Impact of Secondary Liver Cancer on Pharmacokinetics of Chemotherapy Medications

This article discusses the impact of secondary liver cancer on the pharmacokinetics of chemotherapy medications. It explores how advanced liver cancer can alter the absorption, distribution, and metabolism of drugs, affecting their effectiveness in treating the disease. The article also compares the mechanism of action of current chemotherapy medications with an alternative medication and explains why chemotherapy medications can cause nausea and vomiting. Additionally, it discusses a potential adverse reaction to morphine administration and how it can be managed.

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Consider Smith’s secondary liver cancer – how might this impact on the pharmacokinetics
of his chemotherapy medications? Ensure that you include appropriate consideration of
hepatic first-pass metabolism in your answer.
Pharmacokinetics is the movement of medicines into, through and out of the body
(Versypt, Harrell and McPeak 2017). The existence of a malignancy alters several parameters in
the body, and therefore, the pharmacokinetics of anti-cancer drugs cannot be extrapolated from
healthy persons to people with cancer. Pharmacokinetic drug-drug interactions are because of
changes in absorption, distribution, metabolism along with the elimination of medications
(Versypt, Harrell and McPeak 2017).
Absorption of chemotherapy medications and its distribution in the body might be altered
by advanced liver cancer resulting in abnormal bioavailability. The decreased plasma protein
binding also affects penetration of medications into tissues and drug distribution. As a result of
advanced liver cancer, bile acid is reduced in the intestines which may impair the absorption of
chemotherapy medications. Furthermore, protein binding of medications might be affected by
increases in the bilirubin along with bile acids in plasma concentrations hence impacting
distribution of drugs along with metabolism (Sane and Sinz 2017).
Medicine metabolism has the highest effect on clearance for most medicines, and it is
thus probable to significantly affect a person's beneficial along with adverse reaction at a
prescribed dosage. The lung cancer spread to the liver resulting to secondary liver cancer, and
this impact the pharmacokinetics of chemotherapy in that when administered the cancer cells
develop drug resistance through changes in drug transportation resulting in decreased
intracellular drug accumulation.

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In secondary liver cancer, reduction in blood flow in the organ along with diversion of
blood via collateral varices declines clearance of high-clearance medications (Almazroo, Miah
and Venkataramanan 2017). In liver metastasis, there is capillarization of the sinusoid, that is, the
sinusoidal endothelial cells which line the hepatic microcirculation mislay their fenestrae and
create a basement membrane. Capillarization generates a barrier to diffusion of oxygen, which
results in a substantial decrease in hepatic adenosine triphosphate along with oxidative
metabolism.
Drug metabolism is not globally reduced in liver metastasis, but the metabolism of
chosen medications may be markedly affected (Almazroo et al., 2017). Serum albumin may
reduce, which will change the disposition of medications which are highly bound to albumin.
Cationic chemotherapy medications might be preferentially bound to α1-acid glycoprotein,
which is always increased in cancer people rather than to albumin. Extensive replacement of
liver tissue may result in a decline in metabolic capacity. Bile flow disruption by malignancy
invasion of intrahepatic bile ductules or via extrahepatic biliary obstruction can reduce the
elimination of medications which are primarily excreted into bile (Almazroo et al., 2017).
Describe how his chemotherapy medications can be useful in treating his lung cancer.
Anti-cancer medicines can only be useful if they can kill the tumor cells and cease them
from replicating. Lung cancer is the main source of mortalities due to tumors and around 75
percent of individuals are untreatable at recognition (de Castria, da Silva, Gois and Riera 2013).
The common type of lung being non-small cell is around 90 percent of all cases of lung tumor.
For most of the individuals, chemotherapy is a better therapy choice and it is affiliated with
prolonged endurance along with an exclusive life. Nonetheless, therapeutics for persons with
progressive non-small cell lung cancer is reassuring in the sense that it gives relaxation from

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discomfort along with other upsetting manifestations (de Castria et al., 2013). Medications which
include cisplatin plus another drug of which Mr. Smith uses docetaxel are the most broadly
utilized medication combinations although they can be affiliated with inadmissible noxiousness.
Therefore, it would be sensible to have a therapy which is effectual but with less contamination
(de Castria et al., 2013).
Docetaxel is among the drugs that are called mitotic inhibitors. It is categorized as a
taxane, a plant alkaloid, and an anti-microtubule agent (Ravichandra, Ramesh, Swamy,
Purushotham and Rudramurthy 2018). It is a cytotoxic anti-microtubule agent which attaches to
the β-tubulin subunit of microtubulin leading to preserving microtubules and impeding
depolymerization that results in hindrance of microtubule dynamics along with cell cycle arrest
and finally apoptotic cell death (He, Li, Wu and Yang 2015). Microtubules are part of the cell’s
apparatus for dividing and multiplying itself (Heuer et al., 2017). Impeding these structures
ultimately leads to the death of cells and stops cancer cells from replicating. Moreover, they
prevent the body from producing the proteins which cancer cells require to develop hence
treating cancer effectively (Szczyrek et al., 2017).
Cisplatin is categorized as an alkylating agent, and alkylating agents are most operational
in the resting stage of the cell. It offers a correct instance of how minor alterations in molecular
structure can result in extreme contrasts in biological action (Alvarado-Luna and Morales-
Espinosa 2016). Within a cell, cisplatin mislays its two chloride ions, generating a sensitive
species which form a connection with DNA bases (Messori and Merlino 2016). Due to the comic
geometry of the relationships, the cisplatin quickly creates crosslinks amid bases. Here, Cisplatin
interferes with the replication of DNA, or DNA repair mechanism leading to DNA distortion and
consequently actuating apoptosis in cancer cells.

