HC16+17: Pharmacology I&II

WHO 6STEPS

To determine what therapy is effective, it is necessary to make a therapeutic plan. This can be done according to the WHO 6STEPS method:

1. Step 1: evaluate the problems of the patient
2. Step 2: identify the goals of therapy
3. Step 3: list the treatment options (indication related)
4. Step 4: provide the rationale for the best treatment for this patient
5. Step 5: write a definitive therapy plan (prescription)
6. Step 6: determine the monitoring parameters/follow-up

To make a therapeutic plan for a specific patient, it is necessary to understand:

• The pathology of the disease
• The target sites of therapy
• The mechanisms of actions of a drug

Determining tumor treatment:

Cancer is a heterogenous disease → it has different causes and requires different treatments. There are 3 main forms of cancer treatment:

• Surgery
• Radiotherapy
• Pharmacological therapy

To make a patient-specific therapeutic plan, the following needs to be determined:

• Type of tumor
• Growth velocity
• Metastases

Sometimes, curation isn’t possible anymore and treatment is palliative. Palliative treatment consists of:

• Pain management
• Supportive care

Core medication list

Groups of medicines:

There are 4 groups of pharmacological therapy which can be used as cancer treatment:

• Cytostatics
• Hormones
• Immunomodulators
• Target therapy

Core medication list:

The core medication list consists of the most used drugs for cancer. It is necessary to know the:

• Indication
• Mechanism of action
• Relevant side effects
• One or 2 drug examples

The core medication list is built up as follows:

• Cytostatic drugs
  • Alkylating and related agents
    • Cyclophosphamide
    • Cisplatin
  • Antimetabolites
    • Methotrexate
    • Fluorouracil (5-FU)
    • Cytarabine
  • Antimitotic
    • Paclitaxel
  • Topoisomerase-inhibitors
    • Doxorubicin
• Hormonal drugs
  • Antihormones
    • Tamoxifen
  • Aromatase-inhibitors
    • Anastrozol
  • Progestagens
    • Megestrolacetate
  • LHRH-analogues
    • Gosereline
• Target therapy
  • Inhibitors of EGF-2 signaling
    • Trastuzumab
    • Cetuximab
  • Inhibitors of VEGF-signaling
    • Bevacizumab
  • Inhibitors of CD20/CD50 signaling
    • Rituximab
  • Tyrosine kinase inhibitors
    • Imatinib
  • (Immune) checkpoint inhibitor
    • Nivolumab
• (Anti-)coagulants/immunomodulators
  • Thrombocyte aggregation inhibitors
    • Clopidogrel
    • Acetylsalicylic acid (aspirin)
  • Vitamin K antagonist
    • Acenocoumarol
  • Heparin
  • Antifibrinolyticum
    • Tranexamicacid
  • Thrombolyticum
    • Streptokinase
  • Coagulation factor
    • Thrombin
  • Xa inhibitor
    • Dabigatran
    • Apixaban

Cytostatics

Cell division:

In normal cells, cell division is regulated by growth stimulating factors and growth inhibiting factors:

• Growth stimulating factors → transcription of proteins that stimulate cell division
• Growth inhibiting factors → transcription of proteins that inhibit cell division

In cancer cells, growth is out of control. This is caused by:

• Upregulated transcription of proteins that stimulate cell division
• Downregulated transcription of proteins that inhibit cell division

The cell cycle consists of 5 stages:

1. G0
2. G1: growth and preparation of DNA synthesis
3. S: DNA replication
4. G2: growth and preparation of mitosis
5. M: mitosis
   1. Prophase
   2. Metaphase
   3. Anaphase
   4. Telophase

Cytostatic drugs act on different phases of the cell cycle. They are used for:

• Curative therapy
• Palliative therapy
• Adjunctive therapy

General principles:

General principles of cytostatic drugs are:

• Affect only one characteristic aspect of cancer cell biology → cell division
• Have no specific inhibitory effect on invasiveness, loss of differentiation or tendency to metastasize
• Induce damage to DNA synthesis and initiate apoptosis
• The main target is cell division → affect all rapidly dividing normal tissues

Toxic effects:

Cytostatic drugs have several general toxic effects:

• Bone marrow toxicity → myelosuppression
• Impaired wound healing
• Loss of hair
• Damage to gastrointestinal epithelium
• Nausea and vomiting
• Depression of growth in children
• Sterility
• Teratogenecity
  • Harmful for pregnant women

Specific side effects depend on the cytostatic drug and its mechanism of action.

Target sites:

The target site of cytotoxic drugs depends on the type of drug:

• Alkylating agents → DNA → interfere in the entire cycle
• Antimetabolites: DNA-synthesis → interfere in the S-phase
• Topo-isomerase inhibitors → DNA transcription and DNA duplication → interfere in the mitosis
• Antimitotics → mitosis → interfere in the G2-phase

Alkylating agents:

Alkylating agents work as follows:

1. Alkylating agents make a reactive covalent binding between an alkylgroup and nucleic acids
   • Usually alkylase unwinds the DNA-strand → alkylating agents prevent this via intrachain or interchain-linking:
     • Intrachain-linking: bridges between a single strand
     • Interchain-linking: crosslinking, bridges between 2 strands
   • Usually nitrogen at position 7 of guanine is the main target
2. Helicases cannot unwind DNA
3. Inhibition of DNA replication and RNA transcription

Alkylating agents are not phase dependent.

