3: Pharmacodynamics

Pharmacodynamics is the study of a drug's biochemical and physiologic effects of a drug on the body. The biochemical interactions through which a medication exerts its clinical or pharmacological effect are called the mechanism of action (MOA). The MOA includes the specific drug target, such as receptors, enzymes, proteins, hormones, or drug pathways.

Receptors are proteins found on the cell surface or within the cell. Substances that interact with receptors are called ligands. Ligands can be endogenous substances (produced inside the body), such as epinephrine, or exogenous substances (produced outside the body), such as a drug manufactured to mimic epinephrine. In both cases, the endogenous or exogenous epinephrine molecule binds to the alpha and beta receptors of the autonomic nervous system. Traditionally, most drugs have been manufactured to bind to specific receptors on the cell surface or within a targeted cell type. However, many other cellular components and non-specific sites can serve as drug targets to create a clinical response. For example, the osmotic laxative magnesium citrate attracts and binds with water molecules, pulling water into the bowel to increase the likelihood of a bowel movement.

An agonist is a drug that binds to a receptor and produces a biological effect. A medication that exerts a strong biological effect is classified as a full agonist. Other types of drug-receptor interaction describe medications that produce an effect weaker than the response of a full agonist and are called partial agonists.

Other medications may prevent an endogenous ligand from binding to the receptor-binding site. This type of drug-receptor interaction is inhibitory, and the drug is called an antagonist. For example, antimicrobial and antineoplastic drugs commonly work by inhibiting enzymes critical to the cell's function. With blockage of the enzyme binding site, the cell microbe or neoplastic cell is no longer viable, and cell death occurs. Antagonists and agonists often compete for binding sites.

Finally, some drugs have a mixed response depending on the cell type and tissue location. A drug may act as an agonist at one receptor type, whereas at another receptor type, the same drug acts as an antagonist. For example, the opioid receptor system includes multiple receptor types (mu and kappa) that interact differently with opioid drugs. Buprenorphine binds to mu and kappa receptors and is classified as a mixed agonist-antagonist: a partial agonist at the mu receptor and an antagonist at the kappa receptor. The figure below shows the range of responses from agonism to antagonism.

Figure 3.1 $\PageIndex{1.1}$: Range of Drug Responses. (CC-BY 4.0; Riley Cutler)

The protein targets for many drugs can be divided into four broad classes shown in panels A–D. Panel A shows two different drugs that are binding to a receptor. Receptors play an important role in the communication pathway that coordinates the function of various cells within the body. Agonist medications may bind to numerous receptor types (see panels A–D below). Once an agonist binds to a receptor, a physiologic mechanism is activated. Currently, in the largest group of drug-receptor interactions, the medication is present in the extracellular space, and the physiologic or effector mechanism resides within the cell; signaling occurs across the membrane. Once bound, the drug modifies some intracellular process, often involving a sequence of second messenger events. This is why receptors are sometimes described as endogenous mediators. Panels B–D describe receptor types in more detail.

Panel B depicts ion channels. Ion channels are gates that open and close to selectively allow an ion or drug to pass through a cell membrane. There are two types of ion channels: ligand-gated and voltage-gated. Ligand-gated ion channels open when an agonist is bound and are classified as receptors. Voltage-gaited ion channels respond to a change in the transmembrane potential rather than molecular binding. Medications can interact with an ion channel in several ways. A medication may directly bind to the channel protein. For example, local anesthetics bind to voltage-gated sodium channels. Examples that follow allosteric binding (the drug binds to a site on the channel other than the binding site for the molecule that activates the channel; the neurotransmitter GABA in the case of benzodiazepines) are benzodiazepines, dihydropyridines and sulfonylureas. Other medications may indirectly interact with an ion channel by activating a G protein-coupled receptor. Finally, some medications may alter the level of expression of ion channels on the cell surface. For example, gabapentin reduces the number of active presynaptic calcium channels and the subsequent release of excitatory neurotransmitters.

Some antagonists modulate the opening and closing of a channel, whereas other medications block the channel's entry or the channel from within, as shown in panel B.

Panel C shows enzymes, which many medications target. An important case is when a medication is a prodrug. Prodrugs are medications that require enzymatic metabolism or degradation to convert them to their biologically active form. Understanding prodrugs is essential because they are associated with drug toxicity. One of the first prodrugs used was aspirin. Aspirin is metabolized into salicylic acid; salicylates inhibit the activity of cyclooxygenases (COX-1 and COX-2), reducing inflammation. Often, a medication acts as a substrate analog or decoy that competes with the target enzyme. For example, captopril acts on the angiotensin-converting enzyme. Other medications act as false substrates and produce an abnormal product that disrupts the normal metabolic pathway. An example is fluorouracil (5-FU), which replaces uracil in purine biosynthesis, ultimately preventing DNA synthesis and cell division.

Panel D shows transporters. Ions and small molecules move across cell membranes through channels or with the help of transporters. Many molecules are too polar (a weak lipid-soluble molecule) to penetrate the lipid bilayer independently. Several different types of transporters have been identified. Transporters of pharmacologic importance are ion transporters in the renal tubule, the intestinal epithelium, the blood-brain barrier, and those that transport Na⁺/Ca²⁺ out of cells. The transporter often requires ATP to transport substances against the electrochemical gradient and maintain cell functioning. Examples include the sodium pump and the multi-drug resistance (MDR) transporter, also called the P-glycoprotein (Pgp) transporter. The Pgp ejects cytotoxic substances from the cell, including medications. For example, the Pgp ejects cytotoxic cancer drugs from cancer and microbial cells, conferring resistance to these therapeutic agents. Sometimes, the transport of organic molecules is coupled to the transport of ions (often Na⁺), as in the transport of neurotransmitters. Transporters are becoming increasingly recognized as a source of individual variation in the pharmacokinetics associated with certain medications such as azithromycin.

