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64 Cards in this Set
- Front
- Back
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What is bioavailability?
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Bioavailability (F) is the fraction (%) of administered dose that reaches systemic circulation.
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What factors affect absorption of an oral formulation?
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1. The chemical nature of the drug and excipients
2. The dissolution rate of the drug (possible rate-limiting step for oral absorption) 3. CR/SR formulations (these slow absorption and reduce Cp fluctuations. 4. Blood perfusion of GI tract (inc. speeds absorption) 5. Presence of bile/mucous (inc. slows absorption) 6. Gastric emptying (often rate-limiting step) (food slows) (dec. motility decreases absorption) 7. GI flora (may break down drug before it is absorbed) |
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pH > pKa?
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Deprotonated form dominates (deprotonated acids are ionized; deprotonated bases are unionized)
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pH < pKa?
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Protonated form dominates (protonated acids are unionized; protonated bases are ionized)
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Where in the GI tract will weak acids be protonated/deprotonated and thus ionized/unionized?
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Weak acids (pKa 2-7) will be protonated in the low pH of the stomach. At this point they will be unionized and readily absorbed. Weak acids will be unprotonated in the high pH of the small and large intestine. At this point they will be ionized and therefore not readily absorbed.
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Where in the GI tract will weak bases be protonated/deprotonated and thus ionized/unionized?
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Weak bases (pKa 7-10) will be protonated in the low pH of the stomach. At this point they will be ionized and not readily absorbed. Weak bases will be deprotonated in the high pH of the small and large intestines. At this point they will be unionized and readily absorbed.
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What is passive diffusion?
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Diffusion acoss concentration gradient dependent upon:
1. lipid solubility of the drug 2. size of the drug molecule 3. degree of ionization 4. are of absorptive surface (ex: water, urea, glycerol) |
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What is facilitated passive diffusion?
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Energy independent diffusion across a membrane by way of a carrier protein
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What is active transport?
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The energy dependent transport of hydrophilic molecules across a membrane. Requires carrier protein, is independent of gradient, and is limited to drugs that structurally similar to endogenous substances.
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What is the 1st pass effect?
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The process by which an oral medication is absorbed by the GI tract and enters the portal circulation. The drug is then processed by the liver, where bioavailability may be substantially reduced.
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What is enterohepatic recycling?
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The process by which a drug is absorbed by the GI tract, conjugated, and then excreted back into the GI tract where bacteria remove the conjugate, allowing the drug to be reabsorbed by the GI tract. (ex: iron)
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Give an example of a drug for which alterations in 1st pass cause extreme changes in Cp.
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Propanolol. Normal dose is 120 mg. Pts with cirrhosis get 10-20 mg b/c they cannot metabolize drug as well.
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What parameters are associated with the rate of absorption?
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Ka, Tmax
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What parameters are associated with the extent of absorption?
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Cmax, AUC
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Which absorption parameters are Ka dependent?
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Tmax, Cmax (AUC is Ka independent)
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What is the equation for finding absolute bioavailability of an oral drug?
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F=(AUC-po x Dose-iv)/(AUC-iv x Dose-po)
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What is the equation for finding relative bioavailability of oral drug?
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F=(AUC-po1 x Dose-po2)/(AUC-po2 x Dose-po1)
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What parameters are affected when chaning F and dose?
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AUC, Cmax (tmax unchanged)
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What parameters are affected when change Ka?
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Tmax, Cmax
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What parameters are affected by higher rate of absorption (Ka)?
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earlier Tmax, higher Cmax (no change in AUC)
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What parameters are affected by higer rate of elimination (Ke)?
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Tmax earlier, lower Cp, lower AUC
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What variables are associated with the drug and dosage form?
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F, Dose, Ka
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What variabes are associated with drug and patient?
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Ke, Vd
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What are hepatocytes?
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Liver cells that allow exchange of toxins, drugs and nutrients between the plasma and the liver and between the liver and the bile.
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What is hepatic elimination?
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The volume of blood in which a drug is completely removed from the liver per unit time. Intrinsic clearance.
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How are drugs with low or high intrinsic clearance affected by inhibitors and inducers?
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1. Drugs with low clearance are greatly affected by inducers and inhibitors. (Think I Love Lucy candy conveyor. The liver enzymes already have more candy than they can handle. Adding or subtracting enzymes has a relatively big effect.)
2. Inducers and inhibitors have little effect on drugs with high intrinsic clearance. (They already have a bunch of enzymes so adding or subtracting some has relatively small effect. However, this group is limited by hepatic blood flow--the speed of the conveyor belt.) |
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What patient factors affect hepatic elimination?
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1. Hormonal regulation [ex: thyroid (inc. metab), pituitary, gondads--androgens and estrogens (inducers)
2. Gender (women less P450 activity in liver and GI tract) 3. Pregnancy 4. Race (2C9 and 2D6) 5. Circadian variation (metab inc. at night--statins) |
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What is the effect of hepatic disease on phase I metabolism?
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Impairs mixed function oxidases. Otherwise depends on cause.
1. NAFLD, mild hep, early cirrh: little effect 2. Cirrh, alcoh hep: dec activ 3. Chronic alcoh use: inc activ 4. Acute alcoh use: dec activ 5. Toxin exposure (cigs): inducer |
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What is the effect of hepatic disease on phase II metabolism?
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Conjugation and glucoronidation are well preserved.
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Parameters measured in Child-Pugh Liver Function score?
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1. albumin
2. total bili 3. PT time 4.ascites 5. hepatic encephalopathy |
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Parameters measured in MELD score?
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1. SCr
2. INR 3. total bili |
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What factors should be considered when dosing drugs for patients with hepatic disease?
