Oncology v0.1

Understand the difference between enteral and parenteral nutrition

Plus it's really expensive (to produce and administer because it's sterile AND needs to be given with a needle)

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Can even lead to intangible costs, like psychological changes○

It's annoying to the patient (invasive)•

And complications can arise, like phlebitis (inflammation of veins) or infections etc.

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Important point: Use the gut if you can, or as soon as possible. If the gut is partially working, use it as much as possible. This is to prevent loss of function in the gut.

Terminology (might want to skip this and read this as a summary)

Parenteral nutrition is nutrients given from a route outside the gut (see below)•Total Parenteral nutrition (TPN) is where the patient gets 100% of their nutrients, needs to be a large volume and is completely water soluble. We will prepare these quite frequently

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Peripheral nutrition is smaller volumes delivered via a peripheral vein•Nutritional support is delivering a constant stream of nutrients to the blood (can be either enteral or parenteral) for special cases like cystic fibrosis (can't get enough nutrients quickly due to thick mucus layer)

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Basic differences

Basically, enteral means through the gut (GI system), while parenteral is anywhere but the gut

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Orally○

Different tubes (e.g. nasogastric tubes)○

Stoma (piece of gut is exposed to the environment)○

Enteral could be given:•

Generally more suitable for larger volumes which are not iso-osmolaric

Therefore, can be used for long-term Total Peripheral Nutrition (TPN, where all their nutrients are delivered this way)

Patients may have protracted diarrhoea, chronic obstructions (or pseudo obstructions) of the GI system, or short bowel syndrome (too much GI system cut out due to surgery, think about inflammatory bowel conditions like Crohn's disease or ulcerative colitis)

Central line- Jugular or subclavian vein, but it's inserted via the arm○

Generally suitable for smaller volumes, but must be iso-osmolaric

Therefore, used for short terms (like after surgery)

Peripheral line- out in the arm○

Parenteral is generally giving via IV (can also be IM or IC) which can be at two different sites

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OVERALL: the goal is to get nutrients into the bloodstream of the patient. The gut processes larger molecules into smaller ones, while parenteral nutrition focuses on getting these nutrients directly into the bloodstream to bypass the gut

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Aseptic Dispensing

Oncology

Contents of nutrition liquids

Both types of liquid will contain all the components of the food we normally eat, such as carbohydrates, fats and amino acids, trace nutrients etc.

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Enteral formulations are quite simple, being made from more complex molecules like proteins and long chain carbohydrates

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In addition, because it's being added centrally, we need to make sure it's compatible with the blood

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Which means the fats need to be suitably water solubilised (as a suspension) and the osmolarity may need to be adjusted.

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Parenteral formulations need to have these complex molecules to be broken down to simple molecules, BECAUSE the gut is being bypassed (remember: the gut is normally responsible for the important function)

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Understand the importance of adequate nutrition in debilitated patients – whether in hospital or in the community.

You need to eat, it's kinda important.

Effects of malnutrition

So obese people are technically malnorished due to a lack of balance○

Malnutrition is where a proper balance of nutrients isn't achieved•

Leads to breakdown of various proteins and organ failure

Patients can be in a catabolic state, where their body is breaking down proteins because the person isn't getting enough nutrients

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Leads to tiredness, exhaustion and death

Patients could be in a normal metabolic state, but might not be getting enough energy

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There are two types of malnutrition we can look at•

Costs of malnutrition

Slower healing times (longer visits are more expensive)○

Increased chance of infection○

Other complications, like muscle wasting (catabolic state)○

Costs of product and production (aseptic production is costly)○

Tangible•

Psychological○

Non-tangible•

Refeeding syndrome

© Arnold Lee

Oncology

Insulin secretion is tied to several electrolytes, such as potassium intake into cells and phosphate

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Leads to a reduction of electrolytes inside cells○

After a long time of starvation, the body will adapt slowly to changes, such as reducing the insulin secretion

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Causes death due to a multitude of problems○

If a person is suddenly fed a lot of food after this state, insulin secretion will kick in and cause electrolyte imbalance (especially blood phosphate decreases due to absorption into cells)

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Appreciate the role of the pharmacist in an Aseptic Production Unit (APU) with regard to parenteral nutrition

Aseptic versus Sterile

VERY important difference•

Usually achieved with autoclaving or high temperatures etc.○

Sterile is an absolute, a black or white state where the product contains no contaminants whatsoever.

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Does not guarantee sterility, but it's hoped it's sterile○

i.e. this definition isn't as black and white when it comes to contaminants○

Aseptic production is where a product is prepared from sterile products in a very clean (aseptic) workplace.

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Examples are bacteria, viruses or even fungi

Viable contaminants are able to grow and give someone an infection (can lead to death by sepsis)

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Examples are bits of glass or dust

FILTERS ARE IMPORTANT, they keep them out to prevent this issue

Non-viable contaminants can't grow, but still cause problems, such as occlusion of blood vessels or may be pyrogens

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Contaminants come in viable and non-viable flavours•

TPN bags

May be divided into three compartments (glucose, amino acids and fat compartment) for enhanced stability. Must be combined before use

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Note: after combination, inspect bags for creaming of the lipid suspension (this is where the suspended lipids gather together to form larger particles, might kill your patient if given)

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TPN bags contain a liquid for TPN•

TPN bags can generally be purchased and given in that state•

Gives a lot more flexibility, tailoring it to specific patient requirements, but this is very costly due to running the APU and hiring a pharmacist to make it.

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But they can be individualised within an aseptic production unit (APU)•

Understand the principles behind aseptic preparation AND Be familiar with basic aseptic manipulation

Skin particles carry stuff○

We could cough or sneeze stuff out○

Therefore, we need to wear appropriate protective equipment○

We are the number one source of contamination•

Regularly checked to see if it's clean (taking swabs to see if anything will grow)

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Air is filtered

Within the APU is a clean room•

Oncology

Air is filtered○

Everything is flush against the wall (no overhangs or anything)○

Horizontal cabinets blow air towards you, protects the product only (which means it can blow nasty chemicals like cytotoxics in your face)

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Vertical flow cabinets will blow air downwards, protecting both the product and the operator.

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A laminar air flow cabinet is in these clean rooms•

Generally speaking, these points are where the liquid is going to touch the equipment

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This includes needle/syringe/filter tips, the inner ribs of the syringe etc.○

Make sure you don't touch critical points•

Reconciliation is where the products taken into the clean room are matched with what's leaving the clean room.

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This is in addition to other standard operating procedures, error reports, GMP requirements etc.

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Make sure the paperwork gets done•

There's a window which allows you to observe and check on the tech.○

NOTE: the person in the clean room might be a technician. Therefore, we are responsible for anything they do

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Why is safety important?

These cytotoxics are carcinogenic/toxic so we need to protect the people handling these compounds

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Protect staff•

Prevent complications○

Protect patients•

Administration

Short infusions for cytotoxics (or peripherial nutrition) need to be controlled specifically by a pump

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Advantage is this allows for greater mobility, can let them go home instead, saves the hospital money.

Longer infusions (such as for TPN) can also be controlled by a pump, or they may use an elastomeric pump, which uses rubber to push liquids at a slow rate.

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TPN or cytotoxics are usually not delivered by the pharmacist, but they need to tell these people how to.

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Potentially fatal mistake with vesicants (blistering agents)□

"Not for intrathecal (spinal)" use is NOT acceptable. Use "For IV use only"

Be as specific as possible○

Be careful to check it's the right patient, dose etc.○

Because we need to tell how these medicines are used, we need to be very clear when writing labels

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This is where the IV fluid leaks out into the surrounding tissues (so it's called being 'tissued' by nurses)

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Patients need to be told to report discomfort or pain ASAP

In the case of vesicants (blistering agents) this can cause massive necrosis.○

Be wary of extravasation•

Intrathecal drugs tend not to be given very often, so the pharmacist in charge will personally deliver it to prevent mistakes

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Also, you can only give a few millilitres via the intrathecal route (larger volumes are used for IV route), so the size difference should tip off the nurses as well

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Note: For intrathecal drugs•

Oncology

Patient Information

Such as for extravasation○

Or if the elastomeric pump breaks at home○

How to counter side effects (like anti-emetics for vomiting)○

Need to tell the patient what to do•

Can vary greatly between patients and within patients

e.g. changing organ function, reduced effect or tolerance etc.

Doses○

Biological (contamination)

Chemical (reactions occurring)

Physical (precipitation or light sensitivity)

Stability○

Allergies

Pregnancy (debatable, risks to foetus need to be considered)

Contraindications○

Check for:•

We need to know what can happen, and may have to advise on how to counter them

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Important information is the side effects which will affect the patients•

Adverse reactions

Note: REMEMBER, the cytotoxics will usually affect growing cells. These side effects are usually caused by affecting dividing cells like the bone marrow or mucosal surfaces etc.

Oral and GI mucosal damage due to cytotoxics affecting their regeneration and repair

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Oral hygiene becomes much more important○

Patients need to report abdominal pain or bleeding○

Mucositus•

White blood cells and platelets are reduced by cytotoxics○

Must report bleeding due to reduced platelets○

Can also cause neutropenic sepsis (means low neutrophils plus infection) where temperature is high, chills, sore throat, pain on urination etc.

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Myelosuppression/immunosuppression•

Lysis of tumour cells releases calcium, uric acid and potassium○

This can lead to gout, need to treat with allopurinol and keep hydrated○

Tumour lysis•

Hair grows back wavy○

Usually temporary and not harmful, but don't let the patient be surprised○

Alopecia•

Be competent at calculations

Sometimes we might be adding extra nutrients or electrolytes to the TPN bags for specific requirements for the patient. So we need to be able to make calculations.

Generally, we already have these electrolytes in a solution, so we need to know what volume of these liquids we're adding.

Try to understand why the calculations/formula works. Saves you from having to rote learn AND helps to pick up on any mistakes

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Potassium ions can be supplied by potassium dihydrogen phosphate or potassium chloride

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Watch out for other sources of electrolytes!•

General tips:

Oncology

So when you're adding phosphate, you have to add potassium

potassium chloride

The TPN bag might come with some electrolytes, make sure you take away these electrolytes from your calculations

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Premade TPN bags can generally hold 20% more fluid /)^3^(\•

In other words, adding calcium gluconate just after potassium dihydrogen phosphate (or vice versa) will lead to calcium phosphate formation

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This is VERY BAD, because calcium phosphate is insoluble, it will block your filter or piss off your patient with phlebitis if you don't kill them first

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Don't replace filters, they can cost $5US per filter○

To avoid this problem, just use another solution first (like sodium chloride if you have to add it) OR just rinse with water for injection

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Important consideration: Calcium phosphate WILL form if calcium ions are in contact with phosphate ions

Example calculation

A patient needs 68mmol potassium ions and 40mmol phosphate ions in the TPN bag. The TPN bag already contains 48mmol potassium and 20mmol phosphate. You have the following solutions available:

Potassium chloride 2mmol/mL (contains 2mmol/mL of potassium)Potassium dihydrogen phosphate 1mmol/mL (contains 1mmol/mL of potassium and phosphate)

What must you do to fulfil the prescription?

Start off by calculating how much of each electrolyte you need. In this case, the TPN bag already contains some of the electrolytes, so we need to subtract them:

Potassium: 68mmol - 48mmol = 20mmolPhosphate: 40mmol - 20mmol = 20mmol

We can see both are short by 20mmol, but we have two solutions we can use.We can't use potassium chloride, otherwise we'd have an excess once we try to add the phosphate because the phosphate solution also has potassium in it.

Lucky for us, the shortage is a 1:1 ratio, so we can just use the potassium dihydrogen solution only to make up the 20mmol shortage.

