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IV administration
Vascular space Liver
Renal secretion:
OAT1-3, OCT2, MRP2,
MRP4, P-gp
Brain
Kidney
Urinary excretion
Brain transport:
P-gp, BCRP, MRP2
OAT3 (OATP-A, MCT) Interstitial space
Renal reuptake:
OATP-A, PepT2
------------
unionized
• pH = Pka + log A-
• ----------
• (HA)
• Ionized species BH or A has very low lipid solubility and virtually
unable to permeate membrane
Except where specific carrier is required
• Lower the ph relative to pka greater the fraction of drug
in protonated form
• Uncharged form is more lipid soluble
• More of a weak acid will be lipid soluble at acidic ph
• While more of basic drug will be in lipid soluble form at
alkaline ph, B or AH will depend on the chemical nature
of drug
• For many drugs the uncharged species is sufficiently lipid soluble to
permit rapid permeation except amino glycosides due to oH group
makes it hydro philic
• The ratio between the two forms is determined by PH at the site of absorption and
by the strength of the weak acid or base presented by pka
• protonated
• Log ---------------- = Pka - pH
• unprotonated
• Lower the ph relative to pka, stronger the acid, greater the fraction in protonated
form
• If the con. Of ionized drug = unionized drug = 1
• Log 1 is 0 under this
• pH = pka
• 50% ionized= 50% unionized
• If ph is increased by 1
• A
• ---------- =10 times increase in ionization
• HA
• If pH is reduced by 1
• A- 1
• ____= ------
• HA 10
Ion Trapping cont:
Body fluids where a pH difference from
blood pH will favor trapping or
reabsorption: stomach contents
small intestine
breast milk
aqueous humor (eye)
vaginal secretions
prostatic secretions
Ion Trapping:
Kidney:
Nearly all drugs filtered at the glomerulus:
Most drugs in a lipid-soluble form will be absorbed
by passive diffusion.
To increase excretion: change the urinary pH to favor
the charged form of the drug:
• Weak acids: excreted faster in alkaline pH (anion
form favored)
• Weak bases: excreted faster in acidic pH (cation
form favored)
• A 3year old child is brought to the emergency deptt ingested
overdose of promethazine( weak base) with pka 9.1
• Urinary excretion accelerated by administration of NH4Cl an
acidifying agent
• U.excretion accelerated by giving NaHCO3 AN ALKANIZING
AGENT
• MORE OF DRUG IONIZED AT BLOOD ph THAN STOMACH PH
• Absorption of drug faster from stomach than from s.intestine.
• Aspirin is a weak acid with pka 3.5
• What percentage of a given dose will be in
lipid soluble form at a stomach ph of 2.5
• About 10%
• About 1%
• About 90 %
• about 99%
Absorption
• Movement of drug from site of its administration into circulation
• Fraction of administered drug
• Rate of absorption
• Factors affecting absorption
• 1 aqueous solubilty
• 2 concentration
• Morphine, quinine
• 4 Vascularity of the surface
• 5 routes of administration
• Oral
• Absorption in stomach is slow due to thick mucosa
• Acidic drugs are absrbed in unionized form in acidic
medium e.g. aspirin, barbiturates
• Larger surface area e.g. lungs and intestine
• 6 Presence of food
• Dlutes the drug and retard absorption
Food delays gastric emptying most drugs are absorbed when taken on
empty stomach
• 7 Presence of other agents
• Poorly absorbed complexes e.g tetracycline with milk
• Vit C increase iron absorption
• 8 degree of ionization
• Highly ionized drugs e.g.gentamicin, neostigmine poorly absorbed
orally
• Penicillic G by acid
• Insulin by peptidases
• Enteric coated and sustained release prepration used to overcome acid
lability, gastric irritancy and brief duration of action.
• 9 Diseases
• Diarrhea
• Malabsorption
• 10 Drugs
• Metoclopromide
• Anticholinergics
• 11 Particle size
• Smaller the particle size better absorption
• E.g. corticosteriods
• Formulation
• Lactose, sucrose, starch, phosphate used as excipient in tablets
• 12 Chemical nature of molecule
• Inorganic iron prep are better absorbed
from GIT than organic
• 13 Blood flow
• In shock, vasoconstrictor
• BF is dec to intestine
Luminal effect
• Absorbtion is affected by other concurrently ingested
drugs
• E.g. formation of insoluble complexes
• Tetracyclines with iron prepration and antacids
• Can be minimized by 2-3 hour interval
• Gut wall effect
• Altering motility (anticholinergic , antidepressant)
• Causing mucosal damage (neomycin, methotrexate)
• S/c or I/m
• Absorbtion is slower s.c than I.m.
• Application of heat and muscular exercise
increase absorp by blood flow
• Adrenaline retard
• Topical site
• Depend on lipid solubility
• Can cause systemic toxicity e.g.hydrocotisone
Bioavailability
Measure of fraction of administered dose of a drug that
reaches systemic circulation in unchanged form
F=f х (1-ER)
E.g. morphine
f=extent of absorp
ER = extraction ratio
E.g. morphine
f = 1 completely absorbed so that loss is negligible
ER = 0.67
Bioavailability = 33%
Representative plasma concentration–time relationship
after a single oral dose of a hypothetical drug.
•
• AUC oral
• Bioavailability=-------------------×100
• AUC injected
Factors affecting bioavailability
Factors influencing bioavailability
3_graphs_0_order.jpg
• Individual Variation in Metabolic Differences
• Age: In general, drugs metabolized more slowly in fetal, neonatal, and geriatric
populations
• Disease state
• Each of these factors may vary from patient to patient (inter-individual variation), and
indeed in the same patient over time (intra-individual
• Two related drugs are bioequivalent if they show comparable
bioavailability and similar time to acheive peak blood conc
• Bioinequivalence
• Two related drugs with a significant difference in bioavailability
• Therapeutic equivalence
• Two similar drugs are therapeutically equivalent if they have
comparable efficacy and safety
• Clinical effectiveness depends on
• Max drug conc.
• Time after administration required to reach peak conc
• So two drugs are bioequivalent may not be therapeutically
equivalent
Bioavailability
• F=f х (1-ER)
• f=extent of absorp
• ER = extraction ratio
• E.g. morphine
• F = 1 completely absorbed so that loss is negligible
• ER = 0.67
• Bioavailability = 33%
• Representative plasma concentration–time relationship after a
single oral dose of a hypothetical drug.
• Measure of fraction of administered dose of a drug that reaches
systemic circulation in unchanged form
•