• Neuropharmacology

  • the study of how substances affect our nervous system and behavior

    • one of the main areas of neuroscience research today

  • usually starts with animal research, once safety is established moves to human clinical studies

  • often (but not always) involves comparing active substances to a placebo (saline solution)

    • may use “active” placebo and may use double-blind research design

• Basic terms

  • Agonist --- increases NT activity

  • Antagonist --- decreases NT activity

  • Placebo --- an inert substance that is given to an organism instead of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug

    • sometimes creates same effect as the drug

Research terms

• Half-life --- time it takes 1/2 of the drug to leave the body

  • used as a safety and maintenance factor

  • must examine drug “metabolites” as well as active ingredients

  • Drug metabolism: the process by which the body breaks down and converts medication into altered chemical substances

  • can be active or inactive

    • may not cause desired effect but affect other things; active = produce effect, inactive don’t

  • Elimination of a drug characterized by more than one half-lif every time half is eliminated = half-life

  • Time required for a drug concentration to reach steady state is determined by half-life

  • in most clinical situations, the attainment of steady state can be assumed after 3-5 half-lives

  • When the drug concentration is around 5% it is said to be negligible, therefore around 4 or 5 half-lives must elapse until the drug is eliminated

  • Time for drug “negligibility” = half-live * 5

• Dose-response curve

  • a graph of the relationship between drug doses and the effects

  • attempts to find effective and safe dose of drug

  • can be used to plot the results of many kinds of experiments; X-axis usually drug/hormone concentration, Y-axis plots response (can be almost anything)
    

  • the specific measurement (DV) will be defined b/c pharmacological agents can have multiple effects

  • plots increasing drug dose (usually on a logarithmic scale) against increasing strength of the response being studied

  • the dose at which the drug shows half of its maximal effect is termed the effective dose 50% (ED50)

  • Therapeutic window--- many drugs only work at specific doses; high and low often have little effect

  • Nonmonotonic DRC --- a DRC that is normal up to a point but then reverses and the measured response begins to decrease with larger doses

• Dose-response functions

  • Minimum effective dose (ED50) --- lowest dose to produce desired effect in 50 % of clinical subjects

  • Median Toxic dose (TD50) --- dose which produces the first signs of toxicity in 50% population

    • high build-up in blood

  • Threshold dose --- smallest dose to produce detectable change

  • change must be defined by therapeutic effect

  • We can assess the relative potency of two drugs by comparing their ED50 values

  • Maximum response (max dose) --- the greatest degree of response that can be achieved with a specific drug

    • usually there is a plateau effect past which further dose do not increase effect

    • sometimes higher doses decrease effect (like amphetamines) because other effects begin to interfere with desired effect

    • We can compare drug efficacies by evaluating maximal responses, rather than doses

    • Partial agonist/antagonist - a drug of only moderate efficacy

  • Therapeutic index (TI) --- the separation between the effective dose and a toxic one

    • Safe index - ratio between TD50/ED50

    • TI = 100x safe (over-the-counter), TI =10x hazardous

    • becomes an issue with uncontrolled recreational use---tolerance to recreational effect occurs very quickly

• Clinical efficacy---refers to the degree to which a drug is able to induce a given effect

  • related to maximal response

  • DRC can allow the comparison of difference drugs

• Potency-- the amount of a drug needed to produce a desired effect

  • lower the needed dose, more potent

Drug interactions

• Affinity - capacity of a compound (drug) to maintain contact or be bound to a receptor

• binding affinity = the degree of chemical attraction between a ligand and a receptor

  • a drug with a high affinity for its receptor will be effective at very low doses

  • when two substances are being taken, one with the most affinity will have greater effect

  • penicillin and alcohol

Tolerance/Dependency

• Tolerance - when there’s a decreased susceptibility or increase in amount of drug being taken needed

  • represented by a rightward shift in the dose response curve

  • has a physiological and psychological component

• Factors

  • Metabolic tolerance --- organ systems become more effective at eliminating the drug

  • Elevation in Hepatic Microsomal Enzyme (HME) - reduces drug to metabolites so they become ineffective and easier to eliminate

    • ‘hepatic’ = liver

    • creates inactive and easier-to-eliminate metabolites

    • with repeated use of the brain creates more HMEs

    • associated with cross-tolerance to related substances

      • tolerance to once drug gives pre-existing tolerance to another (ex. surgical, analgesics, and narcotics)

    • creates dangerous interactions between drugs that share the same HMEs---sedatives and alcohol

      • biotransformation produces active metabolites that may produce side effects

  • Functional tolerance: target tissue may show altered sensitivity to the drug

  • up and down-regulation of receptors

  • with repeated drug use nervous sys can respond by altering the density of post-synaptic receptors

  • increase density = up-regulation, antagonist

  • lower density= down regulation; agonist

• Drug dependent

• Physical dependency: when