14.1 Basic Principles of Pharmacology

Route of administration

The route of administration refers to how a drug is introduced to the body. Although there are several different methods for drug administration, they fall broadly into two categories: enteral administration, which involves the gastrointestinal system, and parenteral administration, which does not. The route of administration plays an important role in determining the onset of action, or the amount of time it takes to experience a drug’s effect. In general, enteral administration is associated with slower onset compared to parenteral administration. Furthermore, the route of administration is often dependent on the chemical structure of the drug since certain formulations may only be effective when delivered a specific way. A few of the more common routes of administration are discussed below and diagrammed in Figure 14.2.

Figure 14.2 Routes of drug administration and time of action onset

Oral administration is one of the most frequently used forms of drug administration because it is generally safe, simple, and convenient to self-administer. Drugs designed for oral administration are often formulated as capsules, pills, or tablets, but can also be delivered through a liquid solution. Once ingested, the drug moves through the stomach into the small intestines where it is absorbed into the portal vein and passed through the liver before entering the main circulatory system. This process is known as first-pass metabolism. Enzymes in the liver can chemically alter the drug, resulting in less of it reaching the binding site. Certain protein-based drugs, such as insulin, are destroyed by gastric acids in the stomach before even being absorbed into the portal vein. This is why insulin is typically administered via a subcutaneous (under the skin) injection. The onset of action for orally administered drugs typically ranges from 20 minutes to an hour.

Intravenous (IV) administration is the delivery of a drug directly into the bloodstream via a hypodermic needle. In contrast to oral administration, IV administration has a very rapid onset of action (within 1 minute). Furthermore, bioavailability is essentially 100% seeing as this route of administration bypasses the gastrointestinal system and first-pass metabolism. While this is certainly advantageous when fast effects are needed, this form of administration can also lead to overdoses or other adverse effects if the drug is impure or if the dose is not calculated correctly. IV drug use can also pose additional health hazards when done without sterile equipment.

Inhalation is a route of administration that allows the drug to be absorbed into the circulatory system via the lungs. For this method of delivery, the drug must be burned to create smoke (such as with a cigarette) or volatilized into a vapor. The inhaled smoke or vapor passes through the lungs and is absorbed by the surrounding pulmonary capillaries, which quickly carry the drug into the circulatory system. For this reason, drug delivery by inhalation also produces a fairly rapid onset of action. However, inhalation of non-gaseous particles can cause damage to the airways and lungs.

Intranasal drug delivery is achieved by inhaling a substance through the nostrils or directly applying the drug to the mucous membranes of the nasal passage. The drug is then absorbed into the blood vessels that line the nasal cavity and carried into the circulatory system. Oxytocin, a peptide hormone involved in social bonding and reproduction (see Chapter 11 Sexual Behavior and Development), is sometimes delivered intranasally through a spray to facilitate breastfeeding after childbirth. Although this route of administration also results in a rapid onset of action, contaminants present in the drug may irritate the nasal passage and lead to tissue damage.

Transdermal administration delivers drugs through the skin’s surface into the underlying blood vessels via a skin patch or ointment. This route is unique from topical administration, in which the drug is intended to remain on the skin surface. Hormonal contraceptives that contain estrogen and progesterone can be administered transdermally through a skin patch. This route of administration allows for a sustained diffusion of drugs over an extended time, which eliminates the need to remember to take a daily pill or injection. Although transdermal administration has a slow onset of action, it can provide extended periods of drug delivery (up to a week in some cases). The utility of this route of administration is limited by the fact that only certain types of drugs can penetrate the skin.

Absorption and distribution

As discussed earlier, a drug must be absorbed into the bloodstream and distributed throughout the body to reach its target binding site. The speed at which this occurs depends on the route of administration. Drugs delivered directly into the bloodstream will be absorbed and distributed much faster than drugs that must travel through the gastrointestinal system. For enteral methods of administration, most drug absorption occurs in the small intestines. Therefore, the time it takes the drug to reach the bloodstream is heavily dependent on how long it takes for the stomach to empty into the small intestines. The absorption process can also be affected by food being digested in the stomach. For example, calcium molecules found in dairy products, such as milk, yogurt, and cheese, can bind to certain antibiotics and prevent them from being absorbed. Similarly, medications used to treat hypothyroidism, such as levothyroxine, need to be taken on an empty stomach to enhance absorption.

