Basic Principles IV Flashcards
1
Q
biotransformation of toxicants
A
- can have a widespread influence on drug use
- route of admin
- dose
- effectiveness
- tox, safety
- duration of effect
2
Q
purposes of biotransformation
A
- one method of clearing drug from the plasma
- rate will depend on endogenous enzyme systems
1. drug detox- change structure and thus activity
2. prepare for drug excretion- reduce drug characteristics to make it easy to absorb - make it larger, add charges, make it more water soluble- esp important
- can make drugs active or inactive
3
Q
sites of biotransformation
A
A. liver
1. on cellular structural components, SER- lipid enviro- enhances equil with lipid soluble drugs
2. cytoplasm
3. mitochondria
B. anywhere else in the body- plasma, RBC, synaptic cleft, bone
4
Q
phase I
A
- xenobiotic to primary product
- exposes or adds functional groups
- oxidation, reduction, hydrolysis
- primary product can be excreted
- takes substance from lipophilic to hydrophilic
- activities of drug vs activities of metabolites
- may have variable results on activity
- both in the target tissue and on secondary receptors in the other tissues- tox
5
Q
phase II
A
- primary product to secondary product
- biosynthetic conjugation
- conjugation-synthesize a new molecule by combining the drug or metabolic product of phase I with a molecule provided by the cell
- metabolic energy is used and a covalent bond is formed
- resulting molecule is larger, charged, water soluble, and inactive
- liver has to be healthy
6
Q
hepatic microsomal drug metabolizing systems
A
- system in liver we use to measure the metabolism
- microsomal is SER
- both phase I and phase II processes
- induction- increase metabolism of primary drug or other drugs, can manifest as an increase in first pass metabolism
- inhibition- use a drug to block the metabolism of another drug or endogenous compound
- if phenobarb given, dicumerol decreases, and therefore so does PT (faster clotting)
7
Q
non-microsomal systems
A
- other organs, plasma, red cells
- usually phase I- acetyl cholinesterase, alcohol dehydrogenase
- inhibition but no induction- enzymes are not near the nucleus they were made by and therefore not autoregulated or getting feedback
8
Q
enzyme system
A
- can be relatively specific for certain drugs or endogenous compounds, or more likely nonspecific and have a broad range of activity for classes or types of molecules
- mass action
- products of phase I become substrates of phase II
9
Q
drug oxidation
A
- add oxygen or change proportion of oxygen in molecule
- most common metabolic transformation
- hepatic mixed function oxidase system
10
Q
hepatic mixed function oxidase
A
- NADPH, cytochrome p450 reductase (flavoprotein), cytochrome p450 (hemoproteins) Mg++, phospholipid, O2
- usually metabolize lipid soluble drugs- concentrates in SER
- reductase changes iron from Fe +++ to fe ++ and becomes oxidized in the process
- O2 then binds, and drug becomes oxidized
- fe gains electrons (is reduced while reductase is oxidized) so O2 can come in and take them
11
Q
p450
A
- 12 groups in humans
- some for toxins and others for endogenous compounds
- low specificity
- very large genetic variations in populations of people
- catalyzes reductions and oxidations
- 10:1 ratio of p450 to a reductase- constant cycling (reductase is faster, can do one p450 after another)
- number of variations- CYP1a2, 2e1, 2c, 3a, 2d6
- most by 3a, but 2d6 is most trouble
- system also influenced by disease factors- liver disease/ perfusion
- age and sex- fetal-geriatric
12
Q
CYP2D6
A
- largest degree of identified genetic variations
- about 70 nucleotide variations exist
- resulting in an inactive enzyme or reduced catalytic activity
- 4 phenotypes-
1. poor- toxicity possible
2. intermediate
3. extensive
4. ultrarapid- potential no effect- high first pass - variation by race- caucasians 5-10% poor
- SE asian 1-2% poor
