MIMS Oncology 2018

9. MOTOR INHIBITORS Motor inhibitors, IMiDs 193

The mammalian target for rapamycin 10. IMiDs
(mTOR) is a mediator of tumour progres-
sion and forms part of the PI3K/AKT/mTOR Thalidomide was developed in the first half
pathway.52 Activation of the mTOR kinase of the 1950s as a sedative and hypnotic
activity by phosphorylation results in the anti-emetic drug to treat morning sickness
interpretation of a variety of growth and in the first trimester of gestation, but was
survival signals received by the cancer removed from the market after discovery
cells and the upregulation of proteins of its teratogenic effects.53,54 Since then,
needed for the cell’s survival.26,52 findings of thalidomide’s anti-angiogenic
Everolimus and temsirolimus are inhibi- properties have led to the investigation of
tors of mTOR.26,52 These agents prevent thalidomide as an anticancer agent in
mTOR-mediated phosphorylation of key patients with vascular tumours.53,54 Al-
kinases by binding with high affinity to the though the precise mechanism of action is
intracellular receptor FKBP12.26,52 The inhib- not understood, thalidomide as an anti-
itor-FKBP12 complex binds to mTOR and angiogenic agent leads to the develop-
prevents downstream signalling.52 The ment of new immunomodulatory agents DRUG-CLASS OVERVIEW
cancer cell’s cell cycle is arrested at the (IMiDs), with thalidomide as the parent
G1E-vpehraosliemausndanadngteiomgseirnoelimsisuiss inhibited.52 compound with possibly fewer side ef-
are indicat- fects.53,54 The use of thalidomide is restrict-
ed for palliative monotherapy treatment ed to patients and/or doctors and phar-
of advanced renal cell cancer.13 macists in the Pharmion Risk Management
Programme (PRMP) and indicated for use
Side effects13 in multiple myeloma.13

n Infections Lenalidomide is an analogue of thalido-
n Rhinitis mide with immunomodulatory, antiangio-
n Folliculitis genic, and antineoplastic properties.142
n Pneumonia Lenalidomide is indicated for the treatment
n Anaemia, thrombocytopaenia of multiple myeloma, in combination with
n Neutropaenia, leukopaenia, dexamethasone, in patients who have re-
ceived at least one prior therapy. It is also
lymphopaenia indicated for transfusion-dependent
n Allergic reactions anaemia due to low- or intermediate-1-risk
n Dyspnoea, cough, epistaxis myelodysplastic syndromes associated
n Anorexia with a 5q deletion abnormality with or
n Hyperlipidaemia, hyperglycaemia, without additional cytogenetic abnormal-
ities and mantle-cell lymphoma patients
hypercholesterolaemia whose disease has relapsed or progressed
n Hypokalaemia, hypophosphataemia after two prior therapies, one of which in-
n Dysgeusia cluded bortezomib.
n Conjunctivitis
n Hypertension, venous Side effects13

thrombo-embolism n Teratogenesis
Contra-indications, special precautions n Sedation
and drug interactions: See MIMS Monthly, n Constipation
MDR or manufacturer’s product literature. n Asthenia
n Peripheral neuropathy
n Orthostatic hypotension
n Neutropaenia
n Severe skin reactions
n Leukopaenia
n Increased appetite
n Mood changes
n CNS effects, cardiac arrhythmias
n Bradycardia/tachycardia
n Thrombo-embolisms
n GI disturbances

HANDBOOK OF ONCOLOGY

194 DRUG-CLASS OVERVIEW 11. HORMONES

n Allergic reactions Hormonal therapy is considered as effec-
n Facial oedema tive as chemotherapy in hormone-sensi-
n Photosensitivity tive cancers as it involves the manipula-
n Menstrual irregularities tion of the endocrine system through
n Peripheral oedema administration of specific hormones or
drugs that alter the production or activity
Contra-indications, special precautions of these hormones, and therefore influ-
and drug interactions: See MIMS Monthly, ences the growth and survival rate of sen-
MDR or Manufacturer’s product literature. sitive cancers.26

HANDBOOK OF ONCOLOGY ANTI-OESTROGENS
Selective oestrogen receptor
modulators (SERMs)

