Module 2

Federal Drug Administration (FDA) Oversight and Drug Development

• Drug Regulation: The FDA is responsible for reviewing and approving both prescription and over-the-counter (OTC) medications. This process ensures safety and efficacy before products can be legally marketed to consumers.

• Blood and Biologics: The agency ensures the safety of blood products, vaccines, and various biological products utilized in medical treatments.

• Public Health Protection:     * Issuance of recalls, safety alerts, and guidance to protect the public from harmful products.     * Provision of science-based information to assist individuals in making informed health decisions.

• Other FDA Functions:     * Regulation of cosmetics and dietary supplements.     * Oversight of food safety and medical devices.     * Tobacco control.     * Inspection of facilities and enforcement of regulations.

The Drug Development Process

• Phase 1: Basic Science Research     * Duration: $2-5 \text{ years}$.

• Phase 2: Preclinical Testing     * Duration: $1-2 \text{ years}$.

• Phase 3: Clinical Trials     * Duration: $5-7 \text{ years}$.

• Phase 4: Government Approval     * Duration: $\frac{1}{2}-2 \text{ years}$.

• Final Stage: Approved Drug.

1997 FDA Modernizing Act

• Fast Tracks: Created accelerated approval paths for treatments related to AIDS, cancer, and other life-threatening conditions.

• Notice of Discontinuation: Manufacturers are required to provide a $6 \text{ month}$ notice before they stop producing/discontinuing a drug.

• Pediatric Testing: The FDA gained the authority to require drug testing in children.

• Database: Establishment of a clinical trial database.

• Off-label Use: Drug companies are permitted to provide information regarding "off-label" uses of medications.

Drug Nomenclature and Information

• Drug Names (Exemplified by Acetaminophen):     * Chemical Name: N-acetyl-para-aminophenol.     * Generic Name: Acetaminophen.     * International Name: Paracetamol.     * Trade Name: Tylenol.

• Drug Labeling and OTC Drugs:     * The drug label is located on the package.     * Over-the-Counter (OTC) drugs are available without a prescription.     * Problems associated with OTC drugs include self-treatment masking underlying conditions.     * Example: Use of Tums (antacids) and its effect on the gastric environment.

Drug Enforcement Agency (DEA) and Controlled Substances

• Drug Law Enforcement: Investigates and prosecutes organizations and individuals involved in illegal manufacture, distribution, and trafficking.

• Controlled Substances Regulation: Oversees legal production and dispensing to prevent diversion to illegal markets.

• International Drug Control: Coordinates with foreign governments to combat global trafficking networks.

• Scheduling and Classification: The DEA assigns substances to schedules based on medical value and abuse potential.

• Prescription Monitoring: Regulates pharmacies, hospitals, and healthcare providers.

• Other Roles: Asset forfeiture, intelligence gathering, chemical control, and public safety.

DEA Drug Schedules

• Schedule I: High abuse potential; no currently accepted medical use (e.g., heroin, LSD).

• Schedule II: High abuse potential; accepted medical use (e.g., morphine, oxycodone).

• Schedule III: Moderate abuse potential; accepted medical use.

• Schedule IV: Low abuse potential; accepted medical use.

• Schedule V: Low abuse potential; accepted medical use.

Nursing Responsibilities in Drug Therapy

• Administering Drugs: Requires obtaining baseline data and following specific protocols.

• Assessment:     * Verifying the "Five Rights."     * Checking the correct dosing range.     * Implementing appropriate safety measures.

• Intervention:     * Providing patient education.     * Implementing non-drug measures to enhance therapy.     * Making PRN (as needed) medication decisions.

• Monitoring:     * Evaluating the therapeutic response.     * Promoting patient compliance.

Major Concepts: Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics: The effects of the body on the drug (Movement of the drug).

• Pharmacodynamics: The effects of the drug on the body (Biological response).

• Clinical Implications: Both concepts influence drug dosing, drug effect, and the overall physiologic response.

Pharmacokinetics: Four Phases

1. Absorption

• Routes of Administration:     * Enteral: Oral, rectal, or via tubes (NG, Gastrostomy, Dubhoff).     * Parenteral: Intramuscular (IM), Intravascular (IV), Subcutaneous.     * Topical: Transdermal, Inhaled.

• Factors Affecting Absorption/Distribution:     * Rate of dissolution.     * Blood flow to the site of administration.     * Lipid solubility of the drug.

• Long-Acting Medications (Suffixes):     * LA (Long Acting), SR (Sustained Release), EC (Enteric Coated), XL (Extended Release), -contin (Continuous release).     * Example: Oxycodone (immediate) vs. Oxycontin (long-acting).

2. Distribution

• Definition: Movement of medication from the bloodstream into the cells.

• Blood Flow to Tissue: Highly perfused organs like the lungs and kidneys vs. lower perfusion areas like bone and feet.

• Exiting the Vascular System:     * Passing through typical capillary beds.     * Crossing the Blood-Brain Barrier (BBB).     * Placental and breast milk transfer.

• Protein Binding: Many drugs bind to albumin; only unbound (free) drug is active.

3. Metabolism

• First Pass Effect: Extensive metabolism of oral drugs in the liver before reaching systemic circulation.

• Hepatic Drug Metabolizing System:     * Cytochrome P450 (CYP) System: A major enzyme system for drug metabolism.     * Grapefruit juice can inhibit these enzymes, leading to toxicity or overdose.

