Week 2 - Pharmacokinetics Flashcards
To produce its effect, a drug must reach…
appropriate concentrations at the site of action
2 Phases of Drug Activity Identified
- Pharmacokinetics
2. Pharmacodynamics
Pharmacokinetics
Process by which drugs are distributed within the body (drug moving in the body)
Kinesis = movement; They are absorbed, distributed, metabolized (leaving), and excreted (left)
What are the Stages of Pharmacokinetics
ADME!
Absorption
Distribution
Metabolism
Excretion
Absorption
Stage 1 of Pharmacokinetics
Drug into the blood or lymph
Ends once in the bloodstream
Distribution
Stage 2 of Pharmacokinetics
Drug goes from blood to cells and body compartments (ex: liver, bones, etc)
Metabolism
“Biotransformation”
Stage 3 of Pharmacokinetics
Alteration of Drug Structure
Direct line to the liver allows for metabolism
Excretion
Stage 4 of Pharmacokinetics
Elimination of Drug
Pharmacodynamics
process by which drugs influence cell physiology
dynamics - actions - what the drug actually does
Most drugs are absorbed how?
From the GI tract, but they can come from IV and topical sites - but in the end everything needs to end up in the bloodstream
What is the main organ for metabolism
Liver - others have capabilities but not like this
What can alter metabolism of drugs
liver damage from alcohol or hepatitis
What are the 2 major ways of excretion
Bile/Stool
Urine through the Kidneys (main one)
Drugs are stuck with __ failure
renal
When a drug permeates a cell, it must transverse…
the plasma membrane
What are 4 important considerations (chemically) for pharmacokinetics
Molecular Size and Shape (Small moves better across membranes)
Solubility - more soluble means easier to combine and move
Degree of Ionization - charged particles do not move across phospholipid bilayer easy
Concentration - things move from high to low
Permeation of cell membranes methods
Passive Process
Active Process
Facilitated Transport
Passive Process
most common form of permeation - passive diffusion and filtration
Active Process
Some drugs are actively moved with energy and a carrier making them harder or more intensive to move through the membrane
Facilitated Process
mix of passive and active
carrier mediated with no energy used and movement cannot occur against an electrochemical - required for movements that would be too slow as well like with glucose or insulin (endogenous)
What is the most common process of drug movement across membranes
passive diffusion (and filtration)
Diffusion
passive process
If the drug is water soluble, it will diffuse with the flow of water
Factors affecting Diffusion
Concentration Gradient
Lipid Solubility
Ionization
How does concentration gradient impact diffusion
things want to move from high to low until equilibrium is reached
How does lipid solubility impact diffusion
the more lipid soluble, the greater and more rapid absorption across the membrane the drug can do (distribution)
How does Ionization impact diffusion
If ionized the drug cannot cross the cell membrane as well, and this is related directly to lipid solubility
The opposite of lipid solubility
For Diffusion to occur, what factors would we like to see
Low concentration gradient on other side
high lipid solubility
low ionization
How are lipid solubility and ionization related
they are in verse of each other
the greater the ionization the less lipid soluble a drug is and vice versa
Most drugs are what kinds of acids and bases? Why?
Weak acids and bases because things too strong will cause damage
Weak Acid Drugs
tend to be un ionized in acid solution (stomach)
stay themselves in an acidic environment
Weak Base Drugs
tends to be un ionized in basic solution (intestine)
stay themselves in a basic environment
What happens to a weak acid in the intestines
it will charge/ionize and not move across membranes well - it may even just stay in the area
Filtration
simple diffusion but through channels or pores in the membrane rather than across the whole thing
Bulk flow of water will carry dissolved drugs through the channels and this allows for large molecule entrance
If molecules are too big or do not move / distribute well what may be needed?
a carrier and active transport against the concentration gradient
this can allow large and poorly lipid soluble molecules to move
Absorption is defined as
movement of the drug from site of administration into the bloodstream
Important Principle of Pharmacokinetics
Drugs must cross cell membranes and many conditions will enhance or impede the process
Pharmaceutical Phase
the first step of absorption
Dissolution
the initial rate limiting factor of drug therapy and absorption during the pharmaceutical phase
Absorption will depend on drug solubility!!!
