W11 Pharmacogenomics of the GI system Flashcards
What is Pharmacogenomics?
The study of how a persons genetic makeup influences their response to medications.
What are pro-drugs?
A pharmacologically inactive substance that is converted in the body (as by enzymatic action) into a pharmacologically active drug
Water-soluble parts of the active ingredient that are unable to penetrate the BBB are transformed into prodrugs soluble in lipid
e.g.
Omeprazole is a prodrug which is converted to its active form (esomeprazole) only at the site of action, namely the parietal cell. There it binds irreversibly with H+-K+-ATPase (the gastric proton pump), which causes an effective and long-lasting inhibition of gastric acid secretion.
What are the Basic principles of pharmacogenomics? (5)
- Genetic Variability: Individuals have unique genetic profiles that can affect how they metabolise and respond to drugs. These differences are due to variations in genes that encode for drug-metabolising enzymes (DME), drug transporters, drug receptors, and targets
- Drug Metabolism: Genes can influence the levels and activity of DME. For instance, some people have genetic variants that make them metabolise drugs more quickly or slowly than others
- Drug Targets: Genetic variations can also affect drug targets such as receptors or proteins, altering the drug’s effectiveness
- Drug Safety: Certain genetic profiles can increase the risk of adverse reactions to drugs.
- Tailoring Treatment: Pharmacogenomics aims to tailor drug therapy to individual patients based on their genetic makeup, maximising efficacy and minimising adverse effects
Metabolism:
What can drug metabolism be affected by?
- “First Pass” effect e.g. morphine
- Hepatic blood flow
- Liver disease
What occurs in Phase 1 of metabolism?
Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a process known as ‘functionalisation’. This group then serves as the point of attack for the conjugating system to attach a substituent such as glucuronide
Phase 1 reactions (e.g. oxidation, reduction or hydrolysis) are catabolic, and the products are often more chemically reactive and hence, paradoxically, sometimes more toxic or carcinogenic than the parent drug.
What is Cytochrome P450?
It is a superfamily of membrane-bound haemoprotein isoenzymes
-20 isoenzymes of cytochrome P450 in liver
-Families CYP1–4 are involved in drug metabolism.
CYP Enzymes involved in the GI system:
CYP1A- Important for methylxanthines and paracetamol; induced by smoking
CYP2A- Limited number of substrates; significant inter individual variability
CYP2B- Limited number of substrates
CYP2C- CYP2C9 is an important isoform; CYP2C19 shows genetic polymorphism in omeprazole tx
CYP2D- Metabolises numerous drugs; CYP2D6 shows genetic polymorphism
CYP2E- Metabolises alcohol
CYP3A- Main isoform in liver and intestine; metabolises 50–60% of current drugs
CYP4- Metabolises fatty acids
Personalised Medicine:
What are 4 aims of treatment?
- Optimised Dosage: It allows for the adjustment of drug dosages to suit individual needs, reducing the trial-and-error approach to finding the right dose.
- Reduced Adverse Drug Reactions: By predicting how a patient might react to a certain drug, pharmacogenomics can help reduce the likelihood of adverse drug reactions.
- Increased Drug Efficacy: It can improve drug efficacy by identifying which medications are most likely to be effective for specific patients.
- Avoiding Ineffective Treatments: It helps in avoiding prescribing drugs that are unlikely to work due to genetic reasons.
Role of Pharmacogenomics in Gastrointestinal Disorders:
Complex pathophysiology
IBS – involves multiple central and peripheral mechanisms that may constitute targets for therapy
Management of condition remains challenging - a trial-and-error approach with modest or no improvement in symptoms
Understanding genetic differences promises to overcome this challenge
Comorbidities, genetic makeup and drug-to-drug interactions
Inflammatory bowel disease (IBD)
Crohn’s disease
Ulcerative colitis
Treatment – anti-inflammatory azathioprine
Key genetic factors that influence the treatment of various gastrointestinal disorder
- Irritable Bowel Syndrome (IBS):
* Serotonin Transporter Gene (SLC6A4): T
* CYP2C19 and CYP2D6 Genes - Inflammatory Bowel Disease (IBD):
* TPMT (Thiopurine S-methyltransferase)
* NOD2/CARD15 Genes - GERD and Peptic Ulcers:
* CYP2C19 Gene - Colorectal Cancer
* DPYD Gene
* UGT1A1 Gene
Azathioprine
What is its indication?
Contraindications?
Side effects? (3)
Indicated for severe acute Crohn’s disease, Maintenance of remission of Crohn’s disease, Maintenance of remission of acute ulcerative colitis
Contra-indications: Absent thiopurine methyltransferase (TPMT) activity; very low thiopurine methyltransferase (TPMT) activity
Side-effects may require drug withdrawal.
* Hypersensitivity reactions - immediate withdrawal
* Neutropenia and thrombocytopenia Neutropenia is dose-dependent. Management of neutropenia and thrombocytopenia requires careful monitoring and dose adjustment.
* Nausea - usually resolves after a few weeks without an alteration in dose.
TPMT testing before azathioprine therapy?
- Azathioprine is an immunosuppressant treatment for various autoimmune diseases.
- It is a prodrug of mercaptopurine, a substance that is subsequently metabolised by several alternative pathways, one of which involves the enzyme TPMT.
- Some people have a deficiency of TPMT because of genetic mutations
- Great risk of developing severe, potentially life-threatening bone marrow toxicity when treated with conventional doses of azathioprine or mercaptopurine.
Pre-treatment screening & implications in personalised medicine
NICE recommend TPMT testing before starting treatment with azathioprine, mercaptopurine, or thioguanine therapy.
Seek specialist advice for those with reduced or absent TPMT activity.
- Dosage Adjustment: People with low or absent TPMT activity metabolise thiopurine drugs more slowly, leading to higher concentrations of the active drug metabolite. This increases the risk of potentially life-threatening myelosuppression. Identifying these patients through genetic testing allows for dose adjustments or alternative treatments to be chosen.
- Treatment Efficacy: For patients with high TPMT activity, standard doses of thiopurines may be less effective. Adjusting the dose can improve treatment outcomes.
- Predicting Side Effects: Genetic testing for TPMT activity can predict the likelihood of adverse drug reactions, helping to avoid severe side effects.
TPMT (Thiopurine methyl transferase)
- Thiopurine drugs are widely used in the treatment of inflammatory and autoimmune diseases, leukaemia and prevention of rejection post organ transplant.
- Thiopurines are catabolised to inactive metabolites by thiopurine methyl transferase (TPMT), which in effect reduces concentrations of the active metabolite, 6-thioguanine nucleotides (6TGN).
- TPMT activity exhibits genetic variation. In a Caucasian population approximately 89% have normal enzyme activity, 11% low activity and 0.3% undetectable levels (deficient).
- Measurement of TPMT activity should be performed prior to starting thiopurine drugs. * Patients with undetectable activity are generally not treated with thiopurine drugs due to the increased risk of severe side effects including myelosuppression.
Recent blood transfusions can affect results and may mask a deficient TPMT. - Patients already receiving thiopurine drugs can show enzyme induction leading to increased TPMT activity.
What is Azathioprine used to treat?
This medication is frequently used in the treatment of autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel diseases like Crohn’s disease and ulcerative colitis. It’s also used in organ transplant patients to prevent rejection.
