PSYC 181 Lecture 2
Overview of the Pharmaceutical Industry and Drug Development
Drug development is one of the most resource-intensive industries, involving significant expenses dedicated to research and development (R&D).
The industry is characterized by high risk; a vast number of drugs are developed, but only a small fraction successfully reaches the market.
Basic research is the initial stage, focused on identifying the specific mechanisms of clinical conditions. This work is usually performed by public institutions and universities.
Once a mechanism is discovered—such as a specific elevated protein level associated with a hypothetical "disease x"—pharmaceutical companies begin designing compounds to target that biological process.
Preclinical testing involves creating several prospective compounds to determine which might effectively hit the intended biological target. Promising candidates undergo testing in animals before moving to human trials.
Patents and the Regulatory Review Process
The duration of a drug patent is strictly limited to years from the time of filing.
Filing for a patent must occur early during the investigation of a new target to protect the intellectual property before the findings are published.
Because of the lengthy time required for clinical trials and regulatory review, a drug might only have between years of patent protection while actually being available on the market.
Companies must recoup all R&D investments within this limited market window.
Before clinical trials begin, researchers must file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA). The FDA requires published literature on early findings to conduct a favorable review.
Following successful clinical trials, the drug is submitted for final FDA review and approval.
Post-Market Surveillance and Economic Realities
Post-marketing surveillance involves ongoing monitoring after FDA approval to identify adverse reactions, defects, long-term side effects, and complex drug interactions that only appear after years of use (e.g., years).
It is not feasible for a single company to test a drug against every possible variable or interaction before the drug becomes widely available.
Profitability statistics: only approximately (roughly drugs) that make it to the market will earn back their development costs.
The pharmaceutical industry structure is highly competitive. Unlike the automobile industry, which is an oligopoly dominated by companies like Toyota, Honda, Ford, and Volkswagen, the drug market features many more companies competing with diverse products.
Animal Research Models and Scientific Specialization
Comparative genetics: Rats and mice are genetically and biochemically similar to humans but differ greatly in environmental exposure. Due to their proximity to the ground and historical exposure to toxins, they are more resistant to certain pathogens than humans or primates.
Toxicity and efficacy testing in non-human primates is critical; skipping this stage has historically resulted in human fatalities during trials.
Labor dynamics in Pharma:
R&D scientists are highly specialized; an expert in psychiatric medication may not have knowledge of cancer treatments. This specialization leads to job instability if a specific drug project is canceled.
Lab technicians, who specialize in general methodologies and experimental techniques, have more transferable skills and higher job stability.
Regulatory Standards and Manufacturing
Manufacturing facilities are subject to extremely sterile environments and intense regulation.
Facilities are inspected hourly and daily by internal administration, peer competitors, and government agencies like the FDA and the Drug Enforcement Administration (DEA).
Good Manufacturing Practices (GMP): A set of onerous regulations specifying how research must be conducted for drugs intended for human use.
Many regulations are specific byproducts of past historical incidences where subjects were injured or died during the development process.
Sources and Classification of Psychoactive Agents
Naturally Occurring Drugs: Extracted directly from plants without chemical modification. Examples include Cocaine (coca plant), Opium (poppy plant), and Ephedrine (plant indigenous to China).
Semisynthetics: Naturally occurring substances that are chemically modified in a lab to alter potency or side effects. Example: Heroin is created by adding two acetyl groups to morphine.
Synthetics: Compounds built entirely in a lab from the ground up. Examples: Methadone (synthetic opiate) and Amphetamine (synthetic stimulant).
Drug Nomenclature: Drugs can be referred to by chemical name, laboratory designation (internal codes like MK-804), chemical group (e.g., phenethylamines), generic/nonproprietary name (e.g., Ibuprofen), proprietary/brand name (e.g., Zyrtec), or street names (e.g., "weed").
Classification systems: Classified by origin, therapeutic use (antidepressant), mechanism of action (dopamine receptor agonist or SSRI), chemical structure (tricyclic antidepressants), behavioral effects (CNS depressant, narcotic analgesic, hallucinogen), or legal schedule.
Foundations of Pharmacokinetics and Bioavailability
Pharmacokinetics refers to the factors affecting how a drug moves throughout the body, specifically absorption, distribution, metabolism (inactivation), and elimination.
Bioavailability: The total amount of the drug that successfully reaches the systemic circulation and target site relative to the total amount taken ( pill vs. amount absorbed).
