A drug must get from its site of administration into the systemic circulation before it can reach its target. The rate and extent of absorption determine how quickly and how much drug is available.

The slide's weak-acid example (pKa 3.4) compares gastric pH 1.4 with plasma pH 7.4. By Henderson–Hasselbalch, the weak acid is mostly unionised in the stomach (ionised:unionised ≈ 0.01) but overwhelmingly ionised in plasma (≈ 10,000:1). The unionised species crosses a lipid membrane most readily; once it enters the more alkaline side, ionisation reduces back-diffusion—an example of ion trapping.

Once a drug reaches the bloodstream, it distributes to various body compartments. The free (unbound) fraction is generally the fraction immediately available to cross membranes, bind receptors, be filtered and be cleared. Bound and unbound drug continuously re-equilibrate, so protein binding is a reservoir relationship rather than a permanent inactive pool.

The lecture provides a critical table of organ blood flow:

Why this matters: The kidneys receive the highest normalized blood flow — this is why they are such efficient excretory organs and also why they are so vulnerable to drug-induced toxicity (high drug exposure per unit mass). Adipose tissue has very low blood flow per kg, meaning lipophilic drugs accumulate slowly but persist for a long time (think diazepam, thiopental).

This table is directly from the lecture and is classic exam material:

Most drugs bind to albumin (acidic drugs) or α1-acid glycoprotein (basic drugs). Only the free fraction is active.

Clinical relevance:

• In hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition), the free fraction of highly protein-bound drugs increases → increased effect/toxicity at the same total plasma concentration
• This is why a "therapeutic" total phenytoin level may coexist with a toxic free level in hypoalbuminaemia. Albumin-correction equations are estimates; measure unbound phenytoin when binding is substantially altered or the clinical picture and total level disagree. ^[16]

• Drug can cross barriers by passive diffusion, aqueous pores/paracellular pathways, carrier-mediated transport or vesicular transport. Efflux transporters such as P-glycoprotein can return substrate to the blood or lumen and limit tissue exposure.
• Perfusion-rate limitation: highly perfused organs (kidney, heart, liver and brain in the slide's table) equilibrate earlier than poorly perfused adipose tissue. High flow explains speed of delivery, not necessarily the final amount stored.
• Capacity matters as well as flow: adipose receives little flow per kilogram but can eventually store large amounts of a lipophilic drug. Conversely, a highly protein-bound drug may remain largely intravascular because only its unbound fraction crosses the capillary membrane.

Phase 1 metabolism (Cytochrome P450): Oxidation, Reduction, Hydrolysis Phase 2 metabolism (Transferase reaction): Glucuronidation, Acetylation, Methylation, Glycine conjugates, Glutathione conjugates, Sulphate conjugates ^[1]

Why the numbered phases can mislead: they are categories, not obligatory sequential steps. A drug may undergo Phase II directly (e.g., morphine glucuronidation), and hydrolysis is Phase I even when no CYP is involved. The slide's visual also depicts Phase III transport: membrane transporters export parent drug or metabolites into bile, urine or other compartments. Metabolism does not guarantee inactivation; it may activate a prodrug or create an active or toxic metabolite.

From the supporting material: CYP3A4 metabolizes approximately 50% of all drugs — it is the most abundant and most clinically significant isoenzyme. ^[4] The other key isoenzymes are CYP2D6, CYP2C9, and CYP2C19. ^[5]

Factors affecting drug metabolism: Pharmacogenomics, Race and ethnicity, Age and gender, Diet, Metabolic drug interaction, Disease condition, Drug-drug interaction ^[1]

The route of excretion determines which organ impairments require dose adjustment:

The renal image separates processes that are often incorrectly collapsed into “renal excretion”:

1. Glomerular filtration: only small unbound drug in plasma water is filtered.
2. Active tubular secretion: transporters move drug from peritubular blood into tubular fluid; this can be saturable and is a site of drug–drug competition.
3. Passive tubular reabsorption: unionised, lipid-soluble drug may diffuse back into blood. Urine pH, urine flow and the drug's pKa therefore alter net urinary recovery.
4. Urinary excretion: the final amount in urine is filtration + secretion − reabsorption.

Renal impairment can change more than filtration: it may alter secretion, protein binding and nonrenal clearance. Use the kidney-function measure and dose recommendations specified for the individual drug rather than applying one universal “renal dose reduction” rule. Current FDA renal-PK guidance generally favours patient-specific, non-indexed kidney function in mL/min when translating renal function into dosing. ^[14]

• Onset occurs when concentration first exceeds the minimum effective concentration (MEC); duration is the time spent above it. At tmax, the absorption/input rate equals the elimination rate for an extravascular dose.
• The upper horizontal boundary on slide 12 is labelled “minimum safe concentration.” That wording is internally inconsistent: it represents a maximum tolerated/safe concentration or minimum toxic concentration, depending on convention. The therapeutic window lies between the efficacy and toxicity boundaries, but these are population guides rather than guarantees for an individual.
• The route comparison is qualitative, not a set of universal onset times. Faster input usually gives earlier tmax and a higher peak; slower input gives a later, flatter peak. A true IV bolus has no rising absorption phase (a rising IV curve instead resembles an infusion).
• Equal doses need not give equal AUC because AUC = F × dose / CL in linear PK. If absorption is slower than elimination, the terminal slope may reflect absorption (“flip-flop” kinetics), so a terminal half-life is not automatically the elimination half-life.