Selective oestrogen receptor modulators
(SERMs), such as tamoxifen and
toremifene, competitively bind to oestro-
gen receptors, opposing the peripheral
effects of oestrogen on receptive tissues
such as oestrogen-sensitive tumours,
breast and other tissue.4,26
Steroid hormones, such as oestrogen, in-
fluence normal physiology by regulating
cell growth and differentiation by influenc-
ing gene transcription and DNA synthe-
sis.38 The SERM-receptor nuclear complex
prevents DNA synthesis and therefore in-
hibits oestrogen’s effects on hormone-sen-
sitive tissues.26
SERMs halt cancerous cells in tphreevGe0natinndg
cGe1ll phases of the cell cycle,
growth.26
Tamoxifen and toremifene are indicat-
ed for the treatment of metastatic breast
cancer in postmenopausal patients with
oestrogen-receptor positive or unknown
tumours.4,55 Recent studies indicate that
tamoxifen may counteract drug resist-
ance mechanisms in drug-resistant ovari-
an cancer.95

Side effects4,55

n Hot flushes
n Oedema
n Vaginal bleeding
n Pruritus vulvae
n GI disturbances
n Dizziness
n Rashes
n Hypercalcaemia
n Tumour pain
n Thrombocytopaenia and leukopaenia
n Headache
n Depression
n Fatigue

n Confusion Hormones 195DRUG-CLASS OVERVIEW
n Leg cramps
n Alopecia hormone-receptor-positive early
n Dry skin breast cancer
n First-line treatment of postmenopausal
Contra-indications, special precautions women with hormone-receptor-
and drug interactions: See MIMS Monthly, positive or hormone-receptor-
MDR or manufacturer’s product literature. unknown locally advanced or
metastatic breast cancer
Pure oestrogen receptor antagonists n Second-line treatment of advanced
Fulvestrant is a pure oestrogen receptor breast cancer in postmenopausal
antagonist, therefore competing with oes- women with disease progression,
trogen for the receptor.56 Unlike the SERMs, following tamoxifen therapy
fulvestrant downregulates the oestrogen
receptor itself.56 Fulvestrant is indicated for Letrozole
the treatment of hormone-receptor-posi- n Adjuvant treatment of
tive metastatic breast cancer in postmen-
opausal women with disease progression postmenopausal women with
following anti-oestrogen therapy.57 hormone-receptor-positive early
breast cancer
Side effects of fulvestrant include injec- n Extended adjuvant treatment of early
tion-site pain, musculoskeletal pain, nau- breast cancer in postmenopausal
sea and vomiting, arthralgia, headache, women, who have received five years
fatigue, hot flushes, anorexia, asthenia, of adjuvant tamoxifen therapy
cough, dyspnoea and constipation.57 n First-line treatment of postmenopausal
women with hormone-receptor-
AROMATASE INHIBITORS positive or unknown locally advanced
In premenopausal women, most of the or metastatic breast cancer
oestrogen is synthesised in the ovaries.58 In n Treatment of advanced breast
postmenopausal women, oestrogen is cancer in postmenopausal women
mainly synthesised in the adrenal, muscle with disease progression following
and adipose tissue.58,59 Breast adipose tis- anti-oestrogen therapy
sue is able to synthesise a significant
amount of oestrogen, a potent inducer of Side effects60,61
tumour proliferation in women with oestro- n Hot flushes
gen-receptor-positive breast cancer.59 n Asthenia
Adipose oestrogen biosynthesis is cata- n Arthritis
lysed by the enzyme aromatase where n Pain
androgens (androstenedione and testos- n Arthralgia
terone) are converted into oestrogens n Pharyngitis
(oestrone and oestradiol).58,59 Aromatase n Hypertension
inhibitors prevent the conversion of andro- n Depression
gens into oestrogens and have demon- n Nausea and vomiting
strated efficacy in patients with breast n Rash
cancer resistant to anti-oestrogens.59 n Osteoporosis
n Fractures
Aromatase inhibitors are categorised as n Musculoskeletal pain
steroidal or nonsteroidal inhibitors.59 Steroi- n Headache
dal-type aromatase inhibitors irreversibly n Peripheral oedema
bind to the active site of the enzyme, n Increased cough
whereas nonsteroidal aromatase inhibitors n Dyspnea
bind competitively and reversibly to aro- n Pharyngitis
matase enzymes.59 n Lymphoedema

