALCIUM BLOCKERS
 Can be taken with or without food and
BENAZEPRIL Uses: hypertension
are suitable for patients with mild
WITH SE: headache,
AMLODIPINE hypotension, dizziness, hepatic insufficiency.
peripheral edema, Side effects: angioedema
hyperkalemia, cough DRUGS Uses and SE
TRANDOLAPRI Uses: hypertension CANDESARTAN Uses: hypertension,
L AND SE: dizziness, headache, HF
VERAPAMIL blurred vision, cough, SE: dizziness,
hypotension, bradycardia, hypotension,
chest pain, hyperkalemia, hyperkalemia, back
fatigue, constipation, pain,
arthgalgia, edema hyperbilirubinemia,
PERINDOPRIL Uses: hypertension rhinitis,
ARGININE SE: dizziness, cough, pharyngitis,
AND headache, peripheral elevated hepatic
AMLODIPINE edema, tachycardia, enzyme, infection
BESYLATE bradycardia, hypotension, EPROSARTAN Uses: hypertension
chest pain, depression, SE: cough, fatigue,
dyspnea, visual rhinitis,
impairment, constipation, pharyngitis,
hyperkalemia sinusitis,
abdominal pain,
ANGIOTENSIN-II RECEPTOR constipation,
BLOCKERS (ARBs) orthostatic
hypotension
 Similar to ACE inhibitors they prevent
IRBESARTAN Uses: hypertension,
the release of aldosterone, a sodium-
diabetic
retaining hormone. neuropathy,
 They act as RAAS proteinuria
 ARBs block angiotensin II from the SE: dizziness,
angiotensin I (AT1) receptors found in cough, fatigue,
many tissues. orthostatic
 ARB cause vasodilation and decrease hypotension,
peripheral resistance. edema, rhinitis,
pharyngitis,
 ARBs should not be taken during
abdominal pain,
pregnancy and unlike ACE, ARBs do
dyspepsia, pyrosis,
not cause constant, irritated cough diarrhea
LOSARTAN Uses: hypertension,
78
POTASSIUM diabetic cramps, nausea,
neuropathy, diarrhea
proteinuria, prevent NEBIVOLOLVALSA Uses: hypertension
stroke RTAN SE: dizziness,
SE: dizziness, drowsiness,
cough, headache, hypotension,
orthostatic hyperkalemia,
hypotension, syncope, vomiting,
weakness, edema, rash, pruritus,
nasal congestion, erectile dysfunction
pharyngitis, nausea,
infection DRUG Uses and SE
OLMESARTAN Uses: hypertension EPLERENON Uses: hypertension, HF,
MEDOXOMIL SE: dizziness, E AMI
headache, SE: dizziness,
orthostatic bradycardia, fatigue,
hypotension, hyponatremia,
peripheral edema, hypertriglyceridemia,
hypercalcemia, hypercholesterolemia,
sinusitis, diarrhea, cough,
pharyngitis, rhinits hyperkalemia,
TELMISARTAN Uses: hypertension, hyperuricemia, edema
prevent MI and
CVA
DIRECT RENIN INHIBITORS
SE: chest pain,
orthostatic ALISKIREN
hypotension,  Treats hypertension, which binds with
sinusitis, dizziness, renin and causes a reduction of
back pain, edema, angiotensin I, angiotensin II, and
cough, aldosterone levels.
hyperkalemia,  Effective for mild and moderate
diarrhea, infection hypertension
VALSARTAN Uses: hypertension,  Can be used alone or with another
heart failure antihypertensive agent
SE: orthostatic
 When used as monotheraphy, has not
hypotension,
hyperkalemia, proven to be as effective in reducing BP
rhabdomyolysis, in African American population.
elevated hepatic DRUG Uses and SE
enzymes ALISKERI Uses: hypertension
AZILSARTAN Uses: hypertension N SE: hypotension,
SE: orthostatic hyperkalemia, peripheral
hypotension. edema, diarrhea,
Dizziness, fatigue, hyperuricemia, gout,
cough, muscle pharyngitis, cough
79
  Flushing
CALCIUM CHANNEL BLOCKERS  Headache
 Found in myocardium (heart muscle)  Dizziness
and vascular smooth muscle (VSM)  Ankle edema
cells.  Bradycardia
 Also known as Calcium antagonist and  AV block
calcium blockers, which block the DRUGS Uses and SE
calcium channel in VSM, promoting PHENYLALKYLAMINE
vasodilation. VERAPAMIL Uses: hypertension,
 Highly protein bound but have a short angina, dysrthymia
half-life SE: dizziness, headache,
3 GROUPS OF CALCIUM BLOCKERS confusion, fatigue,
DIPHENYLALKYLAMINE orthostatic hypotension,
VERAPAMIL blurred vision, peripheral
 Used to treat chronic hypertension, edema, erectile
dysfunction, nausea,
angina pectoris, and cardiac
constipation
dysrhythmias
BENZOTHIAZEPINE
 Act on the arterioles and the heart DILTIAZEM Uses: hypertension,
BENZOTHIAZEPINE HYDROCHLOR angina, dysrthymia
DILTIAZEM IDE SE: dizziness, headache,
 Act on the arterioles and the heart peripheral edema,
DIHYDROPYRIDINES – largest group of dyspepsia, bradycardia,
calcium channel blockers; most of these are hypotension, weakness,
used to control hypertension. dyspnea, pharyngitis,
NIFEDIPINE rhinitis, infection, fatigue
 Decrease BP in older adults and in DIHYDROPYRIDINES
those with low serum renin values. AMLODIPINE Uses: hypertension, heart
failure
 Nifedipine and verapamil are potent
SE: orthostatic
calcium blockers hypotension,
 In its immediate-release form (10- and bradycardia, chest pain,
20-mg capsules), has been associated tachycardia, palpitations,
with an increased incidence of profound pulmonary edema,
hypotension, MI, and death, especially dyspnea, hyperglycemia
in older adults; therefore only extended- FELODIPINE Uses: hypertension
release preparations of nifedipine are SE: dizziness, headache,
recommended for chronic hypertension. peripheral edema,
 Immediate-release nifedipine is usually palpitations, weakness,
prescribed for acute rises in BP only an hypotension, rash, cough
ISRADIPINE Uses: hypertension
as-needed basis in the hospital setting.
SE: dizziness, headache,
Side effect
palpitations, flushing,
 Reflex tachycardia fatigue, hypotension,
80
 angina, tachycardia,
abdominal pain,
peripheral edema
NICARDIPINE Uses: hypertension,
HYDROCHLOR angina
IDE SE: dizziness, headache,
palpitations, weakness,
flushing, orthostatic
hypotension, angina,
tachycardia, peripheral
edema, nausea, vomiting
NIFEDIPINE Uses: hypertension,
angina
SE: : dizziness,
headache, palpitations,
weakness, flushing, Four chambers of the heart
peripheral edema, Right atrium Receives
nausea, pyrosis, tremor, deoxygenated blood
hypotension, muscle from the circulation
cramps, nasal Right ventricle Pumps blood through
congestion, cough, the pulmonary artery
dyspnea, fatigue to the lungs
NISOLDIPINE Uses: hypertension Left atrium Receives oxygenated
SE: pharyngitis, blood
sinusitis, dizziness, Left ventricle Pumps the blood into
headache, palpitations, the aorta for systemic
flushing, orthostatic circulation
hypotension, 4 valves
tachycardia, peripheral Tricuspid and Pulmonic and aortic
edema, visual mitral (2 (2 semilunar)
impairment, atrioventricular)
hypokalemia
Myocardium Heart muscle,
THERAPY FOR HEART FAILURE surrounds the
ventricles and atria
Pericardium Heart fibrous
covering, which
protect it from injury
and infection
Endocardium Three-layered
membrane that lines
the inner part of heart
chamber
2 coronary arteries

81
 Right coronary artery Left coronary artery
CONDUCTION OF ELECTRICAL
IMPULSES
The myocardium can generate and conduct its
own electrical impulses. The cardiac impulse
normally located in the originates in the
sinoatrial (SA) node posterior wall of the right
atrium. The SA node is frequently called the
pacemaker because it regulates the heartbeat
(firing of cardiac impulses), which is
approximately 60 to 80 beats/min in the normal
adult.
The atrioventricular (AV) node, located in the
right side of the interatrial septum, has a
continuous posterior tract of fibers called the
bundle of His, or the AV bundle. The AV
node has an adult rate of 40 to 60 beats/min. If
the SA node fails, the AV node takes over as
the pacemaker, thus causing a slower heart
rate; the AV node sends AV impulses to the
ventricles. These two conducting systems, the
SA and nodes, can act independently of each
other. The ventricle can contract independently
30 to 40 times per minute.
Drugs that affect cardiac contraction include
calcium, digitalis preparations, and quinidine
and its related preparations. The autonomic
nervous system (ANS) and drugs that stimulate
or inhibit it influence heart contraction system
and drugs that stimulate it decrease heart rate.
REGULATION OF HEART RATE AND
BLOOD FLOW
The heart beats approximately 60 to 80 times
per minute in an adult, pumping blood into the
systemic circulation. As blood travels,
resistance to blood flow develops, and arterial
pressure increases. The average systemic
arterial pressure, known as blood pressure,
is 120/80 mmHg. Arterial blood pressure is
determined by peripheral resistance and cardiac
output, which is the volume of blood expelled
from the heart in minute, calculated by
multiplying the heart rate by the stroke volume.
The average cardiac output is 4 to 8 L/min.
Stroke volume, the amount of blood ejected
from the left ventricle with each heartbeat, is
approximately 70 mL/beat.
Three factors--preload, contractility, and
afterload-determine the stroke volume. Preload
refers to the blood flow force that stretches the
ventricle at the end of diastole. However, an
increase in preload can increase stroke volume,
and a decrease in preload can decrease stroke
volume. Contractility is the force of
ventricular contraction, and afterload is the
resistance to ventricular ejection of blood,
which is caused by opposing pressures in the
aorta and systemic circulation. If afterload
increases, stroke volume will decrease, and if
afterload decreases, stroke volume will
increase. Specific drugs can increase or
decrease preload and afterload, affecting both
stroke volume and cardiac output. Most
vasodilators decrease preload and afterload,
thus decreasing arterial pressure and cardiac
output.
CIRCULATION
There are two types of circulation,
Pulmonary circulation, the heart pumps
deoxygenated blood from the right ventricle
through the pulmonary artery to the lungs. The
pulmonary artery carries blood that has a high
concentration of carbon dioxide. Oxygenated
blood returns to the left atrium by the
pulmonary vein.
Systemic circulation, also called peripheral
circulation, the heart pumps blood from the
82
left ventricle to the aorta and into the general
circulation. Arteries and arterioles carry the
blood to capillary beds. Nutrients in the
capillary blood are transferred to cells in
exchange for waste products, Blood returns to
the heart through venules and veins.
Blood
 Composed of plasma, red blood cells
(RBC; erythrocytes), white blood cells
(WBC; leukocytes) and platelets.
Function:
 Provide nutrients including oxygen to
the body.
 Most of oxygen is carried on the
hemoglobin of RBS
RBC
 Life span: 120 days
WBC
 Major defense mechanism of the body
and act by engulfing microorganisms.
 Produce antibodies
 Life span : 2 to 24 hours
Platelets
 Large cells that cause blood to
coagulate
LABORATORY TEST TO DIAGNOSE
HEARY FAILURE
Atrial Natriuretic Hormone or Peptide
Reference values: 20 to 77 pg/mL; 20 to 77
ng/L (SI units)
AGENTS USED TO TREAT HEART
FAILURE
Cardiac Glycosides
 Digitalis use began as early as CE 1200,
making it one of the oldest drugs. It is
still used in a purified form.
 Digitalis is obtained from the purple
and white foxglove plant, and it can he
poisonous.
 Digitalis preparations have come to be
known for their effectiveness in treating
heart failure (HF), also known as
cardiac failure (CF), and previously
referred to as congestive heart failure
(CHF).
HEART FAILURE/PUMP
FAILURE/CHRONIC HEART FAILURE.
When the heart muscle (myocardium)
weakens and enlarges, it loses its ability to
pump blood through the heart and into the
systemic circulation.
ACUTE HEART FAILURE
When compensatory mechanisms fail and
the peripheral and lung tissues are
congested
The causes of HF include chronic
hypertension, MI, coronary artery disease
(CAD), valvular heart dis-ease, congenital
heart disease, and arteriosclerosis. HF can
be left-sided or right-sided. The patient has
left-sided HF when the left ventricle does
not contract sufficiently to pump the blood
returned from the lungs and left atrium out
through the aorta into the peripheral
circulation; this causes excessive amounts
of blood to back up into the lung tissue.
Usually the patient has shortness of breath
(SOB) and dyspnea.
Right-sided HF occurs when the heart
does not sufficiently pump the blood
returned into the right atrium from the
83
 systemic circulation. As a result, the blood
and its constituents are backed up into
peripheral tissues, causing peripheral
edema.
Left-sided HF may lead to right-sided HF
and vice versa. Myocardial hypertrophy
resulting in cardiomegaly, increased heart
size, can be a major problem associated
with chronic HF. In the cardiac physiology
of HF, an increase in preload and afterload
occurs. The increased preload results from
an excess of blood volume in the ventricle
at the end of diastole. This occurs because
of a pathologic increase in the stretching
and thickening of the ventricular walls,
which allows a greater filling pressure
associated with a weakened heart.
Increased afterload is an additional pressure
or force in the ventricular wall caused by
excess resistance in the aorta. This
resistance must be overcome to open the
aortic valve so blood can be ejected into the
circulation.
In the early stage of HP, there are no
symptoms, and no structural heart damage
occurs. Naturally occurring cardiac
glycosides are found in several plants,
including Digitalis.
DIGITALIS GLYCOSIDES
This group of drugs inhibits the sodium-
potassium pump, which results in an
increase in intracellular sodium. This
increase leads to an influx of iceanIcaium,
which causes the cardiac muscle fibers to
contract more.etfi c
Digitalis preparations have three effects on
heart muscle:
1. A positive inotropic action increases
myocardial contraction stroke volume
2. A (negative chronotropic action
decreases heart rate
3. A negative dromotropic action decreases
conduction of heart cells.
The increase in myocardial contractility
strengthens cardiac, peripheral, and kidney
function by enhancing cardiac output,
decreasing preload, improving blood flow
to the periphery and kidneys, decreasing
edema, and promoting fluid excretion. As a
result, fluid retention in the lungs and
extremities is decreased. Digoxin does not
prolong life; rather, it acts by increasing the
force and velocity of myocardial systolic
contraction. Digoxin is a secondary drug
for HF. First-line drugs used to treat acute
HF include intravenous (IV) inotropic
agents (dopamine and dobutamine) and
phosphodiesterase (PDE) inhibitors, such as
mil-rinone. Other drugs prescribed for HF
include oral diuretics, beta blockers,
angiotensin-converting enzyme (ACE)
inhibitors, angiotensin-receptor blockers
(ARBs), calcium channel blockers (CCBs),
and vasodilators, all of which are more
convenient to self-administer. Oral
administration allows the patient to go
home on these medications. Cardiac
glycosides are also used to correct atrial
fibrillation, cardiac dysrhythmia with rapid
uncoordinated contractions of atrial
myocardium, and atrial flutter, cardiac
dysrhythmia with rapid contractions of 200
to 300 beats/min. This is accomplished by
the negative chronotropic effects
(decreased heart rate) and negative
dromotropic effects talis (decreased
conduction through the atrioventricular
(AV) node).
