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PKPD Exam 4 Review
Terms in this set (148)
what the drug does to the body
- Response rate
- Surrogate marker
- PK variability controlled
- PD variability uncontrolled
Doubled-dose → less than double the effect
What usually happens when you double the dose/infusion rate?
when C <<< EC(50)
Linear phase of Emax model
when C >>> EC(50)
Constant phase of Emax model
when E is between 20% to 80% of Emax
Log-linear phase of Emax model
What model is shown?
Phase 1: Linear model
Phase 2: Log-linear model
Phase 3: Constant model
What are the corresponding IV Bolus-Emax - models of each Phase shown?
when E > 80% of Emax
Phase 3 of IVB Emax model
when 20%≤E≤80% of Emax
Phase 2 of IVB Emax model
when E < 20% of Emax
Phase 1 of IVB Emax model
F(e) approaches F(c)
When Css,max & Css,min << EC50
F(e) = 1
When Css,max & Css,min >> EC50
ALWAYS: PK Fluctuation >> PD Fluctuation
- Reason: Css,max >>> Css,min
the degree of fluctuation in multiple dosing PK/PD-based model
The [C] >> EC50, meaning maximal [C] are still maintained over time (about 4 half-lifes) for maximal E (effect).
How come ACE-Inhibitors can be given once a day despite having a relatively short half-life (t1/2 = 4 hrs)?
- Indirect link
- Indirect response
- Active (agonistic) metabolites
- Combinations of the above
- i.e. S-ibuprofen (analgesic effect ↓ as evoked potential (EP) ↑)
- Functional tolerance
- Active (antagonistic) metabolites
- Combinations of the above
- i.e. intranasal cocaine
characterized by decreasing drug [C] after repeated administration of the same dose, which consequently results in diminishing drug effects in response to these dose
Same dose gives less [C] → less effect (enzyme induction); (PK tolerance)
Same Dose gives less effect at later time points
same dose gives same [C] but produces less effect (PD tolerance)
- tolerance development to the acid inhibitory effect of ranitidine in patients (2 x n = 9)
example of functional tolerance
Distributional delay to the effect site
The following PK/PD profile of the muscle relaxant effect of d-turbocurarine displays what type of trend?
dose adjusted normalized for BSA
Dose estimated a priori
dose adjustment based on renal function
Dose estimated a posteriori
dose adjustment based on measured concentration
dose adjustment based on surrogate marker of response
v = (Vmax * [S])/K(m) = Cl x C
When K(m) >> [S]...
v = (Vmax * [S])/[S] = Vmax
When K(m) << [S]...
zero order kinetis
Alcohol is eliminated via...
first order kinetics
Drugs are usually eliminated via...
Non-linear kinetics (in between 0th & 1st order)
What is the following type of kinetics? What is an example of a drug that follows this elimination order of kinetics?
Cl is not constant due to invalid proportionality between dose and [C]steady state
How is phenytoin clearance different from most other first order drugs?
the [C] steady state more than doubles
For drugs under non-linear kinetics (i.e. phenytoin), what happens if you double the dose?
the [C] steady state decreases more than one half
For drugs under non-linear kinetics (i.e. phenytoin), what happens if you decrease the dose by half?
- ↑Vmax; ↑v
- Same K(m); different Vmax
The following effect is known as
- ↑K(m); ↑v
- Same Vmax; different K(m)
The following effect is known as
↑Cl → ↑ v
How does Induction effect Cl when [C] << Km?
↓ Cl → ↓ v
How does Inhibition effect Cl when [C] << Km?
↑ Cl → ↓[C]steady state
How does Induction effect [C] steady state when [C] << Km?
↓ Cl → ↑ [C]steady state
How does Inhibition effect [C] steady state when [C] << Km?
- Q (liver blood flow)
- intrinsic Cl (Cl(int))
- f(u,p) (fraction of unbound drug in plasma)
three factors affecting hepatic drug clearance
Low extraction drug
Cl(H) = Q x [f(u,p)x Cl(int)]/Q
Cl(H) = f(u,p) * Cl(int)
When Q >> f(u,p) x Cl(int)...