Nonsteroidal aromatase inhibitors Steroidal aromatase inhibitors
Indications60,61 Indications62
Anastrozole Exemestane
n Adjuvant treatment of n Treatment of advanced breast

postmenopausal women with cancer in postmenopausal women in

HANDBOOK OF ONCOLOGY

196 DRUG-CLASS OVERVIEW Goserelin
n In combination with flutamide for the
whom disease has progressed
following tamoxifen therapy management of locally confined
Side effects62 carcinoma of the prostate
n Increased sweating n Palliative treatment of advanced
n Fatigue prostate cancer
n Hot flushes n Palliative treatment of advanced
n Pain breast cancer in pre- and
n Flu-like symptoms perimenopausal women
n Oedema
n Hypertension Triptorelin
n CNS effects n Palliative treatment of hormone-
n Nausea and vomiting
n GI disturbances dependent prostate cancer
n Dyspnoea and coughing
Contra-indications, special precautions Side effects64,66,67
and drug interactions: See MIMS Monthly, n A transient increase in serum
MDR or manufacturer’s product literature.
concentration of testosterone during
GNRH AGONISTS the first weeks of treatment may occur
Gonadotropin-releasing hormone (GnRH) in patients with prostate cancer, with
agonists mimic the hormone GnRH, which worsening of symptoms or onset of
in turn controls human reproductive physi- new symptoms such as bone pain,
ology.4,63 Binding of the GnRH to its recep- neuropathy, haematuria, ureteral- or
tor results in the release of the gonadotro- bladder-outlet obstruction
pin hormones, namely luteinising hormone n CNS effects
(LH) and follicle-stimulating hormone n Cardiovascular risk
(FSH), which in turn are responsible for n Reduced glucose tolerance
spermatogenesis and testosterone pro- n Anaemia
duction in males, and ovulation and n Hepatic impairment
oestradiol production in females.4 n Hypersensitivity reactions
n Decreased bone-mineral density
The potency, dose and duration of n Hot flushes
treatment with a GnRH agonist will deter- n Sexual dysfunction
mine whether gonadotropin hormones n Lethargy
are released (a pro-fertility effect) or the n Oedema
release prevented (antifertility effect) a n Upper respiratory infection and
decrease in LH and FSH and decreased chronic obstructive pulmonary disease
serum testosterone and oestradiol levels.63 n Sweating
n Anorexia
Intermittent administration of a GnRH Contra-indications, special precautions
agonist, increases LH and FSH, but chronic and drug interactions: See MIMS Monthly,
administration of a potent GnRH agonist MDR or manufacturer’s product literature.
(such as the GnRH agonists listed below)
results in inhibition of GnRH secretion and ANTI-ANDROGENS
suppression of ovarian and testicular Anti-androgens compete with endoge-
steroidogenesis.4,64,65 nously produced and exogenously sup-
plied androgens for the androgen recep-
Indications64-67 tors at the target organs. Stimulating
Leuprolide effects of the androgens on receptive tis-
n Palliative treatment of advanced sue are therefore prevented and further
production of androgens is diminished
prostate cancer due to a reduction in GnRH release.68-70
n Adjuvant therapy to surgery in breast
Indications68-70
cancer Cyproterone acetate
n Anti-androgen treatment in
Buserelin
n Palliative treatment of hormone- inoperable prostate cancer

