Session 10: Anti-arrhythmics and Cancer Drugs Flashcards Preview

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Flashcards in Session 10: Anti-arrhythmics and Cancer Drugs Deck (78):
1

How can an arrhythmia occur?

To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity

Relaxation must occur between contractions (not true for other types of muscle [skeletal muscle exhibits tetany => contracts and hold contraction for certain length of time])

Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues.

Arrhythmias: heart condition where disturbances in

    Pacemaker impulse formation

    Contraction impulse conduction

    Combination of the two

This results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO). 

2

Describe how arrhythmias can affect the cardiac cycle and explain about atrial and ventricular arrhythmias

Cardiac arrhythmias can affect the cardiac cycle by being too fast (e.g. atrial fibrillation, AV re-entry tachycardia, ventricular tachycardia or Torsades de Pointes) or too slow (e.g. Sinus Bradycardia or 1o-3o heart block). Cardiac arrhythmias can be caused due to enhanced automaticity, delayed after-depolarisations, early after-depolarisation or re-entry circuits.

In atrial arrhythmias such as in atrial fibrillation, there is chaotic activity in the atria. The sinoatrial node is ‘switched off’.

Ventricular arrhythmias are common in most people and are usually not a problem but they are the most common cause of sudden death

  •     Ventricular arrhythmias are the most common cause of sudden death.
  •     Majority of sudden death occurs in people with neither a previously known heart disease nor history of ventricular arrhythmias.
  •     ECG shows abnormal ectopic beat (could be a sign of automaticity or scar tissue formation after an MI). The depolarisations could be too early or too late.

3

Describe the electrophysiology of the cardiac action potential. What would you seen on a normal ECG?

    A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell.

    Caused by unequal distribution of ions inside vs outside cell

  • Na+ higher outside than inside cell
  • Ca2+ much higher outside than inside cell
  • K+ higher inside cell than outside

    Maintenance by ion selective channels, active pumps and exchangers (can be passive, ligand-gated or voltage-gated)

4

Describe the four phases of the fast cardiac action potential

    Phase 0: rapid Na+ influx through open fast Na+ channels

    Phase 1: Transient K+ channels open and K+ efflux returns transmembrane potential to 0mV

    Phase 2: Influx of Ca2+ through L-type Ca2+ channels is extremely balanced by K+ efflux through delayed rectifier K+ channels

    Phase 3: Ca2+ channels close but delayed rectifier K+ channels remain open and return transmembrane potential to -90mV

    Phase 4: Na+, Ca2+ channels closed, open K+ rectifier channels keep trans membrane potential stable at -90mV

5

What are the effects of blocking Na+ channels?

    Marked slowing conduction in tissue (phase 0) – slope is shifted to the right

    Minor effects on action potential duration 

    Sodium Channel Blockers: They will bind to the sodium channels (same as local anaesthetics) and inhibit the action potential propagation in the cardiac myocytes, thus affecting myocytes in the phase 0 of depolarisation. They can be further further classified into 1a, 1b and 1c depending upon their rate dissociation from the channels (intermediate, fast and slow respectively)

6

What are the effects of beta-blockers?

    Diminish Phase 4 depolarisation and automaticity

    Minor effect on Phase 2

7

What are the effects of blocking K+ channels?

    Increase action potential duration – extension of Phase 3

Class III agents: Amiodarone, Sotalol, ibutilide, dofetilide

    They block outward K+ channels thus affect phase 3 of the cardiac action potential, increasing the action potential periods and thus suppressing re-entry circuits by closing excitable gaps (rhythm control)

8

What are the effects of blocking Ca2+ channels?

    Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarisation

    Effect plateau phase of action potential

    Not a big change in AP duration

    Also slow down conduction velocity 

9

Describe the effect of Ca2+ channel on the pacemaker action potential

10

What are the drugs that affect automaticity?

   Beta-agonists

    Muscarinic agonists

   Adenosine

11

Arrythmia Mechanisms: what could abnormal impulse generations be due to?

    Abnormal impulse generation: could be due to

Automatic rhythms (could be due to)

  • Enhanced normal automaticity (increased Action Potential from SA node) OR
  • Ectopic focus (AP arises from sites other than SA node e.g. abnormal electrical conduction due to ventricular ectopic foci)

Triggered rhythms (could be due to)

  • Afterdepolarisations

12

Explain about afterdepolarisations

Delayed afterdepolarisation (arises from the resting potential) occur in late phase 3 or early phase 4 when the AP is nearly or fully repolarised. The mechanism is poorly understood however is associated high intracellular Ca2+ concentrations. The triggered impulse can lead to a series of rapid depolarisation e.g. a tachyarrhythmia.

Early aftepolarisation (arises from the plateau)- occur during late phase 2 or phase 3 and can lead to a salvo of several rapid action potentials or a prolonged series of APs.

NB: afterdepolarisations are triggered by a preceding action potential and can result in either atrial or ventricular tachycardia. They occur either during phase 3 or phase 4. Triggered activity is more likely to occur when the AP duration is abnormally long such as in long Q-T syndrome and drugs that prolong the AP duration e.g. potassium-channel blockers can sometimes precipitate triggered activity. 

13

Arrythmia Mechanisms: what could abnormal conduction be due to?

    . Abnormal conduction could be due to Conduction block (this is when the impulse is not conducted from the atria to the ventricles) or due to Reentry

Conduction block (could be due to)

  • 1st degree
  • 2nd degree
  • 3rd degree

Reentry (most common arrhythmia mechanism)

  • Circus movement
  • Reflection (2 pathways for rhythm to go down; slow and fast). First pathway is blocked so the impulse from this pathway travels in a retrograde fashion (backward) (2.). 3. The cells here will be re-excited (first by the original pathway and the other from the retrograde)
  • The blockage could be due to an area of infarct leading to a re-entry loop developing.

14

What happens in Wolff-Parkinson-White Syndrome?

    Abnormal Anatomic Conduction

Present only in small populations

Leads to excitation => Wolf-Parkinson-White Syndrome (WPW)

The accessory pathway here is called the bundle of Kent (abnormal accessory electrical conduction pathway between the atria and the ventricles). Electrical impulses stimulate the ventricles to contract prematurely, resulting in a unique type of supraventricular tachycardia referred to as an atrioventricular reciprocating tachycardia

15

Describe the pharmacological rationale behind antiarrhythmic drugs

Action of Drugs

  •     In case of abnormal generation: affect automatacity by affecting the slow action potential so decrease phase 4 slope (in pacemaker cells) and raise the threshold (so action potential is higher)
  •     In case of abnormal conduction: decrease conduction velocity (affect Phase 0) and increase effective refractory period (so the cell won’t be excited again)

Pharmacologic Rationale and Goals

  •     Restore normal sinus rhythm and conduction
  •     Prevent more serious and possibly lethal arrhythmias from occurring
  •     Antiarrhythmic drugs are used to:
    • Decrease conduction velocity
    • Change the duration of the effective refractory period (to try and stop extra beats)
    • Suppress normal automaticity

16

Describe Sodium Channel Blockers: Class Ia

Absorption and elimination (oral or IV)

Effects on cardiac activity: intermediate binding offset kinetics

  • Decrease conduction (decrease phase 0 of the action potential)
  • Increase refractory period (increased action potential duration (K+) and increased Na inactivation)
  • Decrease automaticity (decrease slow of phase 4, fast potentials)
  • Increase threshold (Na+)

Quinidine has anticholinergic (atropine like action) to speed AV conduction used with digitalis, Beta-blocker or Ca2+ channel blocker. Quinidine is also an alpha receptor antagonist (need to be careful in people with hypertension or renal disease).

