THE UNIVERSITY OF
WESTERN
AUSTRALIA
DENT 3005:Introduction to
Pharmacology
**Pharmacokinetics**
Dr Thuy Linh Truong
thuy.truong@uwa.edu.au
Acknowledgement: Sheetal Maria Rajan
![]()
Description of the figure: A presentation slide with the title DENT 3005:Introduction to Pharmacology, with a background of various pills, focusing on Pharmacokinetics, presented by Dr Thuy Linh Truong.
# **DENT 3005: Introduction to Pharmacology**
## **Pharmacokinetics**
Dr Thuy Linh Truong
thuy.truong@uwa.edu.au
Acknowledgement: Sheetal Maria Rajan
**Acknowledgement**
of country
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.
<img Artist: Dr Richard Barry Walley OAM> </img>
## **Acknowledgement of country**
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 outcomes
**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 <img src="https://i.imgur.com/k9bT6O6.png" alt="A diagram illustrating the concepts of absorption, distribution, metabolism, and excretion (ADME) for a drug in the human body.">
# **Learning outcomes**
## **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
**DENT3005: assessment breakdown**
| Assessment \# | Assessment Task | Weight \% | Assessment Period/ date | Module assessed | Waiver |
| :---: | :---: | :---: | :---: | :---: | :---: |
| 1 | SAQ | 50% | 30/09/25 9AM – 11AM | General Medicine and Pharmacology: all lectures content | No |
| 2 | MCQ | 50% | Main Campus: Semester 2 examination period | General Medicine and Pharmacology: all lectures content | No |
**Recommended readings**
1) NPS MedicineWise. Prescribing Competencies Framework: embedding quality use of medicines into practice (2nd Edition). Sydney, 2021 - https://www.nps.org.au/assets/NPS/pdf/NPS-MedicineWise_Prescribing_Competencies_Framework.pdf
2) Prescribing medicines in pregnancy database [Therapeutics Goods Administration] - https://www.tga.gov.au/prescribing-medicines-pregnancy-database
3) Drugs and Lactation Database (LactMed) - https://www.ncbi.nlm.nih.gov/books/NBK501922/
4) Rang & Dale's Pharmacology 9th Edition
5) Clinical Pharmacy and Therapeutics, 6th Ed
6) Australian Medicines Handbook - This can be accessed through UWA Library [Type Australian Medicines Handbook]
7) Therapeutic Guidelines - This can be accessed through eTG app (students must download the app onto the electronic device and remain logged into UWA one search for access)
8) eMIMSelite - This can be accessed through UWA Library Onesearch
9) Fundamentals of Pharmacology 8th Edition
A hand holding a pen filling in bubbles on a multiple-choice answer sheet.
**What is pharmacology?**
flowchart TD
subgraph Core Concepts
A[Pharmacology]
B[Pharmacokinetics/drug metabolism]
C[Biochemical pharmacology]
D[Molecular pharmacology]
E[Chemotherapy]
F[Systems pharmacology]
G[Neuro-pharmacology]
H[Cardiovascular pharmacology]
I[Gastrointestinal pharmacology]
J[Immuno-pharmacology]
K[Respiratory pharmacology]
B --> A
C --> A
D --> A
E --> A
F --> A
F --> G
F --> H
F --> I
F --> J
F --> K
G -. links to .-> M[PSYCHOLOGY]
H -. links to .-> Q[VETERINARY MEDICINE]
I -. links to .-> S[BIOTECHNOLOGY]
J -. links to .-> U[PATHOLOGY]
K -. links to .-> W[CHEMISTRY]
end
subgraph Related Disciplines
M[PSYCHOLOGY]
N[CLINICAL MEDICINE THERAPEUTICS]
O[VETERINARY MEDICINE]
P[PHARMACY]
Q[BIOTECHNOLOGY]
R[PATHOLOGY]
S[CHEMISTRY]
end
subgraph Applied Disciplines
T[Psycho-pharmacology]
U[Clinical pharmacology]
V[Veterinary pharmacology]
W[Pharmaceutical sciences]
X[Biopharmaceuticals]
Y[Toxicology]
Z[Medicinal chemistry]
end
subgraph Related Fields
AA[Pharmacogenetics]
BB[Pharmacogenomics]
CC[Pharmacoepidemiology]
DD[Pharmacoeconomics]
end
subgraph Foundational Sciences
EE[GENETICS]
FF[GENOMICS]
GG[CLINICAL EPIDEMIOLOGY]
HH[HEALTH ECONOMICS]
end
M -. relates to .-> T
N -. relates to .-> U
O -. relates to .-> V
P -. relates to .-> W
Q -. relates to .-> X
R -. relates to .-> Y
S -. relates to .-> Z
T -. derives from .-> A
U -. derives from .-> A
V -. derives from .-> A
W -. derives from .-> A
X -. derives from .-> A
Y -. derives from .-> A
Z -. derives from .-> A
AA -. derives from .-> EE
BB -. derives from .-> FF
CC -. derives from .-> GG
DD -. derives from .-> HH
AA -. is part of .-> A
BB -. is part of .-> A
CC -. is part of .-> A
DD -. is part of .-> A
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style I fill:#fcd3a4
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style EE fill:#c2f0a8
style FF fill:#c2f0a8
style GG fill:#c2f0a8
style HH fill:#c2f0a8
style A fill:#ffb399
Rang & Dale's Pharmacology, Tenth Edition
Types of drug names and which one to use while prescribing?
