Lecture 3 - ADME Flashcards
Pharmacokinetics
What does pharmacon mean?
drug
what does kinetikos mean?
putting in motion
what is pharmacokinetics?
it is a branch of pharmacology that is dedicated to the determination of the fate of substances administered externally to a living organism
we talk about how the drug is deposited in the body but the term concenerns all compounds digested or delivered externally to an organism - nutrients, metabolites, hormones, toxins
What areas are pharmacokinetic divided into?
ADME
absorption
distribution
metabolism
excretion
What are the classifications of drug passages?
- transcellular transport
- intercellular transport
Explain the way transcellular transport works
it is the most significant
it means the drug goes across cell-membranes, layers or pores
what are the different ways a drug can move transcellularly?
Diffusion
- passive - majority
- free
filtration
facilitated diffusion
active transport
pinocytosis
Explain how the intercellular transport is functioning
across the gaps or intracellular channels
between the endothelial and epithelial cells
- filtration
What is meant by semipermeable membrane?
membrane that allows certain molecules or ions to pass through it by diffusion or occasionally specialized facilitated diffusion
Give an example of an semi-permeable membrane
lipid bilayer
what is the rate of passage through a semipermeable membrane dependent upon?
- pressure
- concentration
- temperature of the molecules or solutes on either side
- permeability of the membrane to each solute
what features concerning the membrane or the solute will determine the passage of a solute by affecting the permeability?
- solute size
- solubility properties
- chemistry
what is an example of a natural material that is thicker than a membrane but still is semipermeable?
thin film on the inside of an egg
Describe the arrangement of the semipermeable membrane:
phospholipid bilayer
a group of phospholipids - phospahte head + 2 fatty acid-tails
double layer
outside: hydrophilic phosphate head exposed to water
inside: hydrophobic fatty-acid tails
what solutes can most easily pass a phospolipid bilayer?
small, uncharged solutes
what is the fluid mosaic model?
the combination of the phospholipid bilayer and protein channels that float through the phospholipids
What way of semipermeable transport is the most common?
diffusion
What may influence the diffusion?
the lipid-water partition coefficient of the drug
concentration gradient of the drug across the cell membrane
the thickness of cell membrane
surface area of cell membrane
what is the lipid-water partition coefficient of a drug?
the ratio of solubility in an organic solvent to solubility in an aqueous solution
absorption increases as lipid solubility increases
In what state can drugs diffuse across biological membranes?
un-ionized
what is the degree of ionization of a weak acid or base determined by?
the pK of the drug and pH of its environment according to the Henderson-hasselbach equation
How is the henderson-hasselbch equation for a weak base?
When do we have equal numbers of ionized and un-ionized species (drugs)
when the pK of a drug equals the pH of the surroundings
what does a low pK indicate?
stronger acid
What does a low pK indicate?
a strong base
How will drugs with different pK values move?
they will diffuse across membranes at different rates
How does the pH of the biological fluid influence the drug?
the degree of ionization and therefor the rate of the drug transport
What is filtration?
the bulk flow of solvent and solute throough protein channels in the membranes
what molecules are usually filtrated?
smaller ones, molecular weight less than 100
what affects the rate of filtration?
the concentration gradients
what is facilitated diffusion? and what are the properties of it
the movement of a substance down a concentration gradient
it is carrier mediadet, specific and saturable
does not require energy
What is active transport? its properties
energy dependent process that can move drugs against a concentration gradient
protein mediated transport systems
occurs only in one direction
saturable
what drugs are usually activly transported?
drugs that resemble actively transported endogenous substances
sugars, amino acids and nucleosides
what is meant by absorption in pharmacology?
the movement of a drug into the blood stream (not IV)
What must happen before the drug can be absorbed
it needs to be administered: oral, skin, in a spesific dosage form
What happens with absoprtion in case if intraperitoneal, intramuscular injections, parenteral nutririon and others?
