L01 Clinical Pharmacology Introduction and Dose decisions (Pharmacokinetics 1)

Overview

This lecture introduces Pharmacokinetics — what the body does to a drug — and shows how the four ADME processes translate a prescribed dose into a plasma concentration, and therefore into an effect. It opens with the PK/PD chain and the therapeutic window (the band between the minimum effective and minimum toxic concentrations) as the target that dosing aims at. It then works through each determinant of where a drug’s concentration-time curve sits: the route of administration, oral availability and first-pass metabolism, how drugs cross lipid membranes (including ionisation and ion trapping), clearance, and distribution. The final part assembles these into the three parameters used for dose decisions — volume of distribution, clearance and half-life — and shows how they give the loading dose and the dosing interval, and how patient factors alter them.

Course context and objectives

• Aims: introduce pharmacokinetics in drug dosing and therapeutic management; understand the four main components of pharmacokinetics (ADME); prepare for the attendant PK workshops in ELM2 Clinical Pharmacology the following week.
• Warning given on the objectives slide: apply these concepts to all subsequent therapeutic lectures, to build up an understanding of how drugs are handled by the body.
• Computer lab: 3rd Floor Adams Building Rm 304, next week according to stream. Details on Moodle; an LT KuraCloud invite arrives on the university email and requires sign-in with the University account. Bring a laptop, no lab coat.
• Reading: lecture slides on Moodle; the attendant PK workshop; Instant Clinical Pharmacology (Begg, Blackwell) pp. 1–16; Goodman & Gilman’s The Pharmacological Basis of Therapeutics 14th edn, Chapter 2 (subsection on Clinical Pharmacokinetics); http://www.icp.org.nz/index.html. Available in the Med Library.

Pharmacokinetics vs pharmacodynamics: the sequence of events

The chain of clinical pharmacological events runs in this order:

1. Drug dose (oral, i.v., s.c., etc.)
2. Pharmacokinetics — what the body does to the drug
3. Drug concentration at the site of action
4. Pharmacodynamics — what the drug does to the body
5. Drug effect/s

Drug concentration at the site of action is the handover point: everything before it is PK, everything after it is PD.

A second, clinically framed version of the same chain (Doogue & Polasek 2013) spells the PK steps out as A, B, C, D:

• Prescription → Dose, mediated by adherence.
• A = Administration: adherence, route.
• B = Bioavailability: absorption, first-pass metabolism, ± activation. Takes dose → concentration.
• C = Clearance: metabolism, excretion. Acts back on concentration.
• D = Distribution: diffusion, transport. Takes concentration → effects, via concentration at target, affinity to target, molecular effects, physiological effects.
• Administration, bioavailability and clearance are grouped as pharmacokinetics; the target/affinity/effect steps are grouped as pharmacodynamics. Effects then determine patient health.

Transcript flag (slide 7): the pdftotext layer for this slide contains only a row of dots ("……………..") as a placeholder under the title; all content above is read from the reproduced figure image.

ADME

ADME represents the four stages of pharmacokinetics: Absorption, Distribution, Metabolism and Excretion.

The sequence, as drawn: a dose (capsule, injection or topical gel) undergoes systemic absorption (A) into the blood; from the blood the drug undergoes distribution (D) into body compartments, with two-way exchange between blood and compartments; from the blood the drug undergoes clearance (elimination), which comprises metabolism (M) plus excretion (E).

All these factors are critical in determining:

• the optimal plasma concentration
• the route of administration
• the dose
• the dosing interval

The therapeutic window and the concentration-time profile

Objective of dosing: keep the plasma concentration (Cp) between the minimum effective concentration and the minimum toxic concentration.

• Minimum Effective Concentration (MEC): the lower bound. Below it there is failure to treat adequately.
• Minimum Toxic Concentration (MTC): the upper bound, marked on the slide with a poison symbol. Above it, toxicity.
• Optimal Therapeutic Range: the band between MEC and MTC.

Profile after a single oral dose: Cp rises (rising limb = absorption), peaks below the MTC, then falls (falling limb = elimination) back below the MEC. The interval between the two points where the curve crosses the MEC is the effective duration of drug action — the time for which Cp stays above the MEC and below the MTC.

With repeated oral dosing the curve rises steeply, progressively flattens, and approaches a plateau: the steady state plasma concentration (Cpss), which should sit between MEC and MTC. Repeated dosing therefore accumulates towards steady state within the therapeutic window.

Area under the curve (AUC)

• AUC corresponds to the fraction of the administered dose that reaches the systemic circulation, i.e. body exposure.
• Units: concentration (mg drug) × hours / volume (L).
• AUC depends on the dose administered and the rate of drug elimination.
• Calculated by the trapezoidal method: divide the area beneath the curve into trapezoids with vertical lines and sum all of them.

