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Normal animal exam 3 > Pharmokinetics > Flashcards

Pharmokinetics Flashcards

1
Q

Pharmacokinetics

A

what the body does to a drug
absorption, distribution, metabolism, elimination(ADME)

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2
Q

molecular weight

A

smaller drugs cross membranes more easily
most drugs are <400-500 Da
drugs binding to protein effects size

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3
Q

plasma protein binding

A

drug enters circ and binds to protein
drug+protein=too big
protein bound drugs remain in plasma until they are no longer protein bound

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4
Q

solubility

A

lipid (lipophilicity) vs water (hydrophilicity)
lipophilic drugs more easily diffuse through membranes
hydrophilic confined to plasma, ECF

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5
Q

ionization

A

unionized (nonpolar, lipophilic) drugs distrubute more widely
dependent on pH, pKa
weak acids become unionized in acidic environments
weak bases become unionized in basic environments

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6
Q

concentration gradient

A

higher concentration (can alter w dose and route)= more drugs for diffusion
assumes there is enough blood flow to area of drug aministration

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7
Q

passive diffusion

A

no external energy required
at equilibrium, net transfer is 0
non selective
non saturtable (1st order linear kinetics)
rate of diffusion proportional to concentration gradient**

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8
Q

Carrier mediated transport

A

drugs lacking sufficient solubility for passive diffusion
carrier may be specific to drug
competition for carrier
transport for this mechanism can be saturated
these drugs typically mimic an endogenous substance

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9
Q

carrier mediated facilitated diffusion

A

special transport proteins in the plasma membrane
goes with concentration gradient
does not require energy

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10
Q

active transport

A

carrier mediated
goes against concentration gradient
can be saturated
requires energy

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11
Q

intravenous

A

drug injected into bloodstream- skips absoptive phase (100% absorption)
advantages: highest concentrations and potentially highest efficacy
disadvantages: highest risk of toxicity, technically difficult, risk of intracarotid injection (goes directly to brain= bad)
prefered in ER (ensures drug is delivered)

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12
Q

intramuscular

A

muscles are highly vascular, absorption is often high
advantages: easy to perform (large animals easier than smaller)
disadvantages: possibility of admin in vessel, painful, may cause muscle necrosis, abcess, infection
often 2nd choice in ER if you cant hit a vein

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13
Q

Subcutaneous

A

moderate to high absorption (more variable than IM)
advantages: easy to perform, less painful than IM
disadvantages: during dehydration and/or shock the skin receives less blood flow

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14
Q

are lipid soluable drugs absorbed faster or slower than aqueous?

A

slower than aqueous

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15
Q

enteral vs parenteral

A

enteral: admin per GI tract (ex. oral, rectal)
parenteral: everything else (IV/IM/SQ)

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16
Q

oral administration (PO)

A

absorption ranges from 0-100% (most variable)
slowest
many species differences
effected by feeding/diet
not prefered in ER
advantages: cheap, can be easy
disadvantages: drug loss (during admin, vomit, degredation by stomach acid, rumen), affect on GI flora

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17
Q

reasons for poor oral bioavailability

A
  • Drug not delivered from its formulation to absorption site in GIT
    –Needs to be Water soluble enough to go into solution but Lipid soluble enough to be absorbed across the GI membrane
    –Drug must go into solution before it can be absorbed! (May be a rate limiting step for lipid soluble drugs)
    –Drug formulations may have solubility enhancers to improve absorption (Compounding??? solubility is questionable)
  • drug is decomposed in GIT
  • drug is complexed in GIT (bind to other things)
  • drugs need a carrier mediated transport and dont have one
  • ion trapping (ionized drugs trapped inside cell walls, NSAIDS in stomach- ulcers)
  • some drugs metabolized in gut or liver (first pass metabolism)
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18
Q

first pass metabolism

A
  • A large percentage of drug absorbed is immediately metabolized in the gut or liver prior to absorption into the systemic circulation
  • Drugs with high first-pass metabolism are often not suitable for PO administration
  • Do not reach adequate plasma concentrations
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19
Q

ways to avoid first pass metabolism

A

alter route of administration
* alter route of adminstration (transmucosal, per rectum, transdermal)
* not all drugs are suitable for enteral admin
* suitable drugs are lipid soluable, hightly potent (lots of drug is lost), and unionized at mucosal pH

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20
Q

oral transmucosal

A

Aka buccal or sublingual
Membranes are relatively permeable
Rich blood flow
Rapid uptake of a drug into systemic circulation to avoid first pass metabolism