the absorption is straight forward, less variability in absorption, bioavailability is often near 100%
How is the drug, most oftenly, getting into the bloodstream?
through the mucous surface of the digestive tract
when the drug gets into the blood stream, it should also be able for the target organ or cell to take it up, what factors may influence this and cause the reduce of the extent to which a drug is absorbed after administration?
some natural barriers causes problems: BBB, placenta
poor compound solubility
chemical instability in the stomach
inability to permeate the intestinal wall
what determines the compunds bioavailability?
absorption
what is the bioavailability of a drug?
the fraction of the drug that reaches the bloodstream unaltered
what administration method of drugs have highest bioavialbility?
intravenously administration
what does the absolute bioavailability measure?
the availability of the active drug in the systemic circulation after non-intravenous administration
How is the bioavailability determined?
pharmacokinetic study
plasma drug concentration vs time plot under the curve for the drug after both intravenous and non-intravenous administration
how do we calculate the bioavailability?
it is the dose-corrected area under the curve non-intravenous divided by AUC intravenous
what is the relative bioavailability?
the bioavailability of a certain drug when it is compared with another formulation of the same drug
usually the have an established standars, but administered via a different route
How do we classify the routes of administration?
topical/external
internal
Where are drugs applied when they are applied topically or externally?
on the skin
mucous membranes, eye, nose, mouth, rectum
the blood should not absorb too much - defects - antiparasitic
how are drugs applied when theya re applied internal?
- enteral :oral. rectal
- oro-naso-gastric
- intra-ruminal
- intra-abomasal
parenteral: injectable drugs, IV, SC, IM = most frequent - intradermal, peritoneal, arterial,pleural.medullar. cerebral, epidural, retrobulbbar, lingual = less frequent
what are some special routes for veterinary applications?
intramammary application
intrauterin infusion
which administration is the most convenient, economical and common route of administration?
oral
what are the sites of absorption for orally administered drugs?
stomach
small intestine
what drugs are absorbed directly from the stomach?
lipid-soluble drugs and weak acids
un-ionized at low pH of gastric content
why are not weak bases and strong acids absorbed from the stomach?
they are usually protonated at the pH of the gastric content - iontrapping
why is the small intestines the primary site of absorption of most drugs?
very large surface area where the drugs, including the partially ionized weak acids and bases may diffuse
is acids mostly absorbed from the stomach or the small intestines?
even though the intestines have a higher pH they are nromally absorbed here
what is the key target for controlling the duration of the drugs effect?
the rate of dissolution
How can a drug be released more gradually over time with a longer duration of action?
when it is supplied in a form that is nor readily dissolved
what are the advantages of slow release dosage forms?
What equation describes the rate of dissolution?
Noyes-Whitney equation
What are some factors that may alter the time and passage of drug to the intestines?
- gastric content
- intestinal motility
- decreased emptying time
How is the gastrointestinal blood flow playing a role in the drug absorption?
it will continously maintain the concentration gradient across the epithelial membrnaes
small very lipid soluble molecules: blood flow limited absorption
highly polar molecules are: blood flow independent
Why is enteric coating useful?
it will prevent the stomach acid and inactivating enzymes to destru certian drugs, prevent the breakdown by the acid pH
what is the first-pass effect and how does it influence the affect by the drug?
- it is the metabolism of the liver or the bilary secretion which will alter the absorption of the drug.
