ADME Flashcards
what does ADME stand for
-Absorption
- Distribution
- Metabolism
- Excretion
what does ADME describe
the key kinetic principles
what is absorption
how a drug moves from its site of administration into the bloodstream
what is distribution
movement of the drug between blood and tissues
what is metabolism
conversion of drugs into more hydrophilic metabolites
what is excretion
removal of drugs and/or metabolites from the body
where are the majority of drugs absorbed
in the small intestine
what conditions can slow the absorption of drugs
- gastroparesis in DM
- colectomies
what features predict drug movement
- molecular size
- degree of ionization
- lipid solubility
- protein binding
to pass through lipid membranes drugs must be:
non ionized
to be water soluble, drugs need to be:
ionized
what happens when a strong acid interacts with water
a complete irreversible reaction
what happens when a weak acid interacts with water
a reversible reaction
most drugs are either:
weak acids or weak bases
what happens to an acidic drug in an acidic pH
it is non-ionized and protonated
what happens to a acidic drug in a basic pH
ionized, deprotonated
what happens to a basic drug in acidic pH
ionized, protonated
what happens to a basic drug in a basic pH
non-ionized, deprotonated
acids are _____ when protonated
non -ionized and fat soluble
bases are _____ when deprotonated
non-ionized
what is pKa
the pKa is the pH at which there are equal amounts of protonated and non-protonated
when pH = pKa:
protonated equals non protonated
when pH < pKa:
protonated form predominates
when pH > pKa:
non-protonated form predominates
only the ______ form of the drug can readily cross the lipid membrane
non-ionized
ratio of ________ and ______ influences the rate of absorption
non-ionized and ionized
what is ion trapping
because ionized molecules cant cross the membrane, can effectively trap them and enhance excretion
how do acidic environments of abscesses affect ionization state of local anestehtics
- local anesthetics are basic and have a high pKa
- abscesses have a lower pH
- when a basic drug is in an acidic pH the protonated and ionized form predominates - water soluble
- the anesthetic will hang in the abscessed fluid which makes it harder to cross membrane and harder to numb
what anesthetic would take the longest time to work in an abscessed area
bupivicaine
what anesthetic would be the fastest to numb in an abscessed area
mepivacaine
absorption is the movement of a drug from its site of administration into the ______
central compartment
absorption is the process of:
dissolution and diffusion
what is bioavailability
fraction of drug that reaches the systemic circulation intact
what is the bioavailability of IV drugs
100%
bioavailability is affected by:
route of administration
what is hepatic extraction ratio
fraction of drug in blood that is irreversibly removed during one pass through the liver
what is first pass clearance
extent to which a drug is metabolized by the liver during its first pass in the portal blood through the liver to systemic circulation
drugs with low hepatic extraction will have _____ first pass clearance
low
first pass effect occurs due to metabolism in:
- gut bacteria
- intestinal brush border enzymes
- portal blood
- liver enzymes
describe low hepatic extraction
- low first pass clearance
- change in hepatic enzymes wont have significant effect on first pass clearance
describe high hepatic extraction
- high first pass clearance
- bioavailability is lower
- changes in enzyme function will have large effect on first pass effect
what is an example of a drug with high hepatic extraction
morphine
what is an example of a drug that undergoes enterhepatic recirculation
clindamycin
what are the 2 types of routes of administration
enteral and parenteral
what is parenteral route of transmission
any drug that bypasses the GI system to get to the blood
what are the advantages and disadvantages of enteral administration
-A: most common route, safest, easier, most economical
- D: limited absorption, emetogenic potention, subject to first pass, absorption may be affected by food or other drugs, irregularities in absorption or propulsion
what are the advantages and disadvantages of parenteral administration
-A: not subject to first pass, most rapid onset, ability to titrate, doesnt require patient cooperation
- D: greater patient discomfort, requires additional training to administer, concern for bacterial contamination, infection associated risks
what are the infection associated risks with parenteral administration
- extravasation
- intra-arterial injection
- limb loss
in oral administration absorption is governed by:
- surface area for absorption
- blood flow to site of absorption
- dosage form administered
- ionization status ( lipo vs hydrophilic)
- concentration at site of absorption
what orally administered drugs have enteric coating
drugs destroyed by gastric secretions, low PH, or that cause gastric irritation
what is the risk associated with enteric coating on orally administered drugs
risk of bezoar formation
orally administered drugs have ____ release
delayed
what are the parenteral routes of administration
- intravenous
- intramuscular
- subcutaneous
- intradermal
- inhalation
- intranasal
- intrathecal/epidural
- topical
- subgingival
describe intravenous injections and their bioavailability
- 100%
- immediate onset, bypasses GI absorption
- best for emergencies
describe intramuscular injections and their bioavailability
- 75-100%
- irritatnig drugs given this route
- not as rapid response as IV
- depot preparations (sustained release)
describe subcutaneous injections and their bioavailability and give examples
- 75-100%
- slower absorption than IV or IM
- little risk of intravascular injection
- ex: insulin, mechanical pumps, heparin
describe intradermal injections and examples
-small amounts of drug
- tuberculosis skin test, local anesthetics
describe inhalation route and its bioavailability
- 5-100%
- almost as rapid as IV (method of abuse)
- delivered directly to lung (good selectivity) - minimal systemic side effects
- gases, aerosols of solutions and powders - good for respiratory conditions
describe intranasal administrations and their bioavailability
- 5-100%
- vasopressin for tx of diabetes insipidus, calcitonin (osteoporosis)
- method of drug abuse
describe intrathecal/epidural injections and examples
- subarachnoid space of spinal cord into CSF
