Term
| What is CT (sub T, sorry)? |
|
Definition
| Target drug concentration in plasma |
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Term
|
Definition
| Steady State drug concentration- the ideal |
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|
Term
|
Definition
| Bioavailability- the fraction, or %, of administered drug that reaches the circulation via a given route |
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Term
| How do we calculate the amount of drug reaching the systemic circulation, knowing bioavailability of the drug and the dose given? |
|
Definition
Drug reaching systemic circulation=
Fx Dose Given |
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Term
| What is the bioavailability of an IV administered drug? |
|
Definition
| 100% There is no absorption component, assume everything goes in |
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|
Term
| How is Bioavailability determined graphically? |
|
Definition
Bioavailability=
Area under curve oral admin/
Area under curve IV admin |
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|
Term
| What is the First Pass Effect? |
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Definition
| The amount of a drug broken down by the liver on its first pass through |
|
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Term
| What method of administration has the most First Pass Effect? |
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Definition
| Oral- Rectal also has this, but to a lesser extent |
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|
Term
| What method of administration of drug has slow absorption, no first pass effect, and prolonged duration of action? |
|
Definition
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|
Term
|
Definition
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|
Term
| What are the limitations of oral (PO) drug administration? |
|
Definition
| Drug not absorbed from GI tract; drug inactivated by digestive enzymes; clinical conditions are inappropriate (vomiting, coma); blood flow and surface area; First Pass Effect |
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Term
If you administer a drug sublingual, where does it absorb?
Give an example |
|
Definition
Into the SYSTEMIC CIRCULATION
A good example is Nitroglycerine, which is very fast and lipid soluble |
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|
Term
| What is buccal drug administration? |
|
Definition
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|
Term
If you administer a drug rectally, how much bypasses the liver?
What are the disadvantages of rectal administration |
|
Definition
About 50%
Irregular absorption; rectal irritation |
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|
Term
| What is parenteral drug administration? |
|
Definition
| By some other means than through the GI tract |
|
|
Term
| What is intramuscular drug administration? |
|
Definition
| Into skeletal muscle- good absorption but RATE DEPENDS ON DRUG FORM AND SOLUBILITY |
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|
Term
| What is epidural administration, and when is it used? |
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Definition
| Injection into the epidural space; spinal analgesia, local anesthetic, steroids, opioids |
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|
Term
| What are the risks of intraperitoneal drug administration? |
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Definition
| Infection, adhesion, PAIN |
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|
Term
| What are the characteristics of inhalation drug administration? |
|
Definition
In respiratory disease, drug goes right to target organ
-lungs have large surface area for good absorption, rapid onset, short duration |
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Term
| What determines the rate of PO absorption in prolonged (extended) release medication? |
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Definition
| The rate of dissolution of the drug in the GI tract, accomplished by kinetics or by adding a coating |
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Term
| What are the advantages of prolonged release medications? |
|
Definition
| Less frequent dosing; therapeutic effect lasts OVERNIGHT; less incidence and severity of side effects; better patient compliance |
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Term
| Give two examples of transdermal drugs: |
|
Definition
| Nitroglycerine- for angina; Scopoloamine- for motion sickness- absorbed behind the ear |
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|
Term
| What are the primary and secondary vehicles of drug administration in the human body? |
|
Definition
The primary, major vehicle, is blood
A secondary, but important, vehicle is lymphatics |
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Term
| What are some intrinsic properties of a drug that affect its distribution? |
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Definition
| Size, charge, ATTRACTION FOR ENDOGENOUS MOLECULES (like plasma proteins) |