Routes of administration

Two families:

1. Enteral — involving any part of the enteric system (GI tract): oral, sublingual and rectal.
2. Parenteral — not via the enteral route:
   • systemic delivery: IV bolus/infusion, IA, IM, SC
   • approximately non-systemic: topical, inhalation, etc.

Sites labelled on the body diagram (Lippincott’s): parenteral IV, IM, SC; sublingual; inhalation; oral; transdermal patch; topical; rectal.

IV vs oral shape of the curve: the IV curve rises almost vertically to a high early peak then declines; the oral curve rises slowly to a later, lower, broader peak then declines, the two crossing on the way down. IV gives a rapid high peak, oral a delayed and blunted one.

Enteral routes

Route	Advantages	Disadvantages
Oral (P.O.), e.g. paracetamol	Easy to administer; inexpensive formulation	Possibly slow onset; impossible in unconscious/vomiting patient; harsh GI environment; subject to 1st pass metabolism
Sublingual (S/L), e.g. glyceryl trinitrate (GTN)	Rapid absorption into buccal venous drainage; avoids 1st pass metabolism	Patient may swallow the drug
Rectal, e.g. diazepam in epileptic seizure crisis	Rapidly effective in the unconscious patient; 50% of drug avoids hepatic 1st pass metabolism	Absorption can be irregular and incomplete; certain drugs can irritate the rectal mucosa

Parenteral routes

Route	Advantages	Disadvantages
Intravascular (IV/IA) — bolus (small volume) or infusion (maintenance), e.g. alteplase	Rapid delivery and effect; useful for drugs poorly absorbed or unstable in the GI tract; avoids 1st pass metabolism	Can be difficult to reverse; risk of infection; needs skill in administration (particularly the IA route)
Subcutaneous (SC), e.g. insulin	Rapid, easy delivery	Small volumes only
Intramuscular (IM), e.g. adrenaline	Moderately quick delivery; allows larger volume than subcutaneous	Can be painful, with risk of bleeding

Intravascular delivery allows complete systemic administration of the drug. The paired graph shows an IV bolus driving Cp almost vertically up to target, and a constant IV infusion then holding it as a flat plateau at Cpss between MEC and MTC — the bolus achieves the target concentration immediately, the infusion maintains it.

Injection depth and angle (skin layers from the surface inwards: epidermis, dermis, subcutaneous tissue, muscle):

• Intradermal: 10–15° angle, needle stays within the dermis
• Subcutaneous: 45° angle, needle reaches subcutaneous tissue
• Intramuscular: 90° angle, needle reaches muscle

Inhalation

Absorption onto and via the large surface area of the lungs. Useful for:

• Bronchial airways treatment — direct rapid delivery to the bronchial airways, avoiding the systemic circulation at low doses (e.g. bronchodilators).
• Inhalational gaseous anaesthesia — rapid exchange across pulmonary membranes allows immediate control of plasma concentration (e.g. sevoflurane, absorbed and eliminated at the lungs).

Bioavailability (oral availability)

Definition: the fraction of dose (F) that reaches the systemic circulation in the active form following administration, dependent on the oral availability of the individual drug.

• IV administration delivers the drug directly to the circulation, so F for an IV drug is 1.
• Oral delivery is subject to absorption and first-pass metabolism, with or without drug activation.
• F for an oral drug is calculated as a percentage of the IV drug:

$F\%=\frac{AU{C}_{oral}}{AU{C}_{IV}}\times 100$

The illustrating figure plots an IV curve (area = $AU{C}_{iv}$) against an oral curve (area = $AU{C}_{oral}$), the oral curve labelled frusemide 40 mg.

What determines oral availability

Drug absorption — transport from the site of administration (gut lumen) into the central compartment (systemic circulation). Impacted by:

• drug lipid solubility
• gastric pH
• pKa
• surface area
• blood flow
• GIT transit time
• presence of other drugs

First-pass metabolism of drugs from the GI tract, dependent on:

• gastric pH and gastric motility
• metabolic enzymes in the gut lumen, gut wall (enterocytes) and liver that break the drug down before it reaches the circulation
• hepatic mass / perfusion (affected by liver damage, age, etc.)
• concomitant presence of other drugs

The four metabolic systems of first-pass metabolism

First-pass metabolism reduces oral availability. The primary systems involved:

1. Enzymes in the gastrointestinal lumen
2. Gut wall enzymes
3. Bacterial enzymes
4. Hepatic enzymes (CYP3A4, etc.)

Fate of an orally administered drug (Roden & George 2002): an oral capsule releases drug into the small intestine lumen → the drug crosses the enterocyte of the intestinal wall → absorbed drug travels via the portal vein to the liver → from the liver, drug/metabolite passes into the systemic circulation → on to the circulation–tissue interface (for example the blood–brain barrier) → target tissue. From the liver, material is also secreted into bile. Elimination routes shown: kidney → urine, and gut → faeces. Figure key: blue circle = drug, green square = metabolite, green arrow = processes that decrease drug delivery to targets, dark blue arrow = processes that enhance drug delivery to targets.

