Buxton Block 1 week 7 Flashcards by Danielle Hayes

What are the physicochemical factors in transfer of drugs across membranes?

Lipid-water partition coefficient (ratio of hydrophobicity to pass through membrane)
Size of the molecule
Concentration gradient
pH of the environment for acids and bases
Active versus passivetransport
Paracellular (intercellular) transport

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what kind of groups readily cross plasma membranes?

nonionizable groups

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If you want your drug to be excreted you want to trap it in what form?

the ionizable form ( A- + H+)

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(blank) are involved in all aspects of drug absorption distribution metabolism and excretion

Transporters

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(blank) of the genes in the human genome code for transporters or transporter-related proteins.

~7%

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The functions of membrane transporters may be participate in what two types of transpot?

active and facilitated

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What are the two big families of transporters? which one is active and which one is facilitated?

ABC (ATP binding cassette, Active)

SLC (solute carrier, Facilitated)

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ATP binding cassette (ABC transport) hydrolyzes ATP to drive the drug across (blank).

Membrane

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What is P-glycoprotein and why is it important?

It is a ABC transporter and is over expressed in cancer and a multi drug resistant cell (it transports drugs out of the cell)

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Serotonin transporter (SERT); dopamine transporter (DAT) are examples of what kind of transporters?

solute carrier transporters

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Getting drugs to target tissues depends on profusion of (blank).

blood flow

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What organs will a drug reach first based on profusion of blood flow?

1) brain, heart, liver and kidneys
2) skeletal muscle and skin
3) adipose tissue

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The primary desired effect of drug metabolism is to accelerate (blank)

elimination

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Drugs can be transformed into what 2 metabolites?

inactive and active metabolites

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What are the three metabolizing reactions?

oxidative
hydrolytic
conjugative

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What are the 2 phases of metabolism?

metabolism, conjugation

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Prozac can act on what?

the SLC transporter to keep serotinin in the synapse to increase feeling good

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What are the three ways that drugs act on targets in an adverse way?

drugs can act on clearance organs by decreasing ability to rid body of drug (kidney liver)
drugs can act on toxicological (organs that rid body of toxins) target organs by increasin uptake of drug and decreasing efflux of drug i.e. alcohol
drugs can act on target organs by forcing them to not take up necessary endogenous compounds

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Why is the blood brain barrier so good at keeping drugs from getting in?

because of tight endothelial junctions and P-glycoprotein acting as bouncer

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What is a good example of drugs that can act on target organs by forcing them to not take up necessary endogenous compounds?

the effects of inhibitors on bile acid.

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What are the two secondary active transports?

symport and antiport

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What are the three processes of passive diffusion?

partition
diffusion
repartition

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Does facilitated diffusion require energy?

No, but it does require a gradient

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What kinds of diffusion go down an electrochemical potential gradient?

facilitated and passive

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What is primary active transport? | What is secondary active transport?

using ATP hydrolysis to go against a concentration gradient Using ATP hydrolysis to create a concentration gradient for another ion to passively diffuse across membrane.

(blank) is important for efficient metabolism because it is an oxidizing agent.

cytochrome P450 (CYP)

(blank) occur because you want the drug to be soluble and therefore easily eliminated from the body.

Oxidation reactions

In order to make a drug soluble for excretion, what are the two reactions that need to occur?

phase 1: oxygenases | phase 2: transferases

What family of genes have about 57 genes and overlapping specificity, can lead to ADR if they are competitively inhibited, polymorphisms and differing expression levels explain individual differences in drug clearance?

