Basic Pharmacology Flashcards
Enzymes Enzyme Inhibitors Dose-Response Drug Elimination Pharmacokinetics
why is it difficult to determine Vd in a patient?
because the drug is being steadily eliminated over time
How is the volume of distribution used clinically?
to determine dosage
How will Vd change for a drug that is restricted to the vascular compartment?
it will decrease
what are the characteristics of drugs that are restricted to the vascular compartment? (why is Vd lower?)
large, charged molecules often protein bound Warfarin Vd = 9.8L
what is the equation for half life?
t1/2 = [(0.7)(Vd)]/Cl
What percent is remaining after 1 half life? 2? 3? … 6?
0 = 100%
1 = 50%
2 = 25%
3 = 12.5 %
4 = 6.25%
5 = 3.12%
6 = 1.56%
In general, how many half lives are needed for the drug to be removed from the body? (Steady state)
4
What is steady state?
dose administered = amount of drug eliminated
takes 4 or 5 half lives when giving a repeated dose to a patient over time
Define maintenance dose
just enough drug to replace what was eliminated
when do you give a patient the loading dose of a drug?
given when time to steady state is high
when t1/2 is very high
in kidney/liver disease why may the maintenance dose fall?
less eliminated per unit time so less needs to be replaced with each dose
*note loading dose stays the same****
what is the equation for maintenance dose?
dose rate = elimination rate = [Drug]*Cl
If bioavailability is <100% how does the maintenance dose change?
dose has to be increased to account for this dose
rate = target dose/F
what is the equation for loading dose?
loading dose = ([Drug]*Vd)/F
What is pharmacokinetics?
how a drug moves through the body
what are the different ways a drug can be administered?
enteral = uses GI tract -
oral/sublingual/rectal parenteral = does NOT use GI tract -
IV/IM/SQ inhalation intranasal intrathecal = directly into spinal canal
topical
What is bioavailability?
(F) percent of drug that reaches the systemic circulation unchanged from its original form
What is 1st pass metabolism?
drug can be rapidly metabolized by the liver on the 1st pass to the systemic circulation
In what disease is the amount of drug removed from 1st pass metabolism decreased?
liver disease
What is the equation for bioavailability?
(AUC oral/AUC IV)(100) (see graph)
*note - AUC = area under the curve
what is the bioavailability of a drug administered through IV?
100%
what is the volume of distribution? (Vd)
theoretical volume a drug occupies
how is Vd determined experimentally?
inject a known dose and then measure the concentration of the drug that ends up in the bloodstream
what is the equation for Vd?
total Amt in body/[plasma] = Amt injected/C0
How will Vd change for a drug that accumulates in the tissues?
Vd will increase
What are the characteristics of drugs that will accumulate in tissues? (why is Vd increased?)
small, lipophilic molecules
uneven distribution in the body
Chloroquine Vd = 13000L
What is the main plasma protein that drugs bind to to hold them in the vascular space?
Albumin
What effect does protein binding have on Vd?
Decrease
Liver disease and nephrotic syndrome cause an underproduction of what plasma protein?
albumin = hypoalbuminemia
What happens in a patient with hypoalbuminemia?
less plasma protein binding more unbound drug = moves to peripheral compartments
Vd increases
Required dose of the drug may change
What is clearance?
volume of blood “cleared” of a drug
volume of blood that contained amount of drug
number in L/min (volume flow)
What is the equation for clearance?
Cx = excretion rate/Px
What are the body fluid compartments?
TBW = total body water = 60% of body weight
1/3 = 12L = extracellular = 3L plasma & 9L interstitial
2/3 = 24L = intracellular
What are the 2 main organs used for drug clearance?
Liver and kidneys
how does clearance via the liver differ from the kidney?
in the liver a biotransformation of the drug into metabolites then excreted into the bile
in the kidneys the drug is excreted in the urine
How do you calculate clearance from Vd?
elimination donstant Ke (K sub e)
Cx = (Vd)(Ke) or Ke = Cx/Vd
How do you use AUC to get clearance?
Cl = dose(g)/AUC(g*min/L)
What is half-life?
time required to change amount of drug in the body by 1/2
what 2 variables does 1/2 life depend on?