84

Digitalis (Digoxin) Toxicity
Overdose or accumulation of digoxin
causes digitalis toxicity. Signs and
symptoms include anorexia, diarrhea,
nausea and vomiting, bradycardia (pulse
rate below 60 beats/min), premature
ventricular con-tractions, cardiac
dysrhythmias, headaches, malaise, blurred
vision, *Jai illusions (white, green, or
yellow halos around objects), confusion,
and delirium. Older adults are more prone
to toxicity.
Cardiotoxicity is a serious adverse reaction
to digoxin, and ventricular dysrhythmias
result. '
Three cardiac-altered functions can con-
tribute to digoxin-induced ventricular
dysrhythmias:
1. Suppression of AV conduction
2. Increased automaticity
3. a decreased refractory period in
ventricular muscle.
The antidysrhythmics phenytoin and
lidocaine are effective in treating digoxin-
induced ventricular dysrhythmias.
Lidocaine should be limited to short-term
treatment.
ANTIDOTE FOR
CARDIAC/DIGITALIS GLYCOSIDES
Digoxin- immune Fab may be given to treat
severe digitalis toxicity. This agent binds
with digoxin to form complex molecules
that can be excreted in the urine; thus
digoxin is unable to bind at the cellular site
of action. Serum digoxin levels should be
closely monitored, and signs and symptoms
of digoxin toxicity should be reported
promptly to the health care provider.
Digitalis toxicity may result in first-degree,
second-degree. Or complete heart block.
PHOSPHODIESTERASE INHIBITORS
PDE inhibitors are another positive
inotropic group of drugs given to treat acute
HE. This drug group inhibits the enzyme
PDE, which promotes a positive inotropic
response and vasodilation. A drug in this
group is milrinone lactate. This drug
increases stroke volume and cardiac output
and promotes vasodilation. It is
administered intravenously for no longer
than 48 to 72 hours. Severe cardiac
dysrhythmias might result from the use of
PDE inhibitors, so the patient's
electrocardiogram (ECG) and cardiac status
should be closely monitored. Milrinone is a
high-alert medication that may cause
significant harm to a patient when given
inappropriately.
Other Agents Used to Treat Heart
Failure
Vasodilators can he used to treat HF. The
vasodilators decrease r take venous blood
return to the heart and result in a decrease
in cardiac nary filling, ventricular
stretching (preload), and oxygen demand
on the heart. Arteriolar dilators act in three
ways: they (1) reduce cardiac afterload,
which increases cardiac output; (2) dilate
the arterioles of the kidneys, which
improves renal perfusion and increases
fluid loss; and (3) improve circulation to-
the skeletal muscles.
ACE inhibitors are usually prescribed for
HE ACE inhibitors dilate venules and
arterioles, which improves renal blood flow
85
and decreases blood fluid volume. ACE
inhibitors also moderately decrease the
release and of aldosterone, which in turn
reduces sodium and fluid retention. ACE
inhibitors can increase potassium levels, so
serum potassium levels should be
monitored, especially if potassium-sparing
diuretics such as spironolactone are being
taken concurrently. Angiotensin II-receptor
blockers (ARBs) such as valsartan and
candesartan have been to a approved for HF
in patients who cannot tolerate ACE
inhibitors.
Diuretics are the first-line drug treatment
for reducing fluid volume. They are
frequently prescribed with digoxin or other
agents.
Spironolactone, a potassium-sparing
diuretic, is used in treating moderate to
severe HF. Aldosterone secretions are
increased in HF. This promotes body loss
of potassium and magnesium needed by the
heart and increases sodium and water
retention. Spironolactone blocks the
production of aldosterone. This drug
Improves heart rate variability and
decreases myocardial fibrosis by its
cardioprotective effect of emerge blocking
aldosterone in the heart and blood vessels
to promote cardiac remodeling. The
recommended dose for HP is 12.5 to 25
mg/day. Occurrence of hyperkalemia
(excess serum potassium) is rare unless the
patient is receiving 50 mg/day and has renal
insufficiency. However, the serum
potassium level should be closely
monitored. In the past, all beta blockers
were contraindicated for patients with HF
because this drug class reduces cardiac
contractility. With dosage control, beta
blockers (carvedilol, metoprolol, and
bisoprolol) have been shown to improve
cardiac performance. Doses should be low
initially and gradually increased. It may
take 1 to 3 months for a beneficial effect to
develop.
Nesiritide is an atrial natriuretic peptide
hormone that inhibits antidiuretic hormone
(ADH) by increasing urine sodium loss. Its
effect in correcting HF is achieved by
promoting vasodilation, natriuresis, and
antidiuresis. It is useful for treating patients
who have acute decompensated HF with
dyspnea at rest or who have dyspnea with
little physical exertion.
ANTIANGINAL DRUGS
 Used to treat angina pectoris, a
condition of acute cardiac pain caused
inadequate blood flow to the
myocardium due to either plaque
occlusions within or spasms of the
coronary arteries. With decreased
blood flow, here is a decrease in oxygen
to the myocardium, which results pain.
Anginal Pain
 Frequently described by the patient as
tightness, pressure in the center of the
chest, and pain radiating down the left
arm.
 Last for only few minutes
TYPES OF ANGINA PECTORIS
 Classic (stable) angina – occurs with
predictable stress or exertion
 Unstable (preinfarction) angina –
occurs frequently with progressive
severity in related to activity and is
predictable regarding stress/exertion
and intensity
86
  Variant (prinzmetal, vasospastic) Defined as any deviation from the normal rate
angina or pattern of the heart beat
o occurs during test
Includes heart rates that are:
The first two types are caused by narrowing or  Too slow (bradycardia)
partial occlusion of the coronary arteries.  Too fast (tachycardia)
NONPHARMACOLOGIC MEASURES TO  Irregular
CONTROL ANGINA CARDIAC ACTION POTENTIALS
 Proper Nutrition Five phases:
 Adequate Rest Phase 0 – rapid depolarization
 Relaxation Techniques Phase 1 – initial repolarization
 Moderate exercise after consulting with Phase 2 – plateau
health care provider Phase 3 – rapid repolarization
Phase 4 – resting membrane potential between
AVOID: heartbeats
 Heavy Meals
 Smoking TYPES OF ANTIDYSRHYTHMIC DRUGS
 Extreme Weather Changes Class I Sodium channel blockers: IA, IB, IC
Class II Beta blockers
 Strenuous Exercise
Class III Potassium channel blockers
 Emotional Upset
Class IV Calcium channel blockers
TYPES OF ANTIANGINAL DRUGS
MECHANISMS OF ACTION
1. Nitrates
 Blocks adrenergic stimulation of the heart
➜ It is the first agents used to relieve
angina.  Depresses myocardial excitability and
2. Beta Blocker contractility
➜ Beta blockers are effective as  Decreases conduction velocity in cardiac
antianginals because by decreasing the tissue
heart rate and myocardial contractility  Increases recovery time of myocardium
they reduce the need for oxygen  Suppresses automaticity
consumption and consequently reduce
anginal pain. TYPES OF ANTIDYSRHYTHMIC DRUGS
3. CCBs
➜ CCBs relax coronary artery spasm TYPES ACTION
(variant angina) and relax peripheral CLASS I SODIUM Decreases sodium
arterioles (stable angina), decreasing CHANNEL influx into cardiac
cardiac oxygen demand. BLOCKERS cells
ANTIARRYTHMIC DRUGS CLASS II BETA Decrease conduction
BLOCKERS velocity,
automaticity, and
CARDIAC DYSRHYTHMIA
recovery time
(refractory period)
87
CLASS III Prolong dyspepsia, vomiting,
POTASSIUM repolarization during abdominal pain and
CHANNEL ventricular diarrhea
BLOCKERS dysrhythmias QUINIDINE Mode of action:
CLASS IV Prevents calcium SULFATE Its effects in fast
CALCIUM from entering the inward sodium
CHANNEL cells of the heart and current is known as a
BLOCKERS arteries “use-dependent
block”
CLASS IA: SODIUM CHANNEL Therapeutic use:
BLOCKERS For atrial,
DISOPYRAMIDE Mode of Action: ventricular, and
PHOSPHATE It inhibits the fast supraventricular
inward sodium dysrhythmias
current Adverse effect:
Headache, dizziness,
Therapeutic uses: fatigue, weakness,
For ventricular palpitations, fever,
tachycardia nausea, vomiting,
esophagitis, pyrosis,
Adverse effects: diarrhea, and rash
Dizziness, headache, CLASS IB: SODIUM CHANNEL
fatigue, blurred BLOCKERS
vision, dry mouth LIDOCAINE Mode of action:
and skin, urinary Lidocaine blocks
retention/urgency, cardiac sodium
nausea, flatulence, channels shortening
abdominal pain and the action potential
constipation Therapeutic use:
PROCAINAMIDE Mode of action: For ventricular
HYDROCHLORID Works by slowing dysrhythmias
E the nerve impulses in Adverse effects:
the heart and Erythema, pruritus,
reducing the edema, injection site
sensitivity of heart reaction, petechiae,
tissues. dizziness, nausea,
and vomiting
Therapeutic use: MEXILETINE Mode of action:
For ventricular HYDROCHLORID Inhibits the inward
tachycardia and E sodium current,
cardiopulmonary reducing the rate of
resuscitation rise of the action
potential
Adverse effect: Therapeutic use:
Anorexia, nausea, For ventricular
88
 dysrhythmias supraventricular
Adverse effects: dysrhythmias
Weakness, nausea, Adverse effects:
pyrosis, vomiting, Dizziness, fatigue,
diarrhea, tremor, headache, anxiety,
dizziness, headache, dyspnea, dysgeusia,
blurred vision, nausea, vomiting,
palpitations, chest constipation,
pain, and ataxia weakness, edema,
CLASS IC: SODIUM CHANNEL infection influenza,
BLOCKERS and blurred vision
FLECAINIDE Mode of action:
Blocks fast inward CLASS II: BETA BLOCKERS
sodium channels and ACEBUTOLOL Mode of action:
slowly unbinds HYDROCHLOR Acebutulol is a selective
during diastole, IDE (BETA1 β1- receptor
prolonging the BLOCKERS) anatagonist. Acebutulol
refractory period of blocks these β1
the heart receptors, lowering the
Therapeutic use: heart rate and blood
For atrial, pressure
ventricular, and Therapeutic use:
supraventricular Treatment of premature
dysrhythmias ventricular contractions,
Adverse effects: and hypertension
Dizziness, fatigue, Adverse effect:
headache, anxiety, Palpitations,
visual impairment, bradycardia,
tremor, dyspnea, hypo/hypertension,
dysrhythmia tachycardia, chest pain,
exacerbation, hyper/hypoglycaemia,
weakness, chest pain, diabetes mellitus, lupus-
HF, nausea, and like symptoms,
constipation hyperbilirubinemia,
PROPAFENONE Mode of action: dyspnea
HYDROCHLORID Works by slowing Life threatening:
E the influx of sodium Agranulocytosis,
ions into the cardiac thrombocytopenia, HF
muscle cells, causing ESMOLOL Mode of action:
a decrease in (BETA1 Blocks the agonistic
excitability of the BLOCKERS) effect of the
cells sympathetic
Therapeutic use: neurotransmitters by
For atrial, competing for receptors
ventricular, and binding sites
89
 Therapeutic action: headache, palpitations,
Treat atrial flutter, and weakness, nausea,
fibrillation, vomiting, and dyspnea
supraventricular
tachycardia and CLASS III : POTASSIUM CHANNEL
hypertension BLOCKERS
Adverse effect: ADENOSINE Mode of action:
Bradycardia, Agonism of adenosine
hypotension, dizziness, receptors A1 and A2
drowsiness, reduces conduction time
hyperhidrosis, infusion- in the atrioventricular
site reaction, headache, node of the heart
confusion, agitation, Therapeutic use:
and nausea For Paroxysmal
PROPRANOLO Mode of action: supraventricular
L It exerts its response by tachycardia  and Wolff-
HYDROCHLOR competitively blocking Parkinson-White
IDE beta-1 and beta-2 (WPW) syndrome
adrenergic stimulation Adverse effect:
in the heart, which is Headache, dizziness,
typically induced by flushing, dyspnea, chest
epinephrine and pain, hypotension,
norepinephrine anxiety, and paresthesia
Therapeutic uses: AMIODARONE Mode of action:
For atrial and HYDROCHLOR It blocks potassium
supraventricular IDE currents that cause
dysrhythmias repolarization of the
Adverse effect: heart muscle during the
Dizziness, agitation, third phase of the
cold extremities, cardiac action potential,
fatigue, visual increases the duration of
impairment, the action potential as
bradycardia, well as the effective
hyperkalemia, seizures, refractory period for
and erectile dysfunction cardiac cells
SOTALOL Mode of action: (myocytes).
HYDROCHLOR Beta-adrenorecepter Therapeutic use:
IDE blocking For life threatening
Therapeutic use: ventricular tachycardia
For atrial flutter, and and fibrillation
fibrillation and Adverse effect:
ventricular tachycardia Corneal deposits,
Adverse effect: anorexia, nausea,
Bradycardia, HF, vomiting, constipation,
fatigue, dizziness, hypothyroidism,
90
 injection site reaction, fatigue, dizziness,
pneumonitis, headache, palpitations,
photosensitivity weakness, nausea,
DEFETILIDE Mode of action: vomiting and dyspnea
Blocks cardiac ion
channel carrying the CLASS IV: CALCIUM CHANNEL
rapid component of the BLOCKERS
delayed rectifier VERAPAMIL Mode of action:
potassium current HYDROCHLOR inhibits the calcium ion
Therapeutic use: IDE influx through slow
For atrial flutter and channels into conductile
fibrillation and contractile
Adverse effect: myocardial cells and
Headache, dizziness, vascular smooth muscle
insomnia, chest pain, cells
infection, dyspnea, and Therapeutic use:
nausea For angina, cardiac
IBUTILIDE Mode of action: dysrhythmias, and
increases action hypertension
potential duration, Adverse effect:
blocks the rapid Peripheral edema,
component of the constipation, dizziness,
cardiac delayed rectifier fatigue, confusion
potassium current headache, blurred
Therapeutic use: vision, erectile
For atrial flutter and dysfunction,
fibrillation bradycardia, and
Adverse effect: orthostatic hypotension
Headache, palpitations, DILTIAZEM Mode of action:
nausea, tachycardia, inhibits the inflow of
bradycardia, orthostatic calcium ions into the
hypotension, and cardiac, smooth muscle
dysrhythmia during depolarization
exacerbation Therapeutic use:
SOTALOL Mode of action: For angina, Paroxysmal
prolongs the action supraventricular
potential and tachycardia, atrial flutter
refractoriness of cardiac or fibrillation and
tissue hypertension
Therapeutic use: Adverse effect:
For atrial flutter and Headache, peripheral
fibrillation and edema, dizziness,
ventricular tachycardia weakness, bradycardia,
Adverse effect: hypotension, fatigue,
Bradycardia, HF, infection ,dyspnea,
91
 pharyngitis, rhinitis, and
dyspepsia Elevated LDL = greater risk for developing
DIGOXIN Mode of action: atherosclerotic plaques and heart disease.
