General Pharmacogenetics Concepts Flashcards
Contrast pharmacogenetics and pharmacogenomics
Pharmacogenetics:
Usually describes a variation in a single gene band how it influences a response to a single drug
-a component of precision medicine
Pharmacigenomics:
-a broad term which takes into account how all of the genes in the genome influence responses to a drug
-might be useful in the development of new drugs and identification of new drug targets
What are the main applications of pharmacogenetics?
- Malignant hyperthermia: phenotype is seen only if the patient is exposed to a particular pharmaco agent
- Warfarin dosing is affected by two genes: one gene encodes the target of the drug (VKORC), & another is involved in its excretion (CYP279)
- Codeine sensitivity: effect of a standard dise varies depending on alleles of CYP2D6 which encodes a p450 enzyme that converts codeine to its active form (morphine)
6-mercaptopurine dosing: dosage will vary depending on genotype of patient
G6PD deficiency: may cause hemolytic anemia in a person who is exposed to oxidizing agents-an idiosyncratic effect
What is malignant hyperthermia?
-potentially fatal genetic disorder of skeletal muscle
- triggered in susceptible individuals by genetic anesthesia:
- halothane- volatile halogenated inhalation anesthetics
- succinylcholine- depolarizing skeletal muscle relaxants
Malignant hyperthermia: one of the main causes of death due to anesthesia
Contrast halothane and succinylcholine fir general anesthesia
Halothane- widely used and typically safe anesthetic
Succinylcholine- muscle relaxant: facilitates intubation by suppressing coughing and choking
Describe the frequency ofmalignant hyperthermia
Transmitted as an autosomal dominant trait
Incidence is rare, about 1:15,000
Potentially life threatening, so all anesthesiologists are trained to look for it’s signs
What are the symptoms of malignant hyperthermia?
Symptoms of malignant hyperthermia appear soon after exposure:
- tachycardia
- hypertension
- severe muscle rigidity
- hyperthermia
- hyperkalemia
- acidosis
What are the factors associated with malignant hyperthermia?
All are associated with sustained muscle contraction due to unrestrained and massive Ca2+ release from muscle fiber sarcoplasmic reticulum
-Caused by depletion of ATP, and severe muscular contractions
- Mutations in the ryanodine receptor gene(RYR1)
- Approximately 70-80% of known cases (majority)
- One other gene has been discovered (encodes a Ca2+ channel)
- Approximately 1% of cases(rare)
- Other genes are thought to exist that may cause ,aligning hyperthermia
- waiting to be discovered
How large is the RYR1?
RYR1 gene encodes a protein of about 5,000 amino acids
RYR1 gene has more than 100 exons
Many different possibilities for mutation
-not all are known
Very complex gene; many different mutation types have been found in different affected individuals
What is the role of ryanodine receptor in muscle contraction?
- Action potential from motor neuron
- Release of Acetyl choline (ACh) at NMJ
- Action potential on the sacrolemma of the muscle fiber
- membrane depolarization
- causes change in conformation of DHPR
- DHPR releases from ryanodine receptor
- Allows Ca2+ release from sarcoplasmic reticulum
- Ca2+ facilitates actin/myosin interaction and muscle fiber contraction
Explain the cause of malignant hyperthermia
A mutation of the RYR1 gene causes the ryanodine receptor to trigger unregulated release of calcium from the SR in response to anesthetics which are safe for most people in the population
Halothane- anesthetic, but also directly interacts with RYR1
Succinylcholine-muscle relaxant: acts via depolarization
Halothane and succinylcholine—> synergistic Ca2+ release via RYR1 in susceptible individuals
For unknown reasons, some individuals with an RYR1 mutation will not have the adverse event after exposure. This is an example of reduced penetrance
What is the role of increased Ca2+ concentration in malignant hyperthermia ?
- The increased Ca2+ concentration increased causes sustained muscle contraction which generates heat
- Accelerated levels of aerobic metabolism produce CO2 while depleting O2 & ATP
- A switch to anaerobic metabolism worsens acidosis with the production of lactate
- energy stores get depleted
- muscle fibers are damaged leading to hyperkalemia and myoglobinuria
- Damaged mu#cle fibers release creatine phosphokinase (CPK) enzyme (bio marker)
What is the most reliable test for malignant hyperthermia susceptibility?
