Lecture 15- Precision Medicine II Flashcards
(18 cards)
Pharmacogenomics
Pharmacogenomics (PGx)- part of precision medicine and studies how genetic variation affects response/interaction with drugs
PGx + genomic medicine = linked as a patients disease genetics relates to genes that are targeted for treatment / impact drug interactions
Pharmacogenomics in clinical practice
PGx combines pharmacology + genomics to develop effective, safe meds that can be prescribed based on a persons genetic makeup
Adverse drug reactions
Excludes therapeutic failures; overdose, drug abuse, non compliance + med errors
Important since they are one of the leading causes of morbidity + mortality in health care
-4th leading cause of death
-have significant media exposure
Patient care may suffer/ may lose confidence in a drug
Most ADRs are detected in premarkerting clinical trials which are reported in prescribing info but latent ADRs are often missed
Trials exclude the young + old, pregnant women + patients with co-morbidities + polypharmacy
Risk factors;
-simultaneous use of several different drugs + drug-drug interactions
-very young/ old
-preg/ breastfeeding
-co-morbidities/ disease states which may affect ADME
-genetic factors
Pharmacogenomics testing
PGx= integrates genomic info into drug development + prescription
PGx testing = determines drug response/ADRs + function as genetic biomarkers in FDA drug labelling
PGx testing success + benefits
Safer use of existing medicines- Abacavir
- nuceloside reverse-transcriptase inhibitor used to prevent + treat HIV/AIDS
Benefits;
*Reduces hospital admissions- slide 14
*Clinical trials; genetic biomarkers used in clinical trials for; proof of efficacy, optimisation of dose + safety and tolerability
PGx in healthcare; stakeholders
Stakeholder roles within the healthcare system that have an interest in clinical decision making;
-regulator, pharmacist, clinicians, patient, hospital, payer, wholesaler and therapeutic/diagnostic manufacturer
Pharmacists;
-work in community, industry + hospitals
-provide value by understanding + managing patients total drug profile
-point of care; for dosing + administration and warn of potential ADRs
-speciality pharmacies= provide assistance to patients
PK + PD
PK= absorption, distribution, metabolism + excretion (ADME) - describes how the body handles a given drug + this determines the drug-plasma over time
Study of the relationship between the drug plasma + observed pharmacological effects = PD + variable relating PK + PD = DRUG
Drug metabolising enzymes;
Cytochrome P450 superfamily isoenzymes
Most important metabolic enzymes with clinically relevant genetic variation
CYP= highly polymorphic + impact the functional activity of several isoenzymes
Combination of alleles- used to classify individual metabolising status/phenotypes + can include active, partially active, inactive + overactive forms
Metabolising status/ phenotypes
Slide 23
Clinical consequences of altered enzyme activity/ status depends on whether;
- the pharmacology activity resides with the parent drug or the metabolite of a prodrug
- the enzyme is susceptible to inhibition by the drug
Active drug vs Prodrug (bioactivation)
Number of drugs are administered as a prodrug and need to be bioactivated before they can exert their effects whereas conversion from the parent compound in either the gut/liver occurs before reaching circulation
Efficient conversion= good E of the active drug (EM)
Inefficient conversion= more parent compound will reach circulation
Over efficient conversion= ??
Drug metabolising enzymes
On chromosome, 22 translates to a 497 AA enzyme that metabolises over 100 drugs including;
- antidepressants; fluoxetine
- neuroleptics; haloperidol
- beta-blockers; propranolol
- analgesics; codeine
CYP2D6*1= Wild-type allele and phenotypically considered as EM and normal where the key loss of function alleles is *4 (inactive) and phenotypically PM
^- C4- intronic splicing defect, truncated and inactive enzyme
-C10- non-synonymous change in exon 1= reduced enzyme activity throughout the enhanced protein degredation
-C* 17= deficient hydrolyse activity due to reduced substrate-binding affinity
-C*2xn= excess enzyme and phenotypcally UM
CYP2D6
Clinical complications;
- individuals with PM polymorphisms may require reduced dosing in order to avoid toxicities due to decreased metabolism which can be severe/ fatal
- individuals with UM polymorphisms may require the polar opposite therapeutic course through Inc dosing = avoid symptoms of drug in efficacy
- highlights of the potential of PGx - provides a mechanistic basis to why individuals belong to a specific ethnic group may respond very differently to a given drug + may allow a means for more precise dosing
PGx + ADRs; codeine/ morphine
Morphine; analgesic used in moderate-severe pain
Patients initially administered the PRODRUG codeine; methylmorphine
Codeine= metabolised in the liver by cytochrome P450 2D6 where the enzyme demethylates codeine into active drug- morphine
Codeine/Morphine dosing guidelines
Patients with different genetic versions of CYP2D6 gene affect the enzymes ability to convert the prodrug to codeine to morphine
^may leave some patients having a reduced/no pain relief response while in others morphine will act as a proficient analgesic, side effects!!
Drug transporter proteins
Drugs available for absorption may be ‘taken up’ through the GI wall + distributed to the portal blood flow by influx and efflux transporters and are subject to genetic variation like the metabolising enzymes e.g. CYP2D6
Transporters can also impact bioavailability; 2 fams
*solute carrier (SLC) transporters e.g. organic anion transporting polypeptides OATP1
*ATP binding cassette (ABC) transporters e.g. P-glycoprotein (P-gp)
Pharmacodynamics
Phenotypic response to genetic variation for drug-target proteins differs from metabolising enzymes/drug transporters
Genetic variation in PK genes= in distinct phenotypes; IM, PM + UM= giving a bimodal phenotype distribution
Effects on PD targets= more subtle = help explain response variability across a single distribution curve
PD effects of drug= determines its overall therapeutic utility + is the relationship between drug exposure and pharmacological response + effects being related to target proteins; enzymes, hormones + factors, ion channels/transporters, receptors and dna
PGx + enzymes as drug targets; ALOX5 + CCR5
Enzymes also serve as PD targets for drugs including Arachidonate 5- lipoxygenase (ALOX5), essential to the biosynthesis of cysteinyl leukotrienes and a PD target for drugs such as Zileuton
The cysteinyl leukotrienes (LTC4, LTD4, and
LTE4) serves as inflammatory mediators to
increase bronchoconstriction and mucus
secretion, triggering an asthmatic response.
They are produced in leukocytes by oxidation
of AA and the enzyme arachidonate 5-
lipoxygenase.
Zileuton inhibits ALOX5, which decreases the synthesis of cysteinyl leukotrienes
and provides symptomatic relief for the asthma patient
PGx and receptors as drug targets; CCR5
Chemokine (C-C motif) receptor 5 = belongs to chemokine receptor of G protein-coupled receptors involved in immune system