Inhibits sodium
potassium ATPase, A 12 - 14 hour fasting lipid profile is the test
promoting an increased ordered to determine total cholesterol and
force of cardiac triglyceride concentration in the body.
contraction, cardiac
output, and tissue
Serum Lipid Values
perfusion
Therapeutic use: Lipids Desirable (mg/dL)
For atrial fibrillation Cholesterol 150-200
Adverse effect: Triglycerides 40 - 150
Bradycardia, lipoproteins
hallucinations, bowel LDL <100
necrosis, palpitations HDL >60
DRODENARON Mode of action:
E Works by blocking Elevated cholesterol, triglycerides, and LDL
potassium, sodium, and levels = Risk of CAD
calcium channels and
exhibits antiadrenergic APOLIPOPROTEINS
properties.  Are proteins that bind and transport
Therapeutic use: lipids in the blood
For atrial fibrillation
Adverse effect:
Receptors:
Rash, pruritus, nausea,
diarrhea, vomiting,  ApoA1-HDL
abdominal pain,  ApoB100 – LDL & VLDL
weakness, bradycardia,  ApoB48 – chylomicron remnants
and prolonged QT  ApoE-IDL & chylomicron remnants
interval.
NONPHARMACOLOGIC METHODS
ANTIHYPERLIPIDEMICS  Diets (low fat & cholesterol)
 Drugs that maintain or decrease blood  Exercise (aerobic exercises)
Lipid concentrations.  Don’t smoke
 Therapy is a lifetime commitment
Non-drug therapy should be recommended
Lipoproteins first to lower cholesterol. However,
4 Major Categories: Nonpharmacologic methods will still be
➜ High-Density Lipoprotein (HDL) included in the interventions even if the drug
➜ Low-Density Lipoprotein (LDL) therapy is initiated.
➜ Very-Low Density Lipoprotein (VLDL)
➜ Chylomicrons LIPOPROTEIN PHENOTYPE
TYPE MAJOR LIPIDS
92
 Increased a statin or niacin.
chylomicrons &
I Side effect:
triglycerides
(uncommon)  Constipation
Increased LDL &  Abdominal pain
IIA cholesterol  Bloating
(common)  Vomiting
Increased VLDL,  Diarrhea
LDL, cholesterol, &  Excessive
IIB
triglycerides (very flatulence
common)  Heartburn
Moderately increased  Peptic Ulcer
cholesterol &  Gallstones
III
triglycerides
 Vitamin
(uncommon)
A,D,E,& K
Increased VLDL & Deficiency
markedly increased
IV
triglycerides (very Must be taken with
common) and followed by
Increased sufficient fluids.
chylomicrons, VLDL FIBRATES (fibric Mode of action:
V
& triglycerides acid) Lower blood
(uncommon) triglyceride levels by
 Fenofibrate reducing the liver's
BILE-ACID Mode Of Action: ( hypercholester production of VLDL
SEQUESTRANTS Bile acid olemia) and speeding up the
sequestrants bind  Gemfibrozil removal of
 Cholestyramine bile acids in the (hyperlipoprotei triglycerides from
(One of the first intestine and ns & the blood thus
antihyperlipide increase the hypertriglycerid increasing HDL.
mics) excretion of bile emia)
 Colestipol acids in the stool. Therapeutic Use:
Hydrochloride  Prevents
 Colesevelam Therapeutic Use: pancreatitis &
(First choice  Used for heart attacks.
drug) Hypercholesterol  Used to reduce
emia and is primarily
effective against Hyperlipidemia
Hyperlipidemia type IV and is
type II. also effective for
 Lowers LDL Hyperlipidemia
Cholesterol type II.
levels.  Highly protein-
 Used in bound
combination with
93
 Side effect: side effects and
 Nausea, stomach are given at large
upset, and doses.
sometimes  Used together
diarrhea. with Aspirin
 Liver (following
inflammation. careful drug
 Gallstones when titration and
used for several concomitant)
years.  Available in
 Muscle damage immediate and
when taken slow-release
together with forms.
statin
medications SIDE EFFECTS:
 GI Disturbances
CONTRAINDICA  Elevated serum
TION: Should not liver enzymes
be taken with  Peptic Ulcer
anticoagulants (ex.  Orthostatic
Warfarin) or hypotension
anticoagulant dose  itching
should be reduced.  Flushing (Niacin
Should not be Flush)
combined with  Hyperglycemia
statins.  Hyperuricemia &
Mode Of Action: Gout
Reduces the Should not be given
production of to those with hepatic
proteins that impairment
transport cholesterol Recommended to be
and triglycerides in used only with
the blood. triglyceride levels of
over 500 mg/dL or if
Therapeutic use:
NIACIN (nicotinic intolerant to other
 For treatment.
acid or vitamin B3) Hypercholesterol Mode Of Action:
emia Reduces cholesterol
 Effectively from dietary
decreases VLDL CHOLESTEROL
absorption.
and LDL, ABSORPTION
especially INHIBITORS Therapeutic Uses:
Cholesterol (Ezetemibe)
 For
levels. Hypercholesterol
 Has numerous emia
94
  Acts on the cells enzyme levels.
of the small (ALP, AlT, &
intestines. GGT)
 Can cause a  GIT
small increase in Disturbances
HDL  Rhabdomyolysis
 Usually  Cataract
combined with a Formation
statin.
CONTRAINDICA
SIDE EFFECTS: TIONS
 Diarrhea,  Hepatic Disease
 arthralgia,  Encephalopathy
 abdominal &  Pregnancy &
 back pain, Breastfeeding
 fatigue, ATORVASTATIN Therapeutic Use:
 infection,  Lowers LDL by
 cholelithiasis 43% to 60%
 myalgia  Average Dose:
Therapeutic Uses: 10 -80 mg
STATINS (HMG-  Inhibits  Highly protein
CoA Reductase cholesterol bound (98%)
Inhibitors) synthesis in the Usually
liver. prescribed once
 Atorvastatin  Decreases serum daily.
 Calcium cholesterol,  Half-life = 14
 Pitavastatin LDL, VLDL, and hours
 Rosuvastatin triglycerides.  Excretion: feces
 Pravastatin  Slightly elevate
Sodium HDL. Pharmacodynamics
 Simvastatin  Combined with :
 Fluvastatin other drugs to  Avoid grapefruit
Sodium decrease blood juice.
 Lovastatin pressure and  Taken with no
blood clotting. regard to meals.
COMBINATION:  For  Therapeutic
ANTIHYPERLIPI Hypercholesterol effect
DEMIC DRUGS: emia & effective normally seen
against around 2 to 4
 Amlodipine & Hyperlipidemia weeks.
Atorvastatin Type II.  Peak time: 1 to 2
 Ezetimibe and hours.
Simvastatin Side effect:  Lowers lipids
 Increase liver around 3 to 5
95
 days.
STATINS Complementary & Alternative
Therapies
Black cohosh - may potentiate an increase in
liver enzymes.
Chinese Skullcap - may increase drug levels
of Rosuvastatin
Cranberry - may increase side effects of
simvastatin.
Gingko Biloba - may increase drug levels of
statins.
Green Tea - may increase side effects of
statins.
St. John's Wort - may decrease effect and
drug levels of statins.
Miscellaneous Antilipidemics
Icosapent Ethyl - decreased lipogenesis in the
liver; and increased plasma lipoprotein lipase
activity.
Lomitapide - inhibition of the microsomal
triglyceride transfer protein (MTP).
Mipomersen - used to decrease levels of
cholesterol and other fatty substances in the
blood in people who have homozygous familial
hypercholesterolemia
Alirocumab & Evolocumab- human
monoclonal antibody that binds to proprotein
convertase subtilisin kexin type 9 (PCSK9).
Laboratory Tests
Homocysteine Test
 Reference Values: 4 to 17 mmol/L.
 Homocysteine is a type of amino acid, a
chemical your body uses to make proteins.
 High levels = risk for CVD, Stroke, &
Alzheihmer Disease.
 Usually lowered by Vit. B6, B12, and folic
Acid
 Fast (not eat or drink) for 8–12 hours
before a homocysteine test.
High- Sensitivity C-reactive Protein Test
(hsCRP)
 Reference Values: 1 to 3 mg/L.
 The CRP is produced in the liver in
response to tissue injury or inflammation.
 A valuable test for predicting CAD.
 Usually ordered along with cholesterol
screening.
 Avoid very strenuous exercise before the
test.
 May require fasting
Drugs to Improve Peripheral Blood flow
Peripheral arterial disease (PAD), or
Peripheral Vascular Disease (PVD).
 It is characterized by numbness and
coolness of the extremities, claudication
(pain and weakness of a limb when
walking but no symptoms at rest), and
possible leg ulcers.
 The primary cause is arteriosclerosis
and hyperlipidemia, resulting in
atherosclerosis, which the arteries
become occluded.
 Most common in adult
Peripheral Vasodilators increase blood flow to
the extremities. They are used in peripheral
vascular disorders of venous and arterial
vessels. They are more effective for disorders
that result from vasopasm (Raynaud disease)
than from vessel occlusion or arteriosclerosis
(arteriosclerosis obliterans, thromboangiitis
obliterans (buerger disease). In Raynaud
disease, cold exposure or emotional upset can
96
trigger vasopasm from the toes and fingers; NE  Nausea/vomiting
these patients have benefited from vasodilators.  classified as a  Blurred vision
Patients with diabetes mellitus are more likely hemorrheologic  Confusion
to have PAD by two to four times the usual rate agent  Constipation
and are at risk of intermittent claudication  Improves  Cholestasis
microcirculation  Tachycardia
PERIPHERAL VASODILATOR and tissue  Edema
Direct-acting Mode of Action; perfusion by  Hypotension
vasodilator: Acts directly to inhibit decreasing Contraindications:
platelet aggregation blood viscosity
 The drug should
CILOSTAZOL and cause and improving
be taken with
vasodilation, the flexibility of
food, and he
 An especially in femoral erythrocytes,
patient should
antiplatelet vasculature thus increasing
avoid smoking
that has a tissue
because nicotine
dual purpose Therapeutic Uses: oxygenation.
increases
of inhibiting  Peripheral  It inhibits vasoconstriction.
platelet vascular disease aggregation of
 Patients taking an
aggregation  Claudication platelets and red
antihypersensitive
as well as blood cells, and
drug along with
causing Side effect: because it
pentoxyfylline
vasodilation  Dizziness decreases blood
may need to have
to treat  Nausea/vomiting viscosity, it
the
intermittent  Tachycardia helps increase
antihypesensitive
claudication  diarrhea flow through
dosage decreased
peripheral
 Angina to avoid side
vessels.
 Palpitation effects.
 HF
 Orthostatic BLOOD COAGULATION AND
hypotension ANTICOAGULANT
 Peptic ulcer
 Gout Coagulation of Blood
 Diabetes mellitus The process requires coagulation
 Cholelithiasis factors, calcium, and phospholipids.
 Peripheral edema
 Melena During this process, the fibrinogen is converted
 Flushing into fibrin. Fibrin threads get attached to the
 Flatulence loose platelet plug, which plugs the ruptured
 nasopharyngitis part of blood vessels and prevents further blood
loss completely.
Blood viscosity Therapeutic uses:
reducer agent:  Claudication FACTORS INVOLVED IN BLOOD
CLOTTING
PENTOXIFYLLI Side effect:
97
Coagulation of blood occurs through a series of
reactions due to the activation of a group of
substances necessary for clotting are called
clotting factors.  Low Molecular Weight Heparin (LMWH)
STEPS OF BLOOD CLOTTING
1. Formation of prothrombin activator
2. Conversion of prothrombin into
thrombin
3. Conversion of fibrinogen into fibrin
Anticoagulant
Anticoagulants are given to prevent thrombosis
and used in drawing and storing blood.
Types of anticoagulants:
 Heparin
 Low molecular weight heparins (LMWH)
 Oral Anticoagulants (e.g., warfarin)
 Selective Factor Xa Inhibitors
 Direct-Acting Thrombin Inhibitors:
Anticoagulants II (Intravenous)
 Anticoagulant Antagonist
HEPARIN
Heparin introduced in 1938 is a natural
substance in the liver that prevents clot
formation. It was first used in blood transfusion
to prevent clotting; heparin is indicated for
rapid anticoagulant effect when thrombosis
occurs because of a DVT, PE, or evolving
stroke.
Heparin is poorly absorbed through the
gastrointestinal mucosa and as such is
destroyed by heparinase, a liver enzyme.
Partial thromboplastin time (PTT) and
activated partial thromboplastin time (aPTT)
are laboratory test is to detect deficiencies of
certain clotting factors and these tests are used
to monitor heparin therapy.
Anticoagulants
Studies have shown that by extracting only the
low molecular weight fractions of standard
heparin to depolymerization, the equivalent of
anticoagulation can be achieved with a lower
risk of bleeding.
Low-molecular-weight heparin produces a
more stable response at recommended doses.
As a result, frequent laboratory monitoring of
aPTT is not required because LMWH does not
have the standard effect of heparin.
Contraindication:
LMWHs are contraindicated for patients with
stroke peptic ulcers and blood anomalies.
These drugs should not be given to patients
having eye, brain, and spinal surgery.
Oral Anticoagulants
Oral anticoagulant inhibits hepatic synthesis of
vitamin k does affect the clotting factors II,
VII, IX, and X. Warfarin is an oral
anticoagulant synthesized from dicumarol.
Oral anticoagulants prolong clotting time and
are monitored by the prothrombin time (PT), a
laboratory test that measures the time it takes
blood to clot in the presence of certain clotting
factors which more often affects. International
normalized ratio (INR), is a laboratory test
most frequently used to report PT results.
