4_DISTRIBUTION.pptx
- 2. DRUG DISTRIBUTION Dr Sindwa Kanyimba Lecturer, Pharmacology 2
- 3. Distribution of drugs is the process by which a drug leaves the bloodstream and enters extracellular fluids and tissues of the body Drug distribution to the various body’s tissues depends on its physico-chemical properties Drug distribution to various body tissues requires that the drug crosses several biological membranes. Distribution therefore involves the same processes as absorption, i.e. filtration, diffusion, carrier mediated transport and endocytosis. INTRODUCTION 3
- 4. Various factors determine the rate and extent of distribution, namely lipid solubility, ionization, blood flow, and binding to plasma proteins and cellular proteins INTRODUCTION …. CONT’D 4
- 5. LEARNING OBJECTIVES Explain the factors that affect distribution Describe plasma protein drug binding and explain its pharmacokinetic implications Explain the concept of volume of distribution 5
- 6. FACTORS AFFECTING DISTRIBUTION • Cardiac output and capillary permeability • Tissue perfusion • Plasma protein binding • Tissue binding • Placental barrier • Blood brain barrier 6
- 7. FACTORS AFFECTING DISTRIBUTION…. CONT’D Cardiac output and capillary permeability Affect the regional blood flow and perfusion of tissues Tissue perfusion Well perfused tissues such as kidney, liver, heart and brain have a rapid uptake of drugs, and the drug is distributed there first. Adipose and muscle tissue are poorly perfused hence drug uptake is slower and the drug reaches these areas later 7
- 8. FACTORS AFFECTING DISTRIBUTION: TISSUE BINDING • Some drugs get bound to certain tissue constituents because of special affinity for them • Tissue binding delays elimination and thus prolongs the duration of action of the drug • Tissue binding also serves as a reservoir of the drug 8
- 9. FACTORS AFFECTING DISTRIBUTION: PLACENTAL BARRIER • The placental membrane is lipid in nature and readily allows un-ionized, lipid soluble drugs to cross the membrane. Thus some drugs taken by the mother can affect the fetus. • Lipid soluble drugs cross the placental barrier more easily than polar drugs • Drugs with a molecular weight of less than 600 cross the placental barrier better than larger molecules • Drug transporters, such as the P-glycoprotein transporter, transfer drugs out of the fetus 9
- 10. FACTORS AFFECTING DISTRIBUTION: BLOOD BRAIN BARRIER (BBB) • The endothelial cells of the brain capillaries lack intercellular pores and instead have tight junctions. Brain capillaries are therefore less permeable than other body capillaries Furthermore, glial cells envelope the brain capillaries and together they constitute the BBB. • Only lipid soluble, un-ionized drugs can cross the BBB • The BBB may not be fully developed at the time of birth • Inflammation such as resulting from meningitis may increase the permeability of the BBB, and thus increase the ability of ionized, poorly lipid soluble drugs to cross 10
- 11. PLASMA PROTEIN BINDING Drugs bind to proteins in the plasma in varying degrees The most important plasma proteins that can bind drugs are: 1. Albumin 2. Alpha-1 acid glycoprotein 3. Lipoproteins Acidic drugs are generally bound more extensively to albumin and basic drugs to alpha-1 acid glycoprotein and/or lipoproteins 11
- 12. PLASMA PROTEIN BINDING …. CONT’D • It is the unbound drug concentration that is more closely related to drug concentration at the active site and to drug effects • Protein binding decreases the concentration of free drug in circulation therefore there is a limited amount of drug available to travel to the site of action • Only free drug is able to diffuse into tissues, interact with receptors, and produce biological effects. Protein bound drugs are pharmacologically inactive. 12
- 13. PLASMA PROTEIN BINDING …. CONT’D • It is also the free drug that is available for metabolism and excretion • Protein binding serves as a reservoir of the drug. When the free drug levels in the plasma fall, bound drug is released. Plasma protein binding, therefore, can prolong the duration of action of the drug. 13
- 14. PLASMA PROTEIN BINDING: DRUG INTERACTIONS • Many drugs may compete for the same binding sites • Thus one drug may displace another from the binding sites resulting in a greater proportion of free drug • This effect may increase the free drug to toxic levels • However, there is a compensatory increase in elimination of the displaced drug since the drug released from the binding sites becomes more available for metabolism and excretion 14
- 15. VOLUME OF DISTRIBUTION (Vd) • Vd is the proportionality constant that relates the amount of unchanged drug that reaches the systemic circulation (dose x bioavailability) to the plasma concentration achieved Vd = (Dose x Bioavailability)/Plasma conc • Vd is an indicator of the extent of distribution and does not represent the actual distribution of drugs in bodily fluids • Drugs that distribute extensively have relatively large Vd values and vice versa 15
- 16. VOLUME OF DISTRIBUTION …. CONT’D • Drugs that are lipid soluble and highly tissue bound have a high Vd and a low plasma level • Drugs that are water soluble have a low Vd and a high plasma level • Drugs that are highly bound on plasma proteins have low volumes of distribution while those that are extensively bound on tissues have high volumes of distribution • Vd may vary with changes in tissue permeability and protein binding • Vd may be influenced by age, sex, weight and disease processes (e.g. oedema, ascites) 16
- 17. VOLUME OF DISTRIBUTION …. CONT’D • Vd enables us to estimate the plasma concentration expected for a given dose and the dose required to produce a given concentration: Plasma Conc = Vd/Dose • However it provides little information about the specific pattern of distribution 17