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HOW DO DRUGS GET
INTO THE BODY?
This Lecture power point is courtesy of
Dr. Edwin Jackson,
American Society of Pharmacology and Experimental Therapeutics
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WHY BE CONCERNED ABOUT
HOW DRUGS GET INTO BODY?
Bioavailability - % of dose that gets into body
Bioequivalence - similarity between two formulations of same drug
Speed of Drug Onset - how long it takes the drug to begin working
Dosing Interval - how often the drug should be given
Site of Action - whether the drug stays local or acts systemically
This issue importantly affects:
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HOW DO DRUGS GET
INTO THE BODY?
Unless injected directly into the blood stream,
drugs must be absorbed.
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WHAT IS DRUG ABSORPTION?
The movement of drug molecules across biological
barriers (mostly layers of cells) from the site of
administration to the blood stream.
BIOLOG
ICALBARRIER Vascular SystemSite of Administration
DRUG
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WHAT AFFECTS DRUG ABSORPTION?
Rate of release of drug from pharmaceutical preparation
Membrane permeability of drug
Surface area in contact with drug
Blood flow to site of absorption
Destruction of drug at or near site of absorption
The rate of drug absorption will be affected by:
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
Solutions: No Delay, Immediate Release
Capsules & Tables: Delay (Dissolution) Followed by Rapid Release
Creams, Ointments & Suppositories: No Delay, but Slow Release
A: DOSAGE FORM
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
Decrease Rate of
Dissolution
Binders
Lubricants Coating Agents
B: ADDITIVES (EXCIPIENTS)
Increase Rate of
Dissolution
Disintegrants
Variable Effects on
Rate of Dissolution
Diluents
Coloring Agents Flavoring Agents
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARTAION?
Tablet Compression - Hard tablets dissolve more slowly
Tablet Shape - Round tablets dissolve more slowly
Tablet Size - Large tablets dissolve more slowly
C: MANUFACTURING PARAMETERS
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICAL
PREPARATION?
Enteric Coating - Dissolve in intestines, not stomach
D: DELAYED RELEASE PREPARATIONS
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WHAT DETERMINES RATE OF
RELEASE OF DRUG FROM
PHARMACEUTICALPREPARATION?
Reservoir Diffusion Products - Drug diffuses from pill corethrough membrane shellMatrix Diffusion Products - Drug diffuses through matrix
in which it is embedded
Matrix Dissolution Products - Drug released as matrix dissolves
Osmotic Tablets - Drug pumped out of tablet by osmotic forcesIon-Exchange Products - Drug bound to resin exchanges
with endogenous ions
E: SUSTANED RELEASE PREPARATIONS
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WHAT DETERMINES MEMBRANE
PERMEABILITY OF DRUGS?
Presence of Aliphatic and Aromatic Structures
Absence of Polar Groups
A: LIPOPHILICITY increases membrane
permeability
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WHAT DETERMINES MEMBRANE
PERMEABILITY OF DRUGS?
Weak acids in intestines are mostly ionized
(intestinal pH ranges from 6.6 to 7.5)
Weak bases in stomach are mostly ionized
(stomach pH ranges from 1 to 2)
B: IONIZATION decreases membrane
permeability
For other polar molecules, see next slide
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Factors Affecting Drug Absorption
Transport active vs. passive
pH
Physical factors
blood flow
surface area
contact time
ATP
ADP
+ Pi
A-
BH+
A good example of pH effectis illustrated in next slide
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Ion Trapping: Anesthesia Correlation:
Placental transfer of basic drugs
Placental transfer of basic drugs from mother to fetus:local anesthetics
fetal pH is lower than maternal pH (what does this mean?)
lipid-soluble, nonionized local anesthetic crosses theplacenta converted to poorly lipid-soluble ionized drug
gradient is maintained for continual transfer of local
anesthetic from maternal circulation to fetal circulation
in fetal distress, acidosis contributes to local anestheticaccumulation
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ION TRAPPING
(a form of sequestration)
Ion Trapping
Occurs when a drug is ionized across a cell
membrane and the pH of the transmembrane
medium favors retaining the ionized form of the
molecule: a gradient is established
The ion is said to be trapped or enters a sink
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WHAT DETERMINES SURFACE
AREA FOR ABSORPTION?