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21
Q

non oral transmucosal routes

A

Inhalation, nasal, ocular, vaginal, rectal

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22
Q

per rectal

A

advantages: access when unconsious or vomiting, no taste, can recover drugs before absorption is complete, can bypass first pass metabolism
disadvantages: limited surface area, lower fluid content, microbes, too far cranial drains into portal vein (first pass metabolism), drug may not stay where you put it

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23
Q

transdermal

A

drug absorbed through skin into circ
not the same as topical (stays on top of the skin)
few drugs work this way

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24
Q

Cmax

A

maximum plasma concentration
* units: mass/volume (ug/ml, ng/ml)
* typically highest for IV, lower for PO/IM/SQ
* Cmax often determines the magnitude of effect and adverse effects

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25
Tmax
time to maximun plasma concentration * units: hour or min * for IV dosing 2-3 min, variable for PO/IM/SQ * Tmax often tells you when the effect/adverse effect will occur; used for drug monitoring
26
area under curve (AUC)
Influenced by Cmax, Tmax Indicates how much drug is absorbed units: concentration/time (ug/ml hr)
27
bioavailability (F%)
Percentage of administered drug that appears in the bloodstream after dosing Two types – absolute and relative
28
A- bigger AUC closer to IV drug
29
Absolute bioavailability
Absolute bioavailability compares EV drug to IV drug Calculations F=AUCev/AUCiv * 100 (dont memorize)
30
relative bioavailability
Compares EV (extravascular) drug to EV drug May be routes of administration May be different formulation Calculations F=AUCev/AUCev * 100 (dont memorize)
31
A- IM
32
A- solution
33
bioequivalence
Basically says two drugs will have the same effect FDA proprietary = generic formulations Generic = generic FDA approved/generic vs compounded??? (not always bioequivalent) AUCs and Cmaxs should be within 20% of each other
34
FDA and generic
35
GI disease effecting absorption
enteral absorption affected * diarrhea, vomiting, proliferative diseases (of small intestine)
36
liver disease affecting absorption
Liver disease can decrease first pass metabolism and therefore increase oral absorption of some drugs that normally undergo high first pass effects.
37
dehydration affecting absorption
first affects SQ route Dehydration, unless very severe, will most affect drugs administered via the SC route, resulting in decreased drug absorption
38
drug distribution
Reversible transfer of drug between the blood and the extravascular fluids and tissues of the body
39
path of drug distribution
From plasma, drug 1st distributes into the interstitial fluid AKA extracellular fluid Between and outside the cell Next, the drug may cross biological membranes to enter into intracellular fluid, protected tissues
40
solubility affecting distribution
Nonionized lipid soluble drugs- Easily cross membranes and distribute widely Ionized water soluble drugs -Can’t easily cross membranes and most remain in the plasma and ISF
41
molecular weight affecting distribution
Low molecular weight * Cross membranes easily High Molecular weight * Includes monoclonal antibodies * Includes protein bound drugs * Can’t cross membranes and remain in the plasma
42
pH and pKa affect on distribution
Blood is very slightly alkaline…and always should be! Average 7.35-7.45 Acidic low pKa drugs will be mainly ionized- Limited ability to cross membranes Basic low pKa drugs will be mainly nonionized- Cross membranes more readily
43
blood flow affecting distribution
Initially distribute to high blood flow, low volume organs- Brain (lipophilic), liver, kidneys Next – lower blood flow, high volume organs- Muscle Finally – low blood flow organs- Fat (lipophilic, can store drugs in fat depot then slowly release- essentially inactivating drug), skin (SQ most affected by dehydration!)
44
protein binding affect on distribution
Only a fraction of drug in circulation will be bound Which means a fraction of drug is free in circulation ONLY FREE DRUG IS ACTIVE!!! ONLY FREE DRUG CAN CROSS MEMBRANES Bound drugs act as a reservoir- Only free drug gets metabolized and eliminated As free drug concentration decreases, bound drug becomes free to maintain equilibrium (constant free drug fraction; liver)
45
blood brain barrier affect on distribution
Can’t go between cells….have to go through cells -Tight junctions between cells -Basal membrane -Pericytes -Layer of astrocyte foot processes Go through cells via: -Lipid soluble, nonionized, unbound OR -Carrier-mediated; active transport
46
P-glycoprotein efflux pumps
Carrier mediated active transport Pump drugs OUT present at protected sites (blood brain barrier, eye, prostate, placenta, alveoli) MDR1 mutations are the lack of these pumps (accumulation of drugs, toxicity)
47
inflammation effect on drug distribution
