What is meant by pharmacodynamics?

This is an area of pharmacology that is often defined as “what the drug does to the body”. It is a subject concerned with both the therapeutic, and adverse effects of a drug on the body systems.

How does a drug exert its effects on the body?

To be considered active, a drug must bind to a target and induce/ block a change/ response. There are many targets that a drug can bind to, the main ones being: (1)

1. Ion channels
2. Receptors
3. Enzymes
4. Transporters

We will look at each of these targets in turn, linking a dentally relevant example where possible. Specific targets/ receptors will be covered in various pharmacology lessons, this lesson is designed to be something you can refer to and help you visualise what is happening when a drug acts on a target.

Drug targets

Ion channels (1)

These are pores in the cell membrane that allow ions to diffuse down their concentration gradient. 

There are two subtypes:

1/ Ligand-gated ion channels

• These channels are associated with a receptor (which we will cover later in this lesson)

• They open or close depending on the binding or unbinding of a ligand.

• Ion channels often have a main orthosteric binding site, as well as allosteric binding sites which modulate the channel. In more simple terms, they have a primary receptor site for the primary ligand associated with activating/inhibiting the channel, as well as other binding sites which can change the properties of the ion channel (e.g. enhance or reduce how responsive the channel is to the ligand).

Example:GABA-A receptors are ligand-gated ion channels. GABA (a neurotransmitter) is the primary ligand and can bind to one of two main binding sites, activating the receptor. Benzodiazepines bind to a separate allosteric binding site, acting as a positive modulator for the ion channel. (2)

2/ Voltage-gated ion channels

• These are affected by voltage changes across the cell membrane and will open or close depending on the potential difference of the environment.

Example: Local anaesthetics such as lidocaine physically block voltage gated Na⁺channels.

Receptors (1)

Receptors can be a broad term in pharmacology, but in here we will use it to mean a particular binding site on a protein. Often receptors are linked to other proteins or channels in such a way that activation of the receptor causes a change in the associated molecule. 

We can break receptors down into 4 major types:

1/ Ligand-gated ion channel receptors

• As discussed above, there are receptors (binding sites) found on ligand gated ion channels which can stimulate, inhibit or modulate the channel.

• When these receptors are activated they have a relatively fast onset of action– i.e. the ion channel opens and allows the ions to diffuse through, creating a rapid change in the environment.

2/ G protein coupled receptors (GPCRs)

• Compared to ligand-gated ion channels these have a slower onset of action as they usually involve a signalling pathway, and not just the simple movement of ions.

• They are found on the membrane of the cell, and span the entire width.

• They consist of a receptor attached to a G protein via multiple transmembrane domains.

• The G protein is made up of three subunits; α, β and γ (there are many different varieties of each subunit, and so G-protein coupled receptors are extremely diverse)

• GPCRs can have an excitatory or inhibitory effect depending on the structure of the subunits.

• GPCRs are involved in different signalling pathways depending on the structure of the subunits.

• The basic action of these receptors is more easily explained with a diagram:

In brief, the main point of a G-protein coupled receptor is to transmit a message from the receptor itself, to effector enzymes or proteins within the cell. This message then brings about a change, whether it is excitatory or inhibitory.

Note: To prevent the risk of delving too deeply into cell signalling pathways (they are very complex!) we will just name two G-protein coupled receptors pathways, but for more information on the specifics, please see the references (1).

Two examples of transmission pathways that are affected by G-protein coupled receptors:

Adenylyl cyclase/cAMP system:

• Activation of this pathway via the G-protein coupled receptor results in increased or decreased protein kinase A. 

• Protein kinase enzymes phosphorylate proteins which have further downstream effects within the cell.

Phospholipase C / inositol phosphate system:

• Activation of this pathway via the G-protein coupled receptor results in increased diacylglycerol (DAG) and inositol trisphosphate (IP₃).

• DAG activates protein kinase C which phosphorylates proteins, causing further downstream effects within the cell.

• IP₃ releases Ca²⁺from intracellular stores, raising the concentration of intracellular Ca²⁺. Ca²⁺ is involved in many cellular activities and so this concentration change also causes downstream effects within the cell.

These receptors are the most common drug targets in the human body, and so throughout the pharmacology lessons we will encounter many drugs that exert their effects via this route. (1)

3/ Receptor kinases (1)

• Found on cell membranes, these include receptors for growth factors, as well as insulin.

• In general, when activated there is a conformational change which allows the receptors to dimerise (pair up). This change in structure allows autophosphorylation (addition of a phosphate group, to the receptor kinase itself).

• This structure change results in a final product which is now able to bind to intracellular proteins, allowing further intracellular signalling and downstream effects.

4/ Nuclear receptors (1,3)

Found inside the cell, there are two classes:

Type I: Found in the cytoplasm.

