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Introduction To Pharmacology I > Drug Distribution > Flashcards

Drug Distribution Flashcards

1
Q

Which one of the following factors negatively affects the distribution of a drug?
A.) Concentration gradient
B.) Lipid solubility
C.) Binding capacity
D.)Nonionized status of the drug

A

C.) Binding capacity

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2
Q

What is the central compartment?

A

Blood stream

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3
Q

Once a drug reaches systemic circulation what must occur for it to be utilized?

A

Once it reaches systemic circulated it must be distributed from central compartment to periphery/ peripheral tissues.

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4
Q

When it comes to drug absorption, distribution, metabolism, and excretion, what order will you see these things occur in?

A

No order, they are dynamic and occur simultaneously.

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5
Q

Are all drugs released into systemic circulation at once and metabolized? Why could this be problematic in food producing animals?

A

There are numerous tissues to which a drug may be distributed
• In some cases, drugs may be stored in tissues and slowly released back into the systemic circulation (low blood flow/mass ratio)
• If the animal is a food-producing species, such tissue storage may result in residues in the edible meat products

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6
Q

What are the major factors that determine a drugs drug distribution to and from tissues?

A

• Lipid solubility/ ability to penetrate cell membranes
• regional blood-flow
• concentration gradient between blood/ tissue
• Degree drug is bound to plasma/ tissue proteins.
• Presence of transport proteins.

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7
Q

What tissues have a high blood flow/ mass ratio?

A

Brain
Heart
Liver
Kidney
Endocrine Glands

Kevin Brings His Labrador Everywhere

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8
Q

What tissues have an intermediate blood flow/ mass ratio?

A
  • Muscle
  • Skin
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9
Q

What tissues have a low blood flow/ mass ratio?

A
  • Adipose Tissue
  • Bone
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10
Q

What area of the kidney receives the highest blood flow? Which receives less?

A
  • Renal cortex - 25% of cardiac output
  • Renal medulla small fraction of this blood flow
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11
Q

What is responsible for the transport of drugs? What transport method is least important?

A

• Drug distribution os associated with plasma proteins
• RBC can also transport drugs but less frequent
• Transport via lymph less important

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12
Q

When it comes to lipid soluble drugs, what drugs tend to bind to albumin?

A

Weakly acidic drugs tent to bind to Albumin

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13
Q

When it comes to lipid soluble drugs, what drugs tend to bind to α1-glycoprotein?

A

Weakly basic drugs tent to bind to α1-glycoprotein

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14
Q

When it comes to lipid soluble drugs, what do weakly acidic drugs tend to bind to ?

A

Albumin

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15
Q

When it comes to lipid soluble drugs, what do weakly basic drugs tend to bind to ?

A

α1-glycoprotein

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16
Q

What kind of bond is the bond between drugs and plasma proteins? Is it irreversible?

A

It is a non covalent bond, it is reversible.
◦ Drug will move throughout circulation until it dissociates from plasma protein

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17
Q

When does a drug dissociate from its plasma protein?

A

◦ Dissociation occurs when affinity for another tissue component is greater than that for the plasma protein

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18
Q

What can affect drug distribution? Does it prevent the drug from reaching site of action?

A

• Plasma protein binding can affect the drug distribution since only the free drug is able to cross cell membranes.
• Binding does not prevent drug from reaching the site of action but does slow it down.

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19
Q

How does protein binding affect glomerular filtration? Metabolism, Secretion of drugs?

A

• Protein binding limits glomerular filtration/ slows down rate of metabolism/ secretion of drug.
◦ Drugs can be secreted if bound to plasma proteins.

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20
Q

Why must drugs bind to plasma proteins?

A

• Must bind to plasma proteins so they could make it to their target organ. They hitch a ride.

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21
Q

What is protein binding expressed as?

A

Protein-binding are expressed in terms of percent of drug bound

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22
Q

When does plasma protein binding occur?

A

When a compound has a high affinity for a protein (e.g., albumin)

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23
Q

When does the percent of drug bound fall?

A

• The percent falls when the drug concentration exceeds the value that saturates the binding site

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24
Q

What causes displacement of drug from plasma proteins?

A

• Competition for same site on plasma proteins may have important consequences, especially when one of the ligands has a very high affinity

25
Q

If drug A were bound 87% and 10% of it is displaced by drug B, the amount of free drug A would?

A

increases from 13% to 21.7%

26
Q

If drug A were bound 45% and 6% of it is displaced by drug B, the amount of free drug A would?

