Classification, pharmacology

and interactions of chemotherapeutic

agents

Pharmacists with out borders

PWB 2020
Topics
• How does chemotherapy work?
• Classification
• Pharmacology
• Interactions
How does chemotherapy work?
• Chemotherapy is transported through the body and is
transported to the cells through the blood
• When the chemo reaches the tumor it inhibits and
stops cell division
• Cytotoxic agents also affect the normal cells in the
body, but they have greater ability to repair the
damage, therefore side-effects are often temporary
• Cytotoxics in combination:
• Often more effective due to different
pharmacological effects on the cell
• Possible to reduce side-effects since it is
possible to give lower effective doses when
using combination therapy. Single agent therapy
often require higher doses.
Classification of chemotherapy`
Traditional chemotherapy:
• Alkylating agents
• Antimetabolites
• Cytotoxic antibiotics
• Platinum cytotoxics
• Plant derivatives
• Topoisomerase inhibitors
New cancer therapies:
• Monoclonal antibodies
• Signal inhibitors
Separate lecture
• Immune therapy
 Examples of cytotoxics in the different
cytotoxic classes
Alkylating agents Antimetabolites Cytotoxic
antibiotics
Folic acid antagonists Pyrimidine Purine antagonists (anthracyclines)
antagonists

Cyclophosphamide Methotrexate Fluorouracil Fludarabine Doxorubicin

Ifosfamide Pemetrexed Cytarabine Cladribine Daunorubicin
Melphalan Gemcitabine Epirubicin
Bendamustine Idarubicin
Carmustine Mitoxantrone
Bleomycine

Platinum cytotoxics Plant derivatives Topoisomerase

inhibitors
Taxanes Vinca alkaloids Podophyllotoxines

Cisplatin Paclitaxel Vinblastine Etoposide Irinotecan

Carboplatin Docetaxel Vincristine Topotecan
Oxaliplatin Vinorelbine
Vindesin

Drugs in «fat» font present at the ward at Black Lion.

Not all cytotoxics are listed.
Site of action
Inhibition through the cell cycle
 Chemotherapy – single agents:
Antimetabolites - combine with cellular enzymes, blocking
DNA- and RNA-producing pathways by acting as false
substrates for the enzymes involved in these pathways
Methotrexate, Pemetrexed (Alimta®), 5-fluorouracil, capecitabine
(Xeloda®), Gemcitabine (Gemzar®), Cytarabin.

Methotrexate Folic acid

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 Chemotherapy – single agents:
Alkylating agents - act by linking guanine molecules on opposing
strands of the DNA helix, preventing the DNA from uncoiling and thereby
halting cell division
Cyclophosphamide, ifosfamide, dacarbazine, temozolomide (Temodal®)

• One of the metabolites of cyclophosphamide and ifosfamide irritates the

bladder, so it is important to give mesna and hydration fluid!

Cytotoxic antibiotics (Anthracyclines) - damage the DNA in cancer

cells
Daunorubicin, Doxorubicin, Epirubicin, Mitoxantrone, Mitomycin-C, Bleomycin
• Dose dependent cardiotoxicity (cumulative dose)

9 Doxorubicin
 Chemotherapy – single agents:
Topoisomerase inhibitors – block the enzyme topoisomerase,
which is essential for uncoiling DNA during cell replication
Etoposide, irinotecane
• Etoposide: risk of lowered blood pressure during infusion
Platinums – damage DNA cells and stop them from dividing
Carboplatin, cisplatin
• Cisplatin: Very emetogenic, as well as risk of kidney damage and
hearing loss

Carboplatin Cisplatin
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 Chemotherapy – single agents:
Mitotic inhibitors – block cell growth by stopping mitosis (cell
division)
• Taxanes – paclitaxel, docetaxel, Abraxane
• Vinca alkaloids – vinorelbine, vinblastine, vincristine
– Can be neurotoxic, both reversible and sometimes irreversible – ask the
patient about changed feeling in their hands or feet.
– Should NEVER be given intrathecally! It is in most cases fatal