<div markdown="1">
| **Chemical name** | |
|---|---|
| • Describes the chemical structure of drugs |  |
| • Often complex | **N-(4-Hydroxyphenyl) acetamide** |
</div>
<div markdown="1">
| **Generic name (Most commonly used)** | |
|---|---|
| • Simplified drug names – often have roots & endings that provide clues to their origins, use, actions, or structure | |
| • *E.g. ibuprofen, ketoprofen, naproxen…* | |
</div>
<div markdown="1">
| **Brand name (Trade/Proprietary names)** | |
|---|---|
| • Invented by drug companies | **Panadol, Tylenol**  |
| • Intended to be catchy and memorable | |
</div>
**Pharmacodynamics vs. Pharmacokinetics**
| | Pharmacodynamics | Pharmacokinetics |
|---|---|---|
| **Definition** | What the **DRUG** does to the **BODY** | What the **BODY** does to the **DRUG** |
| **Image Component** | Pharmacodynamics: Dose $\rightarrow$ Mechanisms $\rightarrow$ Activity | Pharmacokinetics: The principles of ADME (Absorption, Distribution, Metabolism, Excretion) |
**Pharmacodynamics**
* **Pharmacodynamics**
* Dose
* Mechanisms
* Activity
**Pharmacokinetics**
* **Pharmacokinetics**
* The principles of ADME
* Medicine
* **Absorption**
* How will it get in?
* **Metabolism**
* How is it broken down?
* Liver
* **Distribution**
* Where will it go?
* Transporters
* **Excretion**
* How does it leave?
**Pharmacodynamics = What the DRUG does to the BODY**
**Pharmacokinetics = What the BODY does to the DRUG**
A red circular arrow symbol is shown between the pharmacodynamics and pharmacokinetics diagrams, indicating a relationship or flow between the two concepts.
Other
considerations
1.Efficacy
2.Selectivity
3.Safety
4.Predictability
5.Reversible actions
6.Interactions
7.Stability
8.Administration
9.Name
An image of a light blue gradient background.
**Pharmacokinetics**
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
<br>
**Pharmacokinetics**
The principles of ADME
*Medicine*
**Absorption**
How will it get in?
**Metabolism**
How is it broken down?
*Liver*
**Distribution**
Where will it go?
Transporters
**Excretion**
How does it leave?
EUPATI
European Patients'A Academy
on Therapeutic Innovation
www.eupati.eu
**Routes of drug absorption**
mermaid
graph TD
subgraph Administration
Oral_or_rectal --> Gut
Percutaneous --> Skin
Intravenous --> PLASMA
Intramuscular --> Muscle
Intrathecal --> CSF
Inhalation --> Lung
end
subgraph Absorption and distribution
Gut --> Portal_system
Portal_system --> Liver
Gut --Orange dashed line--> PLASMA
Skin --Orange dashed line--> PLASMA
Muscle --Orange dashed line--> PLASMA
Brain --Orange dashed line--> PLASMA
CSF --Orange dashed line--> PLASMA
Lung --Orange dashed line--> PLASMA
Liver --> Kidney_M[Metabolites]
Liver <--Dashed line--> Bile
Kidney_M --> Kidney
PLASMA --Orange dashed line--> Gut
PLASMA --Orange dashed line--> Skin
PLASMA --Orange dashed line--> Muscle
PLASMA --Orange dashed line--> Brain
PLASMA --Orange dashed line--> CSF
PLASMA --Orange dashed line--> Lung
PLASMA --Orange dashed line--> Liver
PLASMA --Orange dashed line--> Kidney
PLASMA --> Breast_sweat_glands
PLASMA --> Placenta
Placenta --Orange dashed line--> Fetus
Fetus --Orange dashed line--> Placenta
end
subgraph Elimination
Kidney --> Urine
Gut --Dashed line--> Faeces
Breast_sweat_glands --> Milk_sweat
Lung --> Expired_air
end
style Administration fill:#cce0ff
style Elimination fill:#ffffcc
%% Connections that go to and from PLASMA
Gut_to_PLASMA(Gut) --> PLASMA
Skin_to_PLASMA(Skin) --> PLASMA
Muscle_to_PLASMA(Muscle) --> PLASMA
Brain_to_PLASMA(Brain) --> PLASMA
CSF_to_PLASMA(CSF) --> PLASMA
Lung_to_PLASMA(Lung) --> PLASMA
Liver_to_PLASMA(Liver) --> PLASMA
Kidney_to_PLASMA(Kidney) --> PLASMA
