A4: Pharmacokinetics, pt. 2 Flashcards
What is the main aim of “biotransformation” and why?
to inactivate and make non-polar / lipophilic molecules more polar and water soluble so they can be excreted by the kidneys (rather than reabsorbed in the DCTs)
What are the 3 main types of phase I reactions in biotransformation?
And what enzyme system catalyzes the majority of them?
Oxidation, Reduction and Hydrolysis
Most oxidations done by CYP450 family enzymes
There are CYP450-dependent and -independent oxidation reactions in biotransformation…
what are the -dependent ones (10 total in 5 categories)?
(prob don’t need to know them off the top of yr head but i could see an mcq asking “which of these rxns are CYP450-dependent” + needing to be able to recognize them)
- aromatic + aliphatic hydroxylation
- epoxidation
- N- or O-dealkylation
- N- or S-oxidation
- De-sulfuration, -chlorination and -amination
There are CYP450-dependent and -independent oxidation reactions in biotransformation…
what enzymes catalyze the CYP450-independent oxidations? (3)
- flavin monooxygenase
- amine oxidases
- dehydrogenases
What kind of reduction and hydrolysis reactions occur in phase I biotransformation?
- Reduction: azo-, nitro- and carbogen reduction
- Hydrolysis of esters and amides
Aside from turning active compounds into inactive metabolites…
what are 3 other situations that can occur in phase I biotransformation?
(examples?)
- active compound > active metabolite - codeine > morphine; phenacetin > paracetamol; diazepam > oxazepam
- inactive prodrug > active metabolite - enalapril > enalaprilat (ACE inhib.)
- active compound > toxic metabolite - paracetamol > N-acetylbenzoquinone
Phase II of biotransformation is a conjugation reaction.
What 5 molecules / functional groups are the phase I metabolites be conjugated with in phase II?
What is the general consequence?
- glucuronide
- sulfate
- acetyl
- methyl
- glycol
Generally further inactivates and water solubilizes the molecule
Name 3 exceptions to the general rule that phase II conjugation inactivates drugs.
(From slide, maybe not essential)
- Morphine-6-OH glucuronide is still active
- Minoxidil sulfate is the active phase II metabolite of prodrug minoxidil
- N-acetyl Isoniazid - not sure how it’s an exception, just in the slide
What 2 processes occur to increase activity of CYP enzymes when they are “induced”?
What are some examples (5) of CYP inducers?
- increased transcription CYP genes and inhibited degradation of existing CYP enzymes
- phenobarbital, rifampicin, ethanol, smoke + air pollution all induce CYP enzymes
What are 2 ways that CYP enzymes can be inhibited from metabolizing drugs?
(Give some examples of CYP inhibitors … from slide)
- Competitive Inhibition (different substrate competes with drug for same CYP isozyme) Non-substrate Inhibition (compound which is not substrate of that isozyme still inhibits it)
- Ketoconazole, cimetidine, chloramphenicol, ethinylestradiol … all inhibit CYPs
What are the terms for people whose CYP polymorphism causes them to metabolize a drug more slowly or more quickly?
Give 2 CYP isoforms for which polymorphisms have significant metabolic consequences (extra: which drugs/people).
(Many isoforms are important; these 2 are from the slides.)
- Poor metabolizers vs. extensive metabolizers
- CYP2D6 - metabolizes anti-depressants/-psychotics (haloperidol) and antiarrhythmics (propafenon); 5-10% whites are PMs
- CYP2C19 - diazepam / omeprazole; 15-20% asians are PMs
Give an example of a phase II biotransformation reaction for which enzyme polymorphism plays an important role.
What is its significance?
- N-acetylation of drugs such as isoniazid, procainamide (Na channel blocker; anti-arrhythmic) and nitrazepam
- Many people are “slow acetylators” (90% egyptians, ~55% whites, 15% asians)
- Isoniazid has significant side fx… hepatotoxicity + incr. SLE risk
What are the 3 main processes in renal excretion / elimination of drugs?
- Glomerular Filtration - non-protein bound drug filters thru glomerulus; lipid solubulity and pH do not affect this, but GFR / protein binding do.
- Active Tubular Secretion/Reabsorption - PCT secretion by non-selective (+ thus competitive) anion/cation transporters
- Passive Diffusion - in DCT, nonpolar / uncharged molecules can be reabsorbed; can be manipulated by changing urine pH (discussed in previous cards)
What other routes can drugs be eliminated by?
(examples?)
(first route is most signifcant / in slides; others just from book)
- Biliary Excretion - digoxin, morphine, chloramphenicol + ethinylestradiol eliminated via bile in feces
- Lungs - anesthetic gases
- Breast Milk
- Sweat, Saliva, Tears, Hair and Skin
What kind of kinetics does the metabolism of most drugs follow? Explain it.
What is the equation for this?
(on answer card, image shows a drug concentration vs. time graph, both normally and semi-logarithmically … just for… fun)
First-Order / Linear Kinetics
- rate of drug metabolism/elimination is directly proportional to concentration of free drug
- a constant fraction of drug is eliminated per unit time
- V = Vmax * [C] / Km
- (V = rate of metab. / Vmax = rate when system is saturated / [C] = drug conc. / Km = conc. when rate is 1/2 Vmax)
What are zero order / non-linear kinetics?
When does it occur? (Examples?)
What are the consequences of zero order kinetics for elimination speed?
- rate of elimination is independent of concentration
- occurs when the elimination process is saturated either in all or part of the concentration range (occurs with ethanol and phenytoin)
- means that elimination is slower than first-order and half-life can’t be determined (fraction of drug eliminated per unit time is not constant)
What is the “two compartment open model” as it relates to the concentration vs. time curve?
(I’ll call it the 2COM in the answer card to save space)
- 2COM describes the conc. vs time curve as having two phases: the rate of α phase describes the i_nflow of the drug into the peripheral compartment_ (fat, skin, muscle), the rate of β phase describes the rate of elimination (a third γ phase may represent the deep compartment)
Considering half-life applies to both accumulation and elimination…
how does the time required to reach Css compare to the time required for elimination of the drug after the end of an infusion?
- They are the same.
- At least theoretically… though it seems like practically they would be different.
In intermittent administration…
How does altering dose (but keeping dosing interval constant) alter Css?
And how does it affect max-to-min concentration fluctuations within a single dosing interval?
- Altering dose directly alters Css; i.e. increased dose = increased C<strong>ss</strong> (because it essentially increases dosing rate which we said was main Css determinant)
- It also increases max-to-min conc. fluctuations within a single dosing interval.(the amplitude of the “teeth” on the graph below)
- Fluctuation be calculated as Cmax – Cmin = D / Vd
How does altering the dosing interval (keeping dose fixed) affect the Css?
- It also essentially increases dosing rate and thus increases Css
- Since the dose is not changing, there is no increase of fluctuation between max and min concentrations within a single interval
In intermittent dosing…
How does volume of distribution (Vd) affect the fluctuation between max and min concentrations of a drug within a single dosing interval?
(assume the dosing rate is fixed as we change Vd)
(Bonus: How does this affect drug concentrations in thin vs. fat people?)
- Fluctuation and Vd are inversely proportional
- Just think, if the drug is spread out over a larger volume, its concentration will not spike and drop as drastically.
- (in the image, the red curve is a larger Vd while the blue is a smaller Vd)
- (Bonus: lipid soluble drugs will have larger concentration fluctuations in thin people with less adipose tissue for the drug to distribute in)
