Introduction to Pharmacodynamics

Pharmacodynamics

Pharmacodynamics is the branch of pharmacology that describes all the various ways drugs exert their effects on our physiology. In other words, what the drug does to the body. The inverse of this—what the body does to the drug—is a separate branch called pharmacokinetics.

Drugs exert their actions by interferring with a target in some way to bring about a change in physiology. The most obvious way that drugs can act is to directly inhibit a molecule causing harm. Alternatively, drugs can act by inhibiting production of the harmful molecule by interferring with upstream processes. Other ways drugs can act is by enhancing beneficial physiological processes to combat the harmful process. Clearly, drugs have diverse and varied ways of causing changes in the body. The description of how a particular drug exerts its effects on physiology is the "mechanism of action" or "MoA".

Common Targets of Drugs

All drugs exert their physiological effects by interacting with biological molecular targets. The vast majority of drugs target two types of biological molecules: receptors and enzymes. Drugs which targets other biomolecules (such as DNA or signalling molecules) do exist but are much less common.

You may recall what receptors and enzymes are from your cell biology or biochemistry studies. Receptors are proteins which alter the cell's functioning in response to a stimulus. Enzymes are proteins which catalyse a huge variety of chemical changes, ranging from very small chemical changes to splitting molecules in half. Importantly, receptors and enzymes are highly specialised and each will only do a very specific action. This is how drugs have their specific actions—by interfering with the specific functions of receptors or enzymes.

Two Examples of Drugs Acting on a Receptor

Adrenaline and Adrenoceptors

In your previous studies (or elsewhere) you may have heard of adrenaline (also known as "epinephrine" in some parts of the world), a hormone that dominates during the "fight or flight" response. You've probably experienced this response yourself if you've ever given a presentation or performance and felt a strong pounding or fluttering feeling in your chest known as "stage fright". Adrenaline has many effects all over the body but its most well-known effect is increasing the rate and strength of the heart beat.

Adrenaline exerts its effects by binding to adrenoreceptors. Adrenoreceptors come in five types—α1, α2, β1, β2 and β3—each with slightly different functions and anatomical distributions. The table below gives examples of where adrenoreceptors can be found in the body and some of their effects on physiology.

Major adrenoreceptor subtypes, their locations and effects when activated by adrenaline

Adrenoreceptor subtype	Location	Effect(s)
α1	Vascular smooth muscle	Blood vessel constriction
	Eye	Pupil dilation
α2	Vascular smooth muscle	Mixed effects
	Pancreas	Decreased insulin secretion
β1	Heart	Increased heart rate and contractility
	Kidney	Increased blood pressure
β2	Bronchial smooth muscle	Airway opening
	Vascular smooth muscle	Blood vessel dilation
β3	Fat tissue	Fat breakdown
	Bladder	Relaxation of detrusor muscle

The heart muscle expresses β1-adrenoreceptors (β1-AR) on the cell surface. Adrenaline binds to the β1-AR and activates a signalling cascade which results in increased rate and contractility. Substances which bind to a receptor and activate it are called "agonists" so adrenaline is an agonist at the β1-adrenoreceptors. (NOTE: you may hear adrenoreceptors also called "adrenoceptors" or "adrenergic receptors"). There's an old analogy used in pharmacology which describes receptors as locks which can be unlocked by agonists (like a key).

The following sections consider two examples of drugs—propranolol and isoprenaline—which cause changes to heart muscle physiology by acting on the β1-AR

Antagonist: propranolol

Some people experience stage fright so strongly that they require medication to overcome the powerful physical response when giving presentations or performances. Hopefully, you can see a promising way to achieve this. By designing a drug which binds to the β1-adrenoreceptors but does not activate it, we could block adrenaline's effect on the heart muscle! Such a drug exists, propranolol. See the figure for an illustration of the mechanism of action of propranolol.

Propranolol, which binds to the receptor but does not activate it, is known as an "antagonist". You may also hear antagonists called "blockers" or "inhibitors" (for example, propranolol is often called a "beta blocker"). In the "lock-and-key" analogy, propranolol is like a key with the head snipped off: It can be inserted into the lock but cannot be turned to unlock it.

Agonist: isoprenaline

On the other hand, there are some patients who have dangerously LOW heart rate. Instead of a β1-AR antagonist therapy (which would lower their heart rate even further), they require agonist therapy. An example of a β1-AR agonist is isoprenaline. See the figure for an illustration of the mechanism of action of isoprenaline.

Receptor Selectivity

If you've been paying attention, you might wonder why these patients are treated with the agonist isoprenaline when adrenaline is also a β1-AR agonist. The answer lies the drug's selectivity. Isoprenaline is selective for β1-AR on the heart muscle so mostly affects heart rate. Adrenaline is non-selective and activates α1, α2, β1, β2 and β3-AR all over the body causing various effects. Therefore, isoprenaline is a desirable drug because it can lower heart rate without causing the other "off-target" effects. This issue of selectivity is a major concern in pharmacology and can explain the side effects of many drugs.

In fact, propranolol, the β1-AR antagonist, is an example of a drug that is not very selective; it also acts an antagonist at the β2-AR. Using this knowledge and the information in the table above, you should be able to predict some of the important side effects of propranolol.