PLASMA --> Gut_from_PLASMA(Gut)
PLASMA --> Skin_from_PLASMA(Skin)
PLASMA --> Muscle_from_PLASMA(Muscle)
PLASMA --> Brain_from_PLASMA(Brain)
PLASMA --> CSF_from_PLASMA(CSF)
PLASMA --> Lung_from_PLASMA(Lung)
PLASMA --> Liver_from_PLASMA(Liver)
PLASMA --> Kidney_from_PLASMA(Kidney)
%% Styling - dashed orange line connections to/from PLASMA, double arrowhead where shown
linkStyle 7 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 8 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 9 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 10 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 11 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 12 stroke:#ff8c00,stroke-dasharray: 5 5
linkStyle 14 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 15 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
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linkStyle 17 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 18 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 19 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 20 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 21 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 24 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
linkStyle 25 stroke:#ff8c00,stroke-dasharray: 5 5,stroke-width:2px;
%% Other connections
style Gut fill:#ffccb3
style Skin fill:#ffccb3
style Muscle fill:#ffccb3
style Brain fill:#ffccb3
style CSF fill:#ffccb3
style Lung fill:#ffccb3
style Liver fill:#ffccb3
style Kidney fill:#ffccb3
style Breast_sweat_glands fill:#ffccb3
style Placenta fill:#ffccb3
style Fetus fill:#ffccb3
style PLASMA fill:#99cc99,stroke:#99cc99
%% Explicitly re-define connections based on the image's flow (using the nodes defined in the graph above)
%% Gut absorption/distribution
Oral_or_rectal --> Gut
Gut --> Portal_system
Portal_system --> Liver
Gut --> PLASMA
%% Skin absorption/distribution
Percutaneous --> Skin
Skin --> PLASMA
%% Intravenous absorption/distribution
Intravenous --> PLASMA
%% Intramuscular absorption/distribution
Intramuscular --> Muscle
Muscle --> PLASMA
%% Intrathecal absorption/distribution
Intrathecal --> CSF
CSF --> PLASMA
%% Inhalation absorption/distribution
Inhalation --> Lung
Lung --> PLASMA
%% Liver/Kidney metabolism/distribution
Liver --Dashed line--> Bile
Bile --> Gut
Liver --> Kidney_M
Kidney_M --> Kidney
%% Distribution from PLASMA (Two-way arrows implemented by drawing two links)
PLASMA --> Gut
PLASMA --> Skin
PLASMA --> Muscle
PLASMA --> Brain
Brain --> PLASMA
PLASMA --> CSF
PLASMA --> Lung
PLASMA --> Liver
PLASMA --> Kidney
PLASMA --> Breast_sweat_glands
PLASMA --> Placenta
Placenta --> Fetus
Fetus --> Placenta
%% Elimination
Kidney --> Urine
Gut --> Faeces
Breast_sweat_glands --> Milk_sweat
Lung --> Expired_air
linkStyle 0 stroke-dasharray: 5 5
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end
Rang & Dale's Pharmacology, Tenth Edition
**Absorption**
* The transfer of drugs from the site of administration into the systemic circulation.
How does it cross the cell membrane?
* **Filtration** – Paracellular uptake $\to$ Small molecules
* **Passive diffusion** – Transcellular uptake $\to$ Lipophilic
* **Facilitated diffusion by carrier proteins** or transporters $\to$Efflux and/or Influx
* **Pinocytosis**
EXTRACELLULAR
MEMBRANE
INTRACELLULAR
| Diffusion through lipid | Diffusion through aqueous channel | Carrier |
|---|---|---|
| | | |
Rang & Dale's Pharmacology, Tenth Edition
![]()
Diagram illustrating different ways substances cross the cell membrane, including diffusion through lipid, diffusion through an aqueous channel, and carrier-mediated transport.