Low Surface Area:eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines
High Surface Area
small intestines, lungs, liver
ANATOMY
Low surface area: generally smooth
Large surface area: villi and cavitation
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Internal Structure of Small Intestine
showing increase of surface area for
absorption
=NutrientAbsorption
Villi
Epithelial
cells
Note the
microvilli
Note the
folds of
lining of
intestine
Note the
capillary
network
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WHAT DETERMINES
TISSUE BLOOD FLOW?
Low Blood Flow:eyes, stomach, large intestines,
rectum, subcutaneous tissue
High Blood Flow
small intestines, lungs, muscle, buccal cavity, nasal cavity,liver, brain
A. PHYSIOLOGY
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WHAT DETERMINES
TISSUE BLOOD FLOW?
Some Drugs Are Vasoconstrictors
Some Drugs Are Co-Administered With Vasoconstrictors
Some Drugs Are Vasodilators
In other words, some drugs alter their own
absorption and distribution
B. PHARMACOLOGY
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WHAT DETERMINES
WHETHER A DRUG IS DESTROYED
AT OR NEAR SITE OF ADMINISTRATION?
Liver - hepatic enzymes (first pass effect)
Colon - intestinal microflora
Stomach - digestive enzymes and acids
BIOCHEMISTRY
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THINKING CAP TIME
QUIZ:
What molecular group of drugs will NOT likelysurvive as an intact molecule when in thestomach?
What molecular group of drugs will NOT beabsorbed from the stomach?
(possible answers: proteins, lipids, weak bases, strong bases, weakacids, strong acids, carbohydrates, ionic molecules)
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WHAT ARE THE ROUTES OF
ADMINISTRATION FOR DRUGS?
Oral
Sublingual
Rectal
ENTERAL(Digestive tract)
Intravenous (IV)
Intra-arterial (IA) Subcutaneous (SC) Intradermal (ID)
Intramuscular (IM) Intraperitoneal (IP)
Lungs (Inhalation) Skin (Topical)
PARENTERAL
Nose (Intranasal)
Eye (Opthalmic) Ear (Otic) Vagina Urethra
Urinary Bladder
Intrathecal Epidural Directly Into Target Tissue
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LowHigh
High
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
SAFETY
High LowOral > SC > IM > IV
Oral > SC > IM > IV
CONVENIENCE
Low
COSTIV > IM > SC > ORAL
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LowHigh
DelayedImmediate
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
BIOAVAILABILITY
High and Reliable Low and/or VariablIV > IM = SC > ORAL
IV > IM > SC > Oral
ONSET OF ACTION
PATIENT COMPLIANCEIV > IM > SC > Oral
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LowHigh
LowHigh
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
INTERACTIONS WITH FOOD
Risk No Risk Oral > IV = IM = SC
Oral > IM = SC = IV
COMMERCIAL AVAILABILITY OF DOSAGE FORMS
VOLUME OF DRUGOral = IV > IM > SC
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LowHigh
WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF
ORAL, IV, IM AND SC ADMINISTRATION?
AVAILABILITY OF SUSTAINED RELEASE
DOSAGE FORMS
High LowIM > Oral > SC > IV
TOLERANCE TO FUNKY VEHICLES
Oral = IM = SC > IV
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WHY CONSIDER OTHER ROUTES OF
ADMINISTRATION?
Sublingual - Rapid absorption
that bypasses liver
Rectal - Great for patient that
is vomiting or cannot (will not)
swallow medication
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WHY CONSIDER OTHER ROUTES OF
ADMINISTRATION?
Lungs (Inhalation) Skin (Topical)
Nose (Intranasal) Eye (Opthalmic)
Ear (Otic)
Vagina
Urethra Urinary Bladder
Intrathecal Epidural
Directly Into Target Tissue
IS OFTEN DESIRABLE TO CONCENTRATE
MEDICATION AT TARGET SITE TO
INCREASE EFFICACY AND
DECREASE TOXICITY
(The purpose here is to limit systemic absorption)
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Now you know!!
HOW DO DRUGS GET
INTO THE BODY?
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WHERE DO DRUGS GO?
