Pharmacologic Principles, Drug Absorption, and Distribution Flashcards
Substance bound to receptor at cell surface, engulfed by membrane, taken into cell in newly formed vesicle, then released [vitamin B12 and iron]
endocytosis
Published values for Vd have units of ___ and are calculated based on ____
L / kg
a patient’s weight
Extent of Absorption, aka
-(known as Bioavailability (F or f [%] for Fraction bioavailable)
dissociation of a proton from an acid produces an ____ drug, whereas dissociation of a proton from a base produces an ____ drug
ionized
unionized
how is it possible that 2 drugs that have similar pKa’s (and similar % non-ionization) are absorbed differently?
based on their inherent lipid solubility of the non-ionized form
select drug and dose is based on what?
Pharmacodynamics - Disease Targets - Drug Regulation
what is the rate of onset of action and bioavailability of sublingual-buccal routes?
- onset of action w/in minutes
- F is generally HIGH
how can the period of drug absorption be altered INTENTIONALLY with subcutaneous drug administration?
- w/ insulin preparation (varying particle size, protein complexation, and pH)
- local anesthetics (addition of vasoconstrictor)
- contraceptives (pellet implantation under skin)
Bioavailability (F) for oral administration depends on what 4 factors?
- Survival of drug in GI environment (acidity, digestive enzymes)
- Ability to cross GI membranes, determined by physiochemical characteristics of the drug: lipid solubility, size (molecular weight), and % of drug in the unionized state
- Efficiency of drug metabolism by the gut wall or in liver (termed first-pass effect); wide variation among drugs and between individual patients
- Patient compliance
how do you determine Vd?
a single dose of drug Ab is administered IV and Cp at time 0 (C0) is determined-> then determine Vd by:
Vd= amount of drug in body (Ab)/ concentration of drug in plasma
what does pKa refer to?
refers to the pH of a solution at which the concentrations of the protonated and non-protonated forms of the drug are equal (and is a constant for any given drug)
what is the relationship between Cp and Vd?
inverse relationship- the more of the dose that remains in the plasma the less the distribution volume
what is the rate of onset of action and bioavailability of rectal routes?
- onset NOT rapid
- F is variable but generally greater than oral route
Displacement of first drug from protein binding site by second drug administration results in ____ levels of unbound first drug, but note that levels of TOTAL drug are ___ because the administration rate is unchanged
increased
unchanged
*increase is often small and transient as free drug distributes to tissue and subject to metabolism and excretion
Acids are capable of ____ a proton (and thereby become charged)
Bases are capable of ____ a proton (and thereby become charged)
releasing
taking up
what are potential advantages of controlled-release preparations of oral meds?
- decreased frequency of administration (increasing compliance)
- maintenance of therapeutic effect overnight
- elimination of peaks (decreased incidence/intensity of undesired effects) and non-therapeutic troughs in plasma levels
At equilibrium, ____ concentration of drug is the ___ on both sides of the membrane, but TOTAL concentration of drug is ____ on side where ionization is greater - drugs are trapped where they are predominantly ____
UNIONIZED
SAME
greater
ionized
Vd for drugs highly water soluble that enter cells poorly. Examples?
Extracellular water (12-15L)
Ibuprofen 11 L
Gentamicin 22 L
what are 3 clinical significant cases on ion trapping?
- Alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion. E.g., alkalinization of urine can trap weak acid aspirin in overdose situations.
- Greater potential to concentrate basic drugs (e.g., opioids) in more acidic breast milk.
- In forensic pathology, weak base toxins (e.g., phencyclidine, methamphetamine) are found concentrated in the acidic stomach contents.
the rate of absorption of drugs from parenteral routes of administration is generally determined by what? Examples?
the specific route rather than individual drug characteristics as follows (for the most commonly used routes of administration):
fastest to slowest:
intravenous = inhalational - intramuscular - subcutaneous - oral
Acids become nonionized in ___ medium. Bases become nonionized in ___ medium.
acid
alkaline
Vd allows the prescriber to determine the effect any given dose [D] will have on the ___
plasma concentration [Cp],
** i.e., it can be considered as a “dilution factor”
____ is the key element in pharmocotherapeutics, and is designed to ______
- Dose Regimen
- ensure that the desired steady state drug level [Cpss (avg)] is maintained within the therapeutic window by balancing the rate of drug elimination with the prescribed rate of drug administration.
what is the rate of onset of action and bioavailability of IV route?