**Factors affecting drug absorption**
| Icon | Factor |
|---|---|
| | Size (Molecular weight) |
| | Solubility |
| | Polarity / Charge |
| | Transporters |
**Ideal drug properties to enhance optimal oral absorption**
**According to Lipinski's rule:**
* No more than 5 hydrogen bonds
* No more than 10 hydrogen bond
* A molecular mass less than 500 Daltons (g/mol)
* An octanol-water partition coefficient log P<5
* <5 freely rotating bonds (RB)
```mermaid
flowchart TD
subgraph Rule of Five by Lipinski
A[Structure Representation: PSA <140Å] --> E{Partition coefficient (P)= Con. In the lipid phase/ Con. In the aqueous phase}
A --> B[Structure Representation: MW<500 g/mol]
B --> F[Structure Representation: RB<10]
E --> G[Structure Representation: LogP<5]
G --> H[Structure Representation: HBA<10 HBD<5]
E --> I(Predicts ability of drugs to cross membranes)
B --> J(Oral absorption decreases with size)
F --> K(Less rotation, no gigantic reduction in entropy, better free energy for binding)
H --> L(Drugs can't be too hydrophilic/hydrophobic, to aid in drug solubility)
style J fill:#f9f, color:red
style I fill:transparent, color:red
style K fill:#f9f, color:red
style L fill:#f9f, color:red
end
```
**Importance of pH!**
**MOST drugs exist as a weak**
**acid or weak base**
* **Acid vs Base**
* Weak acids $\rightarrow$ negatively charged
* Weak bases $\rightarrow$ positively charged
* **Varying pH in different body**
compartments $\rightarrow$ shift in ionised or
unionised states
* **Remember:** passive diffusion
through membranes
* Charge state affects absorption
* **pKa:** the pH value at which 50% of
the drug is ionised
<img alt="Diagram showing the equilibrium between unionized (Non-Polar) and ionized (Polar) forms of a drug, influenced by pH and pKa, and their ability to permeate a lipid bilayer membrane. Unionized drug is labeled as permeable and Ionized drug is labeled as less permeable."> </img>
| | Acid drug | Basic Drug |
| :--- | :--- | :--- |
| Acidic Environment | Non-ionised** | Ionised |
| Basic Environment | Ionised | Non-ionised** |
Rang & Dale's Pharmacology, Tenth Edition
**Strong acid in water**
HC l $\rightarrow$ $\mathbf{H^+}$ + Cl$^{-}$
Unionized Ionized
**Strong base in water**
NaOH $\rightarrow$ Na$^{+}$ + $\mathbf{OH^-}$
Unionized Ionized
**Strong acids/bases –**
**Complete dissociation**
**– highly ionized,**
**hence poorly**
**absorbed**
**Weak acid in water**
R-COOH $\rightarrow$ R-COO$^{-}$ + $\mathbf{H^+}$
Unionized Ionized
**Weak acids/bases –**
**incomplete**
**dissociation –**
**unionized, absorbed**
**Weak acid in acidic medium**
**R-COOH** $\rightleftharpoons$ R-COO$^{-}$ + $\mathbf{H^+}$
**Unionized** $\mathbf{H^+}$ Ionized
The H$^{+}$ ions will prevent the
dissociation of a weak acid into
ionized forms
**Increased unionized**
**form, increased conc.**
**for absorption**
<div style="text-align: center;">
| 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 | **Ionisation greatest at alkaline pH** |
| | | Anion A$^-$ | |
| **Pethidine** | | | |
| **Weak base** | | | |
| **pK$_a$ 8.6** | > $10^6$ | 100 | 30 |
| | **Ionisation greatest at acid pH** | Protonated base BH$^{+}$ | Free base B |
</div>
Rang & Dale’s Pharmacology, Tenth Edition
## **Strong acid in water**
HC l $\rightarrow$ $\mathbf{H^+}$ + Cl$^{-}$
Unionized Ionized
## **Strong base in water**
NaOH $\rightarrow$ Na$^{+}$ + $\mathbf{OH^-}$
Unionized Ionized
**Strong acids/bases – Complete dissociation – highly ionized, hence poorly absorbed**
## **Weak acid in water**
R-COOH $\rightarrow$ R-COO$^{-}$ + $\mathbf{H^+}$
Unionized Ionized
**Weak acids/bases – incomplete dissociation – unionized, absorbed**
## **Weak acid in acidic medium**
**R-COOH** $\rightleftharpoons$ R-COO$^{-}$ + $\mathbf{H^+}$
**Unionized** $\mathbf{H^+}$ Ionized
The H$^{+}$ ions will prevent the dissociation of a weak acid into ionized forms
**Increased unionized form, increased conc. for absorption**
<div style="text-align: center;">
<table>
<tr>
<th style="text-align:center;">Compartment</th>
<th style="text-align:center;">Gastric juice</th>
<th style="text-align:center;">Plasma</th>
<th style="text-align:center;">Urine</th>
</tr>
<tr>
<td style="text-align:center;"><b>pH</b></td>
<td style="text-align:center;">pH 3</td>
<td style="text-align:center;">pH 7.4</td>
<td style="text-align:center;">pH 8</td>
</tr>
<tr>
<td style="text-align:center;"><b>Aspirin</b></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td style="text-align:center;"><b>Weak acid</b></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td style="text-align:center;"><b>pK<sub>a</sub> 3.5</b></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td style="text-align:center;"><b>Relative concentration</b></td>
