unit 1 Flashcards
pharmacology
study of the action of drugs in organisms
neuropharmacology
drug induced changes in functioning of nerve cells
psychopharmacology
drug induced changes in behavioral responding
neuropsychopharmacology
drug induced changes in the function of select neurons that influence specific behaviors
drug action
molecular changes within cells produced by the drug binding to a particular target site/ receptor (VERY specific)
drug effect
molecular changes within and between cells that lead to alterations in physiological/ psych function (broader)
therapeutic effects
drug/ receptor interactions that produce the desired physiologic and or behavioral effect(s)
side effects
all other drug effects varying from annoying to deadly
specific drug effects
due to physical or biochemical interaction of a drug with a target
nonspecific drug effects
not based on drug/ target interaction due to individual characteristics (influences by experience or attitude or varied neurochemical state at time of exposure
-ex= placebo effect
pharmacokinetics
how drugs move through the body (speed/ duration) -multiple factors influence drug action in CNS main factors: -route of admission -absorption and distribution -binding characteristics -inactivation -elimination from system
proximal small intestine
most drugs are absorbed here (first 12 inches) and can take longer to absorb if food (especially fatty) is in way
enteric-coated formulations
used for drugs inactivated at low pH (coating protects drugs from stomach acid)`
buffered formulations
used for drugs that increase stomach acidity
absorption
drug movement from the site of administration to blood circulation
oral administration (PO)
most popular, safe, cheap, easy
- capsules, pills, tablets, liquids
- must dissolve in stomach and pass to small intestine and MUST be resistant to strong acids and enzymes in stomach
- most PO drugs aren’t absorbed until reach SI
- amount of food influences speed of absorption
first pass effect
PO drugs absorbed into blood stream go directly to liver and metabolism here reduces the amount of drug available to circulation and so concentration in blood is irregular and difficult to predict
intravenous administration (IV)
most rapid and accurate method (avoids first pass effect)
- best for Med; worst for illicit
- quick onset leaves little room for corrective measures
- easy monitoring
intramuscular administration (IM)
slow and even delivery of drug (absorption usually 10-30 min post-injection); non-aqueous additives (lipophilic) provide slow release; often painful
-common IM sites= deltoid, ventrogluteal, rectus femurs, vastus lateralis
subcutaneous admin (SC)
absorption dependent upon blood supply to the site (point of injection); often slow and steady oil delivery (insulin at waist)
gaseous (inhalation) admin
rapid absorption due to large surface area of pulmonary capillary system (most dangerous for illicit bc hard to fix); quick drug onset
topical admin
direct application to mucosal membranes (nasal, vaginal, ocular, colon)= rapid absorption and rapid effects
transdermal application
slow absorption bc skin is a barrier for aqueous and need lipophilic… transdermal patches= lipids; controlled and sustained method
excipients
chemicals added to drugs to allow drugs to exist in diff forms
-formulation controls rate of delivery ONLY when liberation rate is less than absorption rate
bioequivalence
if two drug formations have equal bioavailability and rate of absorption then the resulting plasma level will be similar
tolerence
dose-dependent phenomenon (less tolerant to PO drugs)
rate of drug passage
=across various cell layers between sit of admin and blood is the single most important factor in determining plasma drug levels
lipid-soluble drugs
move across membranes via passive diffusion
-movement down concentration gradient
-depends on concentration gradient and lipid solubility
(extremely hydrophobic and hydrophilic don’t diffuse as easily because they get stuck in the plasma membrane)
-diffusion occurs in steps (two barriers= hydrophilic heads on both sides of the membrane)
salt forms of drugs
substitute hydrobromide/ sulfate for hydrogen
- useful for long-lasting drugs (popular, many applications, save money and time)
- dosage delivery can be an issue (drug weight includes the salt- less drug)
drug acidity
closer to neutral the drug is, the easier it is to be absorbed
drug ionization characteristics (pKa)
weak acids ionize more in basic environment- weaker acids ionize less in acidic environment
- highly ionized drugs are poorly absorbed in body and cannot be admin orally
- drugs closer to non-ionized the better (increases movement and goes into cells)
distribution of drug influences
blood flow and diffusion of drug out of circulation to target sites
and selective barriers to diffusion
apparent volume (Vd)
describes distribution ability of drug to the body- heavily influenced by lipid solubility (greater Vd= increased lipid solubility)
Vd= amount of drug that leaves circulation and enters the body (defined in L)
-total body volume= 42L, so drug with Vd=42L will distribute to the whole body
first phase
due to preferential blood flow to brain, it receives blood first and drug conc in blood decreases as drug conc in brain increases
second phase
due to drug solubility in other body tissues
- drug entering other body tissues reduces overall drug concentration in the blood
- drug leaves brain for blood
third phase
drug leaves blood to enter fat stored in reservoir
redistribution
process of drug leaving one site for another based on blood flow and lipid solubility
blood brain barrier
vascular endothelial cells- connect by tight junctions and secrete basement membranes (tight junction and basement membrane force mcls to diffuse through matrix, which forces bigger toxins to not enter)
astrocytes
project astrocytic feet around basement membrane- together they form the barrier to diffusion of polar molecules (force drugs to diffuse across basement membranes)
fenestration
molecules can leave blood through these gaps in capillary covering