Now, we know each 1ml of the solution contains 1mmol of both potassium and phosphate, but we need 20 mmol of both, so we divide 20mmol by 1mmol/mL

20mmol / 1mmol/mL = 20mL

Notice how the units will fit (mmol will cancel each other out, and since the ml is on the bottom, it gets flipped up after division), showing you did the right type of calculation

So the answer is we need to add 20mL of potassium dihydrogen phosphate to the TPN bag to fill the prescription.

Oncology

Objective: Understand the biological basis of cancer

Tightly regulated with several checkpoints○

Cell division occurs through the cell cycle•

The process is called oncogenesis○

Suppressor genes

Proto-oncogenes/ Activator genes

Associated with two families of genes○

Cancer occurs because cell growth becomes unregulated•

Inherited○

Chemical○

Physical○

Infectious○

Several factors are known to damage cells to cause them to have their growth unregulated

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Summary

The cell cycle

G0- "Growth 0" phase. The cell is at rest, no division is occurring (lots of cells are like this in the body, as they are terminally differentiated)

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The instruction can be from a hormone, growth factor, a change in local conditions etc.

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G1- "Growth 1" phase. The cell prepares to divide, BECAUSE it's received an instruction to divide. As a result, it will now synthesise proteins and enzymes required for division

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Antimetabolites, such as methotrexate will work here○

S- "Synthesis" phase. The cell will now replicate DNA. This is the longest stage clocking in at 6-8 hours.

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G2- "Growth 2" phase. The cell has two copies of DNA, and it will now produce proteins required for mitosis to occur. Takes 2-3 hours.

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Oncogenesis

Oncology

Antimotility agents, such as paclitaxel will work here○

M- "Mitosis" phase. The cell will now split, taking one copy of the DNA, to produce two identical cells. This is the shortest phase, clocking in at 1 hour. The cell will now return to G0 phase, and can re-enter the cycle if stimulated.

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A homeostatic mechanism exists in the body to keep things under control○

Cells will be killed off due to apoptosis over time○

While other cells will be triggered to grow to replace these dying cells○

Normally, we would expect the number of dying cells to equal the number of cells created to keep the number of cells in the body constant

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So the cell cycle is tightly regulated to stop this from happening○

If the homeostatic mechanism fails, then we get cancer.•

Cell division checkpoints

DNA damage is harmful to cells, as it can cause a loss in function, which includes not making a correct protein, or it could even become cancerous.

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Once that mutation passes down through the cell cycle, it becomes fixed into the DNA permanently, because the cell doesn't have an original copy of the DNA to check against.

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Therefore, cells have defence mechanisms against mutations from being passed down during mitosis

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G1 arrest- the cell cannot enter the cell cycle

G2/M arrest- the cell cannot enter mitosis

If the cell fails to pass the checkpoint test, the cell cycle is immediately halted to allow for repairs to occur before continuing:

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If the DNA cannot be repaired, the cell will undergo apoptosis○

So the cell cycle has several 'checkpoints' where the integrity of the DNA is checked to stop mutations from occurring.

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p53 is especially important, as it is a part of the G1 checkpoint, can induce DNA repair and induce apoptosis if needed

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Therefore, many tumours will have p53 deactivated○

p53 and the Rb (retinoblastoma) genes are important in cell cycle control, as they will regulate the cell cycle.

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Telomeres are straight pieces of DNA at the end of a chromosome○

The straight ends cannot be perfectly copied, so they shorten with each cell division

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Once the telomeres are short enough, the cells are triggered to undergo apoptosis

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The reason for this is to make sure cells have an automatic 'expiry date' to prevent them from accumulating too many mutations, and becoming cancerous.

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Therefore, it's also another common mutation seen in cancers

To counter this, a cancerous cell can activate telomerase, which increases the length of the telomeres to prevent apoptosis from being triggered

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Another important mechanism is the use of telomeres•

Oncogenesis

Remember: the cell cycle is tightly regulated, so the cell has quite a few barriers which it needs to overcome to become cancerous

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For example, to become cancerous, the cell would have to ignore apoptotic signals (p53), grow independent from growth factors, have factors to promote angiogenesis (production of blood vessels), avoid the immune system etc.

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An important fact is one mutation is not enough to cause cancer•

Oncology

system etc.

But if the checkpoints are non-functional (either inherited or mutated), then it's much easier for these mutations to occur, so it's easier for the cell to become cancerous

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REMEMBER: normally a person will carry two copies of the gene, both must be broken to get cancer ('dominant' gene, so hetrozygous people are still at higher risk of getting cancer as a result)

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Normally, these mutations will be prevented by the checkpoints put in place•

If you live long enough, by chance you will accumulate enough mutations○

Because the cell needs multiple mutations to become cancerous, cancer is a disease which is concentrated in the elderly

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Suppressor genes○

Activator genes (proto-oncogenes)○

Also, there are two main groups where mutations will cause cancer, as they are important for regulation of cell growth:

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p53 is again an important suppressor gene, as it contains apoptosis genes○

If BRCA is mutated, the incidence of breast cancer shoots through the roof

BRCA is an important suppressor gene as it is involved in double stranded DNA repair

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Anything inhibiting growth, such as growth regulator genes are important○

Contact inhibition genes- normally these will stop cells from dividing if they are in contact with each other, as it indicates there's no space to grow.

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Suppressor genes will work to prevent cancer, so these should be kept ON•

Angiogenic genes are very important in tumours, as the tumour must be able to get a blood supply set up to grow properly. Otherwise the tumours will be small and most likely unsuccessful.

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Some genes will allow cells to escape immune surveillance, or be immunosuppressive

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Others will help them survive outside the tumour, which allows distant metastasis to occur (surviving outside the original tumour is quite difficult)

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Activator genes are also called proto-oncogenes, as normally they are not cancerous, but if mutated, will cause cancer. Therefore, to prevent cancer, these should be kept 'INACTIVATED' (not completely off, normal body function might need them, like healing)

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How do we get cancer?

As stated before, you need functional suppressor and non-activated activator genes to NOT have cancer.

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Sometimes, people will inherit a non-functional copy (or copies) or suppressor genes…

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Or receive one (or two) copies of an activated activator gene○

Think about it as they've already accumulated mutations required for cancer.

Therefore, these people are at a higher risk of getting cancer○

Inherited•

Carcinogens are chemicals which will cause damage to DNA (either directly or indirectly through metabolites/breakdown products)

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Again, these mutations need to hit a suppressor or activator/proto-oncogene.

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Chemical•

Direct damage to DNA

Ionising radiation○

Damage via production of radicals

Non-ionising radiation○

Physical•

Oncology

Damage via production of radicals

Either will cause DNA damage, which might give you cancer if the wrong genes are turned on/off (see above)

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Quite a range of viruses can do this

Why? Because p53 can trigger apoptosis and ruin their plans

Human Papillomavirus (HPV) and Epsein-Barr virus

Can inhibit p53○

This is probably why hepatitis B and C cause liver cancer

Cause increased division, which leads to more chances of being mutated and causing cancer

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Yeah… this can only end badly

Seen by retroviruses (can enter the host's DNA) like HTLV-1 or HIV

Insertion into oncogenic gene○

Infectious agents•

Oncology

Chronic inflammation can cause cancer○

The immune system can kill cancerous cells○

Can be thought of having a role before AND after cancer•The immune system has a role in cancer (surprise!)

Chronic inflammation and oncogenesis

Inflammation produces some reactive oxygen species which may damage DNA, causing activation/inactivation of genes

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Inflammation also encourages division of some cells (especially immune cells) which can lead to cancer

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It appears chronic inflammation can cause cancer•

NSAIDs have some effect for protecting against cancer○

Therefore, anti-inflammatory cytokines or chemokines may be used to prevent cancer.

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Immune response AGAINST cancer

Destroys the infectious agent which can cause cancer○

Kills any cancerous cells before becoming a tumour○

How is the immune system protective against cancer?•

Neutrophils, macrophages and dendritic cells

Detect foreign cells, and abnormal body cells (due to infection or cancer) to trigger an immune response (produce cytokines and stuff), especially trigger the acquired immune response

Slow down the infection long enough for the acquired immune system to kick in

Innate immune response is the first-line protection mechanisms○

T Lymphocytes for a cellular immune response, B lymphocytes for a humoural (antibody) response

Produces more effective killing cells (natural selection, where lymphocytes with the best receptor against the antigen is stimulated more)

Produces memory cells to prevent long term recurrence

Acquired immune response is the killing blow○

The requirement of a danger signal will also prevent any self-reactive cells from being activated as well

Self-reactive cells are killed off during thymic selection to protect the body against auto-immune reactions

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Recap: innate immune response vs acquired immune response•

All nucleated cells are able to get cancerous○

But all nucleated cells must express MHC-I○

The MHC-I is continuously recycled from displaying an antigen and being drawn back into the cell to find a new antigen to display

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Normally, the immune cells will see all the MHC-I receptors displaying normal body antigens

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But if the cell becomes cancerous, it might start producing antigens the immune system can't recognise

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This will lead to an immune response, and destruction of the cancerous cells

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So… How does that help against cancer?•

The role of the immune system in cancer

Oncology

Because it's MHC-I, it needs the CD-8 co-receptor to stimulate CD8 T cytotoxic cells

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Therefore, the immune response will be mainly carried out by CD8 T lymphocytes (cellular response)

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What kind of immune response?•

Well, it's not the same as the diseases we've seen in the past○

Tumours will make 'Tumour specific antigens' (TSA) which are the mutated proteins the immune system can't recognise

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In addition, they might also make 'Tumour associated antigens' (TAA) , which is where the tumour produces proteins which shouldn't belong in that part of the body

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Lastly, an infectious agent can be causing cancer, these cells will display viral antigens to become a target for the immune system as well.

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Don't we have to worry about auto-immune reactions?•

Danger signals can come from infected cells at least○

Also, if a tumour does form, then the centre of the tumour may become necrotic due to reduced blood supply to the region. The immune system will respond to necrosis with inflammation.

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If cells are kept in anergy, how do we activate them against cancer?•

Plus they are more likely to be subject to mutations due to inactivated suppressor genes.

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Tumours will be subject to natural selection, because vulnerable cancerous cells will be killed off easily, leaving cells which are resistant to immune attack

They can look normal to the immune system by expressing normal antigens on MHC-I

They can shut down antigen presentation (however, see below)

They can produce an environment which can be immunosuppressive

Maybe… but cancers can have immune defences○

Immunosuppressed due to drugs, infectious agents or radiation

Plus as people get older, their immune system strength decreases

Or the person just can't mount a response○

The immune system decides to induce tolerance against the tumour cells, preventing any immune cells from attacking it

Or… the tumour cell or supporting cells will produce immunosuppressive factors like cytokines

So one important result of treatment (radiation, chemo or surgery) is to kill off these immunosuppressive cells and let the immune system clean up

Or the person produces the wrong response○

So our immune system should work against cancer effectively right?•

It's one method to prevent the immune system from noticing○

But Natural Killer (NK) cells will be able to detect if a cell is missing MHC-I○

NK cells are always set to kill, so they need an inhibitory signal to prevent the cell from being killed

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MHC-I provides the inhibitor signal, so cells with MHC-I will survive○

Cells which do not produce display MHC-I cannot send the inhibitory signal, and so they will die.

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What if the cell stops producing MHC-I?•

Oncology

Why is it difficult to treat cancer?