- 65 commonly used drugs metabolized by it
- potential drug interactions when metabolized by same p450 enzymes
- competition with inhibition- potential tox
- induction- decrease effectiveness for a given dose
13
Q
oxidation
A
- adds oxygen to molecule to make it less active
- lose oxygen
14
Q
drug reduction
A
- add hydrogen or change the proportion of hydrogen in the molecule
- gain electrons
15
Q
drug hydrolysis
A
-cleave a molecule by the addition of a water molecule
16
Q
first order
A
- if concentration of D is much less than km, the enzyme is efficient
- V= vmax X D/ Km = constant x [D]
- 98% of drugs
17
Q
biotransformation summary
A
- the enzyme systems may be a rate limiting step in the clearance of a drug from plasma when:
- metabolism is more important than renal elimination
- when enzyme is relatively slow
- biotransformation determines how fast clearance is from plasma
18
Q
zero order
A
- if [D]»_space; km, inefficient enzyme
- V= Vmax x [d] / d, which equals Vmax- constant
- maximum velocity but constant rate
- few drugs
19
Q
renal excretion
A
-most important route of elimination of drugs or metabolites
20
Q
excretion is equal to
A
-equal to amt entering tubule - amt reabsorbed
21
Q
drug enters nephron by
A
- by glomerular filtration- only free drug molecules are filtered
- amount filtered depends on glomerular blood flow and free drug concentration
- also enter by secretion
- active transport, one system for acids and one for bases
- exists for endogenous compounds like uric acid or choline
- inhibition- usually competitive- to make another drug work better and still let system work on endogenous compounds
- saturation- can occur at therapeutic doses or with overdoses
- changes primary process to zero order process
22
Q
drugs are reabsorbed by
A
- passive reabsorption- especially for lipid soluble drugs
- after free water absorption these are concentrated in the loop of henle- reverse concentration gradient
- active reabsorption- active transport for endogenous compounds, works for some drugs
23
Q
amount of drug excreted
A
(glomerular filtration +active tubular secretion)-(passive reabsorption +active reabsorption)
24
Q
enhancing renal excretion
A
- forced diuresis
- manipulate pH of the urine, trapping of ionized drug
- add bicarb to pull pH up and make acidic to pull HA out and bring it into urine
- alkalinization changes the urinary excretion by 4 fold to 6 fold
25
Q
biliary excretion
A
-amount of drug excreted= (amount of drug entering bile)- (amount of drug reabsorbed)
26
Q
enter bile by
A
- secretion- active transport system- acids or bases
- passive diffusion
27
Q
reabsorbed from bile by
A
- passive diffusion and the original absorption mechanism
- enterohepatic cycling can occur
28
Q
other routes of elimination
A
- lungs
- sweat
- saliva
- tears
- breastmilk
29
Q
elimination of drugs from site of action
A
- decrease concentration in the plasma
- redistribution
- biotransformation
- excrtion
30
Q
redistribution
A
-changes the location of the drug
31
Q
biotransformation
A
-primarily hepatic, metabolically changes the drug to metabolites and causes a clearance of the drug from the plasma
32
Q
excretion
A
-primarily renal, produces a clearance of the drug from the plasma and from the body
33
Q
clearance
A
- a combination of biotransformation and excretion
- contribution of each process with vary for different drugs
- a volume of plasma that is cleared of drug per unit time
- clearance total=clearance metabolic + clearance renal
- in hepatic disease, metabolic is reduced
- in renal disease, renal is reduced
34
Q
factors influencing clearance
A
- body surface area
- protein binding
- cardiac output
- renal function
- hepatic function
- blood flow to systemic organs
35
Q
inulin
A
- filtered
- 130 ml/min
- GFR
- all excreted that is filtered
36
Q
glucose
A
- reabsorbed
- 0 ml/min excreted
- all reabsorbed
37
Q
PAH
A
- secreted
- up to 650 ml/min
- renal blood flow