- The drug needs to pass through the liver before reaching the general circulation and its target size
The pH, membrane, blood supply, surface area, transient time and liver-bypass
Buccal
The pH: 7
membrane: thin
blood supply: good, fast absorption w/low dose
surface area:small
transient time: short unless controlled
liver-bypass:yes
The pH, membrane, blood supply, surface area, transient time and liver-bypass
esophagus
The pH: 5-6
membrane:very thick
blood supply: good, fast absorption w/low dose
surface area:small
transient time: short
liver-bypass: yes
The pH, membrane, blood supply, surface area, transient time and liver-bypass
stomach
The pH: 1-3
membrane: normal
blood supply: good
surface area: small
transient time: 30-40min
liver-bypass: no
The pH, membrane, blood supply, surface area and liver-bypass
duodenum
The pH: decompositing weak acid,
membrane: normal
blood supply: good
surface area: very large
liver-bypass: no
The pH, membrane, blood supply, surface area, transient time and liver-bypass
small intestine
The pH: 6-6,5
membrane: normal
blood supply:good
surface area: very large
transient time: 80 cm
liver-bypass: no
The pH, membrane, blood supply, surface area, transient time and liver-bypass
large intestine
The pH:surfacant
membrane: normal
blood supply: good
surface area: not very large, 4-5ft
liver-bypass: no
What are the three major routes for parenteral administration?
intravenous
intramuscular
subcutaneous
What are the general considerations for parenteral administration?
- more predictable bioavailability than oral administration
- Iv - directly into blood stream - no absorption - 100% bioavailability
- usefull in emergencies
- IM and SC administrated drugs, can ften enter the capillaries directly through pores between endothelial cells
- depot preparations for sustained release may be administered by IM or SC routes, but some preparations may cause irritation and pain
What is the advantages of inhalation route and what drugs are used?
rapid absorption becuase of the large surface area and rich blood supply of the alveoli
gaseous anasthetics
epinephrine, glucocorticoids
when is intrathecal administration used?
for drugs that not readily crosses the BBB
injection into the spinal canal
when is sublingual injections used?
useful for drugs with high first pass metabolism -nitroglycerin
bypasses the hepatic metabolism
when is rectal administration used?
used to prevent nausea and vomiting that is common with oral administration
minimizes first-pass metabolism
When is topical administration used?
ehn local effect is desired
minimize the systemic effect - dermatology, opthalmology
non-irritating preparations is essential
may cause systemic effects
What does distribution describe?
the reversible transfer of drug from one location to another within the body
the process by which a drug leaves the bloodstream and enter the extracellular fluids and tissues
movement of a drug from the bloodstream to the various tissues of the body
what is the distribution of a drug between tissues dependent on?
- permeability between tissues (blood and tissues oftenly)
- blood flow and perfusion rate of the tissue
- the ability of the drug to bind plasma proteins and tissue
what is the volume of distribution describing?
it is a property that quantifies the extent of distribution
What is the ratio of body fluids?
ICF: 40% (24liter)
IF: 16% (9,6l)
plasma: 4% (2,4l)
What is an important quality for the drug to diffuse effectivly acrosscellular membranes?
the lipid solubility
what tissues have the fastes initial rate of distribution and the lowest?
brain, liver, kidney > muscle, skin > fat, bone
what is the amount of drug in an organ related to ?
the mass of the organ and its porperties
properties of the specific drug
what is meant by drug redistribution?
it describes when the relative distribution of a drug in the body changes with time
When is drug redistribution sually seen?
highly lipophilic drugs - thiopental
they initially enter the tissues with high blood flow and quickly redistribute to tissues with lower blood flow
How can you find the drug in the plasma?
either in free form or bound to plasma proteins or bound to other blood somponents (RBC)
How is the extent of plasma protein binding drug?
highly variable
ranges from 0%-99% bound
depends on the drug
is the bond between the plasma proteins reversible?
yes
can protein bound drugs pass through capillary walls?
no
what is the consequences of drugs binding to proteins in terms of duration?
extensive binding retards the rate at which the drug reaches its site of action and may prolong duration of action
What proteins binds acidic drugs?
serum albumins
Which proteins binds basic drugs?
