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Rudy's > Pharmacokinetics (Wolff) > Flashcards

Pharmacokinetics (Wolff) Flashcards

1
Q

What are the four basic pharmacokinetic processes?

(Mnemonic)

A

ADME

A-absorption (GI and blood)

D-Distribution (Blood)

M-Metabolism (liver, kidney, action sites, other)

E-Excretion (bile and urine out of body)

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2
Q

What factors affect Absorption

A

rate of dissolution

surface area

blood flow

lipid solubility

pH partitioning

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3
Q

Pros and Cons of oral administration

A

Pros: convenient, slow uniform absorption, safe, economical

Cons: destruction by low pH, poor absorption of large and charged particles, bind with GI contents, irritate intestines

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4
Q

Pros and Cons of Rectal administration

A

Pros: limited first pass metabolism, useful if oral route precluded

Cons: irregular absorption, irritation of rectal mucosa

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5
Q

Pros and Cons of sublingual/buccal administration

A

Pros: rapid absorption, avoids first pass metabolism

Cons: only small amounts absorbed at a time

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6
Q

Pros and Cons of IV administration

A

Pros: Most direct, bypasses barriers to absorption, suitable for large volumes, easy to adjust dosage

Cons: painful, immediate adverse effects, not suitable for oily substances/suspensions

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7
Q

Pros and Cons of IM administration

A

Pros: quick and easy, possible rapid absorption, may use as depot, good for oily substances/suspensions

Cons: painful, bleeding, nerve injury

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8
Q

Pros and Cons of Sub.Q. administration

A

Pros: Quick and easy, rapid aborption, good for suspensions and pellets

Cons: painful, cannot give large amounts

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9
Q

Pros and cons of inhalation administration

A

Pros: vollatile/aerosolized, rapid absorption, selivery to lungs may minimize systemic effects

Cons: variable systemic distribution

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10
Q

Pros and Cons of topical administration

A

Pros: application to specific surface for local effect

Cons: irritation

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11
Q

Pros and Cons of transdermal administration

A

Pros: controlled permeation through skin

Cons: irritation

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12
Q

Three ways for drugs to cross cell membranes

A
  1. facillitated diffusion (rare)
  2. Active transport (p-glycoprotein, gets drugs out of cells)
  3. direct penetration through simple diffusion (most common)
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13
Q

Which will cross the cell membrane better, polar or nonpolar drugs?

A

Nonpolar drugs readily dissolve in nonpolar substances and easily cross the cell membrane

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14
Q

What is an example of a polar drug?

A

Quaternary ammonium compounds have fixed charges and cannot readily cross the cell membrane

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15
Q

When are weak acids and weak bases able to cross cell membranes ?

A

only when in their unionized forms

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16
Q

Define the following:

Ka

S

F

Amount Absorbed

A

Ka=rate constant for absorption

S=salt factor

F=bioavailability, AUC route used/AUCiv

Amount absorbed=SxFxDose

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17
Q

If F=AUCroute used/AUCiv, what is AUC?

A

AUC is the area under the curve

where F equals the fraction of oral dose that enters the plasma

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18
Q

Equation for concentration in plasma (Cp)

Equation for Volume of Distribution (Vd)

A

Cp=SxFxDose/Vd

Vd=amount of drug in body/plasma concentration

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19
Q

What factors affect drug distribution?

A

ability of drugs to enter cells

blood flow to tissues

ability of drugs to exit the vascular suystem

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20
Q

Explain the significance of protein binding of drugs

A

Drugs are only bioactive if they are free (a=fraction unbound)

there is a finite number of protein binding sites in teh plasma, thus new addition of drugs can displace the bound drug

this can be a concern if the drug has a small therapeutic window, example: if drug is normally 90% bound and added drug displaces it so that now 80% is bound, the (a) doubled, from 10% to 20%

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21
Q

The BBB is a barrier to which category of drugs?

A

ionized or polar drugs unless they have a transporter

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22
Q

What is the primary site of biotransformation (metabolism)?

A

the liver which may activate pro-drugs but primarily INACTIVATES drugs

this is crucial for the renal elimination of lipophilic drugs which must be made more polar so they can be trapped in the renal tubular fluid

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23
Q

What are the two phases of metabolism?

A

Phase I: oxidation, reduction, hydrolysis

Phase II: conjugation

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24
Q

What occurs in Phase I of metabolism?

A

Products are made more polar by introducing or unmasking functional groups

oxidative proceses involve enzymes from SER and cytochrome p450

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25
Q

What is the function of CYP inducers

A

increase the enzyme levels, speed up metabolism of other drugs metabolized by same enzyme, lower plasma levels below MEC

examples: phenobarbitol, carbamazepine, ethanol, cig. smoke

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26
Q

Whatis the function of CYP inhibitors?

