Drug 2

• drug distribution 


  reversible passage of drug between tissues, organs and compartments (drugs need to cross lipid membrane to move compartments)
• major body compartments 


  intravascular fluid/plasma, interstitial fluid, intracellular fluid, body fat
• compartment where large, polar, hydrophilic go to

  stay in plasma/intravascular (e.g Heparin), action of drug is related to blood usually
• what happens to lipophilic drug molecules when distributed


  if lipophilic enough can leave into interstitial, highly penetrate tissues, into fat
• factors that influence drug distribution


  solubility of a drug

  local pH

  blood flow

  tissue binding
• how solubility of a drug influences distribution


  hydrophilic drugs stay in extracellular compartment, lipophilic cross membranes and penetrate tissue, highly distributed into tissues and accumulate in fat
• ethanol and properties


  CNS depressant, lipophilic enough to cross blood brain barrier (but not fat) and hydrophilic
• ethanol distribution


  depends on relative water content of all tissues combined, females lower percentage of water content, higher body fat that cant penetrate so into water = higher plasma concentration/BAC
• why are females more likely to be intoxicated

  relative water content of tissues and expression of drug metabolising enzymes before ethanol absorbed
• how local pH influence drug distribution


  many drugs are either weak acids or weak bases resulting in pH dependent ionisation and ion trapping in compartments
• how blood flow effects drug distribution


  distribution occurs first in central compartment (plasma and highly perfused tissues) then into peripheral compartments (poorly perfused tissues)
• how does tissue binding influence drug distribution


  drugs can accumulate in specific tissues/organs, and highly lipophilic drugs accumulate in fat
• where do tetracyclines accumulate and why?

  slowly accumulate in bones and teeth because have high affinity for calcium
• who cant tetracycline be given to and why

  pregnant women and young children, binds to Ca in bones and teeth and inhibits. Ca needed for function and bone growth
• thiopental and its use 


  a intravenous general anaesthetic, fast induction but not maintenance of anaesthesia
• why cant thiopental be used to maintain anaesthesia


  highly lipophilic, slowly accumulates in body fat then slow return from body fat after stop infusion, slow plasma conc drop = hangover effects on CNS
• important plasma proteins for drug binding


  alpha 1 acid glycoprotein and human serum albumin (HSA)
• how plasma protein binding influence drug distribution


  proteins act as carriers for endogenous compounds and xenobiotics (drugs) decreases the free/unbound drug concentration
• binding of drugs to plasma protein


  is reversible, lipophilic drugs are more prone
• what does plasma protein binding effect

  hepatitis metabolism (if bound cant go to liver), distribution into tissues, drug concentration at site of action, therapeutic effect (no effect if bound)
• why is drug distribution into the brain difficult


  tissue barrier and specific blood brain barrier (both cellular layers)
• blood tissue barrier


  endothelial cell layer with fenestrations and basal membrane (matrix of proteins)
• blood brain barrier


  endothelial cell layer with no fenestrations, basal membrane, glial cells joined by tight junctions and transporters
• how is the blood brain barrier protective

  glial cells make it difficult to cross membrane and efflux transporters return drugs to capillaries to protect from harmful drugs
• how the blood tissue barrier functions 


  fenestrations facilitate solute exchange between blood plasma and interstitial fluid, basal membrane (matrix of protein) allows free, small molecules passage (not plasma protein bound)
• organs that express transporters 


  intestine, liver, kidney, brain and placenta
• liver role in drug absorption


  first point of contact following intestinal absorption via portal vein, accumulates and detoxifies xenobiotics
• how is the liver at risk of drug damage


  where drug metabolism occurs before reach systemic circulation (rich in drug metabolising enzymes), liver first exposed to toxic metabolites and susceptible to toxicity
• where are transporters for the liver

  basolateral membrane of hepatocytes, take drugs into liver
• how knocking out transporters influence hepatic drug uptake


  lower transporter mediated hepatic uptake, seen by a higher plasma conc as cannot be transported into liver (e.g knockout OCT 1/2)
• knocking out transporters effect on liver/plasma ratio of drug

  drugs not transported to liver, lower ratio less hepatic uptake
• brain efflux transporters


  MDR1, BCRP, MRP2
• transporters in brain tumour cells 


  over expressed = lower drug efficacy
• ways to increase distribution of a drug into brain that is undergoing efflux


  increase presence of transporter inhibitor or knockout
• imatinib and distribution into brain


  tyrosine kinase inhibitor, MDR1 role in efflux of imatinib
• volume of distribution


  an indication of the extent to which a drug is distributed to the tissues of the body, moved from plasma into tissues
• one compartment model


  plasma conc of drug is same everywhere else volume
• volume of distribution (bw adjusted)


  amount of drug in body (mg) / plasma conc (mg/L) x body weight (kg)
• loading dose of drug


  = Vd x desired plasma concentration (makes sure on first dose plasma conc high enough for therapeutic effects)
• highly protein bound drugs : Vd and plasma conc

  high plasma conc (stay in plasma) and small Vd