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What are the two primary types of factors that influence drug effect?
What are the two primary types of factors that influence drug effect?
Factors related to the drug and factors related to the organism.
Which of the following is NOT a factor related to the drug?
Which of the following is NOT a factor related to the drug?
What is the name for the process by which drugs are broken down in the body?
What is the name for the process by which drugs are broken down in the body?
Metabolism
Which of the following properties of a drug can influence its transport through membranes?
Which of the following properties of a drug can influence its transport through membranes?
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The cis form of chlorprothixene is generally more efficient than the trans form.
The cis form of chlorprothixene is generally more efficient than the trans form.
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What does MTD stand for in the context of drug dosage?
What does MTD stand for in the context of drug dosage?
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What does SPC stand for and what does it include?
What does SPC stand for and what does it include?
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What is the definition of a drug dosage form?
What is the definition of a drug dosage form?
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What is the first generation of drug dosage forms typically referred to as?
What is the first generation of drug dosage forms typically referred to as?
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What does SR stand for in the context of drug dosage forms?
What does SR stand for in the context of drug dosage forms?
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Which of the following describes a scenario where the combined effect of two drugs is greater than the sum of their individual effects?
Which of the following describes a scenario where the combined effect of two drugs is greater than the sum of their individual effects?
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Which of the following is an example of physiological antagonism?
Which of the following is an example of physiological antagonism?
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Non-selective monoamine oxidase inhibitors can increase tyramine bioavailability from food.
Non-selective monoamine oxidase inhibitors can increase tyramine bioavailability from food.
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Which vitamin can decrease the effect of warfarin?
Which vitamin can decrease the effect of warfarin?
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Food can influence drug pharmacokinetics primarily at which level?
Food can influence drug pharmacokinetics primarily at which level?
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Which of these is NOT a factor related to the host organism?
Which of these is NOT a factor related to the host organism?
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In which age group are drugs often dosed based on body surface area?
In which age group are drugs often dosed based on body surface area?
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Premature infants have a larger volume of extracellular fluid compared to full-term infants.
Premature infants have a larger volume of extracellular fluid compared to full-term infants.
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What is the term for the age group typically considered to be 75 years and older?
What is the term for the age group typically considered to be 75 years and older?
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Why is the administration of multiple medications to elderly patients a cause for concern?
Why is the administration of multiple medications to elderly patients a cause for concern?
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The half-life of drugs can be prolonged in elderly individuals due to decreased renal function.
The half-life of drugs can be prolonged in elderly individuals due to decreased renal function.
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Women are generally more sensitive to the effects of some drugs than men due to their lower body weight.
Women are generally more sensitive to the effects of some drugs than men due to their lower body weight.
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Which of the following periods in a woman's life is NOT considered a specific period that can affect drug response?
Which of the following periods in a woman's life is NOT considered a specific period that can affect drug response?
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What physiological changes occur during pregnancy that can affect drug pharmacokinetics?
What physiological changes occur during pregnancy that can affect drug pharmacokinetics?
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Drugs are often dosed based on body weight, taking into account the patient's age.
Drugs are often dosed based on body weight, taking into account the patient's age.
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Which of the following dosage modes is NOT commonly used for drugs?
Which of the following dosage modes is NOT commonly used for drugs?
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What is the name for the study of genetic variations that affect drug response?
What is the name for the study of genetic variations that affect drug response?
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What is the difference between pharmacogenetics and pharmacogenomics?
What is the difference between pharmacogenetics and pharmacogenomics?
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Genetic polymorphism, a variation in gene alleles, is more common than rare gene mutations.
Genetic polymorphism, a variation in gene alleles, is more common than rare gene mutations.
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What is a major complication for pharmacogenetic clinical studies?
What is a major complication for pharmacogenetic clinical studies?
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The CYP2D6 gene is responsible for metabolizing close to 25% of commonly used drugs.
