Pharmacology Introduction and Drug Dynamics

Routes of Drug Administration

• Electronic or ionic charges are attached to the body depending on the method.

• Delivery methods are categorized by whether they target specific areas (local) or provide systemic effects throughout the body.

• Transdermal Therapeutic System: A patch applied to the skin for systemic effects.

• Sublingual: Administration under the tongue.

• Oral: Administration through the oral cavity.

• Rectal: Administration via the anus.

• Inhalation: Administration through the nose or lungs.

• Subcutaneous: Injection into the skin layers.

• Intramuscular: Injection directly into the muscle tissue.

• Intravenous: Injection directly into the vascular network (veins).

• Intrathecal: Injection directly into the spine.

Drug Absorption and Site of Action

• Site of Action (SOA): The specific location where a drug proceeds to produce its effect.

• Dissolution: For absorption to occur, drugs must be dissolved in bodily fluids. They are broken down from larger forms into their most atomic forms and become ionized.

• Biological Barriers: As drugs degrade and travel through the body, they must pass through biological barriers where a portion of the drug may be lost.

• Levels of Site of Action:

  • Extracellular: Outside the surface of the cell.

  • Cellular: Within the membrane of the cell.

  • Intracellular: Inside the cell.

Factors Affecting the Rate of Absorption

• Surface Area: A larger surface area leads to higher rates of absorption ($\uparrow \text{Surface Area} = \text{More Absorption}$).

• Rate of Dissolution: This refers to how fast a drug dissolves. If dissolution is too slow, the drug cannot be absorbed readily. If it is too fast, it may become too diluted. An appropriate, balanced speed is required for effective absorption.

• Lipid Solubility: This determines where a drug can travel.

  • For a drug to reach the brain, it must be lipid-soluble.

  • Water-soluble drugs are rejected by the blood-brain barrier.

• Blood Flow: Faster blood flow increases the rate of absorption, allowing the drug to reach the SOA more quickly.

Drug Distribution and Biological Barriers

• Distribution Process: The transfer of drugs across biological membranes into body components, including intracellular and extracellular fluid compartments.

• Influencing Factors: Distribution depends on chemical properties, solubility, blood flow, vector size, and excretion rates.

• Water-Soluble Drugs: These are readily excreted by the kidneys.

• Blood-Brain Barrier (BBB): Serves as an obstacle to water-soluble drugs. The barrier is composed largely of a phospholipid bilayer, which rejects water-soluble molecules.

• Placenta: While it acts as a barrier, it is also a pathway of transfer. Drugs taken by a pregnant mother can transfer to the growing fetus or embryo.

Biotransformation and Metabolism

• Biotransformation: The process of metabolizing a drug.

• The Liver: The primary organ for drug metabolism, acting as a filter and breakdown center.

• Other Organs: The lungs, kidneys, and glands also play roles due to oxygen exchange, additional filtering, and hormone production.

• Metabolite Types:

  • Water-soluble metabolites: Processed for elimination by the kidneys.

  • Lipid-soluble drugs: Usually processed by the liver.

• Phases of Biotransformation:

  • Phase 1: Conversion of drugs into more ionized molecules.

  • Phase 2: Synthetic reactions where new compounds are introduced to chemically alter the drug.

Drug Clearance and Elimination

• Renal Elimination: Primarily performed by the kidneys, especially for water-soluble drugs.

• Glomerular Filtration Rate (GFR): A key metric used to evaluate kidney function in drug clearance.

• Tubular Processes: Involves tubular reabsorption or tubular secretion.

• Hepatic Elimination: Drugs broken down by the liver are excreted via bile and subsequently in the feces (typically lipid-soluble drugs).

Pharmacodynamics: Dose, Dosage, and the Therapeutic Index

• Dose vs. Dosage:

  • Dose: The amount of drug given to the patient each single time (e.g., a $500\text{ mg}$ tablet).

  • Dosage: The total amount of the drug administered over a specific course of time.

  • Example 1: If a patient receives a total of $500\text{ mg}$ over $5$ days, administered once per day, the dose is $100\text{ mg}$.

  • Example 2: A patient takes a $25\text{ mg}$ pill twice a day for $5$ days. The dosage is $250\text{ mg}$ ($25 \times 2 \times 5 = 250$).

  • Example 3: A dose is a $5\text{ mg}$ tablet. Administered for $5$ days, the dosage is $25\text{ mg}$.