The most frequently used alkylating agent is cyclophosphamide (nitrogen):

• Indication: solid tumors, such as:
  • Leukemia
  • Hodgkin
  • Non-Hodgkin
  • Mamma carcinoma
• Administration:
  • Oral: the bioavailability is variable
  • IV: preferred
• Common side effects: in >30% of cases
  • Nausea
  • Vomiting
  • Myelosuppression

Another alkylating agent is cisplatin, a platinum compound:

• Indication: solid tumors
• Mechanism: after diffusion into the cell, chloride is lost → DNA-crosslinks
• Common side effects: toxicity is very high
  • Severe nausea and vomiting
  • Myelosuppression is relatively low
  • Acute nephrotoxic electrolyte disorder
    • Nephrotoxicity can be prevented with hyperhydration and dialysis
  • Neurotoxicity

Antimetabolites:

Antimetabolites are synthesized to inhibit biochemical processes, resulting in inhibition of DNA and RNA synthesis. They have the following mechanism of action:

1. Antimetabolites compete with the natural substrate for the active site of an enzyme
   • Have a structural similarity to vitamins, nucleosides and amino-acids
2. Mimic action of normal metabolites in the folic acid cycle and the metabolic pathway of purine and pyrimidine synthesis
   • Act during the S-phase
3. Inhibit DNA-synthesis and cell death

Methotrexate is an antimetabolite which competitively inhibits dihydrofolate reductase. Because the bioavailability is unpredictable, IV administration is preferred. 5-FU is the prodrug of methotrexate. Common side effects of 5-FU are:

• Mucositis
• Myelosuppression
• Diarrhea

These side effects are dependent on the duration of administration → different dosing schedules can be used to reduce the side effects:

• Short-term administration: bolus injection
• Long-term administration: continuous infusion

Cytarabine is an antimetabolite which blocks the function of DNA-polymerases → inhibits DNA-replication. Common side effects are:

• Myelosuppression
• Vomiting and nausea
• Diarrhea

Cytarabine is often given via IV administration in combination with cisplatin.

Antimitotics:

Antimitotics are mitosis inhibitors which work as follows:

1. Antimitotics stabilize the microtubules by inhibiting polymerization
2. Microtubules become rigid and non-functional
3. Inhibition of re-organization of the microtubule network → cell-shape changes
4. Inhibition of cell division

An example of a mitosis inhibitor is paclitaxel, which has the following characteristics:

• Administration: by IV
  • Every 3 weeks
  • Every week in a lower dose
• Common side effects:
  • Peripheral edema
  • Alopecia
  • Bone marrow suppression
  • Hypersensitivity reactions
  • Cardiac disturbances

Topo-isomerase inhibitors:

Topo-isomerase enzymes unwind, cut and ligate DNA. They play a crucial role in DNA-repair and completion of mitosis. Topo-isomerase inhibitors inhibit these enzymes and work as follows:

1. Topo-isomerase inhibitors inhibit topo-isomerases
2. Unwinding, cutting and ligation of DNA doesn’t take place
3. The capacity of DNA-repair is decreased and DNA-replication is inhibited

Doxorubicine is the most relevant topo-isomerase inhibitor. Common side-effects are:

• Myelosuppression
• Vomiting
• Nausea
• Alopecia
• Cardiotoxicity

Limitations and resistance of cytostatic drugs

Limitations:

Cytostatic drugs have several limitations:

• Problems with the safety profile of chemotherapeutic agents
  • There are guidelines for safe prescribing, dispensing and administering cytostatic drugs
    • Protocol: therapy, dose, scheduling are described
    • Treatment should be verified by a pharmacist
    • Patient information: treatment, side effects
    • Collection of excreta from patients treated with cytostatics
• Problems with the efficacy of chemotherapeutic agents → resistance to cytostatics
• Predominantly affect rapidly dividing cells → there’s no specific target
• Do not specifically target cancer cells
• Only influence a cell’s ability to divide and have little effect on other aspects of tumor progression such as:
  • Tissue invasion
  • Metastases
  • Progressive loss of differentiation
• Are associated with high incidence of adverse side effects
  • Bone marrow suppression
  • Alopecia
  • Mucositis
  • Emesis
    • Nausea
    • Vomiting

Emesis:

Emesis is a side effect characterized by nausea and vomiting. It is mainly caused by alkylating agents, especially cisplatin:

• Directly: via the circulation by stimulating chemo trigger zone (CTZ) which are located outside the blood-brain barrier
• Indirectly by stimulation of the release of serotonin in the GI tract

The severity of emesis is dependent on the compound/cytostatic drug and the dose:

• Strong emetogenic
  • Cisplatin
  • High doses of cyclophosphamide
• Moderately emetogenic
  • Low doses of cyclophosphamide
• Mildly or not emetogenic
  • 5-FU
  • Methotrexate
  • Paclitaxel

Triggering of the CTZ results in:

1. Acute emesis
   • 1-2 hours after the onset of chemotherapy
   • Lasts for 8-24 hours
2. Delayed emesis
   • Usually 24-72 hours or later after the onset of chemotherapy

Anti-emetics can be used to prevent cytostatic drug induced emesis. This can done by blocking the receptors in the CTZ. Examples of anti-emetics are:

• 5HT3 receptor antagonists
  • Odansetron
  • Granisetron
• D2-antagonists
  • Metoclopramide

This is a form of palliative treatment.

