2. ADME I: absorption and distribution of drugs Flashcards
what does the phrase “route of drug administration” mean
the pathway that a drug enters the body
how does the route of drug administration affect the amount of drug
amount of drug that reaches the target tissue can be altered if proper route is not used
what 2 factors is affected by the route of administration for a drug
rate and extent of drug absorption
what are the 3 main routes of drug administration and what do they mean
enteral (GI tract)
Parenteral (routes other than GI tract)
topical
what are the 2 methods of enteral drug administration
oral (po)
rectal
what are the 6 methods of parenteral drug administration
intervenous intramuscular subcutaneous transdermal respiratory tract sublinggual/buccal
what is enteral drug administration
absorption of drug by GI tract
what does parental IV distribution of drugs allow and what is it useful for
what is done to prevent adverse effects
precise conc in blood and useful for immediate effect
injected over a min/2 to prevent very high conc in injected vein which may lead to adverse effects
why is Intramuscular distribution of drugs unpredictable and erratic
difference in vascularity means that rates of absorption differ based on location and may be slow
what is the drug absorption rate of subcutaneous drug distribution and why
injection under skin drug absorption is slower than intramuscular due to poor vascularity
what is transdermal drug distribution
across skin released into systemic circulation
what is the drug absorption rate of respiratory drug distribution and why
absorbed in large alveolar area which has good blood supply so rapid absorption
what is sublingual and buccal drug distribution
sublingual = under tongue buccal = in cheek pouch
what is sublingual and buccal drug distribution useful for
useful for drugs that are metabolized in gut as vessels in mouth bypass the gut and liver and go straight to systemic circulation
what do topical drug distribution avoid and where does it work
avoids systemic effects
only works where it is applied
is transdermal drug distribution the same as topical? why/why not
topical is intended for effect at drug application location but transdermal is absorbed through skin to reach systemic circulation to get to where they are needed
what are the 2 main paths of drug administration
systemic vs local/topical administration
drugs that need to be distributed throughout the body requires what step
requires entry into systemic circulation
what is the first step in the passage of a drug
when is this not the first step
absorption is the first step unless the drug is directly introduced into the blood stream (eg IV)
what is drug absorption
and what does it require in terms of its passage
transfer of drug from administration site to the systemic circulation
requires passage through biological membranes
why is absorption of the drugs delayed and incomplete for orally administered drugs
several barriers to overcome and it needs to be absorbed
what is the absorption rate
how rapidly the drug gets from site of administration to the systemic circulation
what is the absorption extent
how much of the administered dose enters the systemic circulation
what is the order of rate of absorptions for the following distribution routes
IV, Oral, Subcutaneous, Inhalation, intramuscular, rectal, sublingual
explain why youve placed them in that order
IV (shortest/fastest), inhalation, intramuscular, subcutaneous, rectal/sublingual, oral, transdermal (longest/slowest)
IV fastest as no absorption needed
transdermal slowest as needs to penetrate thick skin to reach circulation
why is topical drug distribution not included in the ordering of absorption rates
only act locally and have minimal penetration in skin layer so low absorption
what is the bioavailability and what does it mean when its =1 and <1
fraction of dose absorbed
=1 means 100% enters circulation
<1 means less than all the dose is absorbed/incomplete absorption
is bioavail related to the rate or extent of drug absorption
extent
For a orally distributed drug, why would the final dose in systemic circulation be less than the amount we started with
Orally, drug has to travel through biological membranes and organs before reaching systemic circulation so portions of dose can be lost on the way
where are the 2 locations where the drug may reduce in dose when taken orally and why
GI tract, intestines, Liver
Oral must cross gut epithelium in wall to enter portal circulation. Gut epithelium cells have efflux transporters, so drug may be returned to gut and excreted from GI tract
Some drugs may be metabolized in intestinal wall
Liver can do extensive metabolism as liver is rich in metabolism enzymes, this is known as the first pass hepatic metabolism