Transcript flag (slide 21): the Roden & George (2002) citation is present in the PDF text layer but is not visible on the rendered page.

Rate of absorption determines whether the dose works

• Too rapid absorption: Cp can reach a concentration over the MTC, i.e. toxicity.
• Too slow absorption: Cp can fail to reach the MEC threshold, i.e. no treatment effect.

The worked graph (MTC = 20, MEC = 10) plots three absorption rates: the fastest peaks at roughly 23 at about 3 hours, above the MTC; the intermediate peaks at roughly 17 at about 4 hours, inside the therapeutic range; the slowest rises gradually to roughly 8.5 at about 8 hours and never reaches the MEC.

Transport of drugs across lipid membranes

Applies at the GI tract, blood–brain barrier and renal cell membranes. The route depends on the chemical property of the drug:

• Passive transport (most drugs), comprising:
  • paracellular transport — solute passing between adjacent cells through the junction
  • diffusion — drug molecules crossing directly through the bilayer down the gradient
  • facilitated diffusion — drug binding a carrier protein in the membrane and being released on the other side
• Active transport (an energy-dependent process): ATP binding transporters, shown as a membrane protein moving drug molecules across the membrane.

Transport processes determine drug concentration and rate of delivery to the site of action, i.e. they impact on absorption, clearance and distribution.

Transcript flag (slide 22): the active-transport label is partly obscured on the slide — the second word beneath the "ATP Binding" text box reads "transporters", i.e. "ATP Binding … transporters".

Physicochemical properties, pKa and ionisation

Physico-chemical properties also affect bioavailability:

• molecular weight and particle size
• hydrophilic/lipophilic nature of the drug, and the factors affecting this
• pKa and ionisation status — most drugs form weak acids or weak bases and are unionised at physiological pH. Strong acids and bases are ionised and not absorbed.

Key principle: a substance becomes more lipid soluble in a solution with a pH similar to its own pKa.

• A weak acid (e.g. aspirin) is less ionised and more lipid-soluble in an acidic solution (e.g. gastric fluids).
• A weak base (e.g. lignocaine) is less ionised and more lipid-soluble in an alkaline solution (e.g. plasma).

pH and pKa defined

• The pH of a solution is dictated by the H⁺ concentration and influences the rate of dissociation of weak acids and bases.
• The pKa of a drug is the pH at which the drug exists 50:50 ionised to unionised.

Equilibria: $HA\rightleftharpoons A^{-}+H^{+}$ (acid) and $B{H}^{+}\rightleftharpoons B+H^{+}$ (base).

• Weak acids have a low pKa — they give up their H⁺ ions and become ionised at high pH. On the illustrating scale (pH 1–11), an acid with pKa 4.5 is 50% ionised at pH 4.5, increasingly unionised below it and increasingly ionised above it.
• Weak bases have a high pKa — they gain H⁺ ions and become ionised at low pH. A base with pKa 9.5 is 50% ionised at pH 9.5, increasingly ionised below it and increasingly unionised above it.

On the % ionisation vs pH plot, the weak acid curve rises from near 0% at low pH to 100% at high pH, crossing 50% just below body pH; the weak base curve starts at 100% at low pH and falls towards 0% at high pH. Body pH is marked just above 7.

Ion trapping

Only the unionised form can cross the membrane. It diffuses down the concentration gradient to the other side, where most of it becomes ionised and trapped.

Worked example, oral aspirin:

• Unionised weak acid (aspirin) in gastric juice at pH 1.4 is membrane-permeant and moves out into the plasma at pH 7.4.
• In gastric juice the equilibrium favours the unionised form: relative concentrations AH [1] vs ionised [0.001].
• In plasma the equilibrium favours the ionised form: AH [1] vs ionised [1000].
• Aspirin therefore becomes ionised and accumulates in the plasma compartment with high pH — the unionised species equilibrates across the membrane while the ionised species is trapped on the high-pH side.
• Equally, a weak base will accumulate in a compartment with low pH, such as the cytoplasm.
• This can be useful to increase the concentration of drugs at various sites.

Transcript flag (slide 25): a vertical numeric label inside the membrane on the left, apparently "1000", is too small/rotated to read with certainty.

Clearance (Cl)

Definition: the volume of plasma cleared of drug per unit time.

