principles of neuropharm -- pt 3

why do drugs vary in their effectiveness?

1. site of action

   1. morphine — inhibits neurons in CNS involved in pain perception

   2. aspirin — reduces production of chemicals producing pain messages

2. affinity

   1. how tightly and quickly ligand binds

describe affinity

where can receptors be found?

• in the cell membrane for water soluble

• in the cell nucleus for lipid soluble

describe agonist and antagonists

• agonist = high affinity, high efficacy

  • when they bind to the receptor, they initiate a cellular response

• antagonist = high affinity, low efficacy

  • when they bind to the receptor, they produce no effects (low efficacy) and prevent the agonist from binding

partial agonist

• less than full agonist, more than antagonist

inverse agonist

• causes a biological response, but different than what an agonist would do

• reduces constitutive activity = baseline receptor activity

competitive drugs…

• shift the curve to the right

  • no change in maximum response

noncompetitive drugs…

decrease the maximal effect

describe what is going on in these graphs

analyze graph

additive effects vs potentiaton

• additive effects

  • combined effect equals the sum

• potentiation

  • combined effect is much larger than the sum

what is dose adjustment for genotype?

• they are theoretical estimations based on people’s ability to metabolize drugs based on their genotype

  • poor metabolizers could have lower than the standard dose, since it takes them longer to metabolize the drug

  • intermediary could have around the standard dose

  • extensive would have a higher than standard dose, since they metabolize faster than normal

  • ultrarapid would have an even larger dose, since they are able to metabolize a lot faster

what is down-regulation?

• it is the cell’s response to an agonist

• because there is a lot of NT in the cleft, then the number of receptors in the postsynaptic cell will decrease to prevent too much activation

what is up-regulation?

• cell’s response to antagonist

  • because there are fewer NTs in the cleft, less binding occurs in the postsynaptic cell. the cell counters this by increasing the number of receptors in the postsynaptic cell so they may become more sensitive and compensate for less effects of endogenous ligand

what is tolerance?

• decrease in responding after repeated administration

cross-tolerance

• diminished effect in a second drug following tolerance to another

  • alcohol and isoflurane (general anesthetic)

what does tolerance depend on?

• dose, frequency, genetics, and environmental factors

what are the four types of tolerance?

1. metabolic

2. pharmacodynamic

3. behavioral

4. cross tolerance

metabolic tolerance

• an increase in metabolic rate of a drug following repeated exposure

  • AKA pharmacokinetic tolerance

• enzymatic induction

  • CYP1A2 with tobacco

  • CYP2E1 with alcohol

pharmacodynamic tolerance

• down-regulation

• large role in withdrawal (physical dependence)

behavioral tolerance

• context dependent

what are significant characteristics of tolerance

• reversible when drug use stops

• dependent on dose and frequency of drug use and the drug-taking environment

• may occur rapidly, after long periods of chronic use, or never

• not all effects of a drug show the same degree of tolerance

• several different mechanisms explain multiple forms of tolerance

sensitization

• reverse tolerance

• increase in a drug effect following repeated use

• psychostimulants do this to the motor system

stereotypy

• repetition of simple actions