Effects on ECG: increased QRS, +/- PR, increased QT

Uses: wide spectrum

  • Quinidine: maintain sinus rhythms in AF and flutter and to prevent recurrent tachycardia and fibrillation
  • Procainamide: acute treatment of supraventricular and ventricular arrhythmias

Side effects: hypotension, reduced cardiac output, proarrhythmia (generation of a new arrhythmia e.g. Torsades de Points – increased QT interval), dizziness, confusion, insomnia, seizure (high dose), gastrointestinal effects (common), lupus-like syndrome (especially procainamide). 

17

Describe Class Ib:

    Lidocaine, mexiletine, phenytoin – no change in phase 0

Absorption and elimination

  • Lidocaine: IV only
  • Mexiletine: oral

Effects on cardiac activity: fast binding offset kinetics

  • No change in phase 0 in normal tissue (no tonic block)
  • AP duration slightly decreased (normal tissue)
  • Increased threshold (Na+)
  • Decreased phase 0 conduction in fast beating or ischaemic tissue

Effects on ECG: non in normal, in fast beating or ischaemic increased QRS

Uses:

  • Acute: ventricular tachycardia (especially during ischaemia)
  • Not used in atrial arrhythmias or AV junctional arrhythmias

Side effects: less proarrhythmic than Class Ia (less QT effect) but CNS effects include dizziness and drowsiness. Lidocaine is rarely used due to significant adverse effects (contra-indications to HF, nystagmus and seizures)

18

Describe Class Ic

    Flecainide, propafenone – marked phase 0

Absorption and elimination: oral or IV. Flecainide is well-absorbed orally, metabolised by CYP 2D6 ad eliminated renally (half life of 10-18 hours)

Effects on cardiac activity: very slow binding offset kinetics (>10s)

  • Substantially decreases phase 0 (Na+) in normal)
  • Decreased automaticity (increased threshold)
  • Increased AP duration (K+) and increased refractory period, especially in rapidly depolarizing atrial tissue.

Effects on ECG: include increased PR, increased QRS and increased QT

Uses:

Wide spectrum – Flecainide is the most commonly used class I anti-arrhythmic.

  • Used for supraventricular arrhythmias (fibrillation and flutter). It contraindicated in history of IHD and fibrillation but used as treatment and prophylaxis against paroxysmal AF.
  • Premature ventricular contractions (caused problems)
  • Wolff-Parkinson-White Syndrome

Side effects

  • Proarrhythmia and sudden death especially with chronic use (CAST study)
  • Increased ventricular response to supraventricular arrhythmias (flutter)
  • CNS and gastrointestinal effects like other local anaesthetics

19

Describe the effects of Class II:

Beta-blockers e.g. Propranolol, acebutolol and Esmolol (very common, normally first line therapy?)

    Will act as negative chronotrophic and inotrophic agents by reducing the autonomaticity to the heart. They can be non-selective (e.g. propranolol), Beta1-selective (e.g. atenolol and bisoprolol) or mixed Beta1alpha1-agonist (e.g. carvedilol)

    Absorption and elimination

  • Propranolol: oral, IV
  • Esmolol: IV only (very short acting half life, 9 minutes)

    Cardiac effects:

  • Increase action potential duration and refractory period in AV node to slow AV conduction velocity
  • Decrease phase 4 depolarisation (Catecholamine dependent)

    ECG: Increased PR, decreased HR

20

Describe the uses and side effects of Beta-blockers

Uses   

  • Treating sinus and catecholamine dependent tachy arrhythmias (prolonged PR interval)
  • Converting reentrant arrhythmias in AV (prevent AF/atrial flutter)
  • Protecting the ventricles from high atrial rates (slow AV conduction)
  • They are used as rate control in AF, secondary prevention of VT or VF and heart failure

Side effects

  • Bronchospasm
  • Hypotension (effect on peripheral vasculature)
  • Don’t use in partial AV block or ventricular failure or asthma. Caution in COPD and acute heart failure. 

21

Describe the action of Amiodarone

Absorption and elimination: oral or IV (half life about 3 months). It is very lipid soluble so has a very large volume of distribution and as a consequence requires a large loading dose and has a half life of 10-100 days. It is metabolised by CYP450 yet due to its volume of distribution, dose adjustments are not required for renal, hepatic or cardiac dysfunction.

Cardiac effects:

  • Increased refractory period and increased action potential duration (K+)
  • Decreased phase 0 and conduction (Na+)
  • Increased threshold
  • Decreased phase 4 (Beta-blockers and Ca2+ blocker effect)
  • Decreased speed of AV conduction

Effects on ECG: increased PR, increased QRS, Increased QT and decreased HR

Uses: very wide spectrum – effective for most arrhythmias. Amiodarone can be used in stable VT and SVT, and the rate control of AF when other anti-arrhythmics are contra-indicated.

22

Describe the side effects of Amiodarone

Side effects: many serious that increase with time (long time use)

  • Pulmonary fibrosis
  • Hepatic injury
  • Increased LDL cholesterol
  • Thyroid disease
  • Photosensitivity
  • Proximal myopathy
  • Peripheral neuropathy

May need to reduce the dose of digoxin and monitor warfarin more closely (due to CYP450 enzymes)

May still be present in body 6-12 months after termination

23

Describe the side effects of Sotalol

Absorption: oral

Cardiac effects:

  • Increased action potential duration and refractory period in atrial and ventricular tissue
  • Slow phase 4 (similar to Beta-blocker(
  • Slow AV conduction
  • ECG effects: increased QT, decreased HR (class II-like activity)

Uses: wide spectrum – supraventricular and ventricular tachycardia

Side effects: proarrhythmia (due to prolongating QT interval), fatigue, insomnia

24

Describe Class IV

Class IV: Verapamil and Diltiazem

   Administration

  • Verapamil: oral or IV
  • Diltiazem: oral

    Cardiac effects

  • Slow conduction through AV (block the inward Ca2+ channels on the SAN and AVN)
  • Increased refractory period in AV node
  • Increased slope of phase 4 in SA to slow HR (very good at affecting slow action potentials) (negative chronotrophic and inotrophic effect)

    ECG: increased PR, increases or decreases HR (depending on blood pressure response and baroreflex)

25

Describe the uses and side effects of Calcium channel blockers

   Uses

  • Control ventricles during supraventricular tachycardia
  • Convert supraventricular tachycardia (re-entry around AV)
  • Main clinical uses are for hypertension, angina, rate-controlled AF but only when beta-blockers are contra-indicated. Contra-indications for their use include heart failure, bradycardia and AV node block.

