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Med Chem Test 3 > Prodrugs and Distribution > Flashcards

Prodrugs and Distribution Flashcards

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1
Q

What is a prodrug?

A

A pharmacologically inactive compound (in vitro) that is converted to an active compound (in vivo) by a metabolic biotransformation.
Undergo a enzymatic and/or chemical transformation in vivo to release the active parent drug.
Constitutes 5-7% of known drugs and a larger percentage of new drugs.

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2
Q

What are the benefits of prodrugs?

A

To improve aqueous solubility, poor oral absorption, chemical instability, rapid pre-systemic metabolism, inadequate brain penetration, toxicity and local irritation, and improve drug targeting.

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3
Q

What is an example of a prodrug that’s bioavailability was improved by increasing the lipophilicity or permeability?

A 
Enalaprialt(Vasotec IV) is less lipophilic than its prodrug Enalapril which has a OB of 50-70%.  The ester is changed into a CA.
Oseltamivir carboxylate(zwitterionic) is less bioavailable than its prodrug Oseltamivir ethyl ester.
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4
Q

What is an example of a prodrug that’s bioavailability was improved because it is more transferable by PEPT1?

A

Acyclovir is less bioavailable than Valacyclovir, the prodrug. An alcohol is replaced by valine to make it more it more transferable by PEPT1.

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5
Q

What is an example of a prodrug that’s bioavailability was improved because it is more transferable by MCT?

A

Gapapentin enacarbil is the prodrug for Gapabentin because Gabapentin enacarbil is a substrate of MCT-1 and has a larger bioavilability.

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6
Q

What is an example of a prodrug that has an increased duration of action?

A

Haloperiodol deconate is the prodrug for Haloperidol because it has a very high log P. It is administered IM once a month because it is taken up by the fatty tissues and is slowly released over time.

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7
Q

What is an example of a prodrug that has improved parenteral administration?

A

Phosphate ester of phenytoin is the prodrug for sodium phenytoin. Phosphate ester of phenytoin is freely soluble in aqueous solutions and is rapidly absorbed by the IM route. It is rapidly metabolized to phenytoin by phosphatases.

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8
Q

What is an example of a prodrug that has an improved ophthalmic delivery?

A

Dipivefrin is a prodrug for adrenaline. It is converted by esterases and is 600 fold more lipophilic than adrenaline. It is used for glaucoma because it can permeate the human cornea 17 times faster.

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9
Q

What is drug distribution?

A

Reversible transfer of drug to and from the site of measurement (usually bloodstream). Once a drug enters the vascular system it becomes distributed through out the various tissues and body fluids. Most drug do not distribute uniformly.

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10
Q

What is the volume distribution of total body water for a 70kg patient?

A

Total body water is 0.6L/kg so for a 70kg patient it would be 42 L.

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11
Q

What is the approximate Vd for body water, extracellular water, blood, fat, and bone for a 70kg patient?

A 
body water = 42L
extracellular water = 14L
blood = 5.5L
fat = 14L to 24L
bone = 5L
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12
Q

What are the drugs that are distributed in the total body water compartment?

A

small water-soluble drugs (ethanol)

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13
Q

What are the drugs that are distributed in the extracellular water compartment?

A

larger water-soluble drugs (gentamicin)

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14
Q

What are the drugs that are distributed in the blood compartment?

A

very large molecules (heparin), drugs which are strongly bound to plasma proteins

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15
Q

What are the drugs that are distributed in the fat compartment?

A

very lipophilic molecules (diazepam)

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16
Q

What are the drugs that are distributed in the bone compartment?

A

certain ions (lead, fluoride)

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17
Q

What is the volume of distribution?

A

The volume of distribution relates the amount of drug in the body to the concentration of drug in the blood or plasma depending on the fluid measured.

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18
Q

Many drugs exhibit volumes of distribution far in _______ of the physical values.

A

Many drugs exhibit volumes of distribution far in excess of the physical values.

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19
Q

Vd has no physiologic or physical basis. T/F

A

True, but it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments.

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20
Q

What does a large Vd mean?

A

More concentrated in extravascular tissues and less concentrated intravascularly. Well-distributed throughout the body or those that are sequestered in tissue reservoirs.

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21
Q

If a drug is highly bound to plasma proteins or remaining in the vascular region what happens to the Vd?

A

Smaller Vd

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22
Q

What factors affect distribution?

A

blood flow, membrane permeability, partition coefficient of the drug, drug binding: plasma proteins, tissues, bone, and teeth, age gender, body composition, and presence of disease.

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23
Q

The amount of drug reaching a tissue during distribution may depend on?

A

The rate of blood flow or perfusion of the tissue.

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24
Q

The rate at which blood flows to different organs varies widely. T/F

A

True

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25
Q

The highest rate of perfusion rates are seen where?

A

brain, kidney, liver, and heart

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26
Q

Cellular and plasma membranes vary little in their permeability characteristics. T/F

A

False, Cellular and plasma membranes vary in their permeability characteristics, depending on the tissue.

27
Q

In the brain, the capillary endothelial cells are surrounded by ________ which slows the rate of drug diffusion into the brain by acting as a __________.

