Week 2: Workshop
# Workshop 2: Pharmacokinetics and Pharmacodynamics in Drug Development and Safety
Main Takeaway: This workshop focuses on understanding the principles of pharmacokinetics (PK) and pharmacodynamics (PD) to ensure safe and effective drug action, particularly concerning bioavailability, first-pass metabolism, genetic variations in drug metabolism, and drug-food interactions. Real-world cases of terfenadine and codeine illustrate the tragic consequences of drug misuse and interactions.
## I. Workshop Objectives
Draw on *pharmacodynamic (PD)** and pharmacokinetic (PK) aspects, with a focus on PK.
Understand issues around bioavailability* and first-pass metabolism.
Discuss processes of absorption, distribution, metabolism, and excretion*.
Recognize the role of *genetically determined alterations** in protein expression in influencing drug effects.
Apply PKPD principles to understanding *safe drug action**, including when to use/not use drugs.
Examine iatrogenic effects* and the importance of careful drug use.
## II. Pre-Workshop Reading & Discussion: Terfenadine and Codeine
### A. Terfenadine
* Metabolism:
Metabolized by cytochrome P450 (CYP) enzymes*.
Specifically, CYP3A4 enzyme*.
* Drug-food interaction: CYP3A4 is inhibited by grapefruit juice and citrus.
* This inhibition leads to increased plasma concentrations of terfenadine.
* Pharmacodynamics (PD):
Developed as an *antihistamine**, targeting H1 receptors.
Designed to be *non-sedating** by not easily crossing the blood-brain barrier.
* Off-target effect: Inhibits hERG (human Ether-à-go-go-Related Gene) channels (potassium channels controlling cardiac rate). This led to QT prolongation.
* Physicochemical Properties: Practically insoluble in water, which impacts excretion.
* Discontinuation: Discontinued in 1998 due to life-threatening arrhythmias (QT prolongation) resulting from drug-drug/food interactions (e.g., with grapefruit juice, certain antibiotics) that inhibited its metabolism.
* Replacement: Replaced by fexofenadine, its active metabolite.
* Fexofenadine also metabolized by CYP3A4, but interactions are moderate.
* Instructions: Take with water, avoid large amounts of fruit juices (opposite effect – may decrease levels).
### B. Codeine
* Nature: A prodrug of morphine.
* Metabolism:
* Undergoes both Phase 1 and Phase 2 metabolism.
Converted to its active metabolite (morphine)* by a CYP450 enzyme (*CYP2D6*).
* Also converted to inactive metabolites.
* Pharmacodynamics (PD):
Morphine binds to mu-opioid receptors* for pain management.
* Overdose effect: Respiratory depression.
* Genetic Variation:
CYP2D6 enzyme exhibits *genetic polymorphism**.
* This leads to different metabolizer phenotypes:
* Ultra-rapid metabolizers: Metabolize codeine quickly, leading to higher morphine levels.
* Extensive metabolizers: (Most of the population).
* Intermediate metabolizers.
* Poor metabolizers: May require alternative analgesics as codeine is ineffective.
* Dosage requirements vary based on an individual's metabolizer status.
## III. Scenario 1: Terfenadine and Grapefruit Juice
### A. Case Summary (1999)
* 24-year-old student took 120 mg terfenadine daily from an old packet.
* Went on holiday, continued medication, and consumed fresh citrus juice.
Experienced shortness of breath* and lightheadedness on day 3.
Fainted on day 4, ECG showed long QT syndrome*.
* Advised to dispose of the drug and follow guidelines.
### B. Discussion Questions & Principles
1. Why are histamine H1 antagonists suitable for hay fever?
Allergic reactions involve histamine release from mast cells*.
Histamine causes vasodilation, plasma exudation, itchiness, pain*.
* H1 antagonists block histamine binding to H1 receptors, stopping these effects.
* Not effective for everyone; local treatments (e.g., nasal spray) can be more effective for localized inflammation.
2. What does PK tell you about the likely distribution of the drug?
* First-pass metabolism: 99% of terfenadine is metabolized, making it difficult to measure absorption/distribution.
Accumulates in liver, lung, and gut* (key metabolizing organs).
* Bound to plasma proteins (80%), but relative affinity is important.
* Water insolubility impedes excretion.
* Terfenadine is a prodrug; its active metabolite is intended for distribution.
3. Common side effects associated with antihistamines:
* Classic anticholinergic side effects: Dry mouth, fever, constipation, blurred vision.
Due to *non-selective action** at muscarinic acetylcholine receptors (despite H1 selectivity).
* Sedation/Lethargy: Occurs if the drug crosses the blood-brain barrier. First-generation antihistamines commonly caused this; terfenadine was designed to be non-sedating.
