Pharmacokinetics

4 steps of drug passing through the body

1. absorption (drug in plasma)

2. distribution (drug distributed to tissues)

3. metabolism (drug metabolites in tissues)

4. elimination (drug and/or metabolites in urine, bile, or feces)

briefly explain distribution through elimination

drug is distributed system wide to different organs and tissues, then the drug starts being metabolized (this is how medication is broken down), this breakdown prepares the drug for elimination

bioavailability

the percentage of the drug that actually reaches the bloodstream (almost always different from how much was actually taken)

what % bioavailability does this drug have:

1. 500mg administered orally, 250 mg make it into circulation

2. 500mg administered intravenously, 500mg directly into circulation

50% bioavailability; 100% bioavailability

absorption depends of what 3 things

route of administration, drug factors, body factors

example of drug factor affecting aborption

bigger sized drugs often have a harder time getting absorbed

example of body factor affecting absorption

absorption varies based on body type

2 types of drug administration routes

1. enteral

2. parenteral

enteral

something to do through the GI tract (oral, sublingual, rectal)

parenteral administration

kind of just something else, something not through GI (ex: inhalation, injection, topical, transdermal, vaginal)

oral administration advantages and disadvantages

A: easy, safe, convenient

D: limited absorption, first pass liv

oral absorption examples

analgesics (pain relievers), sedative hypnotics

what is sublingual administration

administered under tongue to be absorbed

sublingual administration advantages and disadvantages

A: rapid onset, no first pass inactivation

D: must easily absorb into mucosa

sublingual administration examples

nitroglyerin

sublingual absorption under the tongue means that there is some absorption that is ……

not GI because we are absorbing into plasma from mucosal absorption under the tongue (still considered enteral, but more complex)

rectal administration advantages and disadvantages

A: alternative to oral, local effect
D: incomplete absorption since not traveling full GI, irritation

examples of rectal administration drugs

laxatives, antiemetics, suppositories

inhalation administration advantages and disadvantages

A: rapid onset, respiratory effects, high surface area affected

D: irritation, administration compliance

examples of inhalation administration

anesthetics, anti-asthmatics

injection administration advantages and disadvantages

A: 100% bioavailability, rapid, direct to bloodstream

D: infection, none or limited self administration

topical administration advantages and disadvantages

A: local effects, easy to administer

D: can be absorbed into blood stream even it that’s not the goal

examples of topical medications

antibio

transdermal patch administration advantages and disadvantages

A: steady and prolonged delivery

D: limited, drug must penetrate skin unchanged (hard for drug to get to deeper tissue or blood plasma to treat whole body

examples of transdermal patch medications

hormones, nicotine, opioid analgesics

routes of injection (listed)

intravenous (IV), intra-arterial, subcutaneous, intramuscular, intrathecal

IV

steady slow infusion of medication

intra-arterial injection

chemotherapy can be done this way

subcutaneous injection

this is how insulin is done, just under the skin into the fatty tissue, also good for local anesthesia

intramuscular injection

a bit more rapid absorption than oral, but can cause soreness

intrathecal injections

injections going directly into the subarachnoid space of the spinal cord

other routes of administration include __________ drug delivery, ____________ release prescriptions, and _________ drug delivery

implanted; controlled; targeted

examples of implanted drug delivery

PCA (patient controlled anesthesia) pumps and baclofen pumps

(these deliver medication directly into the body sometimes through the spinal cord at the push of a button or at regular intervals)

controlled release preparations

an active ingredient is released at a specific rate to keep medications regular at a certain point in time (ex: extended release adderal)

issue: if this prep that controls the release fails, then the patient gets way too much dose all at once

4 types of targeted delivery

monoclonal antibodies, viral transport, gene therapy, enzyme activation

monoclonal antibodies

specific WBC taken from a patient (like their tumor or something), recreate antibodies in lab, all the subsequent antibodies that we are producing in the lab will then trace back to that cell. this way we only target one specific WBC and not healthy cells

viral transport and gene therapy are hella similar, what are they

links drug to a modified virus that inserts the drug to a certain type of cell, modifies genetic regulation

enzyme activation

drug is activated by the enzyme that is only present in the target tissue or organ

factors related to drug absorption (just list them) - just the one’s about the drug itself not the body

lipid water solubility, molecular and particle size, ionization, physical form, chemical nature, dosage form, formulation, concentration

how does lipid water solubility impact drug absorption in the body

a lipid soluble drug is going to pass easily through those cell membranes which makes this extremely important in absorption

how does molecule/particle size impact drug absorption in the body

if a drug is small enough to pass through great, but if it’s too big then regardless of lipid solubility the drug cannot get in

how does ionization impact drug absorption in the body

if the drug has an electrostatic charge or impacts the electrostatic charge of the membrane that a drug/ion is trying to pass through, then the drugs will impact the ability of ion channels to open and close which will impact the excitability of the cell

how does chemical nature impact drug absorption in the body

most drugs are either weak acids or bases

• weak acids are more readily absorbed in GI tract where pH is low

• weak bases don’t flow as easily

how does concentration impact drug absorption in the body

we always flow from high to low concentration (down gradient) which means no energy needs to be expelled and we therefore absorb drugs better when if can flow into a cell down the gradient

drug absorption factors related to the body (list them)

surface area, vascularity, pH (substances tend to absorb easier when the pH matches the environment,,, ex: acid absorbs more easily in stomach, base easier in small intestine), presence of other substances, GI motility, functional integrity of absorptive surface, diseases

for each drug to reach its target it needs to cross ______________

a membrane

lipid solubility allows a drug to pass through cell membranes via __________

diffusion

membranes affect absorption and distribution from

• GI → bloodstream

• fluid around tissue → cell interior

• cell interior → fluid around tissue

• kidneys → blood stream

movement across the membrane can happen in 4 main ways, what are they?