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 Chemotherapy – combinations:
– CAF = cyclophosphamide + Adriamycin®(doxorubicin) + 5-fluorouracil
– TAC = Taxotere®(docetaxel) + Adriamycin® (doxorubicin)+cyclophosphamide
– AC-T = cyclophosphamide + Adriamycin®(doxorubicin) + Taxol®(paclitaxel)
– AC = cyclophosphamide + Adriamycin®(doxorubicin)
– CMF = cyclophosphamide + methotrexate + 5-fluorouracil
– Adriamycin®(doxorubicin) + Taxol®(paclitaxel)
– Taxotere® (docetaxel) + Xeloda® (capecitabine)
– Flox: Oxaliplatin + 5-fluoruracil + leucovorin
– Fliri: Irinotekan + 5-fluoruracil + leucovorin

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 Combination therapy – never several
drugs the same drug class
Alkylating agents Antimetabolites Cytotoxic
antibiotics
Folic acid antagonists Pyrimidine Purine antagonists (anthracyclines)
antagonists

Cyclophosphamide Methotrexate Fluorouracil Fludarabine Doxorubicin

Ifosfamide Pemetrexed Cytarabine Cladribine Daunorubicin
Melphalan Gemcitabine Epirubicin
Bendamustine Idarubicin
Carmustine Mitoxantrone
Bleomycine

Platinum cytotoxics Plant derivatives Topoisomerase

inhibitors
Taxanes Vinca alkaloids Podophyllotoxines

Cisplatin Paclitaxel Vinblastine Etoposide Irinotecan

Carboplatin Docetaxel Vincristine Topotecan
Oxaliplatin Vinorelbine
Vindesin

Drugs in «fat» font present at the ward at Black Lion.

Not all cytotoxics are listed.
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 Hormone Therapy:
– In case of Estrogen Receptor+ (ER+) and/or Progesterone
Receptor+ (PR+) for breast cancer:
• Tamoxifen (Nolvadex®) - Inhibits the estrogen receptors in breast tissue
• Fulvestrant (Faslodex®) - Inhibits the estrogen receptors in breast tissue
• Letrozole (Femara®), Anastrozole (Arimidex®), Exemestane (Aromasin®) -
Aromatase Inhibitors – stop production of estrogens

– For prostate cancer:

• Goserelin (Zoladex®), Leuprolide, Triptorelin - luteinizing hormone-
releasing hormone (LHRH) agonists
• Flutamide (Eulexin®), Nilutamide, Bicalutamide (Casodex®) -
antiandrogens

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Hormone Therapy

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 Steroids – glucocorticoids
E.g. prednisolone, prednisone and
dexamethasone
• Not cytotoxic drugs
• Hormones that have an immunosuppresive
and anti inflammatory effect
• Inhibits cell proliferation and leads to cell
death
• lymphatic leukaemia cancer cells are very
sensitive to steroids
• Counteracts cerebral edema
• Often used as anti emetics
• Have several side effects, as shown in the
figure
Drug interactions
Drug Interactions
A drug interaction is defined by an alteration of
one drug by another drug or by the presence of
some other substance.
– The Drug whose activity is effected by such an
interaction is called as a “Object drug”.
– The agent which precipitates such an interaction is
referred to as the “Precipitant”.

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Types of drug interactions

1. Drug-drug interactions.
2. Drug-food interactions (alcohol and smoking may also influence)
3. Chemical-drug interactions.
4. Drug-laboratory test interactions.
5. Drug-disease interactions.
• Note! Be aware of drug interactions with herbal medicine e.g. St.
John`s Wort
• Read carefully the medicinal drug summary of product characteristics
and/or label for information on specific drug interactions!

