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| one word definition of drug: |
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| any agent used to produce some desired effect on body, examples: nicotene, caffeine |
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- the study of drug effects and their MECHANISM of action
- what drugs do to the body |
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quantitative description of time course of drug and drug metabolite concentrations in the plasma, tissues, or urine
- drug fate
- what the body does to the drug |
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| molecular mechanism of action |
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| - desired therapeutic effects and undesired side effects |
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| ___ is usually known and is observable, ___ may or may not be known and is not observable. |
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- chemical name (think O-chem names)
- gerneric name
- trade name (tylenol, whats its marketed as) |
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| what does it mean if drug has a low therapeutic window? |
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| - therapeutic range is very close to toxic range |
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| The therapeutic window lies b/w what two lines on a chart? |
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- MEC line: minimum effective concentration
- toxicity
The closer these two lines are together the more dangerous the drug is. |
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| Enteral administration of a drug means via the ____ ___, which can be ____, ___, or ____. |
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Definition
- gastrointestinal tract
- oral
- rectal
- sublingual |
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| Parenteral is often taken to mean ___ but also includes other non-oral routes such as: ___, ___, ___, ____, ____, |
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Definition
- injected
- subcutaneous (SC)
- intramuscular (IM)
- intravenous (IV)
- inhalation
- intranasal |
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| Are most drugs absorbed more in the SI or the stomach? |
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| In order for a drug to be given orally, it must be ___ and be ___ in solution. |
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| Factors absorption can be affected by with oral administration: |
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- variability among patients
- gastric and intestinal pH
- gastric emptying time
- presence or absence of food
- co-administration of other drugs |
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| Diabetes have gastroparesis, so drugs that are absorbed in the stomach will be even more absorbed by diabetics. |
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| Tetracyclines chelate calcium, which prevents absorption. So you cannot have dairy when you take tetracyclines. |
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| For oral administration, the patient must be ___ and ___. |
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| conscious and cooperative |
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| define first-pass metabolism by the liver: |
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Definition
everything absorbed by the stomach gets metabolized by the liver before going to the rest of the body
- thus if a drug is greatly metabolized by the liver, it cannot be given orally |
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| With sublingual drug administration, the area is warm, moist, and has high blood flow. Also there is no __ ___ __ with this route. |
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Definition
no first pass effect with sublingual administration
example of drug administered in this way: nitro glycerin |
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| IV administration of drugs: |
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Definition
- no barriers to absorption
- rapid onset and subsequent control of drug concentration is possible
- drug must be soluble, will not work for non-aqueous solutions
- large fluid volumes are possible
- high cost compared to oral
- must have trained personel
- in patient only= inconvenient
- IRREVERSIBLE
- infections and embolism possible |
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| Lower blood flow in subcutaneous regions leads to ___ ___ ____, which allows for ___ ___. This allows for the injection of drugs that are ___ ___ in water. Give examples of these kinds of injections. |
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Definition
- slower drug absorption
- sustained action
- poorly soluble
- insulin for diabetes, epi for anaphylaxis, depot drugs |
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| Intramuscular injections: |
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Definition
- fairly rapid absorption of water soluble drugs
- time course of absorption is dictated by water solubility of drug and blood flow to the site
- allows injections of depot preparations- benzathine penicillin G
- painful, inconvenient
- possible hematoma |
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| If you don't want a drug to be absorbed as quickly and you are giving it intramuscularly, you can make it less water soluble and more lipid soluble. |
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have a local action, used for lungs, designed so that absorption is minimal
- also general anesthetics are inhaled drugs |
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| why are so many routes used? |
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Definition
- drug characteristics
- time course of action
- drug access
- condition of patient |
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| Factors affecting rate and extend of absorption from injection site to plasma: |
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Definition
- rate of drug dissolution
- concentration gradient
- blood flow
- size of absorbing surface
- lipid solubility
- pH, drug charge and polarity
- condition of the absorbing surface |
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| random side note: burn patient will have more systemic absorption of a topical drug than a non-burn patient |