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|
Term
| Where do lipid-soluble drugs tend to accumulate? |
|
Definition
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|
Term
| Once administered, where do drugs distribute first? |
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Definition
| Rapidly to highly perfused organs and tissues like LIVER, KIDNEYS, BRAIN, MUSCLES, and LUNGS |
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|
Term
| What are some examples of tissues that receive drugs very slowly, and why? |
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Definition
| Bone and adipose, because they are poorly perfused |
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Term
| What is the effect of bulkier tissues on drug distribution? |
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Definition
| Bulkier tissues, like skeletal muscles and skin, tend to contain a larger drug distribution |
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|
Term
| What is the most important drug binding plasma protein and why? |
|
Definition
| Human Serum Albumin; relative abundance |
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|
Term
| What drugs tend to bind most extensively to albumin? |
|
Definition
| Acidic drugs (salicylates, warfarin, ampicillin, levodopa) |
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Term
| What plasma proteins tend to bind basic drugs and give an example? |
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Definition
Glycoproteins; alpha1-acid glycoprotein
Bind basic drugs such as allopurinol, chloroquine, fluphenazine |
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|
Term
| What types of drugs are bound to lipoproteins? |
|
Definition
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|
Term
| Why is there a potential for adverse drug interactions with administering multiple drugs that bind to the same plasma protein? |
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Definition
| Drug A may displace drug B from its plasma protein, thus increasing the amount of available drug B and increasing its toxicity |
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Term
| If in a multi drug regimen, due to competition for plasma proteins, a drug changes its binding to that protein from 95% to 90%, why can this have disasterous consequences? |
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Definition
| If the calculated availability of the drug is only 5%, it just got doubled to 10%. Even though there is only a 5% increase in available drug, this is DOUBLE the intended dose |
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|
Term
| What are some disease conditions that decrease the quality and quantity of drug binding plasma, and what is the result? |
|
Definition
Malnutrition, hepatic and renal disease:
toxicity, if the clinician was counting on a certain amount of the administered drug being protein bound and there is not enough protein binding happening |
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|
Term
| What is the major site of drug metabolism and excretion, and where do drugs and drug metabolites get excreted? |
|
Definition
The liver; excretion is into the bile with bile salts to enter the intestine
THESE DRUGS CAN KEEP CIRCULATING |
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|
Term
| What happens to some drugs in the event of renal disease? |
|
Definition
| They accumulate in the body because there is no way to remove them |
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|
Term
| What protects the brain from drugs? |
|
Definition
|
|
Term
| What does your brain look like on drugs? |
|
Definition
| A delicious breakfast from IHOP |
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|
Term
| What is unique about drug absorption in the circumventricular organs? |
|
Definition
| This is a naturally leaky area of the blood brain barrier through which drugs can enter the CNS |
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Term
| What is the effect of meningitis-induced inflammation on drug distribution? |
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Definition
| The Blood Brain Barrier can be disrupted, so that even larger drugs like penicillin can pass (and potentially be used to treat the meningitis in the brain) |
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Term
| Besides being horrible and deadly, what is the problem with brain tumors as related to drug distribution? |
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Definition
| Brain tumors tend to generate their own blood vessels which lack a strong Blood Brain Barrier, thus allowing drugs to pass |
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|
Term
| What are the characteristics of adipose tissue with regard to drug distribution? |
|
Definition
Poorly perfused so slow accumulation;
reservoir for fat soluble drugs (barbiturates and some opiods);
Redistribution of highly perfused organs/tissues to adipose tissues |
|
|
Term
| How long does it take for drug equilibrium between maternal blood and fetal tissues? |
|
Definition
|
|
Term
