Pharmacodynamics is the scientific study of the actions of drugs in the body, and how these actions generate physiological effects (Rakel, 2024) (Table 1). All physiological processes of the human body (healthy and pathological) are mediated by molecular pathways; these are the series of interactions between groups of molecules.
Key definitions in pharmacodynamics
| Term | Definition |
|---|---|
| Pharmacodynamics | The study of how drugs affect the body and cause changes |
| Enzyme | A protein that speeds up chemical reactions in the body |
| Receptor | A protein that detects specific signals (such as drugs) and triggers a response in the body |
| Ion channel | A protein in cell membranes that lets charged particles (ions) pass through, helping cells work |
| Transporter | A protein that moves molecules or ions into or out of cells |
| Agonist | A drug that activates a target (such as a receptor) to produce an effect |
| Antagonist | A drug that blocks a target to reduce or stop its effect |
| Affinity | How strongly a drug binds to its target |
| Ligand | A molecule, such as a drug, that binds to a specific target |
| Competitive | A drug that competes with another substance (naturally occurring or a different drug) for the same binding spot on a target |
| Non-competitive | A drug that binds somewhere else on a target, changing how it works |
To alter a patient's condition, a drug must target the molecules associated with it. The vast majority of drugs achieve this by binding to their specific molecular targets, which are located either on the cell surface or within the cell (Bardal et al, 2011).
How well it binds to its target is highly dependent on the shape of the drug, in that it maximises contact with its target. This concept is often compared to a jigsaw puzzle or a lock-and-key mechanism, where the drug binds only if it precisely fits the target. However, this analogy is not entirely accurate; drug-target binding exists on a spectrum, varying in strength and duration rather than being a simple ‘bind or not bind’ scenario. Drugs with a low affinity will bind very loosely and transiently to their target, while drugs with a high affinity bind incredibly tightly – some, irreversibly.
Specific molecules involved in a given process can be identified, and their structure or shape mapped (Marion, 2013; Shi, 2014). Biochemists and pharmacologists can then design drugs with shapes complementary to these molecular targets, enabling the drug to bind with appropriate affinity and modulate the molecule's function as intended.
For example, designing drugs to treat asthma and chronic obstructive pulmonary disease required an understanding of the pathways responsible for bronchoconstriction and tracheobronchial inflammation—specifically, the β2-adrenergic receptor and the glucocorticoid system. Following these discoveries, drugs such as salbutamol and fluticasone were developed (Barnes and Breckenridge, 2012).
Understanding where a drug binds – its molecular target – is therefore fundamental to determining its mechanism of action and the resulting impact on the patient. Through identifying specific molecular interactions, the ways in which drugs influence physiological processes and contribute to therapeutic outcomes can be better understood.
Commonly, drug targets fall within one (or more) of four categories of molecules: enzymes; receptors; ion channels; and transporters (Figure 1). Drugs exert either stimulatory (agonist) or inhibitory (antagonist) effects on molecular targets. Agonists activate or enhance target activity, while antagonists block or reduce it.
A simplified visual representation of the four most common types of molecular drug targets, shown straddling the phospholipid bilayer of a cell (not to scale)
If a drug binds to the target's active site (also known as an orthosteric site), it is competitive, vying with natural ligands based on affinity and concentration. Non-competitive drugs bind to an alternative site, known as the allosteric site, modifying target activity without competing for the same binding site. These allosteric interactions can be inhibitory or excitatory.
Enzymes
Enzymes are biological catalysts – molecular ‘machines’, usually comprised of protein – that greatly speed up specific chemical reactions.
Mechanistically, enzymes also rely upon molecular binding to function. To catalyse a reaction, the substrates for that reaction must become bound to the enzyme's orthosteric site. After catalysis, the newly formed product is released from the enzyme into the cell or wider systemic circulation.
Well over 3000 biochemical processes are catalysed by enzymes (McDonald et al, 2009). Some are fundamental, such as adenosine triphosphate (ATP) synthase; this is found in abundance in each of the trillions of mitochondria throughout the human body (Hatton et al, 2023), turning oxygen and glucose into the energy molecule ATP (Althaher and Alwahsh, 2023). Others are more specific, like amylase, which helps process large, complex carbohydrates into readily usable glucose molecules (Peyrot des Gachons and Breslin, 2016). The staggering diversity of enzymes and the reactions they catalyse means that many enzymes are desirable targets for drugs.