Narrow therapeutic range due to targeting the same pathways used by our healthy cells

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We can counter this by combining several drugs at lower doses to prevent extreme toxicity

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The amount of cells we can kill is limited by toxicity•

Leads to increased drug resistance○

Use multiple drugs to help to prevent increased resistance○

Cells are rapidly dividing, and the genomes are prone to mutation due to damaged repair/error checking mechanisms

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Brain and testes○

They can escape to safe sites in the body, where it is hard to get drugs or immune involvement in

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Therefore, we need to apply chemotherapy as soon as possible○

By the time we're treating the cancer, it's already growing slowly, and is less receptive to chemotherapy

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Combination therapy

Again, results in better response (synergy) and reduced side effects and a lowered chance in gaining resistance

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Each drug should work against the cancer○

Each drug should have a different mechanism of action○

Drugs should avoid overlapping toxicities○

AND include a few which are non-cycle specific

Reason for this is because only a certain portion of the cancerous cells will be in the part of the cell cycle, combining the two leads to a better outcome

Target different stages of the cell cycle○

There are a few principles you should keep in mind:•

Infusion over time or frequent dosing

Think of it like the time-dependant kill antibiotics, a long period of time is preferred

Cell cycle specific drugs need to achieve high concentrations over a long period of time, as different cells will enter that specific part of the cell cycle at different times.

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One fast infusion

Think of it like the concentration-dependant kill antibiotics, where the highest concentration needs to be achieved

While non-specific agents just need to be given in one single high dose○

The dosing of a cell cycle specific vs. a non specific agent is different:•

Surgery causes injury which stimulates cells to come out of G0○

Therefore, can hit more of the cancerous cells○

Cell cycle specific drugs should be coordinated with surgery•

Allows the body's normal tissues to recover from the chemotherapy○

But the waiting time between treatments is short enough to prevent the cancerous cells from

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Drugs are given in treatment cycles•

Pathways for antimetabolite drugs to target:

Pharmacology of cytotoxic drugs

Oncology

Inhibits dihydrofolate reductase (DHFR)○

Stops the conversion of dihydrofolate to tetrahydrofolate to stop the production of all nucleotides

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Countered by the cancerous cells by increased efflux or a mutation or upregulation in DHFR

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Methotrexate (MTX)•

Inhibits Ribonucleotide reductase (RR)○

Stops the conversion into deoxyribonucleotides, as that's the form needed to be incorporated into DNA

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Hydroxyurea•

Inhibits IMP dehydrogenase (IMPDH)○

Stops purines from being made (A as AMP and G as GMP)○

6-Mercaptopurine (6-MP)•

Inhibits thymidylate synthase○

Prevents the conversion of dUMP to dTMP to cause a thymineless death (a pyrimidine)

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5-Flurouracil (5-FU)•

Not shown above○

Inhibits DNA polymerase○

Stops nucleotides from being added to DNA to stop production○

Cytarabine•

Azathioprine and 6-MP metabolism

Azathioprine is metabolised to 6-MP•

Highly polymorphic○

Fast metabolisers will produce too much toxic side products○

Slow metabolisers will accumulate 6-MP leading to toxicity○

6-MP is metabolised by TPMT (Thiopurine methyltransferase)•

This is the enzyme which is inhibited by allopurinol○

6-MP tends to be given to patients who need allopurinol to combat tumour

6-MP is also metabolised by xanthine oxidase•

Oncology

6-MP tends to be given to patients who need allopurinol to combat tumour lysis syndrome

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Adjust dose of 6-MP down to compensate○

Folinic acid

Not to be confused with folic acid•Folinic acid can be converted by another enzyme to several different forms, like THF or MTHF, which can readily be used by the cells of the body

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If it is used with 5-FU, it enhances the cytotoxic effect, as MTHF, a cofactor for the thymidylate synthase enzyme is required for binding and inhibition

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Methotrexate depletes useable folate reserves (as THF) as dyhydrofolate reductase has been inhibited

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i.e. stops DHF from being recycled into THF○

Cancerous cells are too damaged by this point to be saved by this folinic acid rescue

Folinic acid rescue after methotrexate use will allow healthy cells of the body to produce nucleotides to prevent side effects

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BUT it could also be used with methotrexate. •

Mitotoxicity hypothesis

DNA damage in normal cells will lead to apoptosis•Therefore, the point of using of agents is to try and stimulate the cancerous cells to undergo apoptosis

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p53 induces apoptosis, it is a part of the G1 checkpoint of the cell cycle○

These cancers are responsive to treatment, as p53 induces apoptosis

Leukemias and lymphomas

Some cancers will keep a normally functioning copy of p53 (wild type)○

Minimally responsive to treatments

Lung, pancreatic and colon cancers

Other caners will get a mutation in p53, apoptosis isn't easily induced○

Problem is, it depends on the function of certain genes/proteins like p53•

Telomeres

2-30 kilobases which repeats 'TTAGGG'○

A 50-300 base single stranded section will loop back onto the DNA and form a stable loop (t-loop)

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Caps at the end of chromosomes•

DNA polymerase isn't able to copy this section perfectly, it shortens with each replication

•

Therefore, old cells which may have gained a lot of mutations won't be allowed to grow anymore

○

Once it reaches a critical length, p53 steps in and prevents the cell from passing the G1 checkpoint, forcing the cell into senescence (remain in G0 forever)

•

Inactivated version of p53 and○

Activation of telomerase, which is an enzyme which adds to the length of telomeres, making them grow again.

○

But cancer cells can get around this:•

These two mutations will cause a cell to become immortal•

Photodynamic therapy

Experimental therapy which has drugs which produce reactive oxygen species when exposed to light

•

Looks like iron contained within a polyphoryn ring•When struck by light, the iron will catalyse the production of free radicals•

Oncology

When struck by light, the iron will catalyse the production of free radicals•Allows for some targeting to specific sites of the body•

DNA repair systems

Caused by natural errors○

Mutations can lead to colorectal cancers○

Mismatch repair•

Single strand breaks (caused by alkylating agents and irinotecan)○

BRCA1 and 2 are slower as they are made for double strand breaks

PARP1 repairs these, but if it is inhibited, BRCA1 and 2 can take over○

Base excision repair•

Addition of substances (such as alkylating agents)○

Nucleotide excision repair•

Double strand breakages (topoisomerase inhibitors and bleomycin induces this, along with cross-linked DNA due to alkylating agents)

○

Homologous recombination repair assisted by BRCA is the best bet, which is where the sister chromatid (remember you carry two copies) lends its information to help join the two strands together

○

Non-homologous end joins is less safe as there's nothing to check against○

Double strand break repair•

Topoisomerase I inhibitor- irinotecan

Relieves coiled tension within the DNA strand (double helix)○

Topoisomerase I is involved in uncoiling the DNA prior to replication•

The enzyme will separate the two strands of DNA○

Cuts one strand○

Unties the strand by passing it over the other strand○

Joins the two cut pieces together to complete the unwinding○

Current model for inhibition is:•

Actually is metabolised into SN-38 which is 1000x more active, but it's highly protein bound and has a very short half life

○

It is cleared by UGTA1, which is lacking in Gilbert's syndrome. Stops the SN-38 from clearing, leading to severe myelosuppression

○

Irinotecan will stop the ends from being joined together, leading to a single strand breakage

•

Topoisomerase II inhibitors

Relieves coiled tension BETWEEN DNA strands (not within the strand)○

Relieves supercoiling of DNA•

Cuts both sides of the DNA strand○

Passes the strand past another strand to relieve the supercoiling○

Joins the two ends back together○

Similar action to above•

Some drugs like anthracyclines will allow the double strand breakage, but won't allow it to come back together

•

Anti-mitotic drugs

Important during the M phase to pull apart and drag the chromosomes○

Both classes of drugs lead to peripheral neuropathy

Also important for intracellular trafficking of chemicals with vesicles○

Attaches to tubulin, which makes up microtubules•

Vinca alkaloids bind to the positive end of beta tubulin to prevent polymerisation of the chain

•

Oncology

of the chain Taxanes on the other hand will bind to the side of beta tubulin. It allows polymerisation, but not depolymerisation (so it become stuck)

•

HER2 and Imatinib (and other signalling pathway blockers)

Some cancers will have unregulated growth due to expressing growth receptors•We can block these receptors to prevent growth•

Use Herceptin (trastuzumab)○

HER2 is a receptor which can be expressed in breast cancer•

Imatinib blocks a tyrosine kinase associated receptor to prevent growth in Chronic Myeloid Leukaemia

•

Oncology

Intro

Otherwise, the chemo can kill the patient before it kills the cancer○

We want to specifically kill cancer cells over normal cells (selective toxicity)•

Compared to antibiotics, which exploit differences in biochemical pathways between us and them

○

Problem is, cancerous cells tend to use the same biochemical pathways as normal cells, which is why it's very toxic

•

Some normal cells are rapidly dividing (gut, bone marrow, liver) so they are affected by chemo

○

But some cancerous cells won't divide rapidly, so chemo won't work well against them

○

So we tend to target rapidly dividing cells to target the cancer•

Leads to more drug resistance and treatment failure○

Rapidly dividing cells are bad for treatment, because they tend to accumulate more mutations

•

But it's limited by the toxicity of the drugs○

We want to maximise kill count (hopefully on a log scale)•

Oral forms are desired○

Finally, we also want to have them in a form which is easy to administer•

Vesicant- a substance which is able to cause blistering. Quite a few chemo drugs tend to be vesicants. This is why patients need to be told to look out for redness, swelling, discomfort or pain around the infusion site.

Alkylating agents

Can't copy or transcribe information from DNA○

Trigger apoptosis due to damage○

Guanine is generally targeted due to its nucleophilic properties (see below)○

Designed to interfere with DNA function•

Guanine is alkylated, so there's this massive group attached to it

This can lead to the elimination of the group as well (the base comes off the DNA, see below)

Either way, the DNA can't work this way, so excision repair enzymes are activated, to cut the DNA to replace these faulty bases

Because repairs can be made, this isn't effective

Modification of DNA bases (mono-alkylation)○

See below for the structure a sulphur mustard

Notice it has two chlorines, so it can alkylate twice

Between chains□

Within chains (more common)□

It can form covalent bonds either:

This will prevent the DNA from coming apart normally for normal function

Effective

Cross-linking within and between DNA strands (di-alkylation)○

Normally, we'd except A goes with T and C goes with G in DNA

But alkylated G can go with T, which is a mistake

This will lead to mutations

Which can lead to a malfunctioning cell, and apoptosis

Nucleotide mispairing○

How does it work? (mode of action):•

Exhibits a 'Janus' effect•

Medchem of cytotoxic drugs

Oncology

Janus is the Roman god of doors. He has two heads, one pointing inside, and the other pointing out.

○

People may have secondary tumours which are completely different to the original tumour after a few years of treatment

Why is this important? Because alkylating agents will kill cancerous cells BUT because they interfere with DNA, they can also CAUSE cancer.

○

Exhibits a 'Janus' effect•

Below is a sulphur mustard, where there's a two carbon bridge between the S and the chlorines. THIS IS IMPORTANT. RECOGNISE THIS.

○

Sulphur mustards are gases, due to low intermolecular bond strength (they don't H-bond to each other) so they are too dangerous to work with

○

So nitrogen mustards were investigated, because they can H-bond to each other, so it's not a gas anymore, so it's safer to handle

○

The alkylating agents will always have a specific moiety•

The two nitrogens in the right side ring presents a electron rich region○

This makes it nucleophilic, attacking the alkylating agent (seen as R)○

Can lead to the ring opening which permanently binds the agent to the base

Or can cause the entire group to come off as a leaving group from the DNA

This addition will lead to a positive charge on the nitrogen, which needs to be removed.

