drug distribution | Capillary | Cerebrospinal Fluid

Drug Distribution

Dr. Robert G. Lamb Professor Pharmacology & Toxicology

Distribution & Volume of Distribution
Distribution: the passage of drugs from blood to tissues. Volume of Distribution (Vd): apparent volume of body water that drug appears to distribute into to produce a drug concentration equal to that in the blood.

Key factor in the onset of drug action.

Distribution of Drugs
Extracellular Fluid PLASMA Drug Bound to Nonactive Sites Intracellular Drug Bound to Nonactive Sites

Body Water Compartments
BODY WATER COMPARTMENTS: 50Kg (110 lb) Total body water (60% body weight) = 0.6 L/Kg, 30 L & & 100Kg (220 lb) 60 L 20 L 4L 16 L

Drug

Free Drug DISTRIBUTION Capillary Endothelium

Free Drug

Extracellular Plasma

(20% body weight) = 0.2L/Kg,

10 L &

(4% body weight) = 0.04L/Kg, (16% body weight) = 0.16L/Kg,

2 L & 8 L &

Drug Bound to Receptor Cellular (Biologic Effect) Membrane

Interstitial Intracellular

(40% body weight) = 0.4 L/Kg, 20 L &

40 L

Volume of Distribution (L)
Expressed as liters of body water in a 70 (154 lb) Kg man. Vd = Q/C Q = amount of drug in body (g) C = unbound plasma drug concentration (g/liter) Calculate Vd when 1 g is administered iv and the plasma drug level is 0.024 g/L. Vd = 1 g/.024 g/L = 42 L (Total Body Water)

Volume of Distribution (% BW)
Expressed as % of body weight in a 70 Kg man. Vd = (Q)(100)/(C) (body weight in Kg) Q = drug dose C = plasma drug level Vd = (1 g)(100)/(.024 g/L)(70) = 60% (Total Body Water)

1

Plasma Protein Binding
D + P ↔ DP
Zn ++ , lipids Cholesterol Vitamins A, K, D, E

Cu++ (Ceruloplasmin) Lithium carmine Hemoglobin (Haptoglobin)

γ

β2

β1

α2

α1

Albumin

Ca ++ , Cu ++ , Zn ++ Bilirubin Uric acid Vitamin C Adenosine Tetracyclines Chloramphenicol Digitonin Fatty acids Suramin Quinacrine Penicllin Salicylate Para-aminosalicylate Sulfonamides Steptomycin Acid dyes Phenol red Histamine Triiodothyronine Thyroxine Barbiturates

Plasma Protein Binding of Drugs
D + P ↔ DP (reversible binding) Bound drug is in equilibrium with free drug. Free drug is active and bound drug is inactive. More free drug when binding sites are saturated. Competition between drugs for binding sites.

Fe ++ (Transferrin)

Steroid hormones (Transcortin) Vitamin B 12 Sialic acid Thyroxine

Percent of Protein Bound Drug [I]
Drug is 90% bound to plasma protein.

Percent of Protein Bound Drug [II]
What % of total drug is bound if drug’s Vd is:

Patient is a 30 year old male weighing 70 Kg. What % of total drug is bound if drug’s Vd is: Vd = 3 L (PLASMA) 90% PD × 3 L = 270 PD; 10% D × 3 L = 30 D Total Drug = PD + D = 300; % PD = 270/300 = 90% % of total drug bound (90%) is equal to plasma PD %. Vd = 14 L (EXTRACELLULAR BODY WATER) 90% PD × 3 L = 270 PD; 10% D × 14 L = 140 D Total Drug = PD + D = 410; % PD = 270/410 = 66% % of total drug bound (66%) is less than blood PD %.

Percent of Protein Bound Drug [III]
What % of total drug is bound if drug’s Vd is: Vd = 42 L (TOTAL BODY WATER) [70 Kg] 90% PD × 3 L = 270 PD; 10% D × 42 L = 420 D Total Drug = PD + D = 690; % PD = 270/690 = 39.1%

Passage of Drugs Across Membranes
Barrier Capillary membrane Cell membrane Intracellular fluid Mechanism responsible for passage
Filtration

Fluid compartments Plasma Drug characteristics
Small molecule

Interstitial fluid

Fick’s Law % total drug bound (39.1) is less than plasma PD % . As Vd increases the % of total drug bound decreases. Carrier Key Factor

Lipid-soluble

Diffusion

Lipid-insoluble Large molecule

No active transport Active transport

Protein-bound

2

Phenobarbital[PB] Poisoning
ECF pH 7.4 7.0 6.5 Less PB Membrane Give I.V. NaHCO3 ↑ ECF pH; ↓ Brain PB 7.0 7.0 7.0 More PB Brain Less PB

Blood Flow to Various Tissues
Rapidly perfused (ml/100 g/min) tissues respond quickly Brain (55) Liver (20) Kidney (450) Less rapidly perfused tissues respond to drug more slowly Muscle (3) Skin (5) Poorly perfused tissues respond very slowly to drug Fat (1)

PB weak acid pKa = 7.2 CNS Depressant

More PB

Less PB

More PB

Drug Distribution in CNS
Aging Effect on Drug Distribution
Increased fat and decreased lean body mass (higher Vd of some drugs) Decreased total and % body water ( lower Vd of some drugs) Decrease in serum albumin (more free drug)
Intracellular Fluid Compartment of Brain Cells
(capillary endothelium, astrocytic sheath)

Arterial Blood

Blood-Brain Barrier

Blood-CSF Barrie
(capillary endothelium, epithelium of choroid plexus)

Extracellular Fluid Compartment of Brain

Brain - CSF Barrier

(ventricles and space of CNS)

Cerebrospinal Fluid Compartment

Venous Blood

Fetal Drug Distribution
Most drugs readily distribute by passive diffusion Epithelium of villi is the only major barrier Endothelium of capillaries

Drug Reservoirs
Stomach ionizes basic drugs and traps them (pH effect) Albumin binds various drugs and limits distribution Tissues such as the liver can avidly bind drugs (chloroquine) Lipid soluble compounds can localize in fat tissue (thiopental)

Risks
Abortion and abnormal development [Cocaine, Tamoxifen] Malformation [Thalidomide, Methotrexate, Organic Solvents] Alter behavior and intelligence [Alcohol, Cocaine, Amphetamines] Produce cancer later in life [Diethylstibesterol] Dependence/Withdrawal [Heroin, Morphine and Cocaine] Intrauterine growth retardation, prematurity, SIDS [Smoking]

3

Redistribution of Thiopental
100

% of Dose

Plasma Brain

Lean Fat

50

0

1

15

30

60

Time (minutes)

4

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