Drugs Brain and Mind - Chapter 1

drug action

molecular changes produced by a drug when it binds to a target site

drug effects

effects of the molecular changes in pathway function on physiological and psychological processes (e.g. behavior)?

therapeutic effects

drug-receptor interaction that produces the desired changes (physical or behavioral)

side effects

all other effects of a drug-receptor interaction that are not the desired change

specific effects

based on physical and biochemical interactions of a drug with a target site on living tissue

nonspecific effects

effects not based on drug-receptor interaction (e.g. placebo effect)

placebo effect

belief in a drug may produce real physiological effects despite the lack of chemical activity

bioavailability

the concentration of drug present in blood that is free to bind to specific target sites

factors that contribute to bioavailability

R - route of administration

A - absorption and distribution

B - binding

I - inactivation

E - excretion

route of administration

influences how much drug reaches its target and how quickly the effect occurs

absorption

movement of the drug from the site of administration to the blood circulation (must cross semi-impermeable membranes before reaching system circulation unless given intravenously)

oral (PO) administration

drug must pass through wall of stomach or intestine - first pass metabolism

food slows movement of drugs into the intestine

first pass metabolism (pre-systemic metabolism)

potentially harmful chemicals pass via the portal vein (from GI tract) to the liver » chemically altered, reduces bioavailability of the drug

inhalation administration

drug passes directly from lungs into blood through heart to brain, rapid absorption through pulmonary capillaries

rapid effect in brain - within seconds

intravenous (IV) administration

drug passes into heart, then lungs, back through heart, and then to brain

most rapid and accurate method of drug administration

intranasal administration

local (nasal passages) and system effect - moves across single epithelial layer into the blood

bypasses the blood brain barrier (BBB) and has direct access to the CSF, direct transport of drugs to brain via olfactory nerve pathways

gene therapy

application of DNA that encodes a specific protein

lipid-soluble drugs

pass through cell membranes by passive diffusion moving down concentration gradients, can easily enter brain tissue

most drugs are not lipid-soluble

weak acid drugs

more readily ionized in basic environments, less ionized in acidic environments

weak base drugs

more readily ionized in acidic environments, less ionized in basic environments

acid/base drugs

non-lipid soluble drugs

highly ionized drugs are poorly absorbed from the GI tract and cannot be given by PO (orally)

small intestine

most drug absorption occurs at this site

much more surface are and slower movement of material, more permeable

methods of non-lipid soluble transport

facilitated diffusion and active transport

fenestration, intercellular clefts, pinocytotic vesicles

blood brain barrier

separation between brain capillaries and brain/CSF, semi-permeable

protect, shields, and maintains

unisolated areas: area postrema in the medulla, median eminence of the hypothalamus

area postrema

chemical trigger zone in the medulla, senses toxins, induces vomiting reflex

not protected by the BBB

median eminence

hypothalamus, release of hormones induced in the stress response

not protected by the BBB

blood capillary barriers

tighter cellular junctions

protective end feet of astrocytes

no intercellular clefts or fenestration, only carrier-mediated transport

placental barrier

separation of blood circulation between mother and fetus at the placenta

teratogens

agents that induce developmental abnormalities

thalidomide

sleep aid marketed for morning sickness

10,000 cases worldwide documented of abnormal limb development

drug depots

drug binding at inactive sites where no biological effect is initiated

plasma proteins, muscle, and fat

depot binding

affects magnitude and duration of drug action:

• reduces concentration of drug at sites of action

• delays effects

• basis for drug testing

• individual variability in drug response

• can lead to termination of action

• nonselective

• similar drugs can compete for depot » overdose

drug depot termination

rapid redistribution of drug away form the brain into fatty tissue, leads to sequestration in fatty tissue

biotransformation (metabolism)

process by which drugs are eliminated and metabolites are excreted

first-order kinetics

most drug metabolism

constant fraction of drug eliminated per time unit

concentration-dependent

if drug metabolic sites are NOT saturated by the drug!