A

layer of glial cells

thicker lipid barrier

28
Q

Under certain pathophysiologic conditions, the permeability of cell membranes, including capillary cell membranes, may be altered. T/F

A

True. A burn will alter the permeability of the skin and allow drugs and larger molecules to permeate inward or outward. Meningitis would enhance drug uptake into the brain.

29
Q

Drugs that are highly lipid soluble will readily cross cell membranes and thus be more or less distributed?

A

more

30
Q

The more lipophilic the ______ the Vd and the ______ the half-life.

A

higher

longer

31
Q

What does the BBB do?

A

The blood brain barrier serves as an important protective function for the CNS.

32
Q

Transporters on the BBB tend to carry what?

A

essential nutrients (polar molecules such as amino acids and glucose)

33
Q

Small, lipophilic drugs typically have good or bad CNS permeation?

A

good like benzodiazepines

34
Q

Drugs also may be removed by what type of transporters?

A

efflux pumps

35
Q

What are the efflux transporters expressed at the BBB?

A

P-gp, BCRP, and MRPs

36
Q

What are the influx transporters expressed at the BBB?

A

OATP

37
Q

What drugs exploit the use of transporters on the BBB to penetrate the BBB?

A

Levodopa is transported into the brain by the I-type amino acid transporter (LAT)1

38
Q

Loperamide is an opioid, but does not normally cause CNS-related side-effects because it is removed by?

A

P-glycoprotein efflux pumps

39
Q

How can the BBB be a negative factor when it blocks a drug from getting in?

A

When the drug can not get to the site of action. For example treatment of sever fungal, viral, or bacterial infections of the brain.

40
Q

What drug can loperamide not be coadminsitered with?

A

quinidine because quinidine is an Pgp inhibitor and when given together it could result in increased exposure of the CNS to loperamide resulting in respiratory depression.

41
Q

Lipophilic drugs may partition to adipose tissue and be sequestered due to?

A

Both the physicochemical properties of the drugs and the relatively low blood flow to this type of tissue.

42
Q

What drugs are traditionally contraindicated in children due to accumulation in teeth and staining?

A

Tetracyclines because it is a divalent-cation chelating agent.

43
Q

What is the danger of distribution of heavy metals.

A

They can lead to adsorption on to bone surface. Ex: Lead, Radium

44
Q

What is sequestration?

A

Accumulation of a drug in certain organs or types of tissues.

45
Q

Drugs that are sequestered at sites other than plasma proteins typically have lower or higher volumes of distribution?

A

Higher

46
Q

What are the common sequestration sites?

A

Plasma proteins
Adipose tissue
bone

47
Q

Where do lipophilic compounds usually sequester?

A

Adipose tissue

48
Q

Where do chelating agents and heavy metals usually sequester?

A

Bone

49
Q

What are the forces of interactions in drug binding?

A

Electrostatic interactions
Hydrogen bonding
Van der Waal’s forces

50
Q

What are types of electrostatic interactions?

A
  • NH3+ of lysine and N-terminal amino acids
  • S- of cysteine
  • COO- of aspartic and glutamic acid
51
Q

What is plasma protein binding?

A

After absorption, the drug circulates in the blood either in the free form or bound to plasma proteins.

52
Q

Is plasma protein binding reversible or irreversible?

A

reversible

53
Q

Drugs that are bound to plasma proteins are inert or pharmacologically active and why?

A

Inert because bound form of the drug is not easily metabolized or excreted. Because of this plasma proteins act as a reservoir or temporary storage place.

54
Q

In plasma protein binding what do acidic drugs typically bind to?

A

serum albumin (ex: NSAIDs)

55
Q

In plasma protein binding what do basic drugs typically bind to?

A

alpha1-glycoprotein (ex: SSRIs such as fluoxetine)

56
Q

Plasma protein binding can be affected by what disease states?

A

hypoalbuminemia in sever liver disease or nephrotic syndrome; elevated levels of alpha1-glycoprotein in acute phase reaction responses in arthritis

57
Q

What does plasma protein binding limit?

A

The ability of the drug to distribute beyond the blood/plasma compartment.
The metabolism of the drug.

58
Q

What drugs are not bound or are weakly bound to plasma proteins?

A

Acetaminophen (Tylenol) and Atenolol

59
Q

What drugs are moderately bound to plasma proteins?

A

Terbutaline and zidovudine

60
Q

What drugs are strongly bound to plasma proteins?

A

Furosemide (Lasix) and Warfarin (Coumadin)

61
Q

When 2 drugs have affinity for the same plasma protein and are coadminsitered they?

A

compete for the available binding sites.

62
Q

What is an example of drugs that will compete for a plasma proteins and what will happen when they are coadminsitered?

A

Tolbutamide and sulfonamide
the one with higher affinity (sulfonamide) will cause the one with lower affinity (tolbutamide) to increase in free drug concentration.

Phenytoin(Dilantin) and Valproic acid
Phenytoin will be displaced by valproic acid causing and increase in unbound phenytoin.

63
Q

What happens to plasma protein binding when the patient has hypoalbuminemia?

A

Binding may be reduced and high concentrations of free drug maybe attained. (Phenytoin and furosemide)

64
Q

How may some drugs be affected by being highly plasma protein bound?

A

Longer duration of action
Longer half-life
The drug in bound form cannot be metabolized or excreted

Med Chem Test 3 (5 decks)

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