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Principles of Drug Action > Test 3 > Flashcards

Test 3 Flashcards

1
Q

Absorption

A

Process by which unchanged drug proceeds from the SOA to the site of measurement within the body.

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2
Q

Factors influencing absorption

A 
Dose
Dosage form
Route of Administration
Physicochemical properties of drug
A&P at the site of abosrption
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3
Q

Barrier usually passed through in abosrption

A

Biological membrane of tissue barrier

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4
Q

Diffusion

A

Passive. Depends on downward gradient. Obeys Ficks law.

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5
Q

Facilitated diffusion

A

Uses carrier molecules. Still needs gradient.

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6
Q

Active transport

A

Carrier mediated. Needs energy, ATP. Can go against gradient.

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7
Q

Fick’s Law

A

Quantifies amount of substance that diffuses across a given surface area in an amount of time under certain concentration gradient.

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8
Q

Gi Drug absorption

A

Transcellular- Through cells
Paracellular- In between cells. Small polar molecules.
Transcytosis- Uses Vesicle
M-cells- absorb it into lymphatic system. Microfolds of peyers patch

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9
Q

Gastric transit times

A

Stomach- 1 hr fasting, meal 2-8
Small intestine- 2-4
Large- 12-24

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10
Q

What effect does gastric emptying have on drug absorption?

A

Can speed or delay it.

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11
Q

Factors that effect drug permeability.

A

Lipophilicity- -1 to 4 best
Charge - neutral or unionized
size - less than 500mw
Presence of transporters

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12
Q

Absorption may be limited by…

A

Permeability or dissolution

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13
Q

Blood flow can limit the rate of absorption for..

A

Highly permiable drugs

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14
Q

Highly permeable drugs are referred to as…

A

High extraction ration drugs. 70% or more taken up in single pass.

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15
Q

Eternal routes

A

By mouth, sublingual, Rectal (50% first pass)

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16
Q

Parenternal routes

A

IV, IM, Sub-Q, Intraspinal, Intraatrial,

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17
Q

How many genes code for transporters or transporter supporters?

A

2000 or 1/8 total

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18
Q

ABC transporter

A

ATP binding casette. Active, need ATP. P-glycoprotein efflux system and CFTR.

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19
Q

SLC transporters

A

Solute carrier type. Facilitated and ion coupling. Can be drug targets or alter ADME. Serotonin and dopamine reuptake systems.

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20
Q

Distribution is…

A

Reversible. Also non homogeneous, tissues differ in the rate and efficacy of drug uptake

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21
Q

Metabolism and Elimination are…

A

Non-Reversible

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22
Q

Drug distribution refers to?

A

The reversible transfer of free drug circulating in the body

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23
Q

Factor affecting drug distribution

A

Blood flow to clearance organisms, organ size, capillary bed surface area, capillary permeability, Influx and efflux systems, plasma protein binding, and presence of a disease in an organ.

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24
Q

Organ with high rates of blood flow

A

Lung, kidney, brain, and liver. Have high capillary surface area.

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25
Q

Organs with low rates of blood flow.

A

Resting muscle, skin, bone, and fat.

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26
Q

Perfusion or flow limited

A

Compounds in which uptake is sufficiently rapid that transfer is limited by delivery, not permeability. Usually smaller lipid soluble compounds with “high extraction ratios”

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27
Q

Permeability limited

A

Transfer across membrane is rate limiting. Polar, charged, and low lipid solubility usually. “Low extraction ratio”

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28
Q

Fenestra

A

Small porous membranes in some capillaries.

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29
Q

Free drug concentration can be affected by these 2 important factors.

A

Binding to plasma protein, ex, albumin.

Active transport back out of tissues by efflux pumps, ex. P-glycoprotein and MDRP4 systems.

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30
Q

Plasma protein binding

A

Binding by these reduces free fraction of drug. Rarely leads to adverse drug events because of different binding sites.

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31
Q

Albumin

A

Has 3 binding domains each with 2 subdomains.
Sudlow site 1 at 2a, warfarin binds here.
Sudlow site 2 at 3a, diazepam and ibu.

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32
Q

Lipoproteins

A

Allow drugs to piggy back

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33
Q

Exchange between plasma and tissue is based upon…

A

Free drug concentration

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34
Q

Blood Brain Barrier.

A

Very picky to what it allows in. Capillaries lack pores and fenestra. Compounds must dissolve and diffuse across lipoid cell membrane.