Vd & clearance
what is efficacy?
maximal effect a drug can produce
i.e. morphine is more efficacious than Aspirin for pain control
what is potency?
amount of a drug needed for a given effect
what is a dose-response curve?
response to a drug is measured with increasing doses to plot dose (x-axis) vs response (y-axis)
what are the 2 types of dose-response curves?
graded - can measure graded effect with different doses (ex: BP)
quantal - does the drug produce a therapeutic effect? (ex: # pts achieving SBP <140mmHg). yes/no response - can measure “quantal” effect by % of pts responding to dose
What is Emax?
max effect a drug can have
what is E50?
the 50% effect 1/2 of Emax
what is EC50?
effective concentration to get E50 dose at which E50 is achieved
what is the relationship between EC50 and potency?
inversely proportional
low E50 = high potency
what is the relationship between Emax and efficacy?
directly proportional
whichever drug has the higher Emax is more efficacious
how will a competitive antagonist change the dose-response curve?
shift to the right - E50 increases;
Emax unchanged
competes for the same binding site as the receptor agonist - need more drug to overcome antagonist
how will a non-competitive antagonist change the dose-response curve?
binds to a different binding site, changing the conformation and the receptor agonist will no longer work
**can not overcome effect w/ increase in dose
Emax & E50 decreased bc the non-competitive antagonist is permanently changing the shape of the R which is the same thing as removing them entirely
EC50 unchanged
what are “spare receptors”?
receptors that can activate when others get blocked by a non-competitive inhibitor, allowing to achieve a maximal response even though some of the receptors are permanently blocked
dose-response curve of an agonist in the presence of a low dose non-competitive antagonist will resemble that of a competitive inhibitor and can be overcome by increasing the concentration of the agonist
what is a partial agonist?
similar structure to agonist but produces less than full effect on dose-response curve
similar to that of agonist plus non-competitive antagonist
What happens to the % of R bound by an agonist with an increasing dose of a partial agonist?
increasing dose of partial agonist results in an inverse relationship between Receptors bound by agonist vs. partial agonist as more partial agonist is added it binds to the receptors and less of the agonist is bound and eventually 100% will be bound by the partial agonist
what is the relationship between agonist response, partial agonist response, and total response on the dose-response curve?
at first 100% of the R will be bound by the agonist, but as more partial agonist is added they will replace the agonist and the amount of clinical response from the agonist starts to fall and the response from the partial agonist begins to rise resulting in a decreased total response from what was seen when all the R were bound by the agonist
what happens when you raise the dose of a partial agonist?
eventually all of the R’s will be bound by the partial agonist and the response will be diminished
what drugs are partial agonists?
pindolol/acebutolol (old anti-HTN meds) buprenorphine clomiphene
How does pindolol/acebutolol act as a partial agonist?
intrinsic sympathomimetic activity (IMA) activate β-R’s but to a less degree than NE lowering BP
How does buprenorphine act as a partial agonist?
partial μ-opioid agonist treatment of opioid dependence
How does clomiphene act as a partial agonist?
partial agonist of estrogen R’s in the hypothalamus
blocks negative feedback - increase LH/FSH
treats infertility/PCOS
What should you worry about with pindolol/acebutolol?
can cause angina through vasoconstriction
What is the equation for therapeutic index?
LD50/ED50
the _____ the therapeutic index is, the more room you have to work with in terms of dose and vice versa
higher
If a drug has a low therapeutic index, what does it mean?
the smaller the TI the closer the ED50 and LD50 are making it easy to give toxic doses
what is the therapeutic window?
range between minimum effective dose and minimum toxic dose
What drugs have a low therapeutic index?
warfarin
digoxin
lithium
theophylline
measure levels to avoid toxicity to make sure patients are not on too high of a dose
what is zero order elimination?
constant rate of elimination per time
slope is a straight line
no dependence/variation with [drug]
no constant half life
zero order elimination _______ (does/does not) depend on [drug]
does not
in zero order elimination the half life ______ (is/is not) constant, and depends on _____.
is not
[drug]
half life is always changing depending on how much drug is in the plasma
3 classic examples of drugs w/ zero order elimination
ethanol
phenytoin
aspirin
what is the main difference between zero order and first order elimination?
rate varies w/ [drug]
half life (%change) is constant
most drugs are 1st order
what is the equation for elimination rate?
C * [drug]^1
rate of elimination varies w/ [drug]