First order kinetics vs. Zero order kinetics. Only when saturation occurs would non-linear behavior become evident. ^[1]

Why this distinction is critical: With linear PK, doubling the dose approximately doubles exposure provided F and CL remain unchanged. With capacity-limited phenytoin elimination, a small dose increase can produce a disproportionate concentration rise. “Zero-order” is the limiting behaviour when the pathway is saturated; real patients often lie in the transition described by Michaelis–Menten kinetics rather than in a perfectly zero-order state.

This table from the lecture is a must-memorize for understanding drug elimination:

Dose depends on: Potency, Bioavailability, Volume of distribution Frequency depends on: Elimination rate Goal: Maintain peak plasma concentration below toxic concentration, and trough drug level above minimally effective level ^[1]

This is the therapeutic window concept:

The repeated-dose plots on slides 21–24 show that dose size and interval solve different problems. Larger doses tend to move both peak and trough upward; shortening the interval (for the same total daily input) usually reduces peak–trough fluctuation. A regimen is chosen for the drug's relevant exposure target—peak, trough, average concentration or AUC—not because every drug must remain inside a rigid band at every moment.
    Toxic concentration
    ─────────────────── ← Must stay below this
    |  Peak (Cmax)     |
    |     /\           |
    |    /  \          |  ← THERAPEUTIC WINDOW
    |   /    \         |
    |  Trough          |
    ─────────────────── ← Must stay above this
    Minimum effective concentration

If a second dose is given after the first dose was completely eliminated (approx. 5 t½), this dosage regimen does not result in any drug accumulation ^[1]

But in practice, we dose before complete elimination — that's the whole point of maintenance dosing. Each subsequent dose adds to the residual drug from previous doses, and the plasma concentration ratchets upward until input rate = output rate. This equilibrium is steady state.

Worked visual from slide 23: an ideal one-compartment IV bolus gives an initial increment of 200 mg/L and is repeated every one half-life (5 h), so 50% remains at each next dose. The accumulation factor is 1 / (1 − 0.5) = 2: the limiting peak is 400 mg/L and the limiting pre-dose trough is 200 mg/L. Each cycle then repeats even though concentration still oscillates—steady state does not mean a flat line.

Steady state is defined as the dosing interval in which the AUC for that interval is equal to the single-dose AUC ^[1]

As a rule of thumb, steady state can be achieved after 5 elimination half-lives ^[1]

At steady state, the amount entering during each interval equals the amount eliminated during that interval. For linear, time-invariant PK, the AUC over one steady-state interval equals the single-dose AUC for the same dose.

Average Css = (Bioavailability × Dose) / (Interval × Clearance) ^[1]

The slide's equation describes average steady-state concentration (Css,av), not the peak or trough. It tells you:

• ↑ Dose or ↑ F → ↑ Css
• ↑ Interval (τ) or ↑ CL → ↓ average Css
• The equation does NOT depend on Vd — Vd affects how quickly you reach steady state (via t½), not the level itself

Loading dose = target concentration × Vd / F (F = 1 for IV) ^[1]

PK parameters are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single dose or multiple doses. Characterized by FIRST ORDER KINETICS. Plasma concentration at steady state and AUC are proportional to dose. ^[1]

Interpretation: in linear PK, systemic CL and Vd are approximately dose-invariant over the studied range, and exposure is dose-proportional. Route-dependent parameters such as F and absorption rate can still differ, and an oral estimate CL/F is not interchangeable with IV CL.

PK parameters may vary depending on the administered dose. Other kinetics may be involved, e.g., ZERO ORDER KINETICS. Plasma concentration at steady state and AUC will NOT be proportional to dose. ^[1]

First-order elimination applies only to compounds eliminated exclusively by mechanisms not involving enzymatic or active transport processes. At clinical dosages, the majority of drugs do not reach saturation concentrations. ^[1]

Correction: enzyme- and transporter-mediated elimination is commonly first-order below capacity. Nonlinearity emerges when a relevant absorption, binding, metabolism or excretion pathway changes with concentration or time; it is not defined by the mere presence of an enzyme or active transporter.

This slide is extremely high-yield — it gives specific examples at each ADME step:

Clinical practice of measuring a specific drug at designated intervals to maintain a constant concentration. Involves not only measuring drug concentrations, but also the clinical interpretation of the result. Aims at optimizing an individual's dosage regimen. ^[1]

Current interpretation: TDM uses a correctly timed concentration, the dose history and the patient's clinical state to optimise exposure. The aim is not necessarily a constant concentration—some drugs deliberately fluctuate between peaks and troughs, while others are managed by AUC. A number without dose time, sample time, recent dose changes, adherence, organ function and interacting medicines is often uninterpretable.

