Lecture 8

1.
What are the methods of eliminating drugs?
"Metabolism, excretion"
2.
What are the drugs that undergo metabolism?
Lipid soluble
3.
What mediates drug conversion?= =Enzymes
4.
What drugs are excreted?
Water soluble (no conversion)
5.
How are drugs eliminated?
"Bile, urine, sweat, exhalation, breast milk"
6.
Which is the main pathway for drug excretion?
Urine
7.
Why are lipid soluble drugs not excreted?
Passive diffusion through renal tubule membranes
8.
What does drug metabolism change?
"A drug'=s ability to move, altered effects (receptor binding)"
9.
What else can metabolism change in a drug?
"Increase activity, no change to activity, produce toxic metabolites"
10.
"Other than liver, where else does drug metabolism occur?"
"Intestinal wall enzymes, gut bacteria, lungs, plasma"
11.
What is first pass metabolism?
When an orally administered drug is partially metabolised in GI tract and liver before it enters bloodstream
12.
What are metabolism reactions?
"Oxygenation, reduction, hydrolysis, conjugation"
13.
What does conjugation do?
"Increases molecular weight, increases water solubility"
14.
What are the most important enzymes for metabolism?
Cytochrome p450 dependent mixed function oxidases (CYP450) in smooth ER
15.
Which other enzymes also cause oxidation?
"Alcohol dehydrogenases, aldehyde dehydrogenases, aromatase, amine oxidases"
16.
What are the key isoforms of CYP450 family?
"CYP3A4, CYP2D6, CYP2C9, CYP2C19"
17.
What are the steps to CYP450 oxidation of drugs?
1. binds to substrate 2. oxygen binds 3. oxygen split 4. oxygen to substrate 5. release of metabolite
18.
What does CY stand for?
Cyctochrome
19.
What does CY stand for?
Cyctochrome
20.
What does P stand for?
P450
21.
What does 3A4 stand for?
"Family, subfamily, isoform"
22.
Which is the major CYP isoform?
CYP3A4
23.
What is one example of a drug metabolised by CYP3A4?
Fentanyl
24.
Were are CYP3A4s found?
"Liver (35% of enzymes), intestine (75% of enzymes)"
25.
What drug will CYP2D6 metabolise?
Codeine/Tramadol
26.
"Even though CYP2D6 is less than 5% of liver enzymyes, why is it important?"
Accounts for >20% of all drug metabolism (high activity)
27.
What drug will CYP2D6 metabolise?
Codeine/Tramadol
28.
"Even though CYP2D6 is less than 5% of liver enzymyes, why is it important?"
Accounts for >20% of all drug metabolism (high activity)
29.
What drugs does CYP2C9 metabolise?
Ibuprofen
30.
What drug does CYP2E1 metabolise?
Alcohol
31.
What drug does CYP2C19 metabolise?
Omeprazole
32.
What impacts drug metabolism?
"Lifestyle, organ function, age/sex, diseases, other drugs, genetics"
33.
What are the ADME organs?
"Heart, lever, gut, kidney"
34.
Why is induction of CYP enzymes delayed?
"Time for synthesis, lifestyle, drugs"
35.
How is drug metabolism inhibited?
"Competitive, non competitive and uncompetitive other drugs, diet, heavy metals"
36.
What are the outcomes of inhibition?
"Rapid onset, exaggerated response, increased risk of toxicity"
37.
Which is the main organ for excretion?
Kidney
38.
How does the kidney operate?
"Glomerular filtration, tubular secretion, tubular reabsorption"
39.
What are other modes of excretion?
"Biliary, faecal, body fluids"
40.
What is normal GFR?
120mL/min
41.
How are drugs moved out or into tubule?
Active transport
42.
How are drugs reabsorbed back into blood?
Passive diffusion
43.
What promotes passive diffusion?
Reabsorption of H2O -> increase in osmolarity in tubule -> gradient established to leave tubule
44.
How is excretion calculated?
Excretion equals filtration + secretion - reabsorption
45.
When can drugs not be filtered?
When bound to plasma proteins
46.
What drugs can be secreted by active transport?
Bound and free
47.
What influences renal drug excretion?= "Body size, age, pregnancy, disease, medications (transporter competition)"