• Therapeutic Consequences:     * Accelerated renal drug excretion.     * Drug inactivation.     * Increased therapeutic action.     * Activation of prodrugs (inactive compounds converted to active forms).     * Increased or decreased toxicity.

4. Excretion

• Renal Drug Excretion: Primarily via urine; dependent on renal function.

• Other Routes: Breast milk, bile, sweat, and feces.

• Creatinine Reference Values:     * Males: $0.6 \text{ to } 1.1 \text{ mg/dL}$.     * Females: $0.5 \text{ to } 1.1 \text{ mg/dL}$.     * Infants: >0.2 \text{ mg/dL}.     * Person with one kidney: $1.8 \text{ to } 1.9 \text{ mg/dL}$.

Enzyme Inhibitors and Inducers (Cytochrome P450)

Pharmacodynamics: Drug-Receptor Interactions

• Dose-Response: The relationship between the dose size and the intensity of the response.

• Maximal Efficacy: The largest effect a drug can produce regardless of the dose.     * Example: Meperidine (Demerol) vs. Pentazocine (Talwin) for pain relief.

• Potency: The amount of drug required to produce an effect.     * Example: Morphine is more potent than Meperidine (requires a lower dose for same relief).

• Receptor Types:     * Cell membrane-embedded enzymes.     * Ligand-gated ion channels.     * G protein-coupled receptor systems.     * Transcription factors.

• Mode of Action:     * Agonists: Molecules that activate receptors.     * Antagonists: Molecules that inhibit or block receptors.     * Partial Agonists: Moderate activation; can block further activation by stronger agonists.

• Regulation of Sensitivity:     * Downregulation: Decrease in receptor number (e.g., insulin flooding receptors in Diabetes).     * Upregulation: Increase in receptor number.

Measures of Safety: Therapeutic Index

• Therapeutic Index (TI): A measure of a drug's safety defined by the ratio of the Lethal Dose ($LD_{50}$) to the Effective Dose ($ED_{50}$).     * Formula: $TI = \frac{LD_{50}}{ED_{50}}$.

• Drug "X" (Safer): $TI = \frac{100}{10} = 10$.

• Drug "Y" (Riskier): $TI = \frac{20}{10} = 2$.

• A higher TI indicates a safer drug.

Drug Interactions

• Intensification: Effects are increased (potentiation).

• Reduction: Effects are decreased (inhibition).

• Drug-Drug Interactions: Occur during absorption or metabolism (e.g., enzyme inhibition).

• Drug-Food Interactions: Certain foods (e.g., grapefruit) affect metabolism and can lead to toxicity.

Adverse Drug Reactions (ADR)

• Definition: Undesired effects that may be unpleasant or dangerous.

• Primary Actions: Overdose or an extension of the desired therapeutic effect.

• Secondary Actions: Undesired effects occurring in addition to the pharmacologic effects.

• Hypersensitivity: An excessive response to the primary or secondary effects of a drug.

• Drug Allergy: Formation of antibodies to a drug leading to an immune response upon re-exposure.     * Anaphylaxis: Immediate reaction involving skin, respiratory, and cardiovascular sites.     * Cytotoxic Reactions: Antibody-mediated cell death; results in decreased $H/H$ (Hemoglobin/Hematocrit), WBCs, and Platelets, plus elevated LFTs and BUN/Cr.     * Serum Sickness: Deposition of antibodies in vessels damaging tissues; occurs $1+ \text{ week}$ after exposure; symptoms include high fever and swollen joints.     * Delayed Reactions: Occur hours to days later; involving WBCs and affecting skin/joints.

Drug-Induced Tissue and Organ Damage

• Dermatological: Rashes, Hives, and Stomatitis (inflammation of the mouth).

• Superinfections: Infections occurring during the course of another infection or its treatment.

• Blood Dyscrasia: Bone marrow suppression.

• Ocular/Auditory: Damage to vision or hearing (dizziness, tinnitus, loss of balance).

• Neurological:     * CNS effects: Confusion.     * Anticholinergic effects: Dry mouth, urinary retention, blurred vision.     * Parkinson-like syndrome: Tremors.     * Neuroleptic Malignant Syndrome (NMS).

• Liver Injury: Symptoms include fever, nausea, jaundice, and elevated LFTs. Intervention: Discontinue medicine.

• Renal Injury: Symptoms include changes in urine output and elevated BUN/Cr. Intervention: Decrease dose or discontinue.

• Teratogenicity: Drugs that cause birth defects.

Medication Errors

• Definition: Any preventable event that may cause or lead to inappropriate medication use or harm.

• Common Causes:     * Performance Deficits: $30\%$.     * Knowledge Deficits: $14\%$.     * Miscalculation of Doses: $13\%$.     * Communication Mistakes (handwriting, abbreviations, decimals): $15\%$.     * Name Confusion.

• The Nurse's Role (The 8 Rights):     1. Right Patient.     2. Right Drug.     3. Right Storage.     4. Right Route.     5. Right Dose.     6. Right Preparation.     7. Right Time.     8. Right Documentation.

Challenges to Drug Therapy

• Access to healthcare.

• Alternative therapies.

• Consumer demand for treatment.

• Early discharge from healthcare facilities.

• Media influence and sources of information.

• Off-label drug use.

• Drug abuse and the ongoing Opioid Crisis.

• Critical Need: Patient education.