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).
Genetic Polymorphism in Drug Metabolizing enzymes are considered silent until when?
These are silent until the patient is challenged by the drug
What is the difference in monogenic and polygenic traits graphically?
Monogenic traits:
- Usually show two distinct humps
Polygenic traits:
- usually have one large slope
Why:
- if the trait is influenced by a single gene then its more likely to show sharp variation between individuals who posses differences
- if the trait has several genes causing an overall phenotypic expression then its less likely to be affected by a polymorphism in a trait
What are some possible routes of drug excretion?
- Renal - urine
- Liver/Intestines - Feces
- Lungs - Inhaled agents
- Sweat (minor)
- Saliva (minor)
- Breast Milk
What 3 major processes occur in the kidney that aid in Renal Excretion?
- Glomerular Filtration
- Tubular Secretion
- Tubular Reabsorption
How much of the cardiac output is received by the kidneys?
- how fast is this blood filtered (aka Glomerular Filtration Rate (GFR)) ?
20-25%
- Blood is filtered by the glomeruli at a rate of 110 to 130 ml/min
T or F: Glomerular Filtration is active and therefore nonsaturable
False, it is PASSIVE and nonsaturable
How do we measure Glomerular Filtration Rate (GFR) clinically?
- overall what controls renal excretion?
- Determining the Renal Clearance of Creatinine
- Renal Excretion is controlled by what happens in the tubules
What type of molecules can be filtered OUT of the blood in the glomerulus?
- what can prevent drugs from getting filtered out?
Ions, Glucose, Peptides (not prots.) are easily filtered out
Being tightly bound to large molecules prevents plasma proteins from getting filtered out
How must is filtrate is reabsorbed in the kidney tubules?
90% of filtrate
What are the 3 principle parts of excretion in the kidney?
- Glomerular Filtration
- Tubular Secretion
- Tubular Reabsorption
Where does tubular secretion happen?
- what does this entail?
- Is it passive or active?
Where:
Proximal Tubule
Processes:
- Water Reabsorption and Active Secretion or Weak Electrolytes (especially Acids)
Energy:
This is an Active process MDR2 pumps are required
***Lots of Drug removal and Ion removal happens here
Where does tubular reabsorption happen?
- what does this entail?
- Passive or Active?
Where:
Distal Tubules
Processes:
- NONionized lipid soluble forms of weak acids and bases are Reabsorbed and Returned to general circulation
Why is it favored for lipophilic substances to be absorbed in the distal tubule?
- Water has been removed in proximal Tubule and Ions have been removed so there is a high concentration of lipid in the filtrate relative to a lower concentration in the surrounding tissue and it tends to flow out
What is the pH dependence on weak electrolytes in the urine?
- what drugs are removed by raising pH and which are removed by lowering it?
- Is movement passive or active?
Low urine pH = Basic weak electrolyte removal
High urine pH = Acidic electrolyte removal
why:
- Basic electrolytes will become charged at Low pH and will not be able to diffuse
For a drug that’s filtered but not secreted or reabsorbed what will be renal clearance be in normal subjects?
120 mL/min
**CLr = GFR
How do you know if the drug shows net absorption?
CLr
What can you assume if renal clearance is greater than 120 mL/min?
Tubular Secretion must be contributing to the process (CLr>GFR)
What is equivalent of glomerular filtration in the liver?
- how does it work?
- Biliary Secretion is the Equivalent of Glomerular Filtration
Drugs and Metabolites are actively Released along with bile acids and salts that are released into the digestive tract
What is Enterohepatic cycling?
Drugs (or their metabolites) are released via biliary excretion from the liver and then they (or their active or inactive metabolites) will be reabsorbed while passing through the small intestine causing prolongation of the drug’s effect
