Ch1 Pharmaco Basics Flashcards
neuropharmaco, psychopharmaco, and neuropsychopharmaco
neuropharm = drugs on nervous system
psychopharm = drugs on beh’r/mood
neuropsychopharm = drugs on nervous to alter beh’r/mood
psychoactive drugs 5 kinds
act on brain
CNS stimulants (cocaine/nicotine)
CNS depressants (alcohol/barbiturates)
Analgesics (pain relief morphine)
Hallucinogens (LSD/psilocybin)
Psychotherapeutics (prozac/thorazine)
What is a drug’s action vs drug’s effect
action = molecular changes produced when binding to target site
ex: L-dopa is converted to DA
effect = the effects the molecular change (action) has on physical/psych processes
ex: L-dopa increases DA in striatum = improved motor function
Therapeutic vs side effects
therapeutic = desired changes from drug-receptor interaction (phys. and beh’r)
ALL OTHER EFFECTS ARE SIDE
Specific vs non-specific effects
Specific = based on the phys/biochem interactions of drug and target site (therapeutic and side effects)
Non-specific = not based on drug/receptor interaction (PLACEBO EFFECT, no chem activity but still effects)
emphasizes the need for double-blind experiments to test drug effects vs placebo
pharmacokinetics vs pharmacodynamics
kinetics = what body does to drug (RABIE)
dynamics = what drug does to body
bioavailability and 5 factors of it
bioavail = conc. of drug that is free to bind to target RABIE
Route of Admin
Absorption/Distribution (speed due to how much bloon in area eg. faster to brain)
Binding
Inactivation
Excretion
2 main types of admin route and biggest hurdle
Enteral (GI tract= oral/rectal)
Parenteral
influences how much/quickly drug reaches target
Drug must move from site of admin to blood (absorption), unless IV it must cross semi-impermeable membrane to blood
ORAL (PO) route and 1st-pass metabolism
drug pass through stomach/intestine wall
undergoes first-pass metabolism = passed to liver and is chemically altered from CYP450 enzymes that REDUCE BIOAVAIL of drug
rate of gastric emptying = food slows movement of drugs into intestine (stay longer in stomach). most absorption in small intestine (more SA/slower/more permeable), empty stomach thus speeds absorption
inhalation route
direct from lungs to brain through heart
rapid absorption (many capillaries)
rapid effect on brain seconds
Intravenous IV
passes to heart, lungs, heart again to brain
most rapid and accurate
Intranasal
local effects: nasal passage
systemic effects: moves across single epithelial layer into blood to brain! immediate
BYPASS blood-brain barrier - ‘olfactory transfer’, direct access to CSF via olfactory nerve pathways
“insufflation” = snorting
gene therapy route admin
application of DNA encodes protein (CAR-T cell therapy, mRNA vaccines)
most important factor in plasma drug levels
rate of passage through cell membranes
route admin alters absorption into bloodstream
lipid solubility and ionization rules of thumb
lipid soluble = pass through membranes passive diffusion down conc. gradient (want high lipid solubility to get to brain)
MOST DRUGS NOT LIPID SOLUBLE
ionization depends on pH and pKa
most drugs are weak acids/bases
weak acids ionize in basic
weak bases ionize in acidic
IONIZED ARE POORLY ABSORBED IN GI (CANT BE GIVEN PO).
IONIZED CANT CROSS MEMBRANES (stuck)
aspirin story and ionization
aspirin is a weak acid
in stomach (high acid) it is non-ionized and thus lipid-soluble, absorbed into blood.