- most rapid onset of action (less than 5 min)
- F = 100% by definition
why is the rate of absorption so high (5-10 min) for inhalation?
due to large SA and high blood flow in pulmonary tissue
what is the bioavailability for other routes of administration for systemic drug action including IM/SC/inhalation/sublingual?
F approaches ∼ 100% (75-100%) as tissue environment is generally non-destructive to drugs.
The pH of biologic fluids containing weak acid and weak base drug molecules influences their distribution across membranes by affecting their _____
lipid solubility
Drugs that cause GI irritation or drugs destroyed by gastric secretions can be administered with an enteric coating that _____ until the more basic intestine is reached
prevents dissolution
___ also allows determination of the necessary dose (Ab is the loading dose [LD]) to fill the distribution volume with enough drug to achieve desired steady state plasma level (Cp). Its formula/equation is
Vd
LD= Cp(desired) x Vd
Vd will vary between patients depending on:
- body size (units of L/kg– calculate based on weight)
- composition (fat vs lean)
- Changes in protein binding
will the rate of absorption of a drug be greater from the intestines or stomach? Why?
Greater from intestines bc of its extremely large SA
*even for drugs predominately ionized in the intestine and largely unionized in the stomach
filtration: Limited capacity, channel size varies (generally for drugs of molecular weight less than 100-200)
aqueous passive diffusion
what is the rate of onset of action and bioavailability of inhalation routes?
- rate of onset (less than 5 min)
- F ~ 100% comparable to IV
graphs of Cp vs time determine what?
drug pharmacokinetics
Pharmacotherapy involves selection of the right drug in the right dose to interact with the right drug target to produce the desired therapeutic effects, which are __, ___, ___, or ___
prevention, diagnosis, treatment, or cure of a particular disease
what is the pH in the stomach, SI, plasma, CSF, urine
stomach: 1-1.5 SI: 5-6 Plasma: 7.4 CSF: 7.4 Urine 6 (ranges 4-8)
_____ is concerned with the effects of biologic systems on drugs and deals with the processes of absorption, distribution, and elimination (metabolism and excretion)
Pharmacokinetics
what factors limit a drugs ability to distribute to certain compartments?
large size, protein bound, highly charged, high water solubility
what factors influence the rate of absorption for oral routes? examples?
drug formulation
- increased for: liquid preparations or rapidly disintegrating tabs (time to peak is shortened)
- decreased for: enteric coated products or sustained released preparations (time to peak slowed and Cp max blunted)
Drug bioavailability (% of dose reaching blood) ROUTES
100%-
75-100%-
0-100%-
100%- IV
75-100%- intramuscular, subcuctaneous, sublingual-buccal, inhalation, transdermal (approaches 100% as tissue environment non-destructive to most drugs)
0-100%- Oral (due to GI environment or 1st pass effect metabolic effect)
What tissues have tight junctions between cells, and what effect does this have on drug distribution?
GI mucosa, BBB, placenta, renal tubules
-requires drug to pass through lipid membranes to or from compartment into or out of the blood
Pharmacokinetic Parameters of Distribution
- rate of distribution (seldom of clinical consequence)
- Extent of distribution or volume of distribution (Vd in L/kg)
- Distribution compartments
what are the 4 main effects of drug binding to protein
- Reduces concentration of active, free drug (can limit fetal exposure to drugs)
- Hinders metabolic degradation and reduce rate of excretion
- Decreases volume of distribution by enhancing apparent solubility in blood
- Decreases ability to enter CNS across blood brain barrier
select dosage and frequency (interval) is based on what?