    Side effects:

  • Caution when partial AV block is present. Can get asystole if Beta-blocker is on board.
  • Caution when hypotension, decreased CO or sick sinus
  • Some gastrointestinal problems

26

Additional Antiarrhythmic agents: describe Adenosine

Administration: rapid IV bolus, very short half life (seconds)

Mechanism: natural nucleoside that binds A1 receptors and activates K+ currents in AV and SA node – leading to decreased APD, hyperpolarization => decreased HR (transient temporary heart block). Then normal rhythms start again from the SA.

  • Decreased Ca2+ currents – increased refractory period in AV node

Cardiac effects: slows AV conduction (used for termination of natural arrhythmias)

Uses: convert re-entrant supraventricular arrhythmias. It can be used to distinguish SVT as if given as the tachycardia continues, then the re-entry loop is likely to occur between the atrium and the ventricles, and not at the AVN. Also used for hypotension during surgery, diagnosis of Coronary Artery Disease, but can cause bronchospasm in asthmatics

27

Additional Antiarrhythmic agents: describe Digoxin

Mechanism

  • Enhances vagal activity (increased K+ currents, decreased Ca2= currents, increased refractory period)
  • Slows AV conduction and slows HR
  • It also inhibits the action of Na+-K+-ATPase thus leading to a reversion sodium-calcium exchanger => increased store of Ca2+ in sarcoplasmic reticulum => positive inotrophic effect.

Uses: treatment of rapid AF and atrial flutter

Normally requires a loading dose (given in 2 doses) for rapid onset and is quite lipid soluble so has a large volume of distribution, reflecting in its half life of 36-48 hours. As it is excreted renally, any renal impairment should result in altered dosing in the patient. Main adverse effects are with cardiac toxicity, yet any severe digoxin toxicity can be treated with Digiband. 

28

Additional antiarrhythmic agents: describe Atropine and Magnesium

    Atropine: normally given whilst waiting to put a pacemaker as an emergency

  • Mechanism: selective muscarinic antagonist
  • Cardiac effects: block vagal activity to speed AV conduction and increase HR
  • Uses: treat vagal bradycardia

    Magnesium: treatment for tachycardia resulting from long QT

29

Which drugs oculd be used for AF?

Either rate control (slow action potential) or rhythm control (slow AV conduction => then SA wakes up and starts generating normal rhythms)

Consider Beta-blocker (slows AV node), Calcium Channel Blockers, Flecainide, Digoxin, Amiodarone or Sotalol (the latter two would also affect conduction and slow HR)

30

Which IV drug first for VT? Should Flecainide be used alone for atrial flutter? Best drug for WPW?

    Which IV drug first for VT

  • Lidocaine

    Should flecainide be used alone for atrial flutter?

  • Flecainide slows down conduction but creates flecainide flutter (‘organises’ AF into atrial flutter with 1:1 conduction)
  • The first response would be give Beta-blocker or (possible calcium channel blocker or digoxin) – target AV node conduction

    Best drug for WPW?

  • Flecainide - Slows conduction (bundle of Kent) (slows AV conduction)

31

List drugs used in re-entrant SVT? Which drugs for ectopic atrial tachycardia? Which drugs for sinus tachycardia?

    List drugs used in re-entrant SVT

  • Adenosine – blocks AV, terminates rhythm - IV verapamil for asthmatics
  • + slow conduction e.g. Flecainide (weight-limited) or Amiodarone

    Which drugs for ectopic atrial tachycardia?

  • Beta-blockers (phase 4), Calcium Channel blockers, can use Flecainide possibly if heart structure is normal
  • Use drugs that affect automaticity

    Which drugs for sinus tachycardia?

  • Target automaticity – so use Beta-blockers, Calcium channel blockers (rate control)

32

Describe the clinical burden of cancer in the UK

Around 1 in 3 people will experience cancer in their lifetime, with about 350,000 new cases of cancer in the UK annually.

Overall, cancer is the second most frequent cause of death in the UK with about 160,000 deaths in 2011, or about 25% of all UK deaths.

The scale of the challenge cancer presents is due in part to the survival of many more people into older age, when the ability of the body to deal with cancer on its own is much reduced.

For effective treatment of cancer, chemotherapy is often employed as part of a carefully planned treatment program that often involves surgery and radiation therapy. The combination depends on the type of cancer and its stage of progression.

    Over 80 chemotherapeutic drugs are currently in use in the UK and this number continues to increase as new treatments are approved for use. 

33

Describe the background of chemotherapy

    In the 1940s, investigators used nitrogen mustard to treat lymphoma.

    Some agents were found by chance e.g. Cisplastin (platinum electrodes stopped E coli growth)

    Screening of compounds e.g. trabectedin (extract from the sea squirt)

    Chemical engineering e.g. Taxotere (follow up molecule from tubulin poison in Pacific Yew stem bark).

    Molecular targeting approaches: Imatinib (magic bullet)

  • Rationally designed targets and inhibitors
  • Tumour selective
  • More efficacious
  • Fewer side effects

34

Recap how cancerous cells arise. Describe the two main types of genes mutations are seen in

Cancerous cells arise due to one or more mutations in the normal genome that result in a profound change in the cell’s behaviour, Both the internal and external environment plays a well-documented role in driving these genetic changes, providing a host of carcinogenic factors e.g. radiation exposure from UV light or X-ray, free radical generators, viral triggers, fatty diet etc.

The two main categories of genes acted upon by mutation are recognised as:

  • Proto-oncogenes (inactive) transformed by mutation to oncogenes (active).
    • These genes control cell division apoptosis and differentiation
  • Tumour suppressor genes. The loss of function of these suppressor genes can be critical in triggering carcinogenesis. 

35

Recap the structure of DNA and descrie the clinical importance of tumour growth

Structure of DNA:

  •     Nucleotide = sugar-phosphate-base
  •     DNA = double helix of nucleotides
  •     Purines = adenine and guanine
  •     Pyridimines = cytosine and thymine (uracil in RNA)

Tumour growth

  •     10^9 = clinically detectable
  •     10^12 = exponential tumour growth
  •     Exponential tumour growth in between.

36

Transformation of a normal cell into a cancer cell requires a number of these control elements to be lost. Once this loss has taken place, the following characteristics of cancer cells define the magnitude of malignant threat: loss of cell growth control, de-differentiation and loss of specific function, blood supply, metastasis and invasiveness.