A

increases from 55% to 57.7%

27
Q

What is the distribution equilibrium or steady state?

A

The amount of drug leaving plasma for tissues is equivalent to the
amount of drug leaving tissues for plasma

28
Q

Is there a point where the distribution equilibrium will not be reached?

A

pseudoequilibrium
• DE may not ever be achieved because a drug is continually being eliminated

29
Q

When is distribution equilibrium less likely to be achieved?

A

DE less likely to be achieved in drugs with short half life, especially when given at a long dosing interval

30
Q

When talking about drugs that accumulate, when would it be more likely to reach a steady state equilibrium?

A

• Drugs that accumulate (given at dosing interval that is shorter than half life) is more likely to reach steady state of equilibrium between doses.

31
Q

What are tissue barriers to equilibrium?

A

• some organs have barriers to penetration of drugs/ substabces.

32
Q

What are some of the important tissue barriers in the body?

A

Blood brain barrier, blood testis barrier, prostatic, ocular, synovial, mammary gland, and placental

33
Q

What organs have a tissue barrier to drugs/ substances?

A

Brain, Prostate, Ocular, Testicular, Synovial, Mammary Gland, Placenta

34
Q

What compounds can penetrate the important tissue barriers?

A

◦ Only non ionized lipid soluble can penetrate

35
Q

What makes the blood brain barrier impermeable to ionized water soluble compounds?

A

Blood-brain barrier (BBB): This barrier has a glial cell layer interposed between the capillary endothelium and the nervous tissue

36
Q

What is one way these barriers allow essential nutrients to bypass?

A

A few tissues possess selective transport mechanisms that accumulate specific chemicals against concentration gradients. For example the blood-brain barrier has glucose, L-amino acid, and transferrin transporters

37
Q

What is another feature of the blood brain barrier that removes drugs from the protected sites?

A

The blood-brain barrier also possesses drug efflux transport mechanisms that remove drug from the protected sites
MDR1

38
Q

Where is MDR1 ( ATP- driven efflux transporter) expressed highly?

A
  • Blood Brain Barrier
  • Blood Testis Barrier
  • Kidney
  • Liver
  • Intestines
39
Q

What is the purpose of MDR1 transporter?

A

It is protective, it protects against drugs/ toxins.

40
Q

What causes collies to be sensitive to ivermectin?

A

A mutation causes a non-functional MDR1 protein at the blood brain barrier, which causes the passage of drugs into the CNS

41
Q

What are the clinical signs of neurotoxicity to ivermectin from MDR1 defect in order of occurrence?

A
  • Depression
  • Ataxia
  • Somnolence
  • Salivation
  • Tremor
  • Coma
  • Death
    Dean and Sarah Take Christines Donuts
42
Q

What causes the MDR1 mutation?

A

4 bp deletion causes premature stop codon

very short protein in defective

43
Q

What drugs have an increased toxicity in patients with MDR1 mutation?

A

◦ antiparasitic agents (ivermectin/ doramectin)
◦ antineoplastic drugs (vincristine/ vinblastine/ doxorubucin)
◦ Antiemetics (ondansaton)
◦ cardiovascular therapeutics - Digoxin

44
Q

What drugs have been shown to be safe at therapeutic doses in patients with MDR1 mutation?

A

• Safe at therapeutic doses: antiparasitic -moxidectin and selamectin

45
Q

What drugs have not been involved in a study yet for dogs with MDR1 mutations?

A

• No clinical studies yet in dogs for following medications
◦ Gastric secretory inhibitors : pepcid, cimetidine
◦ antiemetics: metaclopromide
◦ antibiotics: doxycycline, levofloxacin
◦ antifungals: ketoconazole, itraconazole
◦ Glucocorticoids: Dexmethasone, prednisolone
◦ Anticonvulsants: Phenobarbitol, keppra

46
Q

What is the volume of distribution?

A

Vd is the volume to which a drug would have to be distributed if it were throughout the body in the same concentration as that measured in the plasma after IV administration of a known dose

47
Q

What is the equation of volume of distribution of a drug?

A

VD= Dose(mg) / plasma drug concentration (mg/ml)

48
Q

If you want the concentration of beaker A to be 5% ( 50 mg/mL), then the volume of water in the beaker
must be ____ when combining it with 5 g of dextrose?

A

Vd= 100 ml

49
Q

f you want the concentration of beaker A to be 2.5% ( 25 mg/mL), then the volume of water in the beaker
must be ____ when combining it with 5 g of dextrose?

A

Vd= 200 ml

50
Q

What can dramatically affect plasma drug concