ceutics drug disposition

which things are absorbed in the stomach

weak acids and alcohol

which type of drugs are likely to have an instantaneous effect

lipophilic drugs

(ex: anasthesia)

describe the pathway an oral drug travels from ingestion to excretion

ingested

-> stomach (weak acids and alcohol absorbed)

-> intestines

-> liver portal circulation (metabolism)

-> some escapes to target, rest is excreted

in general, what determines the magnitude of the effect of a drug?

concentration of drug at the site of action aka dose (1st order kinetics= higher concentration then higher effect)

t/f: a higher dose is linked to greater magnitude of effect and faster onset

false. usually greater magnitude but does not mean faster onset. onset depends on how fast absorbed, not how much there is

pharmacokinetics vs pharmacodynamics

Pharmacokinetics: What the BODY does on the drugm (ADME)

Pharmacodynamics: What the DRUG does on the body (effect of drug on target cells)

ADME is the study of pharmaco________

kinetics

the effect of a drug on target cells is known as pharmaco_________

dynamics

xenobiotic

foreign substance taken into the body (not endogenous)

- note: some endogenous compounds may also act as xenobiotics (ex: T3 and T4/ thyroxine)

t/f: while xenobiotics are not endogenous compounds, some endogenous compounds may act as xenobiotics

true. ex: thyroxine

how are doses established

trial and error in phase 2

- dose, intervals, and route randomly selected and pt is evaluated

t/f: the magnitude of response of a drug is proportional to the concentration of the drug at the site of administration

false. site of action

2 types of concentration gradients measured in PK

site of ________

site of _______

1. site of administration= absorption. drug is in blood or lymph

2. site of action= tissue cells/ post absorption, blood delivers to target and diffuses to target

t/f: if drug enters blood but complement blows it up or enzyme destroys it, we have high absorption at the site of action

false. high absorption at site of administration but low at site of action (post absorption issue)

what explains why many drugs have side effects

drugs must move from site of administration to site of action. drug will end up distributing to other tissues unintentionally leading to side effects

when drugs that have escaped metabolism are bound to plasma protein, they are related to

a. onset

b. duration

c. intensity

b. duration

why do we not consider metabolized drugs bound to albumin in the ct curve

bc they have no effect. they are inactive and waiting for elimination. but know that they do bind to albumin and take up space

what can happen to a free drug (unbound to albumin) in the plasma (4)

1. exerts effect at site of action (ex: receptor)

2. become sequestered in other tissues (trapped w no effect. ex: fat)

3. become metabolized (liver, lung, GI)

4. may be eliminated directly (kidney, air, sweat, feces)

in which 4 ways can drugs be eliminated

1. feces (via GI)

2. urine (via kidney)

3. expired air (via lungs)

4. secretions (via sweat/sebum)

magnitude of therapeutic response is proportional to concentration of drug at _____________

site of action

concentration vs time curve

y axis:

x axis:

up/down shifts:

left/right shifts:

y axis: blood concentration

x axis: time

up/down shifts: intensity of response

left/ right: time/half life

what methods are used to collect data for a concentration time curve

blood, spinal fluid, synovial fluid, biopsy, urine, feces, expired air

blood vs plasma vs serum

blood: has RBC, WBC, platelets, proteins

serum: plasma + clotting factors

plasma: no clotting factors

t/f: when blood is collected, drug molecules are in the water portion of blood

true. not talking about drugs bound to RBCs or anything like that. refer to drugs in the plasma

t/f: it is impossible to determine the total amount of drug present in the body or at the target site by direct methods

true. even if we take blood sample, we do not know total body concentration of drug. some of drug is in blood, at target, sequestered, not absorbed, etc

in concentration vs time curve,

what does positive slope mean?

negative slope?

positive slope means as time increases, concentration increases= absorption exceeds elimination

negative slope means as time increases, concentration decreases= elimination exceeds absorption

in concentration vs time curve,

what does a peak/horizontal line mean?

elimination and absorption are equal

explain why a change in plasma concentration reflects a change in tissue concentration

bc drug in plasma is in equilibrium w drug in tissue (as plasma concentration changes, drug will redistribute)

- less in blood means less will get into tissue

MEC

Minimum effective concentration - the plasma drug level below which therapeutic effects will not occur.

MTC

Minimum toxic concentration; the lowest concentration at which a toxic effect is achieved.

how can you establish the duration of action of a drug looking at a concentration vs time graph

the duration of time the drug remains above MEC

how can you establish the onset of action of a drug looking at a concentration vs time graph

how long it takes drug to reach the MEC level

t/f: the MEC may not be the therapeutic response we want to achieve

true. MEC is just the beginning of therapeutic response. the peak from MEC is the intensity and determines max effect (proportional to plasma concentration)

intensity of a drugs response is proportional to ____________

plasma concentration

t/f: the duration of action is the time from onset to full elimination

false. its the time spent in MEC. once its below MEC it is not considered in duration

AUC

area under the curve; represents the amount of drug absorbed systemically

given a ct curve, what represents the amount of a drug that is absorbed in the body