One factor that can impact absorption and distribution in the brain is the blood-brain barrier (BBB), a lining of cells that acts as a border between blood vessels and extracellular fluid in the brain (Figure 14.3) (see Chapter 1 Structure and Function of the Nervous System: Cells and Anatomy).

Figure 14.3 Molecule characteristics that influence absorption across the blood-brain barrier

The relatively impermeable nature of the BBB prevents the vast majority of molecules from diffusing into the brain since most compounds found in the blood are large, electrically charged or lipid insoluble. The BBB tightly regulates the entry of select nutrients and molecules into the brain via passive and active transport channels. This selectivity helps to protect the central nervous system (CNS) from pathogens that could cause systemic infection but can also prevent certain drugs from reaching the brain. Drugs with high lipid-solubility, or the ability to dissolve through the cell membrane, are more likely to cross the BBB. Many psychoactive drugs (e.g. cocaine, nicotine, fentanyl) are highly lipid-soluble molecules, a property which allows them to penetrate the BBB and interact with their targets in the brain. The BBB continues to present a challenge for developing pharmaceutical treatments for central nervous system (CNS) disorders since pharmaceutical drugs cannot always be designed as small or lipid-soluble molecules.

Metabolism

Drugs can be chemically altered by enzymes located throughout the body, although the majority of drug metabolism takes place in the liver and gastrointestinal tract. The rate of metabolism for a particular drug is influenced by how quickly these enzymes alter the drug, which differs depending on genetics, age, sex, and body weight. This process can potentially inactivate the drug, thereby reducing bioavailability. For example, alcohol is broken down in the stomach and liver by alcohol dehydrogenase enzymes which transform the drug first into acetaldehyde and then into acetic acid. In contrast, prodrugs are drugs that are inactive until they are metabolized by the body. Codeine, an opiate drug derived from the opium poppy, has very little drug effect until it is metabolized by the liver to produce morphine, a much more potent drug.

There are several ways that changes in liver enzyme function can alter drug metabolism and thereby end up changing how a drug ultimately impacts a person. Liver damage or dysfunction can lead to unpredictable changes in drug clearance and metabolism, for example. Using a drug chronically can increase the number of liver enzymes that degrade it, which over time may reduce the amount of drug that is absorbed into the bloodstream. The administration of multiple drugs at the same time can cause drug-drug interactions, in which one drug impacts the activity of another. In addition, increased levels of one or more of the drugs may accumulate in the bloodstream if they are metabolized by the same enzyme. This phenomenon is known as competitive enzyme inhibition. Essentially, the enzyme that would be helping to break down and clear one drug is too busy breaking down the other drug. For example, cisapride, a drug used to treat gastroesophageal reflux disease, and ketoconazole, an antifungal medication, are both metabolized by cytochrome P450 (CYP) liver enzymes. When these drugs are taken together, blood levels of cisapride can reach toxic levels, which may increase the risk of adverse side effects.

Excretion

The primary way that drugs and their metabolites are removed from the body is via the kidney, which filters the blood and excretes waste materials through urine. Drugs can also be excreted from the body through feces, sweat and saliva. The amount of time it takes for the blood concentration of a drug to reach 50% of its original value is commonly referred to as the half-life. The half-life of a drug can be influenced by the route of administration. Drugs that are taken orally enter and exit the bloodstream more slowly than those injected directly into a blood vessel. A drug with a short half-life may have to be administered multiple times a day to maintain its effects, whereas the effects of a drug with a long half-life may persist for over a day with only a single administration. A long half-life may seem ideal for therapeutic purposes. However, it may also prolong unwanted or dangerous side effects of the drug. These factors, along with absorption and distribution, contribute to the drug plasma concentration over time (Figure 14.4). The length of time a drug remains at a therapeutic or effective concentration is considered the duration of action.

Figure 14.4 Plasma concentration over time Each curve shows the plasma concentration of a drug over time, revealing different absorption rates. Only the middle (blue) curve shows plasma concentrations within the therapeutic range without inducing toxic effects.

Receptors

There are two main categories of ligand-binding receptors, both shown in Figure 14.6 (see Chapter 3 Basic Neurochemistry ).

Figure 14.6 Ionotropic vs metabotropic receptors

Ligand-gated channels (also known as ionotropic receptors) are ion channels composed of proteins embedded in the cell membrane. When a ligand binds to the binding site, the membrane-spanning portions of the receptor open to form a channel that allows specific ions to cross into the cell. If the receptor is on a neuron, which is often the case for psychoactive drugs, this movement can result in either excitation or inhibition of the neuron. This response usually occurs within a millisecond of the ligand binding.

