Term
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Definition
Adsorption
Distribution
Metabolism
Elimination |
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Term
| What are the routes by which solutes can traverse cell membranes? |
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Definition
1) Drugs may diffuse passively through aqueous channels in the intracellular junctions (eq, tight junctions) or through lipid cell membranes
2) Drugs with the appropriate characteristics may be transported by carriers into or out of cells
3) Very important permeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the membrane-limited vesicle out of the cell into the extracellular space (exocytosis) |
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Term
Carrier-Mediated Transport
Tell me more... |
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Definition
-Unusual
-Drug must resemble natural substrate enough for carrier to recognize it |
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Term
Transcapillary Movement
Tell me more... |
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Definition
-Major process for: diffusion through aqueous channel between cells
-Plasma->Capillary wall-> Tissue Interstitial Space |
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Term
Passive Diffusion
Tell me more... |
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Definition
-Diffusion through lipid (bilayer)
-Most drugs move across most membranes by passive diffusion |
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Term
| Most drugs are absorbed and distributed by... |
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Definition
| passive diffusion across membranes |
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Term
| Rate of diffusion across cell membranes is determined by... |
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Definition
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Term
| For most drugs, lipid solubility depends on... |
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Definition
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Term
| What form of a drug crosses membranes much faster? |
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Definition
| uncharged form of a drug diffuses faster than charged form |
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Term
| Drug ________ and _________ thus depend on pH. |
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Definition
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Term
| DRUG CHARACTERISTICS THAT FAVOR PASSIVE DIFFUSION ACROSS LIPID MEMBRANES |
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Definition
1) Uncharged
2) Nonpolar
3) low molecular weight
4) high lipid solubility |
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Term
| What is the definition of an acid? |
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Definition
| Can give up a proton to become negatively charged. (proton donor) |
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Term
| What is the definition of a base? |
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Definition
| Can accept a proton to become positively charged (proton acceptor) |
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Term
| What can change charge in aqueous solution depending upon pH? |
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Definition
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Term
| What is uncharged and more lipid soluble? |
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Definition
1) protonated weak acid
2) unprotonated weak base |
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Term
| What is charged and more water-soluble? |
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Definition
1) unprotonated weak acid
2) protonated weak base |
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Term
| What tells you at what pH the proton transfer takes place? |
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Definition
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Term
| Do the defintions of acids and bases depend on pKa? |
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Definition
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Term
| For most drugs, what is the most important determinant of transport across membranes? |
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Definition
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Term
| When charge is equal, what is the determinant of transport across membranes? |
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Definition
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Term
| Transcapillaty movement goes through... |
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Definition
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Term
| What are exceptions to transcapillary movement? |
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Definition
Tissues with extra barriers- CNS, testis, fetus, retina
Large molecules- albumin, tPA, heparin |
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Term
| Blood-Brain Barrier prevents... |
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Definition
| transcapillary movement through "fenestrations" |
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Term
| What are the routes of Administration (6)? |
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Definition
1) oral
2) intravenous
3) percutaneous/ subQ
4) intramuscular
5) inhalation
6) intrathecal |
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Term
| What are the routes of Elimination? |
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Definition
1) urine
2) expired air
3) milk, sweat
4) feces |
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Term
| Drug administered IV enters... |
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Definition
| directly into the systemic circulation and has direct access to the rest of the body |
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Term
| Drugs administered orally are... |
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Definition
| first exposed to liver and may be extensively metabolized before reaching the rest of the body |
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Term
This concept is known as...
Due to taking drugs orally- it has to go through the portal circulation and liver before it sees the rest of the body=-drugs can vary from 0% to 100% if completely metabolized do not want to give drug orally or we will never see the drug |
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Definition
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Term
| A significant fraction of some oral drugs is cleared by liver before reaching systemic circulation. |
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Definition
| “First-pass” or “presystemic” clearance of an oral dose of drug |
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Term
| If some drugs are cleared so fast, how can they be clinically useful? |
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Definition
-Give larger dose
-Give by a different route of administration that oral
-Lipid-soluble drugs leave the blood rapidly |
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Term
| Why is first-pass metabolism a challenge in the clinic? |
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Definition
-A much larger dose is needed when drug is given orally (than by routes that avoid first-pass)
-Marked individual variation between patients in extent of "first pass"=> unpredictable response |
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Term
| What are the advantages of Oral Administration (Enteral, PO)? |
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Definition