○

But remember: monoalkylation (shown below) can easily be repaired○

Why is guanine (N7 nitrogen) targeted specifically?•

The electronegative chlorine atoms will draw electrons towards itself, causing the adjacent carbons to become slightly positive

○

Chlorine is a good leaving group as it comes of neutral with respects to acid-base chemistry (i.e. even though it's negatively charged, it doesn't have acid base chemistry)

The non-bonding electron pair (NBP electrons) on the nitrogen is attracted to the positive charges, leading to intramolecular nucleophilic attack (SNi)

○

The SNi leads to the formation of the aziridium ion, which is a highly reactive

The mechanism of action of alkylating agents is all the same (and we need to memorise it)

•

Oncology

Bond angles are strained (at 60 degrees instead of normal 108)

Both carbons are positively charged

The SNi leads to the formation of the aziridium ion, which is a highly reactive electrophile (i.e. susceptible to nucleophilic attack)

○

Remember: the molecule is bifunctional as it has two carbons, so it can crosslink DNA (deals more damage)

After nucleophilic attack with the nucleophile (which is likely to be guianine), the base is now alkylated.

○

Forms the aziridium ion too easily then, which will just react with all the cells it comes into contact with

○

So we need to tie up those NBP electrons to stop forming the aziridium ion as easily to reduce toxicity, to reduce side effects

○

If the nitrogen mustard shown above had an aliphatic R group, it is too toxic to use in people

•

Alkylating agents- examples

Mephylan •

The NBP electrons on the nitrogen are partially taken up into the aromatic ring•

It's actually L-phenylalanine (amino acid) attached to the mustard○

The sterochemistry on the carbon is R•

But it's still actively taken up by all cells, leading to side effects…○

They thought the phenylalanine would allow the drug to be taken up into growing cells because it's an amino acid

•

If the phenylalanine comes off, it's still active because the mustard is intact○

If the amino or carboxylate groups are metabolised, again, the mustard is still intact and it's still active

○

This drug has some activity, because the NBPs are somewhat available•

This is the really important one because we use it quite often○

Cyclophosphamide•

It is a prodrug, it must be metabolised first:•

R

Oncology

It is a prodrug, it must be metabolised first:•

In fact, the structure shown on the right can be further broken down to form just a bare nitrogen mustard, which is thought to have most of the activity

○

The NBP electrons in Cyclophosphamide are completely taken up into resonance, so no aziridium ion formation can occur, so there is no alkylation.

•

Need to co-administer with Mesna and make sure to keep the patient very well hydrated with IV fluids and oral fluids

○

Mesna (pictured top left below) has a sulfate group purely for solubility and salt formation, while the active area of the molecule is the thiol (SH) group, which acts as a nucleophile to bind with the acrolein to form a non-toxic compound

○

Problem with cyclophosphamide is acrolein is a side-product which is toxic•

Some cancer cells produce a great amount of glutathione (GSH)○

Remember: thiol is a nucleophile, the active aziridium ion form is very attractive

GSH has a thiol group, which can react with the alkylating agent before it reaches the DNA to deal damage

○

Therefore, these cells will be resistant to treatment○

Thiol groups could also be a hindrance to treatment though•

An alkylating agent may be conjugated to a steroid to help it get into specific cells

○

It is only effective in cells which have low ALDH (aldehyde dehydrogenase), which are the well-differentiated blood cells, while the stem cells of the blood are quite high in ALDH, so they tend to be protected

Cyclophosphamide is actually quite targeted if you think about it○

Lastly, some forms are slightly selective•

Alkylating agents- Methansulfonates

Oncology

The oxygens are strongly electronegative, causing a great positive charge on the sulfur and adjacent carbon

○

Busulfan has two methanesulfonate groups (the two sulfur containing groups on the sides)

•

The methanesulfonate group is a good leaving group, so the carbon with the positive charge is able to attack guanine as well

•

But because it's got two groups, its able to cross link DNA•

Alkylating agents- nitrosoureas

These are the drugs which tend to end in 'mustine'•Very useful for brain cancers, as they are lipophilic enough to pass through the BBB

•

Because the non-bonding pairs of electrons on the nitrogen are completely taken up into resonance, so the aziridium ion can't be formed

○

Although they look like normal alkylating agents, they don't have the same mechanism

•

Instead, through a complicated mechanism, it breaks down to form two positively charged carbocations which are the active molecules

•

Platins (alkylating-like agents)

These are not alkylating agents, but shows some similar action (crosslinking of DNA)

•

Cisplatnin is a square planar molecule, with 2 amine and 2 chloride groups in The classical one is cisplatnin•

Oncology

Cisplatnin is a square planar molecule, with 2 amine and 2 chloride groups in a cis configuration:

○

This is because of this equilibrium reaction:○

Interestingly, cisplatnin is formulated in normal saline (0.9% NaCl)•

If the concentration of chlorine is high (as it is in the blood and in normal saline), then the equilibrium lies to the left, which is the inactive form

•

Therefore, platnins are prodrugs○

However, if cisplatnin moves into the cells, the chloride concentration is much lower, the equilibrium moves to the right, and the activated 'aquated' form is produced (pretty much water chucked on)

•

The H2O ligand is a very good leaving group○

The aquated form is active, because the platinum atom can now attach to the N7 atom of guanine (just like alkylating agents)

•

However, this is a intra-strand (within strand) crosslink.○

This will cause the DNA to have a 90 degree kink due to the shape of cisplatnin (square planar)

○

This irregular shape means the DNA is now useless○

Because there are two chloride groups, the same process will happen again, which causes DNA to become cross-linked

•

GSH will also bind to platnins to make them useless○

We can try to shield the platnin with a bulky group, but this is ineffective○

Again, another huge problem is with glutathione•

Therefore, we have newer, second generation platnins which are less reactive/toxic but still just as effective

○

Cisplatnin is too reactive, it is quite toxic•

It has a bi-dentate ligand instead of the two chorines○

This slows down the aquation of the platinum, leading to reduced toxicity○

Pictured above is oxaliplatnin, a second generation platnin•

Antimetabolites

Self directed learning•Up to now, we've looked at compounds which deliberately damage DNA•But antimetabolites will cause DNA damage by preventing the synthesis of DNA, either by producing false metabolites, or interfering with the enzymes responsible for production

•

Oncology

Therefore, this class of drugs are S phase specific for the cell cycle○

for production

Responsible for producing thymine from uracil, uses tetrahydrofolate (THF) as a co-factor

○

Disruption will mean thymine synthesis cannot occur, and the cell will apoptose due to a thymineless death

○

The primary target enzyme is thymidylate synthase•

Antimetabolites- 5-fluorouracil

5-flurouracil has a strongly electronegative group on the 5 position, which makes it quite attractive to the enzyme

•

Note: he doesn't think it's a prodrug, because prodrugs tend to be catabolised (broken down) to its active form. 5-FU is anabolised (built up) to its final form due to the addition of ribose and phosphate

○

It is a prodrug (even though Schmerer disagrees), it must first be converted to its deoxyribonucleotide form (pretty much just attach some phosphates to it to make it look something like a nucleotide)

•

Normally the THF would react with the uracil to form thymine, but this can't happen due to electrical repulsion between the fluorine and the nitrogen 10 of THF

○

When it enters the thymidylate synthase enzyme, it causes the formation of a false complex with tetrahydrofolate (THF) and thymidylate synthase

•

This effectively prevents thymidylate synthase from being regenerated, which stops thymine production

•

This causes the elongation of DNA to be stopped, leading to apoptosis○

Additionally, these false nucleotides may also be incorporated into the DNA and RNA

•

Anti-metabolites- folate metabolism

As stated above folate (as THF) is an important co-factor for thymidylate synthase•

It needs to be reduced back to THF to be used again○

After thymine is produced from uracil, the THF is oxidised to dihydrofolate (DHF)•

It is able to be inhibited○

Also causes a thymineless death○

May be used as a synergistic drug with 5-FU, as they both target the same process

○

The enzyme folate reductase is responsible for this function•

Increases the electron density on the nitrogen at the bottom of the ring, which is essential for binding

Therefore it will be able to outcompete folic acid

Better substrate compared to the endogenous substrate, folic acid due to the amine group

○

Methotrexate will inhibit folate reductase•

Oncology

Bleomycin

This is a problem, as it is hard to scale up to get large yields○

Massive molecule which is synthesised by bacteria•

Although a part of the molecule is cut off, DNA binding sites lie to the right of the molecule shown below. However, it is unable to intercalate with DNA due to too much 3D structure (need to be flat to intercalate)

○

The important bit is the iron in a square planar structure○

Notice how the oxygen is bound to the iron, it displaces the carbamate group

○

The oxygen is reduced to oxygen free radicals, which then damage the DNA○

The action of bleomycin is to bind to the DNA and cause DNA breakages•

The molecule is enzymatically cleaved by hydrolase, which reduces DNA binding and damage

•

The copper is removed to inactivate the molecule to reduce toxicity (it will find iron to chelate to in the body)

○

Normally, it comes as a blue copper complex (the copper sits where the iron is sitting below)

•

It is amazing to see such a large molecule being able to enter the nucleus. The sugars may be used as a recognition site to gain access to the nucleus

•

Because it converts oxygen into free radicals, the compound is associated with oxygen toxicity, leading to pulmonary fibrosis. Need to monitor patients carefully

•

Actinomycin

Flat ring system which isn't fully aromatic. It is still able to intercalate to the DNA

○

Two large lactones made of 5 amino acids, they may differ or be the same

Composed of three basic parts:•

Oncology

Two large lactones made of 5 amino acids, they may differ or be the same○

Planar rings allow pi-stacking○

Lactones will bind via hydrogen bonding (contains amino and carboxyl groups) and Vander Waals' forces (because it's big)

○

The entirety of the molecule will be able to bind to the DNA, causing it to bend out of shape completely

•

Bending it out of shape this badly prevents topoisomerase II from unwinding the DNA properly, so the cell can't replicate or transcribe DNA, leading to death

•

Anthracyclines

Doxorubicin○

Epirubicin○

There are a few anthracyclines in use e.g.•

Although they have 4 rings, they are not tetracyclines•

Tip: rubor is redness, can't forget it's red now○

They are red coloured compounds, and they are renally excreted, causing urine to go red

•

Note: formaldehyde naturally formed by the body will attack the sugar, which can cause covalent bonding of the anthracycline to the DNA

○

That is a good thing○

The 4 flat rings allow for intercalation into the DNA, while the daunosamine sugar (seen at the bottom of the image) will aid with binding to the DNA

•

Prevents transcription and duplication of DNA○

After intercalating with the DNA, it stabilises the interaction of topoisomerase II with the DNA, preventing it from doing anything else

•

Oncology

○

Causes free radical formation, which does have some effect against DNA, but the problem is it also occurs in the cytosol of cells

○

This is why it might be causing cardiotoxicity, as the cells of the heart cannot divide to form new cells, so the cells will take gradual damage over use

○

Therefore, there is a maximum cumulative lifetime dose for all the molecules in the anthracycline family

○

They are also a target for reductase enzymes, this is a major issue•

Oncology

Importance of targeted systems for chemotherapy

Chemotherapy drugs are generally not targeted at specific against cancer cells as we don't have many biochemical differences between cancer cells and normal cells.