what is the first pass hepatic metabolism effect and what does it do to the drug dose
Liver can do extensive metabolism as liver is rich in metabolism enzymes, this process of metabolizing drugs is known as the first pass hepatic metabolism
First pass effect can reduce drug dose to significant amounts and reduce bioavail
what are the 2 most popular routes of drug administration
intravenous and oral
what is the rate and extent of absorption for intravenous drug administration
immediate rate and extent is 100%
what is the rate and extent of absorption for oral drug administration
gradual rate and incomplete extent
what are the advantages of IV administration
6 advantages
rapid
precise control (100% bioavail)
can be administered as bolus/infusion/both
avoids absorption problems or drug breakdown before entering blood
good for orally irritating drugs
what are the disadvantages of IV administration
3 disadvantages
requires hospitalization
careful preparation of injected material (sterile, nonparticulate)
most hazardous (as no recall and exposed to high conc in short time frame so could lead to toxicity)
what are the advantages of oral administration
3 advantages
safest
most convenient (anyone can administer it)
economic
what are the disadvantages of oral administration
2 disadvantages
slow (1/2 - 3hrs for effect)
unpredictable (with regard to rate, extent, reproducibility)
what is absorption like in the oral mucosa and why
limited absorption
thin epithelium and highly vascularized but limited absorption due to short contact time
what is absorption like in the oesophagus and why
no absorption
due to rapid transmit time (doesn’t lie in contact with drug for sufficient time)
what is absorption like in the stomach and why
low
acidic pH and small surface area and lined by thick mucosa layer
what is the stomach a site of absorption for in terms of drug properties and why do these properties allow passage
weak acids and neutral drugs
acidic pH
what is the main absorption site of drugs in the body
small intestine
what does the small intestine have that affects the absorption rate of drugs
villi increases the surface area and is highly vascularized
what is the absorption extent of the large intestine like compared to the small intestine
little absorption occurs in the large intestine compared to the small intestine
what in the large intestine can affect the metabolism of drugs
colon microbiota and metabolizing enzymes can break down drugs
what are drug characteristic factors affecting GI absorption of oral drugs
6 factors
water/lipid solubility ionisation chem stability liability for metabolism dosage form dissoluton rate
what is a drugs chemical stability
drug needs to survive before its absorbed from intestinal fluid
what is an example of chemical stability affecting GI absorption of oral drugs
some drugs prone to metabolism such as hydrolysis of esters
what are 2 solid dosage forms of oral drugs
tablet and capsules
what are the 4 types of tablet drugs
compressed
film coated
enteric coated
controlled release
what are the 2 types of capsule drugs
powder
liquid
what are 2 examples of solid dosage forms that have local effects
lozenges and suppositories
describe the coating if present of compressed tablet drugs
no special coating
describe the function of the coating - if present - of enteric coated tablet drugs and what this means for the tablet
carry medications that can be chemically destroyed by stomach so cant be crushed or chewed
describe the function of controlled release tablet drugs and effect this has on compliance
gradually releases drugs over several hours and there can be multiple coatings depending on thickness of coating
release particles over varying periods so can reduce dosage frequency and increase patient compliance
what are 3 liquid dosage forms
solutions
emulsions
suspensions
what are 2 topical dosage froms
semisolids
transdermal patch
what is a type of parenteral dosage form
ampoules
what are solutions type liquid dosage forms
usually water
what are emulsions type liquid dosage forms
fine droplets of oil and water
what are suspension type liquid dosage forms
medication suspended in water
what are parenteral dosage forms commonly
injections
how do transdermal patches work how are they different from semisolids
topical semisolids = creams and gels not designed to be absorbed in circulation
transdermal = designed to be absorbed into circulation
what is biopharmaceutics
studies methods for achieving effective drug administration
use drugs physio-chem properties to design dosage forms
the dosage form directly influences what 2 things
influences drug release and rate of drug made avail for drug absorption