Side effects
Bleeding is the major adverse effect of
warfarin. Patients should be monitored closely
for signs of bleeding such as petechiae,
98
ecchymosis, GI Bleeding, ocular hemorrhage, ● Warfarin use is not recommended
and hematuria. during pregnancy

Drug interactions Direct thrombin inhibitors

Because warfarin is highly protein-bound, it is These drugs interfere with your body’s use of
affected by drug interactions. Aspirin, thrombin, a key enzyme that helps clot your
nonsteroidal anti-inflammatory drugs blood. Though usually injected under the skin,
(NSAIDs), other types of anti-inflammatory you can take it in pill form as dabigatran
drugs can displace warfarin from the protein- (Pradaxa).
bound site and can cause more free-circulating
anticoagulants. Selective factor Xa inhibitors
This type of anticoagulant stops the Xa factor
Pharmacokinetics in the clotting process from working as it
Heparin should. They are approved for the prevention
The half-life of heparin is dose-related: high of DVT and PE.
doses prolong the half-life. The half-life of
heparin is 20 to 60 hours, in contrast to 30 to ANTICOAGULANT DRUG
150 minutes for heparin. Mode of action;
Warfarin Inhibits reactions that
Warfarin has a long half-life and is highly leads to the clotting of
protein-bound, the drug can have accumulative blood and the formation
effects. Bleeding can occur, especially if of fibrin clots both in
another highly protein-bound is administered vitro and in vivo.
together with warfarin.
Therapeutic uses:
 Prophylaxis and
Pharmacodynamics
treatment of venous
Heparin thrombosis and
● The half-life of heparin, administered Anticoagulants pulmonary embolism
for acute thromboembolic disorders, heparin:  Prophylaxis and
prevents thrombus formation and treatment of
embolism. Heparin thromboembolic
sodium complications
● Heparin does not cross the placental
barrier, unlike warfarin. associated with atrial
fibrillation
Side effect:
Warfarin
 Irritation
● Warfarin is effective for long-term
 Pain
anticoagulants therapy. The PT level  Redness or sore at the
should be 1.5 to 2 times the reference injection site
value to be therapeutic, or INR should  Allergic reactions
be 2.0 to 3.0. such as hives
 Chills

99
 
Fever

Increased liver
enzymes on liver
function test results
MOA:
Warfarin and related
vitamin K antagonists
(VKAs) block the
function of the vitamin K
epoxide reductase
complex in the liver
Therapeutic uses:
 Prophylaxis and
treatment of venous
thrombosis and
pulmonary embolism
 Prophylaxis and
treatment of
thromboembolic
complications
WARFARIN associated with atrial
fibrillation
 Prophylaxis and
treatment of
thromboembolic
associated with
cardiac valve
replacement
Side effects:
 Severe bleeding
including heavier than
normal menstrual
bleeding
 Red or brown urine
 Black or bloody stool
 Severe headache
 Stomach pain
Mode of action:
Selectively binds to
antithrombin III thereby
FONDAPARIN
potentiating the innate
UX
neutralization of activated
factor X (Factor Xa) by
antithrombin
Therapeutic uses:
 Prophylaxis and
treatment of deep
venous thrombosis
(DVT)
 PE
Side effects:
 Pain
 Bruising
 Redness
 Swelling at the
injection site
Mode of action:
Inhibits free factor Xa
and prothrombinase
activity
Therapeutic uses:
 Prophylaxis and
treatment of deep
RIVAROXAB venous thrombosis
AN (DVT)
 PE
Side effects:
 Nosebleeds
 Heavier periods
 Bleeding gums
 bruising
Mode of action:
Orally active factor Xa
Inhibitors that bind
reversibly to the active
site of factor Xa. They
inhibit both free actor Xa
and factor Xa that is
APIXABAN
bound to the
AND prothrombinase complex
Therapeutic uses:
EDOXABAN Prophylaxis and treatment
of deep venous
thrombosis (DVT) and
PE
Side effects:
 bleeding more easily
than normal such as
100
 nosebleeds, heavier injection such as
periods, bleeding redness, swelling or
gums itching
 bruising  hives
Mode of action:
Mode of action: Inhibits reactions that
Factor Xa inhibitors that leads to the clotting of
bind reversibly to the blood and the formation
active site of factor Xa. of fibrin clots both in
They inhibit both free vitro and in vivo.
factor Xa and factor Xa
that is bound to the Therapeutic uses:
prothrombinase complex Prevention and treatment
Therapeutic uses: of venous thrombosis in
Prophylaxis and treatment ENOXAPARI the maternal or placental
BETRIXABAN of venous N SODIUM circulation
thromboembolism (VTE)
Side effects: Side effect:
 nosebleed  nausea
 blood in urine  diarrhea
 major bleeding  fever
 GI bleeding  peripheral edema
 Intracranial  injection site reactions
hemorrhage (rare) (swelling, pain,
 Fatal bleeding (rare) bruising, or redness)
Mode of action: Mode of action:
Binds to antithrombin III Inhibiting thrombin-
and accelerates its catalysed or –induced
inhibition of thrombin reactions, including fibrin
and factor Xa formation
Therapeutic uses:
Therapeutic uses:  treatment of
Low-molecular  Prophylaxis Direct-acting thrombosis in adult
heparin:  DVT thrombin patients with heparin-
 Unstable angina inhibitor: induced
Dalteparin thrombocytopenia
Side effects: ARGATROBA (HIT) or at risk for
 Trouble breathing N HIT undergoing
 Swelling of your percutaneous
throat or tongue coronary intervention
 Itching (PCI)
 Rash  deep venous
 Fever thrombosis (DVT)
and PE treatment
 Reaction at the site of
Side effects:
101
  nausea/vomiting
 diarrhea
 stomach pain
 fever
 headache
 back pain
Mode of action:
Inhibiting thrombin-
catalysed or –induced
reactions, including fibrin
formation
Therapeutic uses:
 Deep venous
thrombosis (DVT)
prophylaxis.
 Heparin-induced
BIVALIRUDI thrombocytopenia
N (HIT) with
thrombosis
Side effects:
 Abdominal pain or
swelling.
 Arm, back, or jaw
pain.
 Black, tarry stools.
 Blood in the eyes.
 Blood in the urine.
Mode of action:
Inhibiting thrombin-
catalysed or –induced
reaction, including fibrin
formation
Therapeutic uses:
Prophylaxis of deep vein
thrombosis
DESIRUDIN Side effect:
 Bleeding gums
 Collection of blood
under the skin
 Coughing up blood
 Difficulty with
breathing or
swallowing
DABIGATRA Mode of action:
Inhibiting thrombin-
catalysed or –induced
reaction, including fibrin
formation
Therapeutic uses:
 prevent stroke
 treat deep vein
thrombosis(DVT)
 pulmonary embolism
(PE) 
N Side effect:
 Acid or sour stomach
 Black, tarry stools.
 bloody stools
 pain or burning in the
throat
 stomach discomfort
 upset
 burning
 pain
Mode of action:
Therapeutic uses:
Heparin reversal
Side effect:
 sudden fall in blood
PROTAMINE
pressure
SULFATE
 slow heart rate
(bradycardia)
 pulmonary
hypertension
 shortness of breath
PHYTONADI Therapeutic uses:
ONE  For vitamin K
deficiency
 Bleeding from
warfarin toxicity
Side effect
 Temporary flushing
 taste changes
 dizziness
 rapid heartbeat
 sweating
 shortness of breath
102
  bluish lips/skin/nails  Thromboembolism, occlusion of an artery
may also rarely occur or vein caused by a thrombus or embolus.
Pharmacokinetics
FIBRINOLYTIC AND ANTIPLATELET
DRUGS The commercial preparation of alteplase is
TERMINOLOGIES! identical to natural human tissue plasminogen
activator (tPA), the enzyme the converts
Fibrinolytic mechanism -The fibrinolytic plasminogen to plasmin.
system functions to remove the clot after the Pharmacodynamics
vasculature is repaired, as well as to degrade
clots that form in the bloodstream.  Alteplase is similar to natural human tissue
plasminogen activator. It promotes
Fibrinolysis – lysis and removal of blood clot
thrombolysis by converting plasminogen to
after stoppage of bleeding and healing of the
plasmin, which degrades fibrin, fibrinogen.
vascular wall.
Alteplase - is a thrombolytic drug, sometimes ANTIPLATELET DRUGS
called a "clot-busting" drug. It helps your body Antiplatelets are used to prevent thrombosis in
produce a substance that dissolves unwanted the arteries by suppressing platelet aggregation.
blood clots. Alteplase is used to treat a stroke Heparin and warfarin prevent thrombosis in the
caused by a blood clot or other obstruction in a veins.
blood vessel.
Antiplatelet drug therapy is mainly for
Ischemia – is a condition in which the blood
prophylactic use in:
flow (and thus oxygen) is restricted or reduced
in a part of the body. 1. Prevention of MI or stroke for patients with
Necrosis - the death of body tissue. It occurs a family history
when too little blood flows to the tissue. 2. Prevention of repeat MI or stroke,
Acute myocardial infarction - is myocardial
necrosis resulting from acute obstruction of a 3. Prevention of stroke for patients having
coronary artery. Symptoms include chest transient ischemic attacks (TIAs)
discomfort with or without dyspnea, nausea, Mode of action:
and diaphoresis. The exact mechanism by
Thromboembolism - the blocking of a blood which anagrelide lowers
vessel by a particle that has broken away from platelet count is unclear.
a blood clot at its site of formation. Evidence from human
trials suggests a dose-
Fibrinolytic drugs ANAGRELIDE related suppression of
 Thrombolytic have been used since the HYDROCHLO megakaryocyte
early 1980s to promote the fibrinolytic RIDE maturation, the cells
mechanism. responsible for platelet
 Thrombolytics should be administered production - blood
within 3 to 4 hours or within 30 minutes drawn from patients
after arriving at the hospital for treatment. receiving anagrelide
showed a disruption to
the post-mitotic phase of
103
 megakaryocyte  Temporary relief of
development and a headache, pain and
subsequent reduction in fever of colds, minor
their size and ploidy. pain of arthritis,
Therapeutic uses: muscle pain,
 thrombocythemia, menstrual pain, and
secondary to toothache.
malignant neoplasms Side effect:
 to reduce platelet  abdominal pain
count and the  nausea
associated risk of Mode of action:
thrombosis. Cilostazol and several of
 Chronic its metabolites are cyclic
myelogenous AMP (cAMP)
leukemia phosphodiesterase III
 Polycythemia vera inhibitors (PDE III
Side effect: inhibitors), inhibiting
 Headache phosphodiesterase
 dizziness activity and suppressing
 palpitations cAMP degradation with
 peripheral edema a resultant increase in
 tachycardia cAMP in platelets and
 abdominal pain blood vessels, leading to
inhibition of platelet
 nausea
aggregation and
 diarrhea
vasodilation.
 weakness CILOSTAZOL Therapeutic uses:
 dyspnea  claudication due to
Mode of action: peripheral vascular
The acetyl group of disease
acetylsalicylic acid binds  PVD
with a serine residue of Side effect:
the cyclooxygenase-1
 Smoking may cause
(COX-1) enzyme,
decrease of serum
leading to irreversible
levels
inhibition. This prevents
 Headache
ASPIRIN the production of pain-
causing prostaglandins.  Nausea
Therapeutic uses:  Nasopharyngitis
• Stroke  Rhinitis
• MI  Dizziness
• TIA  Infection palpations
• atrial fibrillation  Peripheral edema
• Thromboembolism CLOPIDOGRE Mode of action:
prophylaxis. L metabolized to its active
104
 form by valves.
carboxylesterase-1.The  prevention of
active form is a platelet atherothrombotic
inhibitor that irreversibly events in adult
binds to P2Y ADP patients with acute
receptors on platelets. coronary syndrome
This binding prevents Side effect:
ADP binding to  headache
P2Y receptors, activation  dizziness
of the glycoprotein  bleeding
GPIIb/IIIa complex, and  nausea
platelet aggregation.  hypo/hypertension
Therapeutic uses:
 dyspnea
 Thromboembolism
 hyperlipidemia
associated with
 hypercholesterolemia
prosthetic heart
DIPYRIDAMO valves.  epistaxis
LE Mode of action:
 a percutaneous
a P2Y receptor
coronary intervention
antagonist
(PCI) for acute
Therapeutic uses:
coronary syndrome
(ACS)  thromboembolism
prophylaxis
 Stable ischemic heart
disease.  reduce the risk of
cardiovascular death
 Atrial fibrillation.
Side effect:  myocardial infarction
 Dizziness  stroke in patient with
acute coronary
 Headache TICAGRELOR syndrome
 Nausea
Side effect:
 Abdominal pain
 headache
 Dyspnea
 dizziness
 Flushing
 bradycardia
 Chest pain
 bleeding
Mode of action:
 nausea
an thienopyridine and a
prodrug which inhibits  diarrhea
ADP receptors by  cough
irreversibly acting on the  hypo/hypertension
PRASUGREL P2Y12 receptor on  dyspnea
platelets.  Mode of action:
Therapeutic uses: Inhibits platelet
 Thromboembolism aggregation through the
VORAPAXAR
associated with reversible antagonism of
prosthetic heart protease-activated
receptor 1 (PAR-1), also
105
 known as thrombin Combination of antiplatelet drugs
receptor. 
1. Dipyridamole 200mg and aspirin 25mg –
Therapeutic uses:
For stroke prevention, ischemic stroke and
 thrombosis
TIA. May cause headache, nausea, diarrhea,
 MI abdominal pain, dyspepsia, fatigue, bleeding
 PAD and arthralgia.
 Stroke
 reduction of 2.Aspirin (ASA) and omeprazole – For
thrombotic prophylaxis of secondary cardiovascular and
cardiovascular cerebrovascular events. May cause gastritris,
events in patients nausea,diarrhea, anemia, blurred vision,
with a history of bleeding, tinnitus, and hearing loss.
myocardial infarction Other antiplatelet drugs include
(MI) or peripheral anagrelide,clopidogrel, dipyridamole,
arterial disease peasugerel, ticagrelor, vorapaxar, cangrelor,
(PAD) abciximab, eptifibatide and tirofiban, they are
Side effect: known as adenosine diphosphate (ADP)
 bleeding antagonist.
 intracranial/GI
bleeding Clopidogrel is an antiplatelet drug frequently
 anemia used after MI or stroke to prevent a second
Mode of action: event. It may be prescribe singly or with
a selective, reversible, aspirin.
P2Y12 platelet receptor PHARMACOKINETICS
antagonist which inhibits
ADP platelet Clopidogrel is rapidly absorbed and has a high
aggregation. ADP is protein-binding power
typically released by
PHARMACODYNAMICS
damaged blood vessels,
red blood cells, and/or Clopidogrel prevents platelet aggregation by
platelets due to agonists blocking the binding of ADP to the platelet
stimulating platelet ADP receptor.
CANGRELOR activity
Therapeutic uses: RESPIRATORY DRUGS (UPPER
RESPIRATORY)
 prevention of
thrombosis in PCI ANTITUSSIVES
 MI
Side effect: Act on the cough-control center in the medulla
 Bleeding to supress the cough reflex. The cough is a
naturally protective way to clear the airway of
 Dyspnea
secretions or any collected material.