Biological barriers like the blood-brain barrier (BBB) prevent large molecules from entering brain tissue, which necessitates specific drug design strategies to achieve target site concentration.
Routes of Drug Administration
Oral (PO): Per oz; administered via the mouth. Must contend with digestive enzymes and stomach acid.
Parenteral Injections (through the skin):
Subcutaneous (SC): Injected just below skin layers. Slow acting; used for vaccines to allow bodies time to mount immune responses.
Intramuscular (IM): Injected into the muscle. The absolute slowest route of administration for long-term presence. Used for most vaccines. Injections must be placed in large muscles like the glutes to avoid muscle damage.
Intravenous (IV): Injected directly into the bloodstream. Fastest route; reaches the brain in .
Intraperitoneal (IP): Injected into the lower abdomen. Common in quadrupeds/non-human animals; rare in humans because bipedal anatomy makes the peritoneum more prone to infection.
Pulmonary Absorption: Administered via the pulmonary system (e.g., inhalers).
Topical Administration: Applied on top of the skin (e.g., creams, patches). Most are local, but patches (e.g., nicotine, birth control) can work systemically if they stay on the skin long enough to be absorbed into the blood.
Drug Concentrations and Half-Life
Half-life: The time required for drug concentration in the blood to fall to of its peak level. Subjective effects usually start to fade after the first half-life.
Concentration trends: More invasive routes (IV) have higher, faster peaks. Longer-lasting drugs tend to have lower overall peak concentrations.
Oral drugs have lower peaks because they must survive first-pass metabolism, where a portion is destroyed by stomach acid and liver enzymes before reaching the heart.
Factors Impacting Drug Absorption and Transport
The most important factor in absorption is distribution across cell membranes, which are made of lipid bilayers. Drugs must be lipid-soluble (lipophilic) rather than water-soluble (hydrophilic) to cross them.
Passive Diffusion: Molecules move from high concentration to low concentration and from high charge (ionization) to low charge.
pH and Ionization: When drug pH and environment pH match, the drug is less ionized and better absorbed.
Weak Acids: Match in acidic environments (stomach).
Weak Bases: Match in basic environments (bloodstream).
Aspirin Case Study (Weak Acid, pKa ):
Stomach (Acidic): Aspirin is not ionized; well-absorbed.
Intestines (Basic-leaning): Aspirin begins to ionize; absorption decreases.
Blood (Basic): Aspirin becomes highly ionized. It becomes "trapped" in the blood because it is no longer lipid-soluble, preventing it from diffusing back to the stomach.
Intestinal Surface Area: The large and small intestines have huge surface areas, which allows some absorption even if the drug is highly ionized (e.g., antibiotics like "horse pills" require high doses to ensure enough is captured).
The Blood-Brain and Placental Barriers
In normal capillaries, intracellular clefts (holes) allow substances to flow freely. Brain capillaries have no clefts; they are plugged by astrocytes (astroglia).
Most drugs only cross the BBB if they are highly lipid-soluble or can piggyback onto carrier-mediated transport proteins.
Cannula: A hollow tube specifically used to bypass the BBB by direct injection into the brain.
Placental Barrier: Highly lipid-soluble drugs pass from parent to fetus very easily. Fetal blood concentration can reach of the parent's concentration within .
Metabolism, Inactivation, and Elimination
Liver: The primary site for drug inactivation through biotransformation, where drugs are converted into highly ionized metabolites that cannot cross cell membranes.
Kidneys: Filter blood to excrete ionized particles via urine.
Enzymes: Biological catalysts ending in "-ase" that break down substances.
Metabolic Tolerance: Taking a drug over time can induce the production of more enzymes (enzyme induction), making the body more efficient at processing the drug and reducing its duration in the system.
Alcohol Poisoning: Occurs when the intake of ethanol exceeds the body's ability to break down toxic metabolites like acetaldehyde and acetate.
Drug Elimination: Occurs via urine, breath (detected by breathalyzers), sweat, saliva, and breast milk.
Questions & Discussion
Impact of Gastric Environment: A student asked if taking antacids or foods like grapefruit could affect drug absorption. It was confirmed that altering the stomach's acidity level significantly changes how orally administered drugs are absorbed.
Course Requirements: A question regarding the depth of neuroanatomy was raised. It was clarified that students only need to know the specific neuroanatomical details mentioned in the lecture (e.g., that astrocytes form the BBB) rather than general external neuroanatomy.