Chapter 3 Highlights Flashcards
Define Bioavailability
-Fraction of drug reaching systemic circulation
What are the Pharmacokinetics values?
-Absorption -Distribution -Metabolism -Excretion
Define what Pharmacodynamic is
-What the drug does to the body
Pharmacodynamic properties
-Drug-receptor binding -Mechanism of Action (agonist, antagonist?) -Dose-response curves -EC50 (potency), affinity, Kd -Emax (efficacy), Bmax -Therapeutic Index
Pharmacokinetic characteristics of drugs
-Bioavailability -Volume of Distribution -Protein Binding -Metabolism -Excretion
Factors that Affect Absorption
-Physical barriers to drug absorption; (Gastrinointestinal and hepatic transporters and enzymes) -pH trapping (chemical form of drug) -Route of Administration
Physical barriers affect Absorptions
-keratinized epithelium -mucous membranes protected by mucociliary clearance -lysozyme secretion in lacrimal ducts -acid in stomach, base in duodenum -blood brain barrier
What are the routes of adimistration?
-Enteral (oral) -Parenteral (injection) -Mucous membrane -Transdermal
Define Volume of Distribution
-The extent to which a drug separates between the plasma and tissue compartments -Measure of how much drug is getting into tissue
Factors affecting distribution
-Absorption (into bloodstream) -Potential amount of protein binding in blood -Blood flow in different organs —>“space” in each organ to take up the drug
Describe the blood flow in the different organs Ex -Vasculature -Vessel-rich tissues -Muscle rich tissues -Adipose-rich tissues
Vasculature –>Highest with IV bolus administration
Vessel-rich tissues (vessel-rich group (VRG))–>Receives drug first b/c of high blood flow kinetically favoring drug entry
Muscle-rich tissues –>Receives drug second b/c less well perfused, but has a higher capacity due to higher mass
Adipose-rich tissues –>Receives drug last b/c least vascularized, but has the highest capacity
Describe the Pros and Cons of each Route of Adminstration
Importance/Summary of Distrubtion
- Drug needs to get to the body compartment where the site of action is
- Volume of distribution is a pharmacokinetic value that represents the amount of drug getting into tissue
- Factors that affect distribution include absorption, protein binding, and blood flow to different organs
- Low Vd suggests protein binding, very high Vd suggests accumulation in adipose tissue
Importance/Summary of Absorption
- Drug needs to cross physiological barriers to into blood stream
- Chemical form of the drug can affect absorption, example pH trapping
- Bioavailability is a pharmacokinetic value that represents the amount of drug getting into blood and depends on route of administration
Define Biotransformation
enzymatic modification/transformation of drugs so that the body can clear them
Make more polar à enhance solubility so drug can be excreted in urine or bile
Generally describe Oxidation reducation
- Cytochrome P450 enzymes in liver
- Add/uncover a polar group
- 5 human P450’s = 95% of oxidative metabolism of drugs
Cytochrome P450-Mediated Drug Oxidation Steps
- Drug binds to the oxidized (Fe3+) cytochrome P450 to form a complex
- Iron moiety in the P450 enzyme acts as an electron carrier to transfer electrons from NADPH to molecular oxygen
- Reduced oxygen is transferred to the drug resulting in an additional –OH group on the now oxidized drug.
- The –OH makes the drug more hydrophilic
Generally describe Conjugation/hydrolysis reactions
- Hydrolyze to a large, polar molecule
- Enhance solubility and excretion in urine or bile
- Add a group to make more polar
- Glucuronate, sulfate, glutathione, acetate
Factors affecting Metabolsim
1.Drug-Drug Interactions
- Drugs can activate liver enzymes (a specific CYP450), which would increase the metabolism of other drugs
- Drugs might also specifically inhibit one or more of these enzymes, which would decrease the metabolism of other drugs
- Genetic Diversity – Pharmacogenomics
- Potential for First Pass Metabolism
Drug Drug interaction: P450 Induciton
- Drugs, environmental pollutants, industrial chemicals, foodstuffs
- Induction = increased expression of enzyme
- Increased transcription
- Example: Drug A activates the preganane X receptor (PXR) which forms a complex inducing transcriptio
Drug-Drug Interactions: P450 Inhibition
- The metabolism of a drug can be inhibited by other drugs which block its function
- Example:
- Drug D enters the cell and is hydroxylated by a P450 enzyme
- A second drug (drug C) acts as a competitive inhibitor
- A third drug (drug I) acts as an irreversible inhibitor