Based on Pharmacokinetics –> Metabolism – Excretion
when pH is less than pKa, what forms predominate?
protonated forms HA and BH+
what are the basic elements of dosage regimen
Drug, dose, route, frequency, duration
Following filtration at glomerulus (note that large or protein bound drugs are not filtered), renal tubules have ___ ___ back into blood and ___ urinary EXCRETION
reduced reabsorption
-increase
is there the first pass metabolism with rectal drug administration?
~50% of dose will bypass the liver (first pass metabolism) – therefore is less than oral routes
what are the approximate volumes of the various body compartments (for 70kg person)? plasma/blood: Extracellular water: Total body water: Other compartments:
Plasma/blood: 3-5 L
Extracellular water: 12-15L
Total body water: 42L
Other compartments: more than 50L
potential disadvantages of transdermal drug administration
- Prolonged drug levels can be achieved - potential for unexpected drug accumulation and toxicity
- Drug must be potent (doses less than 2 mg); must be able to permeate skin sufficiently for systemic effects
- must be nonsensitizing, nonirritating
physiologic factors that influence drug distribution
- pH of biological fluids in various drug compartments
- tight junctions btwn cells (GI mucosa, BBB-placenta, renal tubules)
- lipid solubility
- protein binding
lower Vd values are generally indicative of what
drugs located mostly inside plasma or ECF (extensive binding to plasma proteins, large size, or low lipid solubility)
Vd for drugs [often high lipid solubility] sequestering at specific sites: CNS / fat / protein. Examples?
Other compartments (more than 50L) Amitriptyline (1050 L) Fluoxetine (2450 L) Chloroquine (13755)
for each log unit the pH is below the pKa there will be increments of ___ more protonated drug
10-fold
what are potential drawbacks of controlled-release preparations of oral meds?
- greater interpatient variability in systemic levels obtained
- dosage form failure resulting in “dose-dumping” and drug toxicity
____ is a measure of ability of body to remove drug from plasma compartment and is related to the elimination rate constant [ke], which is related to the more clinically useful ____
clearance
-half life
how can you calculate Cp (plasma concentration)?
Cp= D/Vd
D=any given dose
**Vd is considered a dilution factor
how does protein binding influence distribution?
only free drug is diffusible
What tissue has NEGLIGIBLE ABSORPTION of drug into blood if administered orally
GI mucosa
factors that influence drug membrane passage
- Molecular size- can be affected by drug binding to plasma proteins
- 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
What pHs are drug absorption favored and when is ion-trapping favored?
- At pHs where the unionized form predominates, drug absorption is favored
- at pHs where the ionized form predominates, ion-trapping is possible
protein binding hinders metabolic degradation and reduces excretion how?
- will DECREASE elimination rate and INCREASE half-life
i. e., acts as circulating drug reservoir that can PROLONG DRUG ACTION
why is the rate of onset and absorption so rapid for sublingual-buccal administrated drugs?
after absorption from 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
is there the first pass metabolism with transdermal drug administration?
No- it is avoided
what is the difference between enteral vs parenteral administration?
enteral- drug is placed w/in GI tract (ex. oral)
parenteral- drug is placed outside GI tract (ex. rectal)
what is bioavailability [F] and what is it used for?
describes extent of absorption of drug from non-intravenous site of administration and is used to convert oral doses to intravenous doses and vice-versa
Distribution of drug may not be homogenous and the actual sites of distribution are often speculative ( Vd is still useful even if “apparent” or real). How can you measure EXTENT of drug distribution
comparing the Vd of a drug with the volumes of the water compartments in the body
important concepts relevant to single or first dose administration include:
- onset of effect- time to reach the MEC
- duration of the action- time above the MEC
- Therapeutic window (or therapeutic index)- difference in [Cp] btwn desired and adverse response MEC
Acidic drugs bind primarily to ____
basic drugs bind primarily to ____
albumin
alpha-1 acid glycoprotein
mechanisms for membrane passage
- passive diffusion- driven by concentration gradient (ie. aqueous and lipid diffusion)
- carrier-mediated diffusion- (active or facilitated)
- endocytosis-exocytosis
drug-drug displacement interactions are very unlikely to be of clinical consequence unless:
- Displaced drug has narrow therapeutic index
- Displacing drug is started in high doses
- Vd of the displaced drug is small
- Response to drug occurs more rapidly than redistribution
Used to determine interval between doses [τ] necessary to maintain the desired steady state plasma level [Cpss (avg)].