dependent advanced prostate
cancer

HANDBOOK OF ONCOLOGY

Flutamide Hormones 197
n Use in combination with GnRH
PROGESTOGENS
agonists for the management of The anticontraceptive, medroxyproges-
lDo2cmalleytacostnaftinicepdrostsatagteeBc2a-Cncaenrd stage terone acetate, is a progesterone deriva-
tive.71 Medroxyprogesterone acetate is in-
Bicalutamide dicated for use as adjunctive therapy and
palliative treatment of inoperable, recur-
n Use in combination therapy with GnRH rent, and metastatic endometrial or renal
agonists for the treatment of stage D2 cancers or metastatic breast cancer.71,93
metastatic prostate cancer
Medroxyprogesterone acetate de-
Side effects68-70 creases the release of GnRH and thus the DRUG-CLASS OVERVIEW
secretion of FSH, LH and oestradiol.71 Side
n Hepatic toxicity effects of medroxyprogesterone acetate
n Impotence include menstrual irregularities and amen-
n Gynaecomastia orrhoea, CNS effects, oedema, weight
n Reduction in the functioning of the changes, cervical changes, cholestatic
jaundice, breast tenderness and galactor-
adrenal cortex rhoea, hypersensitivity and allergic reac-
n Lethargy tions, nausea, somnolence and insomnia,
n Mood changes and CNS effects acne, alopecia and hirsutism.71
n Weight gain
n Hot flushes Contra-indications, special precautions
n Hypertension and drug interactions: See MIMS Monthly,
n GI disorders MDR or manufacturer’s drug literature.
n Anaemia, leukopaenia and
SOMATOSTATIN
thrombocytopaenia Lanreotide 
Contra-indications, special precautions Lanreotide is a somatostatin analogue in-
and drug interactions: See MIMS Monthly, dicated for long-term treatment of acro-
MDR or manufacturer’s product literature. megalic patients who have had an inad-
equate response to or cannot be treated
Enzalutamide with surgery and/or radiotherapy and treat-
Enzalutamide is an androgen-receptor in- ment of patients with unresectable, well- or
hibitor that acts on different steps in the moderately differentiated, locally ad-
androgen-receptor signalling pathway.127 vanced or metastatic gastro-enteropan-
Enzalutamide has been shown to compe- creatic neuro-endocrine tumours (GEP-
titively inhibit androgen binding to andro- NETs) to improve progression-free survival.143
gen receptors and inhibit androgen- Lanreotide  binds to the same receptors as
receptor nuclear translocation and inter- the naturally occurring somatostatin with
action with DNA. Enzalutamide is indicated higher affinity. The inhibitory hormone so-
for the treatment of patients with metastat- mastatin inhibits the release of growth hor-
ic castration-resistant prostate cancer. mone, TSH, insulin and glucagon.

HANDBOOK OF ONCOLOGY

198 DRUG-CLASS OVERVIEW n Breast cancer
n Prostate cancer
12. CORTICOSTEROIDS
CORTICOSTEROIDS AND ANTI-EMETICS
Corticosteroids have a variety of applica- The basis for the anti-emetic potential of
tions in adjunctive cancer management. corticosteroids is unknown.4 Methylpredni-
The clinical applications are mainly de- solone and prednisolone are usually com-
pendent on their pro-apoptotic proper- bined with other anti-emetics such as the
ties, but these agents are also able to re- 5pHreTv3eannttioangoonf iastcsuatendanNdK1dealnatyaegdonnaistussefoar
duce inflammation, reduce the immune and vomiting in patients receiving eme-
response, act as an anti-emetic and im- togenic chemotherapy regimens.4,72
prove the overall wellbeing in critically ill
patients.103 Corticosteroids typically used CORTICOSTEROIDS IN PALLIATIVE
include prednisone, prednisolone, dexa- CARE
methasone and methylprednisolone. Corticosteroids improve symptoms such as
fever, sweating, lethargy and weakness.
CORTICOSTEROIDS IN COMBINATION They are responsible for mild euphoria, im-
WITH CHEMOTHERAPY proved appetite and an overall improve-
Research has shown that pharmacologi- ment in wellbeing. However, because of
cal doses of corticosteroids can inhibit the side effects, only short-term treatment
growth of various tumour systems, with is possible.103
lymphoid cells being the most sensitive to
their pro-apoptotic effects. Although the CORTICOSTEROIDS IN CENTRAL
mechanism of action is not completely NERVOUS SYSTEM TUMOURS
understood, these agents can be used in Corticosteroids reduce peritumoral oede-
combination treatment for endocrine-re- ma from primary and metastatic brain
sponsive cancers.103,104 and spinal cord tumours, alleviating symp-
toms in most cases.103 The corticosteroid of
Cancers treated with corticosteroids choice is dexamethasone as it has no min-
include: eralocorticoid activity and is highly po-
n ALL tent. It is important to note that corticos-
n AML teroids may decrease capillary permea-
n CLL bility and therefore the dose of a cytotoxic
n CML drug at the tumour site.
n Hodgkin’s lymphoma
n Non-Hodgkin’s lymphoma
n Multiple myeloma

