Test 2: lecture 5-6 Flashcards by jillian Bastidas

ADME

absorption
distribution
metabolism
elimination

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F stands for

Bioavailability

absorption: translocation of drug across lipid bilayers into the vasculature

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translocation of drug across lipid bilayers into the vasculature

absorption

F=bioavilability

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distribution of the drug via vasculature and across lipid bilayers from the vasculature to the drug’s target (ie. into the tissues to its target)

Vd= volume of distribution

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hepatic clearance

metabolism of a drug by the liver

CL_H

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drugs can be eliminated in

bile, urine, feces, sweat and breath

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what do you need for passive diffusion

– Small
– Neutral and Nonpolar
– Lipophilic
– large Vd (> 0.6 L/kg)
– Process is not saturable

– Eg. Alcohol, many anesthetics

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what do you need for active transport of drugs

Large
Charged or Polar
Hydrophilic
smaller Vd (≤ 0.6 L/kg)
Process uses transporters and is saturable
Eg. NSAIDs

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the Vd of passive or active transport will be larger?

passive
≥ 0.6 L/kg

means drug will move from plasma into tissues

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what is the ABC family of transporters stand for?

ATP- binding cassette

P-glycoproteins

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where can you find ABC family transporters?

protected spaces:
– GI – Gonads – Kidneys – Biliary system – Brain – Placenta

ATP-binding cassette = ATP dependent
aka P-glycoproteins

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SLC superfamily of transporters stands for —

solute carriers

made of Organic Anion Transporters (OAT) and Organic Cation Transporters (OCT)

ion channels

do NOT require ATP

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— and — are types of SLC family transports

Organic Anion Transporters (OAT) and
Organic Cation Transporters (OCT)

solute carriers: no ATP needed, facilitated transporters and second active transporters

Use ionic gradients or built in transmembrane potentials

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SLC family transportes are — transporters and — transporters

Use — gradients or built in transmembrane potentials

facilitated
second active

ionic

Do NOT need ATP
solute carriers: OAT and OCT

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where can you find SLC superfamily transporters

everywhere

do not need ATP

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what direction does ABC and SLC transporters in the brain work?

will pump drugs out of the brain

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white footed collies will have — mutation that leads to — toxicity

ABCB1= MDR1 deficiency

ivermectin (heartgard)

causes neurotoxicity at high doses

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phase I biotransformation reactions are —- reactions

oxidation- cytochrome P450

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two phase II biotransformation reactions

conjugation:

glucuronidation
acetylation

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what is a prodrug?

drug that needs to be broken down to be activated

the metabolite is MORE active than the substance administered

Cefpodoxime proxetil (aka Simplicef = 3rd generation cephalosporin antibiotic)

Erythromycin-ethylsuccinate (macrolide antibiotic)

Codeine

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— are prodrugs

Cefpodoxime proxetil (aka Simplicef = 3rd generation cephalosporin antibiotic)

Erythromycin-ethylsuccinate (macrolide antibiotic)

Codeine

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Most metabolic products are pharmacologically LESS active

what are three exceptions?

prodrugs (codeine)
toxic metabolites (acetaminophen)
carcinogenic metabolites (polycyclic aromatic hydrocarbons)

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two type of oxidation reactions

hydroxylation

oxidative deamination, dealkylation

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— is an oxidation reaction where Oxygen is incorporated into the drug molecule

hydroxylation

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--- is a oxidation reaction where Oxidation causes the loss of part of the drug molecule

oxidative deamination, dealkylation

--- aka NADPH-cytochrome P450 reductase

Flavoprotein

how does oxidation via cytochrome P450 work

Oxidized (Fe3+ aka **ferric form** of heme) cytochrome P-450 combines with a drug substrate to form a binary complex. NADPH **donates two electrons** to cytochrome P-450 reductase. One of these electrons reduces the Fe3-cytochrome P-450-drug complex to Fe2+ (**ferrous form**) The reduced heme P450-drug complex **binds O2**. The second electron from P450 reductase serves to reduce molecular oxygen and form an "activated oxygen"-cytochrome P-450-substrate complex. This complex in turn **transfers "activated" oxygen to the drug** substrate to form the **oxidized product**. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates. The second activated O atom is used to form H2O.

