Pharmacodynamics

Introduction to Pharmacodynamics

• Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body and the molecular mechanisms by which those effects are produced.
• It is the study of what drugs do to the body and how they do it.
• Drug-induced changes in normal physiologic functions are explained by the principles of pharmacodynamics.

Objectives

• Understand the general concept of pharmacodynamics
• Explain the principles of drug action
• Understand the role of receptors in drug action and response
• Define some pharmacodynamic terms
• Discuss the relevance of pharmacodynamics to professional nursing practice
• Employ the pharmacodynamics of drugs to improve benefits and minimize risks

Benefits of Pharmacodynamics

• Nurses need a basic understanding of pharmacodynamics to participate rationally in achieving therapeutic objectives.
• Nurses must know about drug actions to educate patients and make decisions about drug use, as well as evaluate patients for beneficial and harmful drug effects.
• Nurses need to understand drug actions when conferring with prescribers regarding drug therapy.

Mechanisms of Drug Action

• There are two main mechanisms of drug action:
  • Alteration in cellular environment (non-receptor mediated)
  • Alteration in cellular function (receptor mediated)

Alteration in Cellular Environment

• Some drug actions change the cellular environment physically or chemically.
• Examples include changes in osmotic pressure (e.g., mannitol), lubrication (e.g., liquid paraffin), absorption (e.g., activated charcoal), or conditions on the cell membrane.
• Examples of drug actions include mannitol which changes osmotic pressure in brain cells and reducing cerebral edema. Liquid paraffin, arachis oil, docusate are examples of drugs changing cellular environment through lubrication. Activated charcoal is an example of a drug acting by altering absorption.

Alteration in Cellular Function

• Most drug actions alter an intrinsic physiological process rather than creating a new process.
• Drugs which alter cellular function can increase or decrease certain physiological functions, such as heart rate, blood pressure, GI motility, or urine output.

Targets of Drug Action

• Majority of drugs interact with target biomolecules:
  • Enzymes
  • Ion channels
  • Transporters
  • Receptors (usually a protein)

Enzymes as Drug Targets

• Almost all biological reactions are catalyzed by enzymes, making them major drug targets.
• Drugs can increase or decrease enzyme-mediated reactions.
• Enzyme inhibition is the most common mode of drug action.

Ion Channels

• Some drugs affect specific ion channels to exert pharmacological action by activating (opening) or inactivating (closing) channels.
• Examples include calcium channel blockers (e.g., nifedipine, amlodipine), diuretics (e.g., furosemide), and anesthetic agents (e.g., lidocaine).

Transporters

• Drugs can either enhance or inhibit the activity of carrier/transport proteins.
• Examples include calcitriol for calcium and phosphate absorption, and monoamine reuptake inhibitors (e.g., SSRIs, TCAs) affecting neurotransmitter reuptake. SGLT2 inhibitors are used for diabetes and heart failure treatment.

Drug Receptors

• A receptor is a reactive site, macromolecule or binding site on the surface or inside of a cell.
• It recognizes signal molecules (drugs) and initiates a response, but itself does not have a function.
• Drug receptors are typically proteins or glycoproteins often found on cell membranes.
• The interaction between a drug and receptor site affects biochemical processes in the cell, causing changes in cellular activity, membrane permeability, or metabolism.
• Drug fit to a receptor is like a key fitting to a lock. The closer the shape, the better the fit, and the better the therapeutic response.
• Drug response intensity is related to how good the fit of the drug molecule and the number of receptor sites occupied.

Drug-Receptor Complex

• The pharmacophore is the part of the drug molecule that binds to the receptor.
• The auxophore are the parts of the drug molecule that are not directly involved with binding.

Drug Receptor Interaction

• Drug-receptor interaction is the binding of the drug molecule to a reactive site on a cell or tissue surface.
• A pharmacologic response is produced when a drug binds and interacts with its receptor.

Drug Receptor Interactions: Affinity

• Affinity is the measure of the strength of binding between a drug and its receptor.
• Higher affinity means a faster and stronger binding.
• Affinity is evaluated by the dissociation constant (KD). A smaller KD means a higher affinity.

Drug Receptor Interactions: Efficacy

• Efficacy is the relationship between receptor occupancy and the ability of the drug to initiate a response at the cellular, tissue or system level.
• Efficacy is how well an action is taken after the drug binds to its receptor.
• A high efficacy indicates a good outcome after the drug action.

