Drug Distribution

Drug Distribution Prepared by Prof.Abdulkader.H.El Daibani

Drug Distribution Drug Distribution: • After absorption, drug is distributed through body compartments (plasma"3L“ ,E.C.F"15L" and total body water T.B.W"40L".

Drug Distribution Volume of distribution (Vd): • Volume of fluid in which the drug appears to distribute with a conc. equal to that in plasma (Vd not real value). • Vd= Dose (mg)/Plasma conc.(mg/ml) at zero time (Co).

Drug Distribution • If Vd=3L "then drug confined to blood e.g. warfarine, aspirin. • If Vd=15L "drug confined to E.C.F e.g. maninitol "osmotic diuretic". • if Vd=40L "drug distributed to TBF e.g. ethanol.

Drug Distribution • If Vd>40L, the drug is distributed at extravascular sites or intracellular proteins or stored in adipose tissue "tissue localizion " e.g mepridine"pethidine"cpz 1500L, propofol 4000L and diazepam 820L.

Drug Distribution DrugSite of disposition • Calcium, fluoride Bone and teeth and tetracycline • Iodine Thyroid gland • Chloroquine Liver and retina

Drug Distribution • Dialysis is useful for drugs with low Vd e.g. salicylates but not for drug with large Vd. Drug plasma protein binding • % of total drug blood which is bound to plasma proteins. • [PD] ↔ [D]+[P]. Bound

Drug Distribution Characteristics of P.P.B (plasma protein binding) 1) Reversible. 2)Not specific" more than one drug can compete for some site". 3) Bound drug is inactive and act as a reservoir and prolong duration t 1/2. 4)Free fraction is active and subject to metabolism and excretion.

Drug Distribution • Drugs mainly bind to albumine, aspirin, warfarine but basic drugs also bind α acid glycoprotein e.g. Lidocaine, propranolol, imipramine. • Drug interaction may result from displacement of adrug bound to plasma • Proteins by another drug with more affinity of binding sites-this becomes clinically imp. of: 1)if more than 95% of drug is bound to plasma proteins. 2)Bound drug has low Vd. 3)Bound drug has low T.I (TE50/ED50). e.g. warfarine is displaced by aspirin→ ↑ plasma conc. of warfarin→ hemorrhage so aspirin is contraindicated with warfarin.

Drug Distribution B.B.B.( Blood brain barrier) • No pores between endothelial cells of capillaries and endothelial cells have tight junction (slide), so only lipid soluble drugs can cross B.B.B. • e.g. general anesthesia, BD, other opioids and other C.N.S depressants L-Dopa (but not DA) treatment of parkinsonism INH, Rifampin but not streptomycin. • Inflammation as in bacterial meningitis increase permeability of B.B.B. e.g. to penicillin which is usually doesn't cross B.B.B.

Drug Distribution Placental barrier • Lipid soluble drugs can cross the placenta. • Some drugs may cause congenital abnormalities if given early in pregnancy. • Thalidomide (sedative and hypnotic) :3-10 weeks of pregnancy phoceomelia (seal extremities). • Anticancer drugs 3-10 weeks teratogenic some drugs may cause adverse effects if given to mother just before delivery. • Morphine → Respiratory depression "asphyxia neonatorum" • Warfarin → hemorrhage • Tetracycline → bone deformity and permanent discoloration of teeth.

Drug Distribution