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 Drug Absorption  and Distribution  Drug Absorption  and Distribution

Drug Absorption and Distribution - PowerPoint Presentation

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Drug Absorption and Distribution - PPT Presentation

Alfred L George Jr MD Department of Pharmacology algeorgenorthwesternedu Drug Absorption Absorption refers to the transfer of a drug from its site of administration to the systemic circulation ID: 775623

drug bioavailability drugs distribution drug bioavailability drugs distribution blood administration plasma absorption binding refers systemic circulation administered bioequivalence concentration

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Slide1

Drug Absorption

and Distribution

Alfred L. George, Jr., M.D.

Department of Pharmacology

al.george@northwestern.edu

Slide2

Drug Absorption

Absorption refers to the transfer of a drug from its site of administration to the systemic circulation.

Depends on route of administration

- intravenous administration does not

require absorption

Bioavailability

Bioequivalence

Slide3

Factors Affecting Drug Absorption

Drug-related

Lipid solubilityWater solubilityMolecular sizeParticle sizeDegree of ionizationConcentrationFormulationInterfering substancesFood

Physiology-related

Age

Absorptive surface area

Integrity of absorptive surface

Gastric emptying time

Intestinal transit rate

Blood flow to GI tract

pH of luminal fluid

Gut microbiome

Slide4

Intravenous

Transdermal

Subcutaneous

Intramuscular

InhalationSublingualOralRectal

Bioavailability

is the main criterion for choosing the route of administration

Routes of Drug Administration

Slide5

Enteral (e.g., via GI tract) - Oral, rectalParenteral - Intravenous, intramuscular, subcutaneousTransdermal (topical)Mucosal - sublingual, intranasal, ocular, intravaginalInhalationIntrathecal (spinal fluid)IntraarticularIntraosseousIntraperitonealIntraocular

Routes of Drug Administration

Slide6

Time to Effect vs Route

Intravenous 30-60 secIntraosseous 30-60 secEndotracheal 2-3 minInhalation 2-3 minSublingual 3-5 minIntramuscular 10-20 minSubcutaneous 15-30 minRectal 5-30 minOral 30-90 minTransdermal min to hours

Best for emergencies

Routes of Drug Administration

Slide7

Routes of Drug Administration

Route

Main Advantages

Main Disadvantages

Oral

Easy, inexpensive, safe,

preferred by patients,

Slow time to effect,

conscious

ness required,

requires functional gut,

bioavailability can be limited

Rectal

Easy,

good absorption,

no first pass metabolism,

good for infants/children

Not preferred by patients

Intravenous

Rapid onset, dependable,

100% bioavailability

Requires an I.V. cannula,

expensive, labor intensive,

pain, risk of infection, bleeding

Intramuscular/

Subcutaneous

Relatively fast onset, no first pass metabolism

Absorption can be unpredictable,

pain, risk of bruising/bleeding

Slide8

Routes of Drug Administration

RouteMain AdvantagesMain DisadvantagesTransdermalEasy, non-invasive,high patient satisfactionSlow time to effect, most drugs not absorbed through skinInhalationRapid absorption, limited systemic deliveryEffectiveness depends on patient technique

Choice of route depends on clinical urgency, type and properties of drug

including bioavailability, condition of patient including age and mental status,

and patient preference

Slide9

Oral Drug Administration

Pharmaceutical phase of absorption

Slide10

Oral Drug Administration

Factors affecting oral absorption

Intrinsic physical and chemical properties

Bioavailability

Gastric acidity and digestive enzymes

Gastric emptying time

Relationship to food intake

Drug metabolism by intestinal epithelium (CYP3A4)

Drug efflux from intestinal epithelial cells (p-glycoprotein)

Inhibitors of CYP3A4 and drug transporters

Slide11

Across the Stomach

Across the Small Intestine

Ibuprofen in the Stomach versus Small Intestine

Slide12

The uncharged form of ibuprofen in the stomach is near 100% whereas it is about 1% in the intestineThe surface area of the intestines is several thousand times larger than that of the stomachLarge surface area of the small Intestines accounts for increased drug absorptionLonger transit times: <1 hr in the stomach and >3 hr in the small intestine also contributes.These factors explain why ibuprofen is largely absorbed from the intestine.