Drugs are mainly cleared/eliminated through:

• Metabolic processes, mainly in the liver (less in kidney, lungs, heart, etc.) — covered further in the PK lectures on drug metabolism and CYP450 enzymes.
• Renal clearance of active drug or active metabolites — covered further in the Pharmacology lectures on diuresis (ELM2/3).

$C{l}_{total}=C{l}_{renal}+C{l}_{hepatic}+C{l}_{other}$

Clearance is crucially important in determining the maintenance dose-rate needed to produce a constant Cp.

Clearance is inversely related to AUC:

$Cl=\frac{Dose}{AUC}$

After an IV bolus the curve rises steeply to a peak at $t_{max}$ then decays exponentially. The elimination rate is steeper at high Cp — this is first order elimination kinetics.

Distribution

Once absorbed into the circulation the drug is transported into tissues and extracellular fluids; some drug is retained in the plasma.

Rate of distribution depends on:

• membrane permeability
• organ perfusion
  • highly perfused tissue equilibrates more rapidly (brain, liver, kidney)
  • poorly perfused tissue equilibrates more slowly (skeletal muscle, adipose tissue)

Extent of distribution depends on:

• drug lipid solubility
• pH of the environment and pKa of the drug
• plasma (albumin) and tissue protein binding — no real impact on distribution or on total plasma concentration, unless protein binding is altered by disease or other drugs

It is the free drug that acts on drug receptors to produce an effect: $[\text{Free Drug}]\propto \text{Extent of Drug Effect}$. Free drug concentration at the site also depends on the rate of free drug clearance from plasma, because only unbound drug can be metabolised or renally cleared.

Volume of distribution (Vd)

How well a drug is distributed throughout the body is indicated by its volume of distribution: the more compartments a drug gets into, the greater the Vd. Vd relates the amount of drug administered (Ab) to the concentration of drug in the plasma:

$Vd=\frac{Ab}{C{p}_0}$

Reported in litres, or litres/kg body weight.

Vd is not an actual anatomical volume but a theoretical fluid volume that would be required to contain all of the drug in the body at the concentration measured in the plasma.

Worked comparison, same 40 mg dose:

• One compartment, hydrophilic drug: all 40 mg stays in plasma, $C{p}_0=10$ mg/L, so $Vd=4$ L.
• Two compartments, lipophilic drug: only 0.4 mg retained in plasma ($C{p}_0=0.1$ mg/L) with 39.6 mg distributed to other organs, so $Vd=400$ L.

Lipophilic drugs cross membranes readily and enter more compartments, so they have a larger Vd than hydrophilic drugs. Greater distribution out of plasma lowers $C{p}_0$ and so produces a larger apparent Vd.

Vd is useful clinically when determining the loading dose necessary for a desired blood concentration of a drug.

Calculating Vd:

• Ab at the time of administration is known accurately if given IV.
• $C{p}_0$ is obtained by extrapolation to time zero — the hypothetical drug concentration predicted if distribution had been achieved instantly. On a semi-log plot of $(ln)Cp$ against time, the terminal decay is a straight line of slope K; extrapolating it back to time zero gives $C{p}_0$.
• Worked example: 500 mg injected IV, extrapolated $C{p}_0=5$ mg/L, so $Vd=500/5=100$ L. Adjusted for a 60 kg patient: $100/60=1.66$ L/kg.

Half-life, the elimination rate constant, and dose interval

t½ is a measure of the time taken to eliminate half the drug. It is important in determining what the dose interval should be, and it determines the duration of action after a single dose.

Obtaining t½ by linearising the curve: on a plot of Cp against time (exponential decay), neither the starting concentration nor the half-life can be read directly. Replot with a logarithmic concentration axis — $(ln)Cp$ against time — and the decay becomes a straight line whose slope is the elimination constant K. Extrapolating the line back to time zero gives $C{p}_0$; dropping from the point where concentration has fallen from 10 to 5 (half of $C{p}_0$) to the time axis gives t½.

t½ is the reciprocal function of the drug elimination rate constant, and the rate constant can equally be expressed as a function of half-life. When the initial plasma concentration has been cleared away by half (i.e. when $Cp=0.5\times C{p}_0$):

$k=\frac{0.693}{t_{1/2}}$

where 0.693 is the natural log of 2, $t_{1/2}$ is the half-life, and k is the elimination rate constant expressed as a fraction per unit time. The natural logarithm of 2 is used because we are dividing the end value by 2.

t½ depends on both Vd and Cl:

$t_{1/2}\propto \frac{Vd}{Cl}{t}_{1/2}=\frac{0.693\times Vd}{Cl}$

Effect of patient factors on t½: sepsis, changes in plasma protein binding and oedema increase Vd, which increases t½ (a shallower slope of decay). Pregnancy increases Cl, which decreases t½ (a steeper slope). Knowing Vd and Cl therefore tells you how quickly the dose will drop and how often you will need to re-dose to maintain a therapeutic effect.