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Figure 3.2 $\PageIndex{1.2}$: Agonist & Antagonist Medications (CC-BY 4.0; Hannah Koffman and Riley Cutler)

When a drug or medication attaches to its target, it forms a complex. The drug-target complex causes a biological response, which is that drug or medication's specific mechanism of action. The biological response and the medication's concentration in circulation is expressed through dose-response curves. The dose-response curve describes the relationship between drug concentration on the x-axis and the biological response on the y-axis. The minimum effective concentration (MEC) is the lowest dose where the desired biological effect is noted. For example, the MEC for antimicrobials is the lowest dose at which microbial growth is suppressed. The same dose of a medication can result in different plasma concentrations in different individuals. That difference is related to the pharmacokinetics of the individual and the dose of the medication.

Some drugs bind to a receptor allosterically. Allosteric modulation can be positive or negative. The binding of the neurotransmitter GABA on the GABA receptor is shown below. When GABA binds, it opens the channel and allows for the influx of Cl ions. Benzodiazepines also bind to the GABA receptor but at a different site than GABA. In the presence of the benzodiazepine drug, the neurotransmitter GABA still binds to its site on the GABA receptor, but the BZD causes the channel to stay open longer and more Cl ions to enter. This is an example of a positive allosteric modulator.

Drug-receptor interactions are characterized by the drug's affinity and efficacy. The occupation of a drug on a receptor is governed by its affinity or the strength of the bond between the drug and the receptor. Affinity can be expressed as the K_D or equilibrium constant. K_D is calculated as the K_off/K_on. A drug's on/off rates are specific, and a drug with a high affinity for a receptor may spend more time attached or bound to the receptor than unattached or off. Thus, KD is the reciprocal or inversely related to affinity.Dose-response curves can estimate efficacy and potency. Potency is the concentration at which the medication elicits 50% of the maximal response (EC50). The lower the EC50, the greater the potency of the medication. Efficacy is the maximal response or effectiveness a medication can produce at a tolerable dose (Emax). The graph below shows the dose-response curves for three drugs, A, B, and C. Drug C is the most potent, and Emax is reached at the lowest drug concentration. However, the response to Drug C is not as great as the response to Drugs A and B. The drug concentration increases as you move to the right along the x-axis. Drugs A and B are less potent than Drug C; the ranking of the three drugs for potency from highest to lowest is C>A>B. The dotted line represents the EC50. Drugs A and B have similar efficacy; both curves plateau or flatten out on the same point along the y-axis. The ranking of the three drugs from highest to lowest for efficacy is B>A>C. Efficacy can be expressed numerically from zero to one. A full agonist drug has an efficacy of one, whereas a full antagonist has an efficacy of zero.

Agonist and antagonist drugs compete for binding sites with drugs, hormones, neurotransmitters, and other substances. Whatever molecule has the strongest affinity will out-compete and bind to the receptor. Usually, binding is reversible; the drug-receptor complex separates depending on the drug's affinity to its target molecule or receptor. Binding can also be irreversible. Irreversible antagonists may bind covalently so that the receptor is deactivated. Once deactivated, the non-functional receptor is internalized and recycled. For example, succinylcholine binds irreversibly to the nicotinic acetylcholine receptor, and aspirin binds irreversibly to its target molecule, platelets. The duration of the binding and drug's action depends on the body's ability to metabolize succinylcholine into butyrylcholine and, in the case of aspirin, the body's ability to make new platelets.

When two drugs competing for the same receptor are given simultaneously, there is always the potential for drug interactions. The figure below shows what happens to a full agonist, Drug A, in the presence of two antagonists. The curve Drug A' shows the change in the dose-response curve for Drug A with the addition of a competitive antagonist. The curve for Drug A" shows the dose-response curve for the agonist when a non-competitive antagonist is added. Notice that with the addition of a competitive antagonist, increasing the amount of agonist allows the agonist to reach the maximal possible response observed in the absence of the antagonist. The agonist competes with the competitive antagonist for binding sites. Adding more or increasing the concentration of the agonist allows the agonist to overcome the competitive antagonist. With the addition of a non-competitive antagonist, the agonist Drug A can never reach its maximal possible response.

The dose required to produce a therapeutic effect varies from individual to individual. The dose in the middle of the distribution is the ED50, defined as the dose required to produce the intended therapeutic effect for 50% of the population. This is the standard dose, but some individuals will be under-treated, whereas others will be over-treated. Because you cannot predict an individual's response to the drug, you must monitor the patient for their response and adjust dosing.

The therapeutic index (TI) measures a drug's safety. The larger the difference between a drug's effective and lethal dose, the greater the TI and the safer the drug. In Figure 3.7, the TI for two drugs is shown below. Both drugs have similar ED50 values but different LD50 values. When the gap between the ED50 dose and the LD50 dose is close or narrow, such as the drug in the bottom panel, that drug has a narrow safety margin. Drugs with a narrow TI often have specific monitoring recommendations, such as periodic serum drug levels. Carbamazepine, lithium, warfarin, and phenytoin all have a narrow TI and are subject to therapeutic monitoring.

A drug's safety profile is related to its pharmacokinetic parameters. The area under the curve or AUC represents the entire time a drug is in the body or the extent of exposure to a drug. Ideally, a drug's level will be in the therapeutic range. The AUC is a critical concept in antimicrobial prescribing.