A

Inhibit enzymes

slows the metabolism of any other drug metabolzied but the same enzyme and can lead to toxic levels

examples: erthromycin, ketconazole, metronidazole, grapefruit juice

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27
Q

How does grapefruit juice inhibit the cytochrome p450?

A

Inhibits CYP3A4 enzyme in the intestinal epithelial cells thus increasing the bioavailability of other drugs metabolized by the same enzyme

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28
Q

What is the purpose of Phase II in metabolism?

A

Conjugation occurs to make the drug more water soluble and more excreable since the molecule is highly polar via glucoronidation or sulfation

Acetylation and methylation can also occur to make drugs less water soluble and to inactivate drug

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29
Q

What is the difference between glucuronidation and sulfation in the Phase II reaction of metabolsim?

A

glucuronidation is the major route of metabolism for drugs and endogenous compounds and occurs in the ER, can be induced

Sulfation occurs in the cytoplasm

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30
Q

What happens with oral administered drugs that effect their bioavailbility?

A

They undergo first pass metabolism which can greatly decrease the bioavailability of orally administered drugs

31
Q

How are drugs eliminated?

A

renal (major)

bile, sweat, breath and breast milk (minor)

32
Q

Describe the steps in renal drug excretion

A
  1. Glomerular filtration of small drugs filter out, protein bound drugs do not filter out
  2. Passive tubular reabsorption occurs of lipid soluble drugs and unionized weak acids/bases
  3. Active tubular secretion leads to elimination of protein bound drugs when they temporarily dosplace from protein near basolateral membranes of PCT
33
Q

What are some factors that modify renal drug excretion?

A

pH dependent ionization

competiton for active tubular transport

age-GFR decreases with increasing age

34
Q

What is the excretion rate?

A

mass eliminated per unit time; with first order kinetics, this increases as the plasma concentration increases

35
Q

What is clearance?

what is total clearance?

A

the plasma volume from which all of the solute is removed per unit time (flow rate)

with first order kinetics, this remains constant as plasma concentrations change

Total clearance=renal clearance+hepatic clearance+other clearance

36
Q

What is the Cockcroft-Gault eGFR equation

A

quick estmiate of creatinine clearance (eGFR) from a serum measurement of creatinine concentration

eGFR=[(140-age)xBW(kgs)/72xScr]

if female, multiply by 0.85

37
Q

Why are adverse drug reactions 7x more likely in elderly patients?

A

drug accumulation due to declining renal function

greater severity of illness

use of drugs with a low therapeutic index

poor pt compliance

polypharmacy

presence of multiple pathologies

inadequate supervision

38
Q

What are some of the consequences of drug-drug interactions?

A

synergy/potentiation leading to increased therapeutic and increased adverse effects

antagonism leading to therapeutic effects decreasing and decrease in adverse effects

creates a unique drug response (may be unpredictable)

39
Q

Common adverse drug effects

A

constipation

skin rash

diarrhea

dizziness

drowsiness

dry mouth

headache

insomnia

40
Q

What are some of the various mechanisms of drug-drug interactions?

A

directly chemical/physical

pharmacokinetic (altered ADME, issues with p-glycoprotein like MDR1)

Pharmacodynamic interactions (same receptor, different sites)

combined toxicity

41
Q

Drug allergies and hypersensitivies require what event to occur?

What are common drug allergies?

A

Require prior sensitization and are not dose-dependent

penicillins have the most serious reactions, other common allergies are NSAIDs and sulfonamides

42
Q

What drug will cause apnea of long duration if you lack plasma esterase?

A

Succinylcholine

43
Q

What drug will cause hereditary methemoglibinemia if you lack NADH methemoglobin reductase?

A

Nitrites, sulfonamides, preimaquine, etc

44
Q

What drug will cause increased toxicity if you have low liver actyl transferase?

A

Isoniazid and others

45
Q

What drug will cause drug induced anemia (favism) if you lack G6P dehydrogenase?

A

Primaquine and others

46
Q

what drug will cause acute intermittent porphyria if you lack porphobilinogen deaminase?

A

barbituates, estrogens, sulfonamides, chlorquine

47
Q

What is an example of food affecting drug absorption?

A

Ca in diet can lead to precipitation of tetracyclines in the GI tract

48
Q

What is an example of food/herbs affecting drug metabolism?

A

grapefruit juice is a CYP inhibitor and St. John’s Wort is a CYP inducer

49
Q

What is an example of food affecting drug toxicity?

A

tyramine in wine, cheese and sausages cannot be metabolizd in the presence of MAO inhibitors leading to hyperadrenergic crisis

50
Q

What is an example of food affecting drug action?

A

Na in diet can impact the actions of Li in bipolar disorder

51
Q

How can food interfere with timing of drug administration?

