L36 - Metabolism 1

• What is an IV Bolus injection?

  When a drug is injected all at once

  
• What's IV infusion?

  Drug enters body over a set time period.

  
• Define Elimination.

  
  

  What parameter is it described and quantified by?

  - Irreversible loss of drug by excretion or metabolism.

  
  

  - Defense system that removes foreign substances.

  
  

  - Described by Clearance
• What's the eqn for elimination rate?

  Elimination rate = Clearance X [plasma conc]

  
• Define excretion.

  
  

  What organ(s) mainly carry this out?

  Irreversible loss of chemically unchanged drug, mainly by kidneys.

  
• Define Metabolism.

  
  

  What is it also known as?

  
  

  Main site?

  - Conversion of drug into different chemical species.

  
  

  - Aka biotransformation.

  
  

  - Main site = liver.
• Importance of Elimination


  What does it allow us to predict?- [drug] conc after medicine uptake.

  
  

  - How liver/renal disease may affect [drug].

  
  

  - Interactions affecting elimination of drugs.

  
  

  - Variability in drug therapy.
• What might cause variability in drug therapy?

  - Age.

  
  

  - Genetic differences in metabolising enzymes, eg variation in cytochrome P450 in liver.
• Define Clearance.

  
  

  Units?

  = The volume of fluid (blood/plasma) completely cleared of drug per unit time.

  
  

  = The proportionality factor that relates drug elimination with conc of [drug] in plasma.

  
  

  Units = vol/time, eg mL/min or L/h

  
• How can we obtain clearance from a graph?

  Gradient!

  
  

  - The steeper the gradient the higher the clearance.

  
  

  - Eg for same [plasma] conc of drug I and II, drug I has a greater elimination rate.

  
• How can we work out conc in steady state, Css?

  Rate in (dose/time) = Rate out (Cl x Css)

  
• Describe the Additivity of Clearance.

  Clearance by one organ/tissue adds to clearance by another.

  Elimination rate= rate of Renal Excretion + rate of Hepatic Metabolism

  
• What's the one exception to additivity of clearance?

  Lungs - bc in a different circulatory system

  
• What's the main site of metabolism/biotransformation?

  The liver

  
• What do the 2 phases of metabolism involve?

  Phase I: redox, hydrolysis.

  Phase II:conjugation (addition of ionisable groups to increase solubility).
• EG: Codeine and Supermetabolisers

  - Codeine is a prodrug for morphine.

  
  

  - Codeine has low affinity for opioid receptors.

  
  

  - Toxic for babies when ingested in breastmilk where mothers were supermetabolisers.

  
  

  - Metabolised by P450 enzyme CYP2D6.
• Describe how blood travels in the liver.

  - Receives deox. blood from GI tract via hepatic portal vein.

  
  

  - Receives oxygenated blood from hepatic artery.

  
  

  - Blood from both vessels fuse and enters the liver via sinusoids.

  
  

  - Blood drains into central vein, then hepatic vein goes to vena cava.

  
• Describe the role of the liver.


  - secretes bile acids which empty into intestine via common bile duct, or go to gallbladder for storage.

  
  

  - largest metabolic capacity in body.

  
• Describe Elimination of Drugs in the Liver.

  
  

  What can enter the hepatocyte to be eliminated?

  
  

  What are lipophilic chemicals metabolised into?

  - Elimination processes incl. metabolism + biliary excretion.

  
  

  - Eliminates endo- and exogenous substances.

  
  

  - Only free, unbound drugs can enter hepatocytes to be eliminated.

  
  

  - Lipophilic chemicals metabolised into more hydrophilic ones, so are excreted into urine/bile (become more water soluble).

  
• What conditions must a drug meet to be metabolised by a specific enzyme?

  - Have correct 3D structure to interact with enzyme active site.

  
  

  - Have a certain affinity for this site.

  
  

  - Drugs metabolised by the same enzyme can be metabolised at different rates. Eg cytochrome P450 family oxidises/reduces many drugs.

  
• Describe some characteristics of drug metabolism.

  - Substrate specificity.

  
  

  - Kinetics: follow Michaelis-Menten.

  
  

  - Saturation.

  
  

  - Drug interactions.

  
  

  - Variability.

  
• Give an eqn for Elimination rate based on Michaelis-Menten kinetics.

  Elimination rate = Vmax x C / Km + C

  
  

  where Km = [drug] at which V = 0.5Vmax

  
• What happens to elimination rate at high [drug]?

  - Rate becomes constant and equals Vmax. No longer proportional to [drug].

  
  

  - Saturation mainly occurs at higher [concs] than used therapeutically so rate equalling Vmax is uncommon.
• How might drug interactions influence metabolism?

  - Metabolism can be altered by diet, concomitant drugs and chemicals.

  
  

  - Via enzyme inhibition or induction.
• Describe enzyme inhibition in metabolism.

  Can be direct or competitive.

  
  

  Eg SSRIs inhibit CYP2D6 system, grapefruit inhibits CYP3A4.
• Describe enzyme induction in metabolism.

  A drug/chemical increases enzyme activity.

  
  

  Eg smoking, insecticides, phenobarbitol.
• Describe how enzyme variability affects metabolism.

  - Individuals have dif levels of enzymes, so dif clearance times.

  
  

  - Eg genetic variations in cytochrome P450 family can cause individuals to be fast or slow metabolisers.

  
  

  - Age, physiopathology (eg hepatic diease).
• What might be an issue if a drug is metabolised too quickly?

  It may not reach therapeutic efficacy.
• Monotherapy vs cotherapy

  Monotherapy - when the drug is taken on its own.

  
  

  Cotherapy - drug is taken w/ smth else, eg enzyme inhibitor/inducer