Transcript Drug distribution and Bioav 2012 ishfaq.ppt
Prof. Hanan Hagar Pharmacology Department
What student should know
Major body fluid compartments
Concept of compartments.
Apparent volume of distribution (vd).
Plasma protein binding.
Tissue binding.
Redistribution
Is the process by which drugs leave blood circulation and enters the interstitium and/or the cells of the tissues.
Sites of Administration Absorption & distribution Elimination
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.
Total body fluids (60% of body weight in 70-kg individual)
Total body Fluids (42 Liters) Plasma (4 L) Interstitial fluids (10 L) Intracellular volume ( 28 L)
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
FACTORS AFFECTING DISTRIBUTION 1.Cardiac output and blood flow. 2. Physiochemical properties of the drug.
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Molecular weight
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Pka.
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Lipid solubility.
3. Capillary Permeability 4. Plasma protein binding 5. Tissue binding.
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.
Most lipid soluble drugs cross biological membranes
Hydrophilic drugs do not readily cross membranes but go through slit junctions
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
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.
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).
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.
Binding of Drugs ◦
Plasma proteins binding.
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Tissue proteins binding.
Plasma protein binding
Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein)
Drugs exist in two forms bound and unbound forms in equilibrium Unbound drug (free) bound drug
Drug + Protein ⇄ Drug-Protein Complex (Active, free) (Inactive, bound) Competition between drugs for plasma protein-binding sites may increase the "free fraction," possibly enhancing the effects of the drug displaced. Example: sulfonamides and bilirubin in a neonate
Displacement Competition for the same binding site on the plasma proteins may occur between two drugs displacement of one drug & increasing its concentrations & effects.
Aspirin + Albumin -warfarin Albumin -aspirin + free warfarin bleeding.
Drugs can bind to specific tissue Tetracycline bind to bone Iodides accumulate in s alivary & thyroid glands
bound form of drug Unbound form of drug
non diffusible form
diffusible form
can not combine with receptors
combine with receptors
not available for elimination
available for elimination
has long duration of action (t ½).
has short duration of action (t ½).
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.
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.
Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action
I.V. provides 100% bioavailability i.e F= 1.
Subcutaneous, intramuscular, oral, rectal, and other extravascular routes of administration require that the drug be absorbed first, which can reduce bioavailability.
Bioavailability (F) = AUC oral AUC IV
Absolute bioavailability: The bioavailability of a drug product is compared to its intravenous standard formulation.
complete concentration-time profiles are needed for both the intravenous and other routes of administration.
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Relative bioavailability: This calculation is determined when two products are compared to each other, not to an intravenous standard 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).
E.g Tylenol (paracetamol 500 mg) compared panadol (paracetamol 500 mg)
is important to get an idea of how formulations or routes of administration differ dosage adjustment when changing formulations or routes of administration.
Pharmaceutical industries conduct bioequivalence studies for their new product to decide on formulation for the clinical use.
Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration. 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.
Factors Affecting Bioavailability: 1. Drugs
Molecular weight of drug.
Drug Formulation (rate of dissolution).
(solution > suspension > capsule > tablet)
Drug solubility of the drug
Chemical instability in gastric pH
(Penicillin & insulin )
First pass metabolism
For example, when the B–blocking agent propranolol is given intravenously, its bioavailibilty is 100% but when it is given orally approximately 20% of the administered dose reaches the systemic circulation as intact drug due to first pass metabolism.
Factors Affecting Bioavailability (BAV):
Blood flow to absorptive site Greater blood flow increases bioavailability Intestine has greater blood flow than stomach
Surface area available for absorption.
Intestinal microvilli increases it
Rate of gastric emptying rapid gastric emptying fast transit to intestine
pH of gut
Intestinal motility (Transit Time) Diarrhea reduce absorption
Drug interactions
Food slow gastric emptying generally slow absorption