principles of psychopharmacology pt 2

unionized

• lipid (fat, membranes, brain)

  • unionized particles can accumulate in fat stores

ionized

• water (plasma, urine, extracellular fluid)

  • ionized particles get “trapped” in blood and eliminated

what is ibuprofen?

• a weak acid

• unionized in the stomach and can cross membranes

  • oral bioavailability = 95%

what is morphine?

• a weak base

• ionized in the stomach and does not easily cross membranes

  • oral availability = ~20%

what is elimination?

• excretion of the drug via kidneys, tears, saliva, respiration

what is the half-life of a drug?

• time required to eliminate 50% of the absorbed drug

what is clearance?

• time it takes for drug to completely clear the body

steady-state plasma level?

• absorption/distribution = metabolism/excretion

what does longer half-lives increase?

• the likelihood of toxicity due to drug accumulation

what is metabolism?

• done primarily by enzymes in the liver

  • breakdown/transform molecules

• can make molecules even more active

• enzyme induction

  • the increase in a particular enzyme due to repeated drug use

what induces CYP2E1? describe what happens with CYP2E1

• induced by heavy alcohol use

  • more CYP2E1 activity breaks down alcohol faster, but also breaks down volatile (inhaled) anesthesia drugs

    • i.e. halothane, sevoflurane, isoflurane, enflurane, desflurane

• CYP2E1 converts 10% of acetaminophen into NAPQI

  • can bind to liver cell proteins and membranes and kill them

what happens to NAPQI in non-alcoholics usually?

• usually, the small amount of NAPQI is quickly neutralized via glutathione (GSH) in the liver as it binds to NAPQI and excretes the conjugate

how does chronic alcohol use affect this system?

• it induces CYP2E1, and more acetaminophen is converted to NAPQI even at lower doses

hepatocellular necrosis

• when NAPQI binds to liver cell proteins and membranes and kills them

what is the cytochrome P450 superfamily? characteristics, involved in

• enzymes found in most tissues of the body

  • ~57 different types

• involved in 75% of drug metabolism

  • some are inhibited, some are activated

• major source of adverse side effects and toxicity

effect of grapefruit

• it inhibits CYP3A4, which can INCREASE effect of Adderall, Xanax, Valium, Zoloft, Viagra…

high levels of what is related to colon cancer?

• CYP1A2

• tobacco increases production of CYP1A2

  • it also is involved in breaking down caffeine some antidepressants

CYP2D6

• metbolizes MANY psychotropic drugs

  • antidepressants, antipsychotics, antihistamines, analgesics, muscle relaxers, etc.

  • 25% of all drug metabolism

sex differences

alcohol dehydrogenase

• found in higher concentrations in the stomach of XY individuals

MAO-Inhibitors — description and example

• MAO breaks down dopamine, serotonin, norepinephrine in the brain

• in the liver, it breaks down amines such as tyramine (which is found in wine, beer, cheese, cured meats)

• tyramine regulates blood pressure

  • high levels can cause high BP, migraines and cardiac arrythmias

dose response curve

• magnitude of effect as a function of amount administered

potency

• strength of the drug

efficacy

• point of maximum effect

which is more potent?

• drug A is more potent because it has greater effects at lower doses

therapeutic index

• measure of margin of safety

ED50

desired effect in 50% of sample

LD50

lethal in 50%

TD50

toxic effects in 50%

LD50/ED50

= therapeutic index

TD50/ED50

= therapeutic index

the lower the TI…

the more dangerous

goal of drug?

that is effective at a low dose with no toxicity except at very high doses, the TI will be large for a safer drug

which is more efficacious? which is more potent?

• efficacious = A and B

• potent = A, C, then B