Notes on Pharmacodynamics

 

Notes on Pharmacodynamics

Definition
Pharmacodynamics refers to the study of the biochemical and physiological effects of drugs on the body, as well as the mechanisms of their action. It answers the question, "What does the drug do to the body?"

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Key Concepts

1. Mechanism of Action (MOA)

   • Describes how a drug produces its therapeutic effect at the molecular, cellular, or organ level.
   • May involve:
     • Receptor interactions (e.g., agonists or antagonists).
     • Enzyme inhibition or activation.
     • Ion channel modulation.
     • Non-specific interactions, such as changes in cell membrane permeability.

2. Drug-Receptor Interactions

   • Receptors: Proteins or molecules in the body that drugs bind to in order to produce an effect. Examples include G-protein-coupled receptors, ion channels, and enzymes.
   • Affinity: The strength of the interaction between a drug and its receptor.
   • Efficacy: The ability of a drug to activate a receptor and produce a biological response.

3. Dose-Response Relationship

   • The relationship between the dose of a drug and the magnitude of its effect.
   • Phases of the curve:
     • Sub-therapeutic: Low dose, minimal effect.
     • Therapeutic: Dose at which the desired effect occurs.
     • Toxic: Dose at which adverse effects occur.

4. Types of Drug Actions

   • Agonists: Bind to receptors and mimic the action of the body’s natural substances.
   • Antagonists: Bind to receptors but block the action of agonists or endogenous molecules.
   • Partial agonists: Activate receptors but produce a less-than-maximal response compared to full agonists.

5. Therapeutic Window

   • The range of drug doses that produces therapeutic effects without causing toxicity.
   • Therapeutic Index (TI): Ratio of the toxic dose to the effective dose (TI = TD50 / ED50). A larger TI indicates a safer drug.

6. Potency and Efficacy

   • Potency: The amount of drug needed to produce a given effect. More potent drugs require lower doses.
   • Efficacy: The maximum effect that a drug can produce, regardless of dose.

7. Tolerances and Sensitivities

   • Tolerance: A decreased response to a drug over time due to repeated use.
   • Sensitization: An increased response to a drug following repeated exposure.

8. Pharmacodynamic Variability

   • Genetics: Polymorphisms in receptors or signaling pathways.
   • Age: Changes in receptor sensitivity or signal transduction with age.
   • Comorbidities: Diseases affecting drug efficacy (e.g., liver/kidney function).
   • Drug Interactions: Synergism, antagonism, or potentiation.

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Applications of Pharmacodynamics

• Optimizing drug dosages to maximize therapeutic effects while minimizing side effects.
• Development of new drugs and therapeutic regimens.
• Understanding mechanisms of drug resistance, particularly in antibiotics and cancer treatments.

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Graphical Representations

• Dose-response curves: Show the relationship between dose and effect.
• Log dose-response curves: Used for detailed analysis of potency and efficacy.

Notes on Pharmacokinetics

Definition
Pharmacokinetics is the study of how a drug moves through the body, addressing the processes of absorption, distribution, metabolism, and excretion (ADME). It answers the question, "What does the body do to the drug?"

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Key Components of Pharmacokinetics (ADME)

1. Absorption

   • The process by which a drug enters the bloodstream after administration.
   • Influencing factors:
     • Route of administration (oral, intravenous, intramuscular, etc.).
     • Solubility (lipid vs. water solubility).
     • Bioavailability: The proportion of a drug that reaches systemic circulation in an active form.
       • For IV drugs: Bioavailability = 100%.
       • For oral drugs: Bioavailability may be reduced due to first-pass metabolism.

2. Distribution

   • The transport of a drug from the bloodstream to tissues and organs.
   • Key factors:
     • Plasma protein binding: Drugs bound to proteins (e.g., albumin) are inactive; only free drugs exert effects.
     • Volume of distribution (Vd): Theoretical volume that a drug would need to occupy to achieve the same concentration as in the blood.
       • High Vd indicates extensive tissue distribution.
     • Tissue perfusion: Organs with high blood flow (e.g., brain, liver) receive drugs faster.

3. Metabolism

   • The biochemical modification of drugs, primarily in the liver.
   • Phases:
     • Phase I (Functionalization reactions): Oxidation, reduction, hydrolysis (e.g., via cytochrome P450 enzymes).
       • Converts drugs into more polar metabolites.
     • Phase II (Conjugation reactions): Conjugation with molecules like glucuronic acid, making drugs more water-soluble for excretion.
   • First-pass metabolism: Reduction of active drug concentration due to hepatic metabolism before reaching systemic circulation (common in oral drugs).
   • Metabolism variations:
     • Fast vs. slow metabolizers: Based on genetic differences in liver enzyme activity.

4. Excretion

   • The removal of drugs and metabolites from the body.
   • Primary routes:
     • Renal excretion: Most common, involves filtration, secretion, and reabsorption in the kidneys.
     • Biliary excretion: Drugs are excreted into bile and may undergo enterohepatic circulation.
   • Influencing factors:
     • Renal function: Impaired kidney function reduces drug clearance.
     • Drug properties: Lipid-soluble drugs may require metabolism before excretion.

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Key Pharmacokinetic Parameters

1. Half-Life (t½)

   • The time required for the plasma concentration of a drug to decrease by 50%.
   • Determines dosing frequency; shorter half-life = more frequent dosing.

2. Clearance (Cl)

   • The volume of plasma cleared of the drug per unit time.
   • Major determinants: renal and hepatic function.

3. Steady-State Concentration (Css)

   • The point where the rate of drug administration equals the rate of elimination.
   • Achieved after approximately 4-5 half-lives.

4. Area Under the Curve (AUC)

   • Represents the total drug exposure over time.
   • Used to compare bioavailability between drugs or formulations.

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Routes of Administration and Their Impacts

• Oral: Subject to first-pass metabolism, slower onset.
• Intravenous (IV): 100% bioavailability, rapid onset.
• Subcutaneous/Intramuscular (SC/IM): Absorption depends on blood flow.
• Topical/Transdermal: Local or systemic effect, bypasses first-pass metabolism.
• Inhalation: Rapid absorption due to large surface area of the lungs.

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Factors Affecting Pharmacokinetics

1. Age: Neonates and elderly patients may have altered metabolism and excretion.
2. Weight and Body Composition: Lipophilic drugs distribute more in adipose tissue.
3. Pathophysiology: Liver or kidney disease can impair drug metabolism and clearance.
4. Drug Interactions:
   • Enzyme inducers: Increase drug metabolism (e.g., rifampin).
   • Enzyme inhibitors: Decrease drug metabolism (e.g., grapefruit juice).

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Clinical Applications of Pharmacokinetics

• Designing appropriate dosing regimens.
• Managing drug interactions.
• Adjusting dosages for specific populations (e.g., renal or hepatic impairment).
• Monitoring therapeutic drug levels in patients.

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Pharmacokinetic Graphs

• Concentration vs. Time Curve:
  • Illustrates drug absorption, distribution, metabolism, and elimination phases.
  • Key points: peak concentration, half-life, and steady-state.