•

Remember: treatments tend to be dose-limiting due to toxicity Increasing dose due to better targeting leads to better outcomes

Reduced toxicity as the drugs won't affect normal cell function○

Increased efficacy as more of the drugs will hit the cancerous cells○

Therefore, if we were able to produce a targeted form, it would be better due to:•

Levels of drug targeting

Broadest targeting•Targeting to the capillary bed of the desired organ•Better than nothing•

First order targeting

Targets at a cellular level•Hit specific cells within a region or in the body•

Second order targeting

• Targets a specific part of the cellIn our case, we want to target the nucleus of the cancerous cells to deal the greatest amount of damage to DNA

•

Third order targeting

○ Physicochemical properties of the carrier/drug will help the drug reach its targetIn other words, the body won't active move the drug, it needs to be designed to get there on its own

○

○ Analogous to passive diffusion○ Examples are modifying pH or particle size

Passive targeting•

○ Manipulate the body to actively take the drug to where it's needed○ Analogous to active transport

Examples are antibody based systems○

Active targeting•

To get these levels of targeting, we can consider two types of systems:

Ideal properties of a carrier

Non-toxic•• Cheap

Specific targeting to the desired cells•Doesn't leak the drug while moving to the site of action (might be a liposome)•

• Drug must get to the siteDrug must be released at the site (otherwise the carrier will prevent it from having its action)

•

Drug must remain at the site for as long as possible•

Liposomes- small spheres of phospholipid membranes which has drugs • Nano-particulates- encapsulates the drug to carry it to the site of action

Generally, there are two types of carriers:

Targeted Drug Delivery systems

Oncology

Liposomes- small spheres of phospholipid membranes which has drugs inside (inside is a hydrophilic solvent)

○

○ Emulsions- small spheres of lipids which has the drugs in the lipid compartment (inside is a lipophobic environment)

○ See case 1

Polymers○

○ Proteins (make sure it's human protein to prevent an immune reaction)○ Both of these have long half-lives to give it enough time to reach the site○ See case 2

• Drug-conjugates- drug is attached to the carrier to be enzymatically released at the site

Barriers to drug delivery

○ Tumours are able to cause angiogenesis (required for growth larger than 1-2mm), but they can't produce a drainage lymphatic systemThe blood vessels formed in tumours are very leaky due to increased gaps between the tight junctions of the cells of the endothelium, this allows liquids to move out

○

Liquids tend to be kept in the center due to a thicker extracellular matrix in the core

Pressure tends to be highest at the middle of the tumour, pushing liquids from the core outwards

○

Our drug can be pushed outwards due to this pressure, so chemotherapy is most effective around the outside of tumours

○

High interstitial pressure in tumours•

Perfusion is greatest on the outside of tumours where the growth is occuring, while it is lowest at the core of the tumour, which may be hypoxic and necrotic

○

Our drugs are delivered by the blood, so again, the surface of the tumour is more affected than the core

○

• Non-uniform perfusion

The membrane tends to keep bulky or polar substances from entering the cell, so it's hard for our drug to get in

○

○ To make matters worse, the membrane is studded with efflux transporters like P-gp which kicks out the drugs as soon as they enter

Cell membrane barriers•

Glutathione- contains a thiol group (-SH) which is very attractive for alkylating agents as it is also a good nucleophile. So our alkylating agents will attack glutathione instead of attacking the DNA

○

DNA repair enzymes- if the cell can repair the damage the drugs are causing, then it will be resistant to attack

○

Intracellular inactivation•

Enhanced permeability and retention effect

• Although the lack of a lymphatic system in tumours causes an increased pressure within tumours, this is also an advantage to usThe enhanced permeability and retention effect means our drug is able to enter the tumour easier, because the gaps between the tight junctions are wider (remember, these carriers tend to be quite big)

•

And since there's no lymphatic system, the drug can't be washed away due to lymphatic drainage, so it stays in the tumour for longer

•

Overall, this effect counteracts the increased pressure from the tumour•

Case 1: doxorubicin in PEGylated liposomes

• Normal liposomes use phosphodialcholine to create the phospholipid bilayer

Oncology

• Normal liposomes use phosphodialcholine to create the phospholipid bilayer seen in liposomesPEGylated liposomes will use a phospholipid with PEG (polyethylene glycol) polymer attached to the polar end of the phospholipid

•

What happens is the PEG will be on the outside of the liposome, surrounding it with this polymer

•

○ Low Cmax○ Low AUC○ High clearance○ Short half-life○ Large volume of distribution

• Normal liposomes will generally be ineffective, due to their poor pharmacokinetic variables

○ PEG prevents the cells from detecting and phagocytising the liposomes○ PEG prevents opsonisation, so it can't be picked up as a foreign component

• PEGylated liposomes have much better pharmacokinetic variables, as they are able to evade the reticuloenothelial system (macrophages and monocytes), which is what causes the poor performance of liposomal compounds

Case 2: Doxorubicin-polymer conjugates (PK1)

• Doxorubicin is attached to a polymer through an amino acid spacer

○ Too large to enter through normal tight junctions, but small enough to enter through the leaky tight junctions of the tumour

○ Allows some targeting, as normal cells won't be able to take up this conjugate easily

• The polymer makes the particle size very large

• Once the conjugate has reached the tumour, a tumour cell will take it up via pinocytosis ('cell drinking')

• Once it is inside the cell, the endosome (the vesicle formed from pinocytosis) will be fused with a lysosome

• The enzymes in the lysosome, together with the acidic environment of the endosome will cause cleavage of the amino spacer between the doxorubicin and polymer to be cleaved, releasing the free drug

• The free drug is now free to move around the cell and cause damage as required

Oncology

Intro/Glossary

CureRemoval of all cancerous cells from the body. Ideally, the patient will now have the same life expectancy as someone who doesn't have cancer.

RemissionReducing the cancer, even to below detectable levels. However, the cancer is not completely removed, and may return at any time.

Adjuvant chemotherapyAdditional therapy given with the main method of treatment. For example, adjuvant chemotherapy is chemotherapy given in addition to surgery (the main treatment). Adjuvant therapy may also include radiation as well. All this is done to decrease the chances of reoccurrence of cancer

Neo-adjuvant chemotherapyChemotherapy given BEFORE the main treatment, for example, chemotherapy may be carried out to reduce the size of a tumour before surgery, which can reduce the amount of tissue to cut, reduce the vasculature (that's a good thing, means you'd lose less blood during surgery) and make it shrink away from healthy tissue to save that tissue.NOTE: Remember, chemo is more effective on the outer edge of solid tumours, which causes the shrinkage.

Palliative chemotherapyBy this point, we know the cancer can't be cured, so chemo is given to reduce the tumour sizes to relieve symptoms. PLUS it can be used to extend life. Just remember, we can't cure them by this point, make them more comfortable and live a bit longer.

TMN staging systemT= size of the initial tumour, higher the number, bigger it isN= number of lymph nodes or extent of spread along lymph nodes, higher the number, it's spread more throughout the lymphatic systemM= indicates if it has metastasized, where 0 is no, 1 is yes.e.g. T2N1M0 means it's a medium sized tumour with little regional node infiltration and no distant metastasis.

Metastasis

Bone (leads to bone pain)•Liver (leads to jaundice)•Brain (leads to mental changes)•Lungs (leads to difficulties in breathing)•

Cancer cells are able to split off and travel around the body to for new tumours at different sites of the body. There are four main sites they will go to, leading to a common set of symptoms:

Disease templates

Breast cancer

The most common cancer in females. However, it does occur rarely in males. The disease is also more common in older people, which is common for cancers.

Workshop 1- Solid tumours

Oncology

Age•Family history•Race•BRCA1 and BRCA2 double strand DNA repair mechanism genes are faulty in a high number of cases. This mutation can be passed down, leading to some women developing breast cancer quite early in life

•

Early menarche (menstruating from a young age)○

Not having children○

Increased exposure to estrogen•

Pathophysiology is common to most cancers, where the genetic material of cancerous cells is damaged, leading to unregulated growth. However, there are some specific risk factors:

Solid, hard○

Irregular○

Non-tender○

Solitary○

90% of the time, a small painless lump can be felt•

10% of the time, stabbing or aching pain can occur•Sometimes, it can become tender, and a discharge can be seen•

Regular screening is recommended○

Mammograms and ultrasounds are used to detect them○

Very, very curable if picked up early•

Signs and symptoms:

See above for symptoms if the cancer is advanced.

See common treatment goals

Now days a partial removal (breast saving surgery) is recommended○

Mastectomy (removal of the breasts)•

Note: may be just as effective as mastectomy in some cases○

Radiation therapy (instead of surgery)•

Non-pharmacological treatments:

Pharmacological treatments (see 'Mechanisms of action' and 'side effects' below for details):

5-flurouracil○

Epirubicin○

Cyclophosphamide○

Adjuvant therapy with FEC is common:•

Notice how the above combo has two drugs which are not specific for any parts of the cell cycle, and 5-FU is specific for the S-phase. This makes them synergistic as the treatment will work regardless of what stage the cells are in.

•

Early stage- focus on cure

Paclitaxel○

Taxanes•

Therefore, avoid use.○

CAUTION: anthracyclines have cumulative cardiotoxicity. In other words, if you used Epirubicin during adjuvant therapy, you can't use it again or anything else in that family (like doxorubicin).

•

Late stage- focus on palliative care

Tamoxifen- a estrogen receptor antagonist. Normally, the estrogen Endocrine therapy only if the cancer carries estrogen receptors•

Misc

Oncology

Tamoxifen- a estrogen receptor antagonist. Normally, the estrogen stimulates the growth of the tumour.

○

Endocrine therapy only if the cancer carries estrogen receptors•

Trastuzumab AKA Herceptin is only good for HER-2 positive cancers only•

Long acting formulation + short acting for breakthrough pain

Also give laxatives to prevent constipation

Opioids like morphine are the gold standard○

Paracetamol can work○

NSAIDs can be useful for bone pain○

Bisphosphonate for bone pain○

Pain•

Ondansetron plus dexamethasone○

Lorazepam for anticipatory nausea due to anxiety○

Nausea•

Non-cancer

Prostate cancer

The most common cancer in males, again it is more common in older people. For obvious reasons, it cannot occur in females.

Age (old)•Race (African Americans are more affected)•Family history•

It has been linked to:

Generally little to no symptoms if locallised•Urgency and dribbling if it's starting to spread (the urethra passes through the prostate gland, so if it's starting to grow, it will block it, so you can't piss as easily)

•

Can result in back pain plus other generalised symptoms if advanced•

Symptoms are:

Only carry it out if symptoms are present, or if the person has a high risk○

PSA assay has a low diagnostic value, some people without cancer have increased PSA, while people with cancer can have a low PSA

•

Can confirm cases quite easily and quickly○

Digital Rectal Examination (DRE) has good diagnostic value, but people aren't very keen on having them.

•

Imaging allows points of interest to be mapped out and biopsied (with a needle) to check for cancerous cells, helps to grade the cancer.

○

Transrectal ultrasound•

Population wide screening is not implemented, but there are some ways to diagnose prostate cancer:

Gleason score should be taken, which is where the cancer cells are checked to see if they form glands (well differentiated cells) or not (undifferentiated cells). Undifferentiated cells will cause a worse prognosis.

Importantly, we need to know how hormones affect the tumour:

Oncology

Importantly, we need to know how hormones affect the tumour:

LH-RH (also known as GnRH or gonadotropin releasing hormone) will stimulate the pituitary gland to release LH (Lutenizing hormone) and FSH (follicular stimulating hormone)

•

LH and FSH will stimulate the testes to release testosterones which will stimulate the prostate to grow, making the cancer worse

•

We need to target this pathway for a specific treatment (see below)•

Surgery to remove the prostate is well recommended for a complete cure at early stages (this is the main treatment, and what we're aiming for)

•

It depends on what side effects the patient prefers○

However, radiation is just as effective (external beam therapy, where radiation is fired at the prostate)

•

Plus old people are not candidates for this treatment, need to use a pharmacological treatment

○

At later stages, surgery to remove the testes (orchidectomy) can be performed (not very popular though)

•

Or for some patients, it's better for their life if they just waited and watched the tumour carefully. This is because these people tend to be old, so it might not be worth dragging them through treatment to make the rest of their lives miserable.

