Pharmacokinetics Flashcards
Define Pharmacokinetics?
Factors which determine the concentration of the drug at the target receptors.
4 factors that determine concentration at target site?
- Absorption
- Distribution
- Metabolism
- Excretion
Therapeutic Window
Difference between the minimum effective concentration and the minimum toxic concentration
Absorption following intramuscular and subcutaneous injections
Blood flow to the muscle is higher than the skin, so absorption from intramuscular is more rapid than for subcutaneous. Exercise increases muscle blood flow thus further enhancing rate of absorption
Most absorption of drugs occurs in…
The small intestine, due to its large surface. Stomach has a relatively small surface area and thick mucosa - due to this very little absorption
Tetracyclines
Soluble at acidic pH but insoluble at neutral pH - due to this absorbed in the stomach
Levodopa
Used in treating Parkinson’s –> Uses phenylalanine’s transporter
ATP Binding Cassette (ABC transporters)
Use ATP to drive drug efflux from cells. e.g. MDR1 (p-glycoprotein)
Whats special about the SERT transporter? (Part of the SLC Superfamily)
- Acts as the receptor for Serotonin
2. Has very high substrate selectivity
Gentamicin
Amimoglycoside antibiotic is hydrophilic and cannot readily cross cell membranes. However is small enough to cross endothelium between cells and therefore distributes in plasma and interstitial compartments
Effect of drug binding to tissue or partitioning into fat on Vd (Volume of Distribution)
Increases Vd –> Eg Morphine has a Vd of 250litres. Note: Partitioning in fat is particularly important for lipophilic drugs such as the general anaesthetic, Thiopental
Effect of drug binding to plasma proteins on Vd
Decreases apparent Vd, as plasma now carries a higher concentration of drug
Define Volume of Distribution
It is the volume that would contain the total amount of drug in the body at a concentration equal to the plasma concentration
Vd = Total amount of drug in body (X) / Plasma concentration (C)
Albumin as a plasma binding protein
Present in high concentration = 0.6mmol/litre. Its concentration is much higher than the therapeutic concentration of drugs.
- Has 2 binding sites fro acidic drugs (Warfarin, Silacylic Acid, Phenytoin)
- Also binds many neutral and some basic drugs
Albumin levels fall in… (4)
- Old age
- Liver disease
- Nephrotic disease
- Major burns
Alpha1-Glycoprotein (plasma binding protein)
- Normally expressed at low levels
- Acute phase reactant increased in inflammation or stress
- Binds many beta-blockers and antidepressants as well as other basic drugs
Why is saturation of plasma proteins a problem?
When a low percentage of binding sites are occupied, an increase in dose produces a proportionate increase in Cfree and Cbound. However once binding sites have become saturated, further increase in dose produces a disproportionate increase in Cfree. Important for drugs such as Phenytoin that will saturate albumin in their therapeutic range.
Function of Sulphonamides in neonates
Displace bilirubin from plasma protein binding sites –> accumulation of bilirubin in brain can cause neurological damage + jaundice
Clearance (CL)
Rate of Elimination/ Plasma Concentration
- Note: Independent of the route of administration
Xenobiotics
Foreign chemical substances that are not formed by the normal metabolism of the organism - Drugs are metabolised by the same enzyme systems that defend us from Xenobiotics (Detoxification)
Major sources of xenobiotics?
Plants - contain secondary metabolites involved in the production of pigments/odourants/phytoalexins
- Environmental pollution
- Agrochemicals/ Cosmetic Drugs
- Pharmaceutical drugs
Hydrophillic Xenobiotics
Cell membrane acts as a barrier - so readily excluded. Hydrophillic xenobiotics that have been absorbed can be readily excreted - so not a problem.
Lipophillic Xenobiotics
Not excluded by membranes. Not readily excreted - so accumulate in fat + phospholipid bilayers in the absence of effective metabolism
First pass metabolism
Liver is the main site of drug metabolism, as it contains very high concentrations of metabolic enzymes. Small intestine is also a site of xenobiotic metabolism.
- Metabolism produces a marked decrease in the concentration of drug reaching the systemic circulation
- Reduced bio-availability
Phase 1 Hepatic Drug Metabolism
Functionalisation - introduce/unmask reactive chemical group e.g. OH/COOH/SH. Little effect on water solubility but alters biological properties of the drug
- Catabolic
- Makes a more reactive drug metabolite if prodrug (often drug is inactivated, but not always)
Phase 2 Hepatic Drug Metabolism
Conjugation - reactive functional group is used to add another molecule; increases water solubility (hydrophilic) and molecular weight
- Anabolic
- Less reactive metabolite
What’s special about Paracetamol with reference to hepatic drug metabolism?
Paracetamol already has an appropriate functional group - and therefore does not require Phase 1
