Distribution of Drugs & Volume of distribution

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Distribution of Drugs Distribution is a process by which a drug reversibly leaves the blood stream & enters the extra cellular fluid and / or the cells of the tissues. Re-Distribution: Drug upon its release from sites, re-enters the circulation & is delivered to muscles, most viscera, skin & fat.

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Determinants of Distribution: The rate, extent & pattern of distribution are determined by: Size of the organ. Regional Blood flow. Solubility / Ability of drug to cross membrane. Binding of drugs.

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Size of the organ. Skeletal muscle can take a large amount of drug because conc. in the muscle tissue remains low. Regional blood flow: Heart, liver, kidney, brain & other highly perfused organs receive most of the drug during first few minutes after absorption.

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Ability of drug to cross membrane: Principles involving drug movement across cell membrane have already been discussed e.g.: Lipid soluble drugs cross cell membrane readily. Binding of drugs. Warfarin is strongly bound to plasma albumin which restricts warfarin diffusion out of the vascular compartment.

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Plasma Protein Binding: On entering blood a portion of drug is bound to plasma proteins mainly Albumin and is inactive pharmacologically. A portion is free (unbound) --- is available for pharmacological action at receptors.

Characteristics of PPB drugs : 

Characteristics of PPB drugs Acidic drugs bind to albumin Basic drugs bind to alpha acid glyco protein PPB is reversible There is equilibrium between free and bound drug PPB drug is pharmacologically inactive PPB drug is not metabolized PPB drug is not excreted PPB acts as a reservior for the drug. PPB ↓ fluctuations in action. Competition between two drugs may occur for same binding site.

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Protein binding of drugs may be altered under following conditions: Renal & Hepatic diseases Competition for same plasma protein binding sites e.g. phenylbutazone & warfarin .

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Examples: Phenylbutazone can displace warfarin( oral anticoagulant ) from PPB sites. Leading to increased plasma level of warfarin which can lead to Hge Sulphonamides can displace unconjugated bilirubin from binding to albumin. Increased risk of KERN ICTRUS in new born.

HIGHLY PPB DRUGS (Important for more than 90% PPB): 

HIGHLY PPB DRUGS (Important for more than 90% PPB) Phenytoin Tolbutamide Propranolol Phenylbutazone Warfarin

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Storage of drugs in tissues: Some drugs have selective preference for certain tissues, apart from plasma protein e.g. Cellular Reservior: Chloroquine ---- liver & Retina Arsenic ---- keratinous tissue Bone as Reservior: Calcium , Tetracyclines in growing bone , Heavy metals (Lead, Radium).

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Fat Reservior: Lipid soluble substance in body fats. e.g. Thiopentone sodium, Benzodiazepines, Environmental contaminants i.e. Insecticides. Saturation of stores: Lipid soluble substances are deposited in body fat depots. These depots are in equilibrium with free circulatory drugs.

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Distribution to the brain Unique because of blood brain barrier (BBB) & blood CSF barrier. Lipid soluble non ionized drug can cross BBB Thiopentone Sodium , Inhalational General Anaesthetics Physostigmine Lipid insoluble ionized drugs can not cross BBB e.g. Neostigmine. In inflammation permeability of BBB can change i.e BBB becomes more permeable to Penicillin-G BBB is deficient at CTZ.

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Placental transfer of drugs Potential transfer of drugs across placenta is important. Lipid soluble drugs pass in to fetal circulation by diffusion. Selection of drugs should be done carefully. The BBB in fetus is not well developed The metabolic enzymes are not mature. Congenital anomalies especially in first trimester.

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Drugs causing congenital anomalies are known as teratogens e.g. Thalidomide produced seal limbs (phacomalia) Drugs administered during last trimester can affect vital functions of fetus. Morphine Fetal asphyxia Diazepam Hypothermia & hypotonia Carbimazol Fetal goiter

Volume Of Distribution Of Drugs (Vd) : 

Volume Of Distribution Of Drugs (Vd) Definition: Vd can be defined as a fluid volume necessary to contain all the drug in the body at the same concentration as in the blood or plasma, considering the body as a single compartment . Vd relates the amount of drug in the body to the concentration of drug (C) in blood or plasma. It is not a true identifiable physiological volume. It is just a hypothetical volume .

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Vd= Total amount of drug in the body C (concentration of drug in biological fluid ) C may be Cp , Cb, Cw. UNIT : L/70 Kg.

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Compartment & Volume Examples of Drugs Water: Total body water: (0.6 L/kg) Small water soluble molecules: e.g. Ethanol ECF : 0.2 L/kg Large water soluble molecules: e.g. Gentamicin Blood (0.08 L/kg) ; Plasma ( 0.04 L/kg) Strongly PPB molecules & very large molecules: e.g. Heparin Fat (0.2-0.35 L/kg) Highly lipid soluble molecules e.g. DDT Bone (0.07 L/kg) Certain ions, e.g. lead, fluoride.

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Vd of some drugs: DRUGS Vd(L/70Kg) Heparin 5 Aspirin 11 Digoxin 420 Chloroquine 13000

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Factors affecting the Vd of a drug: Lipid solubility of drug. Degree of PPB ---- highly PPB drugs have smaller Vd. Affinity for different tissue proteins. Fat : lean body mass. Disease like CHF, uremia, cirrhosis.