Absorption is influenced by what factors
Drug solubility
pH
Concentration
Circulation to site of absorption
area of absorbing surface
For absorption we want drugs to be __ soluble
lipid
What sort of things can influence drug solubility
drug form
local conditions - like in GI if the stomach is full it may slow absorption since they need access to stomach wall
processing can enhance or delay - fillers, buffers, etc - these can make it work longer or be slower
pH differences important to know in the body
stomach is acidic - 1 to 2
intestine is alkaline
How does concentration impact absorption
high concentrations are absorbed faster than low ones - but we still do not want to give too much
Why is circulation important for drug absorption
more blood to carry it off for distribution and more blood in the area
What is one way to increase circulation for drug absorption
you could massage the area - like with an analgesic - to activate pressure sensors around the area so it does not hurt as much and also because the circulation to the shot site will make it work faster
this does not apply to drugs like heparin
How does temperature impact absorption
heat will increase circulation through vasodilation but cold does the opposite
What is one of the more important determinants of absorption
Area of Absorbing Surface
very large SA means a lot of medication can be absorbed
Absorbing surface is determined largely by …
ROUTE of administration
what is one the biggest absorbing surfaces
the small intestine
What is the typical natural flow of things regarding pharmacokinetic distribution?
Typically: GI Tract –> Portal Vein carries it off –> Liver –> Inferior Vena Cava –> Heart (Transportation Hub for the Body) –> General Circulation
not all drugs though
What are the routes of administration
Enteral
Parenteral
Percutaneous
Cutaneous
Enteral
This means that the route leads to the GI tract so it can be oral, rectal, etc
__ is the most common route of enteral administration
oral
Advantages of Enteral/Oral
safest (does not have to be clean/sterile)
Most economical (no equipment needed)
Most convenient
Disadvantages of Enteral/Oral
GI irritation to emesis (range - some drugs irritate causing NV)
Destruction by digestive enzymes (like insulin)’
Low gastric pH (acidic in stomach)
Irregularities in absorption (gastric bypass would change absorption of the stomach or rectal scarring)
Patient cooperation needed (cannot force)
Why is enteral/rectal usually saved a more “last resort”
poor predictability and it irritates the rectum
Parenteral
“Outside the GI Tract”
ex; shots, injections, IV
Advantages of Parenteral
absorbed in active form (no waiting for breakdown, can go right into the bloodstream)
more rapid and predictable
patient cooperation not necessary (does not need to be awake necessarily)
Disadvantages of Parenteral
asepsis must be maintained
pain
patient cannot always self medicate with this
expense - more expensive d/t equipment oftentimes
Forms of Parenteral
Subcutaneous
IM
IV
Intrathecal (right to spinal fluid)
(All bypass absorption phase and right to bloodstream)
Parenteral administration bypasses what phase of pharmacokinetics
the absorption phase (since it goes straight to blood)
Percutaneous
absorption from mucous membranes, sub lingual, or inhaled
Forms of percutaneous administration
pulmonary (gas/volatile drugs inhaled)
sub lingual (under tongue)
buccal (cheek)
other - vaginal, GU, nasal, eye ear
Cutaneous
administration via skin absorption
there is a good lipid barrier on skin so its poorly absorbed but if the skin is broken it could cause toxic dosage
skin is thick and stokes many types of drugs
Why are Children and Topical Meds Tricky
- Large skin surface in relation to body weight (lots of skin = more absorption)
- Thin dermis and epidermis leading to greater permeability (not fully developed skin barriers yet either - the child may get it faster and at a greater extent)
- Minimal lipid surface film (which blocks absorption usually)
- Skin is v prone to irritation
Nurses need to know when medications are formulated for what?
long acting or delayed release effects - these meds should not be crushed or broken as it removes the delay effect and leads to large amounts being delivered at once
Delayed Response
technically, refers to drugs w coatings that delay their release until after passing through the stomach
Extended Release
refers to those medications that have effects for a longer interval than an instant release for of that medication
What are some examples of suffixes in drug names that may indicate delayed response or extended release
CR - controlled Delivery CR - controlled release ER - extended release LA - long acting SA-sustained action SR- sustained release XL = "extra" long XR = "extended" release
Regarding controlled response and extended release suffixes what is the problem?
there is no standard interpretation so one cannot easily know whether a medication has a specific effect interval and what that might be
Distribution
Drugs now in the bloodstream and moving throughout the body
How is the pattern of drug distribution done?
it is principally determined by blood flow and has 2 phases once in the bloodstream
2 Phases of Distribution
Initial Phase
Second Phase
Initial Phase
first phase of distribution that reflect cardiac output and regional blood flow
Heart, liver, kidney, brain (highly perfused organ) all receive most of the drug during the first few minutes after absorption - and because the body wants to protect itself above other things, the medication will get to those areas faster due to high blood flow they all have
Second Phase
second phase of distribution
muscle, viscera, skin, and fat all receive drugs (slower than the others) and it may take several minutes to hours after drug absorption until equilibrium is reached
It is limited by blood flow, and involves far larger fractions of body mass - these “not as important” parts are slower acting/distribution to these areas as a result.