Caffeine/halothane test
- requires a relatively large muscle sample from the patient
- Only a few testing centers worldwide
- The most reliable test to establish susceptibility
- Tests muscle contraction in-vitro after exposure to halothane and caffeine
- knowledge if gene not needed fir this test
What is the role of genetics in malignant hyperthermia?
If a person is known to have malignant hyperthermia, then the RYR1 gene may be analyzed in that patient
-If a mutation is found, other at-risk family members may be tested to find out if they have the mutation
Screening is not an option for malignant hyperthermia because false negatives cannot be tolerated fir a potentially lethal condition:
1. 20-30% of cases are due to genes other than RYR1
- There is evidence of reduced penetrance
- RYR1 is a complex gene and is challenging to analyze
What is CYP2D6?
CYP2D6 is a member of the cytochrome P450 family of drug-metabolizing enzymes
- mixed function oxidase
- these enzymes add oxygen to xenobiotic molecules to aid excretion
CYP2D6 metabolizes a large number of drugs, including antidepresssants, antiarrhythmitics, and analgesics
What do cytochrome position p450 enzymes do?
Cytochrome p450 enzymes introduce oxygen onto substrates
-this is an attempt to make the substrate more soluble to enhance excretion in the urine
What are the effects of CYP2D6 polymorphism?
Poor metabolizers
-Have polymorphism that causes slow metabolism of CYP2D6 substrates
- These patients are homozygous fir recessive alleles encoding enzymes with low activity
- 1-5% of the population
Extensive metabolizers(normal)
- Normal range; most people are in this category
- homozygous or heterozygous, for alleles of normal activity
Ultra-rapid metabolizers
-Have multiple copies of the CYP2D6 gene, so these people process CYP2D6 substrates very quickly
-5-10% of the population(more frequently than poor metabolizers)
Why are interindividual differences in CYP2D6 important.?
Inter individual differences are important because CYP2D6 metabolizes many commonly prescribed drugs
What are two examples of drugs are affected by CYP2D6?
Metoprolol
Codeine
How are poor metabolizers of CYP2D6 affected?
- Poor metabolizers May suffer adverse effects when treated with standard doses of drugs such as metoprolol
- Metoprolol is inactivated by CYP2D6, so patient has too much
- Codeine is less effective (or ineffective) in poor metabolizers because it requires CYP2D6-catalyzed conversion to morphine
- Poor metabolizers can’t convert codeine, so the drug doesn’t work for them as well as it would for a normal metabolizer
How are ultra-rapid metabolizers of CYP2D6 affected?
- Ultrarapid metabolizers May require very high doses of drug such as metoprolol
- This is because metoprolol is metabolized and deactivated by CYP2D6
- But, an ultrarapid metabolizer might overdose with codeine, suffering respiratory depression or even respiratory arrest in response to standard doses
- This is because codeine is converted to its active form (morphine ) by CYP2D6
What is the function of debrisoquine hydroxylase ( CYP2D6)?
Conversion of codeine to morphine by debrisoquine hydroxylase/CYP2D6. The pain-killing effects of codeine are dependent on this reaction. Low debrisoquine hydroxylase activity will result in reduced efficacy, whereas high activity will cause excessive pharmacological effect
Ultra-rapid metabolizers might experience adverse affects after administration….
Of a normal codeine dose
What is 6-mercaptopurine used for?
Some forms of leukemia
Functions by inhibitions of the purine biosynthetic pathway which are needed for the formation of nucleotides, and thus production of DNA & RNA
- In this way, 6-mercaptopurine slows proliferation
- Cancer growth is inhibited as nucleotides are needed for cellular proliferation
What is the function of thiopurine methyltransferase?
Catalyzes methylation reaction of mercaptopurine to inactivate the drug
Describe thiopurine S-methyltransferase polymorphism
-Approximately 1/300 individuals are homozygous for a genetic variant that leads to low TPMT activity
- They are at increased risk for life threatening myelosuppresion when treated with standards doses of thiopurine drugs
- Fir these patients, a standard dose is in effect, an overdose
- If 6-mercaptopurine is given, dise must be reduced
