Exam1Lec2Pharmacokinetics Flashcards
What is first pass effect?
Combined action of bacterial and liver enzyme on drugs before reaching systemic circulation. Drug is not 100% absorbed
a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation.
drug administered orally, gi tract, portal vein, liver for bio transformation
Explain the significance of absorption
When a drug is administered orally it goes through the liver/portal vein which is the main detoxification center(like a gate) and then it can reach other organs through the plasma compartment such as the brain, kidney, and heart. IV bypasses absorption (going through liver, GI, etc) and going straight into the plasma compartment whihc can reach other organs
What are the factors that influence drug distribution?
Blood flow, lipid solubility of drug, molecular size, protein binding
How does blood flow affect drug distribution?
The most higly perfused organs recieve most of the drug during the first few minutes after absorption. Delivery of drug to musle , viscera, skin and fat is slower
ex: giving propofol, within a few seconds it can reach the brain
What is the most impt factor for drug distribution?
Blood flow
How does lipid solubility of drug affect drug distribution?
Lipid insoluble drugs that crosses the membrane poorly are restricted in their distribution and hence in their site of action.
propofol and thiopentol can easily cross the BBB cell membrane b/c its very lipophilic
How does Molecular size influence drug distribution?
Extremely large drugs are mainly confined to the plasma compartment
Ex: heparin is an anticoagulant that stays trapped in plasma compartment, it cant go through non brain capillaries
How does protein binding affect drug distribution?
distribution may be limited to drug binding to plasma proteins. Only unbound drugs cross the cell memebrane. ACIDIC drugs bind to serum albumin. Basic drugs bind alpha-one glycoprotein.
Free drug is free to
- leave plasma compartment
- transported into hepatocytes for biotransformation
- go through glomelur filtration in kidneys for secretion
- be actively transported into bile
What are the drug reservoirs?
Plasma proteins, fat, bone, cellular reservoirs
Many drugs bind to plasma proteins. Is this reversible?
Yes
but whatver stays bound is less destined to be eliminated
A drug is always ____ % bound to plasma proteins
90
Fat can act as a drug reservoir for what type of drugs?
Highly lipophilic drugs
high lipid water coefficient
Ex: thiopental.
How do drugs accumulate in the bone?
By absorption onto the bone-crystal surface and eventual incorporation into the crystal lattice
Ex: tetracycline and lead
Drugs accumulate in the muscle or other at ____
higher concentrations than in EC fluids
Ex: antimalarial agent quinacrine in the liver (high affinity for hepatocytes, you dont have much in plasma comp)
The BBB has____ fenestrations
NO
True or False, blood-brain barrier is adaptive
True. Note that BBB has very tight junctions b/w epithelial cells, only very hydrophobic drugs can cross cell membrane and reach CNS.
Think about that if you have so much drug concentration it can be toxic.
Why would we create different maneuvers to increase the permeability of the BBB?
We want more drugs to be able to go through to enhance the efficacy of chemotherapuetic agents used to treat specific infections or tumors localized in the brain.
How can drugs move through non-brain capillaries?
Drugs can move through fenestrations (openings) by bulk flow
How can drugs move thorugh brain capillaries?
Drugs cross the cell membrane by passive diffusioln or carrier mediated diffusion.
Is placenta a drug barrier? Why or why not?
NO because the fetus is to at least some extent exposed to essentially all drugs taken by the mother
What is biotransformation?
Process of which drugs are enzymatically altered in the LIVER and eventually excreted by the kidneys.
Biotransformation ____ water solubility of drugs
increases
What is elimination?
Process by which the drugs are enzymatically altered (biotransf) in LIVER mainly and then eventually excreted by the kidneys.
COMBO of biotrans and excr
Biotransformation can result in?
- inactive metabolite
- metabolite that retain similar activity
- altered activity
- bioactivated metabolites (Pro-drug)
what is the term for loss of effect of drug given orally?
first pass effect
Prodrug
a drug administered in an inactive form (no pharmacological activity) and is designed that when it undergoes biotransformation its converted to its active form.
What are the two main reactions of biotransformation?
Phase 1 and Phase 2
What are phase 1 reactions?
Mainly DEGRADATIVE resulting in inactivation, change in activity, or conversion of inactice cmpd (prodrug) to active drug
What are the main phase 1 reactions?
Oxidation (most impt), reduction, hydrolysis
Pharmokinetics vs Pharmaodynamic
Pharmaokinteics is studying what the body does to the drug vs pharmodynamic is studying what the drug does to the body.
What are phase 2 reactions?
Mainly involved in COUPLING of the drug or frequently its polar metabolite from the phase 1 reaction to an endogenous substrate (ex: glucuronate)
What are the main phase 2 reactions?
Conjugation/transferases
enzyme system most responsible for oxidation reactions is ____ which is found in _____ mainly in ____
Cp450 (CYP) system, microsomal fraction (SER), liver then lung and kindey
Cytochrome P450 system consists of two components. What are they and what do they require?
CytochromeP450 oxidoreductase
Cytochrome P450
it requires molecular oxygen and NADPH
CYP is a family of ____ with ____
isoenzymes with overlapping specificities
2 enzymes can deal with the same drug and a single enzymes can deal with different cmpds.
What is a key step in oxidation?
Insertion of O2 producing a non-stable intermediate which breaks down to yield the final product
What are the main reactions catalyzed by oxidation?
- dealkylation: removal of alkyl group (CH3)
- hydroxylation: adding a hydroxyl group
- sulfoxide: adding oxygen to sulfur group
- N-oxidation: adding oxygen to N
- deamination: removal of amine group
Non-microsomal oxidation system enzymes are
Alcohol dehydrogenase
Aldehyde dehydrogenase
non-microsomal enzymes are located in the cytosol
Hydrolysis reactions are carried out by which enzymes?
1.Esterases: break down ester grp and hydrolyze ester linkage
2.Amidases: break down amide grp
3.Peptidases” break down peptide grp
these enzymes are mainly found in the liver, plasma, and GI tracr
Reduction reaction enzymes can catalyze the reduction of what?
Nitro groups, azo, carbonyl groups.
These enzymes are reductases and can be found in the ER, cytosol of the liver, and other tissues