What factors superimposed onto the patterns of blood flow determine rate of drug diffusion?
- If the drug is lipid INSOLUBLE - it will penetrate poorly and restrict distribution
- Drug Binding
- Drugs may accumulate
- pH (pH partitioning and ion trapping)
What are some special areas of drug distribution
CNS
Placenta
Breast Milk
Drug Reservoi
How is the CNS a special area of drug distribution
drugs move across endothelial membrane and perivascular cell membrane - blood brain barrier
special connective tissue (glia) will favor LIPID SOLUBLE DRUGS - so the drugs either need to be this way or have a brain catheter insertion
How is placenta a special area of drug distribution
it is NOT a barrier, it has the same cell membranes as anywhere else, so drugs can get to the baby very easily - so all drugs for pregnant women must be cleared
How is Breast Milk a special area of drug distribution
It has a lipid membrane (breast) so things can cross into the milk and the pH of the milk leads to weak bases having greater concen. here than in plasma
What is the pH of breast milk compared to plasma
pH milk - 6.6 (weak acid)
plasma - 7.35 to 7.45 average
Why do weak bases accumulate in greater concentration in breast milk
the weak acidic pH of the milk neutralized with weak base drugs and causes some particles to become charged making it hard to get back across the membrane - so then its trapped and gets to the infant
(weak acid can leave and not become trapped)
Drug Reservoirs
body compartments in which drug accumulates (stored)
ex: Plasma Proteins, Cell Reservoirs
How do plasma proteins act as drug reservoirs
the drug attaches to proteins like albumin - but is usually reversible
when attached they do not leave the bloodstream but become undone and then can leave
Protein bind
reversible often times
It is when a drug can come off of a protein bind eventually to be moved
Free Drug
active drug not bound to anything
this is the thing that can be used - bound drug cannot be used
Why does child and infant albumin levels matter with drug dosing
infant albumin doesnt bind well and children have low albumin, so there is less binding occurring which can cause toxic amounts all at once - so they need to lower the dose when low protein levels exist
Cellular Reservoirs
Drug accumulation in muscle and other cells - some areas include adipose tissue and fat, bones, transcellular
Why is fat relatively stable as a drug reservoir
it has lower blood flow (lower distribution) and has affinity for certain drugs (ex: psychotropics)
What sort of drugs have a higher affinity to bind to bone reservoirs
heavy metals like lead and radium
tetracycline
Metabolism / Biotransformation
mechanism by which drugs are altered structurally (biotransformed) usually to facilitate excretion from the body
The ultimate goal for metabolism is
make the drug WATER soluble so it can be excreted via kidney
Kidneys excrete ___ soluble compounds
water
Metabolism can make things more ___ and ___
potent and powerful
What are the two things metabolism can cause a drug to become
less toxic - detoxification
more toxic - biotoxification
Metabolism most often occurs in …
the liver - but some occurs in renal, blood plasma, and intestinal mucosa
CYPs
metabolizing enzymes - 75% of drug metabolism occurs in this group
major enzymes in the liver for metabolism
Most drugs undergo deactivation by them, either directly or by facilitated excretion from the body - but there are some compounds bioactivated by CYPs forming active compounds
Metabolites
compounds derived from original drug
usually less lipid soluble and more polar which embraces secretion
many have pharm activity and may be similar or different from parent drug
end product or by product of the liver
Do metabolites have function
yes they sometimes can and some drugs are planned for becoming metabolites to do the action
Factors that Influence Biotransformation/Metabolism