drugs in solid form must do what and undergo what before they can be absorbed
disintegrate - break into smaller particles
undergo dissolution - dissolve in body fluids
in general absorption of in liquid form has what speed compared to drugs in solid form and why
liquid is faster than solid
solid form needs more time to enter body than drug in liquid form
order the following forms of drugs in rate of absorption from fastest to slowest
capsules, suspensions, tablets, solutions, enteric-coated tablets, coated tablets
solutions > suspensions > capsules > tablets > coated tablets > enteric-coated tablets
what are the 2 kinds of release
intermediate and modified
immediate release solid oral dosage forms lead to what effect on absorption
disintegrate rapidly leading to rapid absorption
when is immediate release needed? ie in what kind of drugs
when rapid drug levels are needed
eg in pain
what does modified/controlled release do to absorption
can slow the release of drug avail for absorption
what are drug dosage form use modified controlled release
enteric coated drugs are stable under acidic conditions but dissolve in high pH solns in small intestines
what is the process required for solid dosage form to turn into granules
disintergration
what is the process required for granules to fine particles
disaggregation
what is the process required for solid dosage form to drug avail for absorption
dissolution (minor)
what is the process required for granules to drug avail for absorption
dissolution (major)
what is the process required for fine particles to drug avail for absorption
dissolution (major)
what is the effect of rate of absorption on concentration profile
how quickly drug reaches peak conc
what are the values on the x and y axis on the conc profile graph
x axis = time in hours
y axis = plasma conc in mg/L
what aspect of action does rate of absorption impact
onset of action
why does drug effect have to be above the min therapeutic level
below the min therapeutic level it will not lead to the desired therapeutic effect
what is the absorption phase on the concentration vs drug effect graph
when you see increase in drug conc
how do you tell on the graph that A and B have same rate of absorption and B is slower than A in terms of absorption rate
reaches max conc around same time so have equal rate of absorption
B takes longer so slowest rate of absorp
what is the effect of extent of absorption on concentration profile
total exposure to the drug in a given time period
exposure to a drug is given by what in the drug conc vs time graph
given by area under plasma conc time curve
what are the 3 patient characteristics that affects the GI absorption of oral drugs
gastric emptying rate
intestinal mobility
drug-food interactions in the gut
what is the gastric emptying rate
how long is the normal gastric emptying rate
time taken for stomach to empty after feeding
normally 4hrs
how does the gastric emptying rate affect drug absorption
its a rate limiting process for drug absorption
gastric emptying rate is an essential consideration for what kinds of drugs
drugs that are broken down in stomach or that cause stomach ulcers
accelerated gastric emptying can have what effect on the rate of drug absorption
accelerated emptying rate = increase rate of drug absorption as most drugs will move to next part of GI tract which is where most drugs are absorbed (small intestine)
the gastric emptying rate is decreased by what 7 factors
volume and content of meal hot meals vigorous exercise emotion pain disease gastric ulcer
what kind of drug administration can influence gastric emptying
co-administered drugs (drugs taken together)
how does intestinal mobility affect the absorption of drugs
explain for high motility and low motility
time taken for drugs to pass through GI tract affects absorption
high motility can prevent adequate absorption as reduces time in contact for absorption to take place
Low motility drug moves too slowly along gi tract so metabolism can increase and can reduce absorption of drugs due to enzymes etc
what is a pathological aspect involving gut that can affect adequate absorption
disease state influences intestinal mobility
eg diarrhoea, gastroenteritis, irritable bowel syndrome,
what do drug food interactions in the gut do to drug absorption
drugs may interact with food in GI tract affecting rate and extent of drug absorption
what does grapefruit juice do to drugs
affects metabolism of co-administered drugs
what do dairy products do to drugs and how does this affect absorption
drugs interact with dairy products to dorm insoluble complex with metal ions
reduces absorption
what is drug distribution and why is it needed
transfer of drug from blood circulation to various tissues in the body
essential for drug to get to its site of action
