Flashcards in Drug Absorption Deck (73):
Pharmacokinetic processes involve...
the passage of drugs across membranes
factors influencing drug membrane passage (4)
degree of ionization
Molecular size --> can be affected by
drug binding to plasma protein
Lipid solubility --> estimated by
oil:water partition coefficient
Degree of ionization --> affected by
tissue pH, will influence lipid solubility
Concentration gradient --> created at...
site of administration
For most drugs, cell membranes act as...
mechanism of membrane passage (3)
carrier mediated diffusion
passive diffusion is driven by?
passive diffusion occurs across (2)
aqueous diffusion - filtration
aqueous diffusion occurs when?
limited capacity, channel size varies (generally for drugs of molecular weight
when is lipid diffusion favored?
if the drug has high lipid:water partition coefficient, often pH dependent; unionized moiety crosses membrane down concentration gradient
what is the most imporant mechanism of membrane passage (with mw 500-800)?
carrier mediated diffusion
many cell membranes contain specialized transporters that regulate entry and exit of important physiologic molecules (sugars, amino acids, neurotransmitters), but some also transport foreign chemicals (xenobiotics) including drugs with structural similiarity
is endo / exo-cytosis important to drug passage?
of minor importance
what is ... substance engulfed by membrane, taken into cell in newly formed vesicle, then released
iron and vit B12
what is... responsible for secretion of substances from cell. Many NTs are released from vesicles into extracellular space upon neuronal activation?
The effect of any given dose of drug on the plasma concentration of that drug (Cp) will depend on the? (2)
rate (time to peak) and
of transfer of drug from the site of administration to the blood
the fraction of unchanged drug reaching the systemic circulation following administration by any route
How do we determine bioavailability?
By comparing AUC (area under the curve from Cp vs time) obtained following a single dose of drug given by any route (most commonly oral route) to the AUC obtained following a sinlge dose by the IV route
F = AUCroute/AUCiv
What does knowledge of drug bioavailability allow for?
Dosage adjustments when the drug is given be different routes of administration (e.g. between the oral and intravenous routes)
IV administration: fraction of dose reaching general circulation [F] is ...
100% as no absorption step is involved (AUC for IV route is taken as the 100% value)
Oral administration: F varies from ...
100% to zero depending on several factors
What factors influence F for oral administration of drug?
Survival of drug in GI environment (acidity, digestive enzymes)
Ability to cross GI membranes
Efficiency of drug metabolism by gut wall or in liver (termed first pass effect);
What characteristics of a drug determine its ability to cross GI membranes
size (molecular weight)
% of drug in the unionized state
first pass-effect =
efficiency of drug metabolism by the gut wall or in liver - wide variation among drugs and between individual patients
What can be a significant factor with oral route drugs?
Other routes of administration for systemic drug action (other than oral and IV) (4)
F approaches 100% (75 to 100) as tissue environment is generally non-destructive to drugs
Rate of absorption ... generally estimated as ...
The peak Cp or time to attain peak Cp plasma levels
Marked interpatient variation exists
Rate of absorption from the oral route.... the drug formulation can be a factor in and the rate can be increased for ______ or ______
or decreased for ____________ or ____________
Increased rate (time to peak is shortened)
rapidly disintegrating tablets
Decreased rate (time to peak is slowed and Cp max is blunted)
enteric coated products
sustained release preparations
Rate of absorption from parenteral routes: generally determined by....
the specific route rather than the individual drug characteristics
From fastest to slowest rate, order of parenteral routes
intravenous = inhalation > intramuscular > subcutaneous > oral
Determining equivalency of Drug Products (given vial oral route) --> FDA requires that manufacturers of generic drugs demonstrate their formulation is bioequivalent to brand name formulation. A generic drug formulation is said to be bioequivalent to a brand name drug formulation if... (2)
rate (estimated by max of peak drug concentration Cmax) and
extend (bioavailability) that the active ingredient drug is absorbed and become available at the site of action (drug entering systemic ciruclation) is similar (Within set limits) to the brand name product
Drugs are considered bioequivalent if ....
the 90% confidence interval of the mean AUC and the mean Cmax of the generic product (T test) is within 80-125% of the brand product
General factors affecting drug absorption (from any site of administration): 5
solubility in biological fluids
rate of dissolution of solid for oral dosage formula or suspended particles for parenteral formulation (can result in differences due to manufacturing considerations [brand vs generic])
concentration of drug at site of administration (creation of concentration gradient)
circulation at site of absorption (can be altered by disease state or exercise)
area of absorbing surface (e.g. stomach vs intestine vs. lungs)
In what way does drug solubility in biological fluids influence absorption?
biological fluids are aqueous (not lipid), the the drug formulation must have some hydrophillicity to dissolve in biological fluids, yet the drug molecule itself must also be lipophilic to cross membranes and distribute to its site of action
What are the most imporant consideration when considering the route of drug administration?
relative rates of onset
Routes for systemic effects (8)
Routes for local effects
What is the most common route for systemic effects?
bioavailability can vary widely (0-100%)
Where are oral drugs mostly absorbed?
