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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