Cytochrome P450

The importance of a CYP450 isoform is not correlated to the concentration of CYP450 isoform in an (blank).

organ

A poor metabolizer is at risk for (blank), while a ultra-rapid metabolizer isn't (blank) by drugs.

toxicity | affected

Where do you find CYP3A?

in the GI tract and liver

``` Most calcium channel blockers Most benzodiazepines Most HIV protease inhibitors Most HMG-CoA-reductase inhibitors Cyclosporine Most non-sedating antihistamines Cisapride ```

What is CYP3A responponsible for metabolism of?

CYP3A is inhibited by what?

antifungals(-zole) and grapefruit juice (competitively antagonist)

What can create all of these problems? Excessive sedation (benzodiazepines), increased Risk of rhabdomyolyis (statins) Hypotension Qt interval prolongation

Grapefruit juice because it inhibits cytochrome P450 3A

What is the active ingredient in grapefruit juice that binds to cyp3A?

Bergamottin

What are some common CYP3A inducers?

carbamezepine Rifampin Rifabutin St. Johns Wort

What is the active ingredient in st. johns wort that inducers CYP3A

hyperforin

CYP 2D6 main job is to metabolize (blank) | and is inhibited by (blank)

Codeine Many beta-blockers Many tricyclic antidepressants Fluoxetine (Prozac) Haloperidol Paroxetine (Paxil) Quinidine

What CYP is hyper active in East africans and absent in some caucasians?

CYP 2D6

``` What is this? Absent in 1% Caucasians and African-Americans Primary metabolism of: Most NSAIDs (including COX-2) S-warfarin (the active form) Phenytoin Inhibited by: Fluconazole ```

CYP 2C9

What is CYP2C19 inhibited by, but also metabolizes?

omeprazole

What CYP is this? What Absent in 20–30% of Asians, 3–5% Caucasians Primary metabolism of: Diazepam Phenytoin Omeprazole Inhibited by: Omeprazole Isoniazid Ketoconazole

CYP 2C19

``` What CYP is this? Induced by smoking tobacco Catalyzes primary metabolism of: Theophylline Imipramine Propranolol Clozapine Inhibited by: Many fluoroquinolone antibiotics Fluvoxamine Cimetidine ```

CYP 1A2

What causes arrhythmia (QT interval elongation) and was removed from the market? Why is it dangerous to couple that drug with ketoconazole, a CYP3A inhibitor.

terfenadine | CYP3A get inhibited by ketoconazole so it is unable to metabolize terfenadine which will lead to toxicity

What are the four common routs of drug admin and list them fastest to slowest.

intravenous subcutaneous intramuscular oral ingestion

What measure the result of liberation as well as absorption? What is the equation?

bioavailability, F(bioavailability)= Area under curve/dose

drug distribution and elimination can be modeled assuming two compartments (blood stream and tissues) and what will the graph look like?

It will reach a peak and slowly decline

What are the two phases of drug kinetics? | What will the graph look like?

distribution and elimination It will have a steep declining slope and then a less steep declining slope. The derivative will be the continuation of the beginning slope.

Different compartments have different (blank) rates

clearance

The minumim to maximum effective concentration of a drug effect is called the (blank).

therapeutic window

How do you find the volume of distribution?

Vd=dose/ amount in blood

Clearance is the exact reverse of what equation?

bioavailability

What is the equation for clearance? | What is the equation for elimination rate?

Cl=dose/AUC | ER= Cl x Cp

Since elimination is not saturated for drugs used clinically, (blank) do not change in a given patient.

clearance rates

Note that (blank) does not indicate how much drug is being removed, but rather the volume of biological fluid such as blood or plasma from which drug would have to be completely removed to account for the clearance per unit of body weight (e.g., mL/min per kg

clearance

Most drugs are eliminated in a (blank)-order way.

first

The rate of (blank) is directly proportional to the concentration of the drug in the blood stream.

elimination

(blank) is an example of a zero order elimination reaction

alcohol

For a first order reaction, clearance rate will be graphed in what fashion?

Linearly

On a linear graph how does a first order reaction appear?

as a curve

On a linear graph how does a zero order reaction appear?

a linear line

On a log graph, how does a first order reaction appear?

A linear line

On a log graph, how does a zero order reaction appear?

A curve