A

food can mitigate GI upste but interfere with absorption of drugs in stomach

52
Q

What are some issues with drug-herb interactions

A

Don’t always know the MOA of interaction so it is difficult to predict how they will influence drug; may cause diuresis, but still unpredictable

53
Q

What are some heaptotoxic drugs?

A

lipid-lowering drugs

antiseizures drugs

tuberculosis drugs

antiretroviral drugs

oral hypoglycemics

antifungals

immunosuppresants

acetaminphen

54
Q

What drugs can cause QT prolongation?

A

Tergenadine with erythromycin or ketoconazole

QT prolongation can lead to Torsades and vfib

55
Q

Drugs are responsible for how many major fetal structural abnormalities?

A

<1%

must see characteristic malformations during a specific window of vulnerability with a dose dependent response

56
Q

What are some examples of drug induced carcinogenesis

A

hard to evaluate, can take years for cancer to crop up.

cancer chemotherapy drugs assx with greatest carcinogenic potential (Tamoxifen for breast cancer, can cause uterine cancer)

DES was used to prevent SAb in high risk women but female fetuses exposed had increased incidence of vaginal and uterine cancers

57
Q

ADME in neonates and infants (increased total body water)

A

Absorption: increased or decreased in GI decreased from IM injection

Distribution: low albumin-high levels of free drugs, BBB not developed, so drugs can enter brain

Metabolism: decresed, so must adjust dose downward

Excretion: decreased, so must adjust dose downward for drugs

58
Q

ADME for geratrics (decrease in water, decrease in lean body mass, increase in body fat)

A

A: no changes, tends to decrease from GI

D: influenced by body comp., albumin levels also fall

M: tends to decrease but varies

E: decreases progressively from early adulthood

59
Q

ADME for children over age one

A

ADE: similar to adults

M: much faster than adults, peaks at age 2

60
Q

What is the placebo effect?

A

measurable, observable, or felt improvement that is not attributable to treatment

1/3 of all pt will respond to placebo and response may exceed that of some drugs

for pain, =75% of patients will respond to placebo

61
Q

Physiological changes in pregnancy that affect drug therapy

A

decreased bowel tone and motility increases time for drug absorption

increased hepatic metabolism

RGF doubles thus increases GFR

(does all of this balance out such that pregnant people do not need changed doses?)

62
Q

What type of drugs cross the placenta?

A

All drugs can cross the placenta, with lipid soluble drugs cross most readily

63
Q

What are adverse drug reactions during pregnancy?

A

teratogenesis

dependence-producing drugs

drugs that change uterine tone

64
Q

How to handle breastfeeding and drug adminstration

A

dose immediately after breastfeeding and avoid drugs with a long halflife

65
Q

What are zero order kinetics

A
  • constant amount eliminated per unit
  • the drug elimination process is saturated
  • consequently, the amount of drug eliminated is independent of the drug concentration
  • can be written as dCp/dt=k, where it is the rate of change in plasma concentration; k is a constant in units of amount per time
  • example: ethanol-rate of metabolism is rapidly saturated so it is effectively zero
66
Q

What are first order kinetics?

A
  • constant fraction is eliminated per unit time
  • drug elimination process is not saturated
  • the mass of drug eliminated is directly related to the drug concentration
  • can be written dCp/dt=kCp where it is the rate of change in plama concentration, k= fractional rate constant in unites of time, Cp equals the plasma concentration of the drug
  • This is the more typical form of drug elimination
67
Q

With first order kinetics, each half life backwards does what to the concentration?

A

doubles it

68
Q

Know these equations

A

kel=Cl/Vd

Cl=kelxVd

kel=first order eliminatino rate constant

Cl=clearance

Vd=is the apparent volume of distribution

69
Q

Calculating clearance

A

Cl=SxFxDose/t/Cp

Cl=clearance

S= salt factor

F=bioavailability

t=dosing interval in hours

Cp=plasma concentration

70
Q

Capicty-Limited reactions

A
  • display zero order kinetics initially
  • displays first order kinetics as the drug concentration falls
  • would be seen with most drugs at high enough concentrations
  • plasma concentration vs. time has a hockey stick appearance
71
Q

Capacity Limited Elimination equation

A

rate of elimination=Vmax x C/Km + C

Vmax=max eliminatino capacity

C=plasma concentration

Km=drug concentration at which rate of elimination is 50% of Vmax

72
Q

How to calculate Cpss

A

Cpss=dosing rate/Cl

=SxFxD/t X 1/kelxVd

73
Q

What is a loading dose?

A

dose needed to rapidly achieve therapeutic drug concentrations for drugs with a very long half life (digoxin)

leading dose=Cpss x Vd/(SxF)

74
Q
A

Rudy's (6 decks)

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