Drug Therapy for Lung Cancer: Pathophysiology, Pharmacokinetics, and Side Effects

This article discusses the pathophysiology of lung cancer, the pharmacokinetics of chemotherapy medications, the effect of chemotherapy, side effects of chemotherapy, adverse reaction of morphine and management. It also compares the mechanism of action of Cisplatin and docetaxel with nivolumab and explains the reason behind the side effects of chemotherapeutic agents.

Running head: DRUG THERAPY
Name of the Student
Name of the University
Author Note

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Introduction:
Lung cancer is the leading cause of cancer associated with death around the world. As
discussed by every year a significant number of Americans die because of lung cancer compared
to other cancers such as prostate, colon and breast cancer. The common symptoms include
persistent cough, chest pain, unexpected loss of appetite, coughing blood, shortness of breath,
lung infections such as bronchitis and pneumonia (Torre, Siegel and Jemal, 2016). The world
health organization suggested that a total of 1,350,000 new cases are diagnosed every year and
161,250 deaths observed because of the high prevalence of lung cancer (Goldstraw et al. 2018).
In 2010, 239,320 new cases of lung cancer were reported, indicating a high prevalence of lung
cancer in western countries (Didkowska et al. 2016). The world cancer research fund reported
that in 2018, 2 million new cases of lung cancer were reported. The survival rates in non-small
cell lung cancer mostly determined by the stage at which the patient was diagnosed, on an
average the survival rate is 5 years (Silverman 2017). The researchers documented that in men,
non-small cell lung cancer is the most common form of cancer which disrupts normal life (Grulich
and Vajdic 2015). Most of the patient experience severe chest pain, especially in the right upper
quadrant, discomfort, coughing (Rafiemanesh et al. 2016). The case study represents primary stage
4 non-small cell lung cancer of Nigel who is 78 years man and he had substantial liver
metastases. He was experiencing pain right upper quadrant which was making him
uncomfortable. This paper will illustrate pathophysiology of lung cancer, the pharmacokinetics
of chemotherapy medications, the effect of chemotherapy, side effects of chemotherapy, adverse
reaction of morphine and management.

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Discussion:
Lung cancer is a type of cancer which begins in the lungs. As discussed by Alexande et
al. (2016), smoking is the leading cause of lung cancer where active and passive smoker both can
be the victim of lung cancer. However, other risk factors such as exposure to radon, exposure to
asbestos, air pollution, certain dietary supplements with beta carotene are also a contributor to
lung cancer (Stone et al. 2018). The researchers documented that these risk factors facilitate the
damage of cell limes of lungs which further causes immediate damage to lung tissues. Taking an
insight into the situation, Nigel was suffering from stage 4 non-small cell lung cancer which
widespread throughout his lungs and showed metastases. Stage IV non-small longer cancer is the
most advanced form of epithelial lung cancer which manifested as difficulties in breathing and
metastasis. The non-small cell lung cancer is developed in patients when epithelial cells of the
lungs become abnormal and begin to grow exponentially. In advance stage, the lung cancer
spread other parts of the body followed by showing an array of signs and symptoms (Vodermaier
et al. 2018). Considering pathophysiology, lung cancer can cause shortness of breath or
dysphonia by blocking airway which results in lack of oxygen and shortness of breath (Gazdar
and Zhou 2018). When air away is blocked by the tumor, the mucus trapped in the lungs can be
infected and causes the shortness of breathing (George et al. 2015). Hence, patients with lung
cancer usually experience difficulty in breathing as observed in this case study.
Considering the metastasis of cancer, the non-small cell lung cancer is any type of cancer
which affects the epithelial cells. While in the advantages of lungs, it can speed to the lymph
node, brain kidney, and liver non-small cell lung cancer (O'byrne et al. 2016). Metastases most
commonly develop when cancer cells break away from the main tumor and reach the
bloodstream or lymphatic system. Since the lungs are situated immediately adjacent to the liver,
the cancer cells break from the main tumor and affect the normal function of the liver by

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affecting lymph nodes closure to liver and damage liver tissue (George et al. 2015). Hence, Nigel
developed substantial metastasis which further resulted in the disruption of a healthy life.
Pharmacokinetics of his chemotherapy medications:
As observed in this case study, the patient was diagnosed with stage four non-small cell
lung cancer which spreader throughout his lungs and substantial liver metastases, indicating
secondary lung cancer. Since the liver plays a major role in the metabolism of drugs, the
pharmacokinetics of drugs may be affected (Kubota et al. 2015). The first pass metabolism is a
phenomenon where drug concentration is greatly reduced before it reaches to the systematic
circulation through the blood (Thapa et al. 2016). Considering the chemotherapeutic drugs that
were given to Nigel, in oral administration, both the drugs are absorbed by the liver for further
metabolized into active drugs. After metabolism, these drugs usually eliminated from the body in
the form of the urine. When chemotherapeutic drugs such as Cisplatin and docetaxel are
administrated in patients, it absorbed by the digestive system and entered into the hepatic system
through the portal vein (Abe et al. 2016). The metabolized the drugs into a small amount of
active drug which emerges to the rest of the circulatory system. Hence, it hepatic first-pass
metabolism greatly reduce the bioavailability of the drug. However, in the current context,
because of secondary cancer in the liver, he was administrated in the form of intravenous
infusion in 3 weeks. In intravenous infusion therapy, the liquid form of chemotherapeutic drugs
is administrated directly into the vein with the help of injection for a long period of time. It is
given at a slower rate to work on the location of the disease. In this case, while the drugs are
injected directly into the vein, the drugs directly reach the bloodstream to act on the location of
disease, in this case, lungs (Cascone et al. 2018). While in oral administration the substantial
amount of drugs are lost because of digestion and metabolism into the liver, the bioavailability of