Drug Receptor Interactions: Potency

• Potency refers to the drug activity in terms of the amount needed to produce an effect.
• A highly potent drug elicits a given response with low concentrations.
• Potency depends on both affinity and efficacy.

Dose-Response Curves

• Dose-response curves illustrate the effect of varying drug concentrations on receptors.
• The curve shows the dose on the X-axis and the measured effect on the Y-axis.

Onset, Peak, and Duration of Action

• Onset of action: The time taken for a drug to reach its minimum effective concentration (MEC).
• Peak action: The point at which the drug effect is highest.
• Duration of action: The length of time the drug has a pharmacologic effect.

Basic Terminologies

• Minimum Effective Concentration (MEC): The lowest drug concentration that produces a desired pharmacologic response.
• Minimum Effective Dose: The minimum dose of a drug needed to produce a therapeutic effect.
• Minimum Toxic Concentration (MTC): The lowest drug concentration that produces toxic effects.
  • Therapeutic Window: The range between the MEC and MTC.
  • Wider therapeutic window = safer drug dosing.

Assignment

• Discuss Therapeutic Index.
  • The formula for measuring Therapeutic Index.
  • How does therapeutic index relate to the safety of drugs (low/high therapeutic index)?
• Nursing considerations when administering drugs with a low therapeutic index.

Drug-Receptor Interactions

• There are four receptor families: Cell membrane-embedded enzymes, Ligand-gated ion channels, G-protein-coupled receptor systems, and Transcription factors.
• The ligand-binding domain is the site where drugs bind to receptors.

Drug-Receptor Interactions

• Receptors have an excellent ability to recognize and bind ligands (drugs).
• Binding can cause changes in the receptor which leads to a cellular response.

Drug-Receptor Interactions: Types

• Cell membrane-embedded enzymes: Drug binding activates enzymes within the cell leading to a response.
• Ligand-gated ion channels: Binding opens/closes channels affecting ions flow into/out of the cell (e.g., sodium, calcium).
• G-protein-coupled receptor systems: Involves a receptor, a G protein, and an effector which is either an enzyme or ion channel.
• Transcription factors: Proteins binding to DNA in the nucleus which affects gene transcription, activation (response) is prolonged.

Drug-Receptor Interactions: Agonists and Antagonists

• Agonists: Drugs that combine with receptors to activate them causing an effect.
• Antagonists: Drugs that combine with receptors without activation, blocking the agonist's effect.
• Partial agonists: Produce a sub-maximal response even when all receptors are occupied.

Receptor Theory

• Receptor theory explains drug behavior/action in the presence of accurate knowledge of receptors.
  • Receptor Occupancy theory (A.J. Clark): Drug response is proportional to the number of receptors occupied. The response ceases when the complex dissociates.
  • Rate theory (Paton): drug effect is proportional to the rate of drug-receptor complex formation.

Other Drug Receptor Theories

• There are other theories like Induced-Fit, Macromolecular Perturbation, Activation Aggregation, and Two State Receptor Models.

Combined Effects of Drugs

• Synergism: Combined effect is greater than the sum of individual effects.
• Additive effect: Combined effect equals the sum of individual effects.
• Supra-additive effect: Combined effect is greater than the sum of individual effects.

Drug Receptor Interaction: Intrinsic Activity

• Intrinsic Activity is the ability of a drug to elicit a response after binding to a receptor.

Drug Effects on Receptors

• Agonist: Binds to and activates receptor. Key fits the lock, opening the door to a response.
• Partial agonist: Binds, activates, but elicits only a submaximal response, even with all the receptors occupied.
• Antagonist: Binds, but does NOT activate the receptor, blocking the agonist from activating.

Types of Drug Antagonism

• Competitive antagonism: Antagonist binds to the same site as agonist, reducing the agonist's affinity and potency. Higher doses of the agonist can reverse the antagonist's effect.
• Non-competitive antagonism: Antagonist binds to a different site than the agonist, changing the receptor's shape so the agonist can no longer bind. Higher agonist doses do not overcome the effect of the antagonist.

Selective Toxicity

• Ideal chemotherapeutic agents target specific enzyme systems in pathogens or diseased cells without affecting healthy cells.
• Penicillin acts as an example of selective toxicity, specifically targeting bacteria.

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