Explain more about loss of cell growth control, de-differentiation and loss of specific function

Loss of cell growth control

  •     The key feature is that the normal mechanism controlling proliferation and ordered cell death (apoptosis) is lost. This does not mean that the cancer cells are necessarily proliferating faster than normal cells, but that the ordered control of cell division balanced by apoptosis is lost in cancer cells.

De-differentiation and loss of specific function

  •     Normal cells have a specific function to fulfil, which is lost when they turn cancerous. The degree of de-differentiation in cancers varies considerably but the greater this loss of original identity, the worse the malignant challenge to the body generally is. 

37

Transformation of a normal cell into a cancer cell requires a number of these control elements to be lost. Once this loss has taken place, the following characteristics of cancer cells define the magnitude of malignant threat: loss of cell growth control, de-differentiation and loss of specific function, blood supply, metastasis and invasiveness.

Explain more about blood supply, metastasis and invasiveness

Blood Supply:

  •     As the cancer cells proliferate to reach the dimensions of a clinically discernible tumour, there is a natural limit to growth due to limited blood supply.
  •     This would restrict tumour growth to about 1-2mm in diameter.
  •     To overcome this limitation, the tumour cells produce their own local angiogenesis factors to promote vessel growth into the tumour so it can continue to develop.

Metastasis and invasiveness

  •     If they didn’t metastasise, they could be targeted through direct surgery and irradiation. However, malignant cells may lose the very specific positional sense and identity within their parent tissue. This arises due to changes in cell surface proteins. These changes allow them to migrate or metastasise throughout the body.
  •     This takes place via the lymphatic or vascular system or more locally by invasion of an adjacent body cavity. They can then proliferate further afield and produce new tumours.
  •     In addition as the cancer progresses over time, further mutations in cancer cells result in increased heterogeneity, with distinct cell lines arising that increase the malignant challenge to be met by chemotherapy.

38

What is meant by Cell Compartmentation

    Given the physiological limitations on tumour growth, not all cells in a tumour are involved in active proliferation and normally belong to one of three compartments. These compartments tend also to relate to their spatial position in the body of the tumour.

    Compartment A: Dividing cells receiving adequate nutrient/vascular supply

  • May represent between 5-20% of the actual tumour cell population and is the one most susceptible to chemotherapy targeting cells at one or more stages in the cell cycle.

    Compartment B: Resting cells remain in ‘G0’ phase but able to re-join Compartment A if there are changes in cell signalling or the local environment – e.g. following surgery. More likely to be situated in the middle of the body of the tumour.

  • Therapeutically the cells present a real problem. They may be affected to some degree by chemotherapy as some resting RNA and protein synthesis will be taking place. But the proportion of chromosomal DNA in G0 that is open to attack is much more limited.
  • This makes the effective kill ratio attainable in this compartment much lower. They will thus be available to re-enter Compartment A, even following intense chemotherapy.

    Compartment C: Cells no longer able to divide, but act to contribute to the overall bulk of a tumour. These present no challenge.

  •     NB: cancer cells can still die off on their own if minimal nutrient supply is not maintained.

    In addition, surgery and radiation can only be effective on dealing with identified tumour sites and not on those smaller metastatic tumours or rogue cancer cells that have evaded detection.

    The above proportions of compartmentalisation also relate to tumour types’ susceptibility to chemotherapy. For example, rapidly proliferating lymphomas are more sensitive than breast, ovarian or bladder tumours that grow at a moderate rate. These in turn are more sensitive than slow growing prostate cancer.

39

Describe the variation in proliferation of the cell cycle

Cell proliferation variation in cycle 9-43 hours between cancer cells

40

Describe the Log Kill ratio

Typically a tumour needs to consist of a cluster of about (10^9) cells before it is clinically detectable or to reach the side of a small group.

A log kill ratio means that if a given treatment kills 10^4 cells or 99.99% of cancer cells, then for a population of 10^9 cells, this would mean a reduction to 10^5 cells or to 0.01% of the original population of 10^9 cells. The 10^5  cancer cells remaining would resemble a sphere the size of a full stop.

This would be four log kill ratio and further treatment would be warranted so another dose of the same four log kill therapy would then result in only 10^1 or just 10 cancer cells remaining.

In this theoretic model this sounds really good, but the factors outlined earlier mean that of the 10^9 cells, perhaps only 10^7-10^8 may be available for direct attack (Compartment A) with the more resistant resting Compartment B cells able to revert hydra like, to aggressive ‘A’ types post therapy.

In reality, more modest kill rations may be attained that require repeated chemotherapy. The kill rate for cancer cells has to be weighed up against the kill rate for healthy cells in susceptible tissue. 

41

Describe the fractional cell kill hypothesis

The fractional cell kill hypothesis (reason for intermittent chemotherapy)

  •     Bone marrow recovers before tumour cells so need to make sure bone marrow has recovered before second dose (bolus) but give second bolus before tumour cells have recovered => leads to a reduction in tumour cells
  •     After successive rounds of chemotherapy, bone marrow cells take longer and longer to recover.

The ‘art’ of chemotherapy therefore is to try and ensure that this kill ratio does not lead to mortality, and that in between each chemo session, the rate of regrowth of healthy tissues is sufficiently ahead of that of tumour cells. This means that the clinical team must work to improve the odds ratio in favour of healthy cells. If this cannot be maintained, then the prognosis is poor.

42

Describe the classification of tumours sensitive to chemotherapy

Classification of tumours according to chemo-sensitivity

  •     Highly sensitive (so majority of treatment is chemotherapy): lymphomas, germ cell tumours, small cell lung, neuroblastoma, Wilm’s tumour
  •     Modest sensitivity (surgery plays the main part of treatment, chemotherapy given before to minimise the size of the tumour – neoadjuvant – or afterwards to kill any remaining cancer cells – adjuvant): breast, colorectal, bladder, ovary, cervix
  •     Low sensitivity: prostate, renal cell, brain tumours, endometrial

43

Give an overview of the cytotoxic agents used in chemotherapy

    There are a wide range of agents that act at particular phases of the cell cycle but they all aim to try and drive a therapeutically higher rate of apoptotic death in cancer cells over that caused in normal cells.

    Their therapeutic indexes are frequently quite small due to their paradoxical therapeutic effect being dependent on their cytotoxicity. They have significant side effect profile 

44

Agents Directly Modifying DNA Structure: describe anthracycline antibiotics

DNA Intercalation and Topoisomerase II inhibition

  •     The anthracycline antibiotics are used in synergistic combination with other drugs with different mechanisms to reduce the risk of additive ADRs.
  •     Members of this group include doxorubicin and daunorubicin. Their discrete molecular ring structure enables to intercalate between the spaces between DNA base pairs. This intercalation would interfere with normal transcription and replication. The anthracyclines particularly affect the activity of Topoisomerase II.
  •     Topoisomerase II enables the breaking, rotation and re-ligation of DNA strands during DNA replication and repair. The intercalated antibiotic molecule physically interferes with this. This action is further augmented by the anthracycline binding to the Topoisomerase II thus forming a tripartite DNA – anthracycline-Topoisomerase II complex.
  •     This hinders its available for deployment elsewhere. The resulting non-ligated free strands of DNA act as a trigger to apoptosis.
  •     As a secondary action, the anthracycline are able to generate free radicals by binding free Fe2+. The locally produced free radicals then go onto further damage the DNA. Overall, the damage caused by anthracyclines is detected by DNA damage sensing mechanisms in the cell which then trigger apoptosis. In contrast to bleomycin, their action is non-cell cycle specific. 

