Pharmacogenetics 10/11/22

Question 1

What is personalised medicine?

Answer 1

The use of genetic information to refine diagnoses, individualise treatments, prevent adverse drug effects, manage epidemics and develop new therapies.

Question 2

What is stratified medicine?

Answer 2

Patients are grouped by disease subtypes, demographics, clinical features, and biomarkers to make their drugs slightly more personalised, however, it is still slightly general.

Question 3

What are the different drug responses people can have to a general drug?

Answer 3

-Drug not toxic and beneficial
-Drug toxic but not beneficial
-Drug not toxic and not beneficial
-Drug toxic but beneficial

Question 4

What different factors can affect someone’s response to a drug?

Answer 4

-Age
-Gender
-Family history
-Genetics
-Commodities
-Taking other drugs
-Weight
-Height
-Environments
-Habits
-Lifestyle (alcohol, smoke, drugs)

Question 5

What is pharmacogenetics/pharmacogenomics?

Answer 5

The study of variations in drug response due to genetic makeup. Using genetics to help get an individual on to the right drug, at the right dose, at the right time.

Question 6

What is pharmacokinetics?

Answer 6

The study of the absorption, distribution, metabolism, and excretion of drugs.

Question 7

What is pharmacodynamics?

Answer 7

The study of the biochemical, physiologic, and molecular effects of drugs on the body, primarily receptor binding, post-receptor effects, and chemical interactions.

Question 8

How are fava beans an example of genetic differences?

Answer 8

G6PD is located on the X chromosome. G6PD is important in protecting red blood cells against oxidative damage. When people with a G6PD deficiency eat fava beans, which increases oxidative stress, they cannot deal with this and therefore develop acute haemolytic anaemia. This means some people can eat fava beans with no issue and some cannot.

Question 9

How is malaria an example of genetic differences?

Answer 9

People with a G6PD deficiency have some natural protection against malaria because G6PD deficiency leads to more oxidative stress as ROS (radical oxygen species) is not removed enough and this gives some natural immunity to malaria as malaria does not work well with ROS. This means When people get malaria, and they are treated with antimalaria drugs this further increases ROS and causes a build-up of it. This can cause Heinz bodies and haemolysis which can be life threatening. Therefore, before being treated with antimalaria drugs people must be genetic screened for the deficiency.

Question 10

What is a Heinz body?

Answer 10

Heinz bodies are indicative of oxidative injury to the erythrocyte. They are clumps of irreversibly denatured haemoglobin attached to the erythrocyte cell membrane.

Question 11

What is the declaration of Helsinki?

Answer 11

*All research including human subjects should be of high quality.
* The potential benefits to the participant or general population should be greater than the potential harm from the research.
* Researchers should obtain documented informed consent from the participant or their guardian.
* Researchers should protect the confidentiality of the participant and research data.
* Study participants are allowed to withdraw from the study at any time, without this action adversely affecting their care.

Question 12

What are the different treatment options for people with cystic fibrosis?

Answer 12

Ivacaftor - targets G551D carriers and enhances channel activity
Ivacaftor/lumacaftor - targets F508del homozygote and enhances channel activity and chaperones CFTR to cell surface
Ivacaftor/tezacaftor/elexacaftor - targets F508del carrier and minimal function variant/unresponsive to Orkambi. Enhances channel activity and increases CFTR on cell surface.

Question 13

Why are there different types of drugs for people with cystic fibrosis?

Answer 13

Cystic fibrosis has different root causes based on the individual’s genetics and classification. If this specific genetic root cause can be targeted, it then the results will be better.

Question 14

How is hearing loss caused in cystic fibrosis?

Answer 14

Aminoglycosides antibiotics are commonly used in cystic fibrosis patients to treat Pseudomonas
aeruginosa respiratory infections. Aminoglycoside-induced hearing loss may occur in 1%-15% of patients with cystic fibrosis, ranging from mild to severe. A mitochondrial DNA A1555G point mutation in the 12S ribosomal RNA gene is associated with non-syndromic deafness and increased susceptibility to aminoglycoside-induced hearing loss.

Question 15

What is wrong with the CFTR in cystic fibrosis?

