pharmacokinetics : drug distribution -dr rahul kunkulol's power point preparations
DESCRIPTION
Dr Rahul Kunkulol's Power point preparationsTRANSCRIPT
ADME
Distribution
Dr. Rahul KunkulolAsso. Professor
Dept. of pharmacology RMC, Loni
Distribution The process by which the drug reversibly
leaves the site of administration and is distributed through out the tissues of the body.
28 litres10 lit4 lit
Volume of Distribution
Volume into which a drug appears
to distribute with a concentration
equal to its plasma concentration
Drugs appear to distribute in the body as if it were a single
compartment. The magnitude of the drug’s distribution is given by the
apparent volume of distribution (Vd).Vd = Amount of drug in body ÷ Conc. in Plasma
PRINCIPLE
(Apparent) Volume of Distribution:Volume into which a drug appears to
distributewith a concentration equal to its plasma
concentration
Importance
If drug does not cross capillary wall its Vd is equal to plasma i.e. approx. 3L
Drugs with high PP binding less Vd and vice versa
Vd more than body volume means drugs are widely distributed
Importance
aVolume of distributio
n (aVd)
Retention Examples
< 5 L Vascular compartment
Heparin, Insulin, Warrfarin
Aprox.15 L Extracellular compartment
Aspirin, Tolbutamide
>20 L Throughout the body
OrPenetration in various tissues
Ethanol , Phenytoin,
Digoxin, Phenobarb, Morphine
Reservoirs for drugs
Plasma proteins Cellular reservoir Fat as reservoir Transcellular fluids Bones
Reservoirs for drugs
Reservoirs Details Example CellularHigh affinity for tissue proteins (lipoproteins or nucleoproteins)
Skeletal muscles, heart
Thyroid
Liver
Digoxin
Iodine
Chloroquine
Fats Highly lipid soluble drugs
Thiopentone sodium
Transcellular Aqueous humor
Joint fluid
Chloramphenicol
Ampicillin
Bones - Tetracyclines , calcium
Plasma Protein Binding Plasma consists of
› ~90% water, › ~8% plasma proteins› ~2% other organic or inorganic
species.
Many drugs bind to the plasma proteins as they have low water solubility.
Plasma protein binding limits distribution.
Plasma Protein Binding A drug that binds plasma protein diffuses
less efficiently, than a drug that doesn’t.
Albumin provides most of the available ‘sites’ for absorption, particularly of acidic drugs. › Warrfarin, Sulphonamides, Penicillins
-globulin and an acid glycoprotein can can become important in binding basic drugs. › Quinine, Imipramine, Lidocaine
Clinical importance
Highly protein bound drugs low Vd Highly protein bound drugs are difficult to
remove by dialysis PPB is capacity limited and saturable process.
› Example: Liver diseases, ureaemia :Hypoalbuminemia--therapeutic dose may become toxic
More than one drug can bind to the same site on albumin and can lead to displacement interactions.
Protein BindingDrug Displacement
Plasma TissueDrug A
protein bound
Drug Afree
Drug Afree
Drug B
Drugs A and B both bind to the same plasma protein
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Displacement interaction and toxicity
Displacement Interactions
Drug A Drug B
% DRUG BEFORE DISPLACEMENT BOUND FREE
991
9010
% DRUG AFTER DISPLACEMENT BOUND FREE
982
8911
% INCREASE IN FREE DRUG CONCENTRATION
100 10Interaction is significant if drug bind more than 95%
Protein Binding Interactions
Importance has been over emphasized. Most interactions can be better explained by other mechanisms
Increased availability of free drug which is displaced from plasma proteins, but compensatory mechanisms maintain free drug concentration
Only important in interpretation of total drug concentrations e.g. phenytoin / VPA
Physiological barriers to drug distribution
• Blood brain barrier
• Blood CSF barrier
• Placental barrier
Blood Brain Barrier
characteristics:1. No pores in endothelial membrane2. Transporter in endothelial cells3. Glial cells surround endothelial cells4. Less protein concentration in interstitial fluid
Distribution
Extent depends on Blood flow Size, M.W. Of molecule Lipid solubility and ionization Plasma protein binding Tissue binding