Loading dose

A loading dose allows a steady plasma concentration (Css) to be achieved quickly.

$LD=Vd\times \text{target }Cp$

Worked example — digoxin loading: digoxin has a Vd of 500 L and a target Cp of 1.5 µg/L, so $LD=500\times 1.5=750$ µg for an IV dose. If F = 80%, the corrected oral loading dose must be 937.5 µg.

Comparison of three regimens on a plot of Cp against time (0–56 hours) with Css marked:

• Continuous infusion: a smooth curve rising gradually and asymptotically approaching Css over roughly 40+ hours.
• Intermittent bolus dosing: a sawtooth of peaks and troughs starting low, climbing over successive doses, only reaching the Css range after several doses.
• Loading dose with intermittent bolus dosing: the sawtooth starts immediately in the target range from the first (loading) dose and oscillates around Css from the outset.

A loading dose therefore achieves the steady-state plasma concentration immediately rather than after several half-lives.

Sex/gender differences in absorption, distribution and excretion

Listed under the heading “Gender differences in absorption and distribution and excretion of drugs”:

Absorption

• slower GI motility and transit time
• lower gastric acid secretion
• less drug enzymes and transporters
• lower absorption rates

Body composition

• lower body weight, organ size and blood flow

Distribution

• greater body fat and lower body water content (higher Vd for lipophilic drugs, lower Vd for water-soluble drugs)
• less α1-acid glycoprotein
• lower cardiac output

Excretion

• lower renal blood flow, glomerular filtration rate (GFR), tubular secretion and reabsorption
• slower clearance of renally excreted drugs
• longer elimination half-life

Other factors

• differences in body weight, cardiac output, plasma volume and regional blood flow

Accompanying drug-handling flow diagram: drug administration feeds into absorption (enteric transport; enteric metabolism) and into distribution (intravascular space; extravascular space; protein binding). Absorption also feeds into distribution. Metabolism (hepatic influx transport; phase I metabolism; phase II metabolism) sits between them, connected to distribution, and leads to three excretion routes: biliary excretion (efflux transport), intestinal excretion, and renal excretion (efflux transport).

CYP enzyme activity, men (M) vs women (W):

Enzyme	Activity
CYP1A2	M > W
CYP2A6	W > M
CYP2B6	W > M
CYP2C9	M = W
CYP2C19	M = W
CYP2D6	Mostly W > M
CYP3A4	Mostly W > M
UDP-glucuronosyltransferases (UGTs)	M > W
Sulfotransferases	M > W
N-acetyltransferases	M < W
Methyltransferases	M > W

Source cited: Eur Heart J, Volume 36, Issue 40, 21 October 2015, pp. 2677–2680.

Transcript flags (slide 37): (1) the bulleted lists on this slide are not labelled by sex on the slide itself — they appear under the heading "Gender differences…" without stating which group each characteristic refers to; (2) the slide spells it "Billary excretion".

Take home points

• Understand the principles of Vd, t½ and Cl.
• Understand how each of these impacts on safe dosing protocols.
• Understand how the route of administration, the drug’s characteristics, and the patient’s physiological/pathophysiological status impact on these parameters.
• Co-administration of other drugs will also impact on these parameters.

Abbreviations and glossary

Prescribing abbreviations

Term	Abbreviation
Orally	p.o.
Intramuscular	i.m.
Intravenous	i.v.
Subcutaneous	s.c.
Rectal	p.r.
Before food	a.c.
After food	p.c.
As required	p.r.n.

Pharmacokinetic terms

Symbol	Meaning
Ab	Administered amount of drug in body
t½	Half-life of drug elimination
Vd	Volume of distribution
CL	Clearance
K	Rate constant of drug elimination
F	Fraction of drug which is bioavailable (%)
AUC	Area under the curve
Tmax	Time to maximum concentration
Cmax	Peak concentration (concentration maximum)
Cp	Concentration in plasma
Cpt	Concentration in plasma at time = t
Cp0	Concentration in plasma at time = 0
Cpss	Concentration in plasma at steady state

Transcript flag (slide 17): this is a section-divider slide (photographs of an infant and an elderly man with capsules and a syringe between them, and a startled baby captioned "PK ! ??"), conveying that PK terms and calculations apply across the age spectrum from paediatric to elderly — but the meaning of the divider image is implied rather than stated in text.

