Term
| The two routes of drug administration are? |
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Definition
Enteral: oral (suffers first-pass effect where drug gets metabolized in the gut wall and liver), sublingual (like nitroglyrcerin which is very lipophilic), rectal (partial avoidance of first-pass effect)
Parenteral: IV, IM, subcutaneous, intradermal (PPD) |
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Term
| Absorption of a drug is the? |
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Definition
| Transfer of the drug form the site of administration to the bloodstream |
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Term
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Definition
Attempt to get through to the site of action passed the various barriers. There are 4 main mechanisms:
Aqueous diffusion
Lipid diffusion
Special carriers
Endocytosis |
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Term
| What are the effects of pH on drug absorption? |
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Definition
A) The protonated form (uncharged) of a weak acid is the more liposoluble form
B) The unprotonated form (uncharged) of a weak acid is the more liposoluble form |
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Term
| What is the Henderson-Hasselbalch equation? |
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Definition
| pH = pK + log ([Unprotonated form]/ [Protonated form]) NB that the most important application of this equation is in the manipulation of drug excretion by the kidney |
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Term
| How does the pH of the urine help accelerate the excretion of drugs? |
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Definition
| Weak acids are excreted faster in alkaline urine; weak bases are excreated faster in acidic urine |
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Term
| When pH=pK, [unprotonated]=[protonated], then? |
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Definition
| For each unit of pH above/ below pK, the [unprotonated] will be 10X more/less than the [protonated] |
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Term
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Definition
| The fraction of the administered drug that makes it to the bloodstream whereas the absorption takes abt the process of the drugs making it to the bloodstream. F = (AUC oral / AUC IV) X 100 |
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Term
| When can you replace a trade drug with a generic drug? |
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Definition
| When the two preparations’ conc.-time plots are superimposable then they are said to be bioequivalent |
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Term
| What plasma proteins are drugs bound to? |
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Definition
| Acidic drugs are bound to albumin; Basic drugs are bound to alpha-1-acid glycoprotein. NB these drugs (sulfonamides) can displace endogenous substances such as unconjugated bilirubin thus leading to bilirubin encephalopathy in newborns. In adults Warfarin has a small therapeutic window and thus causes bleeding if too much are made free. |
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Term
| We talked abt elimination of drugs (irreversible loss) via metabolism and excretion but if we were to talk abt termination of drug effect, then what other mode can we include? |
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Definition
| Redistribution, an example of which is the IV anesthetic thiopental which reaches a max conc. In the brain by one minute and then diffuses into other tissues to drop the blood conc. |
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Term
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Definition
| Liposoluble drugs (also cross the placenta) but not quarternary ammonium compounds |
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Term
| What are the four modes of biotransformation? |
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Definition
Active drug -> inactive drug
Unexcretable drug -> excretable metabolite
Active drug -> toxic metabolite
Inactive prodrug -> active drug |
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Term
| Drugs are metabolised via two modes, which are? |
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Definition
| Phase I (-> inactive or metabolite with modified activity & occurs in the sER – cytochrome P450 system/ monooxygenase) followed by phase II (conjugated & occurs in the cytoplasm). NB that phase II has a less effect with age |
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Term
| Cytochrome P450 reaction is? |
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Definition
NADPH (has a good reducing power?) + H+ + O2 + SH -> NADP+ + H2O + SOH (S – substrate/ drug)
The NADPH provides the 2e- to the ferrous (reduced state from ferric) heme iron via FAD and FMN which help move 1 e- at a time |
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Term
| Humans have how many P450 families and subfamilies? |
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Definition
| 18, 43. Families 1-3 are mostly active in the metabolism of xenobiotics while the others have a more endogenous function |
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Term
| The CYP3A4 isoform is known for? |
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Definition
| Accounting for 30% of CYP450 enzymes in the liver and metabolizes 50% of all drugs |
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Term
| Drugs that induce CYP450 isoforms drugs are? |
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Definition
| Phenobarbital, rifampin & carbamazepine, this occurs via binding to xenobiotic receptors allowing it to translocate to the promoters in the mucleus for various enzymes |
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Term
| COPY SLIDE 82 FOR THE XENOBIOTIC RECEPTORS |
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Definition
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Term
| Why might St. John’s wort be bad for HIV pts? |
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Definition
| It induces CYP3A4 which reduces the therapeutic levels of Indinavir |
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Term
| The four drugs that will inhibit CYP450 are? |
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Definition
Cimetidine (GURD)
Ketoconazole (antifungal)
Erythromycin (antibacterial)
Chloramphenicol (antibacterial) |
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Term
| Drug transporters are need to actively transport drugs across the cell membrane despite the fact that they might be already lipophilic enough, an example of this is? |
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Definition
| Multidrug resistance protein 1 (MDR1) or P-glycoprotein. MDR1 transports the compound back into the lumen of the GIT actively, thus limits oral bioavailability of drugs like digoxin & HIV-1 protease inhibitors |
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Term
| Drug transporters can be induced or inhibited by other drugs, for example? |
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Definition
| Macrolide antibiotics inhibit MDR1 thus leading to an increase of serum digoxin. NB that MDR1 is transcriptionally regulated by PXR thus drugs that induce P450 via PXR also induce MDR1 thus double effect |
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Term
| COPY SLIDE 97 FOR METABLISM OF ACETAMINOPHEN |
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Definition
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Term
| How do u Tx acetaminophen OD (7-10 grams)? |
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Definition
| The antidote is N-acetylcysteine, it supplies the cysteine to make more glutathione and it also binds directly to NAPQI |
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Term
| There are 3 types of interindividual genetic variations that influence pharmacotherapy, which are? |
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Definition
| Pharmacokinetic variation, pharmacodynamic variation & genetic asso. w/ idiosyncratic drug effect |
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Term
| Why might it not be advisable to take drugs with grapefruit? |
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Definition
| It inhibits both CYP3A4 and MDR1 in the SI |
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Term
| How can food and social habits affect drug metabolism? |
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Definition
Polycyclic aromatic hydrocarbons in cigarette smoke cause AhR-mediated P450 enzyme induction.
Charcoal-broiled foods and cruciferous vegetables induce CYP1A enzymes. |
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Term
| How much of a drug will be excreted depending on its polarity? |
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Definition
| 99% will be reabsorbed passively if it is freely permeable (lipophilic???) but the conc increases to 100X of that of plasma if its highly polar. NB that some drugs will be secreted form the liver to the bile – Glucuronides are usually hydrolyzed by the intestinal flora releasing the active drug again, which is then reabsorbed by the intestines (enterohepatic circulation). Drugs such as steroid hormones, digoxin and some cancer chemotherapeutic agents are largely excreted in the bile. |
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