Unit 1 Lectures Flashcards
pharmacotherapeutics
dose regimen
pharmacokinetics
how plasma concentration changes over time (what the body does to drug)
pharmacodynamics
what the drug does to the body
pharmacotherapeutics can use a drug for…(4)
prevention, diagnosis, treatment, cure
In a dosage regimen, select drug and dose based on…
pharmacodynamics, disease target, drug regulation
In a dosage regimen, select route of administration based on…
pharmacokinetics (absorption and distribution)
In a dosage regimen, select dosage frequency based on…
pharmacokinetics (metabolism and excretion)
In a dosage regimen, select duration based on…
disease pathophysiology
Physiology identifies _________ for drug action
potential targets
Pathophysiology determines how the _________ should be _________ in a disease
targets, manipulated
bioavailability
how much drug reaches a target
volume of distribution
what is the drug dose for a desired Cp?
The major organ of metabolism is the ________
liver
The major organ of excretion is the _________
kidney
Therapeutic uses of drugs act via enhancement or blockade of _______________________
normal physiological pathways
Idiosyncratic reactions are adverse drug reactions that occur ____________
not at target site (peculiar to an individual, less common, less predictable)
ke is the _____________ and is used to determine __________
elimination rate constant (slope of ln Cp vs. time), half-life
factors influencing drug membrane passage (4)
- molecular size
- concentration
- lipid solubility
- degree of ionization
bioavailability equation (F)
F = AUC(oral)/AUC(IV)
Bioavailability with oral administration varies based on…
- survival of drug in GI (acidity, digestive enzymes)
- ability to cross membrane (small, uncharged, lipid soluble)
- efficiency of metabolism (first pass effect)
Rate of onset of drug effect is determined primarily by…
route (rather than individual drug characteristic)
The major equivalency test required for generic drugs is…
bioequivalency (therapeutic equivalency)
Generic drugs are bioequivalent to brand name if…
rate (Cmax, Tmax) and extent (AUC-bioavailability) of absorption are within set parameters
factors affecting drug absorption
- drug solubility
- rate of dissolution (concentration of drug at site, circulation, area of absorbing surface)
If you take a drug on an empty stomach, you’re protecting the _______
drug
Subcutaneous route provides a ____________ rate of absorption
slower, more constant
Injection volume of __________ route is more limited than ________ route
subcutaneous, intramuscular
Injection of (solution/suspension) provides rapid onset of action
solution
The sublingual route of drug administration is useful if the drug is __________________
lipid soluble and potent
One advantage of a transdermal patch is that it…
avoids first-pass metabolism
With local effects, the response (is/is not) proportional to plasma concentration
is not
slow speed of onset of drug effect (4)
- oral
- intramuscular
- subcutaneous
- transdermal
Depo-provera lasts…
3 months (IM)
NPH insulin lasts…
10-12 hours (SC)
Duragesic lasts…
72 hours (transdermal)
Depakote ER (seizures) lasts…
24 hours (oral)
Henderson-Hasselbach equation
10^pH-pKa = non-protonated/protonated
Henderson-Hasselbach allows prediction of… (2)
- % of total amount of drug that is ionized
- prediction of pH where absorption will be favored
Protein-binding _________ elimination rate, ___________ half-life, and ________ Vd
decreases, increases, decreases
protein-binding displacement may be problematic if…(4)
- displaced drug has narrow therapeutic index
- displaced drug is started in high dose
- Vd of displaced drug is small
- response to drug occurs more rapidly than redistribution
Vd represents the relationship between ___________ and ____________
dose of a drug, resulting Cp
Vd equation
Vd = dose (amt drug in body)/Cp (concentration drug in plasma)
drugs highly bound to plasma
warfarin, heparin
drugs highly water soluble (don’t enter cells, found in extracellular water)
gentamicin, ibuprofin
drugs that freely enter cells (total body water)
lithium, ethanol
drugs highly lipid-soluble sequestered at tissue sites
amitriptyline, fluoxetine
Vd varies between patients based on… (3)
- body composition (fat vs. lean)
- body size
- changes in protein binding
Loading Dose equation
LD = Cp (desired) x Vd
phase I reaction types
- oxidations
- hydrolysis
- reductions
phase II reaction types
conjugations
phase I enzymes
- CYP450
- esterases-amidases
- reductases
phase II enzymes
transferases
phase I and II genetic polymorphisms are (significant/insignificant)
significant
phase I induce-inhibit
significant
phase II induce-inhibit
possible-less
phase I and II development patterns
variable
phase I age changes
decrease in 1/3
phase II age changes
minimal
phase I saturability
minimal
phase II saturability
substantial
T/F: There is cytochrome P450 development in neonates