oxidation via cytochrome P450 NADPH + H + O2 + drug=

NADP^+ + H20 + oxidized drug

phase II Glucuronidation by UDP-Glucuronosyltransferase can be added to

-OH, -COOH, -NH2, -SH groups phenols, 3°-amines, aromatic amines ## Footnote conjugation reaction

phase II Acetylation by acetyltransferase can be added to ---

on -NH2, -SO2NH2, -OH groups

what happens during acetylation

actyl CoA is added to something NAT enzyme is found in many tissues, including liver can be added to procainamide, histamine and isonizaid

where does phase I and phase II reactions take place?

liver Other sites include the GI, lungs, skin, kidneys, brain, heart

what is enterohepatic recycling

drugs in the liver → bile → excreted into the GI tract, can become activated, or reabsorbed or metabolized (recycles)

ATP requiring --- family pumps for efflux. --- exchangers required for drug absorption from intestine or blood by tissues and in some cases protein carriers.

ABC= ATP-binding cassette= P-glycoproteins SLC family (solute carrier)

Phase I drug metabolizing enzymes: --- enzymes (mixed function oxidases); Flavin Mono oxygenases; Monoamine oxidases, Alcohol/Aldehyde dehydrogenases.

Cytochrome P450

Phase II drug metabolism enzymes: --- and ---, Sulfotransferase, Amino Acid Conjugation, Glutathione-S-transferase

UDP-Glucuronosyltransferase acetyltransferase

what are some factors affecting drug translocation and biotransformation

Species and Breed Differences Within an Individual – Age – Obesity – Hydration Status – Diet – Hepatic Disease – Renal Disease – Drug-drug Interactions

Greyhounds have lower CYP2B11 activity than other dog breeds. this means

lower Vd for lipophilic drug= very slow removal and recovery do not do well with anesthetics (propofol, thiopental)

greyhounds do not do well with anesthetics (propofol, thiopental) because ---

lower CYP2B11 activity lower Vd of lipophilic drugs because of decrease enzyme activity and low body fat

cats don't have CYP2B6 in the --- which leads to

liver hepatic necrosis if you give them diazepam

--- leads to monensin toxicity in horses

low CYP2D ## Footnote phase 1 CYP240 difference

why do micro pigs need higher doses of drugs?

increased activity of CYP ## Footnote phase I CYP450

there are changes within a species for CYP2D6 --- will make you a poor metabolizer

Homozygous carriers (Ex4/4) (~18% of population)

there are changes within a species for CYP2D6 --- will make a normal metabolizer

Homozygous (Ex *1/*1) or WT/WT (60-70% of population)

there are changes within a species for CYP2D6 --- will make you a rapid metabolizer

multiple copies (2-3) (~10-22% population)

should you increase or decrease the dose for poor metabolizers for codeine?

active form is morphine if poor met- need more of drug to get same effect if ultra met- need less of drug to get same effect

Poor metabolizers of codeine will have --- pharmacological effect at normal dose while Ultra metabolizers will have --- level of active compound potentially causing drug toxicity

poor higher than normal

The canine --- is inhibited by fucocumarins (present in grape fruit juice and a other citrus fruits and veggie products), and St. John’s Wort.

CYP3A12

cats have slow aspirin clearance and acetominophen toxicity because ---

lack glucoronidation (UGT1A6 = uridine diphosphate glucuronosyl transferase)

Dogs have N-acetyltransferase deficiency → can’t efficiently metabolize --- resulting in hypersensitivity

sulfonamides

dogs have --- deficiency where Hydralazine (vasodilator) has a much longer halflife than humans

N-acetyltransferase deficiency 11 to 13 h instead of 2 to 4 h ## Footnote phase II difference

dogs have variations in --- which metabolizes azathioprine (immunosuppressant) and active metabolites into inactive metabolites. which dogs have the highest and lowest?

