Lecture 2

Dose Response Curves

• Graph Representation:

  • X-axis: Drug doses ($0\,\text{mg}$ placebo to high doses).

  • Y-axis: Percentage of subjects showing a specific measured effect ($0\%$ to $100\%$).

• Curve Profile:

  • Starts near $0\%$ response at placebo or low doses.

  • Ascends through effective doses as response percentage increases.

  • Plateaus at $100\%$ response; higher doses offer no additional measured benefit.

• Multiple Curves per Drug:

  • Separate dose-response curves exist for each distinct biological effect (e.g., opiates have independent curves for analgesia, constipation, and cough suppression).

Drug Potency and Safety Measures

• Potency:

  • Quantified by horizontal curve position.

  • A more potent drug's curve sits to the left of a less potent drug for a given effect (e.g., morphine analgesia curve is left of ibuprofen's; ibuprofen fever-reduction curve is left of morphine's).

• Effective Dose 50 ($ED_{50}$): Dose producing target response in $50\%$ of subjects.

• Lethal Dose 50 ($LD_{50}$) / Toxic Dose 50 ($TD_{50}$): Dose producing lethality ($LD_{50}$) or toxicity ($TD_{50}$) in $50\%$ of subjects.

• Therapeutic Index ($TI$):

  • Ratio quantifying drug safety:     $\text{Therapeutic Index} = \frac{LD_{50}}{ED_{50}}$

  • Higher $TI$ indicates a safer drug (e.g., marijuana $TI \ge 1000$; heroin $TI \approx 5$).

  • Varies depending on which effect curve is compared against lethality.

• Margin of Safety:

  • Conservative pre-release safety ratio:     $\text{Margin of Safety} = \frac{LD_1}{ED_{99}}$

Effects of Repeated Drug Administration

• Tolerance:

  • Reduction in effectiveness following repeated use (rightward curve shift).

  • Requires higher dose for original effect or $ED_{50}$.

  • Specific to individual drug effects, not the molecule as a whole.

  • Differential Rates: Tolerance develops faster for euphoric effects than lethal effects in opiates, narrowing $TI$ over time and elevating overdose risk.

• Sensitization:

  • Increase in effectiveness following repeated use (leftward curve shift).

  • Lower dose produces target effect or $ED_{50}$.

  • Observed in stimulant behavioral excitation (e.g., cocaine leading to seizures).

• Unchanged Effects: Responses remaining constant despite repeated administration.

• Cross-Tolerance: Tolerance to one drug transfers to another with similar physiological mechanisms (e.g., alcohol ataxia tolerance confers cross-tolerance to barbiturates).

• Cross-Sensitization: Sensitization to one drug transfers to a related compound (e.g., cocaine activation transfers to amphetamine).

Physical Dependence, Withdrawal, and Reinforcement

• Physical Dependence: Defined strictly by the appearance of a withdrawal syndrome upon drug cessation.

• Withdrawal Syndrome: Unpleasant physical/psychological symptoms upon cessation (e.g., caffeine headaches), driving drug resumption.

• Positive Reinforcement: Behavior driven by obtaining a desirable stimulus (e.g., drug euphoria).

• Negative Reinforcement: Behavior driven by avoiding/terminating an unpleasant stimulus (e.g., taking drugs to relieve withdrawal).

Substance Use Disorders (SUD)

• Terminology: DSM-5-TR uses "Substance Use Disorder" instead of "addiction" to eliminate stigma and ambiguity.

• Essential Features: Persistent cognitive, behavioral, and physiological symptoms despite life disruption, brain neurochemical alterations, repeated relapses, and intense cravings.

• Recognized Classes: 9 classes (alcohol, cannabis, hallucinogens, inhalants, opiates, sedative-hypnotics/anxiolytics, stimulants, tobacco, other). Caffeine is excluded from formal diagnosis but listed under Section 3 for further study.

• Diagnostic Severity: Evaluated across 11 criteria in 4 domains (requires minimum 2 criteria; tolerance/withdrawal not strictly required):

  • Mild SUD: 2 to 3 criteria.

  • Moderate SUD: 4 to 5 criteria.

  • Severe SUD: 6 or more criteria.

• 11 Criteria across 4 Domains:

  • Impaired Control: Consuming larger/longer than intended, failed attempts to cut down, excessive time spent, strong cravings.

  • Social Impairment: Role obligation failures, interpersonal conflicts, giving up social/recreational activities.

  • Risky Use: Use in physically hazardous situations, continued use despite known physical/psychological problems.

  • Pharmacological: Tolerance or withdrawal.

Substance Induced Disorders (SID)

• Reversible, substance-specific syndromes occurring directly from recent drug ingestion while active in the body.

• Symptoms resolve upon clearance (e.g., acute caffeinism, high-potency THC psychosis).

Drug Elimination and Half-Life

• Routes of Elimination:

  • Skin/Exhalation: Minor routes (sweat, breathalyzer detection, sour breath in chronic drinking).

  • Hepatic Metabolism & Renal Excretion: Primary route where liver enzymes convert drugs into ionized, inactive metabolites excreted in urine.

  • Prodrugs: Inactive compounds (e.g., Vyvanse) metabolized into active forms (e.g., amphetamine).

• Urinary pH Dependence:

  • Un-metabolized basic drugs (e.g., nicotine) depend on urinary pH.

  • Acidic Urine: Stress acidifies urine, ionizing nicotine, accelerating excretion, and increasing smoking frequency.

  • Alkaline Urine: Alkaline diets keep nicotine un-ionized, promoting reabsorption.

• Elimination Half-Life ($t_{1/2}$):

  • Time required to eliminate $50\%$ of a drug dose (e.g., heroin $t_{1/2} \approx 4\text{--}5\,\text{hours}$; methadone $t_{1/2} \approx 24\,\text{hours}$; THC $t_{1/2} \approx 5\,\text{days}$).

• Clearance Threshold: Clinically drug-free after 6 half-lives ($6 \times t_{1/2}$; e.g., $\approx 30\,\text{days}$ for THC).