Flashcards in BPP IV Deck (21):
What is the purpose of biotransformation? What will its rate depend on? How can you accomplish this feat (two things)?
Clearing the drug from the plasma; endogenous enzyme systems; 1. drug detox (change structure, change intrinsic activity) 2. preparing drug for excretion by reducing characteristics that made it easy to absorb (make it larger, ionized, and water-soluble!!)
What are sites of biotransformation?
A. Liver (Smooth ER, cytoplasm, mitochondria) B. Anywhere else in the body (RBC's, synaptic cleft, areas in bone)
What do the phase I reactions consist of? What will these help make? If the ______ ______ is still too lipid soluble, what reactions can help expedite excretion of the drug?
Reduction, oxidation, hydrolysis (HOR); primary product; conjugation (glucuronidation, acetylation, sulfation; GAS)
What are two systems to help accomplish biotransformation? What processes do they use?
Hepatic Microsomal Drug Metabolizing Systems (HMDMS) and non-microsomal systems; Phase I and II processes with induction (increase metabolism of primary drug or other drugs) and inhibition (use drug to block metabolism of another drug or endogenous compound), vs. organs, RBC's and plasma using Phase I with acetyl cholinesterase and alcohol dehydrogenase, and inhibition
What is an example of a phase I oxidation reaction? What are the key components? What is the ratio of cyt P450 to cyt reductase in e.g. the smooth ER?
Hepatic mixed function oxidase system; Cyt P450, Cyt P450 reductase, NADPH, Mg2+, phospholipid, O2;
10-1 (reductase helps recharge the cyt p450)
Which of the cytochromes has the largest genetic variation? How many commonly used drugs can be metabolized by it? What three qualities make up the 12 P450 groups in humans?
CYP2D6; 65 commonly used drugs;
1. low specificity 2. very large genetic variations 3. catalyze reductions and oxidations
What is a consequence when various drugs are metabolized by the same cyt P450 enzymes? What can the cyt P450 system be influenced by?
Slow metabolism: 1. competition with inhibition (potential toxicity) 2. induction (decreased effectiveness for a given dose);
disease factors (liver disease, poor liver perfusion), and age and sex (fetal vs. geriatric)
What is involved with drug reduction (what's added or modified)? Where are three popular sites of reduction? What is the product of drug hydrolysis?
You add H or change amount of H in the molecule; liver microsome, hepatic microsome, enzymes in cytoplasm and mito in liver cells; you can cleave a molecule by adding water
What does phase I do to a drug's activity? What could come out of phase I reactions (three examples)?
Can have variable results on activity; active drug --> inactive products, active drug --> active product, inactive compound --> active product and inactive product
Where do most phase II reactions occur? What does conjugation involve? What is used and what is formed for conjugation to happen?
Liver; make new molecule by combining drug or metabolic product from phase I with molecule from cell; metabolic energy and covalent bond
What are qualities of the resulting molecule from phase II reactions? What are types of conjugation? What must be happening organ-wise in order for phase II to be working?
Larger, ionized, water-soluble, inactive; glutamine conjugation, glucaronidation, acetylation, methylation, sulfonation, glycine; liver has to be working for glucaronide formation, acetylation, and methylation
For biotransformation, when might the enzyme systems be the rate limiting step in _________ from plasma?
I. metabolism more important than renal elimination (e.g. if drug is lipid-soluble)
II. enzyme is relatively slow
For biotransformation, what is the key equation? When do you have efficient vs. inefficient enzyme systems, and how does that correspond to orders? What's characteristic of hepatic microsomal enzymes and non-microsomal enzymes?
V = Vmax[D]/Km + [D]; efficient would be if Km >> [D], vs. inefficient as [D]>>Km; efficient enzyme systems are first order, inefficient are zero orders;
induction (increased metabolism, caused by drug or other drugs), inhibition (decreased metabolism, caused by another drug), saturation (especially zero order); inhibition only (NOT INDUCED) and saturation
What is the most important route of elimination of drug or metabolites? How do you calculate amount of drug excreted by this manner?
Renal excretion; Amount of drug excreted = amount entering tubule - amount reabsorbed;
How can a drug enter the nepron?
1. Glomerular filtration (only free drug molecules are filtered, amount depends on glomerular blood flow and free drug concentration)
2. Active tubular secretion (active transport, one system for acids and one for bases, also exists for endogenous compounds like uric acid and choline; involves inhibition which is usually competitive, and saturation that occurs at therapeutic doses or with overdoses could change first order processes to zero order processes)
How are drugs reabsorbed? How do you calculate amount of drug excreted especially at renal level?
Passive (especially lipid soluble drugs; after free water reabsorption they are concentrated in the loop of Henle, reverse concentration gradient can occur),
Active (active transport, for endogenous compounds but can work for some drugs); Glomerular filtration + active tubular secretion - (passive reabsorption + active reabsorption)
What can be enhance renal excretion? How can a drug go from the brain to the urine? What can help alkalinize the pH and how does it help urinary excretion? What is the pH of the urine normally?
1. Forced diuresis
2. Manipulate the pH of the urine (trapping of ionized drug); from brain at pH 7.4, to plasma at pH 7.5, to urine at pH of 8; bicarbonate, 4-6x; 5.5;
How is biliary excretion mathematically? How does drug enter the bile? How is it reabsorbed? How else can drugs be eliminated?
Amount of drug excreted = (Amount of drug entering bile) - (Amount of drug reabsorbed); secretion (active transport system, acids or bases) and passive diffusion; uses passive diffusion and original absorption mechanism; lung (anesthetics and ethanol), sweat, saliva, tears, breastmilk (many drugs)
How do you decrease the concentration of drug in plasma (three ways)?
1. Redistribution (change location of drug) 2. Biotransofmration (primarily hepatic, changes drug to metabolites, cause clearance of drug from plasma) 3. Excretion (primarily renal, clearance from plasma and body
How is clearance measured? What clearance is compromised in hepatic disease? Renal disease?
Volume of plasma that is cleared of drug/unit time; Clearancemetabolic; clearancerenal