Pharmacodynamics and Pharmacokinetics

• Activated receptors directly or indirectly regulate cellular biochemical processes like ion conductance, protein phosphorylation, DNA transcription, and enzymatic activation/inhibition
• Molecules that bind to a receptor are called ligands, this binding is specific and reversible
• Ligands can activate or inactivate receptors, influencing cell function, each ligand can interact with multiple receptor subtypes
• Most drugs exhibit relative selectivity; the degree to which a drug acts on a given site relative to others
• Selectivity relates largely to physicochemical binding of the drug to cellular receptors

Drug Affinity and Efficacy

• A drug's ability to affect a receptor depends on its affinity (probability of occupying the receptor) and intrinsic efficacy or activity (degree of receptor activation leading to cellular response)
• Chemical structure determines a drug's affinity and activity
• The duration of the drug-receptor complex (residence time) also contributes to the pharmacologic effect
• Dynamic processes such as conformational changes affect the drug-receptor complex's lifetime via control of drug association and dissociation rates
• Longer residence times can lead to prolonged effects or increased toxicity, an example of this is finasteride and darunavir.
• Transient drug occupancy is desired whereas prolonged occupancy causes toxicity for some receptors

Receptor Regulation

• Physiologic functions are regulated by multiple receptor-mediated mechanisms and steps like receptor-coupling and multiple intracellular 2nd messenger substances
• Several dissimilar drug molecules can produce the same desired response
• External factors and intracellular regulatory mechanisms influence drug binding, baseline receptor density, and stimulus-response efficiency vary across tissues
• Drugs, aging, genetic mutations, and disorders can upregulate or downregulate receptor number and binding affinity
• Clonidine downregulates alpha2-receptors while beta-blockers upregulate beta-receptor density
• Receptor up- and down-regulation affects adaptation to drugs, for example, desensitization, tachyphylaxis, tolerance, acquired resistance, and post-withdrawal supersensitivity

Ligand Binding

• Ligands bind to precise molecular regions (recognition sites) on receptor macromolecules
• The binding site for a drug may be the same as or different from the site for an endogenous agonist
• Agonists binding to adjacent sites or distant sites on a receptor are called allosteric agonists
• Nonspecific drug binding such as to plasma proteins, prohibits the drug from binding to the receptor, inactivating said drug.
• Unbound is available to have an effect

Agonists and Antagonists

• Agonists activate receptors to produce a desired response, conventional agonists increase with the proportion of activated receptors
• Inverse agonists stabilize the receptor in its inactive conformation, functionally similar to competitive antagonists

Antagonists

• Antagonists prevent receptor activation;
• Preventing activation increases cellular function if they block the action of a substance that normally decreases cellular function
• Preventing activation decreases cellular function if they block the action of a substance that normally increases cellular function
• Antagonists are classified as reversible or irreversible.
  • Reversible antagonists readily dissociate from their receptor. Irreversible antagonists form a stable/permanent bond
  • Pseudo-irreversible antagonists slowly dissociate
• Binding of the antagonist to the receptor prevents binding of the agonist in a competitive antagonism scenario.
• Agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the action of the agonist in non-competitive antagonism
• Agonist and antagonist form short-lasting bonds with the receptor, reaching a steady state in reversible competitive antagonism
• In the presence of reversible competitive antagonism, increasing the concentration of the agonist can overcome effects
• Naloxone, structurally similar to morphine, blocks morphine's effects
• Structural analogs of agonist molecules frequently have agonist and antagonist properties called partial agonists or agonist-antagonists.

Dose-Response Relationships

• Dose-response (or exposure-response) is the change in effect on a living organism caused by different degrees of exposure to a substance/different doses of a drug following a defined period
• These relationships vary with individuals and exposure periods
• Dose refers to single drug quantity administered to an individual
• Exposure refers to time-dependent concentration or concentration-derived parameters of a drug after administration (AUC/Cmax)
• Quantifying the response after a different exposure time or route leads to a different relationship and conclusions
• Complexity of biological systems and unknown processes between the external exposure and cellular/tissue response cause limitations

Dose-Response Curves

• Dose-response curves are graphs that depict the relationship between the magnitude of a substance (toxicant concentration, drug amount, etc.) and the receptor's response
• The response observed may be physiological, biochemical, or mortality, data is generated into counts, ordered descriptive categories, or continuous measurements
• Number of effects/endpoints can be studied at organizational levels (population, whole animal, tissue, cell)
• Clinical pharmacology usually plots measured dose on the X axis (milligrams, micrograms, or grams per kilogram) and the measured effect/response of a drug is plotted on the Y axis
• Other dose units include moles per body-weight/animal, and moles per square centimeter for dermal doses
• The logarithm of the dose is plotted leading to an S shape in the curve with the steepest portion in the middle
• Models using dose are preferred over log because the logarithm implies a threshold dose when none exists

Curve Details

• Threshold-dose: The response point above zero
• Undesired effects appear/grow stronger with higher doses
• The more potent the substance, the steeper the curve
• Y-axis often shows percentages representing the number of exposed that register a standard response
• Quantal dose-response curve is a curve that distinguishes it from a graded dose-response curve
• The dose-response curve has features that vary with potency, maximal efficacy/ceiling effect, and slope Biological variation also occurs

Curve Use

• Information helps determine the dose required to achieve the desired effect
• Therapeutic index (ratio of minimum toxic concentration to the median effective concentration) determines the efficacy/safety of a drug
• A greater dose of a drug with a small therapeutic index increases the probability of toxicity or ineffectiveness
• These features differ by population and are affected by patient-related factors such as demographics, age, pregnancy, and organ function (kidney function)

Pharmacokinetics

• Questions about the body's actions on the drug e.g. the fate of a drug within the body
• Pharmacokinetics and pharmacodynamics help to explain the relationship between the dose and response, which is the drug's effects

This lesson explains the concepts of potency, maximal efficacy, and slope in dose-response curves. It differentiates pharmacodynamics (what the drug does to the body) from pharmacokinetics (what the body does to the drug). It also explains the therapeutic index and reversible competitive antagonism.