Pharmacokinetics and Pharmacodynamics

PK/PD Fundamentals - Drug's Dance

• Pharmacokinetics (PK): Body's action on drug (ADME: Absorption, Distribution, Metabolism, Excretion). Governs drug concentration.
• Pharmacodynamics (PD): Drug's action on body. Mechanism, dose-response, therapeutic & adverse effects.
• Interplay: PK (concentration) drives PD (effect). Crucial for effective, safe therapy.
• Significance: Guides dose selection, regimen optimization, predicting interactions, minimizing toxicity.
• Steady state concentration ($C_{ss}$) is typically reached after 4-5 drug half-lives ($t_{1/2}$).

⭐ Achieving steady state ensures consistent therapeutic drug levels, vital for efficacy and minimizing toxicity, especially for chronic therapies.

Pharmacokinetics - ADME Adventure

• Absorption (A): Drug entry to systemic circulation.
  • Bioavailability ($F$): fraction reaching circulation; IV $F$=100%.
  • First-pass metabolism (liver) ↓ oral $F$.
  • pKa & pH affect absorption (📌 "Like absorbs like").
• Distribution (D): Drug spread.
  • Volume of Distribution ($V_d$): $V_d = \text{Amount of drug in body} / C_p$. High $V_d$: drug in tissues. Low $V_d$: drug in plasma.
  • Protein binding: unbound drug active.
• Metabolism (M): Biotransformation (liver).
  • Phase I (CYP450): oxidation, reduction, hydrolysis.
  • Phase II: conjugation.
  • CYP Inducers (e.g., Rifampicin, 📌 "CRAP GPS"): ↓ drug effect.
  • CYP Inhibitors (e.g., Macrolides, 📌 "SICKFACES.COM"): ↑ drug effect.
  • Prodrugs (e.g., Levodopa): activated by metabolism.
• Excretion (E): Renal excretion.
  • Clearance ($Cl$): $Cl = k \cdot V_d$.
  • Half-life ($t_{1/2}$): $t_{1/2} = 0.693 / k$. 4-5 $t_{1/2}$ to $C_{ss}$/elimination.
  • $C_{ss} = \text{Dose rate} / Cl$.
  • Kinetics: First-order (constant fraction/time) vs. Zero-order (📌 "PEA" - Phenytoin, Ethanol, Aspirin; constant amount/time).

⭐ Loading dose depends on Volume of Distribution and target concentration, not clearance. Maintenance dose depends on clearance.

Pharmacodynamics - Receptor Rhapsody

• Receptor Types:
  • Ligand-gated ion channels (e.g., nAChR)
  • G-protein coupled (GPCR) (e.g., Adrenergic receptors)
  • Enzyme-linked (e.g., Insulin receptor)
  • Intracellular (e.g., Steroid receptors)
• Drug-Receptor Interaction:
  • Affinity: Strength of drug-receptor binding.
  • Intrinsic Activity (IA): Capacity to elicit a response (ranges 0 to 1).
• Agonists: Possess affinity & IA.
  • Full Agonist: IA = 1 (max effect).
  • Partial Agonist: 0 < IA < 1. Can act as antagonist with full agonist.
  • Inverse Agonist: IA < 0 (stabilizes inactive receptor form).
• Antagonists: Possess affinity, but IA = 0 (no effect alone).
  • Competitive (Reversible): Binds same site. Shifts DRC right (↑ $ED_{50}$), $E_{max}$ unchanged. 📌 "Right shift, same height."
  • Competitive (Irreversible) & Non-competitive: ↓ $E_{max}$.
• Dose-Response Curves (DRC):
  • Graded: Effect intensity vs. dose.
  • Quantal: % individuals responding vs. dose.
  • Potency: $ED_{50}$ (dose for 50% maximal effect). Lower $ED_{50}$ = ↑ potency.
  • Efficacy: $E_{max}$ (maximal achievable effect).
• Spare Receptors: $E_{max}$ achieved before 100% receptor occupancy.
• Therapeutic Index (TI): $TI = TD_{50} / ED_{50}$. Larger TI = safer drug.

  ⭐ Most clinically used drugs target G-Protein Coupled Receptors (GPCRs). oka

Clinical PK/PD - Dosing Decisions

• Goal: Achieve & maintain target drug conc. ($C_{target}$) in therapeutic window.
  • Loading Dose ($LD$): Rapid effect. $LD = (V_d \cdot C_{target}) / F$.
  • Maintenance Dose ($MD$): Steady state. $MD = (Cl \cdot C_{target} \cdot \tau) / F$.
• Therapeutic Drug Monitoring (TDM):
  • Indications: Narrow Therapeutic Index drugs (📌 Do Little Pharmacists And Therapists? Digoxin, Lithium, Phenytoin, Aminoglycosides, Theophylline), toxicity, adherence, variable PK.
• Factors Affecting Dosing: Age, genetics, renal/hepatic impairment, drug interactions.

⭐ For drugs with long $t_{1/2}$, $LD$ is crucial; steady state on $MD$ alone takes 4-5 half-lives.

High‑Yield Points - ⚡ Biggest Takeaways

• First-pass metabolism significantly reduces oral drug bioavailability.
• High Volume of Distribution (Vd) indicates extensive tissue drug distribution.
• Clearance (CL) is crucial for determining the maintenance dose rate.
• Steady state is reached in 4-5 half-lives (t½), which also dictates dosing interval.
• Zero-order elimination (e.g., Phenytoin, Ethanol, Aspirin - "PEA") means constant amount eliminated.
• Efficacy (Emax) (maximal effect) is clinically more important than potency (EC₅₀).
• Narrow Therapeutic Index (TI) drugs (e.g., Warfarin, Digoxin, Lithium) demand close monitoring.