Exam One

what controls concentration in the body

body size, kidney function, liver function, and disease

what is a dose

what you write on the order → the only thing you can directly control

what is pharmacokinetics

absorption, distribution, metabolism, elimination → set by the patient

what is concentration

drug at the site of action over time → what we measure

what is pharmacodynamics

receptor binding and downstream signaling

what is the effect

cure or toxicity → what the patient actually experiences

what do you control

the dose

what does the patient control

pharmacokinetics

what does pharmacokinetics link

dose and concentration

what does pharmacodynamics link

concentration and effect

what is pharmacokinetics

what the BODY does to the DRUG

dose in → concentration over time

what is pharmacokinetics governed by

absorption, distribution, metabolism, elimination

what are the key parameters of pk

CL, V, t_1/2, F

what is the answer to pk in

mg/ L

what is pharmacodynamics

what the DRUG does to the BODY

concentration → effect, good, or bad

what is PD governed by

receptor binding and downstream response

what are the key parameters of PD

E_max, EC₅₀, MIC

what is the answer of PD

a clinical outcome

what is the therapeutic window

the concentration range where the drug usually works and usually does not harm

what is it called when a dose is below the therapeutic window

subtherapeutic → treatment failure, resistance, relapse

what is it called when a dose is inside the therapeutic window

the target you are dosing for

what is it called when a dose is above the therapeutic window

toxicity → nephrotoxicity, seizures, bleeding, arrhythmia

what do narrow window drugs need

monitoring

wide window drugs..

tolerate imprecise dosing

what is systemic circulation

the blood → only drug that reaches it can act at a distant site

what is disposition

distribution plus elimination → everything after the drug enters the blood

what is elimination

metabolism plus excretion → irreversible loss of the parent drug

what is bioavailability

F; the fraction of the dose that reaches the systemic circulation intact

what is the steady state

rate of drug in equals rate of drug out → concentration stops climbing

what is clearance

volume of plasma cleared of drug, not an amount removed

what are the units for clearance

L/h or mL/min → volume per time

what are the units of volume of distribution

L or L/kg

what are the units for the rate constant

h^-1

what are the units of half life

hours

what units are concentration in

mg/L or mcg/mL (both are the same number)

what units are AUC in

(mg x hr)/ L

what is AUC

concentration multiplied by time, so its units always carry an hour

what are the exponential decay equations

C(t) = C₀ x e^{(-k x t)}

ln C(t) = ln C₀ - k x t

what is a first order equation

when it follows the half life pattern

what happens after 5 half lives

3% remains, which we conventionally call gone

what does first order elimmination mean

a constant fraction is removed per unit of time

what is 0.693

the exponent that doubles → the ln of 2

how do you find the half life

t ½ = 0.693/ k

what log rules do you need to know

ln(a x b) = ln a + ln b

ln(a/b) = ln a = ln b

what would the a plot of time vs ln C look like

a negative slope where each value goes down 0.693

what can the axis of the graphs tell you

the vertical axis is plasma concentration

the horizontal axis is the time after the dose

what does the height of the curve at time zero tell you

concentration zero → it gives you volume of distribution

what does how steeply the curve fall tell you

it gives you k, which can then give you half-life

what does area under curve give

AUC → clearance

linear scale graphs…

• y axis spaced evenly

• first order decay looks like a curve

• hard to read slope by eye

• good for showing the shape of absorption

semi-log scale…

• y-axis spaced by powers

• first order decay becomes a straight line

• slope of that line equals -k

• this is why PK graphs are almost always semi-log

what is absorption

the drug crosses the gut wall and survives the liver to reach the blood

what is distribution

the drug leaves the blood and moves into tissues → reversibly

what is metabolism

enzymes, mostly hepatic, chemically change the drug into a metabolite

what is excretion

the kidney (or bile) removes the drug or metabolite from the body

what is elimination

metabolism plus excretion

what does absorption determine

bioavailability

what does distribution determine

volume

what determines clearance

metabolism and excretion

what part of ADME is reversible

distribution

what part of ADME is irreversible

metabolism and excretion

what does passive diffusion favor

small, lipophilic, un-ionized molecules

what is the ph partitionhypothesis

weak acids are more un-ionized in acid, and weak bases are more un-ionized in base

where does most absorption happen

in the small intestine

what does p-glycoprotein do

actively pumps drug back into the gut lumen which limits absorption and speeds up elimination

where are p-glycoproteins located

in the enterocyte → why it is a gut wall effect not a gut lumen effect

what do p-gp inhibitors do

raise exposure

examples of p-gp inhibitors

clarithromycin, verapamil, amiodarone, quinidine

what do p-gp inducers do

lowers exposure

what are examples of p-gp inducers

rifampin, st john’s wort

explain first pass metabolism

oral drug goes gut wall → portal vein → liver → systemic circulation

where can drug be lost

gut lumen, gut wall, and the liver

high first pass drugs…

have low oral bioavailability

what dosages bypass first pass effect

IV and transdermal routes, and sublingual largely bypasses first pass

what is Fa

first pass in gut lumen → incomplete dissolution or degradation. determines how much can be absorbed

what is Fg

first pass in the Fg → CYP3A4 metabolism plus p-gp pumping drug back into the lumen → reduces what reaches portal blood

what is Fh

first pass through the liver → portal blood passes through the liver before reaching the body → Fh = 1 - E

what is left in systemic circulation

what survives Fa, Fg, and Fh. this fraction is F

explain F = Fa x Fg x Fh

each term is the fraction that survives its barrier so they multiply

Fh = 1 - E_h

the fraction surviving the liver equals one minus the hepatic extraction ratio

what does gut lumen degredation happen

inside the intestine in the tube itself

what is drug lost to in the gut luman

failure to dissolve, acid degradation, chelation by antacids or daily, or simply never being absorbed

what does Fa answer

how much of the tablet can be absorbed

where does degradation in the gut wall

in the intestinal lining itself → specifically the enterocytes

what is drug lost to in the gut wall

CYP3A4 metabolizing it inside the enterocyte, and p-glycoprotein pumping it back out into the lumen

what does Fg answer

of what was absorbed, how much reaches portal blood

what does perfusion limited mean

blood flow controls how fast the drug reaches the tissue

what kind of drugs are perfusion limited

lipophilic/ unionized drugs that cross membranes easily

what is permeability-limited mean

crossing the tissue membrane in the slow stop

what is permeability limited common for

large or polar drugs

what organs receive blood quickly

high blood flow organs like heart, liver, and kidneys

what organs receive drug slower

lower-blood flow tissues like fat, skin, and resting muscle receive drug more slowly

what creates two phases of perfusion

some drugs move quickly into well-perfused tissues first, then more slowly into other tissues

what binds to receptors and leaves the bloodstream

unbound drug

what fu

fraction of drug in plasma that is unbound

what do acidic drugs mainly bind to

albumin

what do basic drugs mainly bind to

alpha-1-acid glycoprotein

what are examples of acidic drugs

phenytoin, warfarin, valproate

what are examples of basic drugs

lidocanie, quinidine

what do most drug levels measure

total drug = bound + unbound drug