adverse effect of cytostatic

7/22/2019 Adverse Effect of Cytostatic

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Adverse Effect of Cytostatic

Indwiani Astuti

Dept of Pharmacology & Therapy

Fac of Medicine

Universitas Gadjah Mada

Yogyakarta

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Learning Objectives

Identify the adverse effect of Cytostatic

especially abdominal complain

To know how to minimizing the side effects

of Cytostatic

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Introduction

Cytostatic /cytostatic/ (stah-statik) 1.

suppressing the growth and multiplication

of cells.

any substance that inhibits cell growth and

division

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What are cytostatic drugs?

The word cytostatic describes the way some anti-cancer

drugs work. Most drugs that are used to treat cancer kill

the cancer cells. The word 'cytotoxic' means toxic to cells,

or cell-killing. Chemotherapy is properly called 'cytotoxic

therapy'.

There are other treatments that do not kill cancer cells.

They work by stopping the cancer cells from multiplying.

So, they stop the cancer growing. For example, hormonetherapies used to treat breast cancer could also be called

cytostatic therapy.

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The treatment can be physically exhausting

for the patient. Current chemotherapeutic

techniques have a range of side effectsmainly affecting the fast-dividing cells of

the body.

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Tumour selectivity of chemotherapy

Most drugs used in cytostatic chemotherapy interferewith the synthesis of DNA and /or RNA, with the

results that cell death occurs or cell multiplication

ceases.

These effects are not confined to malignant cells -

cytostatic agents are also toxic to normal dividing

cells, particularly those in bone marrow, the GIT,

gonads, hair folicles and skin (rapidly dividing cells).

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Rand 50.3


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Narrow therapeutic index/toxic

side effects1. Bone marrow suppression

2. Mucositis throughout GI tract

3. Febrile neutropenia, increased risk of infection4. Alopecia

5. Nausea, vomiting and cachexia

6. Damage to reproductive system

7. Neurotoxicity

8. DNA damagetreatment can be mutagenic,

carcinogenic and teratogenic

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1. Wiser W, Berger A. Oncology. 2005;19:637.

2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.

Incidence of Chemotherapy-Induced

Nausea and Vomiting (CINV) and Pain in

Cancer Patients

Approximately 70%80% of chemotherapy patients

experience nausea and vomiting1

Patients rank nausea and vomiting as 2 of the most

feared side effects of cancer treatment

More than three quarters of cancer patients experience

chronic pain during the course of their disease2

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NCCN Practice Guidelines in OncologyVersion 1. 2007. Antiemesis, MS-1.

Consequences of Unresolved CINV

Serious metabolic derangements

Nutritional depletion and anorexia

Esophageal tears

Wound dehiscence

Deterioration of patients physical and mental status

Degeneration of self-care and functional ability

Discontinuation of therapy

Adverse sequelae of nausea and vomiting in thecancer patient

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Emetogenic Potential of Antineoplastic agents

Navari RM. Pathogenesis-based treatment of chemotherapyinduced nausea and vomitingTwo new agents.

J Support Oncol 2003;1:89-103


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Patient-Specific Risk Factors for CINV

Age men

History of light alcohol use

History of vomiting with prior exposureto chemotherapeutic agents

Other risks

History of motion sickness

History of nausea or vomiting during pregnancy History of anxiety

ASHP.Am J Health Syst Pharm.1999:56:729-764; Balfour and Goa.Drugs. 1997:54:273-298.


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Acute CINV:Nausea and vomiting with in the first 24 hrs of

chemotherapy Delayed CINV:After 24 hrs lasting up to 5 days

Anticipatory CINV:After a negative past experience with

chemotherapy

Breakthrough CINV:Occurs despite patient being treated with

preventive therapy

Refractory CINV:Occur during subsequent cycles of

chemotherapy when antiemeticprophylaxishas failed in earlier

cycles

Types of CINV


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Vomiting Centre

(medulla)

Cerebral cortex

Anticipatory emesis

Smell

Sight

Thought

Pharynx & GIT

Chemo & radio therapy

Chemoreceptor

Trigger Zone(CTZ)

(Outside BBB)

Cancer chemotherapy

Ach, 5 HT Histamine &

Substance P

5 HT &

Substance P

Dopamine

5 HT, substance P

Pathophysiology of CINV

P h h i l f


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Pathophysiology of

Chemotherapy-Induced Emesis


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Twycross R.Palliative Care.3rded, Radcliffe Medical Press. Oxford:1999:114.

