ADME 2 Flashcards
What processes govern the onset of drug action and the peak intensity of Response?
- which determine the duration of action?
Onset and Peak Intensity Determined by:
- Absorption
- Distribution
Duration of Action Determined by:
- Metabolism and Excretion (which eliminate the drug)
- They do this by controlling the RATE of TERMINATION
What is biotransformation?
- The chemical modification of xenobiotics (non-natural substances) by endogenous enzymes
What is metabolism?
Chemical Transformation of both Endogenous and Exogenous Agents
What do biotransformative and metabolic reactions tend to do to a drug?
- Convert the Active compound into the Less active compounds
- Convert them to more polar and less lipid soluble forms that favor drug excretion
**These reactions are meant to detoxify and reduce activity but sometimes they do just the opposite
What kinetics describe Metabolic reactions?
Michaelis Menton
What component determines reaction rate if:
- Enzyme is saturated with substrate
- Substrate is limited
- Reaction is proportional to the level of enzyme at saturating substrate concentrations
- Reaction is proportional to the substrate if the substate is limiting
What are phase I and Phase II Metabolic Reaction?
- consequences of each?
Phase I:
- Add or Unmask functional groups (-OH, -NH2, or -SH) to make the drug more soluble
- *Often result in reactive (free radical) and potentially Toxic products
Phase II:
- Covalent addition of functional group to parent compound or to product of the Phase I reaction (e.g. glucuronic acid, glutathione, amino acids, acetate)
- *Generally make the compound inactive and lead to excretion
What happens to morphine in phase II reactions?
- It gets converted to 6-glucuronide metabolite of moriphine and becomes an even more potent analgesic
- This is the exception not the rule
On the Tissue and Subcellular Level where do most Biotransformative reactions take place?
Tissues/Organs:
- Liver
- G.I.
- Kidneys
- Lungs
- Brain
Subcellular:
- Endoplasmic Reticulum
- Cytosol
Where do most phase I reactions take place?
- phase II reactions?
Phase I: Endoplasmic Reticulum
Phase II: Cytosol
Phase I reaction types?
- Redox (O –> =O; -N=N- or NO2 –> NH2)
- Hydrolysis
Phase II Reaction Types?
- what is the main type?
- Where does it occur?
Glucuronidation:
MAIN CONJUGATION rxn
Occurs in LIVER
UDP-Glucoronsyl Transferases (UGTs) catalyze rxn
Acylation addition
e.g. Sulfonamides
Glycine addition
e.g. Nicotinic Acid
Sulfate (sulfoxidation)
e.g. Morphine and paracetamol
Glutathione (GSH)
- Conjugation of GSH (glutamate-cysteine-glycine) leading to a MERCAPTURIC acid metabolite
Phase II reactions typically make drugs more water soluble (less lipophilic). What is the exception?
Acylation often makes things more lipophilic
What does it mean to say something is a microsomal or nonmicrosomal reaction?
Microsomal - Takes place in the endoplasmic reticulum
Non-Microsomal - Takes place in the cytosol
What is the major catalyst of phase I reactions?
- where are these found?
- What is the general name given to these catalysts?
P450 monooxygenases
Found in the smooth endoplasmic reticulum of lots of tissues with the highest concentration in the liver
**Often referred to as the mixed function oxidase system
Which P450 genes encode the majority of biotransformations?
- which is most active in the GI tract?
CYP1, CYP2, CYP3
CYP3A4 and CYP3A5 subfamily in the GI tract decreases the bioavailability of many drugs
What does a cytochrome-P450 enzyme complex consist of and reaction does it do?
Consists of:
- cytochrome P450 Enzyme
- cytochrome P450 Reductase
Rxn:
- O2 is used and 1 O gets added to the Substrate, the other O gets reduced to H2O
- IT uses NADPH to do this (no ATP required)
What is induction?
- what can it lead to?
Drug Induced Change in metabolism
- Drugs can cause an increase in Liver enzyme activity over time which increases the rate at which drugs are metabolized (even ones other than the one causing induction)
- this means you will have to increase the dose to get the same effect of the drug and the enzyme you induce may work on other drugs too.
What is the time scale for induction?
- can it be reversed?
Induction is Reversible
- Onset - 3-12 hours
- Maximal - 1-5 days
- Persistence - 5-12 days
What is inhibition?
Drug-Induced Change in Metabolism
- Drugs inhibit the metabolism of other drugs (competitive inhibition)
(e. g. Warfarin can inhibit Tolbutamide elimination which leads to Tolbutamide conc. being higher in the blood) - You’ll need to adjust the dose downward when this happens
What is pharmacogenetics?
The genetic basis for differences among the population in drug responses (therapeutic or toxic)
What is pharmacogenomics?
Application of genomic information towards the discovery/development of novel specific drugs.
e.g. drugs that can be targeted for specific use among specific patient populations
What is the consequence of pharmacogenetics and pharmacogenomics on physician responsibility?
Physician is more responsible for knowing which drug to give to which patient
How do genetic polymorphisms factors into pharmacogenomics?
- where are polymorphisms seen to play the biggest role?
If a drug is designed to work on the gene product of a polymorphic gene then there is a much greater chance that the drug will have different effects based on different structural characteristics of that protein
Greatest Effects are seen between people of different gender (and between different species).