High extraction drug
Cl(H) = Q x [f(u,p)x Cl(int)]/[f(u,p)x Cl(int)]
Cl(H) = Q
When Q << [f(u,p)x Cl(int)]...
F* = Q/Q = 1
- Low extraction drug
- No metabolism by the liver
First pass hepatic metabolism when Q >> f(u,p) x Cl(int)
F* = Q/[f(u,p)x Cl(int)]
- High extraction drug
- High intrinsic Cl
First pass hepatic metabolism when Q << [f(u,p)x Cl(int)]
What type of drug dosage forms are NOT subject to first pass metabolism?
oral (extravascular) drugs
What type of drug dosage forms are subjected to first pass metabolism?
[C]steady state, free
What variable is related to the therapeutic effect of a drug?
E(H) < 0.3
What E(H) value defines a low extraction drug?
E(H) > 0.7
What E(H) value defines a high extraction drug?
What are some low extraction drugs?
What are some high extraction drugs?
an inactive parent compound of a drug that gets converted into the pharmacologically active metabolite through enzymatic catalysis
- Aspirin (→ Salicylic Acid)
- Oseltamivir (→ Oseltamivir acid)
- Ramipril (→ Ramiprilat)
*-Conversions into pharmacologically active metabolite
Examples of some Pro-drugs
morphine (active metabolite)
What do the pharmacologically inactive drugs (pro-drugs) codeine & heroine get converted into?
Phase II reactions
Phase 1 reactions
- Phase 1: hydroxylation
- Phase 2: glucuronidation
example of a drug that undergoes both Phase 1 & Phase 2 metabolism
example of a drug that undergoes only Phase 2 metabolism
example of a drug that undergoes only Phase 1 metabolism
What percentage of Phase 1 reactions are done by CYP450 enzymes?
What enzyme(s) metabolizes about 50% of all marketed drugs?
What enzyme is responsible for the little less than half of the Phase 2 reactions? What does this enzyme do?
- Biological (gender, age, renal/liver function, etc.)
- Lifestyle (smoking, alcohol consumption, diet, drug-drug interactions)
Factors of drug metabolism
Where are most CYP450 enzymes found in?
oxidative metabolism of many endogenous compounds
What is the most important mechanism of CYP450 enzymes?
isoenzymes with different, non-absolute substrate specificity (meaning one enzyme can metabolize a drug, but can also be metabolized by other enzymes)
- i.e. Clopidogrel is mainly metabolized by CYP2C19 to form its new active metabolite
Description of CYP enzyme family
when the AA sequence is x% identical to each other in the family/subfamily
CYP3A4 family homology
CYP3A4 subfamily homology
- small intestine
Where are the CYP3A4 enzymes expressed most abundantly?
- Anti-HIV agents ("-navir")
- Anti-HIV agents ("-navir")
- Grapefruit juice
- St. John's wort
What macrolide antibiotic is not an CYP3A inhibitor?
What statin is not an CYP3A substrate?
high variability (marked 5-20x)
Genetic variability in CYP3A enzymes
What enzymes are heavily influenced by genetic factors?
CYP2D6 and quinidine
Example of the following:
"Not all inhibitors are substrates"
notable CYP2C9 drug substrates
notable CYP2C9 inhibitors
notable CYP2C19 drug substrates
Proton pump inhibitors ("-prazole")
notable CYP2C19 inhibitors
notable CYP2D6 drug substrates
All SSRIs (particularly paroxidene)
notable CYP2D6 inhibitors
notable CYP3A4 substrates
- Grapefruit juice
notable CYP3A4 inhibitors
- St. Johns Wort
notable CYP3A4 inducers
notable P-gp drug substrates
notable P-gp inhibitors
- St. John's wort
notable P-gp inducers
Paroxetine causes inhibition of an enzyme → ↑[C] of metoprolol
What does the graph indicate?
Amiodarone inhibits CYP3A4 → ↑[C] of simvastatin (↑myalgia risk)
What does the graph indicate?