true
Drugs that are metabolized by the __________ system are usually highly lipid-soluble
CYP450
Drugs metabolized by the CYP450 system are usually metabolized in the ___________________
smooth ER
CYP3A4
major; gastric mucosa but not large intestine
CYP2E1
turns acetaminophen into a metabolite that destroys liver
CYP2D6
metabolite of opioids, antipsychotics; genetic polymorphisms
CYP2C9
warfarin
The amplichip test detects polymorphisms in __________ and ___________
CYP2D6, CYP2C19
Caucasians tend to be _________ poor-metabolizers which Asians tend to be ___________ poor-metabolizers
CYP2D6, CYP2C19
Some examples of CYP450-dependent phase I oxidations are…
- aromatic hydroxylations
- aliphatic hydroxylations
- oxidative dealkylation
Some examples of CYP450-independent phase I oxidations are…
- monoamine oxidase
- dehydrogenases (alcohol, aldehyde)
Phase I reductions
- azo
- nitro (can produce toxic intermediates)
- carbonyl
Valacyclovir undergoes phase ___ __________
phase I hydrolysis
The products of phase II conjugations are often…
highly water-soluble, readily excreted
Hydrolysis by bacterial B-glucuronidase can lead to ____________
enterohepatic recirculation
Characteristics of N-acetylation (Phase II conjugation)
- some products are less water-soluble
- marked genetic variation
Alcohol dehydrogenation is a ______________
non-P450 oxidation
The mechanism of induction of drug metabolism is mainly due to _________________
increased synthesis of enzyme production (and some decreased turnover)
Which phase enzymes are more prone to inhibition?
phase I
Drug interactions effects are most obvious when…
drugs are given orally (via first-pass effect)
Rifampin interacts with _____________ because it ___________ clearance, thus altering ____
oral contraceptives, increases, Cp (decreased, unplanned pregnancy)
Erythromycin interacts with _________ because it ___________ clearance, thus altering ____
lipitor, decreases, Cp (increased, myopathy)
Saturation is less likely to occur with ____________ than ___________
renal excretory process, metabolism
P-glycoprotein transporters in the GI tract _________________
decrease oral absorption
P-glycoprotein transporters in the liver-kidney _________________
enhance biliary and renal excretion
P-glycoprotein transporters in the blood-brain barrier _________________
limit distribution of drugs
Adult levels of glucuronyl transferases are reached by age ____
3-4
What is the best documented and clinically most important mechanism of drug-drug interaction?
inhibition or induction of metabolism of the drug
Rate of elimination of first order kinetics is proportional to ______________
plasma concentration (constant %/time eliminated)
With half-life, a constant __________ is eliminated per unit time and is ___________ of the total amount of drug present
fraction, independent
*half-life is the same regardless of Cp
equation for clearance
CL = Vd x ke CL = (maintenance dose/tau)/Cp(ss)
Clearance
- volume of plasma that is completely cleared in a given period of time
- proportionality constant that makes Cp(ss) equal to rate of administration
The half-life of a drug depends on ______________
CL (inversely proportional) and Vd (directly proportional)
(Free drug/protein-bound drug) can be metabolized
free drug
The time it takes to reach steady state is independent of ___________
drug dosage
The time it takes to reach steady state depends entirely on ___________
half-life
Loading dose equation
LD = Cp x Vd
tau
time between doses
Steady state level depends on __________
MD/tau
fold-fluctuations
2^n (n=tau/half-life)
More _________ in a dosing interval means greater fluctuation
half-lives, not hours
The amount of fluctuation in Cp that can be tolerated by a drug is determined by its _________________
therapeutic index
Saturation is more likely to occur with __________ than _________ processes
hepatic metabolic, renal excretory
When giving a single dose, what equation do you use to determine plasma concentration?
Cp = dose/Vd
Steady-state is proportional to …
dose/dosage interval
Fluctuations are proportional to …
dosage interval/(t(1/2))
Types of protein receptors (4)
- hormone and neurotransmitter
- receptor, voltage-gated ion channel
- enzymes
- transport proteins
What 3 factors determine binding affinity to a receptor?
size, shape, electrical charge
What effect does a pharmacologic antagonist have in the absence of agonist?
none
Potency depends on … (2)
- affinity (Kd) of receptors for binding drug
- efficiency of drug-receptor complex to generate response
The power of a drug to bring about a response is related to …
Emax
Physiological antagonists act on ______________
a different receptor than agonist
What happens to EC50, Emax, and potency with competitive, reversible inhibitors?
- EC50 increases
- Emax unchanged (surmountable)
- potency decreases
What happens to EC50, Emax, and potency with noncompetitive inhibitors?
