Pharmacodynamics Overview

Pharmacodynamics

• Pharmacodynamics describes the actions of a drug on the body.
• Most drugs work by binding to receptors on or in cells.
• Receptors are specialized macromolecules specific to certain agonists, causing unique responses.
• Drug-receptor complexes trigger changes in cellular function through signal transduction.
• Agonists bind to receptors to activate intracellular processes.
• Second messengers relay signals between the drug-receptor complex and intracellular mechanisms.

Four Major Receptor Families

• Ligand-gated ion channels: These channels open or close in response to a ligand (e.g., a neurotransmitter) binding to them, changing ion flow across cell membranes.
• G protein-coupled receptors: These receptors use G proteins as intracellular messengers to alter cellular activity when a ligand binds. Often involve secondary messengers.
• Enzyme-linked receptors: These receptors have enzymatic activity on the intracellular side. Ligand binding activates the intracellular enzyme.
• Intracellular receptors: These receptors are located inside the cell (cytoplasm or nucleus). Lipid-soluble drugs pass through the cell membrane and activate these receptors.

Ligand-gated Ion Channels

• Drugs bind to receptor sites causing changes in channel shape, allowing ions to flow unidirectionally or bidirectionally.
• Net ion flow affects membrane polarization (depolarization or hyperpolarization). This impacts neurotransmission and muscle contraction.

Transmembrane G Protein-Coupled Receptors

• The receptor changes shape when a drug binds to its receptor site, causing GTP to replace GDP on the G protein.
• This activated G protein subunit disrupts the G protein and activates the adenylyl cyclase.
• The effects of the drug last for seconds to minutes. Upon disassociation, the receptor reverts back to its original shape and the G protein re-establishes its original state.

Enzyme-Linked Receptors

• Drug binding triggers intracellular changes, with the receptor activating itself and other specific proteins through phosphorylation.
• This initiates a cascade of effects within the cell. The effects may last minutes to hours.
• Unbinding of the drug stops the phosphorylation process.

Intracellular Receptors

• Lipid-soluble drugs diffuse through the cell membrane.
• The drug binds to an intracellular receptor (usually in the cytoplasm or nucleus).
• The drug-receptor complex impacts gene transcription, potentially activating or inactivating genes, and affects various cellular components (proteins, enzymes, RNA, ribosomes).
• The effects of intracellular receptors are longer-lasting (taking hours to days).

Drug Binding

• Drug binding is crucial for a drug to elicit a physiological response.
• Different tissues and organs have receptors with unique functions.
• Dose-response relationship: The magnitude of the effect depends on receptor sensitivity and drug concentration.
• Potency measures the amount of drug needed for an effect.
• Efficacy describes the magnitude of response to drug-receptor interaction.

Pharmacotherapeutics

• Pharmacotherapeutics involves using drugs for treatment.
• Empirical therapeutics rely on a provider's experience and observations.
• Rational therapeutics utilize efficient, safe, and cost-effective drugs.

Types of Therapies

• Acute: Short-term treatment.
• Maintenance: ongoing treatment.
• Supplemental/replacement: Replacing a missing component.
• Palliative: Relieving symptoms.
• Supportive: Supporting other treatments.
• Prophylactic: Preventing disease.
• Empirical: Based on experience.

Drug Administration

• Indications are the clinical conditions for a given treatment.
• Desired effect is the intended biological response.
• Side effects are unintended responses (beneficial, neutral, or harmful).
• Adverse effects are unintended and harmful effects.
• Toxic effects are exaggerated forms of the therapeutic response.
• Dose is the amount of drug administered at a given time.
• Contraindications indicate situations where a drug should not be used.
• Special considerations pertain to patient populations or situations requiring dosage adjustments.

Monitoring Response to Treatment

• Therapeutic index assesses drug safety and effectiveness.
• Drug levels (blood tests) monitor the concentration of the drug in the body.
• Clinical response measures the actual observed effect in the patient.
• Tolerances and dependence describe decreased responsiveness over time.
• Adverse effects are the unintended negative consequences.

Drug Interactions and Adverse Effects

• Drug interactions can enhance or diminish drug effects (additive, synergistic, or antagonistic).
• Adverse effects can be allergic, idiosyncratic, hypersensitivity, or others.
• Factors that affect adverse effects include age, gender, ethnicity, environment, polypharmacy, pregnancy, and comorbidities.
• Types of adverse drug reactions include augmented (Type A), bizarre (Type B), continuing (Type C), delayed (Type D), and end-of-use (Type E).

Recognizing Type B Adverse Reactions

• Anaphylaxis is a severe, potentially life-threatening immune response to a foreign antigen.
• Rashes and skin eruptions are common hypersensitivity responses.
• Serum sickness is a hypersensitivity response to animal proteins.

Other Drug-Related Effects

• Medication errors: These errors can have serious consequences.
• Teratogens: agents causing birth defects.
• Mutagens: agents causing DNA/chromosome changes.
• Carcinogens: agents causing cancer.

Clinical Response

• Consider factors such as age, social, psychological, diseases and other individual differences, and how these could impact drug effectiveness.

Tolerance and Dependence

• Drug Tolerance: Decreased response to a drug with repeated administration.
• Cross Tolerance: Tolerance to similar drugs.
• Functional Tolerance: Reduced receptor function.
• Drug Dependence: Physical or psychological need for the drug.

Additional Considerations

• Monitoring drug levels is crucial to evaluate dosages.
• Clinicians need to be aware of medication errors.
• Adverse drug effects, including idiosyncratic reactions, hypersensitivity reactions, and allergic reactions require careful consideration.