1. Monitor drug compliance 2. Maintain drug efficacy especially for conditions with poorly defined clinical endpoints 3. Suspected toxicity 4. Monitor and detect drug interaction ^[1]

Let's unpack each:

1. Adherence assessment: A patient on an antiepileptic who keeps having seizures — is the drug failing, or are doses being missed? A low level may support nonadherence but can also reflect incorrect timing, altered absorption, an interaction or unusually high clearance.
2. Poorly defined or delayed endpoints: For seizure prophylaxis, there is no immediate bedside measure analogous to blood pressure. A validated concentration target can provide an additional dosing signal.
3. Suspected toxicity: A patient on digoxin presents with nausea, visual symptoms or arrhythmia — a correctly timed level supports interpretation but does not confirm or exclude toxicity by itself.
4. Drug interactions: Starting a strong inhibitor or inducer may change exposure; obtain a level only when the drug, interaction and sampling plan make the result actionable.

Criteria: Narrow therapeutic range, Established target concentration range, Significant intra-/inter-subject variability, Significant dose-response relationship, Nonlinear pharmacokinetic profile, Availability of cost-effective drug assay ^[1]

The decisive criterion is an actionable concentration–response or concentration–toxicity relationship: the assay and sampling strategy must improve a dosing decision beyond clinical observation alone. Nonlinearity and variability strengthen the case but do not, by themselves, make routine TDM useful.

Clinical outcome is unrelated to dose or plasma concentration; Dosage need not be individualized; Pharmacological effects can be clinically quantified; Wide therapeutic index ^[1]

The second statement is too broad. A drug may still need dose individualisation for kidney function, liver function, age or interactions even when routine concentration monitoring adds no value. TDM is usually unnecessary when there is a wide safety margin, no validated/actionable concentration target, or a faster and better clinical or laboratory endpoint can be measured directly.

Example of a drug NOT needing TDM: Antihypertensives — you measure BP directly. The clinical endpoint (BP) is easily quantifiable, and you titrate to that endpoint. No need to measure drug levels.

Example of a drug needing TDM: Lithium has a narrow margin, renal clearance and important interactions. Targets depend on indication, treatment phase, age and local protocol; toxicity can occur within a nominal range, so symptoms and laboratory context always matter. Current product information specifies a sample immediately before the next dose when stable—approximately 12 hours after the previous dose—and recommends rechecking after dose, interacting-drug or relevant illness changes. ^[17]

Drugs requiring therapeutic drug monitoring: Digoxin, Lithium, Phenytoin, Cyclosporin, Tacrolimus, Sirolimus ^[1]

Physiological changes with aging affect pharmacokinetics:

• Absorption: Reduced gastric acid, slower gastric emptying → minimal clinical effect for most drugs
• Distribution: Reduced lean body mass, increased adipose → ↑ Vd for lipophilic drugs; reduced albumin → ↑ free fraction
• Metabolism: Reduced hepatic blood flow and mass → reduced first-pass effect and Phase I metabolism (Phase II relatively preserved)
• Excretion: Reduced GFR → reduced renal clearance → drug accumulation

Pharmacokinetic drug–drug interactions: The most frequent involve CYP450 isoenzymes and drug transporters such as P-glycoprotein ^[7]

• Pharmacokinetic interactions alter drug levels (ADME-based)
• Pharmacodynamic interactions alter drug effects without changing levels
• CYP3A4 is the most abundant CYP; key inhibitors (ketoconazole, ritonavir, grapefruit juice) and inducers (rifampicin, carbamazepine, phenytoin, St. John's wort)

Pharmacogenes typically relate to pharmacokinetics (ADME) or pharmacodynamics (target receptor). E.g., 30-35% of warfarin dose variability attributed to CYP2C9, CYP4F2 (PK) and VKORC1 (PD) polymorphisms. ^[6]

• Renally excreted drugs (aminoglycosides, digoxin, lithium, metformin) require dose adjustment in CKD
• Use the renal-function measure specified in the product information or local protocol; Cockcroft–Gault creatinine clearance and eGFR are not automatically interchangeable. When using eGFR to represent an individual's drug-clearing capacity, consider whether de-indexing from 1.73 m² to mL/min is required. ^[14]

From reviewing 4th Summative MCQ/SAQ papers ^[10][11][12], pharmacokinetics questions have appeared testing:

• Definition and clinical application of bioavailability
• Loading dose rationale and calculation
• Steady-state timing (5 × t½ rule)
• Which drugs require TDM and why
• Nonlinear kinetics (phenytoin, ethanol)
• Drug dose adjustment in renal/hepatic impairment
• CYP450 interactions and clinical consequences