Principles of Drug Disposition Flashcards
Pharmacokinoetic principles in:
Absorption?
Distribution?
Elimination?
A - Bioavailability
D - V(d) and Protein Binding
E - Clearance and half-life
4 primary systems affecting first pass effect
GI lumen, Gut wall enzymes, Bacterial Enzymes and Hepatic Enzymes
3 processes that Solids undergo before absorption
Disintegration: solid –> granules
Disaggregation: granules –> smaller particles
Dissolution: solid –> solution
Easily absorbed: Protonated or deprotonated?
Deprotonated
What will you do during a poisoning:
w/ acidic drug?
w/ basic drug?
alkalinize the urine to convert it to ionic form
acidify urine to convert it to ionic form
Other factors affecting absorption:
Concentration?
Area of Absorption?
Gastric Emptying?
Higher concentration injected, higher concentration absorbed
Small intestine absorbs more than stomach, higher SA and more blood flow
Lower Gastric emptying time, higher absorption rate, immediately goes to intestine
Increase in GET: Atropine vs Domperidone?
Atropine; Domperidone decreases
Billroth Syndrome
Gastric dumping syndrome - faster GET, results into diarrhea since undigested food in the intestinal lumen attracts ions and water
Fundamental Relationships to repeated administration:
Steady state?
Fluctuation?
SS is achieved after 4 half lives
independent of dosage
Fluctuation proportional to dosage interval/half-times
PK Principle Bioavailability:
standard universal benchmark?
Vs Bioequivalence?
60% for innovator product;
Ratio of bioavailability of 2 drugs
Factors affecting Distribution
Cardiac output
Vascular perfusion
Tissue permeability to drug
Drug partitioning between tissues and blood
PK Principle: Protein Binding: Weakly acidic drug bind to? Weakly basic drug bind to? Example of highly bound drug? When is binding significant?
Albumin;
Alpha-glycoprotein;
Anticoagulants;
If binding is more than 80% and for drugs with a very narrow margin of safety;
PK Principle: V(d): Pharmacologic or physiologic concept? homogenous or heterogenous w/ blood? Binding to tissues result in? Binding to plasma proteins result in? Formula?
Pharmacologic; Homogenous w/ blood;
Inc V(d) and dec in plasma conc; Dec V(d) and inc in plasma conc;
V(d) = Drug amt in body/Conc or V(d) = (Dose x F)/Conc
If higher V(d), more drug found in ____
If less V(d), more drug found in ____
Extravascular tissue (not homogenously distributed); Vascular compartment;
2 Phases of Metabolism?
Phase I (Non-Synthetic) and Phase II (Synthetic)
Processes involved in Phase I
CHORD
Cyclization, Hydrolysis, Oxidation, Reduction, Decyclization
Just a simple reaction
Processes involved in Phase II
CAMS
Conjugation (glucoronide, glutathione, glycine, sulfate), Acetylation, Methylation, Synthesis (RNA/DNA)
Give the prodrug:
Ampicillin, Alpha-methylnorepinephrine, Enalaprat, Fluorudine Monophosphate, Dopamine, Prednisolone, Methyl-
mercaptopurineribonucleotide
BACampicillin, PIVampicillin || Alpha-methyldopa || Enalapril || Fluorouracil || Levodopa || Prednisone || Methylmercaptopurine
Why do prodrugs need to be ingested orally?
So that they will pass the liver and be metabolized into active metabolites
Most important drug metabolizing reaction?
What enzyme used?
Oxidation
Hepatic oxygenases - CYP450
Most abundant CYP? Least abundant?
CYP is responsible for degradation of ___ and ___.
CYP3A; CYP1A2;
Astemizole (antihistamine, causes arrhythmia)
Chloramphenicol (for typhoid)
Microsomal Drug Metab. Enzyme
Location? Inducible or not?
# 1 inducer?
sER of liver cells;
Inducible; Phenobarbital induce enzyme maturation
Non-microsomal DME
Location? Inducible or not? #1 inducer?
plasma, cytoplasm and mitochondria of liver cells;
Not inducible;
Meaning in Plasma Concentration graph:
Rapid decline
slow decline
Distribution of drug
Elimination of drug
Clearance:
Formula?
Best clearance time? Slow clearance?
CL = Dose / AUC;
from 1 y.o. until puberty; neonates and elderly;
