Pharmacodynamics: Drug Effects and Mechanisms

Pharmacodynamics

• The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors, ultimately responsible for their effects.
• Drug effects include specific molecular changes resulting from binding to target sites or receptors.
• Widespread alterations in physiology and psychology can also result from drug actions.

Drug Actions

• Specific molecular changes resulting from drug binding to a target site or receptor.

Drug Effects

• Widespread alterations in physiology or psychology resulting from drug actions.
• Include both objective and subjective effects.

Objective Effects

• Measurable physiological alterations, such as changes in blood pressure, heart rate, and pupil dilation.

Subjective Effects

• Variable drug effects subject to individual experience, interpretation, and expectations. They are dependent on the patient's history of drug use. factors include dose, administration methods, and environmental contexts.

Multiplicity of Drug Effects

• Therapeutic Effects: Drug-target interactions that produce desired physiological or behavioral changes.
• Side Effects: All other drug effects that are not therapeutic, may or may not be negative.
• Adverse Effects: Undesirable or harmful drug effects.

Terminology

• Diphenhydramine (Benadryl): An antihistamine and decongestant.
• Therapeutic effects: Include drying mucous membranes.
• Side effects: Include drowsiness.
• Abbreviation: 2-(diphenylmethoxy)-N,N-dimethyl-ethanamine (IUPAC name).

Specificity of Drug Effects

• Specific Effects: Occur due to biochemical interactions between the drug and the target receptor.
• Nonspecific Effects: Result from interactions beyond the receptor, such as lipid membranes or fluid compartments. They depend on the individual.

Placebo Effect

• A measurable therapeutic effect of a treatment without specific activity.
• Affected by expectancy and conditioning.

Drug-Receptor Interactions

• Ligand: Molecule that binds to a receptor, can be an endogenous or exogenous molecule.
• Drug: Exogenous ligand that doesn't exist naturally in the body.
• Receptor: Protein molecule that a ligand can bind to and trigger a biological response.

Defining a Receptor

• Saturability: Finite receptors per cell; limited number. Dose-responses to reveal saturability.
• Specificity: High binding affinity to elicit biological responses and is specific to a certain ligand or target.
• Reversibility: Binding to receptors should be reversible; ligand should be dissociable and recoverable.

Receptor Types

• Extracellular receptors: Common target for psychoactive drugs.
• Intracellular receptors: Common target for steroid hormone, drugs, and other lipophilic compounds.
• Ligand-gated ion channels: Postsynaptic neurotransmitter receptors.
• G-protein coupled receptors (GPCRs): Metabotropic receptors.
• Receptor Kinases: Common for cytokine, peptide hormone receptors (e.g. insulin).

Receptor-Ligand Interactions

• Agonists: Elicit a biological effect.
• Antagonists: Prevent or block a biological effect, can be competitive or non-competitive.

Agonism and Antagonism

• Agonists/Antagonists can be described as full/partial/inverse and are spectral.

Examples:

• Dopamine + Partial Agonists: Bring down activity when excessive and bring up activity when low, e.g., psychosis and schizophrenia.

Agonist Function

• Agonist activity can be measured by examining the dose-response.
• Increasing concentration of the agonist leads to greater biological responses.
• Dose-response follows a characteristic sigmoidal shape (S-curve).
• ED₅₀ is the dose required to elicit a half-maximal effect; describes the potency of the drug or ligand.

Potency and Efficacy

• Potency (ED₅₀) is different for each drug; measures differing potencies, while efficacy remains the same.

Therapeutic Index (TI)

• Dose-response can be measured for adverse effects
• TD₅₀: measures the potency of a drug at eliciting a toxic response.
• LD₅₀: measures the potency at eliciting a lethal response.
• Therapeutic index reflects the margin of safety between drug efficacy and adverse effects (TD₅₀ / ED₅₀).

