This document summarizes pharmacokinetics and pharmacodynamics of anticancer drugs. It discusses the absorption, distribution, metabolism and excretion of drugs and how these processes influence drug action over time. Key pharmacokinetic parameters like bioavailability, volume of distribution, clearance and half-life are explained. The document also covers pharmacodynamic concepts such as dose-response relationships, drug potency, efficacy and therapeutic indices. Factors affecting variability in individual responses and the role of therapeutic drug monitoring are summarized. Finally, the document categorizes and provides examples of major classes of anticancer agents.
Definition
Anticancer, or antineoplastic, drugs are used to treat malignancies, or cancerous growths. Drug therapy may be used alone, or in combination with other treatments such as surgery or radiation therapy.
Purpose
Anticancer drugs are used to control the growth of cancerous cells. Cancer is commonly defined as the uncontrolled growth of cells, with loss of differentiation and commonly, with metastasis, spread of the cancer to other tissues and organs. Cancers are malignant growths. In contrast, benign growths remain encapsulated and grow within a well-defined area. Although benign tumors may be fatal if untreated, due to pressure on essential organs, as in the case of a benign brain tumor, surgery or radiation are the preferred methods of treating growths which have a well defined location. Drug therapy is used when the tumor has spread, or may spread, to all areas of the body.
Definition
Anticancer, or antineoplastic, drugs are used to treat malignancies, or cancerous growths. Drug therapy may be used alone, or in combination with other treatments such as surgery or radiation therapy.
Purpose
Anticancer drugs are used to control the growth of cancerous cells. Cancer is commonly defined as the uncontrolled growth of cells, with loss of differentiation and commonly, with metastasis, spread of the cancer to other tissues and organs. Cancers are malignant growths. In contrast, benign growths remain encapsulated and grow within a well-defined area. Although benign tumors may be fatal if untreated, due to pressure on essential organs, as in the case of a benign brain tumor, surgery or radiation are the preferred methods of treating growths which have a well defined location. Drug therapy is used when the tumor has spread, or may spread, to all areas of the body.
CANCER: A group of disease involving abnormal cell growth with the potential to invade or spread to other part of the body.
CHEMOTHERAPY: the term chemotherapy is describe as the use of chemicals or drugs to treat cancer.
CYTOTOXIC DRUG: lysis both normal and cancer cells
Basic principles of chemotherapy/ AMAs covers definition, history of AMAs development, principles of AMAs, problems associated with AMAs, failure of therapy with examples.
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CANCER: A group of disease involving abnormal cell growth with the potential to invade or spread to other part of the body.
CHEMOTHERAPY: the term chemotherapy is describe as the use of chemicals or drugs to treat cancer.
CYTOTOXIC DRUG: lysis both normal and cancer cells
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Principles of cancer chemotherapy: a deep insight, by RxVichuZ!!RxVichuZ
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Precise details have been provided.
Do go through!!
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2. Pharmacokinetic-
Is quantitative study of drug movement in,through and out
of body.
It determines the-
• Route of adminstration
• Dose,latency of onset
• Time of peak action
• Duration of action and frequency of adminstration of
drug
It mainly involve study of-
• ABSORPTION
• DISTRIBUTION
• METABOLISM
• EXCRETION
3. 1. ABSORPTION-Is define as movement of drug from site of
adminstration to circulation.
ROUTE OF DRUG ABSORPTION ARE-
• ENTERAL— Includes-oral,sublingual&rectal
• PARENTERAL ---Includes-intravascular,subcutaneous,
intramuscular
• TOPICAL SITES(SKIN,CORNEA,MUCOUS MEMBRANES)
Pharmacokinetic parameter most closely associated with absorption is
BIOAVAILABILITY--- Defined as fraction of adminstered dose of
drug that reaches the systemic circulation in unchanged form..
It Ranges from 0-100%.Bioavailability of drug injected i.v is 100%.
Bt lower after oral ingestion because absorb drug undergo first pass
metabolism in liver/intestinal wall.
Incomplete bioavailibility after s.c or i.m injection may occur due to
local binding of drug..
[FIRST PASS METABOLISM(Pre-systemic metabolism)-Defined as
metabolism of drug during its passage from site of absorption to
systemic circulation]
5. 2.DISTRIBUTION-Defined as process of reversible transfer of
drug to and from the site of measurement.
Extent of distibution determined by volume of distibution-
defined as apparent volume into which a drug distibutes in
body at equilibrium
Factors affecting drug distribution-
• Lipid solubility(High lipid soluble)
• Tissue permeability
• Extent of binding to plasma and tissue protein(more protein
bound drug nt cross membranes)
• Presence of tissue specific transporters
• Difference in regional blood flow
6. 3.ELIMINATION- Includes-
METABOLISM(BIOTRANSFORMATION)-
Defined as chemical alteration of drug in the body.It is needed to
render nonpolar(lipid-soluble)compounds polar(lipid insoluble)so
that they are not reabsorbed in renal tubules and are excreted.