plasma half-life (T_1/2)

amount of time required for removal of 50% of the drug from the blood plasma - an example of first order kinetics

steady state

absorption/distribution = metabolism/excretion

therapeutic goal

maintain concentration of a drug in blood plasma at a constant level

zero order kinetics

molecules are cleared at a constant rate regardless of concentration

when drug levels are high and routes of metabolism are saturated

rate is concentration independent

type I biotransformation

phase I — CYP 450 enzymes

non-synthetic

could produce a metabolite that is more active than the drug

type II biotransformation

phase II — non-CYP enzymes

synthetic

liver biotransformation

goal: produce inactive metabolites that are water soluble (i.e. ionized)

metabolites formed in the liver are returned to systemic circulation

microsomal enzymes

liver enzymes that metabolize psychoactive drugs

lack specificity - six are responsible for 90% of all oxidizing psychoactive drugs

Phase I reactions

enzyme induction

repeated use of a drug increases number of enzyme molecules » speeds biotransformation

mechanism of drug tolerance and cross tolerance

enzyme inhibition

drug may inhibit an enzyme and reduce metabolism of other drugs

example: monoamine oxidase inhibitor (MAO), major class of antidepressants

drug competition for an enzyme

elevated levels of one drug reduces metabolism of the second, causing potentially toxic levels

urine excretion

most important route for drug elimination

kidneys filter material from blood into urine » excretion of water-soluble (ionized) substances

water and electrolytes reabsorbed into blood circulation; can increase the reabsorption of drugs dependent on pH

pharmacodynamics

what drugs do to the body

partial agonist

drugs that produce a lower response at full receptor occupancy than full agonists

not due to increased affinity for binding

inverse agonist

action that is opposite to that produced by an agonist

indirect agonists

enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the NT receptor (e.g. cocaine, amphetamine, MDMA)

receptor up-regulation

number of receptors increases in response to absence of ligands or chronic antagonism

receptor down-regulation

number of receptors is reduced due to chronic activation

threshold dose

smallest dose that produces a measurable effect

efficacy (E_max)

maximum response achieved by a drug

assumes all receptors are occupied (saturated)

ED₅₀ (50% effective dose)

dose that produces half maximal effect (whole animal) OR

dose at which 50% of the population responds (population)

TD₅₀ (50% toxic dose)

dose at which 50% of the population experiences a toxic effect

therapeutic index (TI)

TD₅₀/ED₅₀

higher is better; high TD₅₀ » larger quantity required for toxicity

potency

absolute amount of drug required to produce a specific effect

dose-response curves

semi-log scale: characteristic S shape

linear portion of curves are parallel » work through the same mechanism

affinity

tenacity with which a drug binds to its receptor

rates of dissociation and association are compared to get an estimate of receptor affinity: dissociation constant (K_d)

• high affinity: low K_d

• low affinity: high K_d

competitive antagonist

bind reversibly to the same receptor site as an agonist

do not initiate intracellular effects

rightward shift of dose-response curve

non-competitive antagonist

reduce the magnitude of maximum response that can be attained by any agonist

effects cannot be negated, no matter how much agonist is present

two mechanisms:

• allosteric site binding

• irreversible competitive antagonism: orthosteric

biobehavioral interaction

multiple outcomes due to interaction between drugs

• physiological antagonism

• additive effects

• potentiation

tolerance

diminished response to the administration of a drug after repeated drug exposure

cross tolerance

tolerance to one drug can diminish the effectiveness of a second drug in the same class

metabolic tolerance

repeated use of a drug reduces amount of the same drug available at the target tissue

acute tolerance

decrease in response within a single exposure to the drug

• occurs independently of changes in BAC

• develops during single administration

  • effects of alcohol during increase are more severe than during elimination

pharmacodynamic tolerance

changes in nerve cell function compensate for continued presence or absence of a drug (e.g. enzyme up-regulation and down-regulation)

behavioral tolerance

tolerance is seen in same environment but reduced in novel environment

operant (Skinnerian) conditioning

may play a role in behavioral tolerance

with repeated exposure and reinforcement, an animal or human can learn to compensate for drug-induced changes in behavior (e.g. the functional alcoholic)

state-dependent learning

tasks learn in the presence of a psychoactive drug may subsequently be performed better in drugged state than non-drugged state

sensitization (reverse tolerance)

enhancement of drug effects after repeated administration of the same dose

some drugs induce tolerance for some effects and sensitization for others

pharmacogenetics

study of the genetic basis for variability in drug response among individuals

goal: identify genetic factors that confer susceptibility to specific side effects or predict therapeutic response

genetic polymorphisms

can influence drug target sites:

• receptors

• transporters

• intracellular signaling cascades