45

Agents Directly Modifying DNA Structure: describe Bleomycin

DNA Scission

    Bleomycin is a glycopeptide antibiotic derived from Streptomyces fungi.

  •     Bleomycin can both bind with DNA and chelate with free Fe2+ ions. Its structure allows it to closely align itself within DNA by both intercalation but also by binding via its terminal NH2 group to DNA.
  •     When it chelates with free cytoplasmic Fe2+ ions, this reaction site then catalyses production of both superoxide and hydroxide free radical species.
  •     These highly free radical species then attack phosphodiester bonds in the DNA strand resulting in a cutting or scission of DNA strands.
  •     This scission is considered to be the primary mechanism underlying its cytotoxicity and is comparable with the anthracyclines in this respect.  The production of free radicals is also considered to underlie its pulmonary toxicity.
  •     Bleomycin is most effective during G2 but also has some effect in non-replicating G0 cells. 

46

Agents Directly Modifying DNA Structure: what does the term Alkylating Agents actually encompass?

Alkylating Agents Related Compounds and the Platins

    Lots of variation in naming which can cause some confusion. For example nitrosourea and the platinum based agents have no alkyl group. However, they are also referred to or commonly considered alongside and grouped with, the ‘alkylating agents’.

    Clinically the name is often used to refer to compounds used in chemotherapy that covalently bind to DNA. The primary underlying mechanism for these related agents is that they typically possess two highly labile or ‘leaving’ groups such as Cl, that are necessary for instigating the covalent reaction with the DNA.

47

Describe the nucleophilic targets for these alkylating agents and compounds

    Nucleophile target sites for these agents are spread along the whole length of DNA.

Along the length of DNA strands the specific molecular target sites are nucelophilic or positive charge attracting, groups. These are very common and their locations are very well defined. These include:

  • N7 and O6 atoms in guanine
  • N1 and N3 in adenine
  • N3 in cytosine

These all have spare electron pairs to donate to a vacant electron orbital. They can therefore, make a covalent bond with those agents the alkylating group. The reactive group on alkylating agents are therefore electrophilic or ‘electron attracting’.

48

Describe Steps 1-5 of the mechanism of alkylating agents

    Mechanistically the alkylating agents undergo a common sequence of chemical reactions with DNA. What these apparently disparate compounds have in common are the steps outlined below

Step 1: the ‘alkylating’ agent is administered IV to allow fine control of the delivery of these cytotoxic drugs delivered to the body

Step 2: in the plasma compartment, the –Cl groups remain attached to the parent molecule via carbon, as the relatively high concentration of plasma Cl-, reduces the degree of dissociation from the parent molecule.

Step 3: the molecules enter the cell where the labile negatively charged – Cl groups are easier to lose, due to the lower cytoplasmic concentration of free Cl-.

Step 4: when close to their exposed DNA target site, the loss of the Cl- groups results in a net positively charged carbonium ion, or in the case of the platins, a positively charged Pt2+.

Step 5: whether it is a single unit positively charged alkyl associated with a carbonium R-C+ ion or a Pt2+ group that remains after the Cl leave, these are able to then react with the nucleophilic (positive charge attracting) groups on the DNA bases referred to above. These nucleophilic groups donate electron pairs to form the stable covalent bonds. 

49

Describe Steps 6-7 and the overall effect of the mechanism of the alkylating agents

Step 6: the existence of two sets of individual electron pair accepting sites on each carbonium ion enables cross-linking at two spatially separate nucleophilic sites on DNA strands.

  • In the case of the platins, the two electron pair accepting orbital sites are located on the platinum Pt2+ or other similar chemotherapeutic electrophilic compound, also enables crosslinking at two spatially separate nucleophilic sites on DNA strands.
  • The key point is even though the single charge carbonium ion is distinct to the double charged Platinum ion, they both react as electrophiles accepting the electron pair from the DNA nucleophilic bases.

Step 7: These can then form inter-strand or intra-strand links to form DNA adducts with the DNA. For example with cis-platin, these covalent links are typically about 55% G-G and 30% A-G adducts with intra-strand linking being most favoured. In addition, cross-linking can also occur between DNA and proteins.

    The physical disruption of DNA interferes with both DNA replication and RNA transcription. It is the inhibition of DNA replication that is the primary cause of cell death.

50

Describe the maximal effect of alkylating agents

    The maximal effect of alkylating agents is during ‘S’ phase.

The action of alkylating agents is considered to be non-cell cycle specific and they can interact with DNA at any point. However, they have maximal effect in cells undergoing a greater rate of replication and exert their greatest effect in ‘S’ phase when DNA is replicating and large sections of DNA strands will be exposed and unpaired.

Similarly, attack can occur at G1 when enzymes, especially those for DNA synthesis, are being transcribed. Disruption here will further interfere with the process of cell division by reducing this enzyme pool. 

51

Describe the effects of Platinum compounds

    Platinum compounds: formation of platinated inter- and intrastrand adducts leads to inhibition of DNA synthesis. DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts.

52

Describe antimetabolites

Antimetabolites – interference with precursors to purine and pyrimidine synthesis.

Antimetabolites used in cancer chemotherapy are structurally related to precursors involved in DNA synthesis. They act to interfere with the production of purine or pyrimidine nucleotides. This is by acting as a direct competitive analogue in DNA or RNA synthesis such as 6-Mercaptopurine (a purine analogue), 5-Fluorouracil or 5-FU (a pyrimidine analogue).

In addition inhibition of key enzymes involved in precursor synthesis is a common therapeutic option, with methotrexate used as a highly potent inhibitor of Dihydrofolate Reductase or DHFR. 

Antimetabolites are cell-specific in their action – ‘S’ phase

  • Predictably the antimetabolites are most effective during the period of maximal DNA synthesis or ‘S’ phase.
  • They would have less effect in cells in the resting state and would not be indicated for use in malignancies with a low growth fraction. 

 

53

Describe normal folate metabolism. What does Methotrexate inhibit?

    Methotrexate acts by inhibiting DHFR to interfere with folate metabolism

Folates are vital for production of purine nucleotides and thymidilate. These feed into the pathway that enables DNA and RNA synthesis. After being actively taken up into the cell, folate is converted into a polyglutamate. Then the polyglutamated folate is reduced in two steps by the enzyme DHFR to produce a tetradhydrofolate, or FH4.