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these drugs in IV infusion is 100% since it can easily avoid first pass metabolism. Hence,
considering secondary cancer in the liver, there will be no impact on the pharmacokinetics of
chemotherapeutic drugs such as Cisplatin and docetaxel. The drugs can directly on the lung by
transported directly through the bloodstream.
The effect of chemotherapeutic drugs in treating lung cancer:
As observed in this case study, 78 years of patient, Nigel was diagnosed with stage four
non-small cell lung cancer which further result in liver metastases. In order to manage the lung
cancers, he was administrated with Cisplatin and docetaxel, IV infusion for every three weeks.
Considering the complexity of cancer chemotherapy, researchers reported that An Active
Combination Regimen of Cisplatin and docetaxel in Non-Small-Cell Lung Cancer is effective in
curing this type of lung cancer (Zhang et al. 2016). Cisplatin is a platinum-based
chemotherapeutic drug which is able to stop tumor growth by cross-linking guanine bases in
DNA double helix. Consequently, DNA strands are unable to separate and uncoil, disrupting the
cell division (Li et al. 2017). In addition, the drug adds methyl group in the DNA causes
miscoding of DNA and disruption of DNA function which further affects the downstream
mechanisms such as RNA transcription and protein synthesis. However, in advance stage of
cancer if this drug failed to reduce the cell growth, then another drug is used in combination (Li
et al. 2017). In that case, Docetaxel is used as a combination with Cisplatin after Cisplatin failed
to cure lung cancer alone. The docetaxel is a semisynthetic taxoid which acts as the synergistic
agent to enhance the activity of Cisplatin (Ahn et al. 2015). It is clinically established anti-
mitotic chemotherapy medication used mainly used in the treatment of ovarian, breast and non-
small cell lung cancer. Docetaxel binds with tubulin with high affinity in a 1: 1 ratio in a reverse
manner. After binding to the microtubules, it disrupts the normal function of microtubule growth.

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It promotes the assembly of microtubules from the tubulin dimers and prevents depolarization
that stabilizes the effect of microtubules (Fennell et al. 2016). Consequently, the stabilization
affects the normal dynamic reform of microtubule network crucial for interphase. It also induces
the abnormal arrays of microtubule throughout the cell cycle. Hence, it disrupts the cell cycle
and multiple asters of microtubules during mitosis. Consequently, this combined regimen is
effective in curing lung cancer.
Comparison mechanism of Cisplatin and docetaxel with nivolumab:
As discussed before Cisplatin and docetaxel are the active combination regimen for
treating non- small lung cancer. However, there is a difference in the mechanism of action of
these drugs in terms of the target site. As discuss above Cisplatin is a platinum-based
chemotherapeutic drug which stops tumor growth by cross-linking guanine bases in DNA double
helix. Consequently, DNA strands are unable to seepage and uncoil, disrupting the cell division.
In addition, the drug adds methyl group in the DNA causes miscoding of DNA and disruption of
DNA function which further affects the downstream (Ahn et al. 2015). The docetaxel is an anti-
mitotic drug which acts as the synergistic agent to enhance the activity of Cisplatin. Hence,
while Cisplatin is a chemotherapeutic drug that works in mostly DNA, docetaxel works in
chromosomal level (Fennell et al. 2016).
Compared to a combination of Cisplatin and docetaxel, nivolumab works in immune
cells. nivolumab is the first-line treatment for metastatic melanoma after progression of cancer or
after platinum-based chemotherapy. Nivolumab is a human ig4 antibody which targets the
immune checkpoint of program cell death called PD1 (Brahmer et al. 2015). The PD1 is a
member of the receptor family of CD28 which is mainly observed in T cells, myeloid and b cells.