Self-test

1. Distinguish pharmacokinetics from pharmacodynamics, and state the point in the chain where one hands over to the other.
2. List the five steps in the sequence of clinical pharmacological events, in order.
3. In the Doogue & Polasek scheme, name what A, B, C and D stand for and state one sub-process listed under each.
4. What do the four letters of ADME stand for, and which two of them together constitute clearance?
5. List the four things the ADME factors determine.
6. Define the minimum effective concentration, the minimum toxic concentration and the optimal therapeutic range.
7. On a single-oral-dose concentration-time curve, what does the rising limb represent, what does the falling limb represent, and what defines the effective duration of drug action?
8. Define AUC, give its units, and state the two things it depends on.
9. Describe how the AUC is obtained from a concentration-time curve.
10. Explain what happens to plasma concentration over successive doses in a repeated oral dosing regimen, and name the plateau reached.
11. Distinguish enteral from parenteral administration and list the routes in each group.
12. Explain why sublingual GTN and rectal diazepam each have an advantage over the oral route, and give the specific figure quoted for the rectal route.
13. List two disadvantages of intravascular delivery.
14. State the needle angle and the tissue reached for intradermal, subcutaneous and intramuscular injection.
15. Explain the two distinct clinical uses of the inhalational route given in the lecture, and why inhalation suits each.
16. Define bioavailability (F), state its value for an IV drug, and write the equation for F% of an oral drug.
17. List the factors that impact drug absorption from the gut lumen into the systemic circulation.
18. List the four factors that first-pass metabolism of drugs from the GI tract depends on.
19. Name the four primary metabolic systems that reduce oral availability by first-pass metabolism.
20. Describe, in order, the path of an orally administered drug from the small intestine lumen to the target tissue, and name the routes by which material is eliminated.
21. Predict what happens to plasma concentration if a drug is absorbed too rapidly, and what happens if it is absorbed too slowly.
22. List the three mechanisms of passive transport across a lipid membrane, and state what active transport requires.
23. Explain why transport processes matter, i.e. which three pharmacokinetic processes they impact.
24. Define pKa, and explain why a weak acid such as aspirin is more lipid-soluble in gastric fluid than in plasma.
25. Explain the mechanism of ion trapping, and use the aspirin example to say in which compartment the drug accumulates and why.
26. Define drug clearance, name the main organ of metabolic clearance, and write the equation for total clearance.
27. Write the equation relating clearance to AUC, and state what clearance is crucially important for determining.
28. Explain why the elimination curve after an IV bolus is steeper at high Cp, and name the kinetics this describes.
29. List the two determinants of the rate of drug distribution, and give the tissue examples for fast and slow equilibration.
30. List the three determinants of the extent of drug distribution, and explain why plasma protein binding usually has no real impact on distribution.
31. Explain why the free drug concentration, rather than the total, determines the extent of drug effect.
32. Define volume of distribution, write its equation, and explain why it is described as a theoretical rather than an anatomical volume.
33. Explain why a lipophilic drug has a larger Vd than a hydrophilic drug, using the 40 mg worked example.
34. Describe how Cp0 is obtained from measured plasma concentrations, and why the curve must be linearised first.
35. A 500 mg dose is given IV and the extrapolated Cp0 is 5 mg/L. Calculate the Vd, and express it per kg for a 60 kg patient.
36. Write the two equations linking half-life to the elimination rate constant and to Vd and Cl, and explain why the constant 0.693 appears in them.
37. Predict the effect on half-life of (a) sepsis or oedema and (b) pregnancy, and explain the mechanism in each case.
38. State what a loading dose achieves, write the equation, and explain how the loading-dose regimen differs from plain intermittent bolus dosing on a concentration-time plot.
39. Digoxin has a Vd of 500 L and a target Cp of 1.5 µg/L. Calculate the IV loading dose, then the corrected oral loading dose if F = 80%.
40. List the changes in absorption, distribution and excretion described on the gender-differences slide, and note the limitation of that slide.
41. Name three CYP enzymes for which activity is reported as W > M and one for which it is M > W.
42. Integrative: a lipophilic drug is prescribed to a septic patient. Explain how sepsis alters Vd, how that in turn alters t½ via the half-life equation, and what this means for the loading dose and the dosing interval.
43. Integrative: an oral drug undergoes extensive first-pass metabolism. Explain how this shows up on a concentration-time curve, how it changes F, and how the prescriber must adjust a loading dose calculated for the IV route.
44. Application: a drug given orally never produces an effect despite a correct total dose, and its plasma curve peaks late and low. Using the lecture’s absorption-rate graph, explain what has gone wrong.