Thiopurine methyltransferase (TMT) Giant Schnazuers had lowest activity (need lower dose) Alaskan malamutes had high activity (need higher dose)

Avian and Reptiles: unique amino acid conjugation - benzoic acid is conjugated to ornithine instead of ---

glycine ## Footnote phase II differences

Dogs with N-acetyltransferase deficiency: --- is not metabolized into the active metabolite (NAPA), however it is still effective

procainamide ## Footnote phase II differences

what deficiency leads to dogs not metabolizing sulfonamides?

**N-acetyltransferase deficiency** * procainamide is not metabolized into the active metabolite (NAPA), however it is still effective * Hydralazine (vasodilator) has a much longer halflife than humans; 11 to 13 h instead of 2 to 4 h

what happens to xyalzine binding in cows

⍺2 receptors G protein acts in different way when binded to xyalzine difference in **pharmodynamics** (drug interacting with receptor)

Vd of polar water soluble drugs is --- in young animals and --- with age eg. gentamicin (antibiotic) dose is --- for “juvenile” animals compared with “adult” animals

highest decreases higher ## Footnote young animals have more water= more movement of water soluble drugs out of plasma into water

Vd for --- drugs tends to increase with age due to increased % body fat

nonpolar lipophilic ## Footnote older people are fat

high percentage of body fat increases the Vd for lipophilic drugs, requiring higher doses to be administered for the same effect; drugs that do not distribute to fat may need to be dosed based on --- to avoid toxicity

optimal body weight

as Cl increases, --- absorption decreases and vice versa

bromide

--- juice - CYP 3A4 in humans/CYP3A12 in dogs inhibitor; highly variable effects; fucocoumarins

Grapefruit

St John’s wort, other herbal products – Inhibits ---

CYP3A4 in humans= **CYP3A12 in dogs** CYP2D6 in humans = **CYP2D15 in dogs** (poor met, normal, ultra met)

Dehydration decreases Vd for --- substances

polar, hydrophilic

what kind of disease can alter drug metabolism and transport

liver disease cardiac (decreased blood flow) viral/bacterial infection (fever= increased met) cancers autoimmune disease CKD

CKD produces uremic toxins which can downregulate --- and ---

CYPs efflux transporters (P-gp, MRP) causes **increased** bioavilablility

CKD leads to decreased excretion by the liver, which goes to the liver and ---

transporters are downregulated leads to more drug **getting past liver** into regulation also causes increased biliary excretion **need to decrease dose cause not being excreted and more is getting to circulation**

three major categories of CYP inducers

* **Phenobarbital** is prototype of one group - enhances metabolism of wide variety of substrates (including its own) by causing proliferation of SER and CYP in liver cells. * **Polycylic aromatic hydrocarbons** are second type of inducer (eg. benzo[a]pyrene). * **Glucocorticoids** (eg. Dexamethasone)

--- family of antifungals inhibit CYP450

azole (ketoconazole)

--- is prototype of one group - enhances metabolism of wide variety of substrates (including its own) by causing proliferation of SER and CYP in liver cells.

Phenobarbital induce CYP450

Ketoconazole inhibits ---

CYP450 and MDR1 (P-glycoprotein) used to decrease metabolism of Cyclosporin

--- inhibits CYP450 and MDR1 (P-glycoprotein). This antifungal is used to decrease metabolism of ---

ketoconazole Cyclosporin (by 75%)

use of ketoconazole with cyclosporin can --- dose of cyclosporine by as much as 75%!

decrease keto is CYP450 inhibitor- **stops breakdown of cyclosporin** which is very $$$ and normally breaks down quickly because it is a CYP450 inducer