reaches blood (weak basic), becomes ionized and stuck in circulation to body (no back-absorb)
when aspirin reaches intestine (weak acid), ionized, slower passage to blood than when in stomach
if take antacid (basic), aspirin becomes ionized and isn’t absorbed to blood when in stomach
blood brain barrier differences
normal capillaries have pores
BBB has no openings (so molecules must be lipid-solube)
separates brain capillaries and brain/csf
functions are protect/shield/maintain
some areas not isolated (circumventricular organs CVOs = area postrema of medulla (chem trigger zone to vomit), median eminence of hypothal)
need lipid-soluble to cross ex: L-dopa instead of dopa, or imodium with helper drug to move it across
placental barrier and teratogens
separates mother and fetus blood
newborns don’t have all necessary enzymes to metabolize drugs
neonatal absitence syndrome = withdrawl in infants due to mother’s drugs
teratogens = drugs that induce devo abnormalities, accutane and thalidomide
drug depots what is and effects of it
binding at inacitve sites, no effect (plasma proteins, muslce, fat)
affects magnitude and duration of drug
REDUCE conc./effect (can terminate action)
DELAYS effect (drug testing, remains in body)
individual variabilty in drug response
depot binding selectivity and termination
depot binding is nonselective - drug remains in body for long time. drugs compete for same binding sites can lead to OVERDOSE
responsible for TERMINATION of drug action - rapid redistribution from brain to fatty tissue (inacitve site) to bind, anesthetics sequester in fat = rapid acting/short duration
biotransformation and two types of elimination rates
metabolism
process by which drugs elimination/excreted
first-order kinetics = exponential
zero-order kinetics = linear
first order kinetics
most drugs
CONSTANT FRACTION ELIMINATED per time unit (ex 50% per hour)
proportional to drug conc.
RATE IS CONC.-DEPENDENT (slows as time goes on)
plasma half life = amt time for 50% drug removal from blood. about 5 half lives
steady state and therapeutic goal
steady state -> absorption/distribution = metabolism/excretion
therapeutic goal -> maintain conc. of drug at a constant level
zero-order kinetics
rare
molecules cleared at constant rate, linear
because metabolism routes are saturated
becomes first order at very end when levels go under saturation level
RATE IS CONC.-INDEPENDENT
ex: alchohol
where most biotrans and goal/two major types
liver. goal = produce inactive, water soluble (ionized) metabolites., return to circulation for kindey excretion
TYPE 1 = Phase 1 (CYP450 enzymes). Non synthetic using Oxidation (most), reduction, hydrolysis. could produce a metabolite that is MORE ACTIVE than drug itself (psylocibin metab. into active)
TYPE 2 = Phase 2 (non-cyp enzymes). synthetic requires conjugation. ex: glucuronide conjugation
can undergo both phases/mulitple
microsomal enzymes
liver enzymes that metab. drugs
LACK specificity
cytochrome p450 family only 6 ARE RESPONSIBLE FOR 90% OXIDATION OF DRUGS, phase 1
4 influences on biotrans
- enzyme induction
- enzyme inhibition
- drug competiton
- individual diffs (age gender genes of metab. enzymes)
enzyme induction
influence on biotrans
repeat drug = MORE enzymes = MORE BIOTRANS
leads to drug cross/tolerance, LOSE DRUG EFFECTS
enzyme inhibition
biotrans influence
drug INHIBITS ENZYME = REDUCE METAB. of other drugs too
ex: monoamine oxidase inhibitors prevents breakdown of tyramine = hypertension from too much tyramine in cheeses
drug competiton
biotrans influence
lots of one drug = LOWER METAB. OF SECOND DUE TO ENZYME COMPETITION
alcohol plus sedative = BAD, compete for same enzyme, OD on one
excretion
urine is most important route
kidneys flter water soluble ionized molecules
water is reabsorbed in kidneys, makes drug conc. HIGH in tubules, could be reabsorbed into blood due to gradients, BUT ionization reduces reabsorb, pH dependent (can change pH of urine)
ligand-receptor binding interaction
most binding is temporary reversible (nerve gas is permanent)
NTs bind and release many times for effects
receptors have specificity for ligands due to shape
receptors can have many subtypes throughout body (5-HT in diff locations)
Receptor agonist vs antagonist
agonist = best fit (best affinity)
antagonist = also has affinity/fit, but prevents active ligands from binding. no effect
partial agonist, inverse agonist, indirect agonist
partial - meh efficacy at max binding
inverse = opposite effect to agonist
indirect = enhances release/effect of drug but doesnt bind to receptor itself
up/down regulation
receptor proteins have dynamic life cycle and #/sensitivity can change
up regulation = inc. # receptors due to absence of ligands or chronic antagonism
down regulation = dec. # receptors bc chronic activation
threshold dose
smallest dose for a measurable effect
Emax
efficacy, max response achieved by a drug.
