2.1.2 Clinical Pharmacokinetics and Pharmacodynamics II Flashcards
Name a Phase I enzyme and what it is involved in
Cytochorome P450 (CyP450)
Oxidation
Reduction
Hydrolysis
What do Phase II enzymes produce?
Glucuronide
Sulphate
Glutathione
N-acetyl
Once drugs gave been broken down by the liver what happens?
Excreted via kidney in the urine
or
Via gall bladder in bile, into faeces
What factors affect drug metabolism?
Size
Lipophilicity
Hydrophobicity
Structural complexity
What are the majority of phase 1 catalysed reactions catalysed by?
CYP450s
Found abundantly in smooth ER in hepatocytes and most other tissues
What is the most important reaction by Phase I enzymes?
Oxidation
What CYPs deal with most reactions?
CYP families 1-4
Label the image
What do CYPs do to drugs?
Active form - inactive (most drugs)
Inactive - active e.g. perindopril - preindoprilat
Active - active e.g. codeine- morphine or diazepam- oxazepam
What can affect CYPs?
Induced or inhibited by endo/exogenous compounds affecting Phase I metabolism
Age- Decreased
Hepatic disease- Decreased
Blood flow- Increased/ decreased
Chronic alcohol- Increased
Smoking- Increased
How does CYP 2D6 differ between populations?
Absent in 7% of european caucasians
Hyperactive in 30% of N/E Africans
More complex now due to more mixing
What are some substrates for CYP2D6?
Beta blockers
SSRIs
Opioids- e.g. codiene may not have any effect for some people
What can inhibit CYP2D6?
Some SSRIs, antiarrhythmics or antidepressants
What is the clinical importance of CYPs?
Drug prescribing and complexity of polypharmacy
What can affect CYPs from OTC or generically?
St John’s Wort
Grapefruit juice
Alcohol
Valerian
What is self induced metabolism?
Drug can induce a CYP and simultaneously be a substrate for the same CYP
e.g. Carbamazepine, induces CYP3A4 and is a substrate for CYP3A4
Makes dosing difficult as can suddenly induce itself
How are drugs removed from the body?
Metabolism and excretion
Primarily via kidney (typically low molecular weight polar metabolites) , sweat,tears, breast milk, genital secretions etc.
Solids- faeces
What is renal excretion affected by?
GFR and protein binding e.g. gentamicin
Competition for transporters such as OATs e.g. penicillin
Lipid solubility, pH, flow rate e.g. aspirin
How is renal excretion measured?
GFR
How can gout be treated?
Make urine alkaline, Uric acid dissociates giving up its protons to neutralise pH of urine
It is then excreted as it cannot be reabsorbed
What type of metabolite does the liver usually excrete?
High molecular weights, conjugated with glucoronic acid
How does the hepatic system excrete metabolites?
Bile- excreted in faeces or reabsorbed
Enterohepatic circulation- recycles drugs from liver e.g. steroid hormones
What can affect hepatic excretion?
Antibiotic drug interactions e.g. warfarin, antibiotic can decrease how much drug gets to liver and ergo less will be broken down
Why does hepatic disease need to be considered when prescribing drugs?
May have reduced excretion so drug will have more affects
