Third lecture set Flashcards
Sites of Drug metabolism
First pass metabolism
- GI epithelium
- Liver
Systemic Metabolism
- Can occur in organs and in the blood stream
What are the classes of Metabolism
Phase 1: Metabolism of the main compound (decarboxylase, oxygenase, deamination)
Phase 2: metabolism through addition, conjugation ( glucuronidation, sulfation)
Phase 3: Transport- multidrug resistance
what are the objectives of drug metabolism
To eliminate the pharmacological activity of a drug
To make a compound continuously more soluble until it cannot escape excretion
How can we accomplish the objectives of drug metabolism
Change the shape of the molecule to block its binding receptor
-Change the molecules lipophilic character to a more hydrophilic character and increase solubility
- Increase the molecules size so it is more readily cleared
- Make the molecule more recognizable by efflux pumps to increase its elimination from target organs
Metabolism of Tamoxifen
Prodrugs can be made to be metabolized and release the active compound
TAM –(CYP3A4)–> NDM
NDM –(CYP2D6)–> 4OH-NDM
Drug metabolism Phase 1
Phase 1: a majority of focus is on the cytochrome P450 family (CYP3A4)
Requirements for oral absorption of monolithic dosage form
-Drug molecules at the surface dissolve to form a saturated solution
- Dissolved drug molecules must diffuse from an area of high to low concentration
-Drugs diffuse through the bulk solution to the absorbing mucosa and are absorbed
What are the effects of particle size?
-Surface area increases when a solid are broken up into smaller pieces
- As we move from tablet to granules to particles surface area increases which means dissolution rate also increases
Define Dissolution
The change in the amount of mass that appears in solution over time
(dM/dt)
- proportional to diffusion coefficient and difference in the concentration gradient (increase rate of diffusion implies increase dissolution)
Relationship between rate of dissolution and thickness of saturation layers
Inversely proportional
- increase of the thickness of saturation layers means less steep concentration gradient
- if both are equal it means that it will take more time for a molecule to move to bulk concentrations
Difference between permeability and Dissolution
permeability is diffusion across a barrier instead of across an unstirred layer
Noyes-Whitney equation
(dM/dt)= (DS/h)(Cd-Ca)
What factors limit oral drug absorption
Solubility, Dissolution, Permeability
How solubility limits drug absorption
- If a drug has poor solubility it is not a good druggable candidate
- Increasing dose doesn’t increase blood levels because the GI fluids are already saturated
How dissolution limits drug absorption
if a drug is unable to dissolve into the solution from the dosage form in sub-saturated fluid
- If dissolution time is greater than the time for absorption in the intestines
- often due to poor formulation
How permeability limits drug absorption
dissolution is fast with sub-saturated fluids
-increasing the amount of drug increases absorption
Define Generic Drug
drug product that is comparable to a brand name product in dosage form, strength, route of administration, quality and performance characteristics, and intended use
why is therapeutic equivalency important when it comes to generic products
it is the gold standard for generic products
it implies the product will have pharmaceutical equivalence and bioequivalnce
If a drug is therapeutically equivalent it means that it has the same identity, strength, quality, safety and efficacy as the reference standard
What does pharmaceutical equivalence mean
It means the dosage forms are administered by the same route, have the same dose, and are in the same class
Pharmacotherapy and pregnancy
Pregnancy causes:
physiologic-induced PK changes
alteration in enzyme activities
change in transporter activities
What is fetal imprinting
developing fetus undergoes rapid changes during the 9 month gestation period
Diet, genetics, environment and more can impact the fetus
other pediatric pharmacology issues
Not much data on any of this but we know exposure can lead to changes in developmental PK/PD
exposure to xenobiotics
goal of pediatric drug development
in years prior we were focused on protecting children from clinical research but we now want to protect children through clinical research
Best Pharmaceuticals in children Act (FDA)
testing drugs in children presents many challenges
some of which include the lack of:
- incentives for companies to study drugs in neonates
-technology to monitor patients and assay very small amounts of blood
-suitable pediatric clinical infrastructure for drug trials
What is unique about pediatric pharmacology
Descriptive pharmacology in pediatric patients is often lacking
- Children are not mini adults their bodies are developing and the drug moves thought out the body differently as the body changes
What are the challenges with pediatrics
Biological
- Ontogenic changes
- Compositional changes
Clinical
- clinical trials
-caregiver requirements
Formulation
- Dosage form selection
-flexibility in dosing
- excipient selection
- taste masking
Pediatric pharmacology challanges that still remain
- age based dosage form selection
-need for descriptive pharmacology in pediatric patients - children are not miniature adults
-animals models need to be refined for prediction - enable clinical studies in children by tackling some of the ethical and financial hurdles
