Week 1 (Quiz 1) Flashcards
PK
Behavior of drugs in the body (ADME- absorption, distribution, metabolism, elimination); based on analysis of plasma concentration of drug over time
Bioavalibility of IV and IA
100%
Volume of distribution formula
Vd = Ab/Cp
If Vd is large…
Wide distribution outside of plasma
If Vd is small..
Drug distributes more to extracellular fluid, including plasma
5 Factors influencing absorption/distribution
- differing characteristics of body tissues
- Disease states that alter normal physiology
- Lipid/water solubility of the drug
- Regional differences in physiologic pH
- Extent of protein binding
pK equation for weak acids
pH = pKa + log(A-/HA)
pK equation for weak bases
pH = pKa + log (B/HB+)
Examples of weak acids
phenobarbital, salicylic acid, methotrexate
Weak acids are trapped in:
alkaline environment
Overdose treatment for weak acids
sodium bicarbonate + diuretic
Examples of weak bases:
amphetamines, cocaine, strychnine, quinidine
Weak bases are trapped in:
acidic environment
Overdose treatment for weak bases:
ammonium chloride or ascorbic acid
Clearance equation
Cl = Vd x Ke
Zero-order kinetics
rate is independent of plasma concentration of the drug
First-order kinetics
rate is dependent on plasma concentration of drug, also means constant fraction of drug appears or disappears per unit time.
Rate of elimination equation
-Ke x Cp
Half-life equation
t1/2 = 0.693 xVd/Cl
input rate equation
Css x Cl
Steady state kinetics dogma 1
Steady-state concentration is only dependent on rate of administration and rate of elimination
Steady state kinetics dogma 2
Time to achieve steady state is 4-5 half-lives
Maintenance dose equation
MD = Css x Vd x Ke
Loading dose equation
LD = Vd x Css
Phase 1 metabolism reactions
Oxidation (most common), reduction, hydrolysis
What protein family is in charge of oxidation reactions?
Cytochrome P450
Where is CYP450 found?
Found in liver, transmembrane, non-soluble proteins that come in a variety of isoforms
What three components do CYP450 require?
- Flavorotein (cytochrome P450 reductase)
- CYP enzyme (contains heme)
- obligatory cofactors: NADPH and O2
What are the two major families of CYP450?
- drug metabolizing (induced by the drugs themselves)
2. carcinogen-metabolizing (induced by polycyclic aromatic hydrocarbons.
What does the CYP1 family do?
carcinogen-metabolizing
What is the induction of CYP1?
nuclear receptor mediated = aryl hydrocarbons bind AH receptor –> forms heterodimer with ARNT in nucleus –> complex binds gene promoters (DRE and XRE )
What are the three main types of CYP1?
CYP1A1, CYP1B1, CYP1A2
Which CYP1 is constitutively expressed in the liver?
CYP1A2
What does the CYP2 family metabolize?
Metabolizes many drugs
What is the induction for CYP2 family?
CAR binds drugs –> forms heterodimer in nucleus with RXR which bind PBREM enhancer elements
CYP2C9
warfarin, phenytoin, NSAIDS
CYP2C19
omeprazole, diazepam, clopidogrel
CYP2D6
codeine, metoprolo, antidepressants, tamoxifen
CYP2As
steroids and nicotine
CYP2E1
ethanol, anesthetics
Multidrug resistance proteins
ATP-dependent TM pumps (found in sanctuary sites like eye, CNS, etc.) that pump xeobiotics out of cells = ATP-binding cassette transporter gene family; they share substrates with CYP3A4
What does CYP3 family do?
Responsible for the metabolism of majority of drugs
Induction for CYP3 family?
Nuclear receptor mediated, exactly like CYP2 family, except using PXR to bind drugs instead of CAR as a receptor
CYP3A4 - Why is it important?
Most abundant isoform in the human liver, metabolizes 1/3 to 1/2 of all P.O. drugs - first pass metabolism; also in gut; main site for drug-drug interactions
Signifiance of terfenadine and CYP3A4
terfenadine has serious cardiotoxicity at high levels and is only cleared by liver = blocked by other antibiotics being metabolized via CYP3A4 –> toxi
What strange thing irreversibly binds CYP34A?
grapefruit juice
CYP3A5
abundent in 10-15% of people
Phase 2 reactions
conjugation = adding electrophilic cosubstrates to nucleophile sites (N, O, S) on drugs that make them more polar and less active, and aid in excretion, defense system against toxins
Enzyme for glucuronidation
Uridine Glucuronyl Transferases (UGTs)
Induction for glucuronidation
AhR, CAR or PXR mediated (ex. bilirubin conjugation by UGT1*1
Gilbert’s syndome
mutation in promoter that down regulates production of UGTs causes mild hyperbilirubinemia
Crigler-Najjar Syndrome
mutation in gene sequence that kills the UGTs enzyme
Sulfation enzyme
sulfotransferases
What is metabolic activation?
when metabolism creates reactive intermediates (electiophilic, unstable products that react with nucleophiles)
What are 4 ways reactive intermediates can be dealt with?
- Bind water
- Bind glutathione (GSH)
- Bind protein
- Bind DNA/RNA
How can reactive intermediates cause organ toxicity?
binding protein
How can reactive intermediates cause mutations/be carcinogenic and toxic?
binding DNA/RNA
How can acetaminophen be toxic?
Hepatotoxic at >7gm, toxic NAPQI when metabolized by CYP2E1 –> when it depletes GSH it is then free to cause damage.
