Session 10: Anti-arrhythmics and Cancer Drugs Flashcards
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).
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.
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)
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
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)
What are the effects of beta-blockers?
Diminish Phase 4 depolarisation and automaticity
Minor effect on Phase 2
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)
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
Describe the effect of Ca2+ channel on the pacemaker action potential
What are the drugs that affect automaticity?
Beta-agonists
Muscarinic agonists
Adenosine
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
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.
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.
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
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
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).
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)
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
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
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.
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.
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
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
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)
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
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
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.
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
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)
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)
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)
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.
Describe the variation in proliferation of the cell cycle
Cell proliferation variation in cycle 9-43 hours between cancer cells
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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’.
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).
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.
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.
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.
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.
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