For instance, various non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen and naproxen) and paracetamol (aka acetaminophen) target cyclooxygenase (COX) enzymes. COX converts arachidonic acid (a lipid found in cell membranes) into a family of molecules called prostaglandins. Some prostaglandins act as inflammatory mediators, causing pain, heat, vasodilation and increased vascular permeability (and therefore redness and swelling). By binding to the orthosteric site of COX enzymes, NSAIDs prevent the substrate from binding, thereby reducing the amount of pro-inflammatory prostaglandins produced. This reduction alleviates inflammation symptoms experienced, but can also impact other physiological processes influenced by prostaglandins, such as gastric protection, renal function, and platelet aggregation (Knox et al, 2024).
Another salient target is angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II in the renin-angiotensin-aldosterone system (RAAS) (Patel et al, 2017; Khurana and Goswami, 2022). RAAS is a natural mechanism for regulating blood pressure and fluid balance through vasoconstriction, sodium and water reabsorption (mediated by aldosterone), and water retention via antidiuretic hormone (ADH). Therefore, drugs that dampen RAAS by inhibiting ACE, such as ramipril, lisinopril, and enalapril, are a common family of antihypertensive medications (Herman et al, 2023).
Receptors
Another common molecular target for drug binding are receptors – proteins that allow the cell to detect signals or stimuli and, subsequently, transmit or transduce their own signal onwards.
The majority of receptors respond to chemical signals; this is the binding of a specific molecule, called a ligand, to the receptor's orthosteric site. In these receptors (also known as G-protein coupled receptors), ligand-binding causes the release of a small protein (called a G-protein) that carries the signal onwards by acting as a ligand with other receptors, causing the release of more messenger molecules or interfering with the action of certain enzymes (Patel, 2021).
Examples of drugs and their molecular targets
| Drug | Example of clinical application(s) | Molecular target | Mechanism |
|---|---|---|---|
| Atropine | Bradycardia, organophosphate poisoning | Receptor: muscarinic acetylcholine receptors | Blocks muscarinic receptors, reducing parasympathetic activity to increase heart rate and reduce secretions |
| Paracetamol | Pain | Enzyme: cyclooxygenase (COX) | Inhibits COX, reducing prostaglandin production. Prostaglandins can contribute to pain |
| Phenytoin | Seizures | Ion channel: voltage-gated sodium channels | Blocks sodium channels, stopping hyperactive nerve signals |
| Adrenaline | Anaphylaxis/cardiac arrest | Receptor: adrenergic receptors (α and β) | Stimulates adrenergic receptors for increased heart rate and bronchodilation |
| Ondansetron | Nausea/vomiting | Receptor: serotonin (5-HT3) receptors | Blocks serotonin receptors to prevent nausea signals |
| Furosemide | Pulmonary oedema/heart failure | Transporter: Na–K–Cl cotransporter | Inhibits ion reabsorption, increasing water excretion in the kidneys |
| Midazolam | Sedation/seizure control | Receptor: GABA-A receptors | Enhances GABA activity for sedation and seizure control |
| Morphine | Pain | Receptor: μ-opioid receptors | Activates opioid receptors, reducing pain perception |
| Naloxone | Opioid overdose | Receptor: μ-opioid receptors | Displaces opioids, reversing their effects |
| Salbutamol | Asthma/chronic obstructive pulmonary disease | Receptor: β2-adrenergic receptors | Activates β2 receptors, causing bronchodilation |
| Diazepam | Seizures | Receptor: GABA-A receptors | Enhances GABA signals, reducing anxiety and seizures |
| Ibuprofen | Pain/inflammation | Enzyme: cyclooxygenase (COX-1 and COX-2) | Inhibits COX enzymes, reducing pain and inflammation |
| Glucagon | Hypoglycaemia | Receptor: glucagon receptors | Stimulates glycogen breakdown, raising blood sugar |
| Lidocaine | Local anaesthesia/arrhythmias | Ion channel: voltage-gated sodium channels | Blocks sodium channels, stopping nerve signals |
GABA: gamma-aminobutyric acid
Commonly, these receptors straddle the phospholipid bilayer – the membrane that forms the outer surface of all human cells. This allows cells with these receptors to detect incoming chemical signals from other cells via the systemic circulation, allowing communication between biological systems.
As with enzymes, receptors are necessary for complex, multicellular life, including every human bodily system. Nervous system functioning relies on communication between neurons in the brain using neurotransmitters (e.g. serotonin, dopamine and acetylcholine) as ligands to receptors embedded in specialised structures called synapses (Sheffler, 2023). The white blood cells of the immune system require various receptors to mount an effective immune response against invading pathogens (Shah et al, 2021; Duan et al, 2022). Again, the diversity of these processes means that receptors can be leveraged as drug targets to treat various illnesses. Insulin and glucagon – important in the management of patients with glycaemic emergencies – are ligands for receptors in the pancreas (Rahman, 2021; Jia, 2022). Morphine provides analgesia by binding to μ-opioid receptors (Stein, 2016).