AUC

an IM injection would shift the CT curve _______ (compared to oral)

left

(less time needed for same amount of absorption== going straight into blood)

(not up/down bc same amount is still absorbed)

peak time and peak absorption in a ct curve

peak time (Tmax): time it takes to reach max concentration

- marker of rate of drug absorption

peak absorption (Cmax): the max concentration

a ct curve starts high and has a negative slope until it gradually becomes horizontal. this is indicative of

a. IM

b. IV bolus

c. IV constant infusion

d. oral

b. IV bolus

bc its going straight to blood. it does not need to be absorbed

IV bolus vs constant infusion concentration time curve

IV bolus: will start off high and gradually lower

constant IV: will start at 0, increase, then plateau to maintain constant concentration level

what would shift a curve downwards?

a. greater absorption

b. greater elimination

c. more drug administered

d. drug given orally instead of IM

b. greater elimination

a downward shift == lower drug levels in plasma. greater elimination (via metabolism or excretion) would reduce the drug concentration, shifting the curve downward

since the response to a drug is related to the concentration of drug at target site, it is also related to ___________

plasma concentration (bc of equilibirum)

2 types of plasma concentration vs effect curves

graded= increment in physiologic or biochemical response as dose or concentration is increased

quantal= percent of the population under study that has a response as the dose is increased

which type of response is this:

response to drug is proportional to concentration and is usually reversible

a. graded response

b. quantal response

a. graded

a reduction in blood pressure with antihypertensives would be an example of

a. graded response

b. quantal response

a. graded response

t/f: a graded response is usually reversible if the concentration of the drug is lowered

true

which type of response is this:

response to drug is only elicited when drug concentration is higher than a certain critical concentration

a. graded response

b. quantal response

quantal

which response is known as an all or none response

a. graded response

b. quantal response

b. quantal

t/f: a drug exhibiting a quantal response may be irreversible

true

examples of quantal responses

death, hypotensive toxicity of antihypertensive agents

a graph displaying plasma concentration vs percent of population with effect is

a. graded response

b. quantal response

b. quantal

(there either is or isnt an effect. a graded response has magnitude of effect)

t/f: in the concentration effect curve, the plateau that we see in terms of effect is the therapeutic effect we are looking for

false. may or may not be therapeutic effect. may have too much toxicity, especially as concentration increases and plateau remains

(minor/major toxicity is actually what drags the effectiveness line down)

t/f: whether you give 1x, 10x, or 100x of a drug dose, then concentration time curve shape will be identical if its same route of administration

true. shape of curve and half life is identical.

BUT maximum concentration will be different (y asymp increases)

t/f: whether you give 1x, 10x, or 100x of a drug dose, then concentration effect curve shape will be identical if its same route of administration

false. effect is higher with higher concentration

[but compare to concentration time curve, where the curve IS the same shape, just different y asymp]

what is the negative slope of a concentration time curve also known as

half life (or elimination rate)

t/f: when compared to 1x of a drug, a 100x drug concentration will have a longer half life

false. half life is the same bc first order kinetics depends on % of concentration, not a certain amount

the rate of drug eliminated from the kidney is

a. lower at 1000x

b. higher at 1000x

c. same at 1000x

c. same

(rate of drug eliminated is the same but the AMOUNT of drug molecules is higher)

ratio of the dose needed to produce a TOXIC effect and the dose needed to elicit DESIRED therapeutic response is known as the _______________

therapeutic index (TI)

t/f: a large TI indicates higher safety

true. large TI (therapeutic index) means large margin between therapeutic and toxic line

t/f: when applying the vertical line test to a quantal graded response curve, if the line does NOT bisect BOTH the desired therapeutic effect and the adverse effects, then there is a larger therapeutic index compared to if they do bisect

true. if they do bisect then therapeutic effect and adverse effects are overlapping= narrow TI

when may response-time curves be more useful than concentration-time curves

when concentrations dont correlate with response

ex: topical creams. we dont know the concentration of a topical on the skin, so response-time curves may be more beneficial

also: anticancer drugs, anticoagulants, digoxin

cases where plasma concentration does NOT correlate with response (overall summary)

- active metabolites (prodrug)

- chirality-structural activity responses

- tolerance and acquired resistance

- single dose therapy (once it returns to homeostasis, concentration doesnt matter)

- duration vs intensity of therapy

- time delays

drug x is more active when given orally than when given IV. what can this indicate?

drug x is a prodrug w active metabolites. therefore the first pass effect is needed for the drug to be active. IV bypasses this

t/f: if a drug has an active metabolite, it is likely that plasma concentration does not correlate with response

true. if the metabolite is active then we need to measure the concentration of the metabolite as well (not just og drug) to determine response

