pharmacology of drugs used in cancer: an overview chemotherapy_pharmacolog… · pharmacology of...

PHARMACOLOGY OF DRUGS USED IN

CANCER: AN OVERVIEW

Sara Fawaz Alsharhan

Pharm.D candidate, KSU

May 2014

Outline

• Introduction

• Chemotherapy classes

Alkylating agents

Antimetabolites

Antimitotics

Cytotoxic antibiotics

Platinum compounds

Others

• Targeted agents

Introduction

• The National Cancer Institute defines chemotherapy as

drugs that treat cancer cells.

• It kills cancer cells by damaging DNA, interfering with

DNA synthesis, or inhibiting cell division.

Introduction

• Chemotherapy agents are classified by their effect on

the cell cycle or their mechanism of action.

• They can be classified also as phase specific agents or

phase non specific agents.

Cell

cycle

and e

ffects

of

repre

se

nta

tive a

gents

on

phases o

f th

e c

ell

cycle

Introduction

• After understanding the mechanisms of the unregulated

growth of cells and the ability to invade tissues and

metastasize, targeted agents were designed

(monoclonal antibodies and tyrosine kinase inhibitors).

• Hormone therapies inhibit tumor growth by blocking the

receptors or by eliminating the endogenous hormone

feeding the tumor.

Chemotherapy classes

Alkylating agents

Antimetabolites


Mitotic inhibitors

Platinum compounds

Alkylating agents

• Alkylating agents involve reactions with guanine in DNA.

• These agents add methyl or other alkyl groups onto

molecules where they do not belong.

• This in turn inhibits their correct utilization by base

pairing and causes a miscoding of DNA.

Alkylating agents

Agent Subclass Route Pharmacokinetic Major toxicities

Busulfan Alkyl sulfonate IV, PO • Well absorbed

orally

• Metabolized by

liver extensively

• Metabolites

eliminated renaly

• Myelosuppression

• Pulmonary fibrosis

• Hyperpigmentation

• Hepatic dysfunction

• Suppression of

testicular, ovarian, and

adrenal function

• Seizures and

venoocclusive disease

with high dose

Melphalan Nitrogen

mustard

IV, PO • Variable oral

absorption on

empty stomach

• Elimination by

hydrolysis

• Minimal renal

elimination


• Alopecia


• Nausea/vomiting


Alkylating agents

Agent Subclass Route Pharmacokinetic Major toxicities

Chlorambucil Nitrogen

mustard

PO • Well absorbed

• Protein bound

• Metabolized by

liver extensively

• Metabolites

spontaneously

degrade

• Minimal renal

elimination

• Myelosuppression;

• Tremor

• Twitching

• Myoclonia

• Agitation

• Ataxia

• Hallucinations



Cyclophosphamide Nitrogen

mustard

IV, PO • Well absorbed

with food

• Activated in liver

• Eliminated by

kidneys


• Hemorrhagic cystitis

• Nausea/vomiting

• Alopecia

• Cardiomyopathy

• Interstitial pneumonitis

• SIADH

Alkylating agentsAgent Subclass Route Pharmacokinetic Major toxicities

Ifosfamide Nitrogen

mustard

IV • Activated in liver

• Renal elimination


• Hemorrhagic cystitis(should

be administered with MESNA)

• Somnolence, confusion,

hallucinations

• Nausea/vomiting

• Alopecia

Carmustine Nitrosourea IV • Crosses the

blood–brain barrier

effectively;



• Pulmonary toxicity

• Nausea\Vomiting

• Hepatic and renal

dysfunction

• Venous irritant

Lomustine Nitrosourea PO Crosses the blood–

brain barrier

effectively


• Nausea/vomiting



dysfunction

Antimetabolites

Antimetabolites

Purineanalogs

Antimetabolites- Folic acid antagonists

Agent MOA Route Pharmacokinetic Major toxicities

Methotrexate • Inhibts

DHFR

• Reduce

folates

IV, PO • Variable absorption

on empty stomach

and may decreased

by milk rich food

• Response may

decreased by folate



• Renal and hepatic

dysfunction

• Mucositis

• Pulmonary toxicity

• Neurotoxicity

Antimetabolites- Purine analogs


Mercaptopurine Inhibits the

first step of

the de novo

purine

synthesis

PO • Absorption highly

variable on empty

stomach

• Hepatic and GI

mucosa metabolism

• Hepatic elimination


• Anorexia

• Nausea/vomiting

• Hepatic

dysfunction

PO • Mean bioavailability

30%

• Hepatic metabolism

•Minimal excretion in

urine


• Hepatotoxicity

(including veno-

occlusive disease)

• Hyperuricemia

• Anorexia, mild

nausea and

stomatitis

Thioguanine

Antimetabolites- Pyrimidine analogs


Capecitabine Prodrug

metabolized to

fluorouracil;