The CYP2D6 gene is responsible for metabolizing close to 25% of commonly used drugs.
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What is the term for the presence of duplicated or multiplied CYP2D6 genes?
What is the term for the presence of duplicated or multiplied CYP2D6 genes?
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The CYP2C9 gene is involved in the metabolism of warfarin, but not phenytoin.
The CYP2C9 gene is involved in the metabolism of warfarin, but not phenytoin.
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Which of the following CYP2C9 alleles is associated with a reduced affinity for the substrate?
Which of the following CYP2C9 alleles is associated with a reduced affinity for the substrate?
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Patients with polymorphisms in the CYP2C9 gene may need lower doses of warfarin to maintain the desired INR level.
Patients with polymorphisms in the CYP2C9 gene may need lower doses of warfarin to maintain the desired INR level.
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What is the name of the enzyme encoded by the VKORC1 gene, and what is its role in warfarin metabolism?
What is the name of the enzyme encoded by the VKORC1 gene, and what is its role in warfarin metabolism?
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The -1639G>A polymorphism in the VKORC1 gene increases a patient's sensitivity to warfarin, often requiring lower doses.
The -1639G>A polymorphism in the VKORC1 gene increases a patient's sensitivity to warfarin, often requiring lower doses.
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Patients carrying two copies of the -1639A allele have a lower risk of warfarin overdosing compared to those with the -1639GG allele.
Patients carrying two copies of the -1639A allele have a lower risk of warfarin overdosing compared to those with the -1639GG allele.
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Which of the following genetic variants is NOT considered a key factor in warfarin dosing?
Which of the following genetic variants is NOT considered a key factor in warfarin dosing?
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The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that pharmacogenetic algorithms be used to predict optimal warfarin doses.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that pharmacogenetic algorithms be used to predict optimal warfarin doses.
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Which of the following drugs is NOT primarily metabolized by the CYP2C19 enzyme?
Which of the following drugs is NOT primarily metabolized by the CYP2C19 enzyme?
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Carriers of the CYP2C19*2 allele have an inactive enzyme, primarily due to a stop codon.
Carriers of the CYP2C19*2 allele have an inactive enzyme, primarily due to a stop codon.
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What is the primary reason for the inactivation of the CYP2C19 enzyme in carriers of the *3 allele?
What is the primary reason for the inactivation of the CYP2C19 enzyme in carriers of the *3 allele?
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Carriers of both *2 and *2 alleles of the CYP2C19 gene have a complete deficit of CYP2C19 enzyme activity.
Carriers of both *2 and *2 alleles of the CYP2C19 gene have a complete deficit of CYP2C19 enzyme activity.
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NAT2 is the primary enzyme responsible for the metabolism of isoniazid.
NAT2 is the primary enzyme responsible for the metabolism of isoniazid.
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Individuals who are slow acetylators of NAT2 have a higher risk of adverse events associated with hydralazine.
Individuals who are slow acetylators of NAT2 have a higher risk of adverse events associated with hydralazine.
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What is the major elimination route for the fluoropyrimidine chemotherapeutic drug 5-FU?
What is the major elimination route for the fluoropyrimidine chemotherapeutic drug 5-FU?
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The most common variant allele in the DPD gene is the *13 allele.
The most common variant allele in the DPD gene is the *13 allele.
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What is the primary role of the UGT1A1 enzyme in the body?
What is the primary role of the UGT1A1 enzyme in the body?
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The *28 allele of the UGT1A1 gene is associated with a decreased risk of toxicity from irinotecan.
The *28 allele of the UGT1A1 gene is associated with a decreased risk of toxicity from irinotecan.
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TPMT is primarily responsible for metabolizing drugs belonging to the thiopurine class.
TPMT is primarily responsible for metabolizing drugs belonging to the thiopurine class.
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What is the primary clinical application of thiopurine drugs?
What is the primary clinical application of thiopurine drugs?
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What type of genetic variation is primarily responsible for variations in TPMT activity?