| How soon after administration of maternal anesthetics should a "wakeful" baby be delivered? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is volume of distribution? |
|
Definition
Vd= the volume necessary to account for the total volume of drug in the body if it were present throughout the body in the same concentration found in plasma
AN ARBITRARY QUANTITY THAT MAY BE GREATER THAN TOTAL BODY VOLUME |
|
|
Term
| What is the total body volume of a 70 Kg man? |
|
Definition
|
|
Term
| What is the ratio of intracellular:extracellular fluid in a 70 Kg man, and what does this make the volumes of each? |
|
Definition
| 2:1; 28L Intracellular; 14L extracellular |
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|
Term
| What is the volume composition of extracellular fluid? |
|
Definition
| Total 14L- 10L of Interstitial Fluid; 4L of Plasma |
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Term
| What does it mean if the Vd of a given drug exceeds the total body fluid? |
|
Definition
| The drug is extensively partitioned into body tissues (not in the plasma) |
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|
Term
| As plasma concentration goes up, volume of distribution (Vd) goes... |
|
Definition
|
|
Term
| As plasma concentration goes down, volume of distribution (Vd) goes... |
|
Definition
|
|
Term
| What are the major media of drug excretion? |
|
Definition
| Urine, feces, expired air, saliva, sweat, breast milk |
|
|
Term
| What is the primary organ of drug excretion? |
|
Definition
|
|
Term
| What is drug metabolism/biotransformation? |
|
Definition
| Reduction of duration of action of drugs by conversion to an inactive form or a less active metabolite |
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Term
| In biotransformation, what do lipophilic drugs get transformed into? |
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Definition
| More polar form for easier excretion |
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Term
| What do we call a drug whose activity is increased by metabolism? Give an example |
|
Definition
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Term
| A mutation in what enzyme causes faster metabolism of codeine and therefore a stronger effect? |
|
Definition
| CYP2D6- converts codeine to morphine in the body- a mutation increases this effect |
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Term
| What happens in Phase I Reactions? |
|
Definition
Drug polarity is enhanced by introducing or unmasking a functional group
IRREVERSIBLE |
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|
Term
| Which reaction is reversible, Phase I or Phase II? |
|
Definition
Phase II reactions are REVERSIBLE
(Phase I reactions are IRREVERSIBLE) |
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|
Term
| Following Phase I reactions, metabolites are most often... |
|
Definition
|
|
Term
| If the product of a Phase I reaction is polar enough, what can happen to it? |
|
Definition
It can be directly excreted
(Most often Phase I metabolites are not directly excreted) |
|
|
Term
| What happens in a Phase II Reaction? |
|
Definition
| Phase I products undergo conjugation reaction with acids in a REVERSIBLE process |
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|
Term
| What describes the products of a Phase II reaction? |
|
Definition
| The products are highly polar, and often excreted |
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|
Term
| What are the acids with which metabolites can be conjugated in a Phase II reaction? (SAGA) |
|
Definition
Sulfuric Acid
Acetic Acid
Glucuronic Acid
Amino Acids |
|
|
Term
What is the major type of chemical reaction that happens in Phase I reactions?
What are the less common reactions? |
|
Definition
Oxidation
Reduction, deamination, hydrolysis |
|
|
Term
| What is the major reaction that happens in a Phase II reaction? |
|
Definition
| CONJUGATION (with an acid)- to increase polarity |
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|
Term
| How is Isoniazid metabolized? |
|
Definition
| Acetylated in a Phase II reaction, then Hydrolyzed in a Phase I reaction |
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|
Term
| What accounts for the 5-10% of Adverse Drug Reactions in Isoniazid administration? |
|
Definition
| Some people have a different form of the acetylating enzyme and metabolize the drug more slowly |
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|
Term
| What is consequence of giving Isoniazid to a Slow Acetylator? |
|
Definition
| Large amounts of parent drug in urine; hepatotoxicity |
|
|
Term
| Where in the liver does drug metabolism happen? |
|
Definition
|
|
Term
| What are the majority of the enzymes in the smooth ER of the liver? |
|
Definition
Mixed Function Oxidases, also called
Monooxygenases |
|
|
Term
| For the oxidation-reduction reactions in the liver, what are the critical requirements? (NORP) |
|
Definition
NADPH
Oxygen
Reductase
Cytochrome P450 |
|
|
Term
| What is the end result of cytochrome P450 reactions? |
|
Definition
| Activated oxygen- a potent oxidizer |
|
|
Term
| Describe the substrate specificity of cytochrome P450? |
|
