Third lecture set

Question 1

Sites of Drug metabolism

Answer 1

First pass metabolism
- GI epithelium
- Liver
Systemic Metabolism
- Can occur in organs and in the blood stream

Question 2

What are the classes of Metabolism

Answer 2

Phase 1: Metabolism of the main compound (decarboxylase, oxygenase, deamination)
Phase 2: metabolism through addition, conjugation ( glucuronidation, sulfation)
Phase 3: Transport- multidrug resistance

Question 3

what are the objectives of drug metabolism

Answer 3

To eliminate the pharmacological activity of a drug
To make a compound continuously more soluble until it cannot escape excretion

Question 4

How can we accomplish the objectives of drug metabolism

Answer 4

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

Question 5

Metabolism of Tamoxifen

Answer 5

Prodrugs can be made to be metabolized and release the active compound
TAM –(CYP3A4)–> NDM
NDM –(CYP2D6)–> 4OH-NDM

Question 6

Drug metabolism Phase 1

Answer 6

Phase 1: a majority of focus is on the cytochrome P450 family (CYP3A4)

Question 7

Requirements for oral absorption of monolithic dosage form

Answer 7

-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

Question 8

What are the effects of particle size?

Answer 8

-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

Question 9

Define Dissolution

Answer 9

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)

Question 10

Relationship between rate of dissolution and thickness of saturation layers

Answer 10

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

Question 11

Difference between permeability and Dissolution

Answer 11

permeability is diffusion across a barrier instead of across an unstirred layer

Question 12

Noyes-Whitney equation

Answer 12

(dM/dt)= (DS/h)(Cd-Ca)

Question 13

What factors limit oral drug absorption

Answer 13

Solubility, Dissolution, Permeability

Question 14

How solubility limits drug absorption

Answer 14

• 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

Question 15

How dissolution limits drug absorption

Answer 15

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

Question 16

How permeability limits drug absorption

Answer 16

dissolution is fast with sub-saturated fluids
-increasing the amount of drug increases absorption

Question 17

Define Generic Drug

Answer 17

drug product that is comparable to a brand name product in dosage form, strength, route of administration, quality and performance characteristics, and intended use

Question 18

why is therapeutic equivalency important when it comes to generic products

Answer 18

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

Question 19

What does pharmaceutical equivalence mean

Answer 19

It means the dosage forms are administered by the same route, have the same dose, and are in the same class

Question 20

Pharmacotherapy and pregnancy

Answer 20

Pregnancy causes:
physiologic-induced PK changes
alteration in enzyme activities
change in transporter activities

Question 21

What is fetal imprinting

Answer 21

developing fetus undergoes rapid changes during the 9 month gestation period
Diet, genetics, environment and more can impact the fetus

Question 22

other pediatric pharmacology issues

Answer 22

Not much data on any of this but we know exposure can lead to changes in developmental PK/PD
exposure to xenobiotics

Question 23

goal of pediatric drug development

Answer 23

in years prior we were focused on protecting children from clinical research but we now want to protect children through clinical research

Question 24

Best Pharmaceuticals in children Act (FDA)

Answer 24

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

Question 25

What is unique about pediatric pharmacology

Answer 25

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

Question 26

What are the challenges with pediatrics

Answer 26

Biological
- Ontogenic changes
- Compositional changes

Clinical
- clinical trials
-caregiver requirements

Formulation
- Dosage form selection
-flexibility in dosing
- excipient selection
- taste masking

Question 27

Pediatric pharmacology challanges that still remain

Answer 27

• 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