Pharmacogentics Flashcards
Describe the central role of the CYP450 enzyme system in drug metabolism.
Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in breakdown od drugs and xenobiotics through metabolism through Phase 1 or phase 2 breakdown within the liver.
Explain the difference between phase 1 and phase 2 metabolism in the liver giving specific drug examples.
Phase 1 metabolism involves various enzymatic reactions that aim to introduce or expose a functional group on the drug molecule, making it more amenable to phase 2 reactions. These reactions typically include oxidation, reduction, and hydrolysis.
Nortriptyline is a tricyclic antidepressant that is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) in the liver. CYP2D6 catalyzes the N-dealkylation of nortriptyline, leading to the formation of its primary metabolite, 10-hydroxy-nortriptyline (OH-nortriptyline). This reaction involves the removal of a methyl group (-CH3) from the nitrogen atom of nortriptyline.
Phase 2 metabolism involves the conjugation of the drug or its phase 1 metabolites with endogenous molecules, such as glucuronic acid, sulfate, glutathione, or amino acids. These conjugation reactions increase the water solubility of the drug, facilitating its excretion from the body.
Isoniazid is primarily metabolized through phase 2 metabolism, specifically via acetylation. The acetylation of isoniazid occurs in the liver through the action of the enzyme N-acetyltransferase 2 (NAT2). NAT2 transfers the acetyl group from acetyl-CoA to the amino group (-NH2) of isoniazid, forming a metabolite known as acetylisoniazid (isonicotinic acid hydrazide). This acetylation reaction converts isoniazid into a more polar and water-soluble compound.
Give an example of a drug hat goes through both Phase 1 and two in its clearance?
Alcohol degradation primarily occurs through phase 1 metabolism in the liver. The enzyme alcohol dehydrogenase (ADH) is responsible for the initial oxidation of alcohol (ethanol) to acetaldehyde. This reaction involves the removal of hydrogen from ethanol and the subsequent formation of acetaldehyde.
Acetaldehyde, the metabolite formed in phase 1 metabolism, is a highly reactive and toxic compound. It can have detrimental effects on various tissues and organs, particularly the liver. Acetaldehyde is further metabolized in phase 2 metabolism through the action of the enzyme aldehyde dehydrogenase (ALDH), leading to the formation of acetate.
With example explain why it is important to understand the phenotype of the metabolism involved enzymes a cancer patient has.
Thiopurine-S Methyl Transferase (TPMT) metabolises thiopurine cancer drugs – e.g. 6-Thioguanine into 6-Methyl Thioguanine
(6-meTG)
The aim if these drugs is for 6-Thioguanine (TG) to intercalate with nucleotides and become 6-Thioguanine Nucleotides (TGN)
which is toxic to cancer cells
Three variant alleles TPMT2, TPMT3A & TPMT*3C some of these posses low / high activity
Low TPMT: Causes more nucleotide intercalation.
Increased Thiopurine
toxicity
Increased Risk for
secondary Neoplasm
(Low TPMT activity patients given 1/10 standard dose)
Very High TPMT:
- Decreased
therapeutic Effect
Give an example of CYP2D6 activation and inactivation of drugs and the mechanism.
CYP2D6 acts to activate the prodrug Codiene into its active forum Morphine although depending on the phenotype of CYP2D6 Ultra metabolizers may require a smaller dose whereas slow metabolisers will need a large dose to take any effect.
CYP2D6 deactivates Nortriptyline a Tricyclic Antidepressant into 10-Hydroxy Nortriptyline
Inactive metabolite ultra metabolisers will need a larger dose and minor metabolisers a smaller dose.
How does copy number variation and Single nucleotide polymorphisms affect drug metabolism with specific examples?
The drug Ionnazid formerly known as primaquine was given as an antimalaria drug however deficiencies within the associated metabolizer Glucose-6-Phosphate dehydrogenase meant that patients were sensitive to Oxidants would experience haemolysis because Glucose-6-Phosphate dehydrogenase maintains levels of NADH which is needed to produce Reduced Glutathione which eliminates reactive oxygen species without this haemolysis occurs due to oxidation. This is the most common defiency and due to it being X linked men are more likely to be affected due to the singular copy.
Explain why pharmacogenetics is important to Succinylcholine (SCC) use in therapy.
Succinylcholine (SCC) is a Neuromuscular blockers (anaesthetic agents) used in surgical procedure. It is Metabolised by butyrylcholinesterase (BCHE) through hydrolyses and inactivates.
Defect is a structurally altered enzyme and BCHE deficiency = prolonged SCC action - paralysis, respiratory failure (apnea)
Identify how Isoniazid is metabolised and why this may have an effect on dosage for Tb patients.
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that catalyzes the oxidation of glucose-6-phosphate (G6P) to 6-phosphogluconolactone. Following this in phase 2 the enzyme NAT2 = N-acetyltransferase enzyme (phase II) transfers an acyl group resulting in inactivation.
NAT2 gene has several alleles (variants) – affect the rate of isoniazid acetylation
‘Rapid acetylator’ – allele considered wild-type
Rapid clearance
‘Slow acetylator’ – alleles have SNPs
High blood levels = toxic – neuropathy and liver damage
Answer.