HANDBOOK OF ONCOLOGY

13. OTHERS Others 199DRUG-CLASS OVERVIEW
TRETINOINS
shown to inhibit DNA, RNA and protein
All-trans retinoic acid or tretinoin induces synthesis.141
cytodifferentiation and decreased prolifer-
ation of acute promyelocytic leukaemia Procarbazine is used as part of the
(APL) cells and is therefore indicated for MOPP (nitrogen mustard, vincristine, pro-
the induction of remission in APL. It is also carbazine, prednisone) regimen in the
suitable for prevention in untreated pa- treatment of stage III and IV Hodgkin’s
tients or those who relapse after, or are re- disease.
fractory to, standard chemotherapy.13,126
RADIUM-223 DICHLORIDE
VACCINES The alpha particle-emitting isotope radi-
Bacillus um-223 (radium Ra-223 dichloride) mimics
Calmette-Guérin (BCG) vaccine calcium and forms complexes with the
The BCG is an attenuated, live culture bone mineral hydroxyapatite at areas of
preparation of the Bacillus of Calmette increased bone turnover, such as bone
and Guérin (BCG) strain of Mycobacteri- metastases.143
um bovis.136 Although the precise mecha-
nism is unknown, BCG induces a granu- The high linear energy transfer of alpha
lomatous reaction at the local site of emitters (80 keV/micrometer) leads to a
administration and is therefore used as high frequency of double-strand DNA
treatment and prophylaxis against recur- breaks in adjacent cells, resulting in an
rent tumours in patients with carcinoma in anti-tumour effect on bone metastases.
situ of the urinary bladder, and to prevent The alpha particle range from radium-223
recurrence of Stage TaT1 papillary tumours dichloride is less than 100 micrometres (less
of the bladder at high risk of recurrence. than 10 cell diameters), which limits dam-
age to the surrounding normal tissue.
PROCARBAZINE
The precise mechanism of action of pro- Radium-223 dichloride is indicated for
carbazine is not known, but it has been the treatment of men with castration-re-
sistant prostate cancer and symptomatic
bone metastases and no known visceral
metastatic disease.

HANDBOOK OF ONCOLOGY

200 DRUG-CLASS OVERVIEW

14. SUPPORTIVE CARE n GI disturbances
ANTI-EMETICS n Hiccups

Nausea and vomiting are among the most Dopamine antagonists
common and unpleasant side effects of Dopamine antagonists are not very effi-
chemotherapy.72 cient as single agents in the prophylaxis of
chemotherapy-induced nausea and
The vomiting centre, located in the me- vomiting and are rarely helpful in severe
dulla, controls the act of vomiting.4 The nausea and vomiting.4,72 Dopamine an-
vomiting centre receives input from the tagonists such as metoclopramide and
chemoreceptor trigger zone situated out- dmoinmepreercideopntoersoinnltyhebclohcekmtohreecDe2ptodrotpriag--
side the blood-brain barrier and is there- ger zone situated outside the blood-brain
fore accessible to emetogenic stimuli in barrier.4 These agents cannot readily cross
the blood or cerebrospinal fluid.4 Neuro- the blood-brain barrier and therefore do
transmitters involved in emesis in the vom- not have the ability to act on the vomiting
iting centre include muscarinic, histamine, centre and have fewer extrapyramidal ef-
neurokinin and serotonin, whereas the fects.4 Prochlorperazine, an anti-psychot-
chemoreceptor trigger zone is rich in dopa- ic, multi-potent receptor blocker, exhibits
mine, opioid, serotonin and neurokinin.4 anti-emetic potential due to blockage of
chemoreceptor trigger zone dopamine
Identification of these neurotransmitters receptors and the central muscarinic re-
involved with emesis has led to the devel- ceptors.4 As prochlorperazine can cross
opment of anti-emetic agents with affinity the blood-brain barrier, it has more CNS
for the various receptors involved.4 effects.4 The antipsychotic, droperidol,
also possesses anti-emetic potential due
5HT3 antagonists to dopaminergic blockage and is highly
sedating.4
Serotonin is the most important neuro-
transmitter in the initiation of chemothera- Side effects4,72
py-induced nausea and vomiting mainly
due to stimulation of tinhteesptienraipl hveargaal l5a-HnTd3 n Extrapyramidal side effects
receptors on extrinsic n Restlessness
sapnintaagl oanfifsetsresunct hnaesrvgersa.4n,7i2se5t-roHnT3arnedceppatloo-r n Drowsiness
nosetron, not only prevent vagal and spi- n Insomnia
nal input in the vomiting centre, but block n Anxiety
athned5c-HhTe3mreocreecpetoprtsoirntrtihgegevrozmonitien.g4 centre n Agitation
n Hypotension
Side effects4,72
G-CSFs
n Headache Granulocyte-colony stimulating factors
n Dizziness (G-CSFs) are haematopoietic growth
n Constipation factors indicated to prevent or treat neu-
n Prolongation of the QT-interval tropaenia in patients receiving chemo-
therapy for myelosuppressive cancers.4
NK1 antagonists The recombinantly produced G-CSFs act
on haematopoietic cells in the bone mar-
The neurokinin 1 (NK1)-receptor antago- row and induce proliferation, differentia-
nist aprepitants’ anti-emetic potential is tion, survival and activation of the phago-
due to the blockage of the NK1 receptors cytic activity of neutrophils.4,73 Filgrastim,
in the vomiting centre.4 Aprepitant can be lenograstim and pegfilgrastrim are all re-
used in combination with 5p-HreTv3ebnltoiocnkeorsf combinantly produced G-CSFs indicated
and corticosteroids for the for accelerating the neutrophil counts fol-
acute and delayed nausea and vomiting lowing a variety of chemotherapy
from highly emetogenic chemotherapeu- regimens.4,73
tic regimens.4