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| site of administration> plasma> interstitial space> intracellular space |
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| intracellular space> interstitial space> plasma |
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| Volume of distribution (Vd): |
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Definition
hypothetical volume of fluid in which the drug is distributed
Vd= total amount of drug in body/ plasma concentration of drug |
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| What kind of Vd would a lipophyllic drug have? |
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Definition
| - lipophyllic drugs= high volume of distribution b/c low plasma concentration |
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| If a drug has a low volume of distribution, this means that the concentration in the plasma is ____. |
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| The blood brain barrier is made up of the ___ cells of the CNS which have ___ ___ and no fenestrations.___ soluble drugs can diffuse across these endothelial cells and basement membrane. But ___ soluble drugs cannot. Some drugs enter the CNS via an ___ ___ process. |
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Definition
- endothelial
- tight junctions
- lipid
- water
- active transport |
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Term
| parent drug> enzyme mediated biotransformation> drug metabolites |
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| 3 routes for drug elimination: |
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Definition
- hepatic metabolism
- renal elimination
- minor routes- breath, sweat, tears |
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| Explain hepatic metabolism: |
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Definition
- Phase I: drug is made more polar either by adding a hydroxyl or by demethylation
- Phase II: conjugation reaction, adds a sulfate or glucouronide
- biliary secretion in stools |
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| Define drug biotransformation: |
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- body's basic strategy for drug elimination
- makes the parent drug more water soluble so that it can easily be excreted by the kidneys |
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| drug biotransformation is made up of phase I and phase II reactions |
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Definition
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| Phase I reactions are performed by ___ ___ and expose or introduce a functional group via ___, ___, or ___, to make it more ___. |
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Definition
- cytochrome P450s
- oxidation, reduction, or hydrolysis
- polar |
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| Phase II reactions are ____ reactions aka ___ aka __ ___. |
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Definition
- conjugation
- glucuronidation
- sulfate formation |
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| After phase II reactions, drugs are generally highly polar and inactive and excreted rapidly in the urine and feces. |
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| For the most part phase II metabolites are ___. |
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| Genetic variations in ____ explains variance in patients responses to drugs and adverse reactions. Up-regulation of ___ is called ____ _____ and will lead to ___ metabolism of drugs. Cyto P450 inhibition will reduce metabolism via ___ or ___ ____. |
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Definition
- Cyto P450
- CYPs
- cyto P450 induction
- increased metabolism
- competition
- irreversible inactivation |
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| Slow assimilators will have ___ concentrations of drugs at a given dose meaning the drug effects will last ___. These patients are more at risk for toxicity. |
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Definition
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| If drug B causes induction of cytochrome p450s that metabolize drug A, how should the dose of a change? |
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Definition
| dose of A should be increased b/c being metabolized more quickly b/c its p450s have been induced |
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| Why is grapefruit juice a problem with certain drugs? |
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Definition
| it competes or irreversibly inactivates the cytochrome P450s that metabolize certain drugs, thus the patient is at risk of becoming toxic |
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Term
Phospholipid bilayer provides a hydrophobic barrier between two aqueous environments.
Cell membranes do not have pores. Drugs cannot “filter” through membranes, they must diffuse through the phospholipid bilayer |
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Absorption and penetration into cells is mainly by passive diffusion.
The rate of passive diffusion varies directly with the concentration gradient. |
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| major factors influencing passive diffusion of drugs: |
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Definition
Concentration gradient
Blood Flow
Size
Charge (pH of environment)
Polarity
Lipid/water Solubility |
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| If a drug is a weak acid or weak base and in its ____ form, it won't access cells easilty. |
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Blood flow is a major factor affecting the concentration gradient of drug throughout the body.
Higher local blood flow maintains steeper concentration gradients and, therefore, faster rates of drug movement from one compartment into another. |
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| the more polar a drug is, is it more or less likely to get to its site of action? |
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| Drugs that are ___ and/or highly ___are more water soluble. |
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| Hydrophilic drugs are ___ and ____ absorbed but ____ excreted in the urine. |
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- poorly and slowly
- rapidly |
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Drugs that are more soluble in lipid are said to be lipophilic or hydrophobic (“water hating”).
