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Pharmacokinetics

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Site of

ActionDosage Effects

Plasma

Concen.

Pharmacokinetics Pharmacodynamics

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Systemic Availability

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A discipline that concerns the study and

characterization of the time course of drug

Absorption

Distribution

Metabolism

Excretion

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Bound Free Free Bound

LOCUS OF ACTION

RECEPTORS

TISSUE

RESERVOIRS

SYSTEMICCIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION

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Passage of drugs across membranes

Structure of the plasma membrane

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Mechanisms of transport

Passive diffusion: passage of drugs through the

lipid surface (major mechanism of drug

absorption)

Lipid-soluble drugs

Small water-soluble drugs

Noncharged form of weak electrolytes

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Membrane permeability versus lipid (olive

oil):water partition coefficientsolubility

The greater the partition coefficient, the

higher the lipid-solubility of the drug, andthe greater its diffusion across membranes.

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Weak electrolytes and membrane permeability

Most drugs are small (MW < 1000)weak

electrolytes (acids/bases). This influences passive

diffusion since cell membranes are hydrophobiclipid bilayers that are much more permeable to thenon-ionized forms of drugs.

The fraction of drug that is non-ionized dependson its chemical nature, its pKa, and the localbiophase pH...

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pH - pKa = logbase

acid

Henderson-Hasselbach equation

For an acidic drug: acid = HA; base = A-

For a basic drug: acid = BH+; base = B

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Acids are increasingly ionized withincreasing pH (basic environment),

whereas

Bases are increasingly ionized with

decreasing pH (acidic environment).

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Filtration: bulk flow of water-soluble drugs

through pores (glomerular, capillary)

Facilitated diffusion: carrier-mediated, ATPnot required (e.g., glucose)

Active transport: carrier-mediated, ATPrequired (e.g., Na+, K+, Ca++)

Endocytosis and exocytosis: (e.g., forvery large compounds)

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Drug Absorption & Route of administration

Absorption describes the rate and extent at

which a drug leaves its site of administration.

Bioavailability (F) is the extent to which a drug

reaches its site of action, or to a biological fluid

(such as plasma) from which the drug has accessto its site of action.

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AUC

injected I.v.

AUC

oral

time

plas

maconcentrationofdru

g

Bioavailability =AUC oral

AUC injected i.v.

X 100

AUC = area under the curve

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Route of administration

ORAL INGESTION , governed by:

surface area for absorption, blood flow, physical

state of drug, concentration.

occurs via passive process.

In theory: weak acids optimally absorbed in

stomach, weak bases in intestine.

In reality: the overall rate of absorption of drugs is

always greater in the intestine (surface area, organ

function).

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Unique characteristics of the oral route

Influences of gastric emptying (accelerates gastricemptying increase the rate of absorption)

Small intestine usually most important because of

large surface area (folds of Kerckring, villi, microvilli)

The motility of the small intestine

Drug inactivation important for oral route

stomach (acid), small intestine (ester/otherenzyme), distal small intestine/colon (gut bact)

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Ingestion of a solid dosage form with a glass of

cold water, fasting, lying on the right side,hyperthyroidism accelerate gastric emptying

Ingestion with a fatty meal, acidic drink, or with

another drug with anticholinergic properties, lyingon the left side, hypothyroidism, sympathetic

output (as in stress) retard gastric emptying.

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Clinical advantages

Safest route Cheapest route

Best patient acceptance

Disadvantages

Delayed effect

Patient cooperation required

Unique problems with GI toxicity

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INJECTION

subcutaneous, intramuscular absorbed by

diffusion and affected by blood flow

intravenous, intraarterial injection avoidsabsorption

MUCOUS MEMBRANE

sublingual, buccal, nasal, vaginal or rectalmucosa: passive diffusion

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LUNG

Inhalation: passive diffusion, rapid absorption,dependent on particle size (6 m cutoff)

SKIN

Transdermal

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Important Properties Affecting

Drug Absorption

Chemical properties

acid or base

degree of ionizationpolarity

molecular weight

lipid solubility or...