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The researchers showed that in patients with lung cancer often shows the high expression of
PD1 (Herbst et al. 2016). Nivolumab blocks this immune checkpoint. The locking mechanism,
in this case, is cytokine-induced up-regulation and the antigen-specific response of Pd1 positive t
cells. Consequently, the inhibition reduces the inhibitory signaling which further restores the
natural tumor-specific t-cell immune response (Brahmer et al. 2015). Hence, these
chemotherapeutic drugs follow a different molecular pathway in order to cure non-small cell
drug cancer. While the response rate for the combination of Cisplatin and docetaxel is 30% to
51% with survival ranging from 9 to 10 month, nivolumab shows a response rate of 42 to 70%
with a survival rate of 9.4 months (Brahmer et al. 2015). Hence, as an alternative drug of the
combination of Cisplatin and docetaxel, nivolumab can be used to cure lung cancer for curing
lung cancer by enhancing the immune response against tumor cells.
The reason behind the side effect of chemotherapeutic agent:
Cisplatin, docetaxel, and nivolumab may cause nausea and vomiting. As discussed by
Rieck et al. (2018), while chemotherapy is effective in the management of lung cancer, they all
show certain side effects. In the current context, the patient was administrated with intravenous
infusion of drugs in order to avoid first-pass hepatic metabolism. The intravenous infusion is
given to the patient in order to achieve a high concentration of chemotherapeutic drugs.
However, intravenous drugs circulate through blood systematically. While these
chemotherapeutic drugs systematically circulated to work on the lungs, the blood containing
drugs also circulated in gastrointestinal (Antonia et al. 2016). Apart from the gastrointestinal
tract, chemotherapeutic trigger zone plays a crucial role in inducing nausea and vomiting. The
gastrointestinal tract provides the signal to the brain when a high concentration of these
chemotherapeutic drugs enters into the tract through blood circulation. The mechanism behind

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this trigger is chemotherapeutic stimuli which activate the chemoreceptors located in the
intestinal wall. The chemoreceptors further sent information in the vomiting center (Antonia et
al. 2016). The information is provided to Chemoreceptor trigger zone which is located to the
medulla of the brain. This zone has a defensive blood-brain barrier for detecting circulating the
toxins in the blood and cerebrospinal fluid. The zone is sensitive to certain agents such as
intravenous copper sulfate, chemotherapeutic toxic agents and infections. The stimulation of the
chemoreceptor trigger zone is facilitated by the release of the aforementioned chemical
transmitters such as 5HT (serotonin) and dopamine because of chemotherapeutic drugs which are
cytotoxic in nature (Koyuncu et al. 2017). After activation of zone, it stimulates integrated
vomiting center which is the key player behind the enhancement of the actual act of emesis. The
stimulation takes place through the release of neurotransmitters called acetylcholine. The
neurotransmitters further stimulate as well as active the vomiting reflex by apparent pathway.
Hence, the patients who are administrated with intravenous infusion, because of the high
concentration of chemotherapeutic drugs experience vomiting and nausea. In order to prevent
nausea and vomiting, Nigel was administrated with Ondansetron, a competitive serotonin type 3
receptor antagonist that prevent these effects.
Adverse reaction of morphine:
Morphine is a powerful opiate analgesic as well as a psychoactive drug which directly
works on the central nervous system in order to decrease the feeling of pain. It can be taken for
both acute pain and chronic pain. Taking an insight into the situation, the patient was
experiencing shortness of breath as well as pain in his chest. He experienced pain in his right
upper quadrant caused significant pain. In order to reduce the pain, he was administrated with

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morphine. However, based on the cases of morphine intoxication in can be said that morphine
can induce pulmonary edema or respiratory depression in patients. As discussed by Grace et al.
(2016), the intravenous morphine causes systematic vasodilation and respiratory depression in
the patients. The reaction is clearly evident in patients who are suffering from hypoxia.
Consequently, a patient may have high blood pressure because of respiratory depression. In order
to manage and prevent the side effects of the morphine, it is recommended to use naloxone as an
antidote (Kelly et al. 2016). Naloxone reduces high blood pressure which by acting as a
competitive antagonist on receptors of CNS. The patient is required to provide dietary
intervention devoid of NaCl and vegetables which can reduce high blood pressure.
Conclusion:
Thus it can be concluded that with a high prevalence of the non-communicable disease,
lung cancer is reported as a leading cause of cancer associated with death around the world. The
researcher suggested that non-small cell lung cancer is one of the common forms of cancer
which mostly affects men around the globe. The risk factors include exposure to radon, exposure
to asbestos, air pollution, certain dietary supplements with beta carotene. This paper explores a
case study 78 years old man, Nigel who was diagnosed with primary stage 4 non-small cell lung
cancer that spread throughout the lungs and showed substantial liver metastases. Considering
pathophysiology, the lung cancer can cause shortness of breath or dysphonia by first blocking
airway followed which result in lack of oxygen and shortness of breath. Considering the
metastasis of cancer, since the lungs are situated immediately adjacent, the cancer cells disrupt
the normal function of the neighboring organ by affecting lymph nodes closure to live. He was
administrated with intravenous Cisplatin and docetaxel and considering the secondary liver
cancer, there would be no effect on the pharmacokinetics of the drugs. These two drugs in

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combination can cure lung cancer by disrupting DNA and chromosomal function. Unlike these
two drugs, nivolumab act in immune cells to reduce the sign and symptoms of lung cancer. The
side effect of these drugs is nausea and vomiting where chemoreceptor trigger zone play a
crucial role. He was administrated with morphine which showed adverse side effects such as
respiratory depression or pulmonary edema. Hence, to promote the wellbeing of the patient, the
patient can be administrated with naloxone as an antidote.

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