In many cases, achieving a desired patient outcome, such as lowering blood pressure, can involve targeting multiple molecular pathways. While ACE inhibitors block the conversion of angiotensin I to angiotensin II, angiotensin-receptor blockers (ARBs), such as losartan, valsartan and candesartan, directly inhibit the binding of angiotensin II to its receptors, thereby preventing vasoconstriction.
Similarly, adrenergic receptors are another key target for hypertension management (National Institute for Health and Care Excellence (NICE), 2023). Alpha blockers (e.g. doxazosin and prazosin) reduce blood pressure by inhibiting alpha-adrenergic receptors, leading to vasodilation, while beta-blockers (e.g. atenolol, bisoprolol and metoprolol) act on beta-adrenergic receptors to decrease heart rate and cardiac output (NICE, 2023).
Ion channels
Like receptors, ion channels are large proteins embedded in the phospholipid membrane of many cells, especially neurons (the cells of the nervous system).
They serve as channels or tunnels for the passage of ions – atoms or molecules with a positive or negative electrical charge – into or out of a cell. Without these channels, the ions' electrical charge repels them from the membrane, making their passage across almost impossible.
This movement of ions across cell membranes is vital for various biological processes. This is central to the operation of the nervous system, where it serves as the basis for electrical nerve signals known as action potentials (Nerbonne and Kass, 2005; Varró, 2021).
In the heart, ion fluxes underlie the electrical activity that generates the rhythm observed on an electrocardiogram.
Neurons (including those in the heart that generate the cardiac rhythm) use sodium and potassium ions to generate these action potentials, which then travel along the neuron to stimulate a muscle to contract, a gland to release a hormone or another neuron to process information. Various drugs bind to ion channels to influence the rate or intensity at which these action potentials are generated. For instance, both phenytoin's ability to prevent seizures and lidocaine's capacity as a local anaesthetic are granted by their binding to and obstruction of sodium ion channels, preventing generation of action potentials.
Similarly, amiodarone, a widely used antiarrhythmic drug, works by blocking potassium ion channels in cardiac cells. This action prolongs the repolarisation phase of the cardiac action potential and, consequently, stabilises the rhythm.
In addition to enzymes and receptors, ion channels are important molecular targets in the treatment of hypertension. Calcium channel blockers, such as amlodipine, work by inhibiting calcium ion entry into vascular smooth muscle cells. This action reduces muscle contraction, promotes vasodilation and, ultimately, lowers blood pressure.
Transporters
Finally, transporters serve as protein pumps that move molecules into or out of cells. While ions travel through ion channels along electrochemical gradients, larger molecules, such as antibiotics or neurotransmitters (Gether et al, 2006; Kristensen et al, 2011; Hua et al, 2016), require transporters to facilitate their movement from one location to another. In some cases, transporters move ions against concentration gradients to create pools of them in specific areas. Many transporters are disrupted by drugs to produce beneficial physiological changes.
Furosemide – used in the management of pulmonary oedema associated with congestive heart failure – inhibits a family of transporters in the kidney, thereby increasing urine production (diuresis) (Knox et al, 2024). Gliflozins or flozins (e.g. canagliflozin and dapagliflozin) are drugs that inhibit the sodium/glucose cotransporter 2 (SGLT2) – a transporter that pumps filtered glucose from the tubule of nephrons in the kidneys back into the blood. As a result, SGLT2 inhibitors reduce the amount of glucose retrieved from the urine and reduce blood sugar levels, making them effective drugs in the management of type 2 diabetes mellitus (as well as reducing the risk of chronic kidney disease and cardiovascular death and heart failure) (Padda et al, 2023).
Conclusion
Understanding pharmacodynamics is essential for comprehending how drugs interact with the body to produce therapeutic effects. By targeting enzymes, receptors, ion channels and transporters, drugs can modulate key physiological processes to treat a wide range of conditions.
It is likely that the ever-increasing demands on paramedics and the constantly evolving nature of their role will occur in tandem with dramatic increases in pharmacological treatments. Indeed, many of these drugs may have novel molecular targets not discussed here, such as DNA or RNA (Qadir et al, 2020).
Having a solid grasp of the foundational mechanisms by which drugs act upon the body's cells will equip paramedics to meet these advances. This understanding provides a nuanced insight into the interactions between drugs and their targets that bring about desirable clinical outcomes.