pharmacokinetic

• Pharmacokinetics


  The quantitative study of drug movement in, through and out of the body. Intensity of effect is related to concentration of the drug at the site of action, which depends on its pharmacokinetic properties
• Pharmacokinetic properties


  • Determine the route of administration, dose, onset of action, peak action time, duration of action and frequency of dosing
• Passive diffusion


  Most important mechanism for most of the drugs. Majority of drugs diffuses across the membrane in the direction of concentration gradient. No active role of the membrane. Proportional to lipid: water partition coefficient
• Passive diffusion


  • No energy required
  • No carriers required
  • No saturation occurs
  • Response to competitive inhibition
• The drugs which are unionized, low polarity and higher lipid solubility are easy to permeate membrane
• The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane
• Henderson-Hasselbalch Equation


  pH = pKa + log ([A-]/[HA]) = pKa + log ([ionized]/[unionized])
• Acidic drugs (largely unionized) are absorbed faster in stomach. Basic drugs (ionized) are absorbed faster in intestines
• Acidic drugs are excreted faster in alkaline urine. Basic drugs are excreted faster in acidic urine
• Carrier Mediated Transport


  Involve specific membrane transport proteins known as drug transporters or carriers - specific for the substrate. Drug molecules bind to the transporter, translocated across the membrane, and then released on the other side of the membrane
• Carrier Mediated Transport


  • Specific, saturable and inhibitable
  • Depending on energy requirement - can be either facilitated (passive) or active transport
• Active transport


  Can move solutes against a concentration gradient, energy dependent. 1o active transporters generate energy themselves (e.g. ATP hydrolysis). 2o transporters utilize energy stored in voltage & ion gradients generated by a 1o active transporter (e.g. Na+/K+-ATPase)
• Major drug transporters


  • ATP-binding cassette transporters (ABC) superfamily (e.g. P-glycoprotein)
  • Solute carrier (SLC) transporters (e.g. Organic anion transporting polypeptides (OATPs), Organic cation transporters (OCTs))
• Pinocytosis


  Involves the invagination of a part of the cell membrane & trapping within the cell of a small vesicle containing extracellular constituents. The vesicle contents can than be released within the cell, or extruded from the other side of the cell
• Absorption


  The transfer of a drug from its site of administration to the blood stream
• Factors affecting absorption


  • Drug properties (lipid solubility, molecular weight, polarity etc.)
  • Blood flow to the absorption site
  • Total surface area available for absorption
  • Contact time at the absorption surface
  • Affinity with special tissue
  • Route of administration
• First pass metabolism


  Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine, reducing the concentration of drug in the systemic circulation
• Bioavailability refers to the rate and extent of absorption of a drug from dosage form as determined by its concentration-time curve in blood or by its excretion in urine. It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form
• Volume of distribution (Vd)

  The volume that would accommodate all the drugs in the body, if the concentration was the same as in plasma
• Factors influencing Vd


  • Lipid solubility (lipid: water partition coefficient)
  • pKa of the drug
  • Affinity for different tissues
  • Blood flow – brain vs fat
  • Disease states
  • Plasma protein binding
• Blood brain barrier (BBB)


  Includes the capillary endothelial cells (which have tight junctions & lack large intracellular pores) & an investment of glial tissue, over the capillaries. Limits the entry of non-lipid soluble drugs
• Only lipid soluble unionized drugs penetrate and have action on the CNS
• Inflammation of meninges of brain increases permeability of BBB
• Placental transfer


  Only lipid soluble drugs can penetrate, limitation to hydrophilic drugs. Placental P-gp serves as limiting factor
• Plasma protein binding (PPB)

  Most drugs possess physicochemical affinity for plasma proteins. Acidic drugs bind to plasma albumin, basic drugs to α1-glycoprotein. The clinical significant implications of PPB include: drugs highly bound to proteins are largely restricted to the vascular compartment & tend to have lower Vd, the PPB fraction is not available for action, there is an equilibration between PPB fraction of drug & free molecules of drug, drugs with high affinity can replace other drugs or endogenous compounds with lower affinity, high degree of protein binding makes the drug long acting, in hypoalbuminemia binding may be reduced & high of [free drug] may be attained
• Tissue storage


  • Heart & skeletal muscles – digoxin
  • Liver – chloroquine, tetracyclines, digoxin
  • Kidney – digoxin, chloroquine
  • Thyroid gland – iodine
  • Brain – chlorpromazine, isoniazid, acetazolamide
  • Retina – chloroquine
  • Iris – ephedrine, atropine
  • Bones & teeth – tetracyclines, heavy metals
  • Adipose tissues – thiopental, ether, minocycline, DDT
• Pharmacokinetics


  The study of the movement of drugs within the body, including the processes of absorption, distribution, biotransformation, and excretion
• Drug transportation


  1. Absorption

  2. Distribution

  3. Biotransformation

  4. Excretion
• Biotransformation of drugs


  Chemical alteration of the drug in the body to convert non-polar (lipid soluble) drugs to polar (lipid insoluble) drugs to avoid reabsorption in renal tubules
• Results of biotransformation


  • Active drug & its metabolite to inactive metabolites
  • Active drug to active product
  • Inactive drug to active/enhanced activity (prodrug)
  • No toxic or less toxic drug to toxic metabolites

  
• Phase I (non-synthetic) biotransformation

  Metabolite may be active or inactive
• Phase II (synthetic) biotransformation

  Metabolites are inactive (except for morphine-6-glucuronide)
• Phase I oxidation


  • Addition of O2 or (-ve) charged radical or removal of H2 or (+ve) charged radical
  • Involve cytochrome P450 monooxygenases (CYP), NADPH, O2
  • Over 100 CYP P450 isoenzymes identified, 3 important families in humans: CYP1, CYP2, CYP3

  
• CYP 3A4/5


  • Carry out biotransformation of largest number (30–50%) of drugs
  • Expressed in liver, intestine (1st pass metabolism) & kidney
  • Several drugs can inhibit CYP 3A4 and interact badly with other drugs
• Non-microsomal enzyme oxidation


  • Oxidation of some drugs by mitochondrial & cytoplasmic enzymes, e.g. alcohol dehydrogenase, MAO, COMT
• Phase I reduction


  Conversion of oxidation, involves CYP 450 enzymes working in opposite direction
• Phase I hydrolysis


  Cleavage of drug molecule by taking up of a molecule of water, e.g. choline esters, procaine, lidocaine, pethidine, oxytocin

  
• Phase I cyclization/decyclization


  Formation/opening of ring structure, e.g. proguanil, phenytoin, barbiturates
• Phase II conjugation


  • Conjugation of drug or its phase I metabolite with polar endogenous substrates (highly ionized organic acid) for excretion

  
• Phase II conjugation reactions

  • Glucuronide conjugation
  • Acetylation
  • Sulfate conjugation
  • Methylation
  • Ribonucleoside/nucleotide synthesis