Side effects4,72

n Fatigue
n Dizziness

HANDBOOK OF ONCOLOGY

Side effects4,74 Supportive Care 201DRUG-CLASS OVERVIEW

n Spleen rupture ERYTHROPOIETINS
n Allergic reactions Erythropoietin (EPO) interacts with erythro-
n Acute respiratory distress syndrome poietin receptors on red cell progenitors
n Bone pain and stimulates erythroid proliferation and
differentiation.4
THROMBOPOIETINS
Romiplostim is a thrombopoietin peptibody Epoetin alfa and beta are forms of re-
indicated for the treatment of thrombocy- combinant human EPO produced in a
topaenia in patients with chronic immune mammalian cell-expression system.4,76
thrombocytopaenia who have had an in- Epoetin alfa is indicated for the treat-
sufficient response to corticosteroids, im- ment of anaemia and reduction of trans-
munoglobulins or splenectomy.4,75 fusion in patients with non-myeloid malig-
nancies where anaemia develops as a
Romiplostim is covalently linked to two result of concomitantly administered
antibody fragments and two Mpl- pep- chemotherapy.76 Epoetin beta is indicat-
tides.4,75 The Mpl-peptide fragment of romi- ed for the prevention and treatment of
plostim is able to bind and activate the anaemia in adults with solid tumours and
thrombopoietin receptor which activates treated with platinum-based chemother-
intracellular transcriptional pathways and apeutics prone to induce anaemia, as
thereby increases platelet production.4,75 well as treatment of anaemia in patients
with multiple myeloma, low-grade non-
Side effects75 Hodgkin’s lymphoma or CCL with a rela-
tive erythropoietin deficiency receiving
n Arthralgia anti-tumour therapy.77
n Dizziness
n Insomnia Side effects4,76
n Myalgia n Hypertension
n Pain in extremities n Thrombotic complications
n Abdominal pain n Allergic reactions
n Shoulder pain n Pure red cell aplasia accompanied by
n Dyspepsia
n Paraesthaesia neutralising antibodies to
n Headache erythropoietin