| Convenient for pt and caregiver, usually safest method of administration |
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Term
| What are the disadvantages of Oral Administration (Enteral, PO)? |
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Definition
-Onset too slow for emergencies
-absorption may be low due to low bioavailability
-pt cooperation required
-problems with vomiting or diarrhea
-palatability (esp. in children)
-first-pass metabolism renders oral route useless for some drugs |
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Term
| effect (before entering the systemic circulation, blood perfusing the GI tract passes through the liver; drugs that are highly metabolized by the liver may attain very low circulating levels relative to those attained after parenteral administration). |
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Definition
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Term
| Tell me about the stomach in terms of Oral Administration (Enteral, PO) |
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Definition
-low pH favors absorption of acidic drugs
-low pH "traps" basic drugs
-variable absorption due to variable gastric emptying time |
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Term
| Tell me about the small intestine in terms of Oral Administration (Enteral, PO) |
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Definition
-large surface area and high blood perfusion makes small intestine the most important site for absorption of most drugs
-intestinal transit time is a critical variable |
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Term
| Tell me about the large intestine in terms of Oral Administration (Enteral, PO) |
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Definition
-usually little absorption of oral drugs because solid nature of intestinal contents impedes drug diffusion
-However, rectal administration is often effective |
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Term
| How is rectal administration often effective? |
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Definition
-Avoids to some extent (≈50%) the "first pass" effect
-Avoids metabolism in stomach and small intestine
-Relatively slow and sometimes erratic administration |
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Term
| Rate of release and absorption of many drugs can be controlled by... |
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Definition
| formulation and packaging(can explain the difference between some generic and first-party drugs) |
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Term
| Sublingual and Buccal Administration |
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Definition
-Rapid absorption of lipid soluble drugs because of extensive vascularization
-Avoids "first-pass" effects and metabolism in GI tract |
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Term
| Parenteral Administration means... |
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Definition
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Term
| Lungs (inhalation; pulmonary)...tell me more |
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Definition
1) Large surface area and close proximity of pulmonary blood vessels insures rapid and extensive absorption of lipid-soluble drugs
2) Major site of administration for gases and aerosols
3) Avoids "first-pass" effect and metabolism in GI tract
4) For volatile anesthetics, rapid onset and rapid elimination
5) Useful "topical" route for agents in lungs or bronchioles (eq, inhaled anti-inflammatories, bronchodilators for asthma)
6) E.g., inhaled insulin (Exubera®) for diabetes now available. |
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Term
Skin (topical, transdermal, percutaneous) Administration
tell me more... |
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Definition
1) Most drugs applied to the skin are intended for local effects; outer layer of epidermis form barrier against rapid penetration of even lipid soluble drugs
2) A very few potent, very lipid soluble drugs can be given in a patch for transdermal absorption; produces stable blood levels and prolonged duration of action
3) Avoids “first-pass” effect and metabolism in GI tract
4) Potential advantages: long-term, stable delivery, noninvasive
5) Potential disadvantages: local irritation, slow onset of action |
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Term
Intramuscular (IM); Subcutaneous (SC, SubQ) Administration
tell me more... |
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Definition
1) rates of absorption primarily dependent on blood perfusion rates
-absorption generally more rapid after intramuscular than after subcutaneous injection
-IM absorption is generally faster than oral absorption from these sites (eg; site of injection, depth of injection, muscle activity, etc.) and one should not assume that complete and rapid absorption will occur
2) Slowly dissolving ("depot") forms of some drugs may be used to prolong drug effects
3) May be painful and pain at injection site may persist
4) Avoids “first-pass” effect and metabolism in GI tract
5) Relatively large volume can be given |
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Term
| What are the advantages of Intravenous (IV) and Intraarterial (IA) Administration? |
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Definition
-Virtually immediate pharmacological response, careful control of blood levels possible by continuous infusion
-100% bioavailability by definition
- Useful when drugs can not be given by other means
-Large volumes may be given |
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Term
| What are the disadvantages of Intravenous (IV) and Intraarterial (IA) Administration? |
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Definition
-Greater risk of toxicity due to rapid delivery and IV drugss cannot be removed
-Rapid injections may lead to very high drug concentrations in aortic arch and carotid sinus, risking alteration of respiration and cardiovascular function
-Anaphylaxis more common than with other routes of administration
-Risk of phlebitis(swelling of a vein), vascular tissue irritation, infections |
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Term
Epidural Administration
tell me more... |
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Definition
-Particularly valuable route of administration for narcotics and local anesthetics, to limit amount of drug reaching other areas of the CNS and body while providing localized administration
-Disadvantage: relatively difficult to administer |
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Term
Intrathecal Administration
tell me more... |
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Definition
-Direct injection into cerebrospinal fluid delivers drugs directly to CNS by breeching the blood-brain barrier, avoiding direct effects on peripheral tissues and peripheral metabolism
-Permits treatment of CNS diseases not responsive to systemic therapy
-Some risk of nerve damage by drug or needle |
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Term
Intraperitoneal (into a body cavity) Administration
tell me more... |
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Definition
-rarely used clinically (risk of infections and adhesions)
-Can administer large volume for local effects
-Widely used for lab animals in preclinical trials |
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Term
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Definition
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Term
| What are the major determinants of Drug Absorption from gut? |
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Definition
1) Partition coefficient (charge, pH, etc.)