GI tracts via passive diffusion - thereby favoring absorption when the drug is in the nonionized (more lipophilic) form
When would you predict that weak acid drugs would be absorbed better?
in the intestine (based on the pH partition effect)
this is because the pH of the stomach is much lower (more protons) than the upper intestine
When would you predicts that weak bases would be absorbed better?
in the upper intestine (based on the pH parition effect) because the pH of the upper intestine is higher (fewer protons)
Where will the rate of absorption of a drug be greater... the small intestine or the stomach... what role does ionization play?
Well... because the extremely large surface area of the intestine, relative to the stomach, the rate of absorption of a drug from the intestine will be greater than that from the stomach, even for drugs predominately ionized in the intestine and largely unionized in the stomach
In what way does gastric emptying time effect drug absorption?
generally, increased GI motility will increase speed of emptying and increase rapidity of absorption by allowing drug to reach the increased absorptive area of small intestine faster
How does food influence drug absorption?
delays by delaying gastric emptying
Purpose of enteric coating
drugs that cause GI irritation or drugs destroyed by gastric secretions can be administered with enteric coating the prevents dissolution until the more basic intestine is reached
controlled release preparations - the rate of drug absorption is slowed by slowing rate of product dissolution allowing a slower, sustained, and uniform absorption of drug lasting 8 hours longer
Advantages - decreased frequency of administration (increasing compliance), maintenance of therapeutic effective overnight, and elimination of peaks (decreased incidence/intensity of undesired effects) and nontherapeutic troughs in plasma levels
Drawback - greater interpatient variabilty in systemic levels obtained and dosage form filure resulting in "dose dumping" and drug toxicity
onset not rapid
bioavailability - variable - generally greater than oral route
When is rectal useful?
when oral route precluded by vomiting, unconsciousness, post-GI surgery, presence of GI irritation, or uncoorperative patient (baby)
Rectal and liver?
Approximately 50% of dose will bypass the liver, thus first pass metabolism is less than for oral route -
absorption is irregular and incomplete, solution absorbed more reliably than suppositories in children
onset - within minutes
bioavailability - generally high
after absorption from the oral mucosa, venous drainage from mouth is to the superior vena cava protecting drug from rapid hepatic first pass metabolism plus faster onset of action
sublingual is useful when?
for drugs that are lipid soluble and relatively potent (
most rapid onset of action (
what is the most direct route of drug aministration?
because factors relevant to absorption (membrane passage) are circumvented
Accuracy and immediacy of drug delivery exceeds all other routes
What is the most hazardous route of drug administration?
Generally approaches bioavail of IV route (100%)
aqueous solutions are absorbed rapidly with rapid onset (5-10min)
What influence IM onset?
onset and extent of absorption can be affected by blood flow at site of injection. Degree of muscle activity can be a factor (via effect on blood flow to area)
Depot forms of IM?
in oil or suspended in other vehicles
exhibit slower, more sustained absorption (drug molecules must be released from vehicle or dissolve prior to absorption)
Generally approaches bioavail of IV (100%)
route often utilized to provide slower, constant rate of absorption
Subcutaneous and rate of absorption alteration?
Period of drug absorption can be altered intentionally as with insulin preparations (varying particle size, protein complexation, and pH)
Inhalation (Gas/volatile liquid)
Rate and Bioavail?
Rate of onset (
inhalation has what type of effect?
What is reponsible for rapid rate in inhalants?
large surface area and high blood flow in pulmonary tissue
treatment of what kind of conditions
what is avoided?
first pass metabolism is avoided
pros - prolonged drug levels can be achieved
cons - potential for unexpected drug accumulation and toxicity
cons - drug must be potent (doses
application of aerosolized particles at site of action in lungs increases local topical effects and reduces systemic effect (dependent on particle size) asthma
inhalation (Aerosol) size dependence
effects dependent on particle size
0.5 microM exhaled (no effect)
1-5 microM deposited into small airways (therpeutic)
10 microM deposited into oropharynx side effects
localized application via skin or mucous membrane for treating local conditions (e.g. inflammation / infection)