Answer 15

CFTR is a member of the ATP-Binding Cassette (ABC) transporter family that functions as a gated chloride channel located in the mucus membranes. Defects in this channel result in the mucus having less osmotic potential and so thicker.

Question 16

What are the traditional treatments of cystic fibrosis and is one treatment enough?

Answer 16

Medicines for lung problems:
* antibiotics to prevent and treat chest infections
* mucus thinner
* bronchodilators
* steroid medicine
Exercise
Airway clearance techniques
Dietary and nutritional advice
Lung transplants

There may be several different treatments used such as a handful of the traditional treatments such as exercise, diet, and airway clearance techniques and some more modern one such as a personalised medication.

Question 17

What drugs have been shown to be highly effective in lung cancer?

Answer 17

Around 13% of non-small cell lung cancers have an activating mutation (gain of function mutation) in the epidermal growth factor receptor (EGFR). These mutations result in the activation of EGFR in the absence of EGF. Cell proliferation, angiogenesis and metastasis. Drugs designed to inhibit the EGFR tyrosine kinase domain can be highly effective in these tumours, e.g., gefitinib and erlotinib.

Question 18

What is neonatal diabetes?

Answer 18

The KATP channel plays an important role in insulin secretion. The most common cause of permanent neonatal diabetes is activating mutations in KCNJ11 and ABCC8.

Question 19

What is maturity onset diabetes of the young (MODY)?

Answer 19

Changes in the transcription factor HNF1A gene cause diabetes by lowering the amount of insulin that is produced by the pancreas. HNF1A is the commonest cause of monogenic diabetes in the UK and accounts for ~50% of cases.

Question 20

What medication is available for neonatal diabetes?

Answer 20

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Question 21

How does metabolism of drugs differ in people?

Answer 21

People can metabolise drugs differently, either normally, poorly, or quickly. In poor metabolism the drug can accumulate to toxic levels, in normal metabolism the drug reaches a steady-state levels within the therapeutic range, and the quick metabolisers fails to maintain serum levels within the therapeutic range, so they are not getting any benefit from the drug.

Question 22

What biomarkers can be used to help see how someone reacts to a drug?

Answer 22

P-go is a biomarker in several different organs such as the liver canalicular, the brain-blood barrier, the intestinal luminal apical, and the kidney basolateral. ABCB1, also known as P-glycoprotein, is an ATP-binding cassette (ABC) transporter expressed at several blood–organ barriers, where it extrudes a wide spectrum of xenobiotic compounds outside the cell, thereby protecting tissues from toxic substances. This can be used to see how someone reacts to a drug as it can show if there is drug resistance and a low bioavailability of drugs by pumping a variety of drugs out of cells at the expense of ATP hydrolysis.

Question 23

What is an example of phase I drug metabolism?

Answer 23

Hydroxylation - typical hydroxylation reactions are carried out by the cytochrome P450
enzymes and result in a more polar hydrophilic molecule.

Question 24

What is an example of phase II drug metabolism?

Answer 24

Conjugation - typical phase II reactions result in larger more soluble molecule.

Question 25

What happens in people with varying levels of CYP2D6?

Answer 25

The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs. In those with little CYP2D6 they will struggle to metabolise some drugs, and this can result in toxicity and the drug not being effective. How much CYP2D6 someone has depends on genetics and varies a lot between individuals.

Question 26

What is Isoniazid?

Answer 26

First medication for the treatment and prevention of tuberculosis. The most prevalent cause of drug-induced hepatotoxicity (DILI), which occurs in 10-36% of patients and is potentially fatal. Inactivated by N-acetyltransferase in the liver. Genetic variation results in rapid and slow metabolisers. Slow metabolisers are at greater risk of side effects.

Question 27

What is Irinotecan?

Answer 27

A topoisomerase I inhibitor, which is important in the cell cycle, is widely used in the treatment of cancer. Genetic variation results in rapid and slow metabolisers. Slow metabolisers for UGT1A1 are at
greater risk of side effects.

Question 28

What are some drug examples of CYP2D6 metabolized drugs?

Answer 28

• β-Blockers: metoprolol an carvedilol
• Antihypertensive drug: debrisoquine
• Antidepressants: fluoxetine and imipramine
• Antipsychotics: thioridazine and haloperidol
• Anti-cancer drug: tamoxifen
• Painkillers: codeine

Question 29

How is morphine formation different in different people?

