DENT 3005: Introduction to Pharmacology¹

Pharmacokinetics

Dr Thuy Linh Truong thuy.truong@uwa.edu.au

Acknowledgement: Sheetal Maria Rajan

Acknowledgement of country²

The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge.

Learning outcomes³

Broad

Understand the pharmacokinetic factors influencing drug-receptor interactions, and the nature of these effects on physiological response profiles

Specific topics we will cover

Different types of drug names
Difference between pharmacodynamics and pharmacokinetics
Drug absorption
Drug distribution
Drug metabolism
Drug excretion
Key pharmacokinetic factors

	Acid drug	Basic Drug
Acidic Environment	Non-ionised**	Ionised
Basic Environment	Ionised	Non-ionised**

Rang & Dale’s Pharmacology, Tenth Edition

Strong acid in water⁴

HC l $\to$ $H^{+}$ + Cl $^{-}$ Unionized Ionized

Strong base in water

NaOH $\to$ Na $^{+}$ + $O H^{-}$ Unionized Ionized

Strong acids/bases – Complete dissociation – highly ionized, hence poorly absorbed

Weak acid in water

R-COOH $\to$ R-COO $^{-}$ + $H^{+}$ Unionized Ionized

Weak acids/bases – incomplete dissociation – unionized, absorbed

Weak acid in acidic medium

R-COOH $⇌$ R-COO $^{-}$ + $H^{+}$ Unionized $H^{+}$ Ionized

The H $^{+}$ ions will prevent the dissociation of a weak acid into ionized forms

Increased unionized form, increased conc. for absorption

Compartment	Gastric juice	Plasma	Urine
pH	pH 3	pH 7.4	pH 8
Aspirin
Weak acid
pK_a 3.5
Relative concentration	< 0.1	100	> 400
		Undissociated acid AH Anion A^-	Ionisation greatest at alkaline pH
Pethidine
Weak base
pK_a 8.6	> 10⁶	100	30
	Ionisation greatest at acid pH	Protonated base BH⁺ Free base B

Rang & Dale’s Pharmacology, Tenth Edition

First pass effect & GI absorption⁵

Drug properties

Size (MW)
Solubility
Polarity/charge
Formulation (capsules, enteric coating)

Physiological properties

Gut content
GI motility
Splanchic blood flow
Physicochemical interactions with gut contents
Genetic polymorphism

Component	Location	Percentage of Dose	Associated Processes
Initial Dose	Entry	100% dose
Dose in Stomach	Stomach	100% Dose
First Pass Effect	Liver	15% of dose enters blood	Phase I CYPs, Phase II, Glucuronidation, Sulphation
Portion bypassing Liver initially	Portal vein onward	70% Dose
Dose in Small Bowel	Small bowel	70% Dose	GUT CYPs and phase II

Transdermal delivery (TDD) Skin Patches: Gendelberg et al

Other considerations⁶

Bioavailability

The fraction (F) of an orally administered dose that reaches the systemic circulation
Depended on enzyme activity of gut wall/liver, gastric pH, intestinal motility…
Relates to proportion of drug reaching the systemic circulation, neglecting the rate of absorption

Bioequivalence

Generic equivalents of patented products
If we substitute one formulation for another, no clinically untoward consequence will occur

Review!⁷⁸

Distribution

The reversible transfer of a drug from one location (e.g. blood) to another (e.g. heart, brain, or lung tissue).
Following absorption $\to$ drugs are dispersion
Doesn’t occur equally
Passive diffusion
COMPLEX

Factors affecting distribution⁹

Solubility

Lipophilic drugs readily cross & penetrate all tissues

Blood flow

$↑$ Blood flow $↑$ Distribution (heart, liver, kidneys)
$↓$ Blood flow $↓$ Distribution (skin, adipose tissue)

Plasma protein binding

Plasma or tissue free drugs /affinity for binding sites/protein
Unbound drug $\to$ active