clearance
select duration is based on what?
disease pathophysiology
important concepts relevant to multiple or maintenance dose administration include:
- Steady state- condition exists when the rate of drug administration [rate in] = rate of drug elimination [rate out]
- time to steady state- attained in 4-5 half lives when maintenance doses are administered at constant intervals
- steady state concentrations- avg. Cp after SS is achieved
- Fluctuation in SS Cp- related the number of half lives in the dosing interval (time btwn doses)
Size of compartment necessary to account for total amount of drug in the body if it were present throughout body at same concentration found in plasma (Cp)
Vd
*It is the volume of the body fluids into which the drug distributes following its administration
when would rectal drug administration best be used?
- Useful when oral route precluded by vomiting
- unconsciousness
- post-GI surgery
- presence of GI irritation, or
- uncooperative patient
*Otherwise, patient acceptance is not high.
Fraction of dose reaching general circulation [F] is 100% as no absorption step is involved
IV administration
*(AUC for IV route is taken as the 100% value)
higher Vd values are generally indicative of what?
drugs located mostly outside plasma (increased tissue binding, high lipid solubility)
what are routes of drug administration for local effects?
- inhalation
2. topical
what is volume distribution [Vd] and what is it used for?
describes extent of movement of drug throughout various body compartments and is used to convert a drug dose to a plasma concentration (Cp), i.e., a dilution factor.
what is the rate of onset of action and bioavailability of intramuscular routes?
- aqueous solutions absorbed rapidly w/ rapid onset (5-10 min)
- approaches F of IV route (~100%)
what factors influence the rate and extent of absorption for intramuscular administration
- blood flow at site of injection
- degree of muscle activity (via effect on blood flow to area)
- depot forms in oil or suspended in other vehicles exhibit SLOWER, MORE SUSTAINED absorption (bc drug molecule must be released from vehicle or dissolve prior to absorption)
Based on the pH-partition effect, one would predict that weak acid drugs would be absorbed better from ____ than ____ and vice versa for weak bases
stomach (pH 1 to 2) than upper intestine (pH 3 to 6)
Most important mechanism for majority of drugs with molecular weights of 500-800
lipid passive diffusion
*unionized moiety crosses membrane down concentration gradient.
The effect of any given dose of drug on the plasma concentration of that drug (Cp) will depend on ____ and ___ from the site of administration to the blood
- the rate (time to peak) and
- extent (bioavailability) of transfer of drug from the site of administration to the blood
how do you determine the % of drug in non-ionized (lipid-soluble) form?
use HH equation
inhalation drug administration effects are dependent on ___. For instance:
particle size
- less than 0.5 µM –> exhaled (no effect)
- 1-5 µM –> deposited in small airways (therapeutic effect)
- greater than 10 µM –> deposited in oropharynx (side effects)
Knowledge of drug bioavailability allows for _____ when the drug is given by different routes of administration, e.g., between the oral and intravenous routes.
dosage adjustments
what is the first-pass effect?
drug metabolism by the gut wall or in the liver before it reaches systemic circulation
what is the rate of onset of action and bioavailability of subcutaneous routes?
- slower constant rate of absorption
- approaches F of IV route (~100%)
what are general factors that affect drug absorption (from any site of administration)
- drug solubility in biologic fluids
- rate of dissolution (solid for oral dosage formulation 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
when pH is more than pKa what forms predominate?
deprotonated forms A- and B
topical drug administrat typically has minimal systemc absorption, BUT there is a greater potential for systemic availability in children due to __
greater ratio of body SA to weight
Pharmacokinetic Parameters of Distribution concerns _____, including specific and non-specific sites of action
passage of drugs from the plasma into the extravascular tissues
- Bypasses absorption barriers, thus can result in introduction of infectious agents
- Most hazardous route, easy to reach toxic levels rapidly, reversal of effect often difficult
IV route of administration
It is possible that some highly lipophilic drugs may concentrate in ___ or be extensively bound to tissue proteins and have volumes of distribution that are _____
fat
much larger than body size (greater than 100-500 liters)
Goal of pharmacotherapy when multiple doses are administered is to
reach and maintain plasma concentrations at steady state within the therapeutic window to produce the desired response with a minimum of toxicity.
the therapeutic window/index is marked by what?
