The Science Behind Painkillers

by Kiana Danesh Manesh

Introduction

Analgesic drugs, or painkillers, are a type of medicine aimed to provide pain relief and management. Although they do not address the underlying cause, they are used to relieve and manage all kinds of pain, such as period pains, postsurgical pains, and chronic pains. However, not all analgesic drugs are the same, as they vary in their potency, method of metabolism, way of absorption, and distribution in the body. A great way of differentiating the vast amount of analgesics is by dividing them into three classes: Simple non-opioid analgesics, which include painkillers such as ibuprofen and aspirin, that are readily available in any pharmacy. Compound analgesics, that contain a ‘mix’ of a non-opioid and opioid, unlike simple analgesics, these are only available through a prescription. Finally, opioid analgesics, which give the strongest type of pain relief; referring to drugs such as fentanyl and morphine.

This cocktail of drugs is, at least to me, fascinating. I want to take you on a deep dive through how analgesic drugs work, how they metabolize, how they affect you, and discuss the importance of medicinal chemistry in the development of such drugs. Among other things. Enough with the introduction, and more on the chemistry of the wide world of analgesics!

Classification

Circling back to the topic of classification, I want to delve into the chemical structures, mechanism of action, and medicinal chemistry aspect of certain drugs in each class. As mentioned before, we have Non-opioid analgesics, Compound analgesics, and Opioid analgesics. Let's begin with the ‘tamest’ class.

Non-Opioid Analgesics

Non-opioid analgesics, also known as NSAIDS (Nonsteroidal Anti-Inflammatory Drugs), are a division of analgesic drugs that mitigate pain, fever, and other inflammatory responses. This class includes medication such as Ibuprofen and Aspirin. I will be focusing on Aspirin. 

NSAIDS can be grouped into three groups, COX-1, COX-2, and non selective COX inhibitors. These inhibitors work to block two types of enzymes called cyclooxygenase, which help enzymatically produce a hormone-like substance called prostaglandins (PGs) from arachidonic acid. Prostaglandins are a group of fats your body produces at a site of infection or tissue damage, causing inflammation - and influencing your pain receptors. They are responsible for inducing labor, activating or inhibiting blood clots, causing fever, and for causing period cramps. COX-1 enzymes help make the type of prostaglandin that protects your stomach and intestinal lining from digestive acids, while also helping your blood clot. COX-1 inhibitors block the inflammatory effects that the prostaglandin produces, but also block the protective and helpful effects that it provides. COX-2 enzymes produce prostaglandins more involved in inflammation, and COX-2 inhibitors cannot inhibit COX-1 enzymes, meaning that the helpful effects of the enzyme are not affected. As you probably guessed, non selective COX inhibitors can block both enzymes.

Aspirin, a salicylate, is classified as a non selective COX inhibitor, and is derived from salicylic acid. It possesses anti-pyretic (anti-nausea), anti-inflammatory and analgesic properties. Although it is commonly used to relieve pain and fever, it also works as a blood thinner, helping lower the risk of blood clots. It is able to produce such effects by blocking the synthesis of prostaglandin, inhibiting the activity of COX enzymes. Aspirin acts as an acetylating agent, transferring its acetyl group to the hydroxyl group of a serine residue (Ser529), which is located at an active site of the COX-1 enzyme. This reaction is called acetylation, and it effectively inhibits the activity of the COX-1 enzyme, therefore causing a reduction of prostaglandin. However, as we mentioned before, this mechanism of action blocks prostaglandin from protecting the stomach and intestinal lining from acids such as hydrochloric acid, which can cause side effects relating to the stomach. For example; a common side effect of aspirin is stomach irritation and discomfort, and a severe adverse effect of aspirin is epigastric pain. 

Figure 1: Chemical Structure of Aspirin

Aspirin contains three functional groups; an ester, carboxylic acid, and an aromatic ring. Aspirin was invented in 1850, and was considered viable for commercial use in 1899 This analgesic compound was modified from salicylic acid, which was discovered from willow bark in 1838. Although salicylic acid provided analgesic properties and relief, it was met with severe gastric problems due to its acidic functional groups, carboxylic acid and a phenol (an alcohol bound to a benzene ring). So, chemists set out a plan to reduce the acidity of salicylic acid, while keeping its medicinal relief. Aspirin is synthesized by reacting salicylic acid with ethanoic anhydride, and with a strong acid such as sulfuric acid to catalyze the reaction. 

Semi-synthetic and Synthetic Analgesics 

Moving on to semi-synthetic analgesics, and synthetic analgesics, these two classes of analgesic medication have to be obtained via a prescription, and they are considered addictive. Semi-synthetic opioids are drugs that have been chemically processed from a natural opioid, these derivatives are mostly morphine and codeine. These drugs include; Heroin, Oxycodone (Percocet), and Hydrocodone (Vicodin). Synthetic opioids, on the other hand, are synthesized in a lab to mimic naturally occurring opioids, and include drugs such as fentanyl. Both classes are most commonly prescribed to treat post-surgical pains, but a patient may be at risk of developing an addiction due to their potent effects. 

Figure 2: Chemical structure of Oxycodone

Oxycodone is a semisynthetic opioid agonist, presenting as a white odorless powder. It contains an alcohol functional group, ketone functional group and ether group. It has a different mechanism of action in comparison to aspirin, instead of inhibiting COX inhibitors, it binds and stimulates opioid receptors located in the central nervous system and activates them, blocking pain signals from reaching the brain and mimicking the effects of endogenous (internal) opioids. This releases effects of analgesia but also effects of euphoria and relaxation on the brain, these feelings may cause someone to become addicted. 

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