Metabotropic receptors (also known as G protein-coupled receptors) also have an extracellular active site, but these receptors do not form an ion channel. Instead, they are composed of seven transmembrane proteins that are physically linked to intracellular proteins called G proteins. When a ligand binds to the active site, the G protein disassociates from the receptor complex. Once unbound, the G protein can go on to open or close ion channels located on the cell membrane or activate or inhibit intracellular signaling cascades. Because metabotropic receptors are indirectly linked with ion channels and signaling transduction, compared to ionotropic receptors, their effects on neuronal activity occur at a slower pace and can persist for a longer period.

Receptor ligands

Ligands can be naturally produced within the body or derived from a source outside of the body. For example, endocannabinoids are neurotransmitters that are produced within the central and peripheral nervous system and bind to cannabinoid (CB) receptors (see Chapter 3 Basic Neurochemistry). Because they are synthesized within the brain, endocannabinoids are considered the endogenous ligand for CB receptors. The primary psychoactive chemical in cannabis (THC) also binds to CB receptors. However, it is derived from a plant and is thus considered an exogenous ligand.

A dose-response curve plots the relationship between the level of receptor response and the dose of the drug (Figure 14.7).

Figure 14.7 Ligand receptor interactions

A full agonist is a ligand or drug that is capable of binding to and activating a receptor with maximal efficacy. Epinephrine is an example of a full agonist at the adrenergic receptor. A partial agonist also can activate a receptor upon binding. However, it elicits a reduced receptor response compared to a full agonist, even with increasing concentration of the ligand. Buprenorphine, an opioid drug used to treat opioid use disorder, is a partial agonist at the mu-opioid receptor (MOR). Buprenorphine’s reduced efficacy at the MOR decreases the risk of overdose.

In some cases, a receptor can produce a biological response in the absence of an agonist binding. This phenomenon is referred to as constitutive activity. An inverse agonist is a drug that inhibits the same binding site as a full agonist but reduces activity in a receptor that would otherwise be constitutively active. For example, certain histamine receptors exhibit agonist-independent activity, which is thought to contribute to many allergy symptoms. Antihistamines, drugs used to alleviate allergy symptoms, bind to histamine receptors and reduce their biological response instead of increasing it, thereby making them inverse agonists.

An antagonist is a ligand that blocks the activation of the receptor by preventing agonists from binding. In contrast to the inverse agonist, an antagonist does not have any intrinsic activity on the receptor itself, it simply blocks agonists from interacting with the receptor. For example, caffeine is an antagonist at adenosine receptors, which typically induce drowsiness when activated by their endogenous ligand.

Another type of agonist interaction sometimes seen with G protein-coupled receptors is biased agonism or functional selectivity. This occurs when the unique structure of a ligand allows it to preferentially activate certain intracellular signaling cascades over others. A major goal in drug development research is to design ligands that induce signaling cascades that promote the therapeutic effects of drugs while minimizing the activation of cascades associated with adverse side effects. In 2020, the Food and Drug Administration (FDA) approved the first biased mu-opioid receptor agonist for the treatment of severe pain. When tested in clinical studies, this drug produced a similar degree of analgesia (pain relief) but less nausea and respiratory depression compared to morphine (DeWire et al., 2013).

Certain ligands, called allosteric modulators, can regulate receptor activity without interacting with a receptor’s orthosteric site, the location where an agonist would typically bind. Instead, allosteric modulators bind to a different part of the receptor (referred to as the allosteric site), which can ultimately alter the effects of ligands that bind to the orthosteric site. Positive allosteric modulators increase the efficacy of agonists that bind to the receptor, whereas negative allosteric modulators reduce the ability of agonists to activate the receptor. Benzodiazepines, drugs used to treat anxiety disorders, are an example of positive allosteric modulators of the GABA_A receptor (Figure 14.8). When both GABA and benzodiazepines are bound to the GABA_A receptor, the ion channel opens more frequently or for a longer period, allowing more chloride ions to enter the cell. This results in a greater inhibitory effect compared to when only GABA is present. In contrast to an agonist, benzodiazepines have no effect on GABA_A receptor activation on their own.

Figure 14.8 GABA_A receptor agonists Many sedatives work by binding to and activating GABA_A receptors.