Test 2: lecture 5-6 Flashcards
ADME
absorption
distribution
metabolism
elimination
F stands for
Bioavailability
absorption: translocation of drug across lipid bilayers into the vasculature
translocation of drug across lipid bilayers into the vasculature
absorption
F=bioavilability
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
hepatic clearance
metabolism of a drug by the liver
CLH
drugs can be eliminated in
bile, urine, feces, sweat and breath
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
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
the Vd of passive or active transport will be larger?
passive
≥ 0.6 L/kg
means drug will move from plasma into tissues
what is the ABC family of transporters stand for?
ATP- binding cassette
P-glycoproteins
where can you find ABC family transporters?
protected spaces:
– GI – Gonads – Kidneys – Biliary system – Brain – Placenta
ATP-binding cassette = ATP dependent
aka P-glycoproteins
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
— 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
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
where can you find SLC superfamily transporters
everywhere
do not need ATP
what direction does ABC and SLC transporters in the brain work?
will pump drugs out of the brain
white footed collies will have — mutation that leads to — toxicity
ABCB1= MDR1 deficiency
ivermectin (heartgard)
causes neurotoxicity at high doses
phase I biotransformation reactions are —- reactions
oxidation- cytochrome P450
two phase II biotransformation reactions
conjugation:
glucuronidation
acetylation
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
— are prodrugs
Cefpodoxime proxetil (aka Simplicef = 3rd generation cephalosporin antibiotic)
Erythromycin-ethylsuccinate (macrolide antibiotic)
Codeine
Most metabolic products are pharmacologically LESS active
what are three exceptions?
prodrugs (codeine)
toxic metabolites (acetaminophen)
carcinogenic metabolites (polycyclic aromatic hydrocarbons)
two type of oxidation reactions
hydroxylation
oxidative deamination, dealkylation
— is an oxidation reaction where Oxygen is incorporated into the drug molecule
hydroxylation
— 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
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
phase 1 CYP240 difference
why do micro pigs need higher doses of drugs?
increased activity of CYP
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
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
phase II differences
Dogs with N-acetyltransferase deficiency: — is not metabolized into the active metabolite (NAPA), however it is still effective
procainamide
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
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
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