Ibuprofen Absorption in the Stomach

vs Small Intestine

Slide13

Bioavailability

Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.

Metabolism in either the intestinal wall or liver before the drug

can reach the systemic circulation reduces bioavailability

Slide14

Bioavailability

Bioavailability refers to the fraction of an administered dose

of unchanged drug that reaches the systemic circulation.

Metabolism in either the intestinal wall or liver before the drugcan reach the systemic circulation

Slide15

First Pass Metabolism

Slide16

Bioavailability

Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.

Examples of Drugs with

HIGH

bioavailability

Acetaminophen

Amoxicillin

Codeine

Diazepam

Metronidazole

Trimethoprim

warfarin

Slide17

Bioavailability

Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.

Examples of Drugs with

LOW

bioavailability due to

first pass metabolism

Morphine*

Demerol*

Lidocaine*

Nitroglycerin*

Propranolol

*not administered orally

Slide18

Bioavailability

Bioavailability refers to the fraction of an administered doseof unchanged drug that reaches the systemic circulation.

Features of a chemical compound that make it a likely orally active drug in humans

Lipinski's rule of five:

No more than

5

hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)

No more than

10

hydrogen bond acceptors (all nitrogen or oxygen atoms)

A molecular mass less than

500

daltons

An octanol-water partition coefficient log

P

not greater than

5

Slide19

80 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Medical history – hypercholesterolemia, stably treated with atorvastatinTemperature – 100, Blood pressure – 170/110, Pulse – 90Muscle tenderness in thighs, upper armsUrine – 4+ hemoglobin, Serum creatinine 4.2 mg/dlCPK – 19,000 (normal level < 100)

Diagnosis:

nontraumatic

rhabdomyolysis with acute kidney injury, possibly secondary to statin therapy

Slide20

80 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Medical history – hypercholesterolemia, stably treated with atorvastatinTemperature – 100, Blood pressure – 170/110, Pulse – 90Muscle tenderness in thighs, upper armsUrine – 4+ hemoglobin, Serum creatinine 4.2 mg/dlCPK – 19,000 (normal level < 100)

Diagnosis:

nontraumatic

rhabdomyolysis with acute kidney injury, possibly secondary to statin therapy

Slide21

80 year old man was hospitalized in Miami Florida after 4 days of generalized muscle pain, fever, dark urine and fatigue. He was on his annual winter vacation in Miami and was feeling well until this illness.Dietary history revealed he had been drinking 8 ounces of freshly squeezed grapefruit juice every morning when taking his medication (atorvastatin).

Chemicals found in grapefruit juice inhibit CYP3A4 and p-glycoprotein

Increases bioavailability of certain medications

May cause toxic elevations of plasma drug concentrations

Slide22

First Pass Metabolism

Slide23

Effect of Grapefruit Juice on Drug

Oral Bioavailability

The magnitude of grapefruit juice effect is related to the inherent oral bioavailability of the drug.

Large effects occur

with low bioavailable

drugs

Slide24

Bioequivalence

Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.

Generic drugs need to meet 3 criteria:

Pharmaceutical equivalenceBioequivalenceEffective and safe

Pharmaceutical equivalence refers to different drug preparations with same active ingredient, concentration, dose, route of administration- Does NOT equate to bioequivalence!

A generic drug must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the original drug.

Slide25

Bioequivalence

Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.

Example of

bioequivalent

generic drug

Slide26

Bioequivalence

Bioequivalence refers to drug preparations that exhibit the same bioavailability and pharmacokinetics.

Example of

non-bioequivalent generic drug

Original

Generic

Slide27

Drug Distribution

The reversible transfer of a drug between the systemic circulation (blood) and extra-vascular (interstitial) fluids and tissues.

Absorption

Elimination

Distribution

Slide28

Drug Distribution to Tissues

Perfusion-limited tissue distribution

- Initial rate of drug distribution to various sites depends on blood flow to the tissue. First phase: Rapid distribution to organs of high blood flow: brain, heart, liver, and kidneysSecond phase: Slower drug delivery to muscle, most organs, skin and fat which have moderate blood flowPermeability-limited tissue distributionCertain compartments have restricted access Central nervous system (blood-brain barrier) Placenta

Slide29

Drug Distribution to Tissues

Affinity of the drug for tissue site

Lipid soluble,

nonionized

drugs are readily distributed to all organs - particularly adipose tissue.

