A medicine's therapeutic effect on the body is described in pharmacodynamics – the study of how drugs act to produce their effects (Patel, 2021; Thain and Webster, 2025). However, for pharmacodynamics to take place, the drug must first enter the body and reach its site of action. This process depends on pharmacokinetics, which explores how the body absorbs, distributes, metabolises, and excretes (ADME) the drug, ultimately determining its concentration and availability at the target site (Figure 1).
Schematic representation of relationship between pharmacokinetics and pharmacodynamics
For a drug to do anything, we need to get it into the body in one form or another, preferably as close to the target site of action as possible. Luckily, we have many routes of administration such as oral, inhalation, intravenous, subcutaneous, transdermal and intramuscular (Verma et al, 2010). The routes of administration of drugs are key in their role of therapeutic action – for instance, penicillin will not be adequately absorbed if taken with meals, and intravenous (IV) furosemide can cause deafness if given too rapidly (Shepherd and Shepherd, 2020). The most common administration method is oral medication, estimated to be responsible for 90% of pharmaceutical formulations (Alqahtani et al, 2021). However, there are different advantages and disadvantages to the routes of administration related to pharmacokinetics (Table 1).
Characteristics of common routes of drug administration in relation to pharmacokinetics
| Routes of administration | Advantages | Disadvantages |
|---|---|---|
| Oral (PO) |
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| Intravenous (IV) |
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| Subcutaneous (SC) |
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| Intramuscular (IM) |
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| Inhalation |
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| Sublingual (SL) |
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| Buccal |
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| Transdermal |
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| Rectal |
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| Intranasal (IN) |
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| Topical |
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Drug absorption factors
Plasma membrane
The first stage of pharmacokinetics is absorption. Drug absorption is the process by which a drug moves from the site of administration into the systemic circulation. One of the key barriers of drug absorption is crossing the plasma membrane. The plasma membrane is a phospholipid bilayer surrounding cells that plays a key role in separating the extracellular (outside a cell) and intracellular (inside a cell) environments, and regulates the passage of substances into and out of the cell. Plasma membranes are semipermeable and have transport proteins, receptors, and channels, which assist the transport from the extracellular to intracellular space (Chillistone and Hardman, 2017).
In general, drugs that are small, unionised and lipid-soluble can easily pass through the plasma membrane through a process of passive diffusion. This is where drugs pass from the extracellular space to the intracellular space from a high–low concentration gradient, without any involvement from the plasma membrane. Sometimes, through a process called facilitated diffusion, carrier proteins combine with drugs to facilitate the movement across the plasma membrane. Additionally, drugs can be transported against the concentration gradient through active transport – a process in which transporter proteins use energy to facilitate movement (Bertram-Ralph and Amare, 2023).
Bioavailability
Bioavailability is ‘the amount of the administered dose of a drug reaching the bloodstream in the form of the active ingredient, which is then available to the body to produce a therapeutic effect’ (Stielow et al, 2023).
Bioavailability is typically referenced against IV administration, as IV delivers the entire drug dose directly into the bloodstream, resulting in 100% bioavailability. Although one of the most common forms of pharmaceuticals, oral medication has the lowest bioavailability, and this is owing to ‘first-pass metabolism’.
First-pass metabolism
First-pass metabolism describes the metabolism of a drug before it has reached systematic circulation, thereby reducing the therapeutic effect of the drug itself. This is common in oral medication, as drugs are broken down in the stomach, and are then absorbed through the gastrointestinal (GI) tract walls before passing into the liver.
The liver and GI tract contain metabolising enzymes, which reduce drug concentration in the bloodstream, thereby limiting the amount of drug that can get to its site of action (Stanley, 2023). It is possible to bypass first-pass metabolism by using differing routes of administration such as intranasal, sublingual, buccal and rectal routes (Table 1). The use of buccal midazolam is very common in treating epileptic seizures and the intranasal use of naloxone is used in opioid overdoses (Yoshinaga et al, 2021; Lapidot et al, 2022).
Distribution factors
The second stage of pharmacokinetics is distribution. Distribution refers to how a drug moves across different compartments of the body, ideally to the target site of action. Once a drug is absorbed into the bloodstream, it is carried to various parts of the body, such as interstitial fluid, fat tissue, bone, and muscle.
Distribution is commonly expressed as the ‘volume of distribution,’ calculated by dividing the drug dose by its concentration in blood plasma (Bertram-Ralph and Amare, 2023). This measure provides an indication of the drug's dispersion; a high volume of distribution suggests significant movement of the drug out of the bloodstream, while a low volume indicates that it has remained primarily within the plasma.