Test acetylator status using sulfadimidime (non-toxic)
Modify isoniazid dose once status is determined.
Using an example explain drug that is both effected by pharmacokinetics and genetics
Warfarin a commonly-prescribed anti-coagulant is subject to CYP2C9 metabolism = pharmacokinetic and its target region Vitamin K Epoxide Reductase (VKORC1) target = pharmacodynamic
CYP2C9 is highly polymorphic – low activity (CYP2C92 and CYP2C93) = decreased inactivation
Encoded by the vitamin K epoxide reductase complex 1 (VKORC1).
VKORC1 - polymorphic gene
Two Common Vitamin K Epoxide Reductase Haplotypes
- Haplotype A (Variants 1 & 2) is Associated with Lower Doses of Warfarin
- Present in ~37% of Caucasians
- Haplotype B (Variants 7, 8 & 9) is Associated with Higher Doses of Warfarin –
- Present in ~58% of Caucasians
Difficluty comes from warfarins |S and R isofofourms and the S isoforms are 3-5x more potent
Explain how Ryanodine Receptor mutations can effect patients
Defects in ryanodine receptor which is a receptor for anesthetic succinylcholine can cause Malignant hyperthermia.
Muscle cell membrane ion channel (Chr 19)
Binds the plant toxin ryanodine – calcium release from sarcoplasmic reticulum causing contact Ca+ release and excessive release of calcium – large-scale membrane depolarisation
Sustained muscle contraction and generation of heat
What do we mean by pharmacokinetic variation? Give 3 examples.
Genetic Variations: Genetic factors play a significant role in pharmacokinetic variability. Genetic polymorphisms in drug-metabolizing enzymes, transporters, and drug targets can affect drug metabolism, distribution, and elimination. For example:
Polymorphisms in the CYP2D6 gene can result in variations in the metabolism of drugs like codeine and tamoxifen, leading to differences in drug efficacy and toxicity.
Age-Related Variations: Age-related changes can impact drug pharmacokinetics. These changes include differences in drug absorption, distribution, metabolism, and excretion due to physiological and metabolic differences at different stages of life.
Drug-Drug Interactions: Co-administration of multiple drugs can lead to pharmacokinetic interactions, resulting in altered drug concentrations and effects. Interactions can occur at the level of drug metabolism, transport, or protein binding. For example:
Inhibition or induction of drug-metabolizing enzymes, such as the cytochrome P450 enzymes, by one drug can affect the metabolism and clearance of another drug, leading to increased or decreased drug concentrations.
What do we mean by pharmacodynamic variation? Give 3 examples.
Pharmacodynamic variation refers to the differences or variability in the way individuals or populations respond to drugs based on their pharmacological effects on the body.
Receptor Sensitivity: Variations in the sensitivity of drug targets or receptors can influence drug responses. Individuals may have different numbers or affinities of receptors, leading to variations in drug efficacy and potency. For example:
Disease State: Underlying disease conditions can affect drug responses and pharmacodynamics. Disease-related changes in the body, such as altered receptor expression, signaling pathways, or physiological processes, can influence drug efficacy and safety
Environmental Factors: Environmental factors can contribute to pharmacodynamic variation. External factors, such as diet, lifestyle, and exposure to chemicals or toxins, can modify drug responses.
Can you relate pharmacogenetics to the intolerance seen in subsets of patients to specific
drugs in terms of pk/pd variation ?
Warfarin is an oral anticoagulant commonly used to prevent blood clot formation in patients with certain cardiovascular conditions. The response to warfarin can vary significantly among individuals, and pharmacogenetics has been instrumental in understanding this variability.
A specific genetic variant that has been extensively studied in relation to warfarin response is the VKORC1 (Vitamin K epoxide reductase complex subunit 1) gene. This gene encodes an enzyme involved in the metabolism and activity of warfarin. A common polymorphism in the VKORC1 gene, known as VKORC1-1639G>A or rs9923231, has been identified as a major determinant of warfarin sensitivity.
Patients who carry the A allele of the VKORC1-1639G>A variant require lower doses of warfarin due to decreased enzyme activity, making them more sensitive to the drug’s anticoagulant effects. On the other hand, patients with the G/G genotype may require higher doses of warfarin for the desired therapeutic effect
Why is it important to consider pharmacogenetics in drug design?
Personalized Medicine: Pharmacogenetics allows for personalized medicine, tailoring drug therapies to an individual’s genetic profile.
Enhanced Drug Efficacy: Genetic variations can influence drug efficacy. By identifying genetic markers associated with drug response, drug designers can develop drugs that target specific genetic variants or pathways, resulting in improved therapeutic outcomes.
Minimized Adverse Reactions: Genetic variations can contribute to differences in drug metabolism, resulting in variable drug concentrations and increased susceptibility to adverse reactions.
Regulatory Considerations: Regulatory agencies, such as the U.S. Food and Drug Administration (FDA), increasingly emphasize the importance of pharmacogenetic data in drug development and labeling.
Efficient Clinical Trials: Including pharmacogenetic data in drug design can aid in designing more efficient and informative clinical trials.