Based on the two graphs, which drug would be better to take with amiodarone: simvastatin (a) or pravastatin (b)?
- metabolizes efficiently by the intestinal CYP3A4
- metabolizes 1/2 remaining [C] by the hepatic CYP3A4
Taken w/grapefruit juice (CYP3A4 inhibitor):
- reduced metabolism by intestinal CYP3A4 (inhibited by grapefruit juice)
- metabolizes 1/2 remaining [C] by the hepatic CYP3A4 (does NOT get inhibited by grapefruit juice)
What does the metabolism of oral felodipine indicate?
typical bioavailibility for amiodarone
typical bioavailibility for felodipine
typical bioavailibility for lovastatin
typical bioavailibility for metoprolol
typical bioavailibility for propanolol
typical bioavailibility for verapamil
notable example of efflux transporter
notable example of uptake transporters
substrate for MDR1/P-gp (ABCB1)
inhibitors of P-gp/MDR1 (ABCB1)
- Role: transports statins to the liver (hepatocytes)
substrates of OATP1B1 (SLCO1B1) and role
Inhibitors: reduces [C] of drug uptake into intestine
Inducers: increase [C] of drug uptake into intestine
How does OATP1B1 uptake induction or inhibition affect drug substrate [C]? (Use the graph with the example of fexofenadine)
an energy-dependent multidrug pump/efflux transporter that is known as a mediator of MDR in cancer cells (high expressed on their surface)
- Liver (in between bile and hepatocytes)
- Small intestine & colon (in between intestinal wall and intestinal lumen)
- Tumor cells
- Kidney (in the nephrons)
- Brain ("BBB")
Where can P-gp be found?
- 60-70% Cl(renal)
- 30-40% Cl(biliary)
percentages of digoxin clearance
- Quinidine competitively inhibits P-gp
- Digoxin ↑[C]intracellularly → toxicity
- Cl(renal) ↓
- Cl(biliary) ↓
- AUC ↑
How does quinidine & digoxin drug interaction work?
- rifampin is able to induce P-gp in the intestine.
- IV dosing: no first-pass effect (meaning, no induction of intestinal P-gp by rifampin)
How come digoxin is induced by rifampin when taken orally rather than IV administration?
- Gemfibrozil inhibits OATP1B1, causing [C] of simvastatin to ↑ (black dot)
Based on the graph, what impact does gemfibrozil have on simvastatin?
- to increase the probability that the drug is being metabolized and/or pumped out of cells
Why do CYP3A enzymes and P-gp efflux transporters work together?
- delayed gastric emptying
- alterations in hepatic blood flow
Notable Food effects on drugs
- Grapefruit juice inhibits CYP3A4, causing ↑ [C] of statins → toxicity (i.e.: rhabdomyolysis, acute renal failure)
What do the following graphs indicated about the interaction between statins & grapefruit juice?
- Effective cure (most amt)
- Severe side effects (least amt)
- genetic variations may contribute to therapeutic response
Three pharmacogenomic groups
drug metabolizing enzymes
Pharmacogenetics & PK
- drug receptors
- drug targets
Pharmacogenetics & PD
Somatic (Tumor) DNA
genetic makeup of an organism
traits of an organism that are expressed
inherited variations in individual drug effects; single gene interactions w/ drugs including disposition, safety, tolerability, and efficacy
large population studies of all many different genes that determine drug effects
- single nucleotide polymorphisms (SNPs)
- Variable Number tandem repeats (VNTR)
three types of genetic variation
non-synonymous (missense) polymorphisms
results in translation of a different amino acid
synonymous (sense) polymorphisms
results in the translation of the same amino acid
Results in the insertion of a stop codon (rendering it non-functional in most cases)
homozygous wild type
- i.e. AACTG ↔ AACTG
- i.e. AACTG ↔ AACAG
- i.e. AACAG ↔ AACAG
descending functionality of genes
***1: wild type allele
***4: "no function" allele
2N: 2 copies of the allele
"star" nomenclature example for
- CYP2D6****2 has normal function
- CYP2C19***2 has NO function
Does the "star" nomenclature system always denote normal function in "wild-type?"
ascending metabolizer order for CYP enzymes
- Genotype reveals information about an allele's phenotype
- i.e. CYP2D6
***4 is a poor metabolizer, therefore the prescribing recommendation is to avoid codeine.
How can genetics impact prescribing?