Blood supply and tissue composition
Blood supply is vital in distribution. Organs with higher blood flow, such as the heart, brain, and liver, receive more of the drug owing to their abundant blood supply, and areas of the body that are rich in adipose tissue will receive less because of their lack of blood supply. In addition to this, adipose tissue may store lipophilic drugs, which can also affect distribution (Lucas et al, 2018).
Protein-binding
Protein-binding in plasma proteins is a key factor affecting distribution. Albumin is the main plasma protein responsible for binding many drugs in the bloodstream. However, the extent of protein-binding varies between drugs; some bind extensively, while others have minimal binding. This has consequences, as only the unbound (free) drug can cross plasma membranes, distribute into tissues, and thereby produce a pharmacological effect. A lower degree of albumin-binding increases the free-drug concentration, which can enhance therapeutic effects, but also raise the risk of toxicity. Liver or kidney disease can lower albumin levels, resulting in a condition known as hypoalbuminemia. This reduction in albumin increases the free-drug fraction in circulation, which may enhance therapeutic effects, but also heightens the risk of adverse effects, potentially leading to severe toxicity and, in extreme cases, mortality (Alves et al, 2018; Bihari et al, 2020). Hypoalbuminemia and hepatic impairment are often a caution for drugs like phenytoin, which are highly albumin-bound, as reduced protein-binding increases the risk of drug accumulation and toxicity.
Prodrugs
Prodrugs are medications administered in an inactive, or less active, form that must undergo metabolism to exert a therapeutic effect.
Prodrugs are typically activated during Phase 1 metabolism, where enzymes modify the drug to produce its active form. A common example is codeine, which is metabolised by the enzyme CYP2D6 into morphine in the body, enabling its analgesic effects (Thorn et al, 2009).
Metabolism
Metabolism is described as ‘the biotransformation of substances which enables its elimination’ (Correia, 2018). The liver is by far the most important drug-metabolising organ; however, the kidney, gut mucosa, lung and skin may also contribute. The goal of metabolism is to modify the drug to increase its excretion, by making it more hydrophilic so it is easier to excrete from the body in a form called metabolites. To increase excretion, the biotransformation is controlled by groups of enzymes, which can be split into two main types of chemical reactions: Phase 1 and Phase 2 (Hughes, 2014).
Phase 1: functionalisation
Phase-one reactions, also known as ‘functionalisation’ reactions, are primarily carried out by Cytochrome P450 (CYP450) enzymes. These reactions involve chemical modifications, such as oxidation, hydrolysis, or reduction, to increase the drug's water solubility. The CYP450 enzyme family is responsible for metabolising over 75% of drugs. Additionally, some drugs can induce CYP450 enzymes, enhancing their activity, while others inhibit them, reducing their activity – both of which have important clinical implications (Zhao et al, 2021). For example, grapefruit juice contains 6’,7’-dihydroxybergamottin – a compound that inhibits CYP3A4, an enzyme responsible for metabolising approximately 50% of drugs. Inhibition of CYP3A4 can lead to increased plasma concentrations of these drugs, such as the pro-drug lovastatin, which has been associated with a higher risk of adverse effects (Fuhr et al, 2023).
Phase 2: conjugation
Phase-two reactions are often referred to as conjugation, which involves adding molecules that are already present in the body (endogenous) to convert drugs into less active or inactive forms. The processes are called acetylation, sulfation, and glucuronidation, with the aim to produce polar and water-soluble metabolites. Inactive metabolites are the altered forms of a drug that don't exert the same pharmacological effects as the original drug. Some metabolites however are toxic by-products. For example, paracetamol is metabolised by CYP2E1 and CYP1A2 enzymes, which leads to the production of N-acetyl-p-benzoquinone imine (NAPQI), a toxic by-product responsible for acute liver damage (Freo et al, 2021).