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Compare the mechanism of action of his current chemotherapy medications (cisplatin and
docetaxel) with an alternative cancer medication that he is not taking, nivolumab.
Cisplatin, docetaxel, and nivolumab are utilized in the therapy of lung tumor. Cisplatin
and docetaxel are predominantly given into a vein. When cisplatin is administered in the blood, it
attaches solidly to plasma proteins which include transferrin and albumin resulting in
inactivation of a large amount of the applied medication. In the cytoplasm, several cellular
elements like RNA along with thiol-containing peptides and proteins might counter with
cisplatin. The primary aim for cisplatin is genomic DNA, while a percentage of one of
intracellular cisplatin is bound to nuclear DNA (Petrović and Todorović 2016). It bounds with
DNA to create intrastrand crosslinks and adducts. The DNA adducts generated by cisplatin
impede DNA multiplication along with the transcription and trigger many signal transduction
pathways terminating in the actuation of apoptosis hence killing the cancer cells.
On the other hand, docetaxel is a taxane derivative which interferes with the regular
operation of growth of microtubule. Docetaxel halts their role by having the opposite impact; it
hyper-stabilizes their framework. This distorts the potentiality of the cells to utilize their
cytoskeleton flexibly. Mainly, docetaxel attaches to the β-subunit of tubulin and its binding locks
this tubulin in place.
The ensuing docetaxel complex or microtubules are not able to dismantle. This
negatively impacts the role of the cell since the lengthening and shortening of microtubules is
appropriate for their purpose as a transportation highway for the cell. For instance, chromosomes
depend on this feature of microtubules during mitosis. Moreover, docetaxel actuates
programmed cell death or apoptosis in cancer cells (Zhang, Li, Li, Xu, Wang and Zhang 2018)

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by binding to apoptosis ceasing protein known as B-cell leukemia 2 (Bcl-2) and hence halting its
operation.
In contrast to cisplatin and docetaxel mode of action, that of nivolumab is different. T
cells defend the body from the disease by destroying specific tumor cells, yet cancer cells
develop proteins hence being shielded from T cells (Gunturi and McDermott 2015). Here,
nivolumab obstructs the defensive proteins; thus, the T cells could destroy the malignancy cells.
Apparent of actuated T cells, there is a PD-1 protein. In case another molecule is known as
programmed cell death 1 ligand 1or programmed cell death 1 ligand 2 (PD-L1 or PD-L2)
attaches to PD-1, the T cell turns inoperative. To such a degree, the body controls the immune
system to avert reactivity. Several malignancy cells create PD-L1 that impedes T cells from
invading the malignancy. Here, nivolumab block PD-L1 from attaching to PD-1, enabling the T
cells to function.
Cisplatin, docetaxel, and nivolumab may all cause nausea and vomiting. Discuss one
main reason why such medications can cause such symptoms, even though none of these
are administered orally — ensuring that you focus on the mechanisms that directly affect
the gastrointestinal system.
Nausea and vomiting are quite common after chemotherapy medications. Nausea occurs
when the medications damage the cells that line in the gastrointestinal tract. Other triggers such
as pain, taste, and smell can stimulate nausea and vomiting. They are affiliated with the worst
memories of treatment and can be dangerous for health, resulting in a variety of other health
complications. When chemotherapy is administered, a particular region of the brain is triggered
and certain parts of the esophagus, that is, the tube connecting the mouth to the stomach, the
stomach, and intestines are triggered.