 Hematoma
 Hematuria A sore throat may cause coughing that
 Intracranial bleeding increases throat irritation. If the cough is

106
nonproductive and irritating, an antitussive Important  diarrhea
may be taken. information to know  constipation
The three (3) types of antitussives are about  dependence
nonopioid, opioid, or combination preparations. Codeine:  tolerance
Antitussives are usually used in combination  Keep the  withdrawal
with other agents medication in a  respiratory
place where depression
BLACK BOX WARNINGS others cannot get  euphoria (AE)
Drug exposes patients and other users to the to it.  apathy (AE)
risks of opioid addiction, abuse and misuse,  Do not give this  drowsiness (AE)
which can lead to overdose and death medicine to  relaxation (AE)
anyone younger
A strengthened warning to mothers that than 12 years old, CONTRAINDICA
breastfeeding is not recommended when taking or anyone under TIONS
codeine due to the risk of serious adverse 18 who recently  Hypersensitivity
reactions in breastfed infants. These can had surgery to to codeine
include excess sleepiness, difficulty remove the tonsils  Significant
breastfeeding, or serious breathing problems or adenoids. respiratory
that could result in death.  Taking opioid depression
OPIOID ANTITUSSIVE medicine during  Children
pregnancy may younger than 12
OPIOID ANTITUSSIVE cause life- years
 The most powerful analgesics that can threatening  Postoperative
relieve any type of pain withdrawal pain
 Act mainly at the level of cortex, CNS symptoms in the management in
 Can produce addiction new-born. children (below
Therapeutic Uses:  Never use codeine 18 years) who
For cough and pain. in larger amounts, have undergone
Side Effect: or for longer than tonsillectomy
May cause drowsiness, dizziness, euphoria, prescribed. Tell and/or
blurred vision, weakness, nausea, diarrhea, your doctor if you adenoidectomy
constipation, dependence, tolerance, feel an increased
withdrawal and respiratory depression. urge to take more Contraindicated
CODEINE (CSS II) Therapeutic Use: of this drug:
medicine Alvimopan
Cough
A class of Pain DEXTROMETHOR Mode of action:
medications called PHAN Decreases
opiate (narcotic) Side effect/Adverse excitability of cough
Analgesics and is effects: Often referred to as center in the
used to treat pain, it  Drowsiness DXM, is a medication medulla
works by changing  Dizziness most often used as a
the way the brain and cough suppressant in Therapeutic Use:
 blurred vision
nervous system over-the-counter cold For temporary
 weakness
respond to pain. and cough medicines. cough relief due to
 nausea
107
It is sold in syrup, doctor's advice.
tablet, spray, and Taking a
lozenge forms. stimulant together
with cough
How should this medicine can
medicine be used? especially for non- increase your risk
Dextromethorphan productive cough of unpleasant side
should only be used due to sore throat, effects.
according to the label irritation, or  Do not use any
or package directions. common cold. other over-the-
Do not take more counter cough,
than the Side effect: cold, or allergy
recommended  dizziness medication
amount of without first
 lightheadedness
dextromethorphan in asking your
 drowsiness
a 24-hour period. doctor or
Refer to the package  nervousness
pharmacist.
or prescription label  restlessness
Dextromethorpha
to determine the  nausea/vomiting n is contained in
amount contained in  stomach pain many
each dose. Taking  confusion combination
dextromethorphan in  fatigue medicines
large amounts can  ataxia available over the
cause serious side  psychosis (AE) counter. If you
effects or death  tachycardia (AE) take certain
 seizures (AE) products together
what to avoid  respiratory you may
 Avoid drinking depression (LT) accidentally take
alcohol. It can  serotonin too much of this
increase some of syndrome (LT) medicine. Read
the side effects of the label of any
dextromethorphan Contraindications: other medicine
. This medication  Asthma you are using to
can cause side  Emphysema see if it contains
effects that may dextromethorphan
 tobacco smoking
impair your Therapeutic use:
 Hepatic disease
thinking or Cough and common
reactions.  Children, infants
cold
 Avoid taking diet  Pregnancy
Side effect:
pills, caffeine  Breastfeeding
GUAIFENESIN and  Drowsiness
pills, or other CODEINE (CSS V)  Dizziness
stimulants (such  Headache
as ADHD  Euphoria
medications)
 Hypotension
without your
 Dependence
108
  Nausea/vomiting  Headache
 Constipation  Confusion
 Urinary  Nausea
retention  Constipation
 Respiratory  Ocular irritation
depression
Therapeutic use:
Cough
Side effect: DECONGESTANTS
 Drowsiness Decongestants decrease the overproduction of
 Dizziness secretions by causing local vasoconstriction to
 Headache the upper respiratory tract.
HOMATROPINE  Euphoria
and  This vasoconstriction leads to a
 Headache
HYDROCODONE shrinking of swollen mucous
 Blurred vision membranes and tends to open clogged
(CSS III)
 Dry mouth nasal passages, providing relief from
 Nausea/vomiting the discomfort of a blocked nose and
 Urinary promoting drainage of secretions and
retention improved airflow.
 Constipation
 dependence  Topical nasal decongestants, oral
NON OPIOID ANTITUSSIVES decongestant, and topical steroid nasal
decongestants are classifications of
 Mild analgesics that treat mild types of
decongestants.
pain as headache
 Act at the level of thalamus & CLASSIFICATIONS
hypothalamus
 No addiction Topical nasal decongestants
Therapeutic Use:  Imitate the effects of the sympathetic
For cough nervous system to cause
Side effect: vasoconstriction, leading to decreased
 Drowsiness edema and inflammation of the nasal
 Dizziness membranes.
 Headache
 Relieve the discomfort of nasal
 Confusion
congestion that accompanies the
 Nausea common cold, sinusitis, and allergic
 Constipation rhinitis.
 Ocular irritation
Therapeutic Use:  Dilation of the nares to facilitate
Cough medical examination or to relieve the
Side effect: pain and congestion of otitis media.
BENZONATATE
 Drowsiness Oral decongestants
 Dizziness

109
  Decrease nasal congestion related to the
common cold, sinusitis, and allergic
rhinitis.
 Shrink the nasal mucous membrane by
stimulating the alpha-adrenergic
receptors in the nasal mucous
membranes.
 This shrinkage results in a decrease in
membrane size promoting drainage of
the sinuses and improving airflow.
Topical nasal steroid decongestants
 The exact mechanism of action of
topical steroids is unknown.
 Their anti-inflammatory action results
from their ability to produce a direct
local effect that blocks many of the
complex reactions responsible for the
inflammatory response.
Indication
Topical nasal decongestants
 Relieves discomfort of nasal congestion
associated with the common cold,
sinusitis, allergic rhinitis.
 Relieves pressure of otitis media.
Oral decongestants
 Decreases nasal congestion associated
with the common cold, allergic rhinitis.
 Relief of pain and congestion of otitis
media.
Topical nasal steroid decongestants
• Treatment of seasonal allergic rhinitis
in patients who are not obtaining a
response with other decongestants or
preparations.
• Relieves inflammation following
removal of nasal polyps.
Contraindications and Cautions
 Caution must be used when there is
lesion or erosion in the mucous
membrane that could lead to systemic
absorption.
 Caution should also be used in patients
with any condition that might be
exacerbated by sympathetic activity.
 If used during pregnancy or lactation,
caution is advised.
 Caution should be used in any patient
who has an active infection, including
tuberculosis because systemic
absorption would interfere with the
inflammatory and immune response.
Adverse effects
 Rebound congestion - An adverse
effect that accompanies frequent or
prolonged use of the drug is a rebound
congestion, technically called rhinitis
medicamentosa.
 Topical nasal decongestants - Adverse
effects associated with topical
decongestants include local stinging
and burning, which may occur the first
few times the drug is used.
 Oral decongestants - Because this drug
is taken systemically, adverse effects
related to the sympathomimetic effects
are more likely to occur, including
feelings of anxiety, tenseness,
restlessness, tremors, hypertension,
arrhythmia, sweating and pallor.
 Topical nasal steroids decongestants
-The most common adverse effects are
local burning, stinging, dryness of the
mucosa, and headache.
Interactions
Cyclopropane or halothane - The use of
topical nasal decongestants is contraindicated
110
with concurrent use of cyclopropane or • Many agents can trigger the release of
halothane anesthesia because serious Histamine from Mast cells and Basophil
cardiovascular effects could occur. WBCs:
 OTC products - Many OTC products, • Foreign antigens (“allergens”)
including cold remedies, allergy
medications, and flu remedies may • Certain drugs (ex: morphine,
contain pseudoephedrine; taking many dextran)
of these products concurrently can • Endogenous chemical mediators
cause serious adverse effects. (ex: kinins)
 Acute infections - Because nasal
steroids block the inflammatory
response, their use is contraindicated in • The H1 Receptor Blockers or referred
the presence of acute infections such as to as antihistamine group can be
Candida albicans infection, divided into first and second
tuberculosis, and any airborne generations.
infections (e.g., chicken pox, measles)
because systemic absorption would
interfere with the inflammatory and
immune responses.
ANTIHISTAMINE
• Histamine is synthesized from the amino
acid HISTADINE
• It is present in all tissues but most abundant

1st Generation Antihistamine

Alkylamine Mode of Action:
derivatives: Brompheniramine is
an antagonist of the
BROMPHENIRAM H1 histamine
INE receptors with
moderate
antimuscarinic
actions, as with
other common
antihistamines such
as
diphenhydramine.
Therapeutic Use:
For the treatment of
in Skin, Lungs, and GIT the symptoms of
• Histamine is stored in Mast Cells and  common cold
Basophil WBCs.  allergic rhinitis,
111
 such as runny  difficulty
nose, itchy eyes, concentrating
watery eyes, and  dry mouth
sneezing.  Headaches
Side effect/Adverse  blurred vision
Reaction: Mode of Action:
Due to its H1- Antihistamine
anticholindergic block the H1-
effects may cause: Receptors and also
 drowsiness Acetylcholine
 sedation Receptors in the
 dry mouth CNS
 dry throat (“anticholinergic
 blurred vision action”
 increased heart Therapeutic Use:
rate. 1. Used to treat
Mode of Action: Allergic and
binds to the Inflammatory
histamine H1 Reactions
receptor. This - Allergic
blocks the action of rhinitis
endogenous - Urticaria
Ethanolamine
histamine, which - Burning
Derivatices:
subsequently leads tongue
to temporary relief syndrome
Diphenhydramine
of the negative and
(Benadryl, Diphen,
symptoms brought geographic
Banophen, Genahist)
on by histamine. tongue
Therapeutic Use: 2. Used to treat
- hay fever and prevent
CHLORPHENIRA - red, itchy eyes Motion Sickness
MINE (conjunctivitis) - Beneficial in
- eczema alleviating
- hives (urticaria) vertigo and
caused by food nausea
allergies and - This effect is
chickenpox produced by
insect bites and the anti-
stings cholinergic
Side effect/Adverse action on the
Reaction: CNS
 feeling sick 3. Used as a
(nausea) Sedative
 Sleepy or 4. Used as Cough
dizziness.
112
 Suppressant mild,
Side effect/Adverse uncomplicated
Reaction: allergic skin
 Most due to the manifestations
blocking of Ach of urticaria and
Receptors in the angioedema.
CNS, it can  Used as self-
cause sedation medication for
and fatigue. temporary relief
 Dry mouth and of symptoms
throat associated with
 Nasal stuffiness the common
 Loss of appetite cold.
Contraindications: Side effect/Adverse
1. Patients with Reaction:
Glaucoma - Drowsiness
2. Patients on - dry mouth, nose,
- CNS Depressants and throat
- Sedatives and - Dizziness
Alcohol - decreased
Mode of Action: coordination
a selective - Nausea
histamine H1 - chest congestion
antagonist and binds - Headache
to the histamine H1 - excitement
receptor. This (especially in
blocks the action of children)
endogenous - Nervousness
histamine, which Therapeutic Use:
subsequently leads  Allergy rhinitis
to temporary relief  Pruritus
CLEMASTINE of the negative  urticaria
FUMARATE symptoms brought Side effect/Adverse
on by histamine. Reaction:
Piperidine  dizziness
Therapeutic Use: derivatives:  drowsiness
 For the relief of  dry mouth
symptoms CYPROHEPTADIN
E  excitability
associated with  euphoria
allergic rhinitis,  insomnia
sneezing,
 blurred vision
rhinorrhea,
 restlessness
pruritus and
acrimation.  wheezing
 Management of  hypotension
113
  tachycardia anti-cholinergic
 urinary retention side effects such
Therapeutic Use: as sedation.
 allergic rhinitis Therapeutic Use:
 chronic urticaria One of the most
Side effect/Adverse common uses for this
Reaction: drug is for a condition
 dizziness called allergic rhinitis.
 drowsiness - Seasonal
Allergic Rhinitis
 blurred vision
Piperazine - Perennial
 hypotension
derivatives: Allergic Rhinitis
 tachycardia - Chronic
LEVOCETIRIZINE
 palpitations Urticaria
 fatigue Side effect/Adverse
 nasal congestion Reaction:
 dyspnea - dizziness,
 urinary retention drowsiness;
 dry mouth - tired feeling;
 diarrhea - dry mouth;
 constipation - sore throat,
Therapeutic Use: cough;
Allergic rhinitis - nausea,
Side effect/Adverse constipation; or
Reaction: - Headache
Combination  dizziness Contraindication:
antihistamine:  drowsiness glaucoma, an increased
 blurred vision pressure in the eye
AZELASTINE and  headache liver problems
FLUTICASONE  tachycardia decreased kidney
 palpitations function
 dysphonia an inability to
 dysgeusia completely empty the
 epistaxis bladder
AZELASTINE Mode of action:
primarily a selective
2ND GENERATION ANTIHISTAMINE antagonist of histamine
CETIRIZINE Mode of action: H1-receptors, with a
(ZYRTEC) - H1- lesser affinity for H2-
Antihistamine receptors, used for the
that does not symptomatic treatment
cross the BBB, of allergies.
and thus not Therapeutic Use:
produce such  allergic rhinitis
 conjunctivitis
114
 Side effect/Adverse Reaction:
Reaction:  drowsiness
 drowsiness,  dizziness
 headache  headache
 blurred vision  weakness
 dry mouth  dry mouth,
 weakness  nervousness
 Dysesthesia.  tachycardia
Mode of action: Mode of action:
considered an “inverse Like other H1-blockers,
agonist” of the H1 Desloratadine competes
receptor because it binds with free histamine for
to and stabilizes the binding at H1-receptors
inactive form of the in the GI tract, uterus,
receptor, preventing its large blood vessels, and
activation and bronchial smooth
FEXOFENADIN subsequent downstream muscle. This blocks the
E effects. action of endogenous
Therapeutic Use: histamine, which
 allergic rhinitis subsequently leads to
 chronic urticaria temporary relief of the
Side effect/Adverse negative symptoms (eg.