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WHY BE CONCERNED ABOUT
WHERE DRUGS GO?Where drugs go determines Where Drugs Act:
Ciprofloxacin [Cipro] penetrates the prostate gland and
therefore is effective in bacterial prostatitis, whereasmost antibiotics do not enter the prostate and
are therefore ineffective in prostatitis.
Fexofenadine [Allegra] is largely excluded from the brain
and therefore is a nonsedating antihistamine, whereas
most antihistamines freely enter the brain and
cause marked drowsiness.
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WHY BE CONCERNED ABOUT
WHERE DRUGS GO?Where drugs go influences Where Drugs Are Eliminated:
Penicillin is actively transported into the proximal tubules and
is therefore rapidly excreted by the kidneys.Can be influenced by PROBENECID
Probenecid inhibits secretion and keeps penicillin in blood
Inhalation anesthetics distribute to alveolar spaces andtherefore are eliminated by the lungs.
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WHY BE CONCERNED ABOUT
WHERE DRUGS GO?
Where drugs go influences How Long Drugs Last In the Body :
Raloxifene [Evista]) (for treatment of osteoporosis in
postmenopausal women) is transported by the liver into theintestines where it is reabsorbed (enterohepatic recirculation).
This greatly increases the time raloxifene lasts in the body.
Iodine is sequestered in the thyroid gland
Lipid-soluble drugs stay sequestered in adipose tissues for a long
time before being slowly released into the blood for action
and metabolism in the liver
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WHAT ARE THE DETERMINANTS OF
WHERE DRUGS GO?
Organ blood flow
Barriers to drug diffusion
Adipose tissue
Tissue protein binding
Determinants of Drug Distribution:
Plasma protein binding
Drug transport
Ion trapping
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WHAT IS THE EFFECT OF ORGAN BLOOD
FLOW ON DRUG DISTRIBUTION?
Organs with high blood flow will have larger amounts
of drug delivered to them per unit time.
Organs with high blood flow will experience initial high
concentrations of drug, but these high concentrations
will diminish as the drug is redistributed
throughout the body to sites
with lower blood flow.
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WHAT IS THE EFFECT OF ORGAN BLOOD
FLOW ON DRUG DISTRIBUTION?
Organs with high blood flow will experience larger initial effects.
Many sedative/hypnotics, such as benzodiazepines (e.g., diazepam
[Valium]) will produce initial, but short-lived,
profound CNS effects following
IV administration.
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Most capillaries have pores between the endothelial
cells lining the capillaries.
These pores allow for rapid diffusion of most drugsinto the interstitial space.
In some capillary beds, however, the endothelial cells
are closely connected by tight junctions, and
such capillaries do not have pores
between the endothelial cells.
WHAT IS THE EFFECT OF BARRIERS
TO DRUG DIFFUSION ON
DRUG DISTRIBUTION?
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In capillaries with tight junctions, drug molecules must diffuse across
(transcellular), rather than around (paracellular)
the endothelial cells.
Only lipophilic drugs rapidly diffuse across capillary beds
with tight junctions, whereas hydrophilic
drugs are mostly excluded.
WHAT IS THE EFFECT OF BARRIERS
TO DRUG DIFFUSION ON
DRUG DISTRIBUTION?
WHAT IS THE EFFECT OF BARRIERS
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Capillaries in brain have tight junctions that contribute to the BBB.
Capillaries in brain are wrapped by pericapillary glial cells that
further contribute to the BBB.
The endothelial cells in brain capillaries have P-glycoprotein that
pumps drugs out of endothelial cells, and this
also contributes to the BBB.
The blood-brain barrier (BBB) is a special case:
WHAT IS THE EFFECT OF BARRIERS
TO DRUG DIFFUSION ON
DRUG DISTRIBUTION?
WHAT IS THE EFFECT OF BARRIERS
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In general, the BBB restricts the movement of hydrophilic
drugs into brain; however, the BBB is broken
by ischemia and inflammation.
The BBB can be exploited to develop drugs with
reduced CNS adverse effects.HOW?
The blood-brain barrier (BBB) is a special case:
WHAT IS THE EFFECT OF BARRIERS
TO DRUG DIFFUSION ON
DRUG DISTRIBUTION?
