ADME Flashcards
A:
D:
M:
E:
Absorption
Distribution
Metabolism
Excretion
Absorption
How a drug moves from its site of
administration into the bloodstream
Distribution
Movement of the drug between blood and
tissues
Metabolism
Conversion of drugs into more hydrophilic
metabolites
Excretion
Removal of drugs and/or metabolites from
the body
Features that predict
movement
(4)
Molecular size
Degree of ionization
Lipid solubility
Protein binding
Rule 1
To pass through lipid membranes, drugs
have to be
To be water soluble, drugs need to be
non-ionized (aka: uncharged)
ionized (aka: charged)
**Most drugs are either
weak acids or weak bases**
Weak acid
Occurs more in a — environment
basic
Weak base
Occurs more in a — environment
acidic
Remember: Acids are non-ionized (fat soluble)
when —, ionized (water soluble) when
—
protonated, deprotonated
Bases are non-ionized when —,
ionized when —
deprotonated, protonated
The pKa is the pH at which
there are
equal amounts of protonated and
nonprotonated
pH = pKa
pH < pKa
pH > pKa
Protonated equals non-
protonated
Protonated form predominates
Non-protonated form predominates
Only the — of a drug can
readily cross the lipid membrane
non-ionized form
Ratio of ionized and non-ionized
influences rate of —
absorption
Henderson-Hasselbalch equation
pH = pKa + log [Ionized]/[Non-ionized]
Ion Trapping
Because ionized
molecules (drugs)
can’t cross the
membrane, can
effectively trap them
and enhance
excretion
Principle is very
useful in toxicology
Acidic environments of abscesses will affect ionization state of
local anesthetics
Acidic environments of abscesses will affect ionization state of local anesthetics
(3)
Local anesthetics = basic, high pKA
Abscess = low(er) pH
When a basic drug is in an acidic pH, the protonated and ionized form predominates
Absorption
(3)
Movement of a drug from its site of administration into the central compartment
Process of dissolution and diffusion
Bioavailability more important
Bioavailability (F)
(3)
Fraction of drug that reaches the systemic
circulation intact
Bioavailability of IV = 100%
Affected by route of administration
First Pass and Hepatic Extraction
(2)
Hepatic extraction ratio
First pass clearance
Hepatic extraction ratio
Fraction of drug in blood that is irreversibly
removed during one pass through the liver
First pass clearance
Extent to which a drug is removed by the liver
during its first pass in the portal blood through
the liver to systemic circulation
First Pass and Hepatic Extraction
Drugs with low hepatic extraction will have
– first pass clearance, and vice versa
low
First pass effect occurs due to metabolism
by/in
(4)
Gut bacteria
Intestinal brush border enzymes
Portal blood
Liver enzymes
Hepatic Extraction
Low extraction
(2)
Low first pass
clearance
Change in hepatic
enzymes won’t have
significant effect on
first pass clearance
High extraction
(2)
Hight first pass
clearance
Changes in enzyme
function will have large
effect on first pass
effect
Enteral administration
ADVANTAGES
(4)
Most common route
Safest
Easiest
Most economical
Enteral administration
DISADVANTAGES
(5)
Limited absorption
Emetogenic potential
Subject to first pass
Absorption may be
affected by food or other
drugs
Irregularities in
absorption or propulsion
Parenteral Administration
ADVANTAGES
(4)
Not subject to first pass
Most rapid onset
Ability to titrate
Doesn’t require cooperation
Parenteral Administration
DISADVANTAGES
(4)
Greater patient discomfort
Requires additional training
to administer
Concern for bacterial
contamination
Injection-associated risks
Injection-associated risks (3)
Extravasation
Intra-arterial injection
Limb loss
Oral Administration
Absorption governed by:
(5)
Surface area for absorption
Blood flow to site of absorption
Dosage form administered
Ionization status (lipo- vs. hydrophilic)
Concentration at site of absorption
Oral Administration
Enteric coating
(2)
Drugs destroyed by
gastric secretions, low
pH, or that cause
gastric irritation
Risk of bezoar
formation
Oral Administration
— Release
Delayed
►Intravenous (IV): F = 100%
(2)
● Immediate onset, Bypasses GI absorption
● Best for emergencies
Intramuscular (IM): 75-100%
(3)
● Irritating drugs given this route
● Not as rapid response as IV
● Depot preparations (sustained release) ie., suspensions, ethylene glycol,
peanut oil- all slow down absorption.
►Subcutaneous (SQ): 75-100%
(3)
● Slower absorption than IV or IM
● Little risk of intravascular injection
● Examples: Insulin, Mechanical pumps, heparin (DVT prophylaxis)
► Intradermal (ID):
(2)
● Small amounts of drug
● Tuberculosis skin test, Local anesthetics
► Inhalation: 5-100%
(3)
● Almost as rapid as IV. (Method of abuse)
● Delivered directly to lung (good selectivity)- minimal systemic side-effects.
● Gases, aerosols of solutions & powders -good for respiratory conditions.
► Intranasal: 5-100%
(2)
● Vasopressin for tx of diabetes insipidus, calcitonin (osteoporosis).
● Method of drug abuse.
►Intrathecal/Epidural:
(1)
● Subarachnoid space of spinal cord – into CSF (Lumbar puncture- Baclofen
in MS, regional anesthetic in delivery, morphine drip)
►Topical: Skin, oral mucosa, sublingual, rectal (avoids 50% of 1st pass metab)
((3)
● When local effect is desired-but can provide systemic effects.