Reaction: nasal congestion, watery
 headache DESLORATADI eyes) brought on by
 nausea NE histamine.
 vomiting Therapeutic Use:
Mode of action:  allergic rhinitis
exerts it's effect by  chronic urticaria
targeting H1 histamine  pruritus
receptors. Side effect/Adverse
loratadine can more Reaction:
accurately be classified - Drowsiness
as an "inverse agonist" - Dizziness
as opposed to a - Headache
"histamine antagonist", - Irritability
LORATADINE and can prevent or - Weakness
reduce the severity of - Insomnia
histamine mediated - Nausea
symptoms. - Vomiting
Therapeutic Use: - Diarrhea
 allergic rhinitis
 pruritus EXPECTORANTS
 urticaria
Side effect/Adverse
115
• Loosen bronchial secretions so they can be
eliminated by coughing
• A medication that helps bring up mucus
and other material from the lungs, bronchi,
and trachea.
• Expectorants are ingredients that increase
airway secretions.
• Hydration is the best natural expectorants
• Patient should increase fluid intake up to 8
glasses per day to help lessen mucus.
GUAIFENESIN Mode of action:
• is thought to act as
an expectorant by
increasing the
volume and reducing
the viscosity of
secretions in the
trachea and bronchi.
• Promotes drainage
of mucus from the
lungs by thinning
the mucus, and also
lubricates the
irritated respiratory
tract.
Side / adverse effect:
• Dizziness.
• Drowsiness.
• Nausea.
• Vomiting.
• Headache.
• Difficulty Breathing
(AE)
• Swelling of Face
(AE)
Contraindications:
• Overactive Thyroid
Gland. SINUSITIS
• Diabetes. - an inflammation of the mucous membranes
• Closed Angle
Glaucoma.
• High Blood
Pressure.
• Significant ACUTE PHARYNGITIS
Uncontrolled High
Blood Pressure.
POTASSIUM Mode of action:
IODIDE • It works by
shrinking the size of
the thyroid gland
and decreasing the
amount of thyroid
hormones produced.
• used to thin mucus
and loosen
congestion in the
chest and throat.
Side / adverse effect:
• Fever
• Tiredness.
• Nausea
• Vomiting
• Difficulty Breathing
(AE)
• Swelling of Neck
and Throat (AE)
• Chest Pain (AE)
• Numbness (AE)
Contraindications:
• Active tuberculosis.
• Goiter.
• High levels of
potassium in the
blood.
• Decreased kidney
function.
• Pregnancy.
• Hashimoto
thyroiditis.
• Urticarial vasculitis.
of one or more of the maxillary, frontal,
ethmoid, or sphenoid sinuses. A systemic
or nasal decongestant may be indicated.
116
- An inflammation of the throat or "sore such as albumin
throat," can be caused by a virus, beta- and secretory
hemolytic streptococci ("strep throat"), or IgA.
other bacteria. It can occur alone or with ➜ These drugs also
the common cold and rhinitis or acute act as
sinusitis. antioxidants and
MUCOLYTICS may therefore
Mode of action: reduce airway
➜ Mucolytics Mucolytics can inflammation
are medicines dissolve thick mucus
that make the and are usually used Doctors use NAC
mucus less thick to help relieve to treat
and sticky and respiratory acetaminophen
easier to cough difficulties. They do N- overdose. It may
up this by breaking ACETYLCYSTEIN also help break up
➜ This can help if down the chemical E mucus in people with
you have a bonds between some lung diseases,
condition that molecules in the like chronic
affects your mucus. This in turn bronchitis.
lungs, including: can lower the a type of medicine
chronic viscosity by altering called a mucolytic.
obstructive the mucin-containing A mucolytic helps
pulmonary components. you cough up
disease (COPD), CARBOCISTEINE phlegm (also called
cystic fibrosis Adverse effects and mucus or sputum). It
and other side effects- works by making
conditions  headache your phlegm less
including  nausea/vomiting thick and sticky. 
common colds  gastric a drug that aids the
marked by excess discomfort body's mucus-
mucus and a clearing processes in
 bleeding
productive cough BROMHEXINE the respiratory tract.
 diarrhea
➜ Several agents It is used to relieve
 rash chest congestion.
can reduce the
viscosity of Contraindications:
sputum in vitro.  should not be This medication is
One group used in children used to improve
consists of under 6 years old breathing and reduce
derivatives of  stomach ulcer the risk of lung
cysteine that PULMOZYME infections in
 acute
reduce the (DORNASE ALFA) people with cystic
bronchospasms
disulfide bridges fibrosis. Pulmozyme
 esophageal
that bind contains an enzyme
varices
glycoproteins to called a DNase that
other proteins, acts like molecular
117
 scissors to cut the
long DNA strands
into smaller pieces.
This makes the
mucus thinner and
easier to cough up.
used for conditions
where there are a lot
AMBROXOL
of thick mucus in the
airway passages
LOWER RESPIRATORY DISORDERS
CHEST CAVITY
➜ a closed compartment bounded by 12 ribs,
the diaphragm, thoracic vertebrae, sternum,
neck muscles, and intercostal muscles
between the ribs
PLEURAE
➜ membranes that encase lungs
LUNG COMPLIANCE
➜ The lung volume based on the pressure in
the alveoli. This volume determines the
lung’s ability to stretch.
Factors that influence lung compliance:
1. Connective tissue (collagen and elastin)
2. Surface tension in the alveoli, which is
controlled by surfactant
BRONCHIAL SMOOTH MUSCLE
Tracheobronchial tube
➜ Composed of smooth muscle whose fibers
spiral round the tracheobronchial tube,
becoming more closely spaced as they near
terminal bronchioles. Constriction of these
muscles constricts airway.
Vagus nerve (Parasympathetic nervous
system)
➜ Releases acetylcholine, which causes
bronchoconstriction
Sympathetic nervous system
➜ Releases epinephrine, which stimulates the
beta2 receptor in the bronchial smooth
muscle, resulting in bronchodilation.
CYCLIC ADENOSINE
MONOPHOSPHATE (cAMP)
➜ The cytoplasm of bronchial cells increases
bronchodilation by relaxing the bronchial
smooth muscles.
➜ Pulmonary enzyme phosphodiesterase can
inactivate cAMP.
RESTRICTIVE LUNG DISEASE
➜ A decrease in total lung capacity as a result
of fluid accumulation or loss of elasticity of
the lungs.
CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
➜ Caused by airway obstruction with
increased airway resistance of airflow to
lung tissue.
ASTHMA
➜ An inflammatory disorder of the airway
walls associated with a varying amount of
airway obstruction.
➜ Triggered by stimuli such as stress,
allergens, and pollutants
➜ When activated by stimuli, the bronchial
airways become inflamed and edematous,
leading to constriction of air passages.
Inflammation aggravates airway
hyperresponsiveness to stimuli, causing
bronchial cells to produce more mucus,
which obstruct air passages.
Symptoms: wheezing, coughing, dyspnea
(breathless), chest tightness, bronchospasm
particularly at night or early in morning.
BRONCHIAL ASTHMA
118
➜ One of the COPD lung disease, is
characterized by period of bronchospasm
(constricted bronchioles) resulting in
wheezing and difficulty breathing.
Bronchospasm or bronchoconstriction, result
when lung tissue is exposed to extrinsic or
intrinsic factors stimulate a bronchoconstrictive
response.
Symptoms: same as asthma except wheezing.
Factors that trigger asthmatic attack:
1. Humidity
2. Air pressure changes
3. Temperature changes
4. Smoke
5. Fumes (exhaust, perfume)
6. Stress
7. Emotional upset
8. Exercise
9. Allergies to animal dander, dust mites,
foods , drugs
Reactive airway disease (RAD)
➜ Cause of asthma that results from
sensitivity stimulation from allergens, dust,
temperature changes, and cigarette
smoking.
CHRONIC BRONCHITIS
➜ Progressive lung disease caused by
smoking or chronic lung infection.
➜ Bronchial inflammation and excessive
mucous secretion result in airway
obstruction.
Hypercapnia (increased carbon dioxide
retention) and Hypoxemia (decreased blood
oxygen) lead to respiratory acidosis.
Bronchiectasis, dilation of the bronchi and
bronchioles is abnormal secondary to frequent
infection and inflammation.
EMPHYSEMIA
➜ A progressive lung disease caused by
cigarette smoking, atmospheric
contaminants, or lack of the alpha1 –
antitrypsin protein that inhibits proteolytic
enzymes that destroy alveoli (air sacs).
Proteolytic enzymes, released in the lung by
bacteria or phagocytic cells.
SYMPATHOMIMETRICS: ALPHA- AND
BETA2 – ADRENERGIC AGONIST
Sympathomimetic drugs are known as
adrenergic agonists. These are stimulant
compounds which mimic the effects of
endogenous agonists of the sympathetic
nervous system.
It increases cAMP, causing dilation of the
bronchioles. In an acute bronchospasm caused
by anaphylaxis, the nonselective
sympathomimetic epinephrine is given. Thus
for bronchospasm associated with asthma or
COPD, selective beta2-adrenergic agonists are
given by aerosol or tablet.
ALBUTEROL
➜ A selective beta2 drug that is effective for
treatment and control of asthma by causing
bronchodilation with a long duration of
action.
METAPROTERENOL
➜ It works by relaxing muscles in the airways
to improve breathing. This can be
administered orally or by inhalation with a
metered dose inhaler or a nebulizer. It is for
acute bronchospasm, asthma and COPD.
➜ Primarily used as beta2 agent
➜ Can be administered orally or by inhalation
with a metered-dose inhaler (MDI) or
nebulizer.
USE OF AN AEROSOL INHALER
For long term asthma treatment, beta2
adrenergic agonists are frequently administered
119
by inhalation. It may be given by MDI or DPI. ● dizziness
Correct use of the inhaler and dosage intervals ● diaphoresis
need to be explained to the patient. ● weakness
● paresthesia
Drug inhalation may cause mouth dryness and
● hypo/
throat irritation. Excessive use can lead
hypergycemia
tolerance and loss of drug effectiveness.
● angina
Ocassionally, bronchoconstriction may also
● palpitations
develop. Frequent dosing may cause tremors,
● tachycardia
nervousness, and increased heart rate.
● hypertension
ADRRENERGIC BRONCHODILATOR ● dysrhymthia
Alpha- and beta- Therapeutic Use: REVEFENACIN Therapeutic Use:
adrenergics: ● It is admistered in ● long term
emergency maintenance
EPINEPRHINE situations to restore treatment of
SULFATE circulation and bronchospasm
Alpha1, beta1 , increase airway associated with
beta2 patency. COPD
● Asthma ● bronchitis
● Acute ● emphysema
bronchospasm Side effect:
● hypotension ● headache
Side effect: ● cough
● Tremors ● infection
● dizziness, ● pharyngitis
● hypertension, ● dizziness
● tachycardia, ● hypertension
● palpitations, ● back pain
● dysrhythmias, FORMOTEROL Therapeutic Use:
● angina ● asthma
● tremors ● bronchitis
● headache ● COPD
● increase blood ● emphysema
glucose levels ● prophylaxis of
EPINEPHRINE Therapeutic Use: exercise-induced
● acute bronchospasm
bronchospasm Side effect:
● asthma ● dizziness
● anaphylaxis ● insomnia
● angioedema ● tachycardia
● nasal congestion ● chest pain
● status asthmaticus ● palpitations
Side effect: ● hypokalemia
● restlessness ● infection
● tremors ● nausea
120
 ● diarrhea ● nasal congestion
● hyperglycemia ● palpitations
LEVALBUTERO Therapeutic Use: ● tachycardia
L ● asthma ● hypokalemia
● bronchospasm ● hyperglycemia
● prophylaxis ● arthralgia
Side effect: ● myalgia
● dizziness TERBUTALINE Therapeutic Use:
● nasopharyngitis SULFATE ● asthma
● nausea / vomiting ● COPD
● diarrhea ● bronchospasm
● headache prophylaxis
● chest pain Side effect:
● hyperglycemia ● dizziness
● hypokalemia ● drowsiness
● tachycardia ● headache
● fever ● chest pain
● candidiasis ● dyspnea
● tremors ● tremors
METAPROTERE Therapeutic Use: ● nausea
NOL SULFATE ● acute ● vomiting
bronchospasm ● palpitations
● asthma ● tachycardia
● COPD ● hypokalemia
Side effect: ARFORMOTER Therapeutic Use:
● headache OL TARTRATE ● COPD
● dizziness Side effect:
● nervousness ● restlessness
● nausea ● tremor
● diarrhea ● headache
● fatigue ● sinusitis
● blurred vision ● muscle cramps
● chest pain ● dyspnea
● hypokalemia ● peripheral edema
● tremor ● back pain
● tachycardia ● hyperglycemia
● palpitations ● chest pain
Therapeutic Use: ● tachycardia
● asthma ● diarrhea
● COPD INDACATEROL Therapeutic Use:
● bronchospasm ● COPD
prophylaxis Side effect:
Side effect: ● Cough
● headache ● headache
● pharyngitis ● nasopharyngitis
121
 ● hyperglycemia  - useful for treating respiratory disorders
● hypokalemia (asthma,COPD), Parkinson’s, cardiovascular
● hypertension disease, urinanry incontinence, psychiatric
● tachycardia disorders, depression, mydriasis, and allergies.
OLODATEROL Therapeutic Use:
ADVERSE EFFECTS
● COPD
Side effect:   - Central effects result from the excess
● cough blockade of cholinergic receptors within the
● nasopharyngitis central nervous system, and peripheral
● hypokalemia adverse effects result from the blockade of
● hyperglycemia exocrine glandular secretion, muscle
● constipation contraction, and end-organ targets of the
● infection peripheral parasympathetic nervous system. 
CONTRAINDICATIONS
ANTICHOLINERGICS
  - myasthenia gravis, hyperthyroidism,
Drugs that block the action of acetylcholine. glaucoma, enlarged prostate, hypertension
Most anticholinergic drugs interact with the (high blood pressure), urinary tract blockage,
muscarinic receptors in the brain, secretory increased, heart rate (tachycardia), heart
glands, heart, and smooth muscle. failure, severe dry mouth, hiatal hernia, severe
constipation, liver disease, and Down
MECHANISM OF ACTION
syndrome. 
  - Competitively inhibit binding of the
TIOTROPIUM Therapeutic effects:
neurotransmitter, acetylcholine. They target
- For maintenance
either muscarinic acetylcholine receptors or,
treatment of asthma
less commonly, nicotinic acetylcholine
and COPD
receptors. 
SIDE EFFECT: Mechanism of
action:
• dry mouth - Blocks muscarinic
• blurry vision cholinergic receptors
• constipation and antagonizes
• drowsiness acetylcholine action
• sedation by inhibiting M3
• hallucinations receptors response to
• memory problems acetylcholine.