HANDBOOK OF ONCOLOGY

202 DRUG-CLASS OVERVIEW

15. PAIN MANAGEMENT COMBINATION ANALGESICS

There are two types of pain, namely noci- For pain relief, nonsteroidal anti-inflamma-
ceptive or somatic pain and neuropathic tory drugs (NSAIDs), such as ibuprofen, are
pain. Neuropathic pain includes a group usually combined with paracetamol and/
of disorders with a variety of origins and or weak opioid analgesics, such as co-
symptoms. deine.80,81 NSAIDs prevent the production
of prostaglandins responsible for pain and
NARCOTIC ANALGESICS inflammation by reversibly inhibiting cyclo-
Narcotic analgesics are the drugs of oxygenase (COX) enzyme 2.80
choice in chronic and malignant pain, as
they are able to alleviate intense pain, as Ibuprofen is a commonly prescribed
well as the anxiety that sometimes ac- medication and is used in a variety of
companies it.78 Narcotic analgesics mimic chronic painful states. Ibuprofen possesses
the effects of endogenous endorphins by anti-inflammatory, analgesic and antipy-
binding to the opioid receptors in the cen- retic activity and can alter platelet func-
tral nervous system important in both tion, but unlike aspirin does not irreversibly
acute and chronic pain.78,79 bind to COX enzyme.80,81 Ibuprofen is
therefore one of the preferred NSAIDs in
Narcotic analgesics interact mainly with the treatment of chronic conditions as its
three opioid receptors, namely mu, kappa gastro-intestinal side effects are generally
and delta in the CNS, nerve terminals in less when compared to aspirin.4
the periphery and gastro-intestinal cells.78,79
The analgesic properties of these agents The mechanism of action of paraceta-
are mainly attributable to their interaction mol is not entirely understood.81 What is
with the mu receptors in the CNS and to a known is that it does not have the same
lesser extent, the kappa receptors in the mechanism of action as the other NSAIDs
dorsal horn.78 as it does not significantly inhibit prosta-
glandin synthesis.81 Due to the lack of ef-
Narcotic analgesics can be classified fective prostaglandin-synthesis inhibition,
according to their affinity for the mu re- paracetamol does not have the ability to
ceptors as either full or partial agonists prevent or reduce inflammation and fur-
(see Table 6).78 thermore does not exhibit side effects as-
sociated with the reduction in prostaglan-
Side effects78 din synthesis.81 A possible serious side
n Respiratory depression effect of paracetamol which can occur
n Euphoria with large doses is hepatotoxicity, which
n Nausea and vomiting occurs when the glutathione stores in the
n Sedation liver are depleted and unable to bind the
n Sweating cytotoxic phase I metabolite of paraceta-
n Urinary retention and constipation mol. This may lead to liver damage.81
n Chronic use can lead to dependence
Codeine’s analgesic properties are
and tolerance mainly attributable to its conversion of the
n Pinpoint pupils prodrug (codeine) into its active form, mor-
phine.78 Although codeine is considered a
Contra-indications, special precautions strong opioid analgesic, only around 10%
and drug interactions: See MIMS Monthly, of codeine is metabolised into morphine.78
MDR or manufacturer’s product literature.

Table 6.78 Classification of narcotic analgesics

Full agonist at mu opioid receptors Partial agonist at Other
mu opioid receptors Tramadol
Strong Moderate Buprenorphine
Hydromorphone Methadone Pentazocine
Morphine Tilidine
Fentanyl Tapentadol 
Oxycodone

HANDBOOK OF ONCOLOGY

Side effects80 Pain Management 203 DRUG-CLASS OVERVIEW
General side effects are mainly due to
COX-1 inhibition and prolonged use. The Research has shown a correlation between
side effects are primarily gastro-intestinal, the pathophysiology of epilepsy, neuro-
haematological and renal in nature. pathic pain and migraine and it is therefore
believed that the mechanism of action re-
Contra-indications, special precautions sponsible for the management of epileptic
and drug interactions: See MIMS Monthly, seizures is also responsible for analgesia.82,83
MDR or manufacturer’s product literature.
Gabapentin and pregabalin bind to the
ANTICONVULSANTS specific sites on voltage-dependent calcium
Anti-epileptic drugs have proven to be ef- channels located in the spinal cord. These
fective in the treatment of diabetic neu- agents inhibit the release of excitatory neu-
ropathy, post-herpetic pain, trigeminal rotransmitters and reduce glutamate avail-
neuralgia and other types of neuropathic ability at N-methyl-D-aspartate (NMDA) and
pain disorders, such as cancer-related non-NMDA receptors, reducing pain.82
neuropathic pain.82,83 It is important to
note that complete pain relief is rarely Side effects4
achieved with anti-epileptic drugs alone n CNS effects
and the addition of an anti-epileptic or n Nausea
antidepressant in addition to an existing n Drowsiness
opioid analgesic is likely to result in modest n Blurred vision
analgesia, with the risk of more adverse n Somnolence
effects.82,83 n Ataxia
n Peripheral oedema
Anti-epileptic agents are classified as ei- n Leukopaenia
ther first- or second-generation. The second- n Impairment of liver function
generation or newer drugs such as gabap- n GI complications
entin and pregabalin are better tolerated, n Dermatological complications
have fewer side effects and drug-drug inter- n Bleeding and platelet disorders
actions and cause less sedation compared n Respiratory depression
to the first generation or older drugs.82 n Reduction of plasma-sodium levels