Answer 29

Ultra-rapid metabolizer - they have an activity score of >2.0 and increased enzyme activity. They have more than two copies of functional alleles and this results in increased formation of morphine following codeine administration and increased risk of adverse events.

Extensive metabolizer - they have an activity score of 1.0-2.0* and normal enzyme activity. They have two functional alleles, or two reduced functions alleles, or one functional allele and one reduced or
non-functional allele. Normal morphine formation.

Intermediate metabolizer - they have an activity score of 0.5* and intermediate enzyme activity.
They have one reduced function allele and one non-functional allele. Reduced morphine formation.

Poor metabolizer - they have an activity score of 0 and low or absent enzyme activity. Two non-functional alleles. Greatly reduced morphine formation and risk of insufficient pain relief.

Question 30

What is warfarin?

Answer 30

Warfarin inhibits blood clotting. It is prescribed for conditions including stroke, deep vein thrombosis, pulmonary embolism, thrombophilia and increased risk of blood clots following surgery. It is the most commonly prescribed anticoagulant in the UK. Relatively small therapeutic window

Question 31

How does warfarin work?

Answer 31

Vitamin K produced by the body helps form the blood clotting proteins. The blood clotting proteins hold blood cells together to form clots. Warfarin reduces the body’s ability to make vitamin K which interferes with protein creation. Lower levels of clotting protein make blood cells less likely to clot. VKORC1 is responsible for the conversion of vitamin K epoxide to vitamin K, which is the rate-limiting step in the physiological process of vitamin K recycling.

Question 32

What can happen in warfarin dosage when someone has a stroke?

Answer 32

Warfarin is the most common prescribed anticoagulant in the UK, and it has a narrow therapeutic window, so getting the right dose is very important. If someone is prescribed warfarin in the hospital after a stroke and while they’re eating hospital food, then their dosage may be different then when they get home and start eating healthy food. This can cause a problem.

Question 33

What is cytochrome P450?

Answer 33

Cytochrome P450s (P450s) are heme-containing DMEs with oxidase activity and are found at highest concentrations in the liver. This enzyme superfamily is responsible for the biotransformation of endogenous compounds, pharmacological agents, and environmental xenobiotics (Nelson et al., 1993).

Question 34

What foods can impact cytochrome P450 activity?

Answer 34

Grapefruit inhibits CYP3A4
St John’s Wort (flower) induces CYP3A4
Broccoli induces CYP1A2

Question 35

What are the pros and cons of personalised medicine in the NHS?

Answer 35

Pros:
-Improved response rates
-Decreased prescribing to those who won’t benefit
-Reduced side effects
-More specific diagnosis and prognosis can lead to more accurate forecasting on healthcare resources requirements

Cons:
-More testing required before prescribing
-Specialist drugs suitable for only a subgroup of patients
-New technology still expensive
-Staff education

Question 36

What are the pros and cons of personalised medicine for patients?

Answer 36

Pros:
-Improved healthcare due to more personalised treatment plans
-Reduced likelihood of adverse events leading to improved compliance
-More informed choice of therapy
-Greater personal involvement in treatment decisions and thus greater likelihood to adhere to treatment

Cons:
-Exclusion of patient without the right mutations
-Focus on profitable disorders so rare disorders and variants miss out
-More education needed by all parties to best use drugs

Question 37

What are the pros and cons of personalised medicine in the pharmaceutical industry?

Answer 37

Pros:
-Safer, more effective medicines
-Focused discovery based on refined phenotypes
-Improved decision making and potentially lower attrition in trails
-Earlier approval of new therapies
-More accurate targeting of marketing

Cons:
-Costs for clinical trial likely to increase
-Smaller market for drugs
-Educating people about your product
-Support diagnostic services needed

Question 38

What are the pros and cons of personalised medicine for the diagnostic industry?

Answer 38

Pros:
-Increased number of diagnostic tests needed
-Opportunity to develop tests for existing drugs
-Research opportunities

Cons:
-Increased regulation

Question 39

What are the pros and cons of personalised medicine for regulators?

Answer 39

Cons:
-Changes in regulatory processes
-Companion tests and other diagnostics must be considered
-Changes in the way clinical trials are run
-Who can the drug be used for?