• trouble urinating Thereby. Relaxing
• confusion smooth muscle of
• delirium bronchi; dilates
• decreased sweating bronchi
• decreased saliva
Side effect:
INDICATIONS  insomnia
 dizziness
122
  depression  Blurred vision
 headache  Tachycardia
 sinusitis  Palpitations
 nasopharyngitis  Epistaxis
 cough  Nasopharyngitis
 dry mouth  Dyspnea
 nausea  Urinary retention
 vomiting  constipation
 abdominal pain ACLIDINIUM Therapeutics uses:
 constipation COPD
 urinary retention bronchospasm
 arthralgia Side effect:
 myalgia  headache
 peripheral edema  blurred vision
 blurred vision  ocular
 oral ulceration hypertension
 infection  urinary retention
 anaphylaxis (AR)  Nasopharyngitis
 angioedema (AR) UMECLIDINIUM Therapeutics uses:
 dehydration (AR) COPD
Side effect:
 hyperglycemia
(AR)  Nasopharyngitis
 chest pain (AR)  Blurred vision
 GI obstruction  Ocular
(AR) hypertension
 Cataracts (AR)  Depression
 Tachycardia
Contraindications:  Urinary retention
- Hypersensitivity  Constipation
to atropine or its  infection
derivatives,
including
ipratropium, MONOCLONAL ANTIBODY
tiotropium, or their OMALIZUMAB Therapeutics uses:
components Asthma
IPRATROPIUM Therapeutics uses: Chronic urticaria
BROMIDE Side effect:
 Allergic rhinitis
 dizziness
 Common cold
 headache
 COPD
 pharyngitis
 Bronchospasm
prophylaxis  sinusitis
Side effect:  arthralgia
 Headache  bone fractures
 rash
123
  peripheral edema UM and  infection
 hypotension VILANTEROL  hypokalemia
 injection site GLYCOPYRR  palpitations
reaction OLATE and  chest pain
 infection FORMOTERO  tachycardia
RESLIZUMAB Therapeutics uses: L  edema /
asthma ACLIDINIUM Peripheral
Side effect: and edema
 pharyngitis FORMOTERO  urinary
 musculoskeletal L FUMARATE retention
pain  insomnia
 dyspnea  constipation
 antibody
formation
 hypotension METHYLXANTHINE (XANTHINE)
DERIVATIVES
 malignancy
DUPLILUMAB Therapeutics uses: ● Second major group of bronchodilators
Moderate to severe used to treat asthma
asthma
Side effect: ● Xanthines stimulate the central nervous
 injection site system (CNS) and respiration, dilate
reaction coronary and pulmonary vessels, and cause
 ocular pruritus diuresis
 conjunctivitis
● Aminophylline, Theophylline, and Caffeine
 blepharitis
 keratitis AMINOPHYLLIN Mechanism of
 xerophthalmia E- action:
 antibody THEOPHYLLINE relaxes the smooth
formation muscles of the
bronchi, bronchioles,
and pulmonary blood
COMBINATION BETA-ADRENERGIC vessels by inhibiting
AND ANTICHOLINERGICS the enzyme
IPATROPIUM Thera Side effect: phosphodiesterase,
and peutic  headache resulting in an
ALBUTEROL use:  blurred vision increase in cAMP,
INDACATER  pharyngitis / which promotes
OL and Nasopharyngiti bronchodilation
GLYCOPYRR COP s Therapeutic effect:
OLATE D  ocular  prevent and treat
OLODATERO hypertension / wheezing,
L and Hypertension  shortness of
TIOTROPIUM  hyperglycemia breath
UMECLIDINI  chest
124
 tightness caused or any component of
by asthma its formulation 
 Chronic
bronchitis,
LEUKOTRIENE RECEPTOR
 Emphysema
ANTAGONIST AND SYNTHESIS
 other lung INHIBITORS
diseases. It
relaxes and opens Leukotriene (LT), chemical mediator that can
air passages in cause inflammatory changes in the lung.
the lungs, making
it easier to Cysteinyl leukotrienes, promote an increase in
breathe. eosinophil migration, mucous production and
Side / Adverse airway wall edema that results in
Effects: bronchoconstriction.
 anorexia LT receptor antagonists and LT synthesis
 nausea/vomiting inhibitors called Leukotriene modifiers, are
 gastric pain effective in reducing the inflammatory
caused by symptoms of asthma triggered by allergic and
increased gastric environmental stimuli.
acid secretion
 Not recommended for treatment of
 intestinal
acute asthmatic attacks rather they are
bleeding
used for exercise-induced asthma.
 nervousness
 dizziness Leukotriene Mode of action:
 headache receptor Acts as a leukotriene
 irritability antagonist: receptor antagonist,
 cardiac reducing inflammation
dysrhythmias ZAFIRLUKAST process and
 tachycardia decreasing
 palpitations bronchospasm.
 marked Therapeutic Use:
hypotension Asthma
 hyperreflexia Side effect:
 Seizures  Headache
 restlessness,  Depression
 insomnia  Chet pain
 Restlessness
Contraindication:  Hyperbilirubinemi
Theophylline is a
contraindicated if the  Peripheral
patient previously neuropathy
developed a  Nausea/vomiting
hypersensitivity  diarrhea
reaction to the drug MONTELUKAST Therapeutic Use:
125
  Allergic rhinitis ROFLUMILAST  Depression
 Asthma  Headache
 For exercise-  Nausea
induced  Diarrhea
bronchospasm  Weight loss
propylaxis  Back pain
Side Effect:
 Agitation
 Insomnia GLUCOCORTICOIDS (STEROIDS)
 Confusion ➜ Used to treat respiratory disorders,
 Depression particularly asthma.
 Influenza ➜ These drugs have an anti-inflammatory
 Palpitations action and are indicated if asthma is
 Angioedema (AR) unresponsive to bronchodilator therapy or if
 Bleeding seizures the patient has an asthmatic attack while on
(AR) maximum doses of theophylline or an
 Suicidal ideation adrenergic drug.
(AR)
 Anaphylaxis (AR) METHODS:
 Thrombocytopenia  MDI Inhalator
(AR) o Not helpful in treating severe
Leukotriene MOA: asthmatic attack because it can take
synthesis inhibitor: It decreases the 1 to 4 weeks for an inhaled steroid
inflammatory process to reach its full effect.
ZILEUTON and decreases o More effective for controlling
bronchospasm. symptoms of asthma that are beta2
Therapeutic Use: antagonist, particularly in the
Asthma reduction of bronchial
Side effect: hyperresponsiveness.
 Headache o Minimizes the risk of adrenal
 Chills suppression associated with oral
 Asthenia systemic glucocorticoid therapy.
 Fatigue  Tablet
 Myalgia  Intravenous
 Abdominal pain
 Dyspepsia Therapeutic Use:
 Nausea Allergic rhinitis
Intranasal Nasal polyps
 Constipation
spray: asthma
 Sinusitis
Side effect:
 infection
BECLOME  Nasopharyngitis
Phosphodiesterase- Therapeutic use:
THASONE  Candidiasis
4 inhibitor: COPD
Side effect:  Dysphonia
 Hoarseness
126
  Epistaxis Side effect:
 Ocular hypertension  Headache
Therapeutic Use:  Candidiasis
 Rhinitis  Pharyngitis
 asthma  Cough
Side effect:  Fatigue
 Headache  Sinusitis
 Weakness  Wheezing
BUDESONI
 Fatigue  Arthralgia
DE
 Dyspepsia  epistaxis
 Nausea Therapeutic Use:
 Diarrhea Allergic rhinitis
 Cough Side effect:
 Rhinitis TRIAMCIN  Ocular hypertension
 epistaxis OLONE  Rash
Therapeutic Use:  Euphoria
 Allergic rhinitis  Blurred vision
 asthma  Nasal irritation
Side effect: Aerosol Inhalation
FLUNISOLI  Nasal irritation BECLOME
DE  Dysgeusia THASONE
 Hoarseness FLUNISOLI
 Ocular hypertension DE
 Dysphoria BEDUSONI
 candidiasis DE
Therapeutic Use: FLUTICAS
Allergic rhinitis ONE
Side effect: Oral and intravenous administration
 Headache CORTISON
Therapeutic Use:
E
 Blurred vision Adrenocortical insufficiency
ACETATE
 Fatigue
DEXAMET Therapeutic Use:
FLUTICAS  Insomnia HASONE Adrenocortical insufficiency
ONE  Arthralgia FLUDROC Therapeutic Use:
 Epistaxis ORTISONE Adrenocortical insufficiency
 Pharyngitis ACETATE (Addison disease)
 Nasal HYDROCO Therapeutic Use:
candidiasis/irritation RTISONE Adrenocortical insufficiency
 Dysphonia METHYLP
 Nausea/vomiting Therapeutic Use:
REDNISOL
Therapeutic Use: Adrenocortical insufficiency
MOMETAS ONE
 Allergic rhinitis Therapeutic Use:
ONE PREDNISO
 Nasal congestion Parenteral use in primary or
FUROATE LONE
polyps secondary adrenocortical
127
 insufficiency histamine and other inflammatory
Therapeutic Use: mediators from mast cells to prevent an
PREDNISO asthma attack
Adrenocortical insufficiency,
NE
Addison disease
Therapeutic Use:
Combination glucocorticoids and beta2
agonist  Allergic rhinitis
 Conjunctivitis
 Headache
 Asthma
 Blurred
vision  Exercise-
induced
 Pharyngitis
bronchospasm
 Tachycardia
prophylaxis
 Palpitate CROMOLYN Side effect:
FLUTICAS  Infection SODIUM  Headache
ONE and  oral  Cough
SALMETE candidiasis
 Hoarseness
ROL  nausea/
 Nausea
vomiting
 Diarrhea
 hyperglycemi
Therape  Palpitations
a
utic Use:  hypokalemia  Tachycardia
 Myalgia
 musculoskele
Asthma
tal pain
COPD
 headache GASTROINTESTINAL SYSTEM
 Nasopharyng
EMETICS
itis
FLUTICAS  candidiasis ➜ Drugs are used to induce vomiting.
ONE  fatigue ➜ When an individual has emetics are
FUROATE  infection indicated to expel the substance before
and  hyperglycemi absorption occurs. Vomiting can be
VILANTER a induced in a number of ways without using
OL  hypokalemia drugs, such as putting a finger in the back
 palpitations of the throat.
 tachycardia ➜ Vomiting should not be induced if caustic
 insomnia substances such as ammonia, chlorine
bleach, lye, toilet cleaners, or battery acid
have been the esophagus.
CROMOLYN
➜ To prevent aspiration, vomiting should
➜ Used for prophylactic treatment of ingested.
bronchial asthma, and it must be taken ➜ Regurgitating these substances can cause
daily. additional injury to also be avoided if
➜ Not used for acute asthmatic attacks petroleum distillates are ingested; these
➜ Does not have bronchodilator properties but include gasoline, kerosene, paint thinners,
instead acts by inhibiting release of and lighter fluid.
128
➜ Activated charcoal is given or gastric  Used to treat nausea and
lavage is done when emesis is vomiting resulting from
contraindicated surgery, anesthetics,
chemotherapy, and radiation
ANTIEMETICS (antivomiting agents) sickness.
 They act by inhibiting CTZ
➜ Vomiting (emesis), the expulsion of gastric
o Butyrophenones
contents, has a multitude of causes,
including motion sickness, viral and  Block the D2 receptors in the
bacterial infection, food intolerance, CTZ.
surgery, pregnancy, pain, shock, effects of  They are used to treat
selected drugs, radiation, and disturbances postoperative nausea and
of the middle ear that affect equilibrium. vomiting and emesis
associated with toxins,
➜ Antiemetics can mask the underlying cause
cancer chemotherapy, and
of vomiting and should not be used until
radiation therapy.
the cause dehydration and electrolyte
o Benzodiazepines
imbalance.
 Indirectly control nausea and
TWO MAJOR CEREBRAL CENTERS vomiting that may occur
with cancer chemotherapy.
Chemoreceptor trigger zone (CTZ), lies near o Serotonin- receptor antagonists
medulla  Suppress nausea and
Vomiting center, caused vomiting when vomiting by blocking the
stimulated. serotonin (5-HT3) receptors
in the CTZ and blocking the
TWO MAJOR GROUP OF afferent vagal nerve
ANTIEMETICS terminals in the upper GI
 Non prescription tract
o Can be purchased as over-the- o Glucocorticoids (corticosteroids)
counter (OTC) drugs.  Dexamethasone and
o Frequently used to prevent motion methylprednisolone are two
agents that are effective in
sickness but have minimal effect on
suppressing emesis
controlling severe vomiting
associated with cancer
resulting from anticancer agents,
chemotherapy.
radiation and toxins.
o Cannabinoids
 Prescription
 The active ingredients in
o Antihistamines and
Cannabis, were approved
anticholinergics
for clinical use in 1985 to
o Dopamine antagonist
alleviate nausea and
 These agents suppress vomiting resulting from
emesis by blocking cancer treatment.
dopamine (D2) receptors in  These agents may be
the CTZ. prescribed for patients
o Phenothiazine antiemetics receiving chemotherapy who
do not respond to or are
129
 unable to take other vomiting
antiemetics. Side effect:
o Miscellaneous antiemetics  Drowsiness
 Trimethobenzamide, in the  Dizziness
class of miscellaneous  Headache
antiemetics because it does  Restlessness
not act strictly as an  Blurred vision
antihistamines,  Anorexia
anticholinergics, or  Dry mouth
phenothiazine.