- lumbar puncture-baclofen in MS, regional anesthetic in delivery, morphine drip
describe topical route of administration and the bioavailability
- skin, oral mucosa, sublingual, rectal
- avoids 50% of first pass metabolism
- when local effect is desired but can provide systemic effects
- sublingual (100%), rectal (50%) bypasses liver - good bioavailability
- transdermal controlled release
what are examples of transdermal controlled release drugs
- scopolamine
- nitroglycerin
- nicotine
- fentanyl
describe subgingival route of administration
- perio specific uses: doxycycline (atridox)
- minocycline (arestin)
what happens in distribution
the administered drug leaves the blood stream and enters other compartments
what is distribution dependent on
- cardiac output
- capillary permeability
-blood flow
what organs get the most to least blood distribution and what is the number of each
- kidney: 360 mL/min/100gm
- liver: 95 mL/min/100gm
- heart: 70 mL/min/100gm
- brain: 55 mL/min/100gm
what are the 3 main compartments
- central
- peripheral
- special compartments
what is in the central compartment
well perfused organs and tissues such as heart, blood, liver, brain, kidney. drug equilibrates rapidly
what is in the peripheral compartment
- less well perfused organs/tissues such as adipose, skeletal, muscle
what is in the special compartments
- CSF, CNS, pericardial fluid, bronchial secretions, middle ear
what are the 2 proteins that bind drugs and what types of drugs do they both bind
- albumin: acidic drugs
- A-glycoprotein: basic drugs
where do drugs accumulate in tissue
- organs
- muscle
-adipose - bone
what is an exmaple of a drug that accumulates in adipose tissue
fentanyl
what is an example of a drug that accumulates in bone and what does this cause
tetracycline- causes staining in the teeth
what is redistribution and what is an example
- from site of action into other tissues or sites
- propofol
describe the distribution in the CNS
- blood brain barrier exists
- efflux transporters
- inflammatory processes
what is the volume of distribution
volume of fluid in which a drug would need to be dissolved to have the same concentration in plasma
- not a real volume
volume of distribution is the relationship between:
dose and resulting Cp
what drugs tend to have a larger Vd
lipophilic drugs
what drugs have a lower Vd
protein bound drugs
where are drugs found with a Vd of more than 5 L
confined to plasma
where are drugs found that have a Vd of 5-15L
distributed to extracellular fluid (RBCs and plasma)
where are drugs found that have a Vd larger than 42 L
distributed to all tissues in the body especially adipose
increased Vd = _____ likelihood that the drug is in the tissue
increased
decreased Vd = _____ likelihood that the drug is confined to the circulatory system
increased
drugs are removed either:
metabolized/biotransformed and eliminated or excreted unchanges
drugs must be _______ to be removed
water soluble
lipid solubility is good for _____ and bad for ______
absorption and distribution; excretion
what does biotransformation do
converts drugs into polar metabolites
- lipophilic into hydrophilic
what does the liver accomplish metabolism of drugs through
P-450
where is the cytochrome P-450 system locatde
liver, kidney, intestines
what are the main most common cytochromes in the cytochrome P-450 system
- CYP 3A4
- CYP 2D6
- CYP 2C9
- CYP 1A2
describe phase 1 of metabolism
- catabolic
- exposes functional group on parent compound
- usually results in loss of pharmacologic activity
- activation of prodrugs
what is an example of a prodrug that is activated in phase 1 of metabolism
fosphenytoin to phenytoin
what are the possible interactions with P450
- substrates
- inhibitors
- inducers
what is an example of a substrate in the P450 system
warfarin
what is an example of an inhibitor in the P450 system
bactrim
what do inducers in P450 do
the drug sends a message to the nucleus to make more CYP protein which lowers the concentration of another drug thus decreasing that drugs efficacy
describe the genetic polymorphisms of the CYP isoenzymes
- great genetic variability in function
- may be poor metabolizers or rapid metabolizers
- this can lead to subtherapeutic effect such as codeine and tramadol
- or this can lead to toxicity such as in diazepam, alprazolam
describe phase 2 of metabolism
- occurs after functional groups are exposed
- anabolic: adds water soluble molecules to structure
- much less inter- patient variability
what are the major reactions in phase II of metabolsim
- glucuronidation
- glutathione conjugation
- sulfate conjugation
- acetylation
what are the primary routes of excretion
kidney, lung and feces
what is excretion
- removal of an unchanged drug
- polar compounds -> lipid soluble compounds
what are the 3 processes of excretion in the kidneys
- glomerular filtration
- active tubular secretion
- passive tubular reabsorption
describe the process of excretion in the kidneys
- dependent on renal function
- only unbound drug filtered
- non-ionized weak acids and bases are passively reabsorbed
- alkaline urine traps ionized acidic molecules and increases excretion
describe excretion through the lungs and what is it affected by
- primarily inhaled anesthesia or volatile liquid
- affected by respiratory rate and blood flow
describe excretion through feces
- unabsorbed orally administered meds
- metabolites excreted in the bile
- un-reabsorbed metabolites secreted into the intestinal tract
what is the main factor that determines rate of passive transport
lipid solubility
how many molecules bind per molecule of albumin
2
extensive protein binding can _____ drug elimination
slow
competition for protein binding can sometimes lead to:
interactions
which protein is more commonly bound
albumin
acids get trapped in ____ environments
basic
gut absorption depends on factors such as:
- GI motility
- GI pH
- particle size
- interaction with gut contents
what catabolic reactions take place in phase I of metabolism
oxidation, reduction, hydrolysis
which phase of metabolism results in more active products
phase I
which phase of metaboslim involves the P450 system
phase I
what is the end result of phase II metaboslim
conjugated, inactive and polar products for excretion
unless they’re protein bound most drugs are filtered through:
the glomerulus
weak acids and bases are actively secreted into:
the renal tubule
lipid soluble drugs are ______ not efficiently excreted
passively reabsorbed