Definition
| Low substrate specificity- targets many different things |
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|
Term
| What is the only commonality among substrates of P450? |
|
Definition
| Substrates are highly lipid soluble |
|
|
Term
| Describe the speed of P450 reactions: |
|
Definition
| SLOW Catalyst- phase I reactions are relatively slow |
|
|
Term
| What two isoforms of P450 account for 50% of the P450 metabolic reactions in humans? |
|
Definition
|
|
Term
| What P450 isoform accounts for 50% of drug metabolism in humans? |
|
Definition
|
|
Term
|
Definition
| Accelerated metabolism after repeated administration of certain drugs, chemicals, or pollutants |
|
|
Term
|
Definition
Enhanced P450 rate of synthesis OR
reduction in rate of P450 degradation
Basically, for whatever reason, the number of available metabolic enzymes is increased |
|
|
Term
| What is the therapeutic consequence of induction? |
|
Definition
| Tolerance, decreased pharmacological action of inducer and other drugs, metabolites being more plentiful may cause more side effects |
|
|
Term
|
Definition
| Reduced therapeutic effectiveness due to enhanced drug metabolism |
|
|
Term
| What causes P450 inhibition? |
|
Definition
| Compromised liver function; certain drugs inhibit activity (P450s get modified) |
|
|
Term
| What are the potential consequences of P450 inhibition? |
|
Definition
| Reduction of metabolism of inhibitor or other substrates; BOTH INHIBITOR AND OTHER DRUGS INCREASE |
|
|
Term
| What are 3 types of non- Mixed Function Oxidase mediated Phase I reactions? |
|
Definition
ALL ARE NON-P450:
-Flavin Monooxygenase
-Amine Oxidases
-Dehydrogenations (ALDH) |
|
|
Term
| What are the requirements in order for something to undergo a Phase II reaction? |
|
Definition
| Must contain suitable chemical groups for coupling/conjugation in order to become more polar and get excreted |
|
|
Term
| What type of conjugation do most agents that undergo Phase II reactions undertake? |
|
Definition
Glucuronidation, with UGTs in microsomes
An example is DIGOXIN |
|
|
Term
| How is acetaminophen metabolized? |
|
Definition
| Glucuronidation and Sulfation (95%) BUT ALSO P450-dependent GSH conjugation pathway (5%) |
|
|
Term
| What is GSH? (Obvious but useful to remember) |
|
Definition
|
|
Term
| What happens in acetaminophen metabolism if sulfation and glucuronidation gets maxed out? |
|
Definition
| Shunts metabolism to CYP2E1 and CYP3A4 |
|
|
Term
| Why does the liver get damaged with excess intake of acetaminophen? |
|
Definition
| Shunting to the P450 pathway creates reactive toxic intermediates- Glutathione doesn't cross membranes well, so it can't be used to bind reactive species |
|
|
Term
| What is the hepatoxic product of the P450 pathway of acetaminophen metabolism? |
|
Definition
| Nucleophilic Cell Macromolecules (Protein-SH) |
|
|
Term
| What should be administered in the event of acetaminophen toxicity, and why? |
|
Definition
Give N-acetylcysteine to bind to reactive species-
Because glutathione doesn't cross membranes well, and has limited capacity for regeneration |
|
|
Term
| What are "Ultra-rapid Metabolizers"? |
|
Definition
| Patients in whom CYP2D6 is over-expressed, meaning they need more drug for the same response |
|
|
Term
| What is the consequence of being a poor metabolizer? |
|
Definition
| Side effects occur more readily because of impaired drug clearance |
|
|
Term
| What is deficient in young children that makes them less able to metabolize drugs? |
|
Definition
| They have less UGT- for glucuronidation reaction- |
|
|
Term
| What are some nutritional and environmental factors that influence drug metabolism? |
|
Definition
| Charcoal broiled food, cruciferous vegetables, cigarette smoke, pesticides |
|
|
Term
| What is an example of a CYP450 1A2 enzyme inducer and what drug does it enhance the metabolism of? |
|
Definition
| Omeprazole- enhances metabolism of Acetaminophen |
|
|
Term
| What is an example of a CYP450 2C9 enzyme inducer and what drugs does it enhance the metabolism of? |
|
Definition
| Barbiturates- enhances metabolism of Celecoxib and Losartan |
|
|
Term
| What are examples of a CYP450 3A4 enzyme inducer and what drugs does it enhance the metabolism of? |
|
Definition
| Macrolides; Saint Johns Wort- enhances metabolism of Diazepam and Spironolactone |
|
|
Term
| What is an example of a CYP450 1A2 enzyme INHIBITOR and what drugs does it enhance the metabolism of? |
|
Definition
| Fluvoxamine inhibits metabolism of Acetaminophen and Tamoxifen |
|
|
Term
| What is an example of a CYP450 2D6 enzyme INHIBITOR and what drugs does it enhance the metabolism of? |
|
Definition
| Paroxetine inhibits metabolism of Codeine and Metoprolol |
|
|
Term
| What are examples of a CYP450 3A4 enzyme INHIBITOR and what drugs does it enhance the metabolism of? |
|
Definition
| Erythromycin and Grapefruit Juice inhibit metabolism of Diazepam and Spironolactone |
|
|
Term
| General inhibitors target what P450 enzyme? |
|
Definition
|
|
Term
| General inducers target what P450 enzymes? |
|
Definition
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