Unit 1. Lec 3- Pharmacokinetics III Flashcards
What is the main phase II reaction?
Conjugation (via transferases)
What are the main mechanism of conjugation reactions?
- Coupling of the drug
- Polar metabolite from phase I rxn uses enzymes known as transferases to an endogenous substrate
List the types (6) of conjugation reactions
- Sulfatation
- Actetylation
- Methylation
- Glucoronidation
- GSH (reduced glutathione)
- Amino acids (e.g. glycine)
Mechanism of Glucoronidation
Conjugation rxn
Covalent addition of glucaronic acid (e.g. morphine)
Mechanism of Sulfatation
Conjugation rxn
Addition of sulfate group (e.g. minoxidil)
Mechanism of Acetylation
Conjugation rxn
Addition of acetyl group (e.g. sulfonamide antibotics)
Mechanism of Methylation
Conjugation rxn
Addition of Methyl group
Mechanism of GSH (reduced gutathione)
Conjugation rxn
Addition of glutathione
Mechanism of amino acids
Conjugation rxn
Addition of amino acids (e.g glycine)
Why are most conjugates highly polar?
- It makes them water soluble and unable to cross the plasma membrane
- Making them almost always pharmacologically inactive and of little or no toxicity
List factors (7) that influence drug metabolism
- Physiologic or disease state
- Genetic Variation
- Drug Dosage
- Age
- Route of Drug Administration
- Enzyme Induction
- Enyzme Inhibition
What can influence a drug’s hepatic clearance?
Pathological factors that alter liver function
How can congestive heart failure (inefficient pumping) affect drug metabolism?
It can decrease hepatic blood flow and distribution of drugs
What can alter the ratio of bound to unbound drug?
Alteration in albumin production
What is the main site of serum-albumin production and drug biotransformation?
Liver
Explain how genetic variation can influence drug metabolism.
- There is a great variation in the activity of N-acetyl transferase enzyme among different population.
- The proportion of drugs metabolized by the major cytochrome P450 enzyme (know about CP450 CYP2D6 is a polymorphic drug-metabolizing enzyme)
If you are a fast acetylator, do you have more or less drug concentration in blood? Do you have more or less tranferase?
Less drug [ ], More transferases
If you are a slow acetylator, do you have more or less drug concentration in blood? Do you have more or less tranferase?
More drug [ ], less transferases
How does dosage influence drug metabolism?
- As drug dosage increases = drug [ ] may saturate metabolic enzyme
- If Phase II enzymes are saturated, it gets metabolized by CYP450 enzymes
- This can lead to an Intermediate that causes Hepatic cell death
ex: high dosage of acetaminophen causing hepatic cell death
How does age influence drug metabolism?
- Young children: (primarily infants) Drugs may be MORE ACTIVE, b/c lack of development of Phase I & II enzymes (No enzymes=NO biotransformation)
- Older childen: Drugs may be LESS active than in adults if the drug is given based on weight. Liver develops faster than the general increase in body weight
- Older people: metabolizing enzymes decline
How does the route of drug adminstration influence drug metabolism?
- If drug is taken orally the first pass effect influences how the drug is metabolized
- First pass effect: Combined action of bacterial enzyme within intestine and liver on the drug taken orally.
How does enzyme induction influence drug metabolism?
- Increases the synthesis or decreases the degrading of certain drug metabolizing enzymes
Increases enzyme that breaks drug down
E.g. Cigarette smokers have a polycyclic aromatic hydrocarbon component that induce the N-demethylation (Phase I) pathway
What two drugs act as Enzyme Inducers?
- Phenobarbital
- Rifampin
Enzyme induction can produce a condition known as ____
Pharmacokinetic Tolerance:drugs can block certain enzymes that are involved in metabolizing other drugs
How does enzyme inhibition influence drug metabolism?
- Some drugs can decrease the metabolism (breakdown) of other drugs
- This inhibition may occur by destruction of drug-metabolizing enzymes, by inhibition of enzyme synthesis
Inhibit enzyme that breaks down anothe drug, therefore increases concentration
Example of drugs that benefit from ezyme inhibition
Activity of the Phenytoin is increased by co-adminstration of Chloramphenicol
List the three processes involved in the excretion of drugs and metabolites in the urine
- Glomerular Filtration
- Active Tubular Secretion
- Passive Tubular Reabsorption
Explain Glomerular Filtration
- If drug is bound to protein, it will NOT go through glomerular filtration
- FREE drugs only
Explain Active Tubular Secretion
- Fixed capacity: Some drugs can get secreted into the urine, some drugs can get reabsorbed
- Limited transporters: they can be saturated
Explain Passive Tubular Reabsorption
- pH of the urine (pH4-8) determines ionization
- Un-ionized form of drug can get readily absorbed in systemic circulation
What is biliary excetion?
- Enterohepatic recirculation (biliary cycling)- Transport system analagous to those found in kidney actively secrete drugs into bile
- Transport drug into bile through active transport, then get reabsorbed from GI tract.
Biliary excretion favors compounds with molecular weight ____
greater than 300
Conjugated drugs can be ____ to the free drug by _____ and ____ into circulation
- hydrolyzed
- intestinal bacteria
- reabsorbed
Enterohepatic recirculation ____ elimination of drugs and ____ duration of action
- reduces
- prolongs
keeps drug in body for long time
keeps drug in body for long time
Milk is slighty ______ compared to plasma
Acidic
What type of drug will get stuck in milk?
Basic
Why is milk important?
For mursing infants and as a residue in diary products
True or False: Drugs can be excreted from the lungs (pulmonary)?
True (anesthetic gases, alcohol)
What other things can drugs be excreted from?
Sweat, saliva, and hair
Define Clinical Pharmacokinetics
Is the process of using drug concentration, pharmacokinetics principles, and pharmacodynamics criteria to optimize drug therapy in individual patients
Explain Bioavailability and what does it measure
- Bioavailability factor (F) is the percentage or fraction of the dose, which reaches the systemic circulation
- Parameter that measures drug absorption
E.g. 0.6=60% in systemic circulation
Explain Bioavailability and what does it measure
- Bioavailability factor (F) is the percentage or fraction of the dose, which reaches the systemic circulation
- Parameter that measures drug absorption
E.g. 0.6=60% in systemic circulation
IV drug will have a bioavailabilty of _______%?
100
Expain Apparent Volume of Distribution and what does it measure
- Is the proportionality constant that relates the amount of the drug in the body to the serum concentration
- Parameter the measure distribution of the drug
Apparent volume of distribution
- Relates…
- Important for
- Measured in
- Relates the dose of the drug to the concentration found in plasma
- Important for Clearing and dosing
- Measured in L and mL
Explain Clearance and Half-life. What does it measure and how is it measured?
- Clearance represents rate of drug removal
- Half-life is the time it takes for thr concentration of drug in the plasma to decrease by 50%
- Parameter that mesures Drug Elimination
- Per unit of time: mL/min, L/hr
- Which of the following is true regarding enzyme inhibition?
a. They increase the synthesis of drug metabolizing enzymes
b. They decrease the degradation of drug metabolizing enzymes
c. Chloramphenicol is an enzyme inhibitor
d. They can produce a condition known as tachyphylaxis
c. Chloramphenicol is an enzyme inhibitor
- What type of drugs are more likely to be trapped in milk
a. Weak Acid
b. Strong Acid
c. Weak Base
d. Strong Base
c. Weak base
- Drugs administered intravenously have a bioavailability of _____:
a. 0.5
b. 0.75
c. 1.0
d. 0.25
c. 1.0