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The main reason why chemotherapy medications cause nausea and vomiting is because
of the triggering of the chemoreceptor trigger zone (CTZ) by the afferent and efferent reflexes.
Nausea and vomiting are regulated by the brain, and vomiting is prompted from a spot in the
brain known as the vomiting center. The vomiting center is the area where the ultimate decision
is made on if to induce an emetic reaction or not. The choice is depended mainly on the input the
CTZ imparts to the remaining vomiting center as well as the chemoreceptors in the
gastrointestinal tract, the information directed to the vomiting center by the vestibular system
together with higher order centers positioned in the cortex.
The CTZ contains receptors for opioids (MU2), acetylcholine (ACH) dopamine (D2) and
serotonin (5-HT3). On the other hand, the Vomiting Center (VC) is based in the medulla
oblongata and contains a blood-brain barrier (Webb 2017). The Vomiting Center, again a
disperse interrelating neural network instead of a definite anatomical structure, gets afferent
information from the CTZ. Also, it obtains afferent information from the thalamus, cerebral
cortex, hypothalamus, the glossopharyngeal and splanchnic nerves, along with the vagus nerve
via the provocation of a stretch of mechanoreceptors and actuation of 5-HT3 receptors in the
gastrointestinal tract.
Stimulation of different receptors is engaged in distinct routes resulting in emesis. The
vagal, along with enteric nervous system inputs, convey information concerning the status of the
gastrointestinal system (Adel, 2017). Consequently, serotonin attaches to intestinal vagal afferent
nerves through 5-HT3 receptors that activate the vomiting reflex through the nucleus of the
solitary tract along with chemoreceptor trigger zone in the central nervous system (Adel, 2017).
Irritation of the gastrointestinal mucosa by anti-cancer drugs actuates the 5-HT3 receptors of
those inputs.

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The emetogenic pathway is the vomiting reflex which leads to peristalsis of the upper
gastrointestinal tract, relaxation of the esophagus and pylorus and contraction of the diaphragm,
abdominal walls along with intercostal muscles culminating in the forced ejection of gastric
constituents via the mucosal pasta closed glottis. However, it is presumed that stimuli deficient in
inducing vomiting may generate nausea via the same pathway.
Discuss one main adverse reaction that may occur as a result of Smith's morphine
administration, and how would this be managed.
Morphine is a phenanthrene opioid receptor agonist whose primary impact is attaching to
and triggering the μ-opioid receptor (MOR) in the central nervous system (Francescangeli,
Karamchandani, Powell and Bonavia 2019). Actuation of the MOR is affiliated with respiratory
depression, sedation, physical dependence along with analgesia. In the nursing environment,
morphine exerts its prime pharmacological impact on the gastrointestinal tract together with the
central; nervous system. Morphine is majorly metabolized in the liver into morphine-3-
glucuronide (M3G) and morphine-6-glucuronide (M6G) through glucuronidation, and an
estimation of 87 percent of morphine dosage is ejected in the urine in seventy-two hours of
dispensation.
The primary adverse reaction of Morphine is suppression of the respiratory control center
(Nwaneshiudu, Emery, Levin, Chavkin and Terman 2015). Morphine is prescribed daily to
relieve pain. Although morphine is ordinarily safe, it can lead to potentially fatal depression of
breathing. Moreover, although it is well known that morphine depresses the brainstem
respiratory control centers, in persons receiving this drug, arousal along with pain status are
specifically crucial in determining the final respiratory output suggesting that conscious
mechanism are also vital.

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Morphine induces μ-opioid receptors articulated on the superficial of neurons in
brainstem respiratory centers. For instance, brainstem consisting of parabrachial nucleus along
with pre-Botzinger and the RTN/pFRG complexes are included in respiratory pattern generation
and indicate opioid receptors (Dahan et al., 2018). Actuation of the opioid receptors by
exogenous opioids might cause breathing hazard, which in several people is temporary or returns
to regular respiration. Because of an opioid over dosage or integration of opioid utilization with
other centrally sedative medications in few individuals, reduced breathing increases into
intermittent respiring and finally into respite. This may result in cardiorespiratory faint along
with premature death (Dahan et al., 2018).
The respiratory control system is inordinately susceptible to exogenous dispensed opioid
drugs like morphine. A vital approach to managing respiratory depression as a result of morphine
administration is co-treatment with non-opioid respiratory stimulants (Dahan et al., 2018).
Effectual stimulants avert respiratory suppression without impacting the opioid drug reaction.
Many of these stimulants act at sections in the brainstem respiratory network entailing
medications which operate at phosphodiesterase-4 inhibitors, α –amino-3-hydroxy-5-methyl-4-
isoxalepropionic acid receptors (ampakines), D1-dopamine receptor agonist, 5-
hydroxytryptaminereceptor agonists, thyrotropin-releasing hormone, and the endogenous peptide
glycyl-glutamine (Dahan et al., 2018).
The ampakines play a vital part in the sustenance of respiratory rhythmogenesis and
inspiratory drive and sites outside the pre-Botzinger complex (Dahan et al., 2018). The
stimulation of AMPA receptors then induces respiratory stimulant. On the other hand, the
stimulation of 5-hydroxytryptamine receptors improves the activity of respiratory neurons hence
decreasing respiratory rhythm variability. The thyrotropin-releasing hormone instigates rhythmic

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bursting in breathing neurons of the tractus solitarius’ nucleus via modulation of membrane
indiscretion (Dahan et al., 2018).

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