Primary site for drug metabolism-liver,other are-kidney,lung
intestine,plasma.
Phases of biotransformation-
1. PHASE-I/NON-SYNTHETIC REACTION-Functional grp is
generated-metabolite may be active or inactive
2. PHASE-II/SYNTHETIC/CONJUGATION REACTION-metabolites
are mostly inactive.
EXCRETION-Defined as irreversible loss of chemically unchanged
drug .i.e.passage out of systematically absorbed drug.
Drugs are excreted in Urine(majority of drug),faeces,saliva &sweat.
7. Pharmacokinetic parameter associated with elimination-
• CLEARANCE-Defined as volume of plasma from which drug is
completely removed in unit time
• PLASMA HALF LIFE-Is time taken for its plasma concentration
to be reduced to half of its original value.Complete drug elimination
occur in 4-5 half lives
Process of elimination involved-
1. FIRST ORDER(EXPONENTIAL) KINETICS-The rate of
elimination is directly proportional to drug concentration ,CL-
remain constant,t1/2-remain constant.
2. ZERO ORDER (LINEAR)KINETICS-The rate of elimination
remain constant irrespective of drug concentration,CL-Decreases
with dose,while t1/2-Increases with dose.
8. LOG KILL HYPOTHESIS
• Chemotherapeutic agents follow first order kinetics.
• According to log-kill hypothesis,chemotherapeutic agents kill a
constant fraction of cell(first order kinetics),rather than a specific
number of cell,after each dose.
SOLID CANCER TUMORS-generally have a low growth fraction
thus respond poorly to chemotherapy.
DISSEMINATED CANCERS-generally have a high growth fraction
&generally respond well to chemotherapy.
9.
10. Pharmacodynamic
Is “study of drug effect”
Drug produces its effect by interacting
with functional proteins that includes -
• Enzymes
• Ion channels
• Transporter
• Receptor
In oncolgy,pharmacodynamic studies
of drug effect focused on toxicity endpoints.
Specific parameter used as independent variable in
pharmacodynamic analysis depend on particular characteristic
of study drug.
11. DOSE RESPONSE RELATIONSHIP
• Dose response relationship has two
componenets-
Dose-plasma concentration relationship
&plasma concentration-response
relationship.
Generally,intensity of response
increases with increase in dose & dose-
response curve is RECTANGULAR
HYPERBOLA.
If dose is plotted on logarithmic
scale,curve become SIGMOID.
Advantages of plotting log-dose
response curves(DRC) are—
1. Wide range of drug doses can be easily
displayed on graph
2. Comparison between agonists and study of
antagonist becomes easier.
12. DRUG POTENCY--Refer to amount of drug needed to produce certain
response.A DRC positioned rightward indicate lower potency.
DRUG EFFICACY—Refer to maximal response that can be elicited by
drug.
EFFICACY IS MORE DECISIVE FACTOR IN CHOICE OF DRUG
THERAPEUTIC INDEX-A gap between the therapeutic effect DRC and
adverse effect DRC is known as SAFETY MARGIN OR
THERAPEUTIC INDEX.
THERAPEUTIC INDEX=MEDIAN LETHAL DOSE(LD50)
MEDIAN EFFECTIVE DOSE(ED50)
13.
14. Variability in pharmacodynamic
/pharmacokinetics response influenced by-
• Age
• Body size and body composition
• Gender(Male gender is associated with maximum elimination capacity of
various anticancer drug e.g.paclitaxel or with increased clearance
e.g.imatinib compared to female gender)
• Concomitant medication(co-adminstration with other chemotherapeutic,
non-chemotherapeutic and alternative medicines may affect the efficacy or
the toxicity ).e.g.
Anticonvulsant drugs lyk pheytoin,phenobarbital may induce drug
metabolising enzymes and and thus increases clearance of anticancer drugs.
Herbal products lyk Ginseng-discourage in pt with estrogen-receptor
positive breast cancer and endometrial cancer as they stimulate tumor
growth.
15. THERAPEUTIC DRUG MONITORING
Useful in following situation-
• Drug with low safety margins.
• Potentially toxic drug used in presence of renal failure.
• In case of failure of response without any apparent reason.
• To check patient compliance.
This monitoring has significantly reduced incidence of serious toxicity
&also improved outcome by eliminating low systemic exposure
levels.
Therapeutic drug monitoring has also been applied to or is currently
under investigation for several more recently developed anticancer
drug,including imatinib and sorafenib.