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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 (T1/2)
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 (Emax)
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 (Kd)
high affinity: low Kd
low affinity: high Kd
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