Pharmacodynamics

In this step, Dr Harriet Scott, Specialty Registrar in Anaesthesia and Pain Medicine at Barts Health, and Dr Lesley Bromley, retired Consultant and Senior Lecturer in Anaesthesia and Pain Medicine at University College London, explain some basic pharmacodynamic principles to help you better understand how opioids exert their effects.

Pharmacodynamics is the study of how a drug causes its desired effects and its unwanted actions (side-effects). This is sometimes referred to as ‘what the drug does to the body’.

Drugs exert their actions by binding to cell proteins called receptors. How enthusiastically a drug binds to a receptor (affinity – ‘fitting the lock’) and the magnitude of response that it will produce once bound (efficacy or intrinsic activity – ‘turning the key’) will determine its pharmacological effects. A drug can, for example, have a high affinity at a particular receptor but no intrinsic activity, in which case it will produce no pharmacological response when bound to that receptor.

Potency is a measure of the quantity of the drug needed to produce a maximal effect.

Agonists produce a biological response once bound to a receptor. A full agonist (eg morphine) will produce a maximal response (ie full intrinsic activity), whereas a partial agonist will produce a submaximal response when it binds to the receptor, even in high concentrations (eg buprenorphine).

Antagonists have high affinity for a receptor but produce no functional response and can prevent an agonist from binding (eg naloxone – a drug used to reverse opioid toxicity).

Partial agonists are particularly interesting because they can behave both as agonists and as antagonists, depending on the situation. If a partial opioid agonist (eg buprenorphine) is acting alone, it will act as an agonist providing analgesia, but with a lower analgesic effect compared to a full agonist like morphine.

If the partial opioid agonist is acting alongside a full opioid agonist, at low doses both drugs will work together to occupy opioid receptors and create an additive analgesic effect.

Now, if the partial opioid agonist (eg buprenorphine) is used with a higher dose of full opioid agonist (eg morphine), it will start occupying opioid receptor sites preventing morphine from binding, ‘pushing the morphine off’. It has become a competition to occupy the opioid receptors. This creates a situation whereby the analgesic effect of the full agonist morphine is being limited by the partial agonist. This is known as competitive antagonism.

The different actions of agonists, partial agonists and antagonists are shown in the graph below, called a logarithmic dose-response curve (a larger, screen-readable version is available to download below).

At low doses, fentanyl and buprenorphine produce greater responses than morphine (ie fentanyl and buprenorphine are more potent than morphine). While fentanyl’s response is dose-related until reaching 100% maximal response, buprenorphine’s response reaches a ‘ceiling’ below this maximal response, beyond which further increases in dose do not increase the magnitude of response. Buprenorphine is therefore a partial agonist: it cannot produce a 100% response like a full agonist (ie fentanyl) can. At higher doses, morphine (a full agonist with low potency) produces a greater response than buprenorphine.