- Age - both extremes have decreased activity (1-64 ok range)
- Disease pathology - especially liver issues from ETOH, hep, and hepatotoxic meds
- Concomitant Drug Therapy
Concomitant drug therapy
drugs enhancing or inhibiting one another (their metabolism)
ex; Drug B speeds up Drug A metabolism but Drug C lowers metabolism
Patterns of Metabolism
- Hepatic Metabolism
2. First Pass Metabolism
Hepatic Metabolism
most drugs undergo this once absorbed, are distributed to sites of action THEN undergo metabolic changes when returned in blood through the liver
First Pass Metabolism
all drugs absorbed from GI tract go to the portal system and liver BEFORE systemic circulation - if some are taken up and metabolized the first time through it is first pass elimination or metabolism and the drug could be completely inactivated this way (ex: nitroglycerin)
What are the 2 ways to overcome First pass metabolism
- Different route bypassing liver
2. give a high dose and some will get through
Why does nitroglycerin get through despite its high first pass
because we give it sublingually so it goes right into the bloodstream and bypasses the first pass liver (this is not oral administration though)
Metabolism is most located…
in the hepatic Endoplasmic reticulum
Microsomal Portion of the Liver
the Hepatic ER of the liver where most metabolism occurs
Microsomal System v Nonmicrosomal Liver
Microsomal - conjugation and most oxidation, some reduction and hydrolysis
Nonmicrosomal - mainly reduction and hydrolysis
Research has shown that metabolism by the microsomal system can be depressed or stimulated by…
disease, drugs, foods, chemicals, etc
How does Depressed metabolism come about
by conditions that have a neg. effect on hepatic fxn like starvation, jaundice, CO poisoning. - Anything that can damage the liver
diseases of renal, liver, or severe cardiac
by some drugs when administered simultaneously (ex: drug A stops Bs metabolism)
Depressed Metabolism =
drug levels rise in the body/blood
What sort of things stimulate metabolism
CNS depressants - barbiturate’s (“downers”)
Xanthines
Pesticides
Food Preservatives
Food Dyes
Some other specific drugs
Non microsomal rxns are primarily in the liver, but…
some can be in plasma and other tissues
What is the major means of Excretion
Renal - often excretion route is the kidney
Some does leave via milk, stool, exhalation, and such but most is via urine
The kidney likes excreting ___ and ___ substances
ionized and lipid soluble
for absorption/distribution it was wanted unionized and lipid soluble
___ is needed for Excretion
transformation (metabolism)
What are some other routes of excretion
feces (oral ingested drugs unabsorbed)
bile - minor route
milk (important d/t effect on infant, not excretion amount)
exhalation (mainly for anesthesia and vapors and ETOH)
insignificant loss - sweat saliva tears hair
What sort of things should be metabolized before secretion and what things largely stay unchanged
change - lipid soluble unionized
little change - water soluble ionized
Renal pH
4.6-8.2
If a drug ionized in urine…
then it will NOT be reabsorbed
What ways can we change urine pH to aid excretion
increase pH to alkaline levels with NaHCO3 (ionizes weak acids) or decrease pH with Vit C (ionize weak bases)
Most drugs leave the body through ___ secretion
tubular secretion (active transports 4/5 drugs)
MEC
Minimum Effective Concentration
Smallest amount of drug in the body for effect
MTC
maximum therapeutic concentration
highest amount we want in bloodstream for effect but not be toxic
Therapeutic Range
area between MEC and MTC
How long is the lag between onset time of effect for oral meds
about 30 minutes - 1 hour
C Max
maximum concentration for a dose of medication
Once a curve drops below MEC…
there is no longer an effect, BUT there is still drug in the body
Onset of Action
point when MEC is reached
When the initial drug dose is given what occurs?