Polyglutamated FH4 acts as a co-factor acting as a methyl group carrier. This methyl group is then used in the transformation of 2-deoxyuridylate or DUMP into 2-deoxythymidylate or DTMP.

This transformation is carried out by the Thymidylate Synthase enzyme.

Along with other related pathways, the production of DTMP contributes to the production of the purines and pyrimidines that act as molecular building blocks for both DNA and RNA.

54

Describe the action of methotrexate

    Methotrexate is structurally very similar to folic acid and is actively transported into the cell and also polyglutamated. Methotrexate on its own has a much higher (x1000) affinity for DHFR. The polyglutamated form of Methotrexate also has a very long half-life within the cell of weeks to months and also has a very high affinity with DHFR.

As a result, both Methotrexate alone and its polyglutamated form act to vastly reduce the metabolism of folate to reduce nucleotide production. The decrease in thymidine levels is the most marked.

The controlled dosages used in cancer chemotherapy are much higher than used in RA and the aim is to reduce cancer cell growth as rapidly as possible by effectively removing nucleotide precursors from the cell metabolite pool.

55

Describe the action of 5-FU

    Metabolised 5-FU acts to irreversibly inhibit Thymidylate synthase

5-FU is an analogue of the pyrimidine base uracil and is actively transported into the cell. As a close analogue of uracil, it is converted in FDUMP the fluoro-analogue of the precursor DUMP used in Thymidilate synthesi.

FDUMP then competes with DUMP for access to the binding site on Thymidilate Synthase. At the active site FDUMP combines with a further coenzyme to produce a stable complex that cannot release any product. This effectively irreversibly inhibits the enzyme and if enough are affected, then cell undergoes ‘thymidine-less cell death’.

56

What is the mitotic spindle?

    Normal cell division proceeds by the cells complement of chromosomes aligning themselves along the equator of the pre-mitotic cell. The mitotic spindle organises this alignment and is responsible for the synchronous separation of the replicated chromosomes into their respective new daughter cells.

The mitotic spindle is made up of special protein subunits, alpha and beta tubulin.

The existence of the spindle is dependent on the subunits polymerising to form microtubules. These tubulin proteins are the specific target sites for two groups of plant derived compounds: the vinca alkaloids and taxanes. The action of both vinca alkaloids and taxanes are cell cycle specific and their action is apparent in the M (mitotic phase).

57

How do vinca alkaloids act?

    Vinca alkaloids acts by inhibiting polymerisation of tubulin

  • There are a number of vinca alkaloids, which are indicated for use in treating different tumour types, but they all act to inhibit microtubule formation.
  • Two examples of this are vincristine and vinblastine. They do this by specifically binding with the Beta-tubulin subunit that then prevents formation of the microfilaments that make up the microtubule. This means the mitotic spindle does not form and the cell cycle is arrested in mitotic metaphase.
  • The chromosomes cannot segregate and affected cells cannot proliferate with the arrest of the normal replication cycle leads to apoptotic cell death.

58

How do the taxanes work?

    Taxanes promote and stabilise formation of tubulin polymer into microtubules but prevent depolymerisation (prevents tubules dissolving)

Whilst the mechanism for taxanes is different to the vinca alkaloids, the final effect is effectively the same.

An example of a taxane is paclitaxel. The taxanes reversibly bind at a separate site to that of vinca alkaloids on the Beta-tubulin subunit. Binding at this site stabilises the microtubules and inhibits their disassembly.

These microtubules are rendered non-functional and they cannot disassemble to pull the chromosome apart, which means the cell is stuck in metaphase. This again triggers apoptotic cell death in both cancer cells and normal cells.

59

What are possible routes of administration for cancer drugs?

Clinical use of all the agents requires very careful consideration by clinicians.

This is because these agents are cytotoxic and each patient will vary considerably in their pharmacokinetic profile. This is especially as they may already present with compromised organ function and the treatment may well take them close to death by precipitating organ failure.

Routes of administration – IV most common

    With many of these drugs, their toxicity rules out oral delivery, as they would severely damage the GI tract.

    In addition bioavailability is often variable and only a few agents are given orally. The patient is more likely to experience nausea and vomiting throughout treatment further limiting practicability of the oral route.

    The most practical route for systemic administration of these agents is intravenous. This allows fine control of delivery by injected bolus an infusion bag or continuous pump infusion. If an emergency arises due to appearance of adverse effects, the infusion can be stopped immediately.

    If a tumour is localised, then direct intralesional delivery may be possible. If it is within a defined space for example the bladder or lung effusion may be performed. Intrathecal (by lumbar puncture) and intraventricular (ommaya reservoir => directly into ventricles) delivery is used for treating tumours in the CNS.

    Other routes of administration include:

  • PO: convenient, dependent on oral bioavailability
  • SC: convenient in community setting
  • Into a body cavity: bladder, pleural effusion
  • Intralesional – directly into a cancrous area – consider pH
  • Topical – medication will be applied onto the skin
  • IM rarely

    NB: PICC line (peripherally inserted central catheter) can be used for a prolonged period of time, patient is able to go home.

    For many types of cancer, chemotherapy regimen will consist of a number of different drugs – combination chemotherapy – usually given an acronym. A drug may be given as a single agent.

60

Describe factors affecting distribution and elimination following administration

Factors affecting distribution and elimination following administration

  •     The general assumptions made about distribution in body compartments with many other drugs do not apply in cancer chemotherapy.
  •     The plasma compartment may be proportionately larger due to the patient having experienced very significant weight loss with an accompanying reduction in body fat.
  •     Liver and renal function along with cardiac output, may also be significantly lower and heavily compromised and drugs in combination may cause changes in Phase I and II pathways by either inhibition or induction.
  •     In addition, many agents are proportionately bound to plasma proteins and presence of other non-chemotherapeutic drugs that associate with plasma proteins will affect free levels.

61

Describe using body surface area and renal clearance to optimise dosing

Using Body Surface Area and Renal Clearance to Optimise Dosing

  •     The above factors can be partly addressed by calculating dose according to body surface area and with reference to their BMI. This normalises, in part, variations due to height and weight as for example, a lean person will have a smaller surface area.
  •     These measures are best employed with measures of both renal function and plasma/urine drug levels.
  •     These can be used to establish clearance and the expected concentration time curve (AUC) to better approximate overall and peak exposure to a drug. 

62

How may abnormalities affect pharmacokinetics?

    Abnormalities in absorption

  • Nausea + vomiting, compliance, gut problems

    Abnormalities in distribution

  • Weight loss, reduced body fat, ascites etc

    Abnormalities in elimination

  • Liver and renal dysfunction, other medications

    Abnormalities in protein binding

  • Low albumin, other drugs

63

Describe drug resistance in chemotherapy

Primary and Acquired Resistance

  •     Traditional agents used in cancer chemotherapy are, by definition, cytotoxic.
  •     Neither healthy or cancer ‘know’ these drugs are being used to defeat a systemic threat to the whole body.
  •     Consequently they will treat many of these agents in the way they would deal with any other potentially toxic xenobiotic molecule.