2) Local blood flow
3) Intestinal surface area
4) Intestinal motility
5) Food in gut
6) Metabolism in gut
7)* Drugs that slow gut motility slow drug absorption (narcotics, anti-muscarinics)
8)* Drugs that enhance gut motility increase drug absorption (AChE inhibitors) |
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Term
| What should I assume with Placenta/Fetus? |
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Definition
| Assume maternal drugs will reach fetus unless proven otherwise. |
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Term
| What should I assume with Milk? |
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Definition
| Assume maternal drugs will reach milk unless proven otherwise. |
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Term
| What will rapidly cross barriers, reach milk, reach fetus? |
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Definition
| Uncharged drugs (ie. alcohol) |
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Term
| What will concentrate in milk (pH 6.5) relative to plasma (pH 7.4)? |
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Definition
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Term
| What is the volume of plasma that would contain the total body content of drug at a concentration equal to that in the plasma? |
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Definition
| Vd (Volume of distribution)- Apparent volume of distribution of a drug (not a real volume) |
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Term
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Definition
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Term
| Can Vd greatly exceed total plasma volume? |
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Definition
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Term
| What is the normal plasma volume? |
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Definition
| 3-4 liters for an adult human |
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Term
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Definition
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Term
| If the Vd is close to plasma volume... |
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Definition
| then assume it stays almost entirely in plasma, may be due to high MW or highly charged |
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Term
| If the Vd is way bigger than plasma volume such as 2500L... |
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Definition
| then assume most of the drug is outside the vasculature |
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Term
| What are the major body compartments? |
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Definition
-plasma (5% of body weight)
-interstitial fluid (16%)
-intracellular fluid (35%)
-transcellular fluid (2%)
-fat (20%) |
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Term
| What is defined as the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma? |
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Definition
| Vd (volume of distribution) |
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Term
| Drugs that are strongly protein-bound stay... |
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Definition
| mainly in the plasma compartment (small Vd)- can be bound to albumin |
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Term
| What reach all compartments, and may accumulate in fat? |
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Definition
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Term
| For drugs that accumulate outside the plasma compartment (eq. in fat or by being bound to tissues)... |
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Definition
| Vd may exceed total body volume |
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Term
| What is the Fraction of uncharged drug that reaches plasma following administration? |
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Definition
|
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Term
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Definition
| 100% F (bioavailability)- by definition |
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Term
| Other methods of administration: x% F |
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Definition
| F ≤100% due to incomplete absorbtion, first-pass elimination, etc. |
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Term
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Definition
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Term
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Definition
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Term
| What is typical F for many oral drugs? |
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Definition
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Term
| What are the units for F? |
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Definition
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Term
| Drugs with a high % bound at therapeutic concentration... |
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Definition
| will be susceptible to displacement |
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Term
| Drugs with a ≈50% bound at therapeutic concentration... |
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Definition
| may cause effects by displacement of other drugs |
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Term
| What is an important drug-drug interaction? |
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Definition
| Drugs with high % bound will be susceptible to displacement. Drugs that occupy 50% or more sites may cause effects by displacement of other drugs. (drugs that bind to plasma albumin) |
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Term
| How are most drugs cleared? |
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Definition
| Some are cleared without metabolism, but most are metabolized |
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Term
| Almost all drugs that are metabolized are... |
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Definition
| converted to more polar molecules, which are eliminated faster than the parent compund |
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Term
|
Definition
inactivates a drug
except:
1) metabolites are also active
2) the compound given is an inactive prodrug which is activated by metabolism |
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Term
| What is the major site of metabolism and site of many drug-drug interactions? |
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Definition
|
|
Term
| How many phases of drug metabolism are there? |
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Definition
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Term
| Tell me about Phase I of drug metabolism? |
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Definition
Creates a DERIVATIVE
examples of Phase I metabolism are...
-oxidation
-hydroxylation
-dealkylation
-deamination
-... |
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Term
| Tell me about Phase II of drug metabolism? |
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Definition
| Creates a Conjugate via Conjugation (most common thing to do is add glucose) |
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Term
| Do all drugs have to undergo phase I and then phase II metabolism? |
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Definition
No...
-Some drugs undergo Phase I but not Phase II reactions.
-Some drugs undergo Phase II but not Phase I reactions.
-Some drugs undergo both Phase I and Phase II reaction (usually in that order).
-Some drugs are cleared intact with no Phase I or Phase II reactions at all. |
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Term
| What is the specific site of some important drug-drug interactions? |
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Definition
| liver cytochrome P450 system |
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Term
|
Definition
| NH4Cl (ammonium chloride) IV |
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|
Term
| To raise urine pH give... |
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Definition
| NaHCO3 (sodium bicarbonate) IV |
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Term
| What is it called when you adjust urine pH to keep the drug in the most charged state? |
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Definition
| "Trapping" a drug in the urine |
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Term
| Why do we want to "trap" some drugs in the urine? |
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Definition
| Prevents reabsorption in kidney tubules and thus enhances clearance. |
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Term
| What do you acidify urine with? and what does it enhance? |
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Definition
-acidify with NH4Cl
-enhances clearance of weak bases |
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Term
| What do you alkalinize urine with? and what does it enhance? |
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Definition
-alkalinize with NaHCO3
-enhances clearance of weak acids |
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Term
| By HOW MUCH does changing urine pH affect clearance of weak acid or weak base drugs? |
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Definition
| Depends on the drug. Could be a little or a lot. |
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