HANDBOOK OF ONCOLOGY

204 DRUG-CLASS OVERVIEW n Decrease in serum calcium
n Increase in serum alkaline
16. OTHER
BISPHOSPHONATES phosphatase
n Increase in transaminases
With cancer cells present in bone, accel- n Reversible proteinuria
erated osteoclast-mediated bone resorp- n Serum creatinine elevations
tion can occur.84 Bisphosphonates are sta- n Renal dysfunction
ble synthetic analogues of pyrophosphate n Musculoskeletal pain
(PPi,) with their main function being to in- n Atrial fibrillation
hibit bone resorption, preventing loss of n GI disorders
bone mass.84,85 Bisphosphonates are there- n Osteonecrosis of the jaw
fore used to treat bone metastasis and
multiple myelomas.85 IMIQUIMOD
Imiquimod is an immune-response modifi-
Although bisphosphonates target the os- er.4,86 Imiquimod is indicated for the treat-
teoclast-mediated bone resorption, new ment of biopsy-proven primary basal cell
evidence suggests that bisphosphonates carcinomas on the trunk, neck, and ex-
have anti-cancer properties as they are tremities.4 Imiquimod is thought to stimulate
able to decrease cancer-cell adhesion and peripheral mononuclear cells to cytokines,
invasion, induce cancer-cell apoptosis, re- activating the local immune cells when ap-
duce cancer-cell viability and proliferation plied topically. Side effects of imiquimod
and exhibit anti-angiogenic effects.84 treatment are mainly localised inflamma-
tory reactions to the applied areas.4
Bisphosphonates are divided into two
classes, namely non-nitrogen-containing MESNA
bisphosphonates (clodronate) and the Sodium-2-mercaptoethane sulphonate
more potent nitrogen-containing bisphos- (MESNA) is a prophylactic agent given
phonates (pamidronate, ibandronate to reduce the risk of haemorrhagic cysti-
and zoledronate). tis induced by ifosfamide.5,87 In the kid-
neys, MESNA interacts with the toxic ifos-
Bisphosphonates bind to, and accumu- famide metabolites, detoxifying the
late in, mineralised bone matrix after ad- metabolites.87 Side effects of MESNA
ministration where they are released dur- therapy include headache, injection-
ing resorption and are selectively site reactions, flushing, dizziness, nausea
internalised by osteoclasts, inducing ap- and vomiting, somnolence, GI upsets, fe-
optosis in these cells.84,85 ver, pharyngitis, hyperaesthesia, flu-like
symptoms and coughing.87
Side effects
n Hypocalcaemia
n Lactic acid dehydrogenase elevations
n Increase in serum parathyroid

hormone associated with
bisphosphonate drug holiday

HANDBOOK OF ONCOLOGY

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HANDBOOK OF ONCOLOGY



12164 Lighten the load from

nausea and vomiting…

Opfrfeaernvdyoecunor ptniaottirennotsl1,2

S4

Prevention and treatment of post-operative nausea and vomiting1
Management of nausea and vomiting induced by chemotherapy and radiotherapy1
The initiation of the vomiting reflex is blocked by the selective 5-HT3 receptor antagonist1
Does not cause sedation or impair psychomotor performance1
Extensive product range, including ZOFER RAPITAB which disperses within seconds when placed on the tongue1

References: 1. Zofer package insert. 2008. 2. Schnell FM. Chemotherapy-induced nausea and vomiting: The importance of acute antiemetic control.
The Oncologist 2003;8:187-198.
For full prescribing information please refer to the package insert approved by the Medicines Regulatory Authority.
Pharmacological Classification: A5.10 Medicines affecting autonomic functions. Serotonin antagonists.
S4 Zofer 4 mg/8 mg tablets. Each tablet contains ondansetron hydrochloride equivalent to ondansetron 4 mg/8 mg. Reg. Nos: 39/5.10/0413; 39/5.10/0414.
S4 Zofer Rapitab 4/8. Each dispersible tablet contains ondansetron 4 mg/8 mg. Reg. Nos: 42/5.10/0662; 42/5.10/0663. S4 Zofer 4 mg/8 mg injection.
Each ampoule contains ondansetron 4 mg/8 mg (as hydrochloride) in 2/4 ml aqueous solution for intramuscular or intravenous injection.
Reg. Nos: 39/5.10/0448; 39/5.10/0449.
Applicant: Ranbaxy Pharmaceuticals (Pty) Ltd, a SUN PHARMA company. Reg. No.: 1993/003111/07. 14 Lautre Road, Stormhill Ext.1, Roodepoort, Johannesburg.
Tel. +27 12 643 2000. Fax. +27 12 643 2001.

www.sunpharma.com

Time for life

ZYTIGA FIRST
SINCE 20141