plasma level rises (then they drop off after peak)
Half Life
amount of time for PLASMA level concentrations to decreased to 50% of the original concentration
Rate of Elimination =
Half Life
How does half life work over time with 10 mg of a drug with a half life of 3 hours given at 9 am
5 mg left at noon
2.5 by 3 pm
etc
Effects of drugs are essentially eliminated by the end of ___ half lives
4
Initial Loading Dose
A larger dose of the drug given to bring level to minimal rapidly - then in increments afterward there is maintenance to keep levels in therapeutic range
ex:” Digoxin has 1 mg initial loading dose but doses after are .25 mg
Pharmacodynamic Phase
what the drug does to the body, not how it moves but what it does
Phamacokinetics are effects of __ on __
body on drugs
Pharmacodynamics are effects of ___ on ___
drugs on body
The effects of drugs occur when…
the medication reaches the target cell and the therapeutic effect occurs
3 General Properties of Drugs
- Drugs do not confer any NEW functions of a tissue or organ - they only MODIFY existing function
- Drugs in general exert MULTIPLE actions rather than a single effect
- Drug action is a result of physiochemical interaction between the drug and functionally important molecules in the body
3 Theories of Drug Action
Receptor Theory
Drug Enzyme Interaction Theory
Non Specific theory
What are the 3 main ideas of how drug actions produce effects
- selectively combine with specific cellular sites (receptors)
- interacting with body systems (probably enzyme)
- non-specific
Most drugs follow what theory of drug action
Receptor Theory - that selectively combining with specific cellular sites (receptors) produces effects
Receptor Theory
Drug interacts at a site of action w/ receptor (specialized macromolecule) –> interaction stimulates a series of events that give rise to observed effect
ex: heart tissue has receptors –> drug comes in (ex: Beta 1 receptor) and acts on this receptor to increase contraction force and BP and speed
- basically drugs just bind to specific receptors
How can binding to a receptor lead to causing an effect
- causing permeability of membrane to be altered and allowing ionic movement
- stimulating an organ response
- causing the release of stimulating substances
Drug Enzyme Interaction Theory
Provision of substrate material - drug combines with enzymes by virtue of structural resemblance to an enzymatic substrate molecule
this can either block normal enzymatic action or result in production of other substances with unique biochemical properties
Antimetabolites
drugs which resemble enzyme substrate and bind to the enzyme as a result
Non Specific theory
Partially Physiochemical theory
Drugs demonstrate no structural specificity such as receptor affinity; presumably act by more general effects on cell membranes and processes
May penetrate cells or accumulate in cell membranes where they interfere (by physiological and chemical means) with some cell function of fundamental metabolic process
Receptor
Specialized macromolecule with which a drug interacts
May be cell or substance
Interaction stimulates a series of events that give rise to the observed effect (get something to happen or stop)
Affinity
propensity of drug to be found at a given receptor site (Most likely drug is at or going to that certain site)
some dont have high affinity for where they should be though!
Efficacy
drugs ability to initiate biological activity as a result of binding with receptor (how effective the drug is )
Agonist (Action)
a drug which causes effects as a result of direct STIMULATION of the functional properties of the receptor with which it interacts (where you can actually cause an effect)
ex: Morphine is an opioid agonist/narcotic agonist - it makes opioid things happen suich as relieve pain, sedate, dilate blood vessels, etc - it makes actions happen
Antagonis
Inhibits the action
drug which causes effects by INHIBITION of actions of specific agonists
ex: Narcan/Naloxone is an opioid antagonist - it stops opioid action - it will go in and bump opioids off receptors then sit there and take up the space to prevent rebinding
Antagonist and Agonist interactions are usually ____, and based on ___
reversible, concentration
Competitive Antagonist
has an affinity for the same receptor site as an agonist
competition site inhibits the action of the agonist
It will block action at “normal” concentrations, but if the agonist concentration is high it may override the antagonist
It is usually reversible and which ever is in higher amount will live on the receptor reversibly
Non Competitive Antagonist
combines with a receptor mechanism and inactivates the receptor itself so the agonist cannot be effective regardless of concentration
This is considered irreversible and nearly so
What is preferable for people: non competitive or competitive antagonists and why?
Competitive antagonists because they are reversible
We do not want to put non competitive irreversible things in the body - this is how pesticides work
Partial Agonists (Agonist-Antagonist)
Have affinity and some efficacy but may antagonize the action of other drugs that have greater efficacy
Some efficacy but impacts other drugs too - the mid way drugs
Some opioids are A-A and are medium effectiveness with less abuse potential
Bioavailability
percentage of active medication absorbed
how much the drug took that is actually available in the body for use
ex: levodopa only 2% is available to the body / brain
Potency
amount of drug needed to cause an effect
Highly potent drugs need ___ doses to cause effects
smaller doses to cause effect
Weakly potent drugs need ___ doses to cause effects
larger doses to cause effect
Is potency how strong a medication is?
NO
It means how much is needed to cause effect
ex: 1 mg of Dilaudid is potent but Morphine needs 15 mg to cause effect
Your patient works the night shift and often cannot sleep during the day. This is an example of what kind of variable ?
health status
environment
life span and gender
lifestyle and diet and habits
Lifestyle Diet and Habits
Absorption of Enteral drugs occur most frequently where?
Small intestine (absorption not administration)
Why is the onset of action rapid after IM injection?
muscles have great blood supply so it gets to the bloodstream very fast
Which of the following is most likely to be affected by ischemia?
Absorption
Distribution
Metabolism
Excretion
Distribution (ischemia is reduced blood flow)