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35
Q

CSF sink effect

A

Small amounts of some molecules that do cross barrier can be carried out with the more CSF flow so brain extracellular levels remain lower than those in the plasma.

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36
Q

Xenobiotics

A

Things that can he harmful to us. The body has mechanisms to excrete such substances.

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37
Q

Drug metabolism

A

Modifications made to drugs in order to get them excreted.Drugs can be activated (prodrugs) or inactivated by metabolism. Each metabolite of a drug had the possibility to be toxic.

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38
Q

Top 2 drug metabolizing organs.

A

Liver and Gi tract.

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39
Q

Phase 1 metabolism

A

Oxidation, reduction, hydrolysis. Small changes to make substance more polar. Usually add O or N.

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40
Q

Phase 2 metabolism

A

Bigger changes to make more hydrophilic.

41
Q

Phase 3 metabolism

A

Excretion. Biliary or renal.

42
Q

Where are phase 1 and 2 enzymes located?

A

Phase 1 - In the Endoplasmic reticulum

Phase 2 - In the cytosol

43
Q

Cyclophosphamide

A

Pro drug. Induces apoptosis in cancer cells.

44
Q

Methotrexate and 5-fluorouracil

A

prodrugs. Block dTMP in cancer cells.

Methotrexate is folic acid analog that is polyglutamated in a cell.

45
Q

Cytochrome P450

A

Major phase 1 enzyme system located in smooth ER. NADPH cofactor required. Phase 2 UGT is nearby, exception to cytsol rule. Causes coupling between these phase 1 and 2 processes.

46
Q

What is homology percentage?

A

How many amino acids are the same in a CYP family.

47
Q

Enzymes that mediate Phase 1 but not CYP

A

Flavin monooxygenase isoenzymes
Alcohol Dehydrogenase
Aldehyde oxidase
Mooamine oxidase

48
Q

Three concers of CYP450 in drug therapy.

A

Inhibition of drug metabolism
induction of drug metabolism
Genetic polymorphism in population

49
Q

Inhibition of P450

A

Some substances compete for P450. EX. one drug can inhibit P450 while another being taken needs it to metabolize. May show saturation if inhibitor is a substrate, usually competitive inhibition, maybe allosteric, and slow parent drug metabolism can raise plasma conc.

50
Q

Induction of P450

A

Stuff to be broken down does so faster, stuff to get activated gets activated faster. Substance makes more P450 be made.

51
Q

Genetic polymorphism of P450

A

Some people just metabolize slower and some faster.

52
Q

APAP toxicity

A

Due to saturation of normal detox path. NAPQI metabolite binds to sulfhyryl groups in important proteins. Loss of intracellular calcium, disruption of mitochondrial function, and cell death.

53
Q

What protects cells form APA toxocity?

A

Glutathione reacts with toxic metabolites.

54
Q

Phase 2 metabolism

A

Covalent conjugation reactions, mostly in cytosol. Attach large hydrophilic endogenous groups. Ex. Glucuronic acid, glutathione, sulfate, acetic acid, and some amino acids.

55
Q

Enzymes that help conjugation?

A

Mainly UGT, sulfotranserases, methyl-T, Acetyl-T, Amino acid-T, Glutathione-T, and fatty acid conjugation.

56
Q

Glucuronidation

A

Most important in phase 2. Glucose and UTP make UDP-Glucose. UDP gulcose dehydrogenase makes UDP glucuronic acid. Finally UGT makes O-Glucuronide.

57
Q

Gilberts syndrome

A

Deffective UGT1A1. Bilirubin cant be conjugated.

58
Q

Enterophepatic Recycling

A

Drug glucuronide complexes excreted to gut can be broken down by B-glucuronidase. The released drug can be returned back to body, forming cycle and increasing drug half life.

59
Q

Acyl Glucuronides

A

Are unstable and can undergo hydrolysis or rearangment from C1 to C2, or C3 to C4 at neutral or alkaline PH. Can create toxic species.

60
Q

Sulfation

A

Done by sulfotransferases. Critical metabolism route for some drugs. Uses energy rigch sulfur donor PAPS.

61
Q

Sulfotransferases.

A

SULT or ST. Cytosolic enzyme in liver, kidney, gut, and brain. High affinity, low capacity.

62
Q

Acetaminophen

A

Is sulfated with sulfotransferase and PAPS. Estrone also does this.