partition coefficient

Physiologic variables

gastric motility

pH at the absorption sitearea of absorbing surface

blood flow

pre absorptive hydrolysis

ingestion w/wo food

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Extent of metabolism occurring before drug

enters systemic circulation

Main site: Liver

Decrease in drug efficacy (orally) can beovercome by using a greater dose

Example: Propranolol (5 mg vs. 100 mg)

Extensive metabolism may render oral admin.impossible

Example: Lidocaine

First-Pass Metabolism

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The fraction of drug eliminated from portal blood

during absorption hepatic extraction ratio(ERH)

ERH = ClH/ QH

Bioavaibilty (F) F = 1- ERH

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Distribution

Only that fraction of drug which is non-protein-

bound can bind to cellular receptors and pass

across tissue membranes, thus being distributed to

other body tissues, metabolized, and excreted.

The actual pattern of drug distribution reflects

various physiological factors and physicochemicalproperties of the drug.

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Plasma protein

albumin- binds many acidic drugs

a1-acid glycoprotein for basic drugs

The fraction of total drug in plasma that isbound is determined by its concentration, itsbinding affinity, and the number of bindingsites.

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Phases of Distribution

first phase

reflects cardiac output and regional blood

flow. Thus, heart, liver, kidney & brainreceive most of the drug during the firstfew minutes after absorption.

next phase

delivery to muscle, most viscera, skin andadipose is slower, and involves a far largerfraction of the body mass.

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Drugs Binding Primarily to

Albuminbarbiturate probenecid

benzodiazepines streptomycin

bilirubin sulfonamidesdigotoxin tetracycline

fatty acids tolbutamide

penicillins valproic acid

phenytoin warfarin

phenylbutazone

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Drugs Binding Primarily to

a1-Acid Glycoprotein

alprenolol lidocaine

bupivicaine methadonedesmethylperazine prazosin

dipyridamole propranolol

disopyramide quinidine

etidocaine verapamilimipramine

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Drugs Binding Primarily to

Lipoproteins

amitriptyline

nortriptyline

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Body compartments where a drug canaccumulate are reservoirs. They havedynamic effects on drug availability.

GIT

plasma proteins as reservoirs (bind drug)

cellular reservoirs

Adipose (lipophilic drugs) Bone (crystal lattice)

Transcellular (ion trapping)

Drug Reservoirs

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Bone Reservoir

Tetracycline antibiotics (and other divalentmetal ion-chelating agents) and heavy metalsmay accumulate in bone. They are adsorbed

onto the bone-crystal surface and eventuallybecome incorporated into the crystal lattice.

Bone then can become a reservoir for slow

release of toxic agents (e.g., lead, radium)into the blood.

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Adipose Reservoir

Many lipid-soluble drugs are stored in fat.

In obesity, fat content may be as high as

50%, and in starvation it may still be only aslow as 10% of body weight.

70% of a thiopental dose may be found in

fat 3 hr after administration.

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GI Tract as Reservoir

Weak bases are passively concentrated in thestomach from the blood because of the largepH differential.

Some drugs are excreted in the bile in activeform or as a conjugate that can be hydrolyzedin the intestine and reabsorbed.

In these cases, and when orally administereddrugs are slowly absorbed, the GI tract servesas a reservoir.

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Redistribution

Termination of drug action is normally by

biotransformation/excretion, but may also

occur as a result of redistribution betweenvarious compartments.

Particularly true for lipid-soluble drugs that

affect brain and heart.

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Redistribution of thiopental after intravenousinjection

Thio

pentalconcentrat

ion

(as

percentofinitiald

ose)

100

50

0

minutes

1 10 100 1000

blood

brainmuscle adipose

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Central nervous system: permeable to lipid-

soluble drugs only; limited permeability to water-

soluble drugs when inflamed

Placental transfer: limited by blood flow, not by a"barrier"

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Plasma protein binding

Specific receptor sites in tissues

Regional blood flow

Lipid solubility

Active transport

Disease

Effects of other drugs

Tissue Distribution - Factors