Pharmacology Chapter 4: Pharmacodynamics

Pharmacodynamics

• Pharmacodynamics is the study of drug action and investigates the mechanisms by which a drug elicits a pharmacologic response.
• Drugs produce their effects by binding to receptors, either stimulating or inhibiting these sites.
• There are two main ways drugs bind to receptors:
  • Binding to the endogenous ligand recognition site
  • Binding to an allosteric site on the receptor molecule

Drug-Receptor Interactions

• Receptors are cellular proteins that bind a transmitter, hormone, or drug and transmit a signal or alter cellular activity.
• The receptor domain to which the ligand binds is known as the recognition site.
• The attraction between a receptor and a ligand is known as the affinity.
• A drug that binds to a receptor and results in the activation of a receptor response is called an agonist.
• A drug that binds to a receptor and prevents its activation by another ligand is called an antagonist.
• Agonists produce maximum activation of the receptor and elicit a maximum response from the tissue.
• Antagonists bind but produce no activation of the receptor and therefore block responses from the tissue.

Intrinsic Activity and Potency

• The intrinsic activity of a drug is the relative maximal response to that agent in a particular experimental model.
• A full agonist causes a maximal response in a particular system.
• A partial agonist is unable to induce a maximal response, even at high concentrations.
• Potency is a property that is frequently used to compare different drugs.
• The more potent the drug, the fewer the number of molecules required to produce a desired effect.
• EC50 is the parameter used to evaluate differences in drug potency.

Forms of Antagonism

• Competitive antagonism occurs when a drug binds without activating its receptor and thereby prevents activation by an agonist.
• Increasing agonist concentration can overcome the binding of a competitive antagonist.
• Non-competitive antagonism occurs when the bonds between the drug and the receptor are strong.
• Increasing agonist concentration cannot overcome the binding of a non-competitive antagonist.
• Functional (physiological) antagonism occurs when two agonists acting via different receptors affect the same variable in opposite directions.
• Chemical antagonism occurs when a chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target.

Therapeutic Index

• The therapeutic index (TI) is a measurement of drug safety.
• TI refers to the relationship between toxic and therapeutic dosing.
• TI = TD50/ED50
• Drugs with a narrow therapeutic window (e.g. theophylline, warfarin, valproate, lithium) have a higher risk of toxicity.
• Drugs with a wide therapeutic window (e.g. most antibiotics) have a lower risk of toxicity.

Introduction to Pharmacology

• Pharmacology is the science of drugs and their interactions with living systems.
• Drugs are used for diagnosis, prevention, and treatment of diseases.
• Drugs can be derived from various sources.

Pharmacokinetics

• Pharmacokinetics is the study of what the body does to the medication.
• It involves the processes of absorption, distribution, metabolism, and excretion.

Absorption

• Absorption is the passage of a drug from the site of administration to the circulation.
• Transportation mechanisms:
  • Simple (passive) diffusion
  • Active transport
  • Facilitated diffusion
  • Pinocytosis
• Factors affecting absorption:
  • Solubility
  • Ionization degree
  • pH of the environment
  • Surface area
  • Contact time at the absorption site
  • Concentration of the drug at the administered site
  • Molecular weight
  • Type of drug formulation
  • Blood flow
  • Drug interactions affecting absorbance
  • Gastric emptying time

Bioavailability and First-Pass Metabolism

• Bioavailability is the relative amount of the administered drug that reaches the systemic circulation in the unchanged form.
• First-pass metabolism is the metabolism of drugs by the liver and intestinal flora before they reach the general circulation.
• Factors affecting bioavailability:
  • Solubility
  • Chemical stability
  • First-pass metabolism in the liver
  • Disorders or previous GI surgery
  • Whether the drug is taken with or without food
  • P-gp transporter

Routes of Drug Administration

• Local routes:
  • Topical
  • Sublingual
  • Rectal
• Systemic routes:
  • Enteral (oral, sublingual, rectal)
  • Parenteral (intravenous, intramuscular, subcutaneous)
  • Other (inhalation, topical, transdermal, rectal)
• Characteristics of administration routes:
  • Onset of action
  • Bioavailability
  • First-pass metabolism

Distribution

• Distribution of a drug in body tissues and fluids.
• Factors affecting distribution:
  • Blood flow (perfusion rate)
  • Plasma protein binding
  • Affinity of the drug to tissue components
• Patterns of distribution:
  • Initial rapid phase to highly perfused organs
  • Slow phase to muscles, viscera, skin, and fat

Metabolism and Excretion

• Metabolism is the process of converting a drug into its metabolites.
• Factors affecting metabolism:
  • Age
  • Liver disease
  • Genetic differences in levels of CYP450 enzymes
  • Inhibition or induction of CYP450 enzymes
• Outcomes of metabolism:
  • Inactive metabolites
  • Active metabolites (in some cases)
• Excretion is the process of removing a drug and its metabolites from the body.### Inhibition and Induction
• Inhibition: results in a decrease in drug metabolism, decreasing the speed of drug metabolism
• Examples of CYP enzyme inhibitors: grapefruit juice, ketoconazole, and omeprazole
• Inhibition leads to a higher plasma concentration of the drug for a longer time

Factors Affecting Drug Metabolism

• Nutritional status: low protein intake reduces drug clearance by reducing oxidative metabolism
• Metabolism by luminal microflora: changes in the environment of intestinal flora affect drug metabolism
• Disorders or previous GI surgery can affect drug bioavailability

Enzyme Induction and Inhibition

• Induction:
  • Occurs slowly over 2-3 weeks
  • Increases enzyme synthesis
  • Increases metabolism rate
  • Decreases duration of drug action
  • Decreases plasma concentration of the drug
• Inhibition:
  • Occurs rapidly
  • Directly inhibits the enzyme
  • Decreases metabolism rate
  • Increases duration of drug action
  • Increases plasma concentration of the drug

Excretion

• Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in the urine
• Other excretion routes: bile, intestine, lung, or milk in nursing mothers
• Enterohepatic cycle: drugs or metabolites are excreted in bile, reabsorbed from the small intestine, returned to the liver, metabolized, and eventually excreted in urine

Glomerular Filtration and Tubular Secretion

• Glomerular filtration: free drug flows out of the body and into the urine-to-be as part of the glomerular filtrate
• Size of the molecule is the only limiting factor
• Proximal tubular secretion: occurs in the proximal tubules by two energy-requiring active transport systems
• Premature infants and neonates have an incompletely developed tubular secretory mechanism

Factors Affecting Drug Excretion

• Reabsorption
• pH changes in the urine
• Blood flow to the liver and kidney
• Kidney disease
• Age
• Drug interactions
• Breast milk excretion: depends on drug properties and patient properties

Half-Life

• Defined as the time it takes to eliminate 50% of the drug in the plasma
• Determined primarily by the drug's rates of metabolism and excretion