SUNO BIOL 304 Module 1c Pharmacokinetics Drug Absorption and Distribution (1)

8/2/2019 SUNO BIOL 304 Module 1c Pharmacokinetics Drug Absorption and Distribution (1)

1/52

HOW DO DRUGS GET

INTO THE BODY?

This Lecture power point is courtesy of

Dr. Edwin Jackson,

American Society of Pharmacology and Experimental Therapeutics


2/52

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:


3/52

HOW DO DRUGS GET

INTO THE BODY?

Unless injected directly into the blood stream,

drugs must be absorbed.


4/52

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


5/52

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:


6/52

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


7/52



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


8/52



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


9/52



PHARMACEUTICAL

PREPARATION?

Enteric Coating - Dissolve in intestines, not stomach

D: DELAYED RELEASE PREPARATIONS


10/52



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


11/52

WHAT DETERMINES MEMBRANE

PERMEABILITY OF DRUGS?

Presence of Aliphatic and Aromatic Structures

Absence of Polar Groups

A: LIPOPHILICITY increases membrane

permeability


12/52

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


13/52


14/52

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


15/52

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


16/52

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


17/52

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


18/52

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


19/52

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


20/52

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


21/52

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


22/52

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)


23/52

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


24/52

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


25/52

LowHigh

DelayedImmediate



BIOAVAILABILITY

High and Reliable Low and/or VariablIV > IM = SC > ORAL

IV > IM > SC > Oral

ONSET OF ACTION

PATIENT COMPLIANCEIV > IM > SC > Oral


26/52

LowHigh

LowHigh



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


27/52

LowHigh



AVAILABILITY OF SUSTAINED RELEASE

DOSAGE FORMS

High LowIM > Oral > SC > IV

TOLERANCE TO FUNKY VEHICLES

Oral = IM = SC > IV


28/52

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


29/52

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)


30/52

Now you know!!

HOW DO DRUGS GET

INTO THE BODY?


31/52

WHERE DO DRUGS GO?


32/52


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.


33/52


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.


34/52


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


35/52

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


36/52

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.


37/52

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.


38/52

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?


39/52

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.



DRUG DISTRIBUTION?



40/52

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:



DRUG DISTRIBUTION?



41/52

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:



DRUG DISTRIBUTION?


42/52

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


43/52

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


44/52

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?


45/52

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



46/52

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.




47/52

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.




48/52

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


WHAT IS THE EFFECT OF ION TRAPPING


49/52

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





50/52

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




51/52

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



52/52

WHERE DO DRUGS GO?

Now you know!!

Documents

SUNO BIOL 304 Module 1c Pharmacokinetics Drug Absorption and Distribution (1)