<td style="text-align:center;">&lt; 0.1</td>
<td style="text-align:center;">100</td>
<td style="text-align:center;">&gt; 400</td>
</tr>
<tr>
<td></td>
<td></td>
<td style="text-align:center;">Undissociated acid AH<br>Anion A<sup>-</sup></td>
<td style="text-align:center;"><b>Ionisation greatest at alkaline pH</b></td>
</tr>
<tr>
<td style="text-align:center;"><b>Pethidine</b></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td style="text-align:center;"><b>Weak base</b></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td style="textalign:center;"><b>pK<sub>a</sub> 8.6</b></td>
<td style="text-align:center;">&gt; 10<sup>6</sup></td>
<td style="text-align:center;">100</td>
<td style="text-align:center;">30</td>
</tr>
<tr>
<td></td>
<td style="text-align:center;"><b>Ionisation greatest at acid pH</b></td>
<td style="text-align:center;">Protonated base BH<sup>+</sup><br>Free base B</td>
<td></td>
</tr>
</table>
</div>
Rang & Dale’s Pharmacology, Tenth Edition
**First pass effect & GI absorption**
**Drug properties**
1) Size (MW)
2) Solubility
3) Polarity/charge
4) Formulation (capsules, enteric coating)
**Physiological properties**
1) Gut content
2) GI motility
3) Splanchic blood flow
4) Physicochemical interactions with gut contents
5) 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
# **First pass effect & GI absorption**
### **Drug properties**
1. Size (MW)
2. Solubility
3. Polarity/charge
4. Formulation (capsules, enteric coating)
### **Physiological properties**
1. Gut content
2. GI motility
3. Splanchic blood flow
4. Physicochemical interactions with gut contents
5. 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 considerations**
**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
# **Other considerations**
### **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!
# **Review!**
**Distribution**
* The reversible transfer of a drug from one location (e.g. *blood*) to another (e.g. *heart, brain, or lung tissue*).
* Following absorption $\rightarrow$ drugs are dispersion
* Doesn't occur equally
* Passive diffusion
* COMPLEX
![]()
Diagram showing the processes of absorption, distribution, and elimination of a drug within the body, illustrating different routes of administration, sites of action, metabolism, and excretion
# **Distribution**
- The reversible transfer of a drug from one location (e.g. *blood*) to another (e.g. *heart, brain, or lung tissue*).
- Following absorption $\rightarrow$ drugs are dispersion
- Doesn't occur equally
- Passive diffusion
- COMPLEX
**Factors affecting distribution**
**Solubility**
* Lipophilic drugs readily cross & penetrate all tissues
**Blood flow**
* $\uparrow$ **Blood flow**
$\uparrow$ **Distribution** (*heart, liver, kidneys*)
* $\downarrow$ Blood flow
$\downarrow$ Distribution (*skin, adipose tissue*)
**Plasma protein binding**
* Plasma or tissue
free drugs /affinity for binding sites/protein
* **Unbound drug $\rightarrow$ active**
**Tissue binding**
* $\downarrow$Plasma concentration $\uparrow$**Distribution in tissues**
Drug distribution, EKG Science
# **Factors affecting distribution**
### **Solubility**
- Lipophilic drugs readily cross & penetrate all tissues
### **Blood flow**
- $\uparrow$ **Blood flow** $\uparrow$ **Distribution** (*heart, liver, kidneys*)
- $\downarrow$ Blood flow $\downarrow$ Distribution (*skin, adipose tissue*)
### **Plasma protein binding**
- Plasma or tissue free drugs /affinity for binding sites/protein
- **Unbound drug $\rightarrow$ active**
### **Tissue binding**
- $\downarrow$Plasma concentration $\uparrow$**Distribution in tissues**
Drug distribution, EKG Science
**The Volume of Distribution $\mathbf{(V)}$**
* **V = Dose (mg) / Plasma concentration (mg/L)**
* Diffusion of drugs to other compartments
* Approximate volume of plasma in 70Kg adult: 3L
* $\text{Vd} \le 0.04\text{L/kg} \rightarrow \text{distribution in plasma}$
* $\text{Vd} \le 0.57\text{L/kg} \rightarrow \text{distribution in ECF}$
* $\text{Vd larger} \rightarrow \text{distribution in tissue}$
* 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 $\mathbf{V}_{\mathbf{DIST}}$ Drug
blood
tissues
Low $\mathbf{V}_{\mathbf{DIST}}$ Drug
blood
tissues
* Note that typical adult body volumes vary from 50 to 100 L
The diagram illustrates two scenarios for drug distribution: High $V_{DIST}$ Drug (more drug in tissues, less in blood) and Low $V_{DIST}$ Drug (less drug in tissues, more in blood).