Key definitions in pharmacokinetics
| Term | Definition |
|---|---|
| Pharmacokinetics | The study of how the body absorbs, distributes, metabolises, and excretes drugs |
| Absorption | The process by which a drug moves from the site of administration into the systemic circulation |
| Bioavailability | The proportion of an administered drug that reaches the bloodstream in an active form, influencing its therapeutic effect |
| First-pass metabolism | The metabolism of a drug before it reaches systemic circulation, reducing its therapeutic concentration |
| Distribution | The process by which a drug is transported to different parts of the body, including tissues and organs |
| Volume of distribution | A measure of how extensively a drug is distributed in body tissues relative to the plasma concentration |
| Protein-binding | The binding of drugs to plasma proteins (e.g. albumin), affecting their availability to cross membranes and exert effects |
| Metabolism | The biotransformation of drugs, primarily in the liver, to make them easier to excrete |
| Phase 1 reactions | Functionalisation reactions (e.g. oxidation, reduction) performed by enzymes like CYP450 to increase drug solubility |
| Phase 2 reactions | Conjugation reactions that add endogenous molecules to drugs, forming polar metabolites for easier excretion |
| Inactive metabolites | Altered drug forms that no longer have pharmacological effects |
| Pro-drugs | Drugs that become active only after being metabolised (e.g. codeine converting to morphine) |
| Excretion | The removal of drugs and their metabolites from the body, primarily through urine but also via bile, faeces, lungs, or sweat |
| Passive diffusion | Movement of drugs across the plasma membrane along a concentration gradient without energy expenditure |
| Active transport | Energy-dependent movement of drugs across the plasma membrane against a concentration gradient |
| Plasma membrane | A phospholipid bilayer that regulates the passage of substances, including drugs, into and out of cells |
| Transporter proteins | Proteins that assist in the movement of drugs across the plasma membrane |
Excretion
Excretion is the process of removing drugs and their metabolites from the body, primarily through urine but also via the lungs, bile, faeces, sweat, and breast milk (Currie, 2018b). It is a key component of pharmacokinetics, determining how a drug is eliminated and influencing its half-life, duration of action, and dosing frequency.
The kidneys serve as the primary route of excretion for many drugs, particularly hydrophilic compounds. Renal excretion involves three key processes: glomerular filtration, tubular reabsorption, and tubular secretion. Glomerular filtration allows small molecules to pass from the blood into the renal tubules for excretion. However, drugs extensively bound to plasma proteins are not readily filtered because of their high molecular weight and charge. Tubular secretion is the active transport of molecules, including drugs, from the peritubular capillaries into the proximal tubule via specialised transporters. When multiple drugs rely on the same transporters, competition may occur, reducing excretion and leading to increased plasma concentrations. Tubular reabsorption determines whether a drug remains in the urine for excretion or is reabsorbed back into the bloodstream. Hydrophilic drugs, such as gentamicin, are excreted unchanged in the urine, whereas lipophilic drugs, such as diazepam, undergo hepatic metabolism to increase their water solubility and reduce tubular reabsorption before excretion (Ramirez and Tolmasky, 2010; Khalid et al, 2021). Renal function is important for drug clearance, which is defined as the volume of plasma cleared of a drug per unit time (Box 2). Reduced renal clearance, as seen in kidney disease, can lead to drug accumulation and toxicity, necessitating dose adjustments (Lea-Henry et al, 2018).
Elimination kinetics and drug stability
Half-life
The half-life of a drug is the time it takes for its concentration in the bloodstream to reduce by half. This determines how long a drug's effects last and guides dosing schedules. For repeated doses, the half-life helps maintain stable drug levels in the blood. In simple terms, it indicates how quickly the body clears half of the drug.
Drug clearance
Drug clearance measures how efficiently the body removes a drug, expressed as the volume of blood cleared per unit of time. High clearance means faster elimination, while low clearance indicates slower removal. Together, half-life and clearance help tailor dosing for safe and effective treatment.
Steady state
A drug reaches steady state – where drug input equals elimination – after about four to five half-lives. This is crucial for maintaining effective drug levels without causing harm. Drugs with short half-lives reach steady state quickly, while those with long half-lives take longer. For urgent effects, a loading dose can achieve therapeutic levels faster while the body stabilises over several half-lives.
Some drugs undergo biliary excretion, where they are conjugated in the liver and excreted into bile. These conjugates may be metabolised in the intestine, regenerating the parent drug, which can then be reabsorbed into circulation. This process, known as enterohepatic circulation, can prolong a drug's half-life and sustain its effects, as seen with morphine (Gao et al, 2014).
Conclusion
Understanding pharmacokinetics is necessary for comprehending how drugs move through the body, influencing their onset, duration, and intensity of action. Insight into the principles of drug absorption, distribution, metabolism, and elimination, can help optimise drug administration to ensure safe and effective treatment. Given the increasing scope of pharmacological interventions in emergency and urgent care, a sound understanding of pharmacokinetics can enable paramedics to make informed decisions, anticipate drug effects, and refine their clinical practice.