● Sublingual (100%), rectal (50%) bypasses liver- good bioavailability.
● Transdermal Controlled Release- Scopolamine, nitroglycerin, nicotine,
estrogens (BCP), fentanyl.
►Subgingival:
Perio specific uses: doxycycline(Atridox); minocycline(Arestin)
Distribution
The administered drug leaves the blood
stream and enters other “compartments”
Dependent upon:
(3)
Cardiac output
Capillary permeability
Blood flow
Kidney: – mL/min/100gm
Liver: – mL/min/100gm
Heart: – mL/min/100gm
Brain: – mL/min/100gm
360
95
70
55
Central
Well perfused organs and tissues (heart, blood, liver, brain, kidney). Drug equilibrates rapidly.
Peripheral
Less well perfused organs/tissues (adipose, skeletal muscle, etc.)
Special compartments
CSF, CNS, pericardial fluid, bronchial secretions, middle ear
Protein binding
Albumin –
α-glycoprotein –
acidic drugs
basic
SKIPPED
Distribution
(5)
Protein binding
Free vs. bound
Competition
Disease impact
Drug levels
Distribution
Accumulation in tissue
(4)
Organs
Muscle
Adipose
Bone
Distribution
Redistribution
(2)
From site of action into other
tissues or sites
E.g. propofol
CNS
(3)
Blood brain barrier
Efflux transporters
Inflammatory
processes
SKIPPED
Blood brain barrier
(2)
Lipid solubility
Clinical effects
Volume of Distribution (Vd)
(2)
Volume of fluid in which a drug would
need to be dissolved to have the same
concentration in plasma. Doesn’t
represent “real” volume
Relationship between dose and resulting
Cp
Lipophilic drugs tend to have a – Vd
Protein bound drugs have — Vd
larger
lower
Drugs with a Vd of:
< 5L:
5-15L:
> 42L:
Confined to plasma
Distributed to extracellular fluid (RBCs + plasma)
Distributed to all tissues in the body, especially adipose
increase Vd =
increase likelihood that drug is in the tissue
increase Vd =
decrease likelihood that drug is confined to the circulatory system
Metabolism
Removal
(2)
Either metabolized/biotransformed and
eliminated or excreted unchanged
Must be water-soluble to be removed
Lipid solubility good for — and
—, bad for —
absorption, distribution
excretion
Metabolism
Process of biotransformation
(2)
Converts drugs into polar metabolites
Lipophilic into hydrophilic
Liver does the heavy lifting
P-450
Cytochrome P-450 system
(2)
70+ forms
Liver, kidney, intestines
Metabolism – Phase I
(4)
Catabolic
Exposes functional group on parent compound
Usually results in loss of pharmacologic activity
Activation of prodrugs
Metabolism and P450 Interaction
(3)
Substrates
Inhibitors
Inducers
Genetic Polymorphisms
Genetic variability in function of CYP
isoenzymes
Genetic variability in function of CYP
isoenzymes
May be poor metabolizers (PM) or rapid
metabolizers (RM), leading to:
(2)
Subtherapeutic effect: CYP2D6 PM – codeine,
tramadol
Toxicity: CYP3A4 – diazepam, alprazolam
(insufficient activity in some Asian populations)
Phase II
(3)
Occurs after functional groups are exposed
Anabolic: adds water soluble molecules to
structure
Much less interpatient variability
Phase II
Major reactions
(4)
Glucuronidation
Glutathione conjugation
Sulfate conjugation
Acetylation
Excretion
(3)
Removal of unchanged drug
Kidney, lung, feces – primary routes
Polar compounds > lipid soluble
compounds
Excretion kidney
3 processes
(3)
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
Excretion- kidney
Dependent upon
Only — drug filtered
Non-ionized weak acids and bases
Alkaline urine “traps”
renal function
unbound
passively reabsorbed
ionized, acidic molecules, increases excretion
Excretion- lungs
(2)
Primarily inhaled
anesthesia or volatile
liquid
Affected by
respiratory rate and
blood flow
Excretion- feces
Unabsorbed
Metabolites excreted
in the
Un-reabsorbed
metabolites secreted
into the
orally
administered meds
bile
intestinal
tract
Drugs have to cross
lipid membranes, can do this by passive (with the concentration gradient) or active (against the gradient) transport
— is main factor that determines rate of passive transport
Lipid solubility
Only — drugs can diffuse across lipid membrane
uncharged
Partition –
acids get trapped in basic environments, vice versa
— most prominent re: protein
binding; binds acidic drugs (~2
molecules/albumin)
Albumin
elimination
Competition for protein binding can
sometimes lead to —
interactions
Drugs with low — are not well
absorbed from the gut
lipid solubility
Gut absorption depends on factors such as:
(4)
GI motility,
GI pH,
particle size,
interaction w/ gut contents
— is fraction of dose that
makes it to systemic circulation to elicit an
effect
Bioavailability (F)
Phase I reactions are
catabolic; involves oxidation, reduction, and hydrolysis
Phase I prepares the drug for Phase II, can result in more active products; often involves
P450 system
Phase II reactions are
anabolic, conjugated, leaving inactive and polar product for excretion
— induction and inhibition are hugely important concepts regarding drug interaction
P450
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
passively reabsorbed,
not efficiently excreted
Can use pH partition concept to facilitate
excretion of certain drugs