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Eh, Metab to active/toxic metabolites, therapeutic index of drug, Er (Q, binding, Cl-int), route of admin
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What changes are associated with chronic hepatic disease?
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1. Dec hepatocyte fx (dec Cl-int, inc F)
2. Shunting of portal blood flow 3. Hepatorenal syndrome 4.Dec protein synthesis (free fraction inc) |
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What is intrinsic clearance?
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Capacity of the liver to eliminate drug in absence of flow limitations.
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What is hepatic extraction ration?
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The efficiency of the liver in removing drug from systemic circulation. (scale of 0-1; influenced by Q, binding, metabolic activ)
Er=(Cin - Cout)/Cin |
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What is a low Er?
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Er<0.3 (ex: warfarin, carbamazepine, phenobarbital, phenytoin,valproic acid)
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What is a high Er?
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Er>0.7 (ex: desipramine, lidocaine, morphine, propanolol)
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What factors affect high Er drugs?
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High Er drugs are perfusion rate-limited. Enzyme ind/inh, binding do not affect. Cl-int is large compared to blood flow.
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What factors affect low Er drugs?
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Low Er drugs are dependent upon enzyme fx and protein binding. Ind/inh have large affect. However, drugs are flow independent.
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What effect does a drug's displacement from protein binding have on hepatic clearance?
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1. Low clearance drug: inc Cl, dec Cp-total, no change in Cp-free
2. High clearance drug: little change |
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What are to the two types of metabolite disposition?
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1. Formation rate-limited (elim of metab is faster than elim of parent drug; gone soon after formed)
2. Elimination rate-limited (elim of metab slower than elim of parent drug; Tss longer for metab than drug; dosing based on PK of parent drug may lead to accumulation of metab) |
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What are the determinates of enterohepatic recycling?
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1.Drug characteristics
2. Transport within liver sinusoids 3. Biotransformation (oxidation, conjugation) 4. Reabsorption 5. Hydrolysis of conjugate by gut bacteria |
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How do you adjust dosage in patients with hepatic impairment?
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1. Don't alter drugs metab by conjugation; conjug preserved
2. Halve starting dose of oxidized drugs 3. Dec if decompensated liver failure 4. Dec dose, maintain interval (lower Css, higer Cmin) 5. Maintain dose, extend interval (Css and Cmin normal) 6. Change dosage form (IV) |
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When would you not change or make a mild change for hepatic impairment?
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1. Mild liver dz
2. Renal elim drug w/ no impairment 3. Er<0.3 or >0.7 if drug given acutely |
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When would you decrease dose by up to 25% for hepatic impairment?
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1. hepatic elim <40% w/o renal dysfx
2. Large TI 3. Er<0.3 for acute drug 4. Er>0.7 for IV drug |
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When woud you decrease dose by more than 25% for hepatic impairment?
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1. chronic drug affected by liver dz
2. narrow TI 3. significant change in protn binding 4. Er>0.7 po drug 5. drug elim by kidney but have renal dysfx |
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What drug inhibits CYP2D6?
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Quinidine**strong**, SSRIs (fluox, parox, norfluox), antipsychotics (fluphen, haloperidol)
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What drugs are substrates of CYP2D6?
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DM, codeine, tramodol, risperidone desipramine, venla, parox, fluox, metoprolol, antiarrythmics
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What drugs are substrates of CYP1A2?
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caffeine, theophylline, tacrine, clozapine, haloperidol, TCAs
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What drugs inhibit CYP1A2?
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Fluvoxamine***strong**, ciproflox, norflox
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What induces CYP1A2?
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cigarette smoking
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What are the gender and racial differences associated with CYP1A2?
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Females<males
Azns<caucasians |
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What drugs are substrates of CYP2C9?
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Warfarin, phenytoin, tolbutamide, NSAIDS
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What drugs are inhibitors of CYP2C9?
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***all weak***, fluvox, fluox, norfluox
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What drugs are substrates of CYP2C19?
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Diazepam, citalopram, imipramine, amitrip, moclobemide, omep, lansop, phenytoin, nelfinavir proguanil
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What drugs are inhibitors of CYP2C19?
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Fluvoxamine>fluox, sert
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How does Ki relate to level of inhibition of CYP enzymes?
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Lower Ki = greater inhibition
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What are drawbacks of in vitro models for replicating metabolism?
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1. Can't replicate blood flow
2. Can't replicate protein binding 3. Can't tell effect of metabolite 4. Can't replicate enzyme induction 5. Interindividual variability |
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What CYP substrates are used in FDA studies?
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1. DM, debrisoquin - 2D6
2. Midazolam - 3A4 3. Caffeine - 1A2 4. Buproprion - 2B6 5. Tolbutamide - 2C9 |
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Variables affecting clinical significance of DDI?
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1. therapeutic index
2. Importance of affected pathway 3. Change in substrate conc |
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What drugs are substrates of CYP3A4?
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Alpraz, midaz, triaz, verap, nifed, diltiazem, lova, lidocaine, quinidine, amiodarone, cisapride, terfen, astemizole, lorati, paclitaxel, docetaxel, cyclosporine, carbam, sert, fluox, nefaza, TCAs
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What drugs are inducers of CYP3A4?
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rifampin, rifabutin, carbam, phenobarb, phenytoin
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What drugs are inhibitors of CYP3A4?
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ketoconazole***strong***, clarithromycin,, erythromycin, grapefruit, ritonavir
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How does Vd change in the elderly?
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1. For water soluble drugs the Vd dec leading to higher conc
2. For lipid soluble drugs the Vd inc prolonging half-life. |