•

Non pharmacological treatments:

GnRH agonist, will attempt to over-stimulate the pituitary gland, and cause the receptors to desensitise to reduce the downstream production of testosterone

○

Occurs because at the beginning of treatment, the GnRH receptors haven't desensitised, so there's a lot of testosterone being produced downstream

Causes 'tumour flare', which causes an increase in symptoms arising from the tumour, plus hot flushes, decreased impotence and tender breasts

○

Goserelin injections- depot of goserelin injected monthly•

Non-steroidal testosterone receptor antagonist○

Prevents testosterone from binding to the receptor, mainly to counteract the tumour flare effect

○

Causes the same side effects as goserelin, but can also cause bone loss (osteoporosis)

○

Flutamide tablets- given daily for a short period of time•

If non-responsive, need to focus on palliative care and maybe some other conventional chemotherapy drugs e.g. vincristine etc.

•

Pharmacological treatments (advanced cancers):

Oncology

Surgery is not an option, because it's metastasized○

Make sure the chemotherapy agent is compatible with the patient○

conventional chemotherapy drugs e.g. vincristine etc.

Colorectal cancer

Very common cancer overall in the population

Age is the main one (again)•Low fibre-high fat diet•Sedentary lifestyle•Hereditary (family history)•Inflammatory bowel conditions (especially Ulcerative colitus, Crohn's disease to a lesser extent)

•

Risk factors:

Changes in bowel motions (chronic constipation)•Weight loss•Abdominal pain and cramps•Malaena, tarry stools with blood•Bloating•

Signs and symptoms:

Most commonly, a barium enema can be used to check for growths•A colonoscopy may also be used•May be anemic, due to blood loss•A DRE can be used to rule out haemorrhoids as the cause of symptoms•

Diagnosis:

Remove the tumour and surrounding tissue to make sure to remove all the traces of cancer for a total cure

○

Colostomy will be performed just after the surgery, which is where one part of the bowel will be open to the outside world to allow food in. Later on, after the ends have healed, the GI tract is put back together.

○

Again, surgery is first line treatment for non-metastasized cancers, with adjuvant chemotherapy (FOLFOX)

•

Adjuvant therapy for local invasion of some tissues○

Radiation is more effective for rectal cancers○

Radiation is not as effective here•

Nutritional support to reverse weight loss•


Not for 'rescue use' as for methotrexate

Instead, it improves the action of 5-FU on thymidylate synthase

Folinic acid○

5-Flurouracil○

Oxaliplatin ○

FOLFOX (first line treatment):•

Capecitabine (prodrug of 5-FU) if not responsive or at late stage•

5-FU○

Folilic acid○

Topoisomerase inhibitor

SEVERE diarrhoea

Irinotecan (instead of Oxaliplatnin)○

FOLFIRI•

Bevacizumab is an antibody which prevents the angiogenesis of metastatic •

Pharmacological treatments:

Oncology

Good for late stage cancers○

Bevacizumab is an antibody which prevents the angiogenesis of metastatic growths, preventing them from growing

•

Common treatment goals

Generally speaking, at earlier stages of cancer, the tumour is small, encapsulated (i.e. cells are completely surrounded and cannot leave) and has not invaded any other tissues. Therefore, a complete cure is possible if the tumour is cut out, with some adjuvant chemotherapy to make sure there aren't any cancer cells left.

However, in later stages, palliative care is more important, trying to reduce the sizes of the tumour and distant metastasis. A multitude of drugs can be given, and surgery is less important because it wouldn’t achieve a cure.

Also, we have to weigh up between treating the cancer and preserving the life quality of the patient. For example, if the person is old and has advanced cancer, then it might not be worth giving them chemotherapy because it would severely reduce their life quality without much of an impact on the life expectancy. See prostate cancer for more examples.

Mechanisms of action

Specifically targets the S-phase of the cell cycle (because it stops DNA replication)

○

Pyridine analogue which gets incorporated into the growing DNA strand. Because it has a fluorine on the 5 position, it stops any more nucleotides from being added to the molecule, stopping synthesis of DNA.

○

Also blocks thymidylate synthase○

5-flurouracil•Antimetabolites

Prevents DNA and RNA from being made

G2 cell cycle specific○

Can trigger apoptosis

Intercalates between bases in DNA to inhibit topoisomerase II and stabilise topoisomerase II once the DNA has been cut

○

Cumulative Cardiotoxicity

WARNING: take care with people with ischemic heart disease

Also generates free radicals. However, this is not important to its action, but it results in some side effects

○

Doxyrubicin, epirubicin•Anthracyclines

Not cell cycle specific○

Can also lead to apoptosis

Binds to nucleophiles, the pyridine bases of DNA, causing alkylation, cross linking within or between strands of DNA

○

Causes haemorrhagic cystitis (bleeding in bladder)

Need to co-administer with Mesna and plenty if IV fluids to counter this

Side product, acrolein, is produced. It causes inflammation of the bladder○

Cyclophosphamide•Alkylating agents

Paclitaxel•Taxanes

Oncology

Anti-mitotic agent, inhibits microtubule formation by attaching to the actin subunit

○

Prevents the M phase (where they build microtubules to split the genetic material between nuclei)

○

Constiaption is common as a result

Strong peripheral neuropathy○

Paclitaxel•

Also prevents mitosis by inhibiting microtubule formation by attaching to the actin subunit

○

Attaches at a different site compared to taxanes○

Prevents the M phase○

Monitor symptoms

Can cause constipation due to reduced gastric motility

Extreme peripheral neuropathy○

Vincristine•Vinca alkaloids

Binds to DNA (crosslinking between strands)○

DNA becomes unusable○

Causes extreme peripheral neuropathy (monitor symptoms)○

Causes sensitivity to cold, avoid cold drinks/ice○

Consider amifostine administration to protect against nephrotoxicity, it contains thiol to prevent damage

○

Monitor renal as well

Increase fluids to prevent renal toxicity

MONITOR: peripheral neuropathy○

Oxaliplatin •Platins

Serotonin 5-HT3 receptor antagonist○

Antiemetic effect○

Ondansetron•

Glucocorticoid○

Enhances the effect of Ondansetron○

Dexamethasone•

Non-cancer agents

Side effects

General side effects and how to avoid them:

Fluid from infusion can seep out into surrounding tissues○

Incredibly dangerous as some drugs are vesicants (blistering agents)○

May be caused by poor circulation (due to incorrect line site, use a central line, which has good flow compared to a peripheral line)

○

Patients must be told to report discomfort or pain at the infusion site so it can be stopped and an antidote can be administered.

○

Extravasation (immediate effect)•

Caused when the drug is detected by the chemoreceptor zone in the brain, triggers nausea and vomiting

○

Ondensetron and Dexamethasone are commonly used○

Nausea and vomiting (immediate effect)•

Will also damage oral linings as well as the rest of the GI tract, leading to Mucositis and diarrhoea (delayed effect) •

Oncology

Will also damage oral linings as well as the rest of the GI tract, leading to diarrhoea

○

Occurs because the mucus membranes contain rapidly dividing cells, and they too are affected by treatment

○

Good oral health and nystatin (anti-fungal drug) are given to prevent oral issues, while loperamide (anti-diarrhoeal) will be given for GI symptoms.

○

Reduced white blood cells and platelets, leading to increased bleeding or susceptibility to infections

○

Again, the bone marrow contains rapidly dividing cells, leading to a shortage in these cells

○

Worst suppression occurs 7-14 days after infusion

Need to monitor blood cell counts weekly○

If neutrophils are very low, they must be put into isolation○

gCSF (granulocyte Colony-Stimulating Factor) can be given to stimulate white blood cells to grow

○

Sore throat

Pain on urination

Feeling pretty shit

Fever may be present

WARNING: must tell patients to look for symptoms of infection:○

Myelosuppression/neutropenia (delayed effect)•

Again due to hair follicles containing rapidly dividing cells○

Use a government subsidised wig or just buy a scarf○

Hair loss and alopecia (delayed effect)•

Specific side effects have been listed with the specific drug

Oncology

Intro

The last clinical workshop dealt with solid tumours. This workshop deals with tumours which do not form solid masses (as they are in the blood). These tumours are diffuse tumours.

Acute Lymphoblastic Leukaemia (ALL)

There shouldn't be any detectable in the blood○

Blast cells, which are immature cells of the circulatory system are present in large amounts in the blood

•

Therefore, most of the symptoms we encounter are from a lack of functioning blood cells (e.g. anaemia)

○

Due to the high volume of blast cells, normal haematopoiesis (production of blood cells) can't occur

•

B and T lymphocytes○

In ALL, a large amount of lymphocytes are being produced•

The most common age is 5 years old (best prognosis between 2-9)•

Pale, tired○

Also shows reduced haemoglobin in the blood○

Anaemia•

Due to thrombocytopenia (lack of platelets)○

Can also be seen as petechiae (purple spots on skin due to minor haemorrhage on the surface of the skin)

○

Easily bruised/ bleeds easily•

Enlarged lymph nodes, liver and spleen•Weight loss•

May have a cold as a result○

Even though number of white blood cells are increased in blood test results (because these cells are useless at fighting off infection)

○

Highly susceptible to infections•

Shouldn't be present in the blood○

Blood tests will also show blast cells in the blood•

May have Philidelphia chromosome (see below), which indicates a worse prognosis

•

Signs and symptoms

Treatments

Bulk of the cells will be killed off here○

Anti-gout medication□

Required to prevent tumour lysis syndrome, which is where cells release uric acid on death

□

Generally required for diffuse cancers due to the sheer number of cells being killed

□

Allopurinol

Vinca alkaloid□

Antimitotic drug□

Severe peripheral neuropathy (loss of feeling and constipation, □

Vincristine

Drugs are:○

Induction•Split into three phases:

Workshop 4- Diffuse tumours

Oncology

Severe peripheral neuropathy (loss of feeling and constipation, consider docusate)

□

Asparginine is an amino acid which can't be synthesized in lymphoblasts (but is produced everywhere else)

□

This enzyme will reduce the amount of circulating asparginine to retard the growth of the cancerous cells

□

Watch out for anaphylactic shock (reaction against enzymes) and hyperglycaemia

□

L-asparginase

Glucocorticoid which causes immunosuppression□

Although it doesn't kill many cells, it's given to stop any further growth

□

Can cause restlessness or increased aggression□

Prednisone

Administered intrathecally (into the spine)□

Anti-folate drug□

Used to destroy cancerous cells in the CNS, as the other drugs can't cross the BBB

□

Caution: may cause seizures, monitor carefully□

Methotrexate

Mixups are avoided as the pharmacist personally delivers the dose

□

The volume which can be delivered intrathcally is small (3-5ml) compared to 100s of ml for IV

□

Caution: do NOT get mixed up with vincristine, as intrathecal vincristine is fatal

Approximately 3 months after remission○

Can use the same drugs at a higher dose

Aggressive chemotherapy to prevent relapse○

Vincristine

Doxorubicin

Etoposide

Cytarabine

Etc.