MEC (minimum effective concentration) for adverse response and MEC for desired response
When the pH is higher than the pKa of the drug there are relatively fewer protons and the unprotonated form of the weak acid _____ or weak base _____ drug will predominate
[ionized-hydrophilic]
[unionized-lipophilic]
exocytosis- Responsible for secretion of substances from cell. Many neurotransmitters are released from vesicles into ____ upon ___
extracellular space upon neural activation
what are the most important variables to consider when determining the route of drug administration?
- bioavailability (fraction of dose reaching the blood)
- relative rate of onset of drug effect (time to peak effect)
- duration of drug action (time above MEC)
A generic drug formulation is said to be bioequivalent to a brand name drug formulation if:
- Rate (estimated by maximum of peak drug concentration [Cmax]) and extent (bioavailability) that the active ingredient drug is absorbed and becomes available at the site of action (drug entering systemic circulation) is similar (within set limits) to the brand name product
- if 90% confidence interval of the mean AUC and the mean Cmax of the generic product is within 80-125% of the brand product
Favored if drug has high lipid:water partition coefficient, often pH dependent
lipid passive diffusion
what elements do a prescription have?
contain basic elements of DOSAGE REGIMEN
drug, dose, route, frequency, duration
when and how can ionized drug molecules cross capillary walls and how since they cannot pass through membranes with tight junctions btwn cells?
- they can cross capillary walls through pores
- can enter plasma circulation following parental administration
- can enter the urine tubular fluid following filtration at the glomerulus
anatomic barriers to drug distribution. Examples?
- tissues w/ tight junctions btwn cells can limit movement of certain drugs (large size, protein bound, ionized, high water solubility) affecting pharmokinetic proccesses
- GI mucosa: negligible absorption
- BBB-placenta: limited distribution
- renal tubules: reduced reabsorption back into blood and increased urinary EXCRETION
MOST drugs are ____ and ____ a central body (plasma) compartment and, since they are rapidly distributed, they act as if they ____
absorbed into
eliminated from
display single compartment kinetics
**a few drugs, the distribution of drug into a second peripheral (tissue) compartment is slow and the drug may display 2-compartment pharmacokinetics
Why is there limited distribution of a drug into brain or fetal circulation?
structural differences between brain and nonbrain capillaries
- Brain capillary: solutes must diffuse through 2 membranes
- Non-brain capillary: solutes move through fenestrations by passive diffusion
When the pH is lower than the pKa of the drug there are relatively more ____ and the ____ form of the weak acid _______ or weak base ___ drug will predominate (greater than 50% of the total)
protons
protonated
[unionized-lipophilic]
[ionized]
select route of administration is based on what?
Based on Pharmacokinetics –> Absorption - Distribution
______ - Many cell membranes contain specialized transporters that regulate entry and exit of important physiologic molecules (ie.. ___ and ___ ), but some also transport foreign chemicals (xenobiotics) including drugs with structural similarity
Carrier-mediated Diffusion
ie. sugars amino acids and neurotransmitters
what route of administration is most commonly used for drugs with narrow therapeutic index
IV
ROUTES: speed of onset of drug effect (time to peak)
Most rapid-
Intermediate-
Slower-
Slowest-
Most rapid (sec to min)- inhalation (volatile gas- aerosol), IV
Intermediate (5-15 min)- sublingual, buccal, intramuscular, subcutaneous
Slower (15-30 min)- oral
Slowest (hrs)- transdermal, oral (enteric-coated and sustained release formulations), IM and SC
what are used to estimate the rate of absorption?
time to attain peak Cp and peak Cp
ie. Tmax and Cmax
with inhalation drug administration, application of ____ at site of action in lungs increases_____ effects and reduces ____ (dependent on particle size). Beneficial in treatment of asthma.
aerosolized particles
- increase local topical effects
- reduces systemic effect
how is bioavailability determined?
by comparing the AUC (area under the curve from Cp vs time) obtained following a single dose of drug given by any route (most commonly the oral route) to the AUC obtained following a single dose by the IV route
(aka F= AUCroute/AUC iv)
How does gastric emptying time affect drug absorption for oral routes?