Lipophilic drugs more easily pass through membranes by passive diffusion are rapidly and more completely absorbed but only slowly eliminated in urine. |
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| hydrophobic drugs are ___ absorbed but ___ excreted in the urine. |
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| _____ ____ ____ is a means for expressing whether a drug is more lipid soluble or more water soluble. How is this determined? |
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Lipid/water partition ceofficient
- drug is mixed with a solution of oil and water, which then separates into two phases. The proportion of drug in the oil and water is then measured, and the result in expressed as a ratio. |
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| The higher the lipid/water partition coeffecient is the more ____ the drug is. |
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Example
Total Drug = 100 units
Drug in lipid phase = 80 units
Drug in water phase = 20 units
Lipid/water = 80/20 = 4
This is a highly lipid soluble drug that will be rapidly and completely absorbed. |
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| Most drugs are ___ ___ or ___ ___. They exist in solution in their _____ and ____ states. The concentration of ___ and ____ forms of a drug are determined by the ___ of the drug and the solution ___. |
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Definition
- weak acids or weak bases
- unionized and ionized
- uncharged and charged
- pKa
- pH |
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| Charged/ionized forms of drugs are ____ to cells b/c cannot pass through cell membranes. |
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considering the equation:
HA>< H+ + A-, if you are an acidic medicine in an acid environment, will you favor the ionized or unionized form? |
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| you will favor the unionized form HA, b/c lots of H+ pushing equation to the left |
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| if you have a base in a basic solution what form will be favored ? give equation. |
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Definition
R3NH>< H+ + R3N
So if a base is in a basic environment there isnt much H+ so equation pushed to right, so unionized form R3N favored |
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Term
| so a weak base medicine in a high pH environment will favor ___ form. |
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| so a weak acid medicine in a low pH solution will favor the ____ form. |
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| does the unionized/ionized form of meds cross plasma membranes? |
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| You can manipulate the ___ of a drug to help promote ___. |
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| How would you promote the excretion of a weak acid drug? |
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Definition
| alkalinize the urine so the the ionized form is favored |
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| How would you promote the excretion of a weak base drug? |
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Definition
| - acidify the urine so that more of the ionized form is favored |
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| how do you treat excessivley high levels of drugs that are weak acids or bases? |
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Definition
| change urine pH to promote excretion |
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| By changing the urine pH to promote excretion, the movement of drugs out of the ___ and into ___ is favored. It is the ___ drug that moves across the membrane. Then once in the altered pH environment of the ___, the drug gets ___ and cannot get back into the tissues, so it is eliminated. |
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Definition
- out of tissues and into plasma
- unionized
- plasma
- ionized |
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Definition
| the pH at which half of the drug is ionized and half of the drug is unionized |
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| Absorption of a ____ ____ cannot be manipulated b/c it has 4 bonds to the nitrogen and thus cannot be manipulated. |
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| describe a tertiary amine: |
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Definition
NR3H+
There is a reversible binding site for H+ on the nitrogen. |
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Definition
NR4+
- The R's are not hydrogen ions, and so cannot dissociate. The drug is a fixed ion, a quaternary salt. Such a drug crosses membranes very poorly. |
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Many drugs are bound to plasma proteins.
Albumin is the principal binding protein in plasma.
The extent and affinity of drug-protein binding differs widely.
Total drug distribution is affected by protein binding. |
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| If its highly plasma protein bound, its not free and cannot cross into cellular compatments. So if highly protein bound, that reservoir has to be filled, before there is any free drug available. |
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| protein binding can affect __ ___ and other pharmokinetic decisions. |
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| Bound drug can act as a ___ or ___for free drug. |
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Definition
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| Bound drug is/is not filtered. |
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| Glomerular filtration and renal excretion are affected by protein binding since bound drug is not filtered |
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| Drug-drug interactions may result from the ___ of drugs competing for binding sites on ___ _____. |
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Definition
- displacement
- plasma proteins |
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| The potential for clinically significant interactions is greatest when the ___ ____ is ___ protein bound, has a ____ volume of distribution, is ___ elminated, and has a ___ therapeutic index. |
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Definition
- displaced drug
- highly
- low
- slowly
- low |
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| Highly lipid soluble drugs become concentrated in ___ ___ and to a lesser extent in the ___. |
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Definition
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| Drug stored in fatty tissues will ____drug back to plasma as the ___ ____ change. |
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Definition
- redistribute
- concentration gradients |
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| Clinically significant redistribution accounts for ___ ___ of drugs. This is most frequently seen the drug is highly ___ ___, it is given in ___ ___, and the drug target is a high ___ ___ __, like the CNS. |
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Definition
- rapid offset
- lipid soluble
- IV bolus
- cardiac output organ |
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| Drug A has a lipid/water partition coefficient of 3.3, while ddrug B has a lipid/water partition coefficient of 0.05. Which one is more at risk of rapid onset and offset? |
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Definition
| drug A b/c more lipid soluble |
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Consider limiting cases:
1) a drug that is fully ionized. Such a drug cannot dissolve into the membrane.
2) a drug that is neutral. Such a drug has the potential to dissolve into the membrane. |
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Definition
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Thiopental is very lipid soluble. Any molecule hitting the blood brain barrier has a very good chance to immediately dissolve.
Pentobarbital is not very lipid soluble. Any molecule hitting the blood brain barrier has at best only a fair chance of dissolving. |
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Definition
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| net result of a high lipid soluble drug that redistributes quickly, like thiopentol: |
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Net result: patient goes down quickly, but comes back up very quickly also.
in addition to thiopental induction of anesthesia, the other famous example is use of diazepam, i.v., to bring status epilepticus under control. |
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Redistribution continued: The drug effect is terminated by the phenomenon of redistribution -- the drug is “redistributed” from initial target to other tissue.
Where did the drug go? (Which tissue is it in?)
follow the cardiac output!!
Muscle
Fat |
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