    The terms primary and acquired resistance are respectively defined as resistance being present prior to drug exposure and subsequent to drug exposure. These resistances in tumour cells can be due to their adapting and up-regulating responses to repeated ‘xenobiotic’ chemotherapeutic challenge, or they can arise as a result of mutations in the cancer cell genome driving increased MDRP expression/activity.

64

Main Factors Contributing to Drug Resistance: a number of distinct factors operate in the cancer cell to contribute to acquired drug resistance. Describe MDRP

Multidrug Resistance Protein –MDRP:

    This P-Glycoprotein (P is for ‘permeability’) is generally expressed throughout most healthy cells at low levels. High levels are notably expressed in the kidney, liver and GI tract. It is a transporter and can lead to decreased entry or increased exit of an agent.

    MDRP functions to generically remove hydrophobic (i.e. charged) large xenobiotics.

    If cancer cells repeatedly encounters one or more of the chemotherapeutic drugs described here than expression of MDRP may increase as a result. Importantly, as MDRP activity is non-specific, it can then act to remove structurally dissimilar molecules used in combination chemotherapy.

    For example, prior exposure to doxorubicin can then also increase efflux and resistance to vinblastine or cis-platin to limit efficacy of future dosing. 

65

Main Factors Contributing to Drug Resistance: a number of distinct factors operate in the cancer cell to contribute to acquired drug resistance. Apart from other MDRP, what other mechanisms are involved?

Other inducible mechanisms: drug exposure can also act to decrease the rate of active uptake of drugs such as methotrexate or cis-platin by down-regulation of the active carrier.

Conversely, drug target enzymes expression can be upregulated to offset the decrease in production of metabolites e.g. DHFR (increased) with methotrexate. Further examples include increased rate of repair of drug induced lesions in DNA or membrane following increased expression of repair enzymes in cancer cells. For example, this is seen with use of the alkylating agents or belomycin, which act to damage DNA. There could also be inactivation of agent in cell e.g. Glutathione binds to drug and neutralises its effect so drug is no longer cytotoxic (e.g. for alkylating agents).

66

Describe the Clinical Indications in chemotherapy and clinical strategies to offset drug resistance

Chemotherapy – Clinical Indications

  •     Aim is very different in different malignancies
  •     Predicted response is also different within the same cancer based on:
  • Performance score (an assessment of the performance status of that patient based on WHO Scoring Tool (0-5); also influenced by comorbidities; poor performance score indicates patient is less likely to recover.
  • Clinical Stage: can they be cured or is it palliative? Consider quality of life. May accept increased toxicity if going to be cured at the end of the day.
  • Prognostic factors or score (often involving biological factors)
  • Molecular or cytogenetic markers
  •  Side effects vs anticipated or best outcome

Clinical Strategies to Offset Drug Resistance

The problem of acquired resistance arises with suboptimal and repeat doses that allow the cells time to manifest those responses. To counter the effects of resistance on therapy and to give the immune system time to recover, the clinician will often use a high dose, short term intermittent repeated therapy with drugs given in optimal combination to treat a specific tumour type. 

67

Describe Common ADRs with chemotherapy

There are a wide range of ADRs associated with use of these agents. As they are primarily targeted at rapidly dividing cells, they also affect normal cells with a higher rate of proliferation. This includes most of the GI tract, especially the buccal mucosa, and hair follicles.

There are however other ADRs, which are manifest with specific groups or drugs.

Common ADRs

    These include severe nausea, vomiting and diarrhoea. Mucositis, alopecia and myelosuppression, impaired wound healing, lethargy, myalgia, local reaction, phlebitis skin toxicity are also common.  

    More specific within group ADRs include neurotoxicity (e.g. neuropathy), cardio, bladder (e.g. cystitis), lung (e.g. pulmonary fibrosis) and renal toxicity. The latter three are irreversible.

    Of the ADRs, the most frequent dose limiting is haematological toxicity and is the most frequent cause of death during chemotherapy e.g. patients could die of neutropenic sepsis so patient education is very important – need to present earluy rather than late. Different agents have varying effects in both degree and lineage e.g. neutrophils and platelets.

    Acute renal failure is also an expected ADR – often multifactoral. Hyperuricaemia caused by rapid tumour lysis during treatment can result in a large increase in purines being released into the circulation. The subsequent increase in purine metabolism generates urates. This can lead to precipitation of urate crystals in renal ubules and in extreme cases subsequent kidney failure and death.

    GI perforation at site of tumour – reported in lymphoma.

    Disseminated intravascular coagulopathy e.g. onset within a few hours of starting treatment for acute myeloid leukaemia.

    Predicting the risk in each individual patient can be difficult, especially with combination therapy and the aim must be to minimise this by close observation during monitoring. 

68

Describe Vomiting and Alopecia

Vomiting

  •     Multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone.
  •     Patterns of emesis
    • Acute phase: 4-12 hours
    • Delayed onset: 2-5 days later
    • Chronic phase: may persist up to 14 days

Alopecia

  •     Hair thins at 2-3 weeks
  •     May be total body hair loss
  •     May re-grow during therapy
  •     Marked with doxorubicin, vinca alkaloids, cyclophosphamide
  •     Minimal with platinums
  •     Help sometimes with scalp cooling (but these caps can lead to terrible headaches, not very well tolerated)

69

Describe Skin Toxicity

Skin toxicity

   Local

  • Photosensitivity, irritation and thrombophlebitis of veins
  • Extravasation (never should have happened, chemotherapy has gone into surrounding tissues not the veins – tissue is not necrotic – needs to be removed)

   General

  • Bleomycin
    • Hyperkeratosis
    • Hyperpigmentation (particularly in Asian patients – with a degree of pigmentation already)
    • Ulcerated pressure sores
  • Bulsulphan, doxorubicin, cyclophosphamide, actinomycin D
    • Hyperpigmentation

    *Beau’s lines: deep grooved lines that run from side to side on the fingernail or toenail (chemotherapy caused delayed growth of the nail)

70

Describe Mucositis

    Gastrointestinal tract epithelial damage

    May be profound and involve whole tract

    Most commonly worst in oropharynx

    Presents as

  • Sore mouth/throat (think mouth ulcers across the whole mouth)
  • Diarrhoea
  • GI bleed

    May require hospitalisation and morphine due to the damage.