PO • Well absorbed

• Moderately protein

bound

• Extensive hepatic

metabolism


• Nausea/vomiting

• Stomatitis

• Hand-foot

syndrome


• Anorexia

Fluorouracil • Incorporates into

RNA and interferes

with RNA function

• Inhibits TS

IV • Hepatic

metabolism

• Minimal renal

elimination

• Mucositis

• Diarrhea


• Dermatologic

• Nausealvomiting

• Hand foot

syndrome

Gemcitabine Inhibits DNA and

RNA synthesis by

inhibiting

ribonucleotide

reductase

IV • Intracellular

metabolism

• Primary renal

elimination


• Flu like syndrome

• Nausea/vomiting

• Edema

Antimtotics

Antimitotics


Vinblastine • Bind to tubulin

• Interfering with

microtubule

assembly

• Mitotic spindle

formation

IV • Hepatic

metabolism

• Biliary elimination


• CNS toxicity

• Nausea/vomiting

• Vesicant

• Hepatic

metabolism

• Fecal elimination

•Neurotoxicity

(sensory and

motor)

• Autonomic

neuropathies

• Constipation

• SIADH

• Vesicant

Vincristine

Vinorelbine • Leukopenia

• Neurotoxicity

• Vesicant


• Anthracyclines:

Stabilizes the cleavable complex between

topoisomerase II and DNA, causing single- and double-

strand DNA breaks; forms oxygen free radicals.


Agent Pharmacokinetic Major toxicities

Daunorubicin

• Extensive binding to

tissues


• Moderate biliary excretion

• Minimal renal elimination


• Mucositis

• Alopecia

• Cumulative cardioctoxicity

• Vesicant

• Nausea/vomiting and diarrhea

• Headache

• Edema

• Neuropathy

• Back pain

• Dyspnea,

• Hand-foot syndrome

Doxorubicin • Myelosuppression

• mucositis

• Alopecia

• Cumulative cardiactoxicity

• Vesicant

• Nausea/vomiting

• fatigue

• Stomatitis

• Rash, hand-foot syndrome



Epirubicin • Highly protein bound


• Moderate biliary excretion



• Mucositis

• Alopecia

• Cumulative cardiactoxicity

• Vesicant

Idarubicin • Extensive extrahepatic

metabolism

• Primarily biliary excretion



• Mucositis

• Anorexia, nausea, vomiting,

diarrhea

• Fever

•A lopecia

• Vesicant

Bleomycin • Enzymatic degradation by a

cytosolic cysteine proteinase

• Widely distributed in normal

tissues except lung and skin


• Erythema,

• Hyperpigmentation

• Pulmonarytoxicity

• Fever, chills

• Vomiting

Platinum compounds

• Mechanism of action:

React with nucleophilic sites on DNA causing DNA

cross-links.

Platinum compounds


Carboplatin

Elimination primarily renal


• Nausea\vomiting

• Peripheral neuropathy

Cisplatin • Nephrotoxicity

• Nausea\vomiting

• Peripheral neuropathy

• Ototoxicity

• Electrolyte disturbances

Oxaliplatin • Highly protein bound


• Anaphylactic reactions

• Peripheral neuropathy,

sensitivity to cold, jaw spasm,

dysphagia

• Nausea, vomiting, diarrhea,

fatigue


Others Agent MOA Route Pharmacokinetic Major toxicities

Etoposide • Inhibits

topoisomerase II

• Stabilizing the

cleavable complex

• Breakage of

double-strand DNA

IV and

PO

• Variable oral

absorption

• Highly protein

bound

• Moderate renal

elimination

• Minimal bile and

fecal elimination


• Nausea, vomiting

• Alopecia

• Mucositis

• Hypotension

(related to rapid

infusion)

• Hypersensitivity

reactions

• Fever

• Bronchospasm

Asparaginase • Hydrolyzes serum

asparagines to

nonfunctional

aspartic acid and

ammonia

• Depriving tumor

cells of a necessary

amino acid

IV Not well

documented

• Allergic reactions

• Reduction of

clotting factors

• Pancreatitis


dysfunction

Targeted agents

Monoclonal antibodies

• Unlike traditional chemotherapy, they selectively target

receptors or their ligands known to potentiate cancer

pathways.

• As result, they minimize toxicity to noncancer cells.

Tyrosine kinase inhibitors

• Small molecules that directly inhibit tyrosine kinase

activation by competing with ATP for biding to the

intracellular tyrosine kinase.

• They include inhibiting cells that may not overexpress

the receptors on their surface or have mutated form of

the receptor that result in its activation.

Sum

mary

References

• Brian K., et al. (2013). Applied Therapeutics.10th ed.

Pheladelphia: 2126-2146.

• Lexi-comp, 2014

• Drugs.com

THANK YOU!

pharmacology of drugs used in cancer: an overview chemotherapy_pharmacolog… · pharmacology of...

Documents