- EC50 unchanged
- Emax reduced
- potency unchanged
Quantal dose-response curves can provide information on dose __________ but not dose ___________
potency, efficacy
Idiosyncratic drug reactions
genetically-determined abnormal response to drug (unpredictable)
Pharmacokinetic drug interactions can result in…
- elevated drug concentrations (toxicity)
- decreased plasma concentrations (sub therapeutic)
Pharmacodynamic drug interactions can result in…
- pharmacologic enhancement or antagonism via same drug target
- physiologic enhancement or antagonism via different effector system
What is an indirect pharmacodynamic effect?
pharmacologic effect of one drug indirectly affects second
Half-life may be (prolonged/shortened) with toxicity
prolonged
When poisoned, how do you decrease absorption?
- gastric lavage
- emesis
- activated charcoal
- whole-bowl irrigation
- cathartics
When poisoned, how do you enhance elimination?
- inhibit toxication or enhance detoxication (give antidote)
- hemodialysis
- manipulate urine pH
(Ipecac/activated charcoal) must be given before (ipecac/activated charcoal)
ipecac, activated charcoal
What is the most rapid and complete method of emptying the stomach?
gastric lavage
How does activated charcoal work to treat toxicity?
binds drug in gut to limit absorption (ion-trapping in stomach)
When should magnesium citrate or sulfate be avoided?
- renal disease
- poisoning with nephrotoxic agents
When should sodium sulfate be avoided?
-CHF
-hypertension
(systemic Na+ absorption leads to edema)
methanol toxication
methanol, alcohol dehydrogenase, formic acid, retinal damage
-inhibit alcohol dehydrogenase with ethanol (substrate and competitive inhibitor)
ethylene glycol toxication
ethylene glycol, alcohol dehydrogenase, oxalic acid, acute renal failure
-inhibit alcohol dehydrogenase with fomepizole (specific inhibitor)
How does hemodialysis inhibit toxication?
removes parent compounds/metabolites
-best for toxins with small Vd and low protein-binding capacity
Acetaminophen is normally eliminated by (Phase I/Phase II) mechanism
phase II (gets saturated with toxic dose)
What is the treatment for acetaminophen toxication?
gastric lavage, supportive therapy, N-acetylcysteine (replenishes GSH)
Treatment for methanol and ethylene glycol toxication act by…
inhibiting toxication
Treatment for acetaminophen toxicity acts by…
enhancing detoxication
Hemodialysis, hemoperfusion , chelation of heavy metals, and forced diuresis act by…
enhancing elimination
What enzyme is responsible for producing the hepatotoxic metabolite of acetaminophen?
CYP2E1
Pre-clinical testing
5-8 years
- acute-chronic toxicity in rodent and non-rodent species
- determine safe dosage range for humans
Phase I drug trial
2-10 years
- Is it safe? toxicity
- pharmacokinetics: absorption, half-life, elimination-metabolism
Phase II drug trial
2 years
- Does it work in patients?
- safety and efficacy, final dosing and regimens
Phase III drug trials
3 years
- Does it work double blind?
- efficacy measured against established therapy
Phase IV
-post-marketing surveillance (include omitted study groups, document low-incidence drug effects
Patents expire ____ years after application
20
What is the difference between pharmaceutical equivalence, bioequivalence, and therapeutic equivalence>?
- pharmaceutical equivalence: drug formulation (ingredients, dose, route of administration, strength)
- bioequivalence: drug molecules
- therapeutic equivalence: therapeutic effect
Bioequivalence
rate (Cp max, Tmax) and extent (bioavailability) that active ingredient is absorbed and becomes available
What is considered a supplement? (4)
vitamins, minerals, amino acids*, herbal medicine
*molecular entity and safe dosage range known
Which drug studies involve testing safety?
Phase I, II, and III
Which are required for determining generic drug equivalence with brand names?
therapeutic equivalence, pharmaceutical equivalence, bioequivalence
Pharmaceutical equivalence, bioequivalence
Criteria for classifying drugs with abuse potential
medical use, physical/physiological dependence, abuse potential
When are drugs required to go through cells as opposed to between? (3)
absorption into small intestine, blood-brain barrier, kidneys
Rate of absorption of a drug is estimated as ________
peak Cp (Cmax) or time to attain peak Cp (Tmax)
_____________ route of administration can only be used with potent drugs
Transdermal
Cp vs. time graphs determine ___________
pharmacokinetics
What type of phase II conjugation does morphine undergo?
glucuronidation
What type of phase II conjugation does acetaminophen undergo?
sulfate conjugation
____________ is the only factor that will keep a drug from being filtered at the glomerulus
protein binding