Answers

Reveal answers

1. Pharmacokinetics is what the body does to the drug (dose → concentration at the site of action); pharmacodynamics is what the drug does to the body (concentration at the site of action → effects). Drug concentration at the site of action is the handover point.
2. Drug dose (oral, i.v., s.c., etc.) → pharmacokinetics → drug concentration at site of action → pharmacodynamics → drug effect/s.
3. A = Administration (adherence, route); B = Bioavailability (absorption, first-pass metabolism, ± activation); C = Clearance (metabolism, excretion); D = Distribution (diffusion, transport).
4. Absorption, Distribution, Metabolism, Excretion. Metabolism plus excretion together make up clearance (elimination).
5. The optimal plasma concentration, the route of administration, the dose, and the dosing interval.
6. MEC is the plasma concentration below which there is failure to treat adequately; MTC is the concentration above which toxicity occurs; the optimal therapeutic range is the band between them, and the objective of dosing is to keep Cp within it.
7. Rising limb = absorption; falling limb = elimination. The effective duration of drug action is the interval between the two points where the curve crosses the MEC, i.e. the time Cp stays above the MEC (and below the MTC).
8. AUC corresponds to the fraction of the administered dose that reaches the systemic circulation, i.e. body exposure. Units: concentration (mg drug) × hours / volume (L). It depends on the dose administered and the rate of drug elimination.
9. By the trapezoidal method: divide the shaded area under the curve into a series of trapezoids with vertical lines and add the areas of all the trapezoids.
10. Cp rises steeply after the first dose, then the rise progressively flattens over successive doses as the drug accumulates, approaching a plateau — the steady state plasma concentration (Cpss) — which should lie between MEC and MTC.
11. Enteral involves any part of the enteric system (GI tract): oral, sublingual, rectal. Parenteral is anything not enteral: systemic delivery (IV bolus/infusion, IA, IM, SC) and approximately non-systemic routes (topical, inhalation, etc.).
12. Sublingual gives rapid absorption into the buccal venous drainage and avoids first-pass metabolism. Rectal delivery is rapidly effective in the unconscious patient and 50% of the drug avoids hepatic first-pass metabolism.
13. Any two of: can be difficult to reverse; risk of infection; needs skill in administration, particularly with the IA route.
14. Intradermal 10–15°, needle stays in the dermis; subcutaneous 45°, needle reaches subcutaneous tissue; intramuscular 90°, needle reaches muscle.
15. Bronchial airways treatment — direct rapid delivery to the airways avoiding the systemic circulation at low doses (e.g. bronchodilators); and inhalational gaseous anaesthesia — rapid exchange across pulmonary membranes gives immediate control of plasma concentration (e.g. sevoflurane, absorbed and eliminated at the lungs). Both exploit the large surface area of the lungs.
16. F is the fraction of dose that reaches the systemic circulation in the active form after administration. F = 1 for an IV drug. $F\%=(AU{C}_{oral}/AU{C}_{IV})\times 100$.
17. Drug lipid solubility, gastric pH, pKa, surface area, blood flow, GIT transit time, and the presence of other drugs.
18. Gastric pH and gastric motility; metabolic enzymes in the gut lumen, gut wall (enterocytes) and liver that break the drug down before it reaches the circulation; hepatic mass/perfusion (affected by liver damage, age, etc.); concomitant presence of other drugs.
19. Enzymes in the gastrointestinal lumen; gut wall enzymes; bacterial enzymes; hepatic enzymes (CYP3A4, etc.).
20. Capsule releases drug into the small intestine lumen → across the enterocyte of the intestinal wall → via the portal vein to the liver → into the systemic circulation → across the circulation–tissue interface (e.g. blood–brain barrier) → target tissue. Elimination: liver → bile; kidney → urine; gut → faeces.
21. Too rapid absorption can drive Cp above the MTC, causing toxicity. Too slow absorption can leave Cp below the MEC, so there is no treatment effect.
22. Passive transport: paracellular transport (between adjacent cells through the junction), diffusion (directly through the bilayer down the gradient), and facilitated diffusion (binding a carrier protein and being released on the other side). Active transport is energy dependent, via ATP binding transporters.
23. Transport processes determine drug concentration and the rate of delivery to the site of action, so they impact absorption, clearance and distribution.
24. pKa is the pH at which the drug exists 50:50 ionised to unionised. A substance is more lipid soluble in a solution whose pH is close to its own pKa; aspirin is a weak acid with a low pKa, so it is less ionised (and therefore more lipid-soluble) in acidic gastric fluid than in plasma.