- observational studies
- randomized clinical studies
- pre-clinical and clinical studies
- case reports
- in vivo PK
- in vitro functional studies
- in vivo functional studies
Gene/drug association for pharmacogenetic-based clinical recommendations
Most important form of pharmacogenetic-based clinical recommendations
- therapeutic index
- severity of disease
- consequences of suboptimal prescribing
- availability of genetic tests
- availability of and evidence for alternative therapy
Clinical actionability for association for pharmacogenetic-based clinical recommendations
clopidogrel is a prodrug
- requires activation in the liver via CYP2C19 into active metabolite
- inactive alleles (associated w/CYP2C19*2) → ↑risk of CV events (toxicity)
- therapeutic index: bleeding vs thrombosis
- severity of underlying disease: stroke, MI
- consequences of suboptimal prescribing: death, serious morbidity
- availability of genetic tests: yes
- availability of and evidence for alternative therapy: yes
example of the important of pharmacogenetics with clopidogrel
- CYP2B6 metabolizes efavirenz into inactive metabolites
- associated with CNS toxicity (i.e. headache) potentially → drug discontinuation
- CYP2B6 516 (G→T): ↑efv [C] + CNS toxicity
- EFV dose reductions may benefit patients with CYP2B6 516 (G→T) without compromising efficacy
example of the important of pharmacogenetics with efavirenz
UGT1A1 converts unconjugated bilirubin into conjugated bilirubin
- atazanavir inhibits UGT1A1
- polymorphisms in UGT1A1 ***
**6 (211 G → A) leads to 30% activity of UGT1A1
-- severe risk factor for severe hyperbilirubinemia among patients taking atazanavir with the polymorphism (must be discontinued and another first line agent for HIV infection should be used)
example of the important of pharmacogenetics with atazanavir & UGT1A1
Consider an alternative agent
what is the pharmacogenetics-based clinical recommendation with voriconazole and CYP2C19 if the ADULT patient is a ultra-rapid or rapid metabolizer of the agent?
Prescribe recommended standard of care dosing.
what is the pharmacogenetics-based clinical recommendation with voriconazole and CYP2C19 if the ADULT patient is a normal or intermediate metabolizer of the agent?
Consider an alternative agent -OR- If voriconazole is warranted, consider the lower than standard dosing with careful TDM
what is the pharmacogenetics-based clinical recommendations with voriconazole and CYP2C19 if the ADULT patient is a poor metabolizer of the agent?
- Consider an alternative agent -OR- If voriconazole is warranted, consider the lower than standard dosing with careful TDM
what is the pharmacogenetics-based clinical recommendations with voriconazole and CYP2C19 if the PEDIATRIC patient is a poor metabolizer of the agent?
- Prescribe recommended standard of care dosing.
what is the pharmacogenetics-based clinical recommendation with voriconazole and CYP2C19 if the PEDIATRIC patient is a normal, rapid or intermediate metabolizer of the agent?
- Consider an alternative agent.
what is the pharmacogenetics-based clinical recommendation with voriconazole and CYP2C19 if the PEDIATRIC patient is a ultra-rapid metabolizer of the agent?
- HLA-B is responsible for presenting peptides to immune cells and plays a critical role in normal immune recognition of pathogens
- A variant allele, HLA-B*57:01, is associated with increased risk of a hypersensitivity reaction to the anti-HIV abacavir
- in the absence of genetic prescreening, hypersensitivity affects about 6% of patients and can be life-threatening with repeated dosing.
Clinical pharmacogenetics implementation for HLA-B genotype and abacavir dosing
Help clinicians understand HOW available genetic test results should be used to optimize drug therapy.
Why are CPIC guidelines important?
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