PK Unit 2 — Concise Exam-Focused Study Notes Summary & Study Notes

📌 Core pharmacokinetic parameters

Cmax — the peak plasma concentration after a dose. Tmax — time to reach Cmax. Short, testable definitions; memorize both.

Area Under the Curve (AUC) — estimate of total drug exposure over a time period (e.g. 24 h or dosing interval). Units = concentration × time. Use AUC to compare extent of exposure between routes.

Bioavailability (F) — fraction of an administered dose reaching systemic circulation. Defined by the formula: $F = \frac{AUC_{non\text{-}vascular}}{AUC_{IV}} \times 100$. If doses differ, correct by the dose ratio ($\text{dose}${IV}/\text{dose}{non\text{-}vascular}).

Bioequivalence — two formulations are bioequivalent only if rate and extent of absorption are the same. In practice, no significant differences in AUC, Cmax, and Tmax.

Volume of distribution ($V_d$) — apparent volume needed to contain the total amount of drug at the plasma concentration. Formula: $V_d = \frac{Q}{C_p}$ where $Q$ = total amount in body and $C_p$ = plasma concentration.

Clearance (CL) — volume of plasma effectively cleared of drug per unit time (organ-specific e.g. renal clearance). Units often mL/min/kg or mL/h/kg.

Half-life ($t_{1/2}$) — time for plasma concentration to fall by 50%. Calculated from a log concentration vs time plot. Remember: $t_{1/2}$ relates to CL and $V_d$ (exam will ask definitions; specific algebraic relationship not given in slides — focus on definition and interpretation).

Kinetic orders

• First-order kinetics: rate ∝ concentration. Exponential decline. Fixed proportion removed per unit time → $t_{1/2}$ independent of dose. (Most drugs.)
• Zero-order kinetics: rate is constant (fixed amount removed per unit time). Decline is linear; $t_{1/2}$ increases with dose due to saturation of elimination pathways. Examples in slides: aspirin, ethanol, phenytoin.

Steady state — with repeated dosing to half-life intervals, peaks and troughs approach a plateau after ≈ 5 elimination half-lives.

Therapeutic window & index — know the concept: threshold for effect, threshold for toxicity; a narrow therapeutic index = low safety margin.

Exam tips (from these slides): be able to define each parameter, state units where given (AUC = concentration×time; CL units), write the bioavailability formula, and contrast first vs zero order behaviour including examples and the 5 half-life rule for steady state.

🧭 Drug distribution, $V_d$ and plasma protein binding

Distribution compartments — after absorption a drug can be in plasma, interstitial fluid, transcellular fluid, intracellular fluid. The body is approximated by compartments (plasma ~5% body weight, interstitial ~16%, intracellular ~35%, fat ~20%).

Volume of distribution ($V_d$) — measure of the apparent volume required to hold the drug at the measured plasma concentration. Use $V_d = \frac{\text{Dose (total amount)}}{C_p}$. Interpretative ranges from slides:

• Very low (0.05–0.1 L/kg): drug largely confined to plasma (large molecules).
• Low (~0.2 L/kg): plasma + interstitial fluid (polar drugs).
• Intermediate (~0.6 L/kg): distributes into total body water.
• Very high (>1 L/kg): accumulates in fat or tissues or intracellular binding.

Why $V_d$ matters — predicts whether drug reaches target at effective concentrations and helps calculate loading dose needed to reach a target plasma concentration.

Factors limiting distribution — molecular size, plasma protein binding, endothelial barrier, ion trapping, lipid solubility.

Plasma protein binding

• Drugs circulate as bound + free forms in equilibrium. Only free drug is pharmacologically active, can cross barriers, be filtered renally, and be cleared.
• Binding ranges widely (0–99%). There are species differences and risk of displacement interactions when two highly protein-bound drugs are co-administered.
• Consequences: alters PK (distribution, clearance), PD (only free drug active), and can cause rare immune reactions to drug-protein complexes.

🔬 Metabolism (hepatic focus) and routes

Main site = liver; extrahepatic metabolism can occur (plasma, gut wall, lung, kidney). Many drugs are metabolised to more polar forms to aid excretion; some metabolites are active. Some drugs are prodrugs and require metabolism to become active (example in slides: enalapril → enalaprilat).

Phase 1: functionalisation (oxidation, reduction, hydrolysis) — makes molecules more polar or exposes groups for conjugation. Phase 2: conjugation (e.g. glucuronidation, sulphation, acetylation) increases polarity and excretion. Slides note metabolism is usually biphasic (Phase 1 then Phase 2).

First‑pass metabolism — extensive metabolism in gut wall, portal blood or liver before reaching systemic circulation; important for oral dosing and reduces bioavailability.

Enterohepatic recycling — conjugates excreted in bile can be hydrolysed in gut, releasing parent drug for reabsorption; this prolongs exposure for some drugs.

Species differences — metabolism pathways and proportions of metabolites vary markedly between species; slides give examples and stress this is important for PK and half-life differences.

🚽 Excretion: renal mechanisms & urine pH effects

Major routes: urine and bile. Water-soluble molecules are more readily excreted.

Renal processes (from slides):

• Glomerular filtration: only free drug is filtered; proteins > ~70 kD not filtered.
• Tubular secretion: active, energy-dependent, selective and saturable (proximal tubule transporters).
• Tubular reabsorption: passive (depends on lipophilicity and ionisation).

Some drugs use multiple renal mechanisms (example: penicillins — partly protein bound, filtered and actively secreted).

Transporter proteins — are key in secretion and appear in many tissues (gut, kidney); they can saturate and be sites of interactions.

Urine pH effect — rate of excretion for weak acids/bases depends on urine pH via ionisation (% unionised vs ionised):

• Animals with acidic urine (carnivores) eliminate weak bases more efficiently.
• Animals with alkaline urine (herbivores on forage) eliminate weak acids more efficiently.

✅ Summary (exam focus from these slides)

• Know definitions and short interpretations for $V_d$, CL, AUC, Cmax, Tmax, $t_{1/2}$, bioavailability and bioequivalence.
• Be able to calculate $V_d$ from dose and $C_p$ and use the bioavailability formula.
• Understand plasma protein binding consequences, hepatic metabolism phases, first‑pass, enterohepatic recycling, and renal clearance mechanisms including urine pH effects.
• Remember species differences in metabolism and clearance are important when comparing animals.

🎯 How to study these slides for the exam (only use what is given)

Focus on clear, testable items present in the lectures: definitions, short formulas, units, and the named examples from slides. Do not add extra topics.

Study routine:

• Memorize each definition (Cmax, Tmax, AUC, F, Vd, CL, $t_{1/2}$).
• Learn formulas exactly as given: e.g. $V_d = \frac{Q}{C_p}$ and $F = \frac{AUC_{non\text{-}vascular}}{AUC_{IV}} \times 100$; remember to correct for dose differences when applicable.
• Be able to contrast first vs zero order kinetics and name the slide examples (aspirin, ethanol, phenytoin for zero order).
• Memorize key rules stated on slides: steady state ≈ 5 half-lives, bioequivalence judged by AUC, Cmax, Tmax.
• Practice one or two simple calculations using the formulas provided on the slides (e.g. Vd calculation) so you can show method clearly in an exam.

Exam presentation tips: define terms first, then give the formula (if provided), then a one-line interpretation or clinical relevance as in the slides. Keep answers to the scope of the lecture material only.