25. Only the unionised form can cross the membrane; it diffuses down its gradient to the other side, where most of it becomes ionised and is trapped because the ionised form cannot cross back. For aspirin, the unionised acid crosses out of gastric juice (pH 1.4, unionised:ionised ≈ 1:0.001) into plasma (pH 7.4, ≈ 1:1000), where it ionises and accumulates. A weak base accumulates instead in a low-pH compartment such as the cytoplasm.
26. Clearance is the volume of plasma cleared of drug per unit time. Metabolic clearance is mainly hepatic (less in kidney, lungs, heart etc.), with renal clearance of active drug or active metabolites. $C{l}_{total}=C{l}_{renal}+C{l}_{hepatic}+C{l}_{other}$.
27. $Cl=Dose/AUC$, so clearance is inversely related to AUC. Clearance is crucially important in determining the maintenance dose-rate needed to produce a constant Cp.
28. Because elimination is first order: the rate of elimination is proportional to concentration, so more drug is removed per unit time when Cp is high, making the early part of the decay steeper.
29. Membrane permeability and organ perfusion. Highly perfused tissue equilibrates more rapidly (brain, liver, kidney); poorly perfused tissue more slowly (skeletal muscle, adipose tissue).
30. Drug lipid solubility; the pH of the environment and the pKa of the drug; plasma (albumin) and tissue protein binding. Protein binding has no real impact on distribution or total plasma concentration unless the binding itself is altered by disease or by other drugs.
31. Only the free (unbound) drug acts on drug receptors to produce an effect, so $[\text{Free Drug}]\propto$ extent of drug effect. Only unbound drug can also be metabolised or renally cleared, so free concentration at the site also depends on the rate of free drug clearance from plasma.
32. Vd indicates how well a drug is distributed through the body — the more compartments it enters, the greater the Vd. $Vd=Ab/C{p}_0$, reported in litres or L/kg. It is theoretical because it is the fluid volume that would be required to contain all the drug in the body at the concentration measured in plasma, not a real anatomical volume.
33. Lipophilic drugs cross membranes readily and enter more compartments, so less drug remains in plasma and Cp0 is lower, giving a larger apparent Vd. With 40 mg: hydrophilic, all retained in plasma, Cp0 = 10 mg/L → Vd = 4 L; lipophilic, only 0.4 mg in plasma with 39.6 mg in other organs, Cp0 = 0.1 mg/L → Vd = 400 L.
34. Plot $(ln)Cp$ against time: the decay becomes a straight line of slope K (the elimination constant), and extrapolating that line back to time zero gives Cp0 — the hypothetical concentration if distribution had been instant. Linearising is necessary because neither Cp0 nor t½ can be read directly off the exponential curve.
35. $Vd=500\text{mg}/5\text{mg/L}=100$ L; for a 60 kg patient, $100/60=1.66$ L/kg.
36. $k=0.693/t_{1/2}$ and $t_{1/2}=(0.693\times Vd)/Cl$. 0.693 is the natural logarithm of 2, used because half-life involves dividing the end value by 2.
37. (a) Sepsis, oedema and changes in plasma protein binding increase Vd; since $t_{1/2}\propto Vd/Cl$, increased Vd lengthens t½ (shallower decay). (b) Pregnancy increases Cl, which shortens t½ (steeper decay).
38. A loading dose lets a steady plasma concentration (Css) be achieved quickly. $LD=Vd\times \text{target }Cp$. With plain intermittent bolus dosing the sawtooth starts low and only climbs into the Css range after several doses; with a loading dose the sawtooth starts in the target range from the first dose and oscillates around Css from the outset.
39. $LD=500\times 1.5=750$ µg IV. With F = 80%, the corrected oral loading dose is 937.5 µg.
40. Absorption: slower GI motility and transit time, lower gastric acid secretion, less drug enzymes and transporters, lower absorption rates. Distribution: greater body fat and lower body water (higher Vd for lipophilic, lower Vd for water-soluble drugs), less α1-acid glycoprotein, lower cardiac output. Excretion: lower renal blood flow, GFR, tubular secretion and reabsorption, slower clearance of renally excreted drugs, longer elimination half-life. Limitation: the slide does not label which sex each bulleted characteristic refers to.
41. W > M: CYP2A6, CYP2B6, and (mostly) CYP2D6 or CYP3A4. M > W: CYP1A2 (also UGTs, sulfotransferases, methyltransferases).
42. Sepsis increases Vd. Since $t_{1/2}=(0.693\times Vd)/Cl$, a larger Vd lengthens the half-life, so plasma concentration falls more slowly and the dosing interval can be longer. But because $LD=Vd\times \text{target }Cp$, the larger Vd also means a larger loading dose is needed to reach the same target concentration.
43. Extensive first-pass metabolism gives a lower, broader oral curve and therefore a smaller $AU{C}_{oral}$ relative to $AU{C}_{IV}$; since $F\%=(AU{C}_{oral}/AU{C}_{IV})\times 100$, F falls well below 1. An oral loading dose must therefore be corrected upwards by dividing the IV loading dose by F — as with digoxin, where an IV LD of 750 µg becomes 937.5 µg orally at F = 80%.
44. Absorption is too slow. As the absorption-rate graph shows, the slowest-absorbed curve rises only gradually to a late, low peak (roughly 8.5 at about 8 hours) and never crosses the MEC, so despite the correct total dose the plasma concentration never reaches the threshold for a treatment effect.