Intrathecal methotrexate□

Prednisone□

Plus the usuals

Any drug can be used , cycle them as required○

Intensification•

May take up to 2-3 years to mop up any remaining cells○

Daily by mouth

Inhibits purine synthesis (required for DNA and RNA)

Be aware of mutations of TPMT, as they can cause overdose (myelosuppression) or underdose (therapeutic failure)

ALSO be aware of interaction with allopurinol, 6-MP is metabolised by xanathine oxidase, the same enzyme which is inhibited by allopurinol to prevent gout

6-Mercaptopurine○

Weekly by mouth

Check to see if prescription is for weekly dosage

Methotrexate○

Rescue mechanism to reduce side effects from methotrexate

Saves normal cells, while cancerous cells can't be salvaged as they are too damaged

Folinic acid○

Maintenance•

Oncology

are too damagedContrast with FOLFOX, where it's used to increase the effectiveness of 5-flurouracil

Chronic Myeloid Leukaemia (CML)

To contrast with the above, CML has the non-lymphocyte cells going crazy•

Chronic phase- little/no symptoms○

Accelerated phase- symptoms start appearing, and blood tests will reveal some blasts (10% of cells)

○

Blast phase- late stage of the disease, a high number of cells are blast cells (30%). Low survival rates

○

Has three phases•

Half of the people with this disease are asymptomatic (in the chronic phase)•Fatigue•Fever•Weight loss•Bleeding•GI discomfort and cramps•

Increased platelets○

Blasts○

Anaemia○

Hugely increased granulocytes (neurophils, basophils and eosinophils)○

Blood tests•

9-22 chromosomes swap around parts (translocation)○

Good for diagnosing○

A bone marrow biopsy will show cells with the Philadelphia chromosome•

Signs and symptoms

Interferon alfa 2b○

Effective in control○

Daily interferon injections•

Thought to be an antimetabolite○

Ribonucleotide reductase inhibitor○

Hydroxyurea•

Tyrosine kinase inhibitor (stops signalling for growth)○

Very effective for maintaining relapse○

May cause myelosuppression, as inhibiting tyrosine kinase prevent growth in other cells

○

Metabolised by CYP3A4○

Can cause flu-like symptoms, nephrotoxicity, hepatotoxicity and cardiovascular effects (hypertension)

○

Imatinib•

Matched donor is required (hard to find)○

Used as a cure (chemo alone can't cure it)○

Bone marrow transplant•

Treatments

Non-Hodgkin's Lymphoma (NHL)

A bunch of cancers of lymphocytes which isn't Hodgkin's lymphoma•So there's a lot of diseases which can fall under this category•

e.g. large B cells with CD20○

Therefore, we can at least say what type of cells are being produced•

Treatments

Oncology

Need to find a suitable donor○

Host can't be too old or weak, otherwise would not survive the treatment○

Bone marrow transplant•

Cyclophosphamide○

Doxorubicin○

Constipation, give docusate prophylactically

Vincristine○

MONITOR: bone density in old women in case of osteoporosis

MONITOR: blood glucose, as it may cause hyperglycaemia

Prednisone○

Mouse monoclonal antibody against CD20+ cells

Infusion reactions (fevers, chills, rash) on the first few times

Give IV antihistamine and paracetamol

Rituximab○

rCHOP•

Prevent tumour lysis syndrome○

Allopurinol•

As always, monitor blood counts for myelosuppression and see if blast cells and B cells decrease over time

•

Treatments

Oncology

Opioids

Works at the opioid receptors in the body•Intention is to treat pain•Pain is a big part of cancer and palliative care•

Formulations of morphine

There are several formulations of morphine available, each with their advantages and disadvantages:

Advantages Disadvantages

Oral liquid Easy to titrate dose (any amount of morphine can be given)

•

Easy to swallow•Good for breakthrough pain•

Tastes bitter•Volumes may be excessive (can fix this)

•

Not very portable, difficult to measure while out.

•

Lower compliance, q4-6h dosing

•

Immediate release tablets

Easy to carry and take, no need to measure.

•

Good for breakthrough pain•

Hard to adjust and titrate doses due to fixed doses

•

Lower compliance, q4-6h dosing

•

Delayed release tablets/pellets in capsule

Good compliance due to q12h dosing

•

Portable and no need to measure anything

•

Good for low grade, consistent pain

•

Crushed tablets will lose their properties, not suitable for people with trouble swallowing.

•

However, capsule granules can be dispersed

•

IM injection Fast absorption•Provides alternative route from oral route

•Not suitable for palliative care, patients tend not to have much muscle to inject into

•

Local reactions possible•Specialist required•

SC infusion Fast absorption•Provides alternative route from oral route

•Potentially painful•Specialist nurses are required to maintain the pump

•

Local reactions possible•

Suppositories Alternative route from the oral route

•

No specialist care required, self-insertion is possible

•

Recommended for people who aren't ready for a pump

•

Some people aren't keen•

Pharmacokinetics of morphine

Metabolism

Initially, people thought these were inactive

Morphine will be glucuronidated to morphine-6-glucuronide (M-6-G) or M-3-G in the liver

•

Workshops 3 and 7- Morphine and palliative care

Oncology

Initially, people thought these were inactive○

But it turns out M-6-G is quite potent and it's slightly selective for the mu1 receptors (associated with analgesia)

○

The way morphine is dosed, M-6-G accumulates over time, which tends to be associated with analgesia and some of the adverse effects (such as drowsiness) to appear if taken for long periods of time.

•

This is due to enterohepatic recycling, where the bacteria will strip the glucose off (the glucuronide bit) which yields the original morphine, which can then be absorbed again

○

Glucuronides tend to stay for long periods of time in the body•

Routes of administration

Removed quickly

Fastest mean residence time (MRT) and half life○

Fastest absorption○

Highest Cmax○

Intravenous•

High bioavailability

Very comparable to IV admin in terms of perimeters○

We prefer to use this route for morphine administration because the IV is usually in use

○

Subcutaneous•

Much slower compared to IV and SC○

But it will lead to enterohepatic recycling, as the liver will be able to metabolise the morphine before it reaches systemic circulation

○

Par orally•

Pretty much useless for systemic effects○

Might be good for local effects (chest pain)○

Nebulised•

We examined four different routes for M-6-G:

Palliative care principles

Firstly, palliative care is looking after people to relieve them of their suffering due to their disease (i.e. improve their quality of life)

•

This means the treatments used in palliative care shouldn't affect the length of survival for the patient, just need to focus on making them feel better

•

Palliative care focuses on more than just health, need to think about things like spirituality, especially because people start to think a lot more as they are going

•

Oncology

spirituality, especially because people start to think a lot more as they are going out.

Doctors○

Nurses (managing the pumps etc)○

Family members (part of the grieving process)○

Social workers (supports the family and the sick person)○

Ministers/Chaplains (for spirituality if required)○

Give advice on how to use the medications

Tell them what adverse effects to expect and watch out for

Can recommend different drugs which may have a reduced side effect profile

Check for interactions between medications (important for morphine pumps)

And pharmacists○

Who is involved in palliative care?•

Morphine and dosing

Note: liquid morphine elixir comes in many strengths, give them a strength which will be big enough to measure accurately, but small enough to be easily swallowed. About 5ml should be good.

○

Note 2: Ask the doctor to give you a specific mitte, even though it's prn. Why? Because if we supplied the maximum prn amount, it tends to be very excessive.

○

Initial dosing can be carried out using oral morphine liquid. Patients will be told to take the morphine as required for a week

•

e.g. if they used 60mg daily on average, then that can be split into 2 doses of 30mg every 12 hours

○

From the use over the week, the doctor can determine a suitable sustained morphine dose

•

Then the doctor will write up a prescription for the slow release tablets/capsules while giving them the oral morphine for breakthrough pain

•

They should also record how much of the extra oral morphine they are taking, just in case they need to make modifications to the dose.

•

Major adverse effect: They will experience drowsiness, nausea and vomiting for the first few days. This will subside after a few days. If it doesn't contact the doctor.

•

Senna (stimulant laxative) and docusate (stool softener) tablets are very effective. They should be taken at night, and they tend to work overnight.

○

Constipation is the other major adverse effect•

Handy for the patient, as the nurse just needs to keep it running for them○

Multiple medications can be given in 1 syringe (but we need to check for compatibility between the drugs)

○

Lastly, if the oral route is not available (either difficulty in swallowing or due to vomiting), then a subcutaneous pump can be used

•

Oncology

Chemotherapy

As we all know, chemo has some seriously nasty side effects•For palliative care, we need to try and reduce these side effects•

Give lubricating eye drops (PVP or cellulose based) to use while the patient is awake

•

Longer lasting, but it occludes vision○

Perfect qualities to have overnight○

Give ointment when asleep•

Dry eyes

CAUTION: Some treatments (e.g. platnins) will cause cold extremities. Do not recommend ice chips.

○

Suck on ice chips or chew on gum to keep the mouth moist•

Artificial saliva can be given (but patients might not like it, tastes and feels bad)•Pilocarpine mouthwash can be prescribed, which will stimulate saliva (it works on the parasympathetic system)

•

Visit dentist regularly○

Practice good oral health/hygiene○

Will lead to dental carried and ulcers if the mouth is kept dry (the saliva has a protective function)

•

Dry mouth

Prokinetic antiemetic (gets stuff out of the stomach quickly to prevent vomiting)

○

Not recommended for use with loperamide, because that slows down the GI tract

○

Watch out for extrapyrimidal effects (Parkinson's like tremors)○

Metoclopramide•

Antihistamine○

Cyclizine•

5-HT receptor antagonist○

Ondansetron•

Corticosteroid○

Take care in elderly women due to osteroporosis○

However, very effective, especially when given with ondensetron○

Dethamexasone•

Nausea and vomiting

2statrun8○

2 immediately, 1-2 capsules after each loose bowel motion and to a maximum of 8 daily

○

Side effect: constipation○

Loperamide is the drug of choice•

But associated with some side effects○

Diphenoxylate and atropine (diastop) can also be used•

Diarrhoea

Constipation

Refer to previous year

Workshop 7- Palliative care and chemotherapy

Oncology

Introduction

i.e. HIV will eventually give someone AIDS, we want to prolong the time this takes, or prevent the symptoms of AIDS by controlling the HIV virus

○

Antiretroviral drugs are used to counter the HIV virus, which in turn prevents AIDS from precipitating

•

Co-receptor antagonists

Fusion inhibitors

Entry inhibitors○

Nucleoside reverse transcriptase inhibitors (NRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Reverse transcriptase inhibitors○

Integrase inhibitors○

Protease inhibitors (PI)○

There are four therapeutic classes:•

HIV virus

The HIV virus belongs to the lentivirus genus (where lente means slow), which is within the family of retroviruses

•

Retroviruses carry RNA which is transcribed into DNA through the action of Reverse transcriptase

•

gp120 is present on the surface of HIV to allow them to bind to these receptors

○

HIV viruses attack T cells of the body by attaching to either the CXCR4 or CCR5 co-receptors present on the surface of T cells

•

Once bound to the co-receptor, the virus fuses with the membrane, allowing its genome to enter the cell

•

Once the genome has been converted to DNA, it may be incorporated into the host's genome through the action of intergrase

•

Viral proteases will break down this large protein, it is also another drug target

○

The DNA can then be transcribed to form RNA for new viruses, along with a large protein, which is broken down into smaller proteins which are used to build new viruses

•

Pharmacology of antiretroviral drugs

Oncology

Entry inhibitors

Maraviroc is the first drug which has been approved

Antagonist at the CCR5 receptor, stops gp120 interacting with CCR5

Used if the patient has treatment resistant HIV

Prevent binding to the co-receptors○

A transmembrane glycoprotein (gp41) is involved in fusion between the viruses' membrane and the T cell membrane

Once activated, they undergo a conformational change, which allows fusion

A drug may be used to prevent the conformational change to prevent fusion

T-20 is made of 36 amino acids which makes up gp41, it can enter into gp41 to prevent a conformational change

Prevent fusion○

There are two pathways available to prevent the entry of HIV viruses into cells:•

Overall: this class isn't used much•

Reverse transcriptase inhibitors (RTIs)

This is the main class of antiretroviral drugs used•

This function isn't needed in humans○

Broad therapeutic index (low toxicity against host)

Therefore, this protein is virus specific, which is a good drug target○

Reminder: reverse transcriptase is used to transcribe RNA into DNA•

Because they resemble nucleosides, they will bind to the active site

Therefore, they are competitive inhibitors

Nucleoside RTIs (NRTIs)○

They do not resemble nucleosides, they won't bind to the active site (i.e. allosteric binding)

Therefore, they are non-competitive inhibitors

Non-nucleoside RTIs (NNRTIs)○

There are two classes•

NRTIs

Tenofivir is an exception, it already has one phosphate group, which makes it a nucleotide. It needs to be hydrolysed into the nucleoside form so it can be built back up into the nucleotide form

The drugs are nucleosides, they must be built up into nucleotides○

Note: Schmerer would say these aren't prodrugs due to this anabolic process, but who's keeping count?