• When activated in the cytoplasm, nuclear receptors move to the nucleus and can upregulate or down regulate gene transcription.

• Binds to ligands such as corticosteroids.

Type II: Found in the nucleus.

• Binds to ligands such as thyroid hormone.

Example: Hydrocortisone (a corticosteroid) binds to nuclear receptors in the cytoplasm of the cell. This complex then travels to the nucleus and inhibits the transcription of certain pro-inflammatory interleukins and cytokines. See “Corticosteroids” lesson for more information.

Enzymes (1)

Enzymes can work as drug targets in multiple ways, some examples are listed below:

Drugs can inhibit enzymes:

• Drugs can bind to active site (orthosteric site) and block binding of the normal substrate.

• Drugs can bind to allosteric site, causing a conformational change of the orthosteric site, meaning it can no longer bind to the substrate. By this mechanism the enzyme is deactivated.

Example: Penicillin inhibits the transpeptidase enzyme in bacteria, preventing peptidoglycan cross linkage, which is a stage involved in bacteria cell wall synthesis. The inhibition of this enzyme is bactericidal. (1)

Drugs can be activated by enzymes.

• Prodrugs are drugs that must be converted to their active form in the body. This process is carried out by enzymes.

Example: Codeine is converted to morphine in the body by host CYP450 2D6 enzymes.

• Some drugs are activated by enzymes in the pathogen that they are targeting. This helps to keep the drug selective for the pathogen, as less of the drug is active in the body.

Example: Metronidazole is an antibiotic prodrug which is activated by bacterial enzymes. (4)

Drugs can act as a false substrate for enzymes

• Drugs can outcompete the endogenous ligand and be utilised as a substrate. Often the products of this processing are inactive (and so halt cell processes), or cytotoxic, (which causes cell death).

Example: Mercaptopurine (a drug used to treat some cancers and autoimmune conditions) is thought to outcompete endogenous purines for incorporation into DNA and RNA, the result of which is cytotoxic. (1,5)

Transporters (1)

• This class of drug target is involved in moving ions or other small molecules across cell membranes, usually against their concentration gradient. Transport against the concentration gradient requires ATP and is referred to as “active transport”.

Example: Proton-pump inhibitors, such as omeprazole and lansoprazole, block the H⁺/K⁺- ATPase transporter which is responsible for pumping H⁺ ions into the stomach to maintain an acidic environment. The reduced acidity of the stomach acid results in decreased reflux symptoms. (6)

Adverse Drugs Effects

Adverse effects of drugs

Now we have covered how a drug can act on the body, it is quite simple to see how a drug can cause adverse effects. Drugs are specific to certain targets, but these targets are often found in multiple places in the body. The action of the drug on a target in the wrong site is sometimes the cause of these side effects. In addition, as drugs often affect a signalling cascade (such as when they act on G-protein coupled receptors), many downstream processes are also affected. We can alter the formulation of the drug to try and minimise these side effects, but it is not always avoidable.

Adverse drug reactions (ADRs) (7)

This term specifically describes a reaction that occurs after administration of a drug, which is harmful or undesired. These can range from mild reactions, such as a minor rash, right up to severe reactions which can be fatal. Often the reactions are categorised into the following groups:

Type A (Augmented reactions):

• These are reactions associated with the pharmacological effects of the drug – they are dose-dependent, predictable effects. Type A reactions cover both therapeutic and non-therapeutic ADRs.

Example: An excess dose of warfarin causing bleeding.

Example: Dry mouth associated with antidepressant medication.

Type B (Bizarre reactions):

• These reactions are unexpected and are not dose dependent. We cannot explain why one person will develop a type B reaction and another will not.

Example: Anaphylaxis after antibiotic administration.

Type C (Continuing reactions):

• These reactions continue for a fairly long time after the drug has been administered.

Example: Osteonecrosis of the jaw associated with bisphosphonate use.

Type D (Delayed reactions):

• These reactions have a delayed onset and may occur weeks or even months after the use of the drug. (8)

Example: Carcinogenesis following treatment with certain anticancer drugs.

Type E (End of use reactions):

• These reactions are associated with the cessation of drug treatment.

Example: Anxiety after withdrawal of benzodiazepines.

Yellow Card Scheme

This is a way of reporting adverse drug effects to the Medicines and Healthcare products Regulatory Authority (MHRA). This is so they can monitor the frequency of side effects, and update product literature as more information is complied. Healthcare professionals should report:

ADRs that are significant, serious or harmful.

Any ADR (serious or not) associated with a Black Triangle product:

• Black Triangle products are new to the market and are subject to close monitoring.

• They are marked in the BNF with an upside-down black triangle.

You can report online, or via a mobile app, see the guidance for more information. (7)