Antagonism

• Reversible Antagonists: Can be displaced by endogenous agonists.
• Competitive Antagonism: Reduces agonist potency but not efficacy.
• Non-competitive antagonists: Cannot be displaced by agonists; reduces drug efficacy.

Non-competitive antagonists

• Irreversible antagonists: Binds irreversibly to the same binding site as an endogenous ligand
• Allosteric modulators: Binds to a different site than the endogenous ligand. They affect receptor function by affecting its conformation.

Partial Agonists

• Bind to the same site as endogenous ligands.
• Elicit a diminished or less-than-maximal biological effect.
• Can decrease efficacy of the endogenous agonist.

Inverse Agonists

• Bind to the receptor with constitutive activity.
• Opposite effect to a full agonist.

Long-term Effects of Drug Use

• Tolerance: Diminished effect of a given dose of drug over time. Often depends on the frequency and dosage of the drug, and can be limited to specific drug effects, with multiple mechanisms.
• Cross-tolerance: Can cause drug interactions, occurs between drugs acting on the same receptor.
• Sensitization: Enhancement of a particular drug effect on repeated exposure.

Forms of Tolerance

• Metabolic tolerance: Increased metabolism of a drug, usually via enzyme induction, leading to reduced bioavailability. Examples are alcohol and other drugs.
• Pharmacodynamic tolerance: Changes in nerve cell function in response to a drug. This often results in receptor downregulation and decreased/diminished efficacy at the cellular level. Examples are some drugs and environmental factors.
• Behavioral tolerance: Context-specific tolerance; learning and memory contribute to tolerance, as demonstrated in familiar versus novel environments.

Drug Dependence

• Drug tolerance can occur rapidly or slowly.
• Persistence of tolerance is heavily influenced by factors (metabolic & pharmacodynamic).
• Drug dependence results from tolerance, contributing to drug addictions.
• Drug dependence is significantly influenced by pharmacodynamic mechanisms.
• Dependence is the requirement for a drug in order to maintain normal function after developing tolerance.

Dependence Mechanisms

• Homeostasis is disrupted by acute administration of drugs.
• Repeated administration leads to adaptive compensatory mechanisms to restore homeostasis.
• Withdrawal of the drug leads to compensatory disruptions in homeostasis.

Demonstration of Dependence

• In vitro studies demonstrate the cellular effects of morphine.
• Acute morphine treatment decreases cellular cAMP.
• Chronic exposure normalizes cAMP levels to restore homeostasis.
• Morphine withdrawal leads to a significant rebound increase in above-normal cAMP levels.

Rebound Withdrawal

• Withdrawal is heavily influenced by drug tolerance and dependence mechanisms (pharmacodynamic).
• Removal of drug upsets homeostasis in the opposite direction of drug use.
• Withdrawal produces neurochemical and behavioral changes (often opposite the effects of intoxication), leading to rebound effects.

Key Points: Pharmacodynamics

• Ligands: Endogenous or exogenous molecules that bind to receptors.
• Receptors: Cell surface or intracellular sites of ligand binding.
• Classical receptors: Saturable, specific, reversible.
• Agonists: Produce biological effects.
• Partial agonists: Produce reduced biological effects.
• Inverse agonists: Produce opposite effects to natural agonists.
• Antagonists: Inhibit or block biological effects.
• Reversible antagonists: Bind reversibly.
• Irreversible antagonists: Bind irreversibly.
• Tolerance: Decreased potency or efficacy over time.
• Sensitization: Increasing drug effect over time.
• Dependence: Requirement for drug use to maintain normal physiological/psychological functioning.
• Cross-sensitization/tolerance: Effects of drugs sharing similar sites of action.
• Metabolic tolerance: Increased metabolism; enzyme induction.
• Pharmacodynamic tolerance: Receptor down regulation; reduced drug efficacy at the target site.

Explore pharmacodynamics, covering drug-target interactions, objective and adverse effects. Learn about receptors, ligands, and the placebo effect. Understand receptor saturability, specificity, and the impact of extracellular and intracellular receptors.