alpha-acid - glycoprotein and globulins
Give some examples of drugs that binds to albumins
bilirubin
bile acids
fatty acids
vitamin c
salicylates
sulfonamides
barbiturates
phenylbutazone
penicillins
tetracyclines
probenecid
Give some examples of drugs that would bind to globulins
adenisine
quinacrine
quinine
streptomycin
chloramphenicol
digitoxin
ouabain
coumarin
name two special transporters
corticosteroid-binding globulin - CBG, transcortin
thyroxine-binding globulin - TBG
What are two important barriers to drug distribution
BBB and the placental barrier
what types of drugs passes the BBB poorly?
ionized or polar drugs
How will inflammation effect the to the passage of drugs through BBB?
menginits may increase the ability of ionized, poorly soluble drugs to cross
when is the BBB not working properly, physiologcaly?
at time of birth
which drugs can cross the placental barrier more easily?
lipid-soluble drugs, and with a molecular weigh with less than 600Da
what drug transporters transfers drugs out of the foetus?
P-glycoprotein transporters
what is meant by volume of distribution?
The volume of distribution is useful in estimating the dose required to achieve a given plasma concentration
how is volume of distribution determined?
by administering a known dose of drug intravenously and then measuring the initial plasma concentration
what are the standard values of volumes of fluid compartments in average (plasma, ECF, Total body water)
in an adult 70kg
plasma - 3l
ECF - 12l
TBW - 41l
what are the standard values of volumes of fluid compartments in average (plasma, ECF, Total body water)
ina 20kg dog
plasma - 0,085l
ECF - 3,5l
TBW - 11,7l
What can a very low Vd value indicate?
extensive plasma protein binding of the drug
what can a very high Vd value indicate?
that the drug is extensivly bound to tissue sites
How are compounds and their metabolites excreted from the body?
through the kidneys or in the faeces
List allt he diffrent routes of excretion
urine
faeces
saliva
sweat
tears
milk
lungs - alcholos and anasthetics
What can happen if the drugs are excreted by the liver into the bile?
they might get eliminated through the faeces or reabsorbed from the intestine - prolonged persistence
What is the net renal excretion?
the result of three separate processes
- amount of drugs filtrated at the glomerulus
- amount of drug secreted by active transport mechanisms in the kidney
- amount of drug passively reabsorbed throughout the tubule
What drugs are filtrated at det glomerulus?
most drugs of low molecular weight are freely filtrated
serum protein binding drugs will not be filtrated
how is the glomerular filtration rate in newborns first year of life?
30-40% lower
in the kidney, there are two transport systems in the proximal tubule that can secrete drugs into the ultrafiltrate. What are these transporting?
one is for organic acids
second for organic bases
why are these transport systems in the prox.tubule a site for potential drug-drug interactions?
becuase drugs may compete with eachother for binding to the transporters
Where does reabsorption occur?
throughout the tubule
How is un-ionized drugs that are weak acids and bases reabsorbed?
- simple passive diffusion
- the rate is dependent upon the lipid solubility and pK of drug
- concnetration gradient of the drug between urine and plasma
what can affect the reabsorption?
the urinary pH
also effects the elimination of weak acids or bases
What does renal clearance measure?
the volume of plasma that is cleared of drug per unit time
what will the glomerular filtration rate be if a drug is excreted by filtration alone?
an equal clearance
What will a drug that is excreted by filtration and complete secretion have clearance equal to?
renal plasma clearance
what clearance values shows us that a drug has been
filtrated, secreted and partially reabsorbed
130 and 650 ml/min
What factors influence the renal clearance?
age
other drugs
disease
what happens in case of renal failure, excretion
clearance is reduced significantly - higher plasma levels
What is the excretion ratio in the liver?
amount of drug removed in the liver divided by the amount of drug entering the organ
What will the hepatic clearance be if a drug is highly extracted?
1500ml/min
What is the first-pass effect?
drugs taken orally pass across the membranes of the GI tract into the protal vein and through the liver before entering the general circulation
What is important to think of when administering a drug into an animal with hepatic diseases?
if they have a high first pass extraction, it might reach te cystemic circulation in higher than normal amounts - dose adjustment is needed