• Therapeutic Index (TI): The margin of safety for a drug, calculated by comparing undesirable effects against the desired therapeutic response.

  • Large TI: The drug is safer.

  • Small TI: The drug is more dangerous and requires careful monitoring.

• Effective Dose ($ED_{50}$): The dose that is effective for $50\%$ of the population.

• Lethal Dose ($LD_{50}$): The dose that is lethal for $50\%$ of the population.

  • Drug A (High TI): $ED_{50} = 10\text{ mg}$, $LD_{50} = 70\text{-}80\text{ mg}$. An accidental dose of $30\text{ mg}$ is not harmful.

  • Drug B (Low TI): $ED_{50} = 10\text{ mg}$, $LD_{50} = 20\text{ mg}$. A small increase in dose could be lethal.

• Antifungal Drugs: These often have a low therapeutic range because fungi are eukaryotic organisms, just like human cells. Drugs may struggle to differentiate between fungal cells and human cells, leading to higher toxicity risk.

Time Response Curves and Administration Timing

• Time-Response Factors:

  • Onset of Time Response: When the drug begins to work.

  • Peak Effect Time: When the drug optimally activates all receptors.

  • Duration of Action: How long the drug remains effective.

  • Threshold Level: The minimum concentration required for a therapeutic effect.

• Concentration Ranges:

  • Below threshold: Sub-therapeutic (ineffective).

  • Above threshold: Therapeutic range.

  • Excessive concentration: Toxic effects (overdose rate).

• Consistency: Taking medication at the same time every day maintains a steady therapeutic curve. Skipping or doubling doses causes erratic concentration levels.

• Loading Dose: A larger initial dose (e.g., the first day of a Z-Pak) used to shrink the latency period by rapidly increasing drug concentration to the therapeutic level.

Variability Factors in Drug Response

• First Pass Effect: Biotransformation occurring after oral administration but before the drug enters general circulation.

• Chemical Properties: Molecular weight, ionic charges, and solubility.

• Physical and Health Factors:

  • Liver and Kidney Disease: Impairs the ability to filter and eliminate drugs.

  • Starvation: Lack of materials for metabolic breakdown.

  • Age: Older patients often have slower liver and kidney function. Drugs may be given over longer periods (retaining the same dosage) to prevent chronic toxic accumulation.

  • Genetics: Individual inability to metabolize certain compounds.

  • Gender: Males may be more susceptible to drugs like barbiturates.

  • Species: Drugs effective in animals (e.g., horses) may be dangerous or ineffective in humans.

  • Circadian Rhythm: The sleep-wake cycle affects hormone levels (e.g., Cortisol in the morning, Melatonin at night), which can alter drug effects.

Toxicology and Toxicity Levels

• Acute Toxicity: Effects occurring within minutes to hours after exposure.

• Subacute Toxicity: Effects occurring after repeated exposures over several days.

• Chronic Toxicity: Effects occurring over months to years. This happens when the rate of exposure exceeds the rate of elimination.

• Environmental Toxicology: Studies the adverse effects of chemicals (e.g., drugs dumped in rivers) on life and the environment.

The New Drug Development Process

1. Preclinical Research: ($1$ to $3$ years) Involves drug design, animal screenings, and evaluations for toxicity and pharmacokinetic properties.

2. Clinical Research and Development: ($2$ to $10$ years)

   • Phase 1: Tested on normal/healthy volunteers.

   • Phase 2 & 3: Tested on patients with the actual condition.

3. New Drug Application (NDA): ($2$ months to $7$ years) Submission and approval phase.

4. Phase 4 (Post-Marketing Research): Observation of the drug's effects on the general population. Data is gathered via inspection reports, surveys, sampling, and testing to decide if the drug remains on the market.

Controlled Substance Schedules (US)

• Schedule I: Highest potential for abuse; no accepted therapeutic usage (e.g., Heroin, LSD, mushroom extracts).

• Schedule II: High probability for abuse; accepted therapeutic use with close restrictions (e.g., Morphine, Methadone, Amphetamines, Barbiturates).

• Schedule III: Lower potential for abuse than I or II; therapeutic usage; low potential for physical dependence but high potential for psychological dependence.

• Schedule IV: Even lower potential for abuse and reduced potential for dependency (e.g., Diazepam).

• Schedule V: Lowest potential for abuse and dependency (e.g., certain Opiums and Atropinates).