 Insomnia
 The drug suppresses
 tachycardia
impulses to the CTZ
MECLIZINE Therapeutic use:
 Metoclopramide,
HYDROCHLORI For prevention and
suppresses emesis by
DE treatment of nausea,
blocking the dopamine
vomiting, and
receptors in the CTZ.
dizziness due to
 Used in the treatment
motion sickness and
of postoperative
vertigo associated
emesis, cancer
with vestibular
chemotherapy, and
disorder.
radiation therapy
Side effect:
NONPRESCRIPTION ANTIEMETICS:  Drowsiness
antihistamines  headache
Motion sickness: Therapeutic use:  ataxia
CYCLIZINE  Prevention and  fatigue
HYDROCHLORI treatment of  blurred vision
DE nausea, vomiting  dry mouth
and dizziness PRESCRIPTION ANTIEMETICS
associated with Antihistamines: Therapeutic use:
motion sickness  Postoperative
 Avoid concurrent HYDROXYZINE nausea and
alcohol use vomiting
Side effect:  Vertigo
 Drowsiness  Anxiety
 Blurred vision  Agitation
 Fatigue  Sedation
 Xerostomia induction
 Anorexia  Give deep in large
 Constipation muscle
 Nasal dryness Side effect:
DIMENHYDRINA Therapeutic use:  Drowsiness
TE Prevent and treat  Dizziness
motion sickness,  Fatigue
dizziness, nausea and
130
  Ataxia  nausea/vomiting,
 Headache  sedation induction
 Blurred vision Side effect:
 Dry mouth  confusion
 Urinary retention  agitation
 constipation  anorexia
Anticholinergics: Therapeutic use:  dry mouth
Nausea/vomiting  constipation
SCOPOLAMINE Motion sickness  blurred vision
(Transdermal patch) IBS  excitability
Side effect:  photosensitivity
➜ alternative ears  Dizziness  fatigue
if using for  Drowsiness  hypo/hypertension
longer than 3d,  Headache  urinary retention
wash hands after  Fatigue
 injection site
applying patch,  Blurred vision reaction
and wear no  Restlessness  incoordination
more than one
 Orthostatic  slate gray skin
patch at a time
hypotension hyperpigmentatio
 Dry mouth n
 constipation  erectile/
Dopamine Therapeutic use: ejaculation
antagonist  Nausea / vomiting dysfunction
Phenothiazine:  Schizophrenia  extrapyramidal
 anxiety syndrome (AR)
PROCHLORPER Side effect:  seizures (AR)
AZINE  Drowsiness  NMS (AR)
MALEATE  Dizziness  Agranulocytosis
 Headache (AR)
Not approved for
 Insomnia CHLORPROMAZ Therapeutic use:
patients with
 Blurred vision INE  Nausea/vomiting
dementia-related
psychosis  Tachycardia  Hiccups
 Hypotension  schizophrenia
 EPS Side effect:
 Erectile/  Drowsiness
ejaculatory  Dizziness
dysfunction  Weight gain
 Constipation  Xerostomia
 Urinary retention  Photosensitivity
PROMETHAZINE Therapeutic use:  Akathisia
 To treat and  Dystonic reaction
prevent motion  pseudoparkinsonis
sickness, m
131
Butyrophenones: Therapeutic use:  headache
 Postoperative  weakness
DROPERIDOL nausea/vomiting  hematoma
 Sedation  fatigue
induction  anorexia
Side effect:  abdominal pain
 Hypo/  diarrhea
hypertension  constipation
 Tachycardia  injection site
 Dizziness reaction
 Drowsiness ONDANSETRON Therapeutic use:
 Anxiety HYDROCHLORI Postoperative and
 Restlessness DE chemo-induced
 Dysrhythmias nausea/vomiting
 EPS Side effect:
Benzodiazepines: Therapeutic use:  dizziness
 For prevention of  drowsiness
LORAZEPAM chemo-induced  agitation
nausea/vomiting  headache
 Anxiety  fatigue
 Insomnia  diarrhea
 Procedural  hypotension
sedation  urinary retention
 Status epilepticus  fever
Side effect:  constipation
 Dizziness PALONOSETRO Therapeutic use:
 Drowsiness N Postoperative and
 Ataxia chemo-induced
 Confusion nausea/vomiting
 Injection site Side effect:
reaction  Headache
 EPS  Dizziness
 Constipation  Hypotension
 Weakness  Flatulence
 Hypotension  Constipation
 Restlessness  Diarrhea
 dependence  Urinary retention
Serotonin (5-ht3) Therapeutic use: DOLASETRON Therapeutic use:
receptor Radiation- and Nausea/vomiting
antagonists: chemo-induced Side effect:
nausea and vomiting  Headache
GRANISETRON Side effect:  Dizziness
 dizziness  Confusion
132
  Edema anesthetics Seizures
 Hypotension EPS
 Palpitations diarrhea
 Constipation APREPITANT Therapeutic use:
Cannabinoids: Therapeutic use: Postoperative and
 Anorexia chemo-induced
DRONABINOL  Chemo-induced nausea and vomiting
CSS III nausea/vomiting Side effect:
Side effect: Dizziness
Fatigue
 Dizziness
Headache
 Drowsiness
Weakness
 Impaired Hypotension
cognition Hiccups
 Euphoria Cough
 Dysphoria Abdominal pain
 Paranoia Dyspepsia
 Ataxia Diarrhea
 Tachycardia constipation
 Hypotension NETUPITANT Therapeutic use:
 Nausea/vomiting and Postoperative and
 Abdominal pain PALONOSETRO chemo-induced
Miscellaneous: Therapeutic use: N nausea and vomiting
Postoperative and Side effect:
METOCLOPRAM chemo-induced Headache
IDE nausea and vomiting Asthenia
HYDROCHLORI Diabetic gastroparesis Fatigue
DE GERD Dyspepsia
Side effect: Urinary retention
Avoid alcohol and Drowsiness constipation
CNS depressants Visual disturbances ROLAPITANT Therapeutic use:
Fatigue Chemo-induced
Restlessness nausea and vomiting
Headache Side effect:
Nausea/vomiting Dizziness
TRIMETHOBENZ Therapeutic use: Anorexia
AMIDE Nausea/vomiting Abdominal pain
HYDROCHLORI Side effect: Dyspepsia
DE Drowsiness Infusion site reaction
Dizziness Hiccups
Avoid CNS Headache Stomatitis
depressants and if Hypotension infections
sensitive to Blurred vision
benzocaine or Muscle cramps
similar local DIARRHEA
Injection site reaction
133
Diarrhea, frequent liquid stool, is a symptom of
an intestinal disorder.
Causes include:
1. Foods (spicy, spoiled)
2. Fecal impaction
3. Bacteria (Escherichia coli, Salmonella) or
viruses (parvovirus, rotavirus)
4. Toxins
5. Drug reactions
6. Laxative abuse
7. Malabsorption syndrome caused by lack of
digestive enzymes
8. Stress and anxiety
9. Bowel tumor
10. Inflammatory bowel disease such as
ulcerative colitis or Crohn disease, Diarrhea
can be mild to severe.
➜ Antidiarrheals should not be used for more
than 2 days and should not be used if fever
is present.
➜ Because intestinal fluids rich in water,
sodium, potassium, and bicarbonate,
diarrhea can cause minor or severe
dehydration and electrolyte imbalances.
The loss of bicarbonate places the patient at
risk for developing metabolic acidosis.
Patients with diarrhea should avoid milk
products and foods rich in fat.
➜ Diarrhea can develop very quickly and can
be life threatening to young patients and
older adults, who may not be able to
compensate for the fluid and electrolyte
losses.
NONPHARMACOLOGIC MEASURES
➜ The cause of diarrhea should be identified.
➜ Nonpharmacologic treatment for diarrhea is
recommended until the underlying cause
can be determined.
➜ This includes use of clear liquids and oral
solutions such as Gatorade (for adults) and
Pedialyte or Rehydralyte (for children) and
IV electrolyte solutions.
➜ Antidiarrheal drugs are frequently used in
combination with nonpharmacologic
treatment.
Travelers’ Diarrhea
Travelers' diarrhea, also called acute diarrhea,
is usually caused by E. coli, it ordinarily lasts
less than 2 days; however, If it becomes severe,
fluoroquinolone antibiotics are usually
prescribed. Loperamide may be used to slow
peristalsis and decrease the frequency of
defecation, but it can also slow the exit the
organism from the Gl tract. Travelers diarrhea
can be reduced by drinking bottled water,
washing fruit, and eating cooked vegetables.
Meats should be cooked until well done.
ANTIDIARRHEALS
There are various antidiarrheals for treating
diarrhea and decreasing hypermotility
(increased peristalsis). Usually, an underlying
cause of the diarrhea needs to be corrected as
well.
The antidiarrheals are classified as
1. Opiates and opiate -related agents
2. Adsorbents
3. Miscellaneous antidiarrheals.
OPIATES AND OPIATE-RELATED
AGENTS
➜ Opiates decrease intestinal motility, thereby
decreasing peristalsis. Constipation is a
common side effect of opium preparations,
Codeine is an example.
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➜ Opiates are frequently combined with other
antidiarrheal agents. Opium antidiarrheals
can cause CNS depression when taken with
alcohol, sedatives, or tranquilizers.
➜ The duration of action of opiates is
approximately 2 hours.
ADSORBENTS
Adsorbents act by coating the wall of the Gl
tract and adsorbing includes these other
antidiarrheals. Adsorbent antidiarrheals include
kaolin and pectin. These agents are combined
as a mild or moderate antidiarrheal that can be
purchased without a prescription and used in
combination with other antidiarrheals. Bismuth
subsalicylate is considered an adsorbent
because it adsorbs bacterial toxins. Bismuth
subsalicylate is an OTC drug commonly used
to treat travelers' diarrhea, and can also be used
as an antacid for gastric discomfort. Side
effects include dizziness, drowsiness,
weakness, headache, tongue and stool
discoloration. and anxiety. Colestipal and
cholestyramine are prescription drugs that have
been used to treat diarrhea due to excess bile
acids in the colon. They are effective, although
they have not been approved by the FDA for
this purpose.
Miscellaneous Antidiarrheals
Various miscellaneous antidiarrheals are
prescribed to control diarrhea. This group
includes rifaximin. Side effects include
dizziness, nausea. dry mouth, flatulence,
constipation, and fatigue.
CONSTIPATION
Constipation, the accumulation of hard fecal
material in the large intestine, is a relatively
common complaint and major problem for
older adults. Insufficient water intake and poor
dietary habits are contributing factors.
Other causes include:
1. Fecal impaction
2. Bowel obstruction
3. Chronic laxative use
4. Neurological disorders plegia
5. Ignoring the urge to defecate
6. Lack of exercise
7. Select drugs such as anticholinergics,
narcotics, and certain antacids.
Osmotic (Saline) Laxatives
Osmotics, hyperosmolar laxatives, include salts
or saline products, lactulose, and glycerine.
Saline products consist of sodium or
magnesium, and a small amount is systemically
absorbed. Serum electrolytes should be
monitored to avoid electrolyte imbalance,
Hyperosmolar salts pull water into the colon
and increase water in the feces to increase bulk
which stimulates peristalsis. Saline cathartics
cause a semiformed to watery stool according
to low or high doses. Good renal function is
needed to excrete any excess salts. Saline
cathartics are contraindicated for patients with
heart failure.
STIMULANT (CONTACT) LAXATIVES
Stimulant (contact or irritant) laxatives increase
peristalsis by irritating sensory nerve endings
in the intestinal mucosa. Types include those
that contain bisacodyl, senna, and castor oil
(purgative). Bisacodyl is the most frequently
used and abused laxative and can be purchased
OTC. Bisacodyl and several others of these
drugs are used to empty the stool, cathartics
result in a soft to watery stool with tone
laxatives Bisacodyl lists the pharmacological
data for the stimulant laxative bowel before
diagnostic tests (barium enema).
Castor oil is a harsh laxative (purgative) that
acts on the small bowel and produces a watery
stool. The action is quick, within 2 to 6 hours,
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so the laxative should not be taken at bedtime.
Castor oil is not FDA approved to correct
constipation, rather it is used mainly for bowel
preparation. LAXATIVES
BULK-FORMING LAXATIVE Osmotic: Saline Therapeutic Use:
constipation
➜ Natural fibrous substances that promote GLYCERIN Side effect:
large, soft stools by absorbing water into Perianal irritation
the intestine, increasing fecal bulk and LACTULOSE Therapeutic Use:
peristalsis. Constipation
➜ These agents are nonabsorbable. Hepatic
➜ Defecation usually occurs within 8 to 24 encephalopathy
hours; however, it may take up 3 days after Side effect:
drug therapy is started for the stool to be Flatulence
soft and well formed. Eructation
Metabolic acidosis
➜ Powdered bulk-forming laxatives, which is
Hypokalemia
sometimes come in flavoured and sugar-
hypernatremia
free forms, should be mixed in a glass of
MAGNESIUM Therapeutic Use:
water or juice, stirred, drunk immediately,
CITRATE Constipation
and followed by a half to a full glass of
Bowel preparation
water.
Side effect:
➜ Insufficient fluid intake can cause the drug Abdominal cramps
to solidify in the GI tract, which can result Flatulence
in intestinal obstruction. Hypermagnesemia
➜ Does not cause laxative dependence and Dehydration
may be used by patients with diverticulosis, MAGNESIUM Therapeutic Use:
irritable bowel syndrome (IBS), and HYDROXIDE Constipation
ileostomy and colostomy. Dyspepsia
CHLORIDE CHANNEL ACTIVATORS Pyrosis
Side effect:
➜ Used to treat idiopathic constipation in Chalky taste
adult Dehydration
Hypermagnesemia
EMOLLIENTS (stool softeners) Stimulants: Therapeutic Use:
➜ Lubricants and stool softeners used to Bowel preparation
prevent constipation BISACODYL Constipation
Side effect:
➜ Decrease straining during defecation
Rectal burning
➜ Work by lowering surface tension and Hypokalemia
promoting water accumulation in the Dependence
intestine and stool CASTOR OIL Therapeutic Use:
➜ Prescribed to patient with myocardial Bowel preparation
infarction or surgery Side effect:
Steatorrhea
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 Pruritus ani XONE Opioid induced
SENNA Therapeutic Use: constipation
Constipation Side effect:
Bowel preparation Abdominal
Side effect: pain/distension
Fluid and Flatulence
electrolytes hyperhidrosis
imbalances PRUCALOPRIDE Therapeutic Use:
Diarrhea Chronic idiopathic
Abdominal cramps constipation
Selective Chloride Therapeutic Use: Side effect:
Channel Activator: Constipation Diarrhea
IBS Flatulence
LUBIPROSTONE Opioid- induced Abdominal pain
constipation TENAPANOR Therapeutic Use:
Side effect: IBS with
Peripheral edema constipation
Fatigue Side effect:
Hypotension Flatulence
Flatulence Diarrhea
Miscellaneous: Therapeutic Use: GI bleeding
Constipation Bulk forming: Therapeutic Use:
LINACLOTIDE IBS Constipation
Side effect: POLYCARBOPHI IBS
Flatulence L Side effect:
Abdominal Anorexia
distension/pain Flatulence
Hypokalemia Abdominal cramps
Hyponatremia Distension
Infection POLYETHELYEN Therapeutic Use:
hypotension E GLYCOL Constipation
NALOXEGOL Therapeutic Use: Bowel preparation
Opiate agonist- Side effect:
induced constipation fecal incontinence
Side effect: abdominal cramps
Flatulence flatulence
Hyperhidrosis METHYLCELLUL Therapeutic Use:
NALDEMEDINE Therapeutic Use: OSE Constipation
Opiate agonist- Side effect:
induced constipation GI obstruction
Side effect: Abdominal cramps
Abdominal pain Diarrhea
Nausea/vomiting PSYLLIUM Therapeutic Use:
Diarrhea HYDROPHILIC Constipation
METHYLNALTRE Therapeutic Use: MUCILLOID Side effect:
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 Esophageal or
intestinal obstruction
Flatulence
Anorexia
Diarrhea
Emollients: Stool Therapeutic Use:
Softeners Constipation
Side effect:
DOCUSATE Throat irritation
CALCIUM; Diarrhea
DOCUSATE Abdominal pain
SODIUM
DOCUSATE Therapeutic Use:
SODIUM WITH constipation
SENNA Side effect:
Hypocalcemia
Hypokalemia
Flatulence
Abdominal cramps
Emollient: Therapeutic Use:
Lubricant Constipation
Fecal impaction
MINERAL OIL Cardiac disorder
Anorectal surgery
Side effect:
fecal
urgency/incontinence
skin irritation
anal leakage
Evacuant / Bowel Therapeutic Use:
Preparation: Constipation
Bowel preparation
POLYETHYLENE Side effect:
GLYCOL- Flatulence
ELECTROLYTE Abdominal cramps
Fecal
urgency/incontinence

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