(ex: amitriptyline and its desmethyl metabolite)

t/f: the R and S enantiomers of a drug do not usually differ in PK and PD

false. enantiomers usually differ. this is why plasma concentration of the total drug may not correlate w response [need to distinguish how much of isomer is in plasma]

explain why plasma concentration of drugs w enantiomers (chirality SAR) does not correlate with response

plasma concentration will show both the R and S form but maybe only 1 is giving effect. so concentration of total drug does not correlate to effect. more specific assays must be done

what does it mean by "less negative elimination slope"

eliminated more slowly/ will be in body longer

__________ is the diminished response to same dosage of a drug, either developed slowly or acutely

tolerance

tolerance vs acquired resistance

tolerance: diminished response to same dosage of a drug, either developed slowly or acutely

- never complete tolerance

acquired resistance: diminished sensitivity of cells (bacteria/ cancer) to a drug

- could have total resistance

t/f: while the degree of tolerance varies but is never complete, acquired resistance may be totally resistant

true. bc bacteria and cancer cells can adapt to be completely resistant (more independant compared to pure physiology)

mechanisms of tolerance

1. decreased concentration of drug at target (we cant rlly measure this)

2. increased clearance rate (greater GFR, metabolism, induction)

3. pharmacokinetic adaptations (maybe not absorbed bc of food or interactions)

4. downregulation of receptors

downregulation

Decrease in receptor number in response to high concentration of drug

- may lead to tolerance to drug

t/f: plasma concentration does not correlate with response in single dose therapy

true. single dose therapy is used to return body to homeostasis. correlation may exist between effect and peak plasma concentration but no correlation beyond peak

if the target for a drug is H. pylori in the stomach, which choice would lead to higher success

a. slow absorption

b. fast absorption

a. slow absorption

we want the drug to stay in the stomach rather than getting absorbed. if its absorbed, then its in blood/lymph and wont be working on the target (h. pylori)

explain why methotrexate is a case where plasma concentration does not correlate with response

what is its response related to?

what does methotrexate do?

response relates more closely to the DURATION of dosing rather than the dose/concentration

methotrexate is an antimetabolite that inhibits the enzyme dihydrofolate reductase. inhibiting for short time is ok but long time= irreversible damage in all dividing cells

why may there be a time delay even if the drug is fully absorbed

must reach equilibrium at the site of action as well. not just site of absorption

(ex: max cardiac action of digoxin isnt seen until an hour after IV bolus)

IV bolus vs constant infusion

IV Bolus: A large dose is given all at once, leading to a rapid peak in drug concentration, which then declines over time

Constant Infusion: A drug is administered at a steady rate, maintaining a stable plasma concentration over time. Useful for drugs with a narrow therapeutic window or when continuous effect is needed.

why does warfarin take a couple of days to have its full effect

warfarin is a vitK antagonist that works by reducing the number of coag factors that the liver makes. warfarin wont work immediately bc we still have coag proteins initially. we need time for those proteins to decrease

t/f: sometimes a fluctuating concentration of antibiotics is more desirable than steady concentrations

true

(depends on bacteria. also dont want to disrupt fluora too much)

ex: ceftazidime doesnt have concentration-dependant killing

ex: gentamicin DOES depend on concentration. larger infrequent doses are more effective than small

if ceftazidime doesnt have concentration-dependant killing, how will the dose-response curve look? what type of kinetics is this?

horizontal line. ZERO ORDER KINETICS. response is constant regardless of concentration

(higher concentration will NOT correlate to amount of bacteria killed)

zero vs first order kinetics

zero order - constant amount of drug is removed per unit of time [if you have 50 or 100 drugs, it's still removing only 10 per hour]

first order - MAJORITY. constant % of drug is removed per unit of time. [ if 20% is removed every hour, then having more drug means more gets cleared per hour]

most kinetic processes in the body follow _____ order kinetics

first

first order kinetics equation

before integration and after? linear form?

rate of process = dc/dt= -K[C]

(change in concentration)/ (change in time)= -(rate constant)(concentration of drug at that time)

C= C0 e^(-Kt)

linear:

log C= log C0 - Kt/2.303

linear first order kinetics equation. what is the slope? y-int?

log C= log C0 - Kt/2.303

slope: -K/ 2.303

intercept: C0 aka initial concentration

in a linear first order kinetics graph, what does the y intercept represent

initial concentration of drug at time zero

how does the elimination rate change in first-order vs. zero-order kinetics as drug concentration increases?

first: higher elimination rate bc depends on initial concentration

zero: constant elimination rate bc does not depend on initial concentration

how does half-life change in first-order vs. zero-order kinetics?

first: half-life is constant (bc a constant fraction is eliminated per unit time)

zero: half-life is not constant and increases as drug concentration increases bc elimination pathways are saturated

t/f: a semi log plot makes a zero order kinetics equation appear as a straight line

false. first order

what does the concentration vs. time graph look like for first-order vs. zero-order elimination?

first: exponential decline (curved downward) but can be linearized via logs

zero: straight-line decline (constant slope)

which type of kinetics (first or zero order) is more likely to result in drug toxicity? why?

zero bc elimination rate is fixed (does not depend on concentration so excess drug keeps accumulating)

what does the slope of a semi log plot of concentration vs time represent

rate of elimination (negative slope)