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Lipophilic drugs will distribute into adipose (fat) tissue.
Distribution of lipophilic drugs into fat may necessitate a larger initial
bolus of drug to achieve the desired effect.
Large depots of drug in fat may necessitate a longer period of
time for drug to be removed from the body.
The distribution of lipophilic drugs will be differentin thin versus obese patients.
WHAT IS THE EFFECT OF ADIPOSE TISSUE
ON DRUG DISTRIBUTION?
QUIZ TIME
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QUIZ TIME
Describe how knowledge of factors affecting
entry of drugs into the brain can be used to
design drugs that can concentrate in the brain.
Based on the above information, how will youdesign a drug that will have primarily
peripheral effect?
SUBMIT YOUR ANSWERS NEXT WEEKTUESDAY FOR GRADING
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Some drugs are highly bound to tissue proteins.
Binding of drugs by tissue may necessitate a largerinitial bolus of drug to achieve the desired effect.
Large depots of drug in tissue may necessitate a longe
period of time for drug to be removed from the body.
WHAT IS THE EFFECT OF TISSUE PROTEIN
BINDING ON DRUG DISTRIBUTION?
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Some drugs are highly bound (> 90%) to plasma proteins.
Acid drugs bind to albumin and basic drugs bind toalpha1-acid glycoprotein.
Binding of drugs by plasma proteins limits the distribution of drugs
out of the vascular compartment, necessitating more drug
initially to achieve the desired effect.
WHAT IS THE EFFECT OF PLASMA PROTEIN
BINDING ON DRUG DISTRIBUTION?
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Binding of drugs may limit the delivery of drugs t
drug elimination mechanisms (for exampleexcretion by the kidney or metabolism by the liver
and this increases the time required for the drug t
be removed from the body.
WHAT IS THE EFFECT OF PLASMA PROTEIN
BINDING ON DRUG DISTRIBUTION?
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Displacement of a highly plasma-protein bound drug by another drug
may lead to drug-drug interactions because of a rapid increase
in the availability of free (unbound) drug.
Displacement of unconjugated bilirubin from albumin by
drugs may precipitate bilirubin
encephalopathy in newborns.
WHAT IS THE EFFECT OF PLASMA PROTEIN
BINDING ON DRUG DISTRIBUTION?
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Transport mechanisms may increase or decrease the distribution of
drugs to certain tissues. For example, most diuretics are
transported by the proximal tubules into the nephron,
a process that delivers the diureticsto their site of action.
Competition for transport may result in drug-drug interactions. For
example, probenecid ( a drug used for gout) blocks the transport
of diuretics into the proximal tubule and thereby markedlyblunts the effects of diuretics on salt and water excretion.
WHAT IS THE EFFECT OF DRUG TRANSPORT
ON DRUG DISTRIBUTION?
WHAT IS THE EFFECT OF ION TRAPPING
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BIOLOGICALBAR
RIER
(=plasmamembrane)
Compartment
with High pH
Compartment
with Low pH
Unionized
Weak Acid
IonizedWeak Acid
Unionized
Weak Acid
IonizedWeak Acid
Higher total
concentratio
of weak acid
WHAT IS THE EFFECT OF ION TRAPPING
ON DRUG DISTRIBUTION?
WHAT IS THE EFFECT OF ION TRAPPING
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B
IOLOGICALBARR
IER
Compartment
with High pH
Compartment
with Low pH
Unionized
Weak Base
Ionized
Weak Base
Unionized
Weak Base
Ionized
Weak Base
Higher total
concentration
of weak base
WHAT IS THE EFFECT OF ION TRAPPING
ON DRUG DISTRIBUTION?
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Ion trapping can be used to distribute drugs into the urinary
compartment to increase the urinary excretion of poisons.
Example: Alkalinization of the urine with systemic administrationof sodium bicarbonate is useful for the treatment of overdoses
of aspirin and phenobarbital. (Explain this)
Example: Acidification of the urine with systemic administration of
ammonium chloride is useful for the treatment ofamphetamine overdoses.
WHAT IS THE EFFECT OF I0N TRAPPING
ON DRUG DISTRIBUTION?
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WHERE DO DRUGS GO?
Now you know!!
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