Drug Absorption Flashcards
drug absorption
absorption is the movement of a drug from its site of administrateion int o the central compartment of systemic circulation
achieves adequate plasma concentration at its site of action in order to produce its pharmacological effects
amount of absorption depends on routes of administration
bioavailability
the fractional extent to which an administered drug reaches systemic circulation
the main criterion for choosing the route of administration
routes of administration
intravenous
transdermal
subcutaneous
intramuscular
inhalational
sublingual and buccal
oral
rectal
oral administration and the stages before therapeutic effect
most common because it is safest, most convenient, and most economical
phases - pharmaceutical, pharmacokinetic, pharmacodynamic, effect
pharmaceutical phase
disintegration of dosage form, dissolution of active ingredients
pharmacokinetic phase
absorption, distribution, metabolism, excretion
pharmacodynamic phase
drug-receptor interaction, drug-drug interaction, individual sensitivity, pathophysiological conditions
physiological parameters of human small intestines
gastric pH is 1.5 to 2.5
duodenum from 5 to 6
jejunum to ileum is 6 to 7 to 7.5
effective surface area 71-250m^2
gastric surface area 155cm^2
direct interactions that affect drug absorption
physiological factors:
gastric emptying time is slowed by foods
drugs may be destroyed by the gastric pH or digestive enzymes
didanosine intake
anti-HIV drug
most effective when taken 0.5-1 hour before or 2 horus after meals
acid-sensitive drug, prolonged gastric time will cause degradation
nitrofurantoin intake
better taken with food because the drug is not very soluble and increased dissolution time in the intestine helps absorption
first pass effect
drugs may be metabolized in the gut and subsequently in the liver before gaining access to the systemic circulation
major drug metabolizing enzyme int he gut
P450 (CYP3A4)
grapefruit jiuce and drug interactions
grapefruit juice could alter drug concentrations via two mechanisms:
inhibiting CYP3A4 drug metabolizing in the gut - irreversible (96 hours to replenish)
inhibiting uptake transporter OATPs - reversible (after 4 hours)
found to enhance antihypertensive effects of felodipine because metabolizing enzymes were inhibited
controlled-release formulations
preparations of drugs designed to produce slow, uniform absorption for 8 or more hours, achieving a stable blood concentration
eliminates extreme peaks and troughs of blood drug concentration
disadvantages of oral administration
first-pass effect and destruction of drug
onset of effect is too slow for emergencies
not able to administrate to unconscious patients or when vomiting is present
rectal administration
alternative to oral when the patient is unconscious or when ovmiting
used to treat local conditions such as hemorrhoids
dosage may include solutions or suppositories
rectal absorption can be erratic
lowered potential for hepatic first-pass metabolism
50% bypasses the liver
parenteral routes of drug delivery
interavenous, intramuscular, subcutaneous
intravenous injection
100% bioavailability, bypass first-pass effects
results in potentially immediate effect, good for emergencies
permits titration of dose
suitable for large volumes, but may have adverse effects because of rapidly attained high concentrations
once the drug is injected, there is no retreat
intramuscular injection
absorption of lipids through diffusion along concentration gradients
absportion of lipid-insoluble drugs goes through interendothelial loose junctions, macula occludens with pore size of 4-5 nm, or transcytosis
absorption may be made slow and sustained by using repository preparations
suitable for moderate volumes, oily vehicles, and some irritating drugs
may be pain at site of injection
subcutaneous injection
similar to intramuscular injection
suitable for some water-insoluble suspensions and for implantation of solid pellets
not suitable for large volumes or irritating substances
concurrent administration of vasoconstrivtor will slow abosrption
intrathecal injections
enhances the entrance of drugs into CNS, circumvents blood-brain barrier and blood-CSF barrier
uses extremely permeable ependymal cells lining ventricles
can be used to treat acute CNS infections with antibiotics
inhalation
gaseous and volatile agents and aerosols are absorbed rapidly via lungs because of large surface area of alveoli, which is perfused by high blood flow
thin membranes separate alveoli from circulation
inhalation of volatile general anesthesia
topical application
through skin or transdermal mucous membranes
skin is a pipoidal membrane barrier, so only highly lipid soluble drugs are absorbed
absorption is faster through mucous membrane than through skin
drugs can be administered sublingually or by dermal patch, avoid first-pass effect
three criteria of generic drugs
pharmaceutical equivalent
bioequivalent
effective and safe
pharmaceutical equivalents
same active ingredients
identical in strength or concentration
same dosage form
same route of administration
bioequivalence
when two pharmaceutical equivalent drugs produce the same rates and extents of bioavailability of the same active ingredient, they are considered to be bioequivalent
reasons why pharmaceutical equivalence does not equal bioequivalence
may have differences in crystal form, particle size, and manufacturing processes
criteria for FDA to approve a generic drug
pharmaceutical equivalence
bioequivalence (80% to 125% of bioequivalence to the brand name drug)
safety and effectiveness for intended use
drug distribution
after absorption, a drug distributes to interstitial and intracellular fluids
process influenced by a number of physiological factors and the particular physicochemical properties of the individual drug
first phase of tissue distribution
rapid distribution to organs of high blood flow: brain, heart, liver, and kidneys
second phase of tissue distribution
drug delivery to muscle, most viscera, skin, and fat which have moderate blood flow
final tissue distribution
depends on the properties of the drug and its affinity for the tissue site
lipid soluble, nonionized drugs are readily distributed to all tissues, especially adipose tissue
ionized drugs in generall will remain in the plasma and intersitial compartments
anitomical properties of the blood-brain barrier
lacks fenestration and vesicles in endothelial cells
tight junctions
limited extracellular spaces, covered by basal membrane, astrocyte end-foot processes and pericytes
biochemical properties of the blood-brain barrier
ABC transporters on luminal surfaces of endothelial cells that pushes drugs back into the blood
entry of drugs into the CNS
permeable to lipid-soluble drugs - entry of drug is proportional to its lipid solubility and concentration gradient
if both ionized and non-ionized forms exist, entry is proportional to the non-ionized form
blood-cerebrospinal fluid barrier
resides in the epithelial cells of the choroid plexu, which have tight junctions
only lipid-soluble drugs get into the CSF from the blood
not as significant as the blood-brain barrier
ependymal cells lining ventricles are not connected by tight junctions an doffer unrestricted passage of drug molecules between CSF and brain cells
pharmacologically inactive
describes a drug bound to a protein such as albumin and can no longer confer function
plasma proteins may be storage to prolong drug action
localized distribution
uptake transporters and enterohepatic recirculation of drugs have been shown to achieve liver-specific distribution of statins, which enhance the therapeutic action of stains in the liver to reduce cholesterol synthesis and reduce the systemic drug level preventing myotoxicity
phenytoin
narrow therapeutic index
hard to control because serum levels increase exponentially depending on albumin binding and other factors
when are drug-drug interactions not of a concern
if the drug has high therapeutic index
if the drug response is slow