Increased drug permeation Increased protein Drug concentrations decrease as inflammation decreases Lipid soluble, nonionized, unbound drugs best
48
Volume of distribution (Vd)
Theoretical volume of fluid into which a drug appears to distribute Vd=dose/max plasma concentration Measure of how far beyond the plasma a drug distributes (Plasma, ISF, intracellular, protected sites) Need to choose a drug that will get to the site of action- does NOT tell us if it gets to a specific tissue Higher doses that result in lower plasma concentrations will seem to have a larger Vd ex: if a dose is admin to the ocean concentration will be low if a dose is admin to a cup of water, concentration will be high ex: small Vd infers the drug stays in the plasma medium Vd infers drug will stay in plasma and interstitial fluid (treat diseases in plasma and ISF) large Vd infers drug distributes to plasma, ISF, intracellular fluid, potentially protected sites
49
what is Vd calculated from?
must be calculated from IV dose need bioavailability must be 100%
50
Drug A compared to Drug B Assuming an equal PPB, which is more lipophilic?
B- can cross more membranes
51
Drug B compared to Drug C Assuming equal lipophilicity, which drug is more protein bound?
B
52
Drug A compared to Drug C Assuming equal lipophilicity and protein binding, which one has a smaller MW?
C
53
age affect on distribution
Neonates have more body water -More water = larger Vd = lower plasma concentrations of water soluble drugs Old people are shriveled and dry -Less water = smaller Vd = higher plasma concentrations of water soluble drugs | Ex: Puppies
54
weight effect on distribution
Neonates have very little fat -Less fat = smaller Vd = higher plasma concentrations of fat soluble drugs Obese animals have lots of fat -More fat = larger Vd = lower plasma concentrations of fat soluble drugs
55
dehydration effect on distribution
Less fluid Higher plasma concentrations of water soluble drugs
56
diseases causing fluid accumulation affect on distribution
Cardiac disease, Renal disease, etc. * Water soluble drugs will distribute to that fluid -Lower plasma concentrations, larger Vd -May need to increase dose * Lipid soluble drugs will not distribute into that fluid -Higher Cp, smaller Vd -May need to dose on lean body mass -weight of animal – weight of fluid
57
prodrugs
converted from inactive to active form during metabolism
58
what is the main organ or metabolism?
liver
59
phase 1 reactions
oxidation, reduction, hydrolysis make drugs more polar performed by **CYP450 enzymes**
60
phase 2 reactions
conjugation (glucuronidation, acylation, methylation, sulfation) uses **UDP-glucuronosyltransferases** species specific differences
61
CYP450
non selective enzymes major source of variability in drug metabolism (within and between species) mostly in liver but can be in GIT, skin, kidney can be induced and inhibited by drugs
62
CYP450 inhibitors
cause body to produce less CYP450 Overall effect is to increase concentrations of other drugs that are substrates of P-gp and CYP450 (inhibit metabolism= increased concentration)
63
CYP450 inducers
cause body to create more CYP450 Overall effect is to decrease concentrations of other drugs that are substrates of CYP450 (increase metabolism of those drugs)
64
What is the consequence of being an ultra-fast metabolizer? What is the consequence of being a slow metabolizer? How does this change with a drug that has an active metabolite? * What if the metabolite is more toxic than the parent drug?
What is the consequence of being an ultra-fast metabolizer? -less efficacy What is the consequence of being a slow metabolizer? -higher toxicity How does this change with a drug that has an active metabolite? * What if the metabolite is more toxic than the parent drug? -ultrarapid metabolizer: more toxic, slow metabolizer: less toxic
65
factors affecting metabolism
age: decreased in young and very old gender disease (hepatic) genetics species!!!!! (and breed) enzyme saturation (zero order kinetics)
66
drug clearance
* Definition: Volume of blood cleared by a substance per unit time * Reported in mL/kg/min (or volume/weight/time) reflects rate of drug elimination from body (elimination and metabolism) encompasses all organs capable of elim drugs Total body Cl = Clhepatic + Clrenal + Clother
67
hepatic clearance
Hepatic clearance is dependent on the blood flow to the liver and the intrinsic metabolizing capacity for the drug (Hepatic blood flow) x (amount of drug extracted by liver)
68
perfusion (flow) limited drugs
* High hepatic extraction ratio drugs * High concentration of metabolizing enzymes in the liver * Liver can metabolize as fast as the blood can deliver- Free drug only, PPB (protein binding) can be rate limiting * Linear or first-order kinetics
69
capacity limited drugs
* Low extraction ratio drugs * Liver has low capacity for metabolism due to low concentrations of metabolizing enzymes * Blood delivers faster than the liver can metabolize * PPB protein binding does not limit, as free drug concentrations exceed metabolizing capacity * Zero-order or nonlinear kinetics
