prof. hanan hagar pharmacology department. is the fraction of unchanged drug that enters systemic...
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Prof. Hanan HagarPharmacology Department
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Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action I.V. provides 100% bioavailability. Oral usually has less than I.V.
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The bioavailability of a drug product is compared to its intravenous standard formulation.
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This calculation is determined when two products are compared to each other, not to an intravenous standard .
E.g Tylenol (paracetamol 500 mg) compared to panadol (paracetamol 500 mg)
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This is commonly calculated in the generic drug industry to determine that the generic formulation (e.g., a tablet) is bioequivalent to the original formulation (e.g., another tablet).
Pharmaceutical industries conduct bioequivalence studies for their new product to decide on formulation for the clinical use.
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Two drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions.
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What student should know
Major body fluid compartments Concept of compartments. Apparent volume of distribution (vd). Plasma protein binding. Tissue binding. Redistribution
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Is the process by which drugs leave blood
circulation and enters the interstitium
and/or the cells of the tissues.
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Sites of Administration
Absorption & distribution Elimination
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The major body fluid compartments are Extracellular fluid (22%)
- Plasma ( 5 % of body weight = 4 liters ).
- Interstitial fluid ( 16 % = 10 liters).- Lymph ( 1 % ).
Intracellular fluid ( 35 % ) fluid present inside all cells in the body (28 L).
Transcellular fluid ( 2%)cerebrospinal, intraocular, synovial, peritoneal, pleural & digestive secretions.
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Total body fluids (60% of body weight in 70-kg individual)
Plasma (4 L)
Interstitial fluids (10 L) Intracellular volume ( 28 L)
Total body Fluids
(42 Liters)
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is the ratio of drug amount in the body to the concentration of drug in blood
Vd (L)= total amount of drug in body (mg) concentration in blood (mg/L)
Large Vd = means long duration of action
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FACTORS AFFECTING DISTRIBUTION
1.Cardiac output and blood flow. 2. Physiochemical properties of the drug.
◦Molecular weight◦Pka.◦Lipid solubility.
3. Capillary Permeability 4. Plasma protein binding 5. Tissue binding.
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The greater the blood flow to tissues, the more distribution that occurs from plasma to interstitial fluids.
Drugs distribute more rapidly to brain, liver and kidney > more than skeletal muscles & fat.
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Most lipid soluble drugs cross biological membranes
Hydrophilic drugs do not readily cross membranes but go through slit junctions
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Drugs with high Vd
Have higher concentrations in tissues
than in plasma.
Relatively lipid soluble.
Distributed intracellularly
Not efficiently removed by
haemodialysis.
e.g. phenytion, morphine, digoxin
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Drugs with low Vd confined to plasma & interstitial fluid. distributed in extracellular
compartments. Polar comp or lipid insoluble drugs. e.g.
Carbenicillin, vecuronium, gentamycin. High MW e.g. heparin – insulin. High plasma protein binding e.g. warfarin. Do not cross BBB or placental barriers.
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Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement & distribution.
Brain has tight junction Blood Brain Barrier (BBB).
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Blood brain barrier (BBB): Only lipid soluble drugs or carrier mediated
transport can cross BBB. Hydrophilic drugs (ionized or polar drugs)
can not cross BBB. Inflammation as in meningitis increase
permeability to hydrophilic drugs e.g. penicillin & gentamycin
Placental barrier Lipid soluble drugs can cross placental
barrier and enter the fetal blood.
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Binding of Drugs
◦Plasma proteins binding.
◦Tissue proteins binding.
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Plasma protein binding Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein).
Drug + Protein Drug-Protein Complex⇄(unbound) (bound)
Drugs exist in two forms bound and unbound forms in equilibrium
Unbound drug (free) bound drug
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bound form of drug
non diffusible form
can not combine with receptors not available for elimination
has long duration of action (t ½).
Unbound form of drug
diffusible form
combine with receptors
available for elimination
has short duration of
action (t ½).
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Characters & consequences of Binding
Usually reversible. determines volume of distribution (vd) Slows drug metabolism & excretion. Prolongs duration of drug action (t1/2). Result in clinically important drug
interactions.
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Displacement Competition for the same binding site
on the plasma proteins may occur between two drugs displacement of one drug & increasing its "free fraction” and effects.
Aspirin + Albumin-warfarin
Albumin-aspirin + free warfarin bleeding.
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Another example: sulfonamides and bilirubin in a neonates (hyperbilirubinemia).
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Drugs can bind to specific tissue
Tetracycline bind to bone
Iodides accumulate in salivary & thyroid glands
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Redistribution of the drug away from its site of action to other tissues where it can not produce an action e.g. thiopental
Termination Biotransformation. Excretion. Redistribution.