* QT prolongation: Unique to terfenadine (due to hERG channel inhibition), a severe cardiac side effect.
* Other histamine receptor antagonists: H2 antagonists (e.g., for gastric ulcers, targeting H2 receptors in parietal cells).
4. Why the advice to dispose of the drug and follow guidelines?
* Terfenadine was withdrawn in 1998 due to severe interactions (e.g., with grapefruit juice, antibiotics) causing life-threatening arrhythmias (long QT syndrome) by inhibiting hERG channels.
* The student used an old, discontinued drug.
This case highlights the importance of *drug-food interactions** and adherence to current guidelines.
* New drugs and their metabolites are now screened for hERG activity.
* Fexofenadine, the active metabolite, replaced terfenadine.
## IV. Scenario 2: Codeine and Breastfeeding
### A. Case Summary
* Mother took codeine + paracetamol for episiotomy pain.
Dose reduced due to somnolence* and constipation (side effects).
* Continued for 2 weeks.
Baby experienced difficulty breastfeeding* and lethargy from day 7.
Day 12: Baby had grey skin*, reduced milk intake.
* Day 13: Baby passed away.
Post-mortem: Blood morphine concentration of 70 ng/mL* (compared to normal 0.2-2 ng/mL).
### B. Discussion Questions & Principles
1. PD/PK issues raised:
Codeine is a prodrug, converted to active morphine*.
Genetic variability in CYP2D6* enzyme activity (ultra-rapid metabolizers).
Drug excretion via breast milk*, transferring both codeine and morphine to the infant.
Potential for paracetamol toxicity* (liver damage) in the infant.
2. Why was morphine measured when codeine/paracetamol were taken?
* Codeine is metabolized to morphine, the active analgesic.
* High morphine levels in the baby (70 ng/mL) significantly exceeded normal therapeutic ranges (0.2-2 ng/mL).
3. Are the drugs the problem? (Need for more information)
* Drug combinations: Codeine + paracetamol is a known combination; interaction is typically synergistic, not antagonistic in terms of pain relief.
* Genotyping: Genetic testing of the mother for CYP2D6 polymorphism.
Mother was heterozygous for SIP 2D6 gene duplication*, making her an ultra-rapid metabolizer.
* Breast milk analysis: Morphine concentrations measured in breast milk (87 ng/mL).
* Baby's metabolizer status: The baby likely also an ultra-rapid metabolizer to accumulate such high morphine levels, given oral bioavailability of morphine (20-40%).
* Other factors: Could other unlisted drugs or underlying conditions in the baby contribute?
* Conclusion: The high concentration of morphine in the baby, absorbed from breast milk of an ultra-rapid metabolizing mother, strongly suggests morphine contributed to the baby's death. Paracetamol's role is less clear but possible.
### C. Case Outcome & Learning
This was a *real case** published in The Lancet, highlighting pharmacogenetics of morphine poisoning in breastfed neonates.
* Codeine was historically available over-the-counter (especially with paracetamol) but is now prescription-only due to issues like this and misuse.
* Scientific Discourse: The case generated debate in the medical community about the conclusions, with some questioning the direct link. However, high morphine levels in breast milk and the infant's blood strongly supported the original findings.
* Clinical Practice Implications:
* Risk vs. Benefit: Balancing pain control for the mother with risks to the infant.
* Alternatives: Avoid codeine during breastfeeding; use paracetamol or NSAIDs.
* Dose management: Avoid high doses.
* Genotyping: While expensive and not routine, it could predict risk for ultra-rapid metabolizers.
* Codeine Metabolism:
Metabolized by CYP3A4* and CYP2D6.
* Only 5-15% converted to morphine.
* Other metabolites (some active) also present.
* CYP2D6 Polymorphism: Leads to varied drug responses (ultra-rapid, extensive, intermediate, poor metabolizers).
Emphasizes the need for healthcare professionals to *listen to patients** who report unusual drug effects.
* Rarity of Cases: The rarity of such severe neonatal toxicity cases from breastfeeding suggests unique circumstances in this specific case, rather than a widespread issue.
## V. Additional Concepts
* Ebbinghaus's forgetting curve: Remembering past information, like terfenadine-grapefruit juice interaction, is a good way to reinforce learning.
* Drug-Food Interactions: Real and require awareness.
* Iatrogenic effects: Drug actions that cause harm.
* Selectivity: Drugs target specific receptors (e.g., H1 receptors) but can have off-target effects (e.g., muscarinic receptors, hERG channels).
* Routes of Administration: Important for local vs. systemic effects (e.g., nasal spray vs. oral tablet for allergies).
* Drug Excretion: Breast milk is a route of drug excretion.
* Steady State: Achieved when the elimination rate equals the dose rate, resulting in stable therapeutic concentrations.