3: Pharmacodynamics

3.0 Overview of Pharmacodynamics

Pharmacodynamics is the study of a drug's biochemical and physiologic effects 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.

3.1 Drug Binding Sites

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 agonist 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 bind to a receptor site but block the receptor's activity. 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 the same 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. Figure 3.1.1 below shows the range of clinical responses from agonism (full activation) to antagonism (full inhibition).

Figure 3.1.1: Drug-Receptor Binding and the Range of Drug Responses. (CC-BY 4.0; Riley Cutler)

Receptor or drug targets are often proteins and can be divided into four broad classes, shown below in Figure 3.1.2 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-gated 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 and block voltage-gated sodium channels, inhibiting signal transmission. Allosteric binding, that is, the drug binds to a site on the channel other than the binding site for the molecule that activates the channel, includes the neurotransmitter, gamma-aminobutyric acid or GABA (in the case of benzodiazepines), dihydropyridines, and sulfonylureas. Other medications may indirectly interact with an ion channel by activating a G protein-coupled receptor. Finally, some drugs 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. Yet other 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 or proteins, which many medications target. Enzymes are biological catalysts that speed up essential chemical reactions for life. Often, enzymes are proteins with the ending ase. Clinically, a critical case to understand is when a medication is a prodrug. Prodrugs are medications that require metabolism or degradation to be converted to their biologically active form. Understanding prodrugs is essential because they are associated with drug toxicity and treatment failures. 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. An individual who has a variant of P450 metabolizing enzymes required to convert a drug to a prodrug may experience treatment failure. Other medications act as a substrate analog or decoy that competes with the target enzyme. For example, captopril acts on the angiotensin-converting enzyme. Medications are also made to 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 disrupting 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. A transporter often requires energy in the form of adenosine triphosphate (ATP) to transport substances against the electrochemical gradient and maintain cell functioning. Examples include the sodium pump and the multidrug 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 3.1.2: Drugs Binding to Receptors, Enzymes, Ion Channels, and Transporters. Description in text. (CC-BY 4.0; Hannah Koffman and Riley Cutler)

Not all drugs bind directly to the active site on the target molecule. Some drugs bind to a receptor allosterically, meaning the drug binds to a distinct site from the active site. Figure 3.1.3 below depicts allosteric binding, also called allosteric modulation, which can be positive or negative. The classic example of this type of binding is the binding of the neurotransmitter GABA to the GABA receptor in the presence of a benzodiazepine (BZD), which 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 BZD, the neurotransmitter GABA still binds to its site on the GABA receptor. However, the BZD causes the channel to stay open longer, allowing more Cl ions to enter. This is an example of a positive allosteric modulator because the BZD enhances the regular activity of the receptor.

3.2 Dose-Response Curves (Graded)

When a drug or medication attaches to its target, it forms a complex. The drug-target complex causes a biological response. The biological response and the medication's concentration in circulation are 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, sometimes called graded dose-response curves. The minimum effective concentration (MEC) is the lowest dose at which 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 other individuals. That difference is related to the pharmacokinetics of the individual and the dose of the medication.

The drug's affinity and efficacy characterize drug-receptor interactions. 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 off and on 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). In Figure 3.2.1, the graph 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. Look at the dotted line representing the EC50 on the graph. Drugs A and B have similar efficacy; both curves plateau or flatten almost at the same point along the y-axis, and Drug A is slightly higher. The ranking of efficacy of the three drugs from highest to lowest is A>B>C. Efficacy can be expressed numerically from zero to one, on a continuum. 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 other 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 cell internalizes and recycles the non-functional receptor. 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 the 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. Figure 3.2.2 below shows what happens to a full agonist, Drug A, in the presence of two different antagonists. The broken line labeled Drug A' shows the change in the dose-response curve for Drug A with the addition of a competitive antagonist. The broken line " Drug A" shows the dose-response curve for the agonist, Drug A, when a non-competitive antagonist is added. Note, 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 (same point on the y-axis for A and A"). 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. However, with the addition of a non-competitive antagonist, the agonist Drug A can never reach its maximal possible response, and the biological response is blunted.

3.3 Quantal Dose Response Curves

The dose required to produce a therapeutic effect varies from individual to individual; a quantal dose-response curve determines the effective doses for a group of individuals or a population. The dose in the middle of the distribution is the ED50, defined as the dose needed 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. High responders will need less drug, and low responders will need more.

Quantal dose-response curves are also used to determine a drug's therapeutic index or window. 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 3.3.2, the TI for two drugs is shown below. Both drugs have similar ED50 values but different LD50 values. When the gap between the ED50 and LD50 doses 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.

3.4 Area Under the Curve (AUC)

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 total exposure of the body to a drug over time. Although AUC is a pharmacokinetic concept, it is mentioned here because of its importance to pharmacodynamics. The relationship between AUC and pharmacodynamics is the understanding that the concentration of a drug at its site of action influences its effectiveness and safety profile. In Figure 3.4.1, AUC and its safety at a given concentration are depicted. The y-axis is drug concentration, the x-axis is time, and the minimum effective concentration, therapeutic range, and toxicity are shown on the right. Ideally, a drug's level will be in the therapeutic range. The AUC is a critical concept in antimicrobial prescribing.