assumes all receptors are saturated
ED50
50% effective dose
dose that produces half Emax for indivdual
or dose at which 50% population responds
TD50
50% toxic dose
dose at which 50% population experiences a toxic effect
therapeutic index
TI = TD50/ED50
higher number is better, means larger quantity needed for toxicity
Potency
absolute amount of drug required to produce a specific effect.
Comparing ED50s of drugs show differences in potency (further right = less potent)
If linear portion of dose response curve is parallel, drugs work in same mechanism
Affinity and Kds
tenacity with which drug binds to receptor
rates of dis/association are compared to get estimate of affinity. Disassociation constant Kd
High affinity = low Kd, readily bind, slowly release
Low affinity = high Kd, slowly bind, quickly release
competitive antagonists and dose response curves
bind reversibly to the same receptor as antagonist (competes) and does NOT produce effects
Shifts the curve right of OG drug bc need more of it now to outcompete
Partial agonist and dose response curve
drugs produce a lower response at saturation than normal agonist. Not due to decreased affinity, just bc weaker activity at receptor
Partial agonist dose curve will be shorter (not reach same Emax as og drug)
Agonist curve in presence of partial agonist is shifted right bc must outcompete it
Non-competitive antagonist
binds at allosteric site (non-competitive) inside receptor
reduces magnitude of max response (Emax) of any amount of agonist
effects CANNOT be negated no matter how much agonist
Shifts dose curve right and shorter (will never reach same Emax and still needs more to do an effect)
For both allosteric binding (noncomp) and irreverisble comp. antagonist at orthosteric site (actual receptor site, bc now can’t do as many receptors if irreversible so lower Emax, and shifted right)
3 biobeh’r interactions of multiple drugs
Physiological antagonism = like wave destruction. Positive A plus negative B = smaller positive effect
Additive effects = like wave constructive. Positive A + Positive B = big positive equal to parts
Potentiaion = whole is bigger than sum. Positive A + Positive B = HUGE positive effect bigger than individual additive
tolerance
diminshed response to a drug after repeat exposure
cross tolerance
tolerance to drug A diminishes effect of Drug B that’s in the same class
Metabolic Tolerance
repeat drug reduces amt of drug available at target tissue
this is due to enzyme induction (more enzymes = more metabolism/biotrans = less drug)
Acute tolerance
decrease in response after single exposure of drug
in alcohol occurs independently of BAC after single administration. during increase of BAC, effects more severe than during elimination even if BAC constant
Pharmacodynamic tolerance
changes in nerve cell function to compensate for continued pre/absence of drug
for homeostasis (up/down regulation)
Behavioral tolerance
tolerance in same environment
reduced tolerance in novel environment
Pavlovian conditioning
food = ucs
saliva = ucr
bell = neutral stimulus
train
bell = cs
saliva = cr
“needle freak” sight of a needle (cs) induces euphoria (cr) for addicts
operant skinner conditioning
plays part in beh’r tolerance too
repeated reinforcement/exposure, compensate drug changes in beh’r
ex: functional alcoholic rewarded for acting normal
state-dependent learning
tasks learned while doing drug are better if do drug again than doing in non-drug state
(take exams in same lecture hall)
Sensitization
reverse tolerance
enhancement of effects after repeat drug (shifts dose curve LEFT!)
some drugs induce tolerance for some effects and sensitize others (opioids tolerance analgesia, sensitize constipation)
pharmacogenetics
study of genetic basis of drug response variability of individuals.
goal to identify genetic factors of the side effect susceptivility or predict therapeutic response
genetic variation for drugs
variation in drug-metab. enzymes = need to adjust dosage. low metab. need less drug (more sticks around)
high metab. need more drug (less sticks around)
genetic polymorphisms also influence drug sites like receptors/transported/intracellular signaling