# **The Volume of Distribution $\mathbf{(V)}$**
- **V = Dose (mg) / Plasma concentration (mg/L)**
- Diffusion of drugs to other compartments
- Approximate volume of plasma in 70Kg adult: 3L
- $\text{Vd} \le 0.04\text{L/kg} \rightarrow \text{distribution in plasma}$
- $\text{Vd} \le 0.57\text{L/kg} \rightarrow \text{distribution in ECF}$
- $\text{Vd larger} \rightarrow \text{distribution in tissue}$
- 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 $\mathbf{V}_{\mathbf{DIST}}$ Drug**
blood
tissues
**Low $\mathbf{V}_{\mathbf{DIST}}$ Drug**
blood
tissues
- Note that typical adult body volumes vary from 50 to 100 L
The diagram illustrates two scenarios for drug distribution: High $V_{DIST}$ Drug (more drug in tissues, less in blood) and Low $V_{DIST}$ Drug (less drug in tissues, more in blood).
**Other
considerations**
**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!
# **Other considerations**
### **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!
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?
# **Review!**
- 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)**
* 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** ($\downarrow$ 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)
<img src="placeholder_image_description.png" alt="Diagram illustrating the biotransformation of a lipophilic drug in the liver to a hydrophilic metabolite, which is then excreted by the glomeruli, contrasted with the retention of the lipophilic drug." />
Drug metabolism, EKG Science
# **Metabolism (Biotransformation)**
- 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** ($\downarrow$ 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 $\rightarrow$ inactive product
Mainly in liver
Groups inserted: glucuronyl, sulphate, methyl, acetyl
Result: polar product $\rightarrow$ excretion in urine
Drug metabolism, EKG Science
**Phase I & Phase II metabolism**
<center>
```mermaid
graph TD
A[X<br>Lipophilic<br>Drug-R] -->|Phase I<br>Oxidation<br>Reduction<br>Hydrolysis| B[X<br>Metabolite<br>OH]
B -->|Phase II<br>Conjugation| C[X-O-A<br>Conjugated<br>Metabolite]
B --> D[↑Polarity<br>↑Solubility]
C --> D
D --> E[Excretion]
A --.->|↑Polarity ↑Solubility| E
F[• Furosemide, atenolol, digoxin: 100-75%]
```
</center>
Lipophilic drugs are changed into more **polar** molecules; since **water-soluble** drugs can be readily **excreted** by the body
Drug metabolism, EKG Science
**Phase I metabolism**
```mermaid
graph LR
A[Lipophilic Drug-R] --> B{Phase I};
B --> C[Metabolite];
B(Phase I)
B -- Oxidation --> C;
B -- Reduction --> C;
B -- Hydrolysis --> C;
B[Phase I] --> D[CYP450];
C[Metabolite]
C -- Drug-R-OH --> E;
C -- Drug-R-NH2 --> F;
```
**CYP 3A4**
* **Cytochrome P450 superfamily** $\rightarrow$ **Family** $\rightarrow$ **Subfamily** $\rightarrow$ **Isozyme**
**Oxidation, reduction, hydrolysis $\rightarrow$ active product**
**Main mechanism of metabolism is through cytochrome P450 (CYP450) system**
* Heme-containing enzymes
* CYP3A4 & CYP2D6
**Genetic polymorphism may play a role in CYP (by causing variation in the enzyme levels)**
* CYP3A4: Most abundant CYP in liver and gut wall
Drug metabolism, EKG Science
**Phase II metabolism**
<img Phase II metabolism diagram showing metabolite undergoing conjugation and resulting in increased polarity and solubility. The conjugated metabolite can undergo further processing via transferases to form Glucuronate, Glutathione, Sulfate, or Acetyl conjugates, each involving specific transferase enzymes. The bottom portion provides text explaining conjugation details. </img>
Conjugation $\rightarrow$ inactive product
Mainly in liver
Groups inserted: glucuronyl, sulphate, methyl, acetyl