○

Anyway, the nucleosides are built up into nucleotides via the addition of phosphate groups.

○

There are three phosphate groups in nucleotides, but none on nucleosides○

They are prodrugs•

Zidovudine is the first NRTI available•

This stopped the elongation of the DNA as it was being transcribed (this process is called chain termination)

○

The 3-OH position is important as it allows binding to the next nucleotide to lengthen the DNA

○

Otherwise, zidovudine is identical to thymidine (mimics the DNA base, which is the top ring, and the ribose sugar, which is the bottom ring)

○

The 3-OH present in thymidine was replaced in zidovudine•

Oncology

As stated above, mimicking either the ribose ring or the DNA base is important for the activity of the drug

•

NNRTIs

These allosteric binding sites tend to develop resistance easier○

Might be due to the fact that changing the active site can lead to reduced activity, while changing an allosteric site might not have an effect on the activity of the enzyme. Therefore, there's reduced selection pressure against these mutations.

○

Reminder: binds to an allosteric site to cause a conformational change, instead of binding directly to the active site

•

H-bond acceptors in the middle○

Aromatic ring on the right○

Hydrophobic on the left○

The SAR is quite complicated•

Integrase inhibitors

Reminder: Integration is where RNA is transcribed into DNA and inserted into the host genome

•

This integration process is vital to the replication of the virus•

Strips a nucleotide from the viral DNA○

Covalently links these ends to cellular DNA○

The enzyme responsible is intergrase, and it has two functions:•

Prevents the DNA from being linked to the host DNA○

Thought to have worked by linking to a magnesium ion at the active site○

This is not true, but it still works○

Not a first-line drug, but is useful for people with resistance○

Raltegravir is the first approved drug•

Oncology

Protease inhibitors

Other major class used•Reminder: cuts up a large immature protein into smaller ones which can be used to assemble the virus

•

By tricking the protease into accepting it as a substrate, the protease is unable to hydrolyse the normal substrate

○

Protease inhibitors work by mimicking the peptide link which needs to be hydrolysed

•

In fact, it doesn't have a peptide bond, so it can't be hydrolysed○

The inhibitor has a different group so it cannot be hydrolysed (see below)•

Resistance is possible again, need to give it in combination with other drugs•

Oncology

Introduction

This workshop deals with HIV and infections in immunocompromisd patients

HIV and AIDS

Initial infection- Flu-like symptoms, with no symptoms at the genitalia○

Latent phase- Viral counts drop, CD4+ cell count is adequate○

AIDS- Eventually, T cells are depleted, preventing the host from mounting an effective response against any pathogens

○

HIV infection involves HIV viruses infiltrating CD4+ cells (which includes T cells), and there are three stages of infection:

•Definition and pathophysiology

Pneumocystitis jervocii pneumonia (PJP), mycobacterium avians, candida in the oesophagus, recurring herpes

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Patient will present with an atypical infection or an AIDS defining illness•

Uses antibodies to form a specific essay to detect viral components○

One set of antibodies in the ELISA well will bind to any components in the plasma

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But these set of antibodies are special, they are bound to an enzyme which converts a colourless substance to a coloured substance to indicate the presence of a protein

After washing out the wells, another set of antibodies will be added, which again binds to the components

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ELISA•

Run viral components with gel electrophoresis and then use an antibody probe to detect specific viral components. Detection of at least two components are needed

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Western Blot•

Note: antibodies take some time to be produced, once seroconversion has occurred, it's too late to cure.

○

Antibodies•

Not used for diagnosis, but good for determining viral levels in the blood○

PCR•

Diagnosis

'Acceptable counts' will vary, can be as high as 500counts/ml○

Starting too early will just expose the person to too many side effects○

Do not start treatment immediately if CD4+ counts are acceptable•

However, start treatment immediately if counts are low (about 200-300/ml) or if the patient presents with an AIDS defining illness

•

We use the new British guidelines, where we ideally pick one drug from each column (A, B and C):

•

Treatment

Regimen A B C

Preferred Efavirenz (n), D Tenofovir (N), B3Abacavir (N), B3

Lamivudine (N), B3Emtricitabine (N), B1

Alternative Lopinavir/r (P)Fosamprenavir/r (P)Atazanavir/r (P)Saquinavir/r (P)

Didanosine (N), B2Zidovudine (N), B3

Workshop 8- Infections in the immunocompromised

Oncology

N = NRTI○

n= nNRTI○

P= PI○

It's classified as B3

Ritonavir (indicated as /r) is a booster. Although it is a PI, it's main action is to inhibit CYP3A4 enzymes to increase the concentration of the other agents

○

If we follow these guidelines, the patient will get 2 NRTIs (B and C)and either a NNRTI or PI (which is similar to older treatments, shown in A)

•

Simple to take, good efficacy and high compliance.○

Atripla is a combination of Efavirenz, tenofovir and emtracitabine in one capsule. This is the recommended treatment in naïve patients with no resistances

•

But remember: a healthcare team would have to weigh up the risks and benefits. None of these drugs are classified as X by the TGA

○

Note: for pregnancy, it appears Atazanavir (not boosted), Didanosine and Emtricitabine combination seems to be the safest, due to their B2 and above classifications.

•

Saquinavir/r (P)

Specific groups Nevirapine (n), B3Atazanavir (P), B2

Drugs

Anemia can be linked to lactic acidosis, monitor bloods

Lactic acidosis○

Take LFTs at baseline and only take LFTs again if symptoms occur. There is no point of constant monitoring

Liver and pancreas toxicities○

Nausea and vomiting○

Headaches○

Don't forget LFTs

MONITOR blood count every 3 weeks for 3 months, then monthly after that○

General effects:•

Specific effect: Efavirenz- vivid dreams•

NRTIs

May develop into Stevens-Johnson (SJ) syndrome, which is an autoimmune disease where the epidermis separates from the dermis

Rash○

Efavirenz is classified as D

Teratogenic○

General effects:•nNRTIs

Strong inhibition of CYP3A4 (major source of interactions)○

Not only does it worsen blood lipids, it also causes fat redistribution in the body, which is unslightly

Dyslipidemia (very bad for people with CVS disease)○

GI symptoms○

General effects:•

Requires an acidic stomach for absorption, contraindicated with omeprazole and other anti-acid medications

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Otherwise, if they don't need a PI, then switch them off PI and use

The unboosted form is the best choice for people with CV disease (and a PI is essential for them), as it causes the least effect on lipids

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Atazanavir has special extras:•

Protease inhibitors

Oncology

Otherwise, if they don't need a PI, then switch them off PI and use nNRTIs because that allows patients to use statins (CYP3A4 metabolised)

Note: if statins are used with PIs, it's a very bad idea. The statins won't be metabolised properly, so they accumulate and cause rhabdomylosis.

Nevirapine needs to be restricted to patients who have less than 250 (females) or 400 (males) CD4+ counts/ml due to a risk of jaundice.

•

Low compliance leads to higher viral copies which strongly encourages resistance to form

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Compliance tends to drop off over time. If patients are starting to slip on compliance, they may go on a 'drug holiday' for a short time. It's much better to have a window of non-compliance compared to a long period of non-compliance.

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Very important to maintain compliance•

Normally, weight loss is common, and low weight is attributed to poor outcomes

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However, for patients on PIs, they need to be careful with lipid intake due to dyslipidemia caused by the PI.

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Nutrition is an important part of therapy•

Needle sharing should be curbed via a national needle exchange program○

Explain the need for safe sex○

Prevention of viral spread is important•


Infections

The following infections occur commonly in the immunocompromised (HIV/AIDS patients or chemotherapy patients)

CD4+/ml Infection

‘Low’ (but higher than above)

Herpes simplex, cytomegalovirus, Karposis scarcoma, candidiasis

200 PJP (PCP)

100 toxoplasmosis

50 Mycobacterium avian

Pneumocystis jiroveci pneumonia (PJP, formerly PCP)

Pneumocystis is a fungus!•

Diffuse nodes in the lungs○

Due to granuloma formation○

Has a distinct X-ray pattern of the lungs•

Can be cultured to confirm diagnosis○

Thick and fluffy sputum produced•

Diagnosis

Lack of oxygen due to fungi in the lungs○

Shortness of breath and cyanosis (looking blue around the lips)•

Thick and fluffy sputum leads to a dry cough•Fever•

Symptoms

Oncology

Fever•Feeling unwell•

It works on fungi… not just an antibacterial agent○

However, it has strong emetic properties. Consider giving metoclopramide or cyclizine or ondesantron for antiemesis

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Need to commence prophylactic treatment at lower doses

Important: if the patient's CD4+ levels are below 200 counts/ml they are at risk of contracting PJP again.

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High dose cotrimoxazole •

Another sulfa drug○

Also suitable for prophylactic treatment○

Second line: dapsone•

Prednisone○

Inflammation in the lungs are also preventing normal air exchange, need to reduce inflammation

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Give treatment for 21 days○

Corticosteroids are important•

Monitor treatment for symptomatic improvement•Then repeat chest X-ray 3 weeks later to check•

Treatment

Likes to cause CNS infections○

Cryptococcus neformans•

Aspergillus•Candida•

Other possible infections:

Febrile neutropenia

This is when the neutrophillic count is at the lowest point○

Caused after about 5-6 days after a course of chemotherapy•

Note: not all cases of neutropenia have a fever, because the neutrophils are involved in releasing pyrogens. If they're gone, then there won't be as much pyrogens around to cause a fever

○

Fever (hence the 'febrile' bit)•

CHECK the infusion sites, they may have become infected•

Pharynx, mouth, chest and perianal area○

CHECK for mucositis (another common site of infection)•

Fast pulse•Fast respiratory rate•Low blood pressure (shock)•Low platelets•Low haemoglobin•

Symptoms and signs

Duration of neutropenia•Extent/severity of neutropenia•Age (older=worse off because of reduced immune function)•

An important one is leukaemia (AML to be exact), as leukaemia will affect neutrophil production

○

Co-morbidities•

Factors affecting prognosis

Empirical IV treatment STAT•Treatment

Oncology

pepericillin (broad spectrum penicillin) and tazobactin (beta lactamase inhibitor).

Tazocin○

It's an aminoglycoside, TDM (Therapeutic drug monitoring) is needed

If serious, also give Tobramycin○

If allergic to beta lactams, use vancomycin or tobramycin○

Empirical IV treatment STAT•

Switch to oral antibiotics once stable○

Give IV antibiotics for 7-10 days or until stable•

Histamine release, give IV antihistamine and paracetamol

Red man syndrome- turns red if infusion is too fast○

Side effect to watch for:•

Serum creatinine (nephrotoxicity)○

TDM as required○

MONITOR:•

Voriconazole is very bioavailable○

IV or oral voriconazole•

Use liposomal forms, less nephrotoxic○

IV liposomal amphotericin B is second line•

Causative agent is usually Candida or aspergillus•

If no improvement, it suggests fungal infection:

Granulocyte colony stimulating factor (GCSF) is funded for people who have been affected by febrile neutropenia

•

Isolation is not necessary, as the infective organisms tend to be commensals (i.e. comes from the person instead of from someone or somewhere else)

•

Ciprofloxacin prophylactic treatment can be considered due to its broad spectrum activity

•

But the most important measure is hygiene, hand washing is important.•

For prevention:

Oncology

Oncology v0.1

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