63
Q

Methytransferase

A

Cystolic. Co-factor SAM. COMT is metabolism of catetholamines. Also done in desmethylimipramine.

64
Q

Thipourine methyl transferase.

A

TPMT. Significant metabolism of 6-Mercaptopurine with this is normal person. If genetically defective low activity of TPMT causes toxicity because of 6-thioguanine nucleotides.

65
Q

Phase 2 acetylations

A

Acetyl-CoA cofactor. Cystolic, NAT-1 and NAT-2 isoforms. In kupffer cells. CoASH left over after RXN.

66
Q

Glutathione conjugation

A

Bonds through nucleophilic cysteine thiol group. Very reactive with electrophilic substances.

67
Q

Fatty acid conjugation

A

Adds hydrocarbon tail onto site of phase 1 metabolism. Defies what we think of phase two because it makes drug more lipophilic.

68
Q

Drug elimination

A

Irreversible loss of drug from the body via metabolism or excretion.

69
Q

Metabolism

A

Loss of drug by chemical conversion.

70
Q

Excretion

A

Loss of drug by diffusion, filtration, evaporation, or transport process.

71
Q

Pharmacokinetics

A

Rate of elimination of a drug as the change in drug concentration with the passage of time. dC/dT.

72
Q

Rate of elimination =

A

-Ke*C^n

73
Q

If n=0

A

Zero order kinetics. aka. saturation kinetics

74
Q

If n=1

A

First order kinetics

75
Q

Zero order elimination

A

Independent of drug concentration.

Half life increases and clearance falls with increased drug conc.

76
Q

First order elimination

A

Dependent on drug concentration
Half life in independent of conc and constant.
Clearance is constant and not related to conc

77
Q

Rate constant, Ke

A

Function of slope of elimination time as conc falls. Dont confuse with elimination rate.

78
Q

Volume of distribution

A

Apparent volume in which a drug appears to be dissolved.

79
Q

Clearance

A

amount of blood from which drug can be metabolized or otherwise eliminated in a unit of time.
Cl=Rate of elimination / Drug Concentration

80
Q

Renal excretion

A

Glomerular filtration- Creates plasma like blood filtration
Tubular reabsorption- Takes useful stuff from filtrate back to blood
Tubular secretion- Removes additional blood waste and adds to filtrate

81
Q

Renal Elimination =

A

Glomerular filtration + tubular secretion - tubular reabsorption

82
Q

Macular densa

A

Special group of cells at distal tubules. Last check

83
Q

Juxtaglomerular apartaus

A

Macula densa and juxtaglomerular cells

84
Q

Clearance depends upon what?

A

Renal funtion. GFR.

Free drug clears easier than bound drug

85
Q

99% of filtered fluid is…

A

reabsorbed in the renal tubules. Occure by passive diffusion and active transport.

86
Q

Factors that influence reabsorption

A

Urine flow
Urine pH
Lipophilicity of Drug
Transport modulation

87
Q

Hepatic Excretion

A

Drugs actively transported from plasma to bile. Bilary excretion not good for drugs under 400 daltons. Conjugating to glucuronic acid helps with this excretion

88
Q

Enterohepatic circulation

A

Drugs excreted in bile un-conjugated by enzymes in GI tract. Reabsorbed in blood and re used. Increases half-life.

89
Q

Mammary secretion

A

Passive diffusion. Milk slightly acidic compared to blood.

90
Q

Toxicology

A

Study of adverse effects on living organisms. Includes symtoms, mechanisms, treatments, and detection of poisoning. Chief criteria for toxicity is amount or dose of substance that causes it.

91
Q

Procrustean Approach

A

Drugs often interact with multiple receptors.

92
Q

Therapeutic index

A

LD50/ED50 . Higher the ratio the safer the drug.

93
Q

Adverse drug reaction

A

Negative outcome due to drug.

94
Q

Adverse drug event

A

A negative outcome that occurs while taking a drug, but not necessarily attributed to it.

95
Q

Basis of allergic drug reactions

A

Most small drugs do not cause reactions. Must be presented to T-cell receptor via MHC. Must react covalently with protein to for a hapten.

96
Q

Acute toxicity

A

Uses a variety of doses and two animal species to determine LD50

97
Q

Subacute toxicity

A

Three doses in two species. Doses try to match those expected to be used clinically

98
Q

Chronic toxicty

A

Rodent and non rodent species, studies 6 months or longer.

Principles of Drug Action (2 decks)

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