Tissue binding

$↓$ Plasma concentration $↑$ Distribution in tissues

Drug distribution, EKG Science

The Volume of Distribution $(V)$ ¹⁰

V = Dose (mg) / Plasma concentration (mg/L)
Diffusion of drugs to other compartments
Approximate volume of plasma in 70Kg adult: 3L
$Vd \leq 0.04 L/kg \to distribution in plasma$
$Vd \leq 0.57 L/kg \to distribution in ECF$
$Vd larger \to distribution in tissue$
Clinical use
- Gives an idea of amount distributed in body
- If Vd is low, haemodialysis successful
- Calculate initial or loading dose

A diagram illustrating the separation of blood components by centrifugation, resulting in Plasma, the Buffy Coat (leukocytes and platelets), and Erythrocytes.

High $V_{DIST}$ Drug blood tissues

Low $V_{DIST}$ Drug blood tissues

Note that typical adult body volumes vary from 50 to 100 L

The diagram illustrates two scenarios for drug distribution: High $V_{D I ST}$ Drug (more drug in tissues, less in blood) and Low $V_{D I ST}$ Drug (less drug in tissues, more in blood).

Other considerations⁶

Blood brain barrier

Very tight junctions between capillary and endothelial cells
Impenetrable … almost
Defense mechanism

Blood placental barrier

Regulates transfer of molecules between and maternal circulation
Fetal harm
Check pregnancy!

Review!⁷⁸

What are some factors affecting distribution?
Which drugs will be tissue bound?
- a) Phenytoin Vd = 0.7L/kg
- b) Metoprolol Vd = 4L/kg
- c) Fluoxetine Vd = 35 L/kg
- d) Chloroquine Vd = 185L/kg
Which drug would be effectively treated with haemodialysis?
what important consideration when a patient is pregnant?

Metabolism (Biotransformation)¹¹

The chemical alteration (i.e. structural modification) of drugs and foreign chemicals (xenobiotics) by drug-metabolizing enzymes (DME) in the body.
Make drug made more polar & water-soluble ( $↓$ logP)
Facilitates excretion
Metabolism usually decreases the half-life of drugs (e.g. blood or plasma T $^{1/2}$ )
Usually reduces biological activity
Pro-drug – inactive drug becomes active, after body processes it (e.g codeine into active morphine by liver enzymes)

Conjugation $\to$ inactive product Mainly in liver Groups inserted: glucuronyl, sulphate, methyl, acetyl Result: polar product $\to$ excretion in urine

Drug metabolism, EKG Science

Other considerations⁶

Concentration and types

Genetic polymorphism
Amount of enzymes
Types of enzymes

Depot binding

Coupling of drugs with inactive sites of body $\to$ drug inaccessible for metabolism
Eg. Highly lipid soluble drugs binding in adipose tissue will have metabolism drastically reduced

Enzyme induction/inhibition

Induction: body compensates by creating more enzymes for drug metabolism $\to$ tolerance
Inhibition: increase sensitivity
Competition: reduced rate of metabolism

Enzyme induction¹²

Enzyme inducers: increase ( $↑$ ) the amount of enzymes produced
Can increase ( $↑$ ) drug toxicity (e.g. paracetamol)
Low/absence of drug activity

Enzyme inhibition

Enzyme inhibitors: block or slow down the action of enzymes
Increase ( $↑$ ) drug half-life
Toxic levels

Drug metabolism, EKG Science

flowchart TD
    subgraph Enzyme induction
        A[Active drug] -->|P450| B[Drug metabolism];
        B --> C[Inactive drug];
        D[P450 Inducer] --+--> P450;
        style B fill:#fff,stroke:#000,stroke-width:2px;
        style C fill:#fff,stroke:#000,stroke-width:2px;
        A --&gt; |&amp;uparrow;Active drug| A-end;
        C --&gt; |&amp;uparrow;Inactive drug| C-end;
        B --&gt; |&amp;uparrow;Drug metabolism| B-end;
    end

    subgraph Enzyme inhibition
        E[Active drug] --x-->|P450| F[Drug metabolism];
        F --> G[Inactive drug];
        H[P450 Inhibitor] --x--> P450_inh;
        style F fill:#fff,stroke:#000,stroke-width:2px;
        style G fill:#fff,stroke:#000,stroke-width:2px;
        E --&gt; |&amp;uparrow;Active drug| E-end;
        G --&gt; |&amp;downarrow;Inactive drug| G-end;
        F --&gt; |&amp;downarrow;Drug metabolism| F-end;
    end

Review!⁷⁸

Excretion

The permanent removal of drugs from the body. Occurs via body fluids, secretions, expired air, or tissue shedding.

