pharmacokinetics (?)

pharmacokinetics (?)

1. ADME

   • Absorption
     • Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation
     • drug factors affecting absorption: molecular size, ionisation, lipophilicity, hydrophilicity, dosage form, formulation, concentration
     • body factors affecting absorption: surface area, vascularity, pH, presence of food in the stomach, gastric emptying rate, integrity of absorptive surface, disease, secreted substances
     • Crossing a membrane: •Direct penetration of lipid membrane •Diffusion through aqueous channels •Transporters (influx & efflux)
       • blood brain barrier:
   • Distribution
     • Distribution describes the reversible transfer of drug from one location to another within the body. Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into interstitial and intracellular fluids
   • metabolism
     • The metabolism of drugs into more hydrophilic metabolites is essential for the elimination of these compounds from the body and termination of their biological activity
       • Metabolism = Biotransformation • Generates more polar (water soluble), usually inactive metabolites • Drugs are changed for rapid excretion • Metabolites may still have potent biological activity (or may have toxic properties) • Generally applicable to metabolism of all drugs as well as endogenous compounds such as steroids, vitamins and fatty acids • Two phases: Phase 1 and Phase 2 • Cytochrome P-450 (CYP) enzymes perform important role in Phase 1
         • phase 1
           • (oxidation) • Converts the parent drug to a more polar metabolite by oxidation introducing or unmasking a functional group (-OH, -NH2, -SH). • Usually results in loss of pharmacological activity • Sometimes may be equally or more active than parent (example: codeine) • CYPs act in Phase I
         • phase 2
           • (conjugation reactions) • Subsequent reaction in which a covalent linkage is formed between a functional group on the parent compound or Phase I metabolite and an endogenous substrate such as glucuronic acid, sulfate, acetate, or an amino acid • Highly polar – rapidly excreted in urine and feces • Usually inactive - notable exception is morphine 6-glucuronide
       • Prodrug • Originally pharmacologically inactive • Converted rapidly to active metabolite Codeine is oxidized to morphine by CYP2D6 – Necessary for codeine’s analgesic effect – Some people do not have therapeutic benefit (≈10%) since they are lacking sufficient CYP2D6 activity
     • Inhibition of Drug Metabolism • Drug metabolism is an enzymatic process that can be subjected to inhibition • Drugs and other substances can inhibit the metabolism of other drugs
   • Elimination
     • urine, faeces, sweat, breath, breast milk, saliva

2. two compartment IV bolus

   • its about distribution - tissues/plasma
   • concave graph

3. one compartment IV bolus

   • straight line graph

4. oral/transdermal etc

   • rise and fall - absorption

5. Therapeutic Range • Useful range of concentration over which a drug is therapeutically beneficial • Therapeutic window may vary from patient to patient • Drugs w/ narrow therapeutic windows require smaller & more frequent doses or a different method of administration • Drugs with slow elimination rates may rapidly accumulate to toxic levels

6. CYP

   • Consequences of CYP induction • Increased rate of metabolism • Decrease in drug plasma concentration • Enhanced oral first pass metabolism • If metabolite is more active than drug, increased drug effects or toxicity
     • Consequences of CYP inhibition • Increase in the plasma concentration of the parent drug • Reduction in metabolite concentration • Exaggerated and prolonged pharmacological effects • Increased likelihood of drug-induced toxicity