Pharmacokinetics : Drug Distribution -Dr Rahul Kunkulol's Power point preparations

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