- Increased GI motility = increased rapidity of absorption (by allowing drug to reach the increases absorptive SA of SI faster)
- food delays absorption of drugs by delaying gastric emptying
Vd for drugs highly bound to plasma proteins. Examples?
plasma/blood (3-5L)
Heparin 4L
Warfarin 10L
drug effects (whether therapeutic or toxic) are directly correlated to what?
plasma concentration (Cp)
protein-binding is rarely of clinical concern unless changes occur ___ therapy has been started
AFTER
____ influences the rate and extent of absorption
routes of administration
slow rate of distribution out of the plasma compartment can lead to what for drugs given IV?
bolus toxicity
Vd for drugs that freely enter cells, e.g., small molecules. Examples?
Total body water (42L)
Lithium 46L
Ethanol 42L
what is the Henderson-Hasselbach equation?
pH - pKa = log [non-protonated: A- or B]/[protonated form: HA or BH+]
Pharmacokinetics of Elimination - Half-life [t1/2] allows quick rule-of-thumb estimates of:
- time for elimination of drug from plasma (4-5 half lives)
- time to reach SS plasma drug levels following multiple doses (4-5 half lives)
- fluctuations in plasma levels between doses (proportional to number of half-lives in dosing interval)
Vd gives an indication of what?
the extent to which a drug passes from plasma to extravascular tissue
*essentially a partition coefficient between plasma and rest of body (values from plasma volume to hundreds of liters).
give 6 examples of drugs that can be administered transdermally
clonidine, nitroglycerin, estrogens, testosterone, fentanyl, nicotine
when will ion trapping be relatively insignificant?
If predominant form of the drug on both sides of the lipid barrier is the non-ionized form
**must have ions present to have ion trapping
Bioavailability is defined as
the fraction of unchanged drug reaching the systemic circulation following administration by any route
Acidic drugs are trapped in the more ___ solutions
Basic drugs are trapped in the more___ solutions
basic
acidic
*Ex. weak base algesic can get trapped in breast milk longer (more acidic than plasma)
Pharmacokinetic and pharmacodynamic principles allow the determination of the relationship between __, __, and ___
the dose of drug given to a patient, the plasma concentration (Cp) that results from that dose, and the clinical effects that will result from that plasma concentration
Most drug absorption from GI tract occurs via _____, thereby favoring absorption when the drug is in the___ and __ form
passive diffusion
-nonionized and more lipophilic form
what are potential disadvantages of intramuscular drug administration?
- absorption may be erratic and incomplete if drug solubility is limited (ie. diazepam)
- pain
- tissue necrosis (if high pH)
- microbial contamination
what is the rate of onset of action and bioavailability of oral routes?
- relatively slow onset of action
- F can vary from 0-100%
what 5 factors can increase systemic absorption in topically administered drugs?
- application over large SA
- application to denuded area
- use of occlusive dressings
- highly lipid soluble drugs
- greater ratio of body SA to weight in children
drug solubility in biologic fluids affects drug absorption (from any site of administration)-
This is an aqueous environment (not lipid):
- Thus the drug FORMULATION must have some_____ to dissolve in biologic fluids,
- yet the drug MOLECULE itself must also be____ to cross lipid membranes and to distribute to its site of action
hydrophilicity
lipophilic
Are ionized or nonionized forms are more readily absorbed?
Nonionized
-ionized forms do not cross lipid membranes
what route of administration is useful for drugs that are lipid soluble and relatively potent (less than 1 mg doses) and why?
- sublingual-buccal route
- as there is a smaller surface area for absorption relative to GI tract