Resistance:

The resistance that neoplastic cells develop to cytostatics can be:

• Primary: present when the drug is first given
• Required: developed during treatment
  • By adaptation or mutation of tumor cells

Possible explanations for resistance are:

• Decreased amount of drug taken up by the tumor cell
  • E.g. methotrexate
• Insufficient activation of the prodrug in the liver
  • E.g. fluorouracil to FDUMP
• Increased inactivation of a drug in the liver
• Increased concentration of the target enzyme
  • E.g. methotrexate
• Rapid repair of drug-induced lesions
  • E.g. alkylating agents
• Altered activity of target enzymes such as topoisomerase
  • E.g. doxorubicin
• Mutation of various genes

Effectiveness of therapy:

Effectiveness of therapy is related to:

• Dose-related plateaus
• Duration of exposure
• Combinations of cytostatic drugs
  • Synergy

Combinations of cytostatic drugs to create synergy are used in several cancer types:

• Mamma carcinoma
  • CMF: cyclophosphamide, methotrexate, 5-fluoro-uracil (5-FU)
  • FAC: 5-fluoro-uracil, doxorubicin, cyclophosphamide
• Ovarian carcinoma
  • TP: paclitaxel, cisplatin

Requirements for combination therapy are:

• Each cytostatic must be active against the tumor type
• Cytostatics must be used in the optimal dose
• There should be no overlapping dose-limiting toxicity

Some tumors are insensitive for the standard dose of a cytostatic. Treatment with a high dose of chemotherapy can be useful to increase the exposure or exposure time:

• Higher dose
• Increased dose frequency → to limit the time of a tumor to recover from cell damage
• Different dosing schedules
  • A low dose every week
  • Every 2 or 3 weeks a higher dose
• Different forms of administration
  • Methotrexate or 5-FU:
    • Short-term administration
      • Bolus injection
    • Long-term administration
      • Continuous infusion

Systemic toxicity can be prevented by local administration instead of systemic administration (oral/IV):

• Intravesicle → bladder carcinoma
  • “Blaasspoeling”
• Intraperitoneal → ovarian carcinoma
• Intrapleural → pleuritic carcinoma

Target cell therapy

Target cell therapy can consist of:

• Monoclonal antibodies
  • Can mark tumor cells on the outside by binding to specific proteins (receptors)
  • Makes the tumor cell recognizable for immune cell attack
  • Can be recognized by the suffix “-mab” in the drug’s name
    • Trastuzumab
    • Cetuximab
  • Are very expensive
• Protein kinase inhibitors
  • Target protein kinases intracellularly → decreases the expression of growth factors
  • E.g. imatinib

Trastuzumab:

Trastuzumab is a monoclonal antibody against the HER-2. HER-2 is expressed on the surface of 25-35% of the primary mamma carcinomas. Trastuzumab inhibits tumor cell proliferation → mediates antibody dependent cellular cytotoxicity by NK-cells and macrophages. The drug isn’t very toxic, but has cardiomyopathy as a side effect in 2-3% of patients.

Cetuximab:

Cetuximab is a monoclonal antibody directed against the epidermal growth factor (EGF) receptor. 30% of epithelial cancers express high levels of EGF-receptors. Expression of EGF-receptors is an indication of:

• Poor prognosis → decreased survival
• Increased metastasis

Blocking EGF receptors results in inhibition of:

• Cell growth
• Cell division
• Migration
• Angiogenesis

Apoptosis is induced → the cell-mediated immune response by attracting cytotoxic T-cells is stimulated.

Side effects of cetuximab can be very serious and may include:

• Allergic reactions
• Acne-like rash
• Dry skin

Bevacizumab:

Bevacizumab is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF) receptor. VEGF is necessary to induce angiogenesis. Because bevacizumab is an angiogenesis drug, it stops tumor from making new blood vessels by:

• Reducing microvascular growth
• Inhibiting metastatic disease
• Causing existing vessels to regress
  • Vasculature is unable to support tumor growth

Side effects are:

• Hypertension
• Proteinuria
• Bleeding

Imatinib:

Imatinib is an inhibitor or protein-tyrosine kinase:

• Inhibits cell proliferation
• Induces apoptosis

Side effects of imatinib are:

• Headache
• Nausea and vomiting
  • Not very severe compared to cytostatic drugs
• Diarrhea
• Dyspepsia