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
biliary excretion
-amount of drug excreted= (amount of drug entering bile)- (amount of drug reabsorbed)
26
enter bile by
- secretion- active transport system- acids or bases
| - passive diffusion
27
reabsorbed from bile by
- passive diffusion and the original absorption mechanism
| - enterohepatic cycling can occur
28
other routes of elimination
- lungs
- sweat
- saliva
- tears
- breastmilk
29
elimination of drugs from site of action
- decrease concentration in the plasma
- redistribution
- biotransformation
- excrtion
30
redistribution
-changes the location of the drug
31
biotransformation
-primarily hepatic, metabolically changes the drug to metabolites and causes a clearance of the drug from the plasma
32
excretion
-primarily renal, produces a clearance of the drug from the plasma and from the body
33
clearance
- 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
factors influencing clearance
1. body surface area
2. protein binding
3. cardiac output
4. renal function
5. hepatic function
6. blood flow to systemic organs
35
inulin
- filtered
- 130 ml/min
- GFR
- all excreted that is filtered
36
glucose
- reabsorbed
- 0 ml/min excreted
- all reabsorbed
37
PAH
- secreted
- up to 650 ml/min
- renal blood flow