What type of genetic variation is primarily responsible for variations in TPMT activity?
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The presence of variant alleles in the TPMT gene can lead to reduced enzyme activity, increasing the risk of toxicity from thiopurine drugs.
The presence of variant alleles in the TPMT gene can lead to reduced enzyme activity, increasing the risk of toxicity from thiopurine drugs.
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Genetic testing for TPMT is now considered a routine practice in clinical settings.
Genetic testing for TPMT is now considered a routine practice in clinical settings.
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ABC transporters play a crucial role in drug absorption, distribution, and metabolism.
ABC transporters play a crucial role in drug absorption, distribution, and metabolism.
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Which of the following is NOT an example of an ABC transporter?
Which of the following is NOT an example of an ABC transporter?
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Genetic polymorphisms in ABC transporters can affect the penetration of drugs into tumor cells.
Genetic polymorphisms in ABC transporters can affect the penetration of drugs into tumor cells.
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What is the primary consequence of low levels of drug accumulation in tumor cells due to ABC transporter polymorphism?
What is the primary consequence of low levels of drug accumulation in tumor cells due to ABC transporter polymorphism?
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Genetic predisposition to certain diseases or adverse events can be either overestimated or underestimated, so a balanced perspective is essential.
Genetic predisposition to certain diseases or adverse events can be either overestimated or underestimated, so a balanced perspective is essential.
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Which of the following factors is NOT a non-genetic factor considered to influence the individual risk of clinical complications?
Which of the following factors is NOT a non-genetic factor considered to influence the individual risk of clinical complications?
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Non-genetic factors can trigger pathogenic processes by affecting the DNA, RNA, or proteins.
Non-genetic factors can trigger pathogenic processes by affecting the DNA, RNA, or proteins.
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Posttranslational modification of proteins can involve alternative splicing.
Posttranslational modification of proteins can involve alternative splicing.
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Study Notes
Factors Influencing Drug Effect
- Factors influencing drug effect are categorized into factors related to the drug and factors related to the host organism.
Factors Related to the Drug
- Physical and chemical properties: These properties influence how a drug moves through membranes, including chemical configuration, molecular size and shape, solubility in water and fats, and acid-base properties.
- Drug dose: The amount of a drug administered significantly affects its effect.
- Drug dosage form: Different forms (e.g., tablets, capsules, injections) affect how quickly and completely the drug is absorbed.
- Drug combinations/interactions: Combining drugs can lead to synergistic (increased effect), additive (combined effect), or antagonistic (reduced effect) interactions.
- Drug-food interactions: Food can alter drug absorption, distribution, metabolism, and excretion.
Factors Related to the Host Organism
-
Age: Drug effects and responses differ between children and elderly people. Dosing and administration are adjusted based on age.
- Children: Dosage often adjusted using body surface area relative to an adult dose
- Elderly: Physiological changes like decreased kidney function or altered metabolism can affect how drugs are processed, requiring adjustments to dosages
- Gender: Women can generally be more sensitive to certain drugs compared to men, potentially due to differences in body weight and specific hormonal variations.
- Weight and body constitution: Dosage can be adjusted according to the patient's body weight, with some drugs dosed per kilogram of body weight.
- Circadian rhythms: The body's internal clock may influence how drugs are processed and affect their therapeutic effectiveness.
- Pathological state of organism: Pre-existing conditions or diseases impact drug processing, and dosages are adjusted for patient-specific comorbidities.
- Genotype / phenotype (pharmacogenetics/genomics): Individual genetic makeup significantly varies how drugs are metabolized, affecting both pharmacokinetic (absorption, distribution, metabolism, excretion) and pharmacodynamic (mechanism of action) processes. Genetic variations in drug-metabolizing enzymes, transporters, and receptors lead to diverse patient responses to drugs.
Drug Dose - Dosis
- Preclinical trials use maximum-tolerated doses (MTD).
