NURS116 lect. 2, 2025

Pharmacotherapeutics Lecture Overview

Course Information

• Instructor: Associate Teaching Professor Helena Schaefer, MN

• Content: Review Chapters 1-10

• Additional Readings: Refer to Course Outline on eClass

Pharmacokinetics: ADME Overview

General Rules

• Absorption & Distribution:

  • Lipophilic, non-ionized, and small compounds are easier to absorb and distribute within the body.

• Excretion:

  • Hydrophilic and ionized compounds are easier to excrete.

Factors Affecting Distribution

• Key Factors Influencing Distribution:

  1. Blood Flow: Variability due to cardiac output, blood-brain barrier, and injuries can alter circulation to tissue.

  2. Tissue Size: Larger tissues may receive more distribution of drugs.

  3. Molecular Characteristics:

     • Lipophilicity, molecular size, and polarity.

  4. Plasma Protein Binding (PPB):

     • Drugs bind to plasma proteins and affect their distribution.

Blood-Brain Barrier (BBB)

• Selective Transport:

  • CNS capillaries have specialized endothelial cells allowing selective substance transport.

• P-glycoprotein Pump:

  • Active efflux transporter that protects the brain from foreign substances.

Plasma Protein Binding (PPB)

• Drug Affinity:

  • The strength with which drugs bind to plasma proteins varies.

  • Examples:

    • Acidic drugs bind to Albumin.

    • Basic drugs bind to Alpha-1-acid glycoprotein.

• Effect of Binding:

  • Bound drugs (not free) are ineffective in therapeutic action.

  • Types of Binding:

    • Competitive, reversible, and saturable binding.

Drugs Extensively Bound to Plasma Proteins

• Examples:

  • Oral anticoagulants: Warfarin

  • Oral antidiabetics: Glimepiride, Glipizide

  • Lipid-lowering agents: Gemfibrozil, Statins

  • Other categories include NSAIDs, loop diuretics, cardiac drugs, anti-infectives, and Benzodiazepines.

Volume of Distribution (Vd)

• Definition & Formula:

  • Vd estimates how extensively a drug is distributed into body tissues.

  • Calculated as:

    • Vd = drug dose / plasma concentration.

  • Example Calculation:

    • If drug dose = 100 mg and plasma concentration = 30 mg/L, then Vd = 3.3 L.

Drug Metabolism

• Primary Organ:

  • Liver is the main site for drug metabolism.

• Other Organs Involved:

  • Lungs, kidneys, intestines.

• Types of Metabolism:

  • Active drug to inactive metabolite.

  • Active to active metabolites (can be benign or toxic).

  • Inactive drug to active metabolite (prodrugs).

• First Pass Metabolism:

  • Oral drugs may undergo metabolism before reaching systemic circulation.

Phase I and II Metabolism

• Phase I:

  • Hydrolysis, reduction, oxidation via Cytochrome P450 enzymes.

• Phase II:

  • Conjugation resulting in ionized and polar metabolites for excretion.

Excretion of Drugs

• Main Organ:

  • Kidneys are the primary excretory organ.

  • Also involves pathways through saliva, bile, and lungs.

• Factors Influencing Renal Excretion:

  • Molecular characteristics, plasma protein binding, metabolic state, urgency of renal function.

Clearance (Cl)

• Definition:

  • The rate of elimination of a drug from the body over time.

• First Order Elimination Kinetics:

  • Clearance is proportional to drug serum concentration.

• Zero Order Elimination Kinetics:

  • Rate of elimination is constant (e.g., ethanol).

Half-life (t ½)

• Definition:

  • The time required for the plasma concentration of a drug to reduce by half.

• Usefulness:

  • Helps estimate the frequency of drug administration; after 4 half-lives, approximately 90% of the drug is cleared from the system.

Pharmacodynamics Overview

• Drug Interaction Mechanics:

  • After distribution, drugs exert therapeutic effects typically through binding to receptors.

• Types of Drug-Receptor Interactions:

  • Agonists: Mimic endogenous substances, actively engaging receptors (e.g., Morphine).

  • Antagonists: Block receptors, preventing substance binding (e.g., Naloxone).

Drug-Receptor Types

1. **G-Protein-Coupled Receptors (GPCR)

2. Ion Channels

3. Nuclear Receptors

4. Enzyme Types

5. Non-Enzyme JAK-STAT Receptors

Drug Tolerance and Resistance

• Drug Tolerance:

  • Results in decreased receptor sensitivity or count; requires higher doses for efficacy.

• Drug Resistance:

  • Changes in drug metabolism leading to inefficacy; distinct from antibiotic resistance.