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Classification of drug Dose

interactions Pharmacokinetic
variability
• Absorption

• Pharmacodynamic • Distribution
• Metabolism
• Excretion
interactions
Plasma
• Pharmacokinetic concentration

interactions Pharmacodynamic
variability
• Receptor
• Pharmaceutical interactions
• Receptor
response
interactions
Clinical effect

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 Pharmacodynamic interactions
These interactions arise when a drug indirectly
or directly affect the drug at its site of action.
In these types of interactions there is no change
in drug concentration.
Examples:
• Administration of two blood thinners will often lead
to bleeding
• Administration of two anti hypertensive medicines
can lead to low bloodpressure

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 Direct pharmacodynamic interactions
Interactions where drugs that have similar or opposing
pharmacological effects are used concurrently. The three
consequences of direct interactions are:
• Antagonism - The interacting drugs have opposing actions
– Acetylcholine and noradrenaline have opposing effects on heart rate
• Addition or summation - The interacting drugs have similar actions
and the resulting effect is the sum of individual drug responses
– Administering two CNS depressants like sedatives and hypnotics
• Synergism or potentiation - Enhancement of action of one drug by
another
– Administering leucovorin concomitant to fluorouracil increases the cytotoxic
effect of fluorouracil

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 Pharmacokinetic interactions
These interactions arise when a drug changes
the absorption, distribution, metabolism or
excretion of another drug.
This type of interaction will change the plasma
concentration of the drug in the body.
Examples:
• NSAIDS and methotrexate
NSAIDS inhibits renal prostaglandin synthesis leads to
reduced renal perfusion which reduces the renal
excretion of methotrexate. Important to remember for
high dose MTX and kidney problems.
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 Types of pharmacokinetic
interactions
• Absorption interactions
• Faster or slower absorption
• More or less complete absorption

• Distribution interactions
• Plasma protein binding

• Metabolic interactions
• Enzymatic inhibition or induction

• Excretion interactions
• Influencing the kidneys or the bile
 Major mechanisms of absorption
interactions
1. Complexation and adsorption.
2. Alteration in GI pH.
3. Alteration in gut motility.
4. Inhibition of GI enzymes
5. Alteration of GI micro flora.
6. Malabsorption syndrome.

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 Distribution interactions
Interactions where the distribution pattern of the object
drug is altered
The major mechanism for distribution interaction is
alteration in protein-drug binding.
• Leading to more drug available in the body than
normal, and therefore increased effect
Displaced drug Displacer Clinical effect

Anti coagulants Phenylbutazone, Increased clotting

chloral hydrate time, increased risk
of hemorrhage

Tolbutamide Sulphonamides Increased

hypoglycemic effect

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 Metabolic interactions

The object drug is altered, leading to a higher or lower

concentration of the drug in the body.
1. Enzyme induction: Increased rate of metabolism.
2. Enzyme inhibition: Decreased rate of metabolism.
It is the most significant interaction in comparison to
other interactions and can be fatal.

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 Excretion interactions

The excretion pattern of the object drug is altered.

Major mechanisms of excretion interactions are:
• Alteration in renal blood flow
• Alteration of urine PH
• Competition for active secretions
• Forced diuresis

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 Pharmaceutical interactions
Also called incompatibility.

Physicochemical interaction that

occurs when drugs are mixed, causing
precipitation or inactivation of active
substances.
Can be both visible or invisible to the
eye.
Examples:
• Oxaliplatin in NaCl – degradation Left: esomeprazole in NaCl 9 mg/ml
Right: esomeprazole in Ringers-Acetate
• Concentration of etoposide in solution
higher than 0,4 mg/ml – precipitation
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The net effect of a drug interaction is:

• Generally quantitative i.e.increased or decreased effect.

• Seldom qualitative i.e. more rapid or slower effect.
• Often lead to increased adverse effects.
• Precipitation will lead to lack of clinical effect, and may
in the worst case give pulmonary embolism.

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 Drug interactions are thus:
• Mostly undesirable and can give clinically very
severe consequences for a patient if they are not
handled correctly
• Rarely desirable (beneficial): for eg.,enhancement
of activity of penicillin when administered with
probenecid.

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Factors contributing to drug interactions:
1. Multiple drug therapy.
2. Multiple prescribers.
3. Multiple pharmacological effects of drug.
4. Multiple diseases/predisposing illness.
5. Poor patient compliance.
6. Advancing age of patient.

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Reducing the risk of interactions
1. Identify the patients risk
factors.
2. Take a thorough drug history of
your patient.
3. Have knowledge about the
actions of the drugs being used.
4. Consider therapeutic
alternatives.
5. Avoid complex therapeutic
regiments when possible.
6. Educate the patient.
7. Monitor therapy.

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