- Clinical trials phase I also use MTD.
- Summary of Product Characteristics (SPC) is part of a medicinal product's marketing authorisation.
- Czech pharmacopoeia is a reference for drug doses.
Drug Dosage Form
- Definition: A substance or combination of substances presented as having therapeutic or preventive properties, administered to confirm a medical diagnosis.
- Different generations of dosage forms exist from conventional to targeted drug delivery (e.g., sustained-release, slow-release, extended-release, transdermal).
Drug Combinations of Drugs
- Synergism: Combined effect of multiple drugs is greater than effects separately.
- Potentiation: Combined effect is greater than that expected from the sum of two drugs.
- Antagonism: Combined effect of multiple drugs is less than effects separately.
Food Intake
- PD interactions: Food can affect the bioavailability of certain drug compounds. Taking some food with MAO inhibitors can lead to increased tyramine levels and possible hypertensive crisis. Other food (e.g., broccoli with warfarin) can alter the effect of drugs.
- PK interactions: Food can impact drug absorption (rate), metabolism, and/or excretion. Food can alter the bioavailability of a drug, potentially increasing or reducing the amount of drug available to produce a therapeutic response.
Pharmacogenetic Drug-Food Interactions
- Food can slow down, decrease or increase drug absorption.
- Food effects are often not present in hypnotics or analgesic drugs.
Factors Related to the Host Organism (continued)
- Weight/body constitution: Dosage adjustment considering body weight.
- Comorbidities: Pre-existing diseases (e.g., kidney, liver, thyroid dysfunction) influence drug processing, necessitating dosage modifications.
Specific Considerations for Age Groups
- Children: Dosing generally adjusted based on body surface area.
- Elderly: Physiological changes (e.g., decreased kidney function) necessitate adjustments for dosage and administration time to reduce potential adverse effects. Pharmacodynamic changes can also produce changes in the drug effect, with increasing sensitivity to some drugs. Specific attention should be paid to polypharmacy and drug-drug interactions.
Changes in Pharmacokinetics (PK) in the elderly
- Absorption: Affected by decreased acidity, altered transport mechanisms.
- Binding to plasma proteins: Reduced binding can lead to increased free drug concentration, increasing risk of adverse effects.
- Elimination: Reduced blood flow and kidney function lead to extended duration of action (prolonged half-life).
- GFR (glomerular filtration rate) plays a critical role here.
Changes in Pharmacodynamics (PD) in the elderly
- Regulatory mechanisms: Dysfunction can affect the regulation of drug response.
- Target structures: Can display changes in sensitivity (e.g. hypersensitivity or under-sensitivity)
- Toxicity and adverse effects often higher in elderly. Drugs that have a direct effect on tissue hypoxia can have a significant impact on elderly patients.
Genetic Factors
- Variability in individual responses due to multiple genetic factors.
- Pharmacogenomics/pharmacogenetics studies this variability in drug response related to genetics factors.
- Specific genes are critical in drug metabolism, absorption, and overall response to the drug.
Enzymes of Cytochrome P450
- CYP2D6 is responsible for the metabolism of approximately 25% of clinically used drugs.
- Gene variants can lead to significant changes in metabolic activity, impacting drug efficacy and/or toxicity. For example, the high activity can lead to rapid drug metabolism, increasing the risk of therapeutic failure. Conversely, slow metabolism can result in drug accumulation and increased risk of adverse effects.
- CYP2C9 impacts warfarin metabolism (S-warfarin S-isomer)
- Multiple polymorphisms of these genes can lead to significant changes in metabolism.
Additional Information
- Important genetic factors can be summarized using the knowledge of specific enzymes and pathways.
- Clinicians should be aware of pharmacogenetics and individual factors influencing drug therapy and consider using appropriate tools or resources (e.g., clinical guidelines) to personalize drug treatment.
- Use of pharmacogenetics and genomics studies can help personalize drug selection and dosage.
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