chemoreceptor trigger zone
area postrema- has no BBB, so it can sense toxins and cause emesis (vomiting)- has 5HT and DA receptors
plasma binding
in blood- affects distribution and alters extent and duration of drug action
- drug binding in blood occurs at inactive sites and these are called drug depots= plasma proteins in blood that bind drugs
- only unbound drugs can diffuse across membrane
- binding to drug depots is non-selective (competition between drugs with diff affinities)
drug metabolism
breakdown of drugs by the microsomal system (p450 system) in liver- several isoforms of enzymes exist and large gene family leads to variability
pharmacogenetics
study of inherited genetic differences in drug metabolic pathways- which can affect individuals
two phases of biotransformation
phase 1- oxidation, hydrolysis, reduction of parent structure; slight charge; usually not enough to metabolize drug from system
phase 2- conjugation w glucuronide, sulfate, acetate, or amino acid; produces highly ionized, biologically inactive molecules
drug half life
time it takes for removal of 50% of the drug in blood
first order transformation (kinetics)
drug clearance rate proceeds exponentially
=enzymes are in excess and the concentration of the drug determines rate of biotranformation
-rapid clearance from system
zero order transformation
drug clearance rate is FIXED- around of drug to transform exceeds the concentration of converting enzymes (rate depends on amount of enzymes)
-slow clearance
factors influencing drug metabolism
- enzyme induction
- enzyme inhibition
- drug competition
- individual characteristics
enzyme induction
increase in concentration of enzymes available for biotransformation
- increase in biotransformation rate of all drugs in system
- ex= excessive alcohol use leads to increased enzyme activity
enzyme inhibition
some drugs directly inhibit metabolizing action of enzymes- decrease in biotransformation rate of all drugs in system; decrease in the biotransf rate of other naturally occurring biomolecules
drug competition
some drugs share metabolizing enzymes
- decrease in biotransformation rate of both drugs in a system
- produce potentially dangerous drug interactions (both need enzymes and set number of enzymes, decrease rate of clearance)
individual characteristics
individual genetics characteristics/ environment differences that can decrease or increase the biotransf rate of drugs in a system
pharmacodynamics
study of physiological and biochemical interactions of a drug with target tissue that is responsible for the drugs effects
- drugs change the system over time
- membrane bound receptors have local effect, cellular receptors often change genetic info and cause widespread effects
first (traditional) view of ligand
receptor interaction= IONOTROPIC
- lock and key model
- ligand binds to R, conformational change, ions can enter
second view of ligand
receptor interaction= METABOTROPIC
-most common.. Rs have acceptor site for ligand and binding causes cascade of action; results in synthesis of secondary messengers (cAMP, DAG, Ca2+)
agonist
binding produces specific cellular response= mimic= potent
antagonist
doesn’t produce cellular response= blocks
dose response curve
describes the amount of biologic/ behavioral effect for a given drug concentration
(increased dose= more receptors occupied and more response seen)
ED50
produces half the maximal effect (50% effective dose)
- drugs with different potencies have differing ED50s
- drugs with different response curve slopes have different mechanisms of action
TD50
does at which 50% patients experience toxic effect- can have multiple TD50s for differing effects
therapeutic range (TR)
gives working range of plasma levels- minimum plasma concentration which benefits vs minimum plasma concentration which is toxic
therapeutic index
calculates the margin of drug safety
=TD50/ED50
direct acting agonist
affinity and efficacy (potency) at NT-R site
- binds R and mimics NT action
- R subtype selective (DAD2 agonist
- R subtype non selective (D1 and D2 agonist)
indirect acting agonist
enhances NT action at R but indirectly
- do not bind receptors but do activate them
- ex= drugs that increase levels of endogenous Its/ extend availability over time)
direct acting antagonist
affinity but no efficacy- bind Rs but do not produce biologic action
competitive antagonist
ligand binding at receptor site- competes with natural NT for binding site (can be reversible or irreversible (deadly toxin))
non-competitive antagonist
binding to regulatory site on R to inhibit access of NT to R
-antagonists increase overall NT amount (left in synapse bc can’t bind)
indirect acting antagonist
decreased action of NT at receptor
-decreases naturally occurring NTs
tolerance
chronic drug use can change drug potency in body= usually the more you take the less response you are to it
pharmacodynamic tolerance
due to chronic drug exposure
-decreased potency due to decrease in efficacy through which drug carries out which action
A) decreased number receptors
B) desensitization- increased phosphorylation of NT-Rs reduces ability of Rs to produce secondary messengers
pharmacokinetic tolerance (biodispositional)
biologic system responds to drug by decreasing drug concentration delivered to target site due to altered pharmacokinetic parameters
-drugs make metabolizing system faster- causes drug dependency
physiological tolerance
due to secondary consequences of drug action- upstream chain effect of drug causes large downstream effects
-review haloperidol example in ppt
behavioral tolerence
decreased potency of drug secondary to intentional change in behavior of consumer based on anticipation of adverse effects
acute tolerance
rapid induction of tolerance (2-24hrs) due to rapid effect on neurons (LSD)
cross tolerance
tolerant to one drug= tolerant to others in same class
-decreased potency of one drug bc of exposure to another drug in the same class
reverse tolerance= sensitization
increased potency of drug following continued exposure to drug- stimulants