Causes of Nausea and Vomiting

in Cancer Patients

Gastric stasis

Drugs Opioids

Chemotherapy

Biochemical Hypercalcemia

Uremia

Raised intracranial pressure

Intestinal obstruction

Pain

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NCCN (National Comprehensive Cancer Network)

Practice Guidelines

Prechemotherapy Emesis Prevention

Highly emetogenic regimens

Day 1: aprepitant, dexamethasone, and a 5-HT3antagonist+/- lorazepam

May be modified on days 24

Moderately emetogenic regimens Day 1: dexamethasone and a 5-HT3antagonist +/- lorazepam

(aprepitant added with select moderately emetogenic regimens)

Modified on days 24

Low emetogenic regimens

Dexamethasone, proclorperazine, or metoclopramide+/- lorazepam

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NCCN Practice Guidelines

Postchemotherapy/Delayed Emesis Prevention

Highly emetogenic regimens

Primary antiemetic regimen continued through period when

delayed emesis may occur

(ie, 23 days after chemotherapy cycle)

Moderately emetogenic regimens

Dependent upon the antiemetic used before chemotherapy

Palonosetron on day 1 only

Aprepitant continued on days 2 and 3

+/- dexamethasone or lorazepam

Dexamethasone or a 5-HT3antagonist +/- lorazepam

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NCCN Practice Guidelines

Breakthrough Treatment

Around-the-clock administration, rather than PRNdosing, should be considered

Additional agents should be from a different drug class

than initial therapy Possibilities include: dopamine antagonists, metoclopramide,

butyrophenones, cannabinoids, corticosteroids, or agents

such as lorazepam

Nabilone (cannabinoid) has recently been approved fornausea/vomiting in patients who have not responded to

conventional antiemetics

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N ti l C h i C N t k(NCCN) G id li


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National Comprehensive Cancer Network(NCCN) Guidelines

High Emetic Risk Chemotherapy- Emesis prevention

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Moderate Emetic Risk Chemotherapy- Emesis prevention

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Neurotransmitter Sites

For Nausea Muscarinic

Dopaminergic Histamine

Serotonin (5HT-3)

Neurokinin 1 (NK 1)

Cannabinoids

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Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:197-203.

Serotonin

(5-HT3)

GABA

Cannabinoids

Acetylcholine

Dopamine

(D2)

N + V

REFLEX

Histamine

Substance P(NK-1)

Endorphins

Drug classes FDA approved in CINV

Diverse Neurotransmitters Mediate Emesis

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Serotonin Receptor

Inhibitors (5HT3)

Granisetron (Kytril)

Dolasetron (Anzemet)

Ondansetron (Zofran)

Palonosetron (Aloxi) : Benefit of longer

duration of action 2-5 days after treatment Best used as a cocktail with steroid

(dexamethasone) and lorazepam

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Serotonin Receptor Inhibitors:

Common Side Effects

Headache

Constipation

Prevent with use of laxatives and stool

softeners

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NK 1 Receptor Inhibitor

Aprepitant (Emend)

Used for acute and delayed nausea

in combination with a serotonin

receptor-blocking drug

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Dexa 8mg b d

Days 1 2 3 4 5 6 7

Ondan 32mg ivDexa 20 mg oral

Days 1 2 3 4 5 6 7

Apre 125mg

Ondan 32mg iv

Dexa 12 mg oral

Dexa 8mg

Apre 80mg

Dose Schedule

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Indications and Dose

FDA approved on March 2003 for prevention of acute and

delayed CINV with single or repeated courses of highlyemetogeneic chemotherapy

125 mg on day 1 (before chemotherapy) and then 80mg on

days 2 and 3(after chemotherapy)

Should be given with a 5HT3antagonist and dexamethsone

Dose of dexamethasone should be reduced by 50%

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Pharmaceutical

Nabilone

Dronabinol

Delta-9-THC &

cannabidiol

Cannabinoids

Botanical

Marijuana

Hashish

Endogenous

Anandamide

2-AG

PEA

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Kalant H.Pain Res Manag. 2001;6:80.