can different tissues/organs receive diff levels of drug and can it remain in diff tissues/organs for diff amounts of time
yes to both
distribution factors can be affected by what 2 factors
access of drug to its site of action
relative distribution of a drug betw blood and rest of body
what are 2 factors affecting access of a drug to site of action
Poor perfusion = area like tumors have limited blood supply so limited drug distribution
Physical barriers
what is the main system to is responsible for drug distribution in the body
circulatory system
what do arteries and veins do
describe the route of blood flow in circulatory circuit
arteries carry blood to tissues and veins return blood back to heart
Systemic circ -> right heart -> pulm circulation -> left heart -> rest of body
what is the path that IV drugs travel before being pumped to rest of body
to right heart -> pulmonary circulation -> left heart -> rest of body
describe capillary permeability and how does this affect drugs travelling in the bloodstream
most capillaries are relatively porous
drugs leave blood regardless of whether they are poorly lipid soluble, charged or polar
what are exceptions for capillary permeability in terms of when drugs cannot leave blood and explain why
brain capillaries have no pores and an additional layer of glial cells
AKA = Blood brain barrier
what is the blood brain barrier and what does it do to the passage of drugs
highly selective permeability barrier
effective barrier against passage of many drugs
what are 3 components of the BBB that affect drug permeability
endothelial cells form tight junctions = CNS entry restricted as blood capillary endothelial cells are tightly joined and have few/no pores
high expression of efflux transporters = transport some chem back into blood
capillaries surrounding astrocytes further restrict access
in the BBB transcellular passive diffusion is restricted to what kinds of drugs
small, unbound lipophilic drugs
tight junctions and lipid membrane of cells limit access of what kind of drugs and why
Tight junctions and lipid membranes of cells limit access of water soluble drugs
also lipid soluble drugs restricted as there are so many lipid membranes to cross
the BBB is less permeable to more ____ drugs than other areas of the body
hydrophilic
why does the BBB only restrict access to many substances and why is it not just an absolute barrier
some drugs undergo active transport
what are the 2 types of fluid in the cells fluid compartments
extracellular fluid
intracellular fluid
what is intracellualr fluid
all fluid enclosed in cells by plasma membrane (fluid in cells)
what is extracellualr fluid
fluid that surrounds cells (outside of cells)
what 2 components make up the ECF
interstitial fluid and plasma of blood
is the boundary between the ECF and ICF porous
no
they are harder to cross
in an average 70kg person how many L of plasma do they have
3L
in an average 70kg person how many L of Interstitial fluid do they have
11L
in an average 70kg person how many L of ICF do they have
28L
temporarily disregarding active transport, how many L of fluid does water soluble and low molecular weight drugs occupy and why
14L
Lower molecular weight drugs or water soluble drugs will occupy volume of plasma as well as interstitial fluid but as they are polar, they cant cross the plasma membrane. These drugs can occupy close to 14L (plasma + interstitial fluid)
temporarily disregarding active transport, how many L of fluid does lipid soluble drugs occupy and why
42L
Lipid soluble drugs are able to diffuse across cell memb to reach ICF so volume these drugs can occupy is close to 42L (volume of total water)
temporarily disregarding active transport, how many L of fluid does high molecular weight drugs occupy and why
3L
they are confined to plasma as they are too big to move out of the capillaries
what is the relationship between drug distribution and blood flow
tissue that receives blood receives more drugs
which 3 organs receive drugs very rapidly and why
kidneys, liver and heart
well perfused with blood
which 3 tissues receive drugs very rapidly and why
muscle, fat and skin
less perfused with blood
what is plasma protein binding
drugs frequently bind to proteins in plasma
what does plasma protein binding do to drug distribution
explain why it has that effect
opposing effects on distribution
bound drug will remain in circulation as they cant penetrate cell memb and therefore will be pharmacologically inactive and is protected from metabolism and elimination
is protein binding reversible
usually yes
what are the 6 routes of contrast administration
explain them in layman’s terms for where they are delivered via
intra:
- arterial = artery
- thecal = CSF