Result: polar product $\rightarrow$ excretion in urine
Drug metabolism, EKG Science
**Other considerations**
**Concentration and types**
* Genetic polymorphism
* Amount of enzymes
* Types of enzymes
**Depot binding**
* Coupling of drugs with inactive sites of body $\rightarrow$ 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 $\rightarrow$ tolerance
* Inhibition: increase sensitivity
* Competition: reduced rate of metabolism
# **Other considerations**
### **Concentration and types**
- Genetic polymorphism
- Amount of enzymes
- Types of enzymes
### **Depot binding**
- Coupling of drugs with inactive sites of body $\rightarrow$ 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 $\rightarrow$ tolerance
- Inhibition: increase sensitivity
- Competition: reduced rate of metabolism
**Enzyme induction**
- Enzyme inducers: increase ($\uparrow$) the amount of enzymes produced
Can increase ($\uparrow$) drug toxicity (e.g. paracetamol)
Low/absence of drug activity
**Enzyme inhibition**
- Enzyme inhibitors: block or slow down the action of enzymes
Increase ($\uparrow$) drug half-life
Toxic levels
Drug metabolism, EKG Science
```mermaid
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
```
## **Enzyme induction**
- Enzyme inducers: increase ($\uparrow$) the amount of enzymes produced
- Can increase ($\uparrow$) drug toxicity (e.g. paracetamol)
- Low/absence of drug activity
## **Enzyme inhibition**
- Enzyme inhibitors: block or slow down the action of enzymes
- Increase ($\uparrow$) drug half-life
- Toxic levels
Drug metabolism, EKG Science
```mermaid
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!
# **Review!**
# **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
<img src="https://i.imgur.com/uR2Zf9M.png" alt="Diagram showing the four steps of drug handling in the kidney, including Filtration, Reabsorption, Secretion, and Excretion.">
1. Filtration
2. Reabsorption
3. Secretion
4. Excretion
Drug excretion, EKG Science
# **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
**Kidneys**
* Most common route of excretion
* Renal clearance
* 3 **fundamental** processes
1) Glomerular filtration
2) Active tubular secretion
3) Passive reabsorption
Drug excretion, EKG Science
![]()
Diagram illustrating the four steps of drug handling by the kidney: Filtration, Reabsorption, Secretion, and Excretion.
**Renal drug excretion**
* Some passive diffuse → blood
* Small lipophilic & nonionized drugs
* **Lipid-soluble drug**: high reabsorption → Excreted poorly
* **Polar drugs**: low reabsorption → Remain in the lumen, concentrated in the urine
* Energy-dependent transporters move drugs from blood into urine
* **OCT**: handles organic bases
* **OAT**: transports acidic drugs
* Free (unbound) drugs in blood are filtered through pores in glomerulus
* Protein-bound drug remains in blood
Drug excretion, EKG Science
**Other
considerations**
**Factors affection excretion**
* Age
* Weight
* Biological sex
* Kidney function
**Altered kidney functions**
* Chronic kidney disease
* Function decreases with age
* Medical conditions eg. Heart failure
**Biliary excretion & Enterohepatic recirculation**
* Transfer of substances from
plasma to bile
* OAT, OCT, PGP
* Drug conjugate concentrated in
bile $\rightarrow$ intestine
* Intestinal bacteria hydrolyses
glucuronide $\rightarrow$ active drug
* Reabsorption of free drug $\rightarrow$ liver
Decreased liver function
* Reduced ability to excrete drugs
* Prolonged effect $\rightarrow$ toxicity
Drug excretion, EKG Science
**Other routes
of excretion**
* Sweat
* Tears
* Reproductive fluids
* Breast milk
* Very important to protect breastfed
child from unwanted drug effects
Review!