71

Describe Cardio- and Lung- Toxicity. Also describe Haematological Toxicity

Cardio-Toxicity

   Cardiomyopathy

  • Doxorubicin ++ (>550 mg/m2)
  • High dose cyclophosphamide
  • Mortality approx. 50%

   Arrhythmias

  • Cyclophosphamide
  • Etoposide

Lung Toxicity

    Bleomycin (used for testicular tumours)

  • Pulmonary fibrosis
  • Beware concurrent (do not give high flow O2 – makes it worse)
  •     Other drugs such as Mitomycin C can also lead to pulmonary fibrosis

Haematological Toxicity of Cancer Therapy

  •     Most frequent dose limiting toxicity
  •     Most frequent cause of death from toxicity
  •     Different agents cause variable effects on degree and lineages: neutrophils, platelets

72

Describe some side effects associated with main cytotoxic groups

    Antimetabolites: the example drugs already given largely exhibit all the general ones listed. With high dose methotrexate treatment, there is a higher risk of renal failure.

    Cytotoxic antibiotics – Cardiotoxicity: the anthracyclines doxorubicin and daunorubicin are especially cardiotoxic due to free radical generation

    Cytotoxic antibiotics – Pulmonary Toxicity: risk of pulmonary fibrosis with bleomycin is high at about 10% with a 1% fatality rate. These effects of both are cumulative and irreversible.

    Alkylating agents – Cis-platin at high dose, peripheral, sensory and motor neuropathy. High frequency ototoxicity is common.

    Mitotic spindle inhibitors: high dose neurotroxicity as ‘stocking and globe’ peripheral neuropathy is often reported.

73

Describe how clinicians need to consider drug-drug interactions

: Drug-Drug Interactions

    The clinician would need to be fully aware of what other drugs the cancer patient may be taking during therapy e.g. diuretics, St John’s wort.

    Carefully planned therapeutic DDIs are central to treating cancer. Even though a number of ADRs are common across these agents the aim is to minimise the overlap of shared toxicity whilst delivering all agents at the highest dose for as short as possible with gaps between dosing.

    This decreases the risk of irreversible ADRs such as pulmonary toxicity or death whilst maximizing the kill ratio of cancer:normal cells. Because shared ADRs are common in chemotherapy, this means doses have to be adjusted downwards for some drugs. The gaps between dosing are necessary to allow the immune system to recover.

    High dose short interval treatment regimes also aim to offset the risk of drug resistance that would emerge with lower (but less toxic) regimes given over a longer period of time.

    Finally, as is evident from the above sections, the distinct target sites of these drugs means that there are more chances to kill heterogeneous cells in the tumour population.

74

Give an example of combination therapy and important drug-drug interactions

An example combination would be methotrexate (target is DHFR in ‘S’ phase; highly myelosuppressive) with agents also having a lower myelosuppressive index

  •     Vincristine (target is Tubulin in ‘M’ phase; high risk of peripheral neurotoxicity ‘stocking and glove pattern’)
  •     Cis-platin (target is DNA synthesis, mainly ‘G1’/’S’ phase; mixed pathway neurotoxicity, ototoxicity common)
  •     Bleomycin (target is DNA synthesis in ‘S’ phase; greater risk of pulmonary toxicity)

Important drug interactions: other drugs may increase plasma levels of the chemotherapy drug (and therefore side effects)

  •     Vincristine and itraconazole (a commonly used antifungal) leads to more neuropathy
  •     Capecitabine (oral 5FU) and warfarin; Capecitabine and St Johns Wort, grapefruit juice
  •     Methotrexate – caution with prescribing penicillin, NSAIDs

75

Describe Clinical Monitoring

    Monitoring during chemotherapy is vital to accurately establish the degree of therapeutic success and the development of side effects, especially if these may lead to compromised organ function and eventual death.

    Dose needs to be altered for the individual patient based on:

  • Their surface area and/or body mass index
  • Drug handling ability (e.g. liver function, renal function…dependent on the metabolism and excretion outes0
  • General wellbeing (performance status and comorbidity).

    Treatment phasing needs to take into account the balance between:

  • Growth fraction
  • The ‘cell kill’ of each cycle of the chemotherapy regimen
  • Marrow and GI tract recovery before next cycle
  • How tolerable is the regimen – both short term organ toxicity and physical side effects and long term damage causing late effects

    Hence weigh up the role and dose of chemotherapy for every cancer patient individually and always remember the aim of the treatment.

    Response of the Cancer: this can be checked with radiological imaging, tumour marker blood tests, bone marrow sampling and cytogenic testing and pathology.

76

How would you monitor pharmacokinetics and end organ damage?

    Pharmacokinetics: Blood/Urine/CSF/Tissue samples for assay allow estimates of half-life and clearance to be made. With repeated measures, AUC estimation can give better individualised estimation of how the patient is handling their chemotherapy to maximise beneficial effect and minimise toxicity.

  • For example, given the unusual kinetics of methotrexate, additional post course rescue therapy with folinic acid to increase normal cell purine synthesis back to normal may be appropriate – methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue.

    Organ functional deficit (check for end organ damage) – Carry out cardiac testing by ECG, echocardiogram, - pulmonary function – FEV, FVC. Hepatic enzyme levels in plasma. Renal function – creatinine clearance in blood/urine etc. Evoke neural responses for conduction time for peripheral neurotoxicity, audiogram with cis-platin. 

77

Awareness of NICE recommendations on adopting  results from recent clinical trials

NICE approval limits UK adoption of new biopharmaceutical treatments

    In current clinical practice many refined protocols exist for specific neoplastic states. These are usually given an acronym that identified the main agents in use. These protocols will and be validated from many clinical trials carried out globally.

    In the UK, media coverage often focuses on new treatments that employ novel molecular targeting agents not receiving NICE approval. This is even though these new treatments offer reduced side effects and moderate improved median survival times of 6-12 months.

    This is in large part due to drug companies pricing yearly courses of treatments beyond the market limit. The NHS ‘market limit’ is currently about £50,000 per year of additional life gained by a treatment. This is doubly unfortunate, as the UK has been at the forefront of research for developing novel treatments. It is not amongst the first countries to reap the clinical benefit due to market forces.

    NB: Kaplan-Meier curve (survival analysis estimate) – overall survival is the ultimate measure

    Chemotherapy is the treatment of cancer with drug therapy. Traditionally this applies to cytotoxic drugs but over the years more classes of drugs have been introduced to treat cancer such as hormones and now targeted drug therapy e.g.

  • Monoclonal antibodies
  • Drugs inhibiting angiogenesis
  • Drugs targeting gene expression
  • Signal transduction inhibitors
  • Drugs interfering with the apoptotic pathways
  • Drugs interfering with cell cycle control
  • Cytokines

78

What does Neoadjuvant and Adjuvant mean?

Neoadjuvant: given before surgery or radiotherapy for the primary cancer

Adjuvant: given after surgery to excise the primary cancer, aiming to reduce relapse risk e.g. breast cancer

Palliative: to treat current or anticipated symptoms without curative intent

Primary: 1st line treatment of cancer…in many haematological cancers this will be with curative intent, initially aiming for remission

Salvage: chemotherapy for relapsed disease