- articular = joint
- synovial = synovial cavity of joint
- cavitary = body cavity (eg uterus, cervix etc)
- peritoneal = peritoneal cavity
what is the most common route for contrast media delivery
where is CM introduced in this delivery option and what is avoided
intravascular = CM introduced to systemic system so bypasses absorption process completely
which way do veins and arteries move blood
veins = towards heart artery = away from heart
what happens to drugs delivered intravenously - what is its path
drug carried through heart and diluted in blood before reaching tissues/organs
what happens to drugs delivered intraarterially - what is its path
drug carried directly into tissues
what is one benefit and one downside to using intra-arterial injection for contrast media
similar contrast enhancement can be achieved with less contrast medium
but is more invasive and less safe
the rate and extent of distribution of contrast media will influence what 2 factors of contrast enhancement
intensity and timing of enhancement
the distribution of contrast media is dependent on what
blood flow
how is contrast media distribution related to tissue perfusion
highly perfused tissues and organs show high contrast enhancement during initial circulation
what happens to the contrast media as it circulates the body and where in the body is this most important
diluted
more diluted in organs distal from injection site regardless of tissue perfusion
how does injection rate affect contrast in vessels
what is the pro and con of faster injection rate
higher rate = higher contrast
Faster injection can increase peripheral venous blood flow which increase rate of distribution allowing contrast delivered quickest to central compartment, but incr blood flow means that contrast doesn’t remain for long time so shortens scan opportunity
why must contrast injection be done at equal rate or greater rate to blood flow
if its too slow, cardiovascular system will signif dilute conc of contrast agent before imaging takes place and rapid injection limits early dilution effect of cardiovascular system
what are the 2 injection factors to consider for contrast media
speed and duration of injection
injection site in relation to site examined
how does injection site in relation to site examined impact contrast media
in terms of central and peripheral veins pros/cons
central venous injections shorter travel distance so quicker peak enhancement but located deeper
peripheral veins smaller and superficial so easier to reach but further away
what is the saline push effect for contrast media
why is this useful x 3 things
immediately after contrast media administration flush with saline - this flushes any remaining contrast media from catheter
thereby it:
- increases the amount of contrast agent avail for distribution
- pushes contrast media bolus further into blood circulation
- decreases contrast media amount in locations where its not needed
what are the 4 patient factors
2 main and 2 less important ones
cardio output and body size important
age/sex and hepatic disease less important
how does body size of patient affect contrast enhancement
explain how
affects its intensity
larger blood volumes in larger patients so greater dilution and reduced conc of contrast in blood = results in lower contrast enhancement
how does cardiac output of patient affect contrast enhancement
explain how
affects timing of contrast enhancement
decreased CO means contrast arrives more slowly and clears more slowly leading to prolonged enhancement
what is the equation for Cardiac output
what is CO and what are the units involved in the equation
CO = HR x SV
amount of blood flowing into circulation per min
SV = ml/beat HR = beat/min
what 5 factors affect cardiac output and how
Exercise = increases both HR and SV
Age = decrease O2 consump and muscles so lower CO
Body size = larger size has larger CO
disease and metabolism = increase metabolism in tissues and O2 use and also releases vasodilator products leading to decrease vessel resistance = increases CO
how does age and sex of patient affect contrast enhancement
explain how
diff betw men and women due to diff in body size and blood volume (M>F)
CO reduces with age so enhancement may be stronger in elderly patients than younger
how does hepatic disease of patient affect contrast enhancement
explain how
may later perfusion and thus enhancement profile
what happens to contrast and the BBB normally vs when there is damage to BBB
can there be adverse reactions if contrast gets into the brain
dont normally cross BBB freely to enter the CNS
contrast media can enter brain when disease alters BBB’s permeability and can produce toxic effects on neurons and astrocytes when they penetrate altered BBB (neurotoxicity)
