Metabolism Flashcards
What is drug metabolism?
The biochemical modification of pharmacological substances usually through the specialised enzyme systems
How is elimination of drug achieved?
Elimination is achieved by excretion of unchanged drug or a metabolite from the body
Which types of drugs are eliminated most effectively?
Water-soluble drugs are eliminated more efficiently than lipid-soluble drugs
Lipid-soluble drugs need to be metabolised to be eliminated effectively
What are the aims of drug metabolism?
1) To make a drug more hydrophilic so it can be excreted by the kidneys
2) To inactivate the drug so it no longer produces the effect
What is the major site of biotransformation?
The liver
Name the sites of drug metabolism
Liver (main organ of drug metabolism)
Gastro Intestinal Tract
– Monoamine oxidase (MAO) found in wall of GIT
Plasma
Skin
Lungs
Brain
What is first pass drug metabolism?
A phenomenon of whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation by means of the hepatic portal vein taking it from the GIT to the liver first, i.e. oral intake
GIT wall=MAO
Liver=cytochrome p450
Describe the aims of each phase of drug metabolism
Phase 1 reactions - convert lipophilic drugs into more water soluble drugs
Phase 2 reactions - are conjugation reactions that add large endogenous molecules to drugs to make them more water soluble
How do phase 1 reactions work?
Biotransform drugs by introducing or masking functional groups (-OH, -NH2, -SH)
Give examples of phase 1 reactions
Oxidation
- p450 in liver, Xanthine oxidase, Monoamine oxidase
Reduction (liver = less common)
- CYP2A6 (warfarin)
Hydrolysis (plasma = less common)
- Ester and amide bonds are susceptible to hydrolysis
What is the cytochrome p450 system?
A large family of enzymes found in Liver
- Heme-containing isoenzymes
- Microsomal mixed function oxidases (MFO)
- Distinct and overlapping specificities for drugs
- 74 different enzymes, 6 commonly used
What does monoamine oxidase do?
Breaks down biologically active amines
Name some of the types of phase 2 reaction
Glucoroidation
Sulfation
Methylation
Acetylation
How does amount of drug effect the relationship with metabolism?
Low dose of drug => proportional to drug metabolism
High dose of drug => become saturated => drug metabolism no longer proportional to dose
What are the two orders of kinetics associated with metabolism of drugs?
First-order: metabolism proportional to drug concentration
Zero-order: drugs metabolised at constant rate Vmax
What is enzyme competition?
Also known as a pharmacokinetic drug interaction
Competition for the active site leading to a reduction in metabolism and an increased plasma concentration of the two drugs due to more than one drug being metabolised by the same isoform of the enzyme
What is induction of metabolism?
Certain drugs can induce isoenzymes of the Cytochrome P450 system at the transcription level
Over 200 Drugs cause enzyme induction and can:
– Increase its own metabolism
– Increase the metabolism of other drugs
– Toxic levels of reactive metabolites can occur
Describe inhibition of enzymes
- Some Drugs inhibit drug metabolism, i.e. Cytochrome P450
- Competition for the same enzyme isoform increase concentration of both drugs
- Inactivation of the enzyme can result in competitive and non-competitive inhibition of Isoenzyme
What are pro-drugs and give an example?
Drugs that are in an inactive form when administered
L-dopa - converted into dopamine in CNS
Describe reasons why drugs may be metabolised differently in different people?
Genetic make up
