Untitled Quiz

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.