**Importance of**
**Pharmacokinetics**
Helps us ensure that maximum benefit is gained when using
drugs in patients
* Avoid drug **underdosing** (lack of benefit)
* Avoid drug **overdosing** (unwanted toxicity)
Ensure we administer correct doses of a drug at appropriate time
intervals
Some key parameters (quantitative)
* The Therapeutic window
* First vs. Zero order kinetics
* Drug clearance (CL)
* Volume of distribution (V)
* Half-life (T1/2) & Elimination Rate Constant (k)
* Bioavailability (F)
**The therapeutic window & plasma concentration-time profiles (single dose)**
<img src="The_therapeutic_window_&_plasma_concentration-time_profiles_(single_dose).png" alt="A graph showing the relationship between drug concentration in blood and time after a single dose. The graph illustrates the Minimum Toxic Concentration (MTC), the Minimum Effective Concentration (MEC), the Therapeutic Window, $C_{max}$, $T_{max}$, and the Area Under the Curve (AUC).">
**DRUG TOXICITY OCCURS**
Drug concentration in blood
$C_{max}$
**Therapeutic**
**Window**
**MTC = (Minimum**
**Toxic**
**Concentration)**
Drugs produce
beneficial effects
when blood
concentrations are
within this range
**DRUG**
**PRODUCES NO**
**EFFECT**
$T_{max}$
Time
**MEC = (Minimum**
**Effective**
**Concentration)**
AUC (Area Under the Curve)
= total drug exposure
**drug dosing**
**Repeated dose administration**
* Dosing regimen →
drug accumulation
overtime
* Steady state: rate of
administration =
rate of elimination
* Individual variation
* Age, weight, liver
function
* Drugs properties
<img alt="A graph showing concentration versus time (elimination half-times) for repeated drug dosing, illustrating the concept of steady state and fluctuations." src="https://i.imgur.com/g8R7c5d.png" />
**Steady state**
* Attained after approximately four half-live(s)
* Time to plateau independent of dosage
**Fluctuations**
* Proportional to dosage interval/half-time
* Blunted by slow absorption
**Steady-state concentrations**
* Proportional to dose/dosage interval
* Proportional to 1/clearance
* Proportional to % of dose absorbed
<B>Elimination kinetics</B>
A fixed **amount** of the drug being cleared per unit of time, no matter how much is left!
Drug Elimination
**Zero Order Elimination** | **First Order Elimination**
--- | ---
elimination rate: 2.5 units/hr 2.5 units/hr 2.5 units/hr | elimination rate: 5 units/hr 2.5 units/hr 1.25 units/hr
Plasma Concentration (Cp) | Plasma Concentration (Cp)
Time (h) | Time (h)
A constant **proportion** of drug being cleared per unit of time
**Clearance (CL)**
* Clearance (CL) is the **volume of blood cleared completely of the drug per unit time**
* Units are volume per time, e.g. **L/hour or mL/min**
* Can refer to **clearance by a specific organ**, e.g. renal clearance
* Renal clearance = Renal filtration + Renal secretion – Renal reabsorption
* Can also refer to **clearance by the whole body**
* Total body clearance = sum of each organ
TOTAL BODY CLEARANCE
![]()
A diagram illustrating total body clearance as the sum of clearance from different organs: Kidneys, Liver, Bile, Skin, and Lungs.
**The half life (T$^{1/2}$) & Elimination rate constant (k)**
- Half-life (T$^{1/2}$): Time for drug
concentration in plasma to
decrease by 50%
- Not a fundamental PK
parameter – depends
on **clearance (CL)** and **volume**
**of distribution (Vd)**
- Follows **first-order**
**(logarithmic) kinetics** –
constant proportion removed
per unit time
- Formula: T$^{1/2}$ = **0.693 x Vd / CL**
<img src="This is a visualization of the drug concentration in plasma (mg/L) over time (h). The curve shows a first-order elimination process, and the half-life ($t_{1/2}$) is illustrated as the time period required for the concentration to halve. Specifically, it highlights a '50% decrease in plasma concentration' over each $t_{1/2}$ interval (from 10 to 5 mg/L in 4 hours, from 5 to 2.5 mg/L in the next 4 hours, and from 2.5 to 1.25 mg/L in the final indicated 4 hours)."> </img>
**Bioavailability (F)**
**<span style="color:blue">Bioavailability (oral drugs)</span>**
<span style="color:blue">Proportion of drug reaching systemic circulation intact</span>
**<span style="color:blue">Key influencing factors in gi tract</span>**
* <span style="color:blue">Membrane transporters (e.g. efflux in gut wall)</span>
* <span style="color:blue">First-pass metabolism (gut wall & liver)</span>
* <span style="color:blue">Stability to gastric acids/enzymes</span>
* <span style="color:blue">Drug formulation (e.g. pill composition)</span>
* <span style="color:blue">Gut motility</span>
* <span style="color:blue">Presence of food (affects pH, absorption, motility)</span>
# **Bioavailability (F)**
**<span style="color:blue">Bioavailability (oral drugs)</span>**
<span style="color:blue">Proportion of drug reaching systemic circulation intact</span>
**<span style="color:blue">Key influencing factors in gi tract</span>**
- <span style="color:blue">Membrane transporters (e.g. efflux in gut wall)</span>
- <span style="color:blue">First-pass metabolism (gut wall & liver)</span>
- <span style="color:blue">Stability to gastric acids/enzymes</span>
- <span style="color:blue">Drug formulation (e.g. pill composition)</span>
- <span style="color:blue">Gut motility</span>
- <span style="color:blue">Presence of food (affects pH, absorption, motility)</span>
**Some take home message**
* 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
# **Some take home message**
- 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!
# **Review!**
**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
# **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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