70
drug excretion
* Irreversible elimination of drug from the body: Unchanged (parent drug) or Metabolites Major routes: kidneys (urine), bile (GIT, feces) minor routes: milk, lungs, saliva, sweat
71
glomerular filtration
filtration, passive small protein unbound molecules much is reabsorbed
72
tubular secretion
in prox tubule active (ATP), carrier mediated saturable (can be competition for carrier)
73
tubular reabsorption
in distal tubule usually lipid soluable drugs, unionized at urine pH ion trapping -acidic drugs are unionized in acidic pH urine- can move back to blood passively (reabsorbed) -basic drugs are ionized in urine and stay in urine more
74
species differences in tubular reabsorbtion
herbivores have alkaline urine (basic drugs more likely to be reabsorbed, very difficult to make urine acidic)
75
renal disease affect on renal elimination
higher plasma drug concentration and prolonged drug effects (less excretion)
76
biliary elimination
secretory process fairly non specific polar, large MW compounds free drug only (not protein bound)
77
biliary elimination in MDR1 dogs
MDR1 dogs have decreased biliary clearance of drugs eliminted into bile increased drug concentration and potential toxicity
78
enterohepatic recirculation
drug is absorbed and enters liver - some of drug is conjugated, extreted into gallbladder - drug excreted into small intestine and unconjugated when gallbladder contracts - drug is reabsorbed and enters liver again, unconjugated and reaches plasma - In overdose situation, administration of binding agents (activated charcoal) may still be effective even hours after drug intake - remeber: not all species have gallbladder (horse, rat) but may still have secondary absorption peak from other factors (formulation factors, colon absorption, urine reabsorption)
79
half life
Time it takes for plasma concentrations of a drug to decrease by 50% It is NOT the time it takes for 50% of the dose to be excreted from the body
80
Why may a drug be effective despite low plasma concentrations? | Dosing interval will be longer than half life
Antibiotics with prolonged PAE- post anitbiotic effect (aminoglycosides) Drugs that accumulate in cells/tissues (e.g., omeprazole) Drugs whose metabolites are active and have long T½ (diazepam) Drugs whose effects are irreversible (aspirin)
81
Why may a dosing interval be shorter than the half life?
drugs with long half lives gives longer therapeutic concentrations less fluctuation, more accumulation
82
drug accumulation
When drug is administered before previous dose is completely eliminated Degree of accumulation depends on: * How much drug is being added to the body * How much is being eliminated from the body during DI Can be controlled by changing the dosing frequency
83
steady state concentration
The amount of drug in the body will continue to accumulate until steady state concentrations in the plasma are reached **Intake of a drug is equal to its elimination Cmax and Cmin are basically the same from dose to dose** Assumes stable dosing interval **Occur after 5 half-lives** Point of maximum effect Point at which adverse drug reactions occur Dose-dependent assumes first order linear kinetics
84
Linear first order kinetics
*** Elimination of a constant drug fraction (%) per unit of time ** * Proportional to the drug concentration * T1/2 does not change with dose “Dose-independent” PK: does does not effect elimination Most therapeutic drugs are first-order within clinical dose ranges linear increase in Cmax as dose increases
85
how many half lives until a drug is 99.9% eliminated in first order kinetics?
10
86
nonlinear, zero order kinetics
**Elimination of a constant drug amount per unit of time ** Not proportional to the drug concentration T1/2 does change with dose “Dose-dependent” PK Most therapeutic drugs will be zero-order at very high doses ***Overdoses** – makes treating them even harder Almost any drug will exhibit zero-order kinetics at high enough doses **Disproportionate increase in plasma concentrations compared to dose**
87
main reasons for non linear kinetics
Mainly: Saturation of metabolizing enzymes in the liver: Capacity-limited; low ER drugs Others: * Saturation of GI metabolizing enzymes * Saturation of carrier-mediated absorption * Saturation of tubular secretion * Inhibition or induction of hepatic metabolizing enzymes (Drug-drug interactions, Auto-induction/inhibition)
88
loading doses
For drugs with long half-lives that require too long to reach therapeutic concentrations 1st dose higher than subsequent
89
constant rate infusions
For drug that have a VERY short half-life For drugs with a narrow TI that require drug concentrations to be maintained within a very narrow range
90
what influnces half life?
Volume of Distribution and Clearance | T1/2 = 0.693*Vd Cl

Normal animal exam 3 (17 decks)

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