Plasma half-life reflects rate of drug elimination
Refers to removal of parent (unmetabolized) drug
Key factor in drug pharmacology & toxicology
Determines duration of drug effect
Main excretion routes:
- Urine (kidneys) – most common
- Faeces (bile) – also common

Bioavailability (F)¹³

Bioavailability (oral drugs) Proportion of drug reaching systemic circulation intact

Key influencing factors in gi tract

Membrane transporters (e.g. efflux in gut wall)
First-pass metabolism (gut wall & liver)
Stability to gastric acids/enzymes
Drug formulation (e.g. pill composition)
Gut motility
Presence of food (affects pH, absorption, motility)

Some take home message¹⁴

Drugs are able to penetrate membrane barriers by several mechanisms
More lipid-soluble a drug is, the more likely it is to penetrate the lipid environment of membranes
Distribution of weak acids and weak bases depends on pH and pKa of drugs
Drug transporters play notable roles in the small intestine, liver, kidneys, and capillaries
Each route of drug administration has its own absorption characteristics
Liver is the most important organ for drug metabolism, employing many key enzymes, most notably the cytochrome P450 enzymes
Drug inhibitors and drug inducers can affect cytochrome P450 enzymes
The kidneys are the most important organs for excreting drugs
First-order Kinetics = constant percentage of drug is eliminated per unit time
Zero-order kinetics = Constant amount of drug is eliminated per unit time
Drugs differ from another in their volumes of distribution, half-life, and clearance

Review!⁷⁸

References

Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. Rang & Dale’s pharmacology. 10th ed. Edinburgh: Elsevier; 2023
Becker DE, Reed KL. Pharmacology and Therapeutics for Dentistry. 7th ed. St. Louis: Elsevier; 2017.
Bullock S, Manias E. Fundamentals of pharmacology. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017
Stringer JL. Basic concepts in pharmacology. 6th ed. New York (US): McGraw Hill Medical; 2022 Feb 18

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L1 - Pharmacokinetics 2025(1)_formatted_text

DENT 3005: Introduction to Pharmacology1

Pharmacokinetics

Acknowledgement of country2

Learning outcomes3

Broad

Specific topics we will cover

Strong acid in water4

Strong base in water

Weak acid in water

Weak acid in acidic medium

First pass effect & GI absorption5

Drug properties

Physiological properties

Other considerations6

Bioavailability

Bioequivalence

Review!78

Distribution

Factors affecting distribution9

Solubility

Blood flow

Plasma protein binding

Tissue binding

The Volume of Distribution (V)10

Other considerations6

Blood brain barrier

Blood placental barrier

Review!78

Metabolism (Biotransformation)11

Other considerations6

Concentration and types

Depot binding

Enzyme induction/inhibition

Enzyme induction12

Enzyme inhibition

Review!78

Excretion

Bioavailability (F)13

Some take home message14

Review!78

References

Footnotes

Graph View

Table of Contents

DENT 3005: Introduction to Pharmacology¹

Acknowledgement of country²

Learning outcomes³

Strong acid in water⁴

First pass effect & GI absorption⁵

Other considerations⁶

Review!⁷⁸

Factors affecting distribution⁹

The Volume of Distribution $(V)$ ¹⁰

Other considerations⁶

Review!⁷⁸

Metabolism (Biotransformation)¹¹

Other considerations⁶

Enzyme induction¹²

Review!⁷⁸

Bioavailability (F)¹³

Some take home message¹⁴

Review!⁷⁸