Ionized drugs in general will remain in the plasma and interstitial compartments

Tissue distribution affects the

apparent volume of distribution

, which in turn affects the half-life of drugs in the body.

Slide30

Apparent Volume of Distribution

A hypothetical volume needed to contain the total amount of administered drug at the same concentration as observed in plasma.

V

D

=

Total amount of drug administered

Plasma concentration

The minimum VD for any drug is ~3L, equivalent to the plasma volume in an adult.

Many drugs can accumulate in tissues, leading to very high V

D

values.

Slide31

Apparent Volume of Distribution

DrugVD (L)*Amoxicillin15Erythromycin55Ethanol49Diazepam77Morphine230Fluoxetine2,500Chloroquine13,000

* per 70 kg body weight

Slide32

Drug Binding to Plasma Proteins

Many drugs are bound to proteins in the blood

Albumin

binds drugs that are

weak acids

Alpha-acid glycoprotein

binds drugs that are

weak bases

Slide33

Drug Binding to Plasma Proteins

Many drugs are bound to proteins in the blood

Protein-bound drugs are pharmacologically inactive

Protein binding lowers the effective concentration

greater binding = less available free active drug

Protein binding slows distribution to extravascular sites

greater binding = less metabolized and eliminated,

resulting in longer half-life

Reversible binding may serve as a storage depot to prolong action

Slide34

Drug Binding to Plasma Proteins

Diseases may affect protein binding of drugs

hypoalbuminemia

(liver failure, malnutrition, kidney diseases with proteinuria) can affect free drug concentration without affecting total plasma concentration.

Drugs may compete for protein binding and cause drug displacement

Example

: sodium valproate can displace phenytoin from albumin and increase free phenytoin concentration

Measurement of free drug concentrations is important

especially when the drug has low therapeutic index!

Slide35

Drug Binding to Plasma Proteins

Effect of low plasma albumin on free phenytoin levels

Slide36

Drug Distribution to Central Nervous System

CNS is less accessible to drugs despite high blood flowLipid-soluble drugs are most permeable to CNSBlood-brain barrier (BBB)Blood – cerebrospinal fluid (CSF) interface

Slide37

Drug Distribution to Central Nervous System

Blood-brain barrier

Anatomic barrier

L

ack fenestration, and vesicles in endothelial cellsTight junctions Limited extracellular spacecovered by basal membrane, astrocyte end-foot processes and pericytes.

Brain capillary endothelial cells:

Slide38

Drug Distribution to Central Nervous System

Blood-brain barrier

Functional

barrier

EffluxTransporters

Slide39

Effect of p-glycoprotein on CNS drug penetration

WT

Ratio

Wild-type (WT)

p-

gp

knockout (KO)

Sprachlin

et al 2005, Drug

Metab

Dispos

33:

165-174

Slide40

Effect of p-glycoprotein on CNS drug penetration

Sprachlin et al 2005, Drug Metab Dispos 33: 165-174

Quinidine is ‘pumped out’ of the CNS by p-gp, whereas ritonavir is not.

WT

Ratio

WT

Ratio

Wild-type (WT)

p-

gp

knockout (KO)

Slide41

Increased drug delivery to the CNS byp-glycoprotein inhibition

Sadeque

et al., 2000, Clin Pharmacol Ther. 68: 231-237

Respiratory depression due to loperamide occurs at the same plasma concentration (60 min) when quinidine is co-administered.

Slide42

Blood-Cerebrospinal Fluid Interface

Slide43

Blood-Cerebrospinal Fluid Interface

A barrier to drug distribution resides in the epithelial cells of choroid plexus, which have tight junctions

Not as restrictive as BBB

Lipid-soluble drugs can penetrate CSF

Choroid plexus capillaries are

fenestrated

The epithelial cells

lining brain ventricles (ependymal cells)

are

leaky and allow

paracellular

transport.

Intrathecal drug delivery of certain drugs successfully bypasses the BBB.