Cannabinoid ReceptorsCB1neuromodulation

Basal ganglia

Hippocampus

Cerebral cortex

Cerebellum

Spinal cord

Afferent nociceptors

CB2immunomodulation

Spleen

Tonsil

Mast cells

Macrophages

Lymphocytes

Microglia

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Mechanism of Action of the Cannabinoids

Neurotransmitter (NT) from

presynaptic neuron activates the

postsynaptic neuron

1

2 3

4

5

Endogenous and Exogenous

Cannabinoids Reduce Neuronal Signaling

Postsynaptic

Neuron

NeurotransmitterReceptor

Endogenous

Cannabinoid

Retrograde Signaling

CB1 Receptor

Presynaptic

Neuron

Inhibition of

Neurotransmitter

Release

EXOGENOUS

Cannabinoid Therapy

Activated postsynaptic neuron

releases endocannabinoids

Endogenous CB1 ligand

diffuses back to and binds to

the presynaptic CB1 receptor

CB1 receptor activates a

G-protein, leading to inhibition

of NT release

Nabilone is thought to activate

CB1 receptors directly,

mimicking the effects of

endocannabinoids

1

2

3

4

5

Adapted from Page 5 of Slatkin NE.J Support Oncol. 2007;5(suppl3):1.Reprinted with permission.1/11/2011 33


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CannabinoidsSupportive Oncology

Established roles CINV

Emerging roles

Analgesia

Spasmolysis

Anorexia-cachexia

Sedative

Antidepressant Antineoplastic

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Dopamine Antagonists

Phenothiazines

Prochlorperazine (Compazine)

Metoclopramide (Reglan)

Trimethobenzamide (Tigan)

Limited role except for mildlyemetogenic drugs and may be helpful

in delayed nausea

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Delayed Nausea

Dexamethasone

Lorazepam (Ativan)

Dopamine antagonists

Prochlorperazine (Compazine)

Trimethobenzamide (Tigan)

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Mucositis (Mouth Sores)

More common with certain drugs:

5-fluorouracil (5-FU)

Methotrexate

Doxorubicin (Adriamycin)

Cyclophosphamide (Cytoxan)

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Mucositis (Mouth Sores)

Prevention

Icing of the mouth during

treatment

Treatment Options

Gel Clear

Magic Mouthwash

Viscous lidocaine

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Diarrhea

Major toxicity of several drugs used to

treat gastrointestinal cancers, for

example, 5-FU and irinotecan(Camptosar)

Acute diarrheal reaction to irinotecanAtropine at time of treatment

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Delayed Diarrhea:

Treatment Anti-Motility Drugs

Loperamide (Imodium)

Diphenoxylate (Lomotil)

Octreotide (Sandostatin)

Somatostatin analogue

Works to prolong GI transit time

Subcutaneous administration

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Diarrhea: Changes in Diet

Increased fluid intake

Increased starch content

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Hand-Foot Syndrome

Pain, redness, swelling, and peeling of the

skin of the palms and soles

Associated with certain agentsCapecitabine (Xeloda)

Liposomal doxorubicin (Doxil)

Infusional 5-FU

Weekly taxane therapy

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Hand-Foot Syndrome:

Treatment Options Dose reduction

Avoid tight-fitting shoes; repetitive rubbing or

prolonged heat to hands and feet Emollients

Eucerin

Bag Balm

Can be used effectively with cotton socks and/or

gloves at bedtime

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Fatigue: Multifactorial

Anemia

Erythropoietin (Procrit)/darbepoetin (Aranesp)

Depression

Selective serotonin reuptake inhibitor (SSRI)

Sleep Disturbance

-- Sleep aid: zolpidem tartrate (Ambien),

eszopiclone (Lunesta) Psychostimulants

-- Methylphenidate (Ritalin)

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Neuropathy

Painful burning sensation

Progressive numbness

Motor weakness

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Neuropathy

Acute, cold induced

Oxaliplatin (Eloxatin)

Chronic, dose related

Oxaliplatin

Taxanes

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Neuropathy: Prevention

Avoidance of cold exposure for 48-72

hours after oxaliplatin therapy

Amino acid therapy (glutamine)

Vitamin B6 (pyridoxine)

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Neuropathy:

Treatment Options

Dose reduction

Gabapentin (Neurontin)

Amitriptyline (Elavil)

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Support Therapy

A. Filgrastim (Neupogen) Granulocyte colony-stimulating factor, prophylaxis of

chemotherapy-induced neutropenia

B. Sargramostim (Leukine) Granulocyte/macrophage colony-stimulating factor, aids

neutrophil recovery in AML patients

C. Pamidronate(Aredia) Prevents hypercalcemia and bone resorption associated with

malignancy

D. Erythopoietin (Procrit)& Darbopoiten Stimulates bone marrow RBC production, treats anemia

resulting from myelosuppressive therapy

E. Leucovorin Folate supplement

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Targeted Cancer Therapy

The dream of the Magic Bullet

Side Effect-Free Cure of Cancer

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adverse effect of cytostatic

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