• passive diffusion

• facilitated diffusion

• active transport

• endocytosis

endocytosis

for larger substances to be pulled into the cell (not common for pharmaceuticals tho)

passive diffusion

• water soluble: finds aqueous channel and just flows down gradient into cell through the channel

• lipid soluble: doesn’t need the channel, just flows down gradient through he membrane

facilitated diffusion

drug binds to drug transporter on membrane, transporter changes shape to let drug into the cell (still down gradient)

active transport

needs ATP to let drug into the cell because it’s against the gradient

usually these proteins have specificity so they only transport certain substances

membranes that affect distribution

cell membranes, capillary walls, blood brain barrier (BBB), placental barrier (not an actual barrier,,, the fetus is still exposed to everything mama consumes)

blood brain barrier (BBB)

fewer things can pass through the BBB, so any drug would have to be able to fit through (1) the tiny tiny spaces to enter the CNS and it would need to be lipid soluble

this, for example, is why penicillin cannot impact the CNS (usually)

factors affecting distribution

blood flow, capillary permeability, binding

how does blood flow impact distribution

it allows drugs to be more rapidly distributed in places that are highly perfused (like muscle)

how does capillary permeability impact drug distribution

inflammation increases capillary permeability

how does binding impact drug distribution

some drugs bind to circulating plasma proteins and if they bind then they cannot leave the blood stream. sometimes things also bind inside a cell

volume of distribution (V_d) = _________________

amount of drug administered (usually mg or mL) / concentration of drug in blood plasma

this is very similar to the concept of bioavailability

if drugs do not immediately go to their target tissue they may be stored, this storage can cause issues. where are some places they can be stored in the body and the effects this can have

fat, bone, muscle, organs

prolonged drug effects, prolonged adverse side effects, organ damage

example of drug accumulating in fat explained

well a drug may be very lipid soluble and so then if it is stored in fat and we eventually start losing fat weight through exercise, when we break that down we can start to see the effects of that drug even if we were on it YEARS ago

metabolites

drug after it is broken down (new altered version, usually inactive/not affecting person)

biotransformation

another word for metabolism

chemical changes in the drug following administration

enzymes do what

break the drug down into metabolites

(usually end in -ase)

metabolism typically takes place where

in the liver, but enzymes are present in the liver, lings, kidneys, GI tract, and skin

first pass metabolism

when a drug is administered orally, it goes to the liver, some of it gets broken down, then it is circulated to the rest of the body. this means we are getting an altered version of the drug since it’s gone through some metabolism in the liver)

lipid soluble drugs must be metabolized into _________________ in order to be excreted by the kidneys

water-soluble drugs

what is the picture describing

first-pass metabolism

3 main types of metabolism

first order kinetics, zero order kinetics, enzyme induction

first order kinetics

the rate of metabolism and elimination is proportional to the concentration of the drug

basically the more or less you take DOES affect the rate of metabolism

zero order kinetics

constant rate of metabolism regardless of concentration of a drug

certain drugs are gonna be metabolized at the same rate regardless of amount taken

ex: alcohol metabolizes at the same rate always, so when you take more you are just increasing the effects since your body can’t break it down any faster and you are just adding

enzyme induction

more exposure of drugs will induce the body to destroy that drug more rapidly, basically the more we have the more enzymes we get to break it down

leads to tolerance

tolerance

reduced therapeutic effect of a substance with the same dosage

fill in the blanks

zero order; first order

purpose of metabolism

make substances water soluble so we can excrete them from the kidney

what liver enzyme foes most of drug metabolism

cytochrome P450 system (CYP450)

(yes mostly in liver, but some in GI)

metabolism in the liver has “2 phases”, what makes up each phase

phase 1: oxidation, reduction, OR hydrolysis

phase 2: conjugation

oxidation

predominant method of metabolism

adding oxygen or removing H

reduction

removing O or adding H

hydrolysis

original compound is broken down into several parts, one of which is water

at the end of phase 1 a drug is usually not water soluble yet, so it moves into phase 2 to “finish that process”

phase 1 breaks things down into _____________

phase 2 reactions ______________

breaks things into metabolites; breaks it down even more

factors affecting metabolism

genetics, disease, drug interactions, age (ex: newborns don’t have fully developed livers), diet, sex (not actually a huge difference but body type does impact this quite a bit,,, like how much adipose tissue)

excretion from the kidneys has 2 major functions which are….

1. make drugs water solute and excrete them

2. get lipid soluble drugs reabsorbed (sent back to the liver in this case)

kidneys filter ____ liters of blood per minute

1

total body clearance = ________________

hepatic + renal + pulmonary + other clearances

half life

the time it takes for 50% of a drug to be eliminated

we are condiered “drug free” after __ half lives

6

2 half lives is how long it takes for ___% of the drug to be eliminated

75

4 half lives is how long it takes for __% of a drug to be eliminated

94

steady state concentration

when the amount of a drug administered equals the amount eliminated so that we can have a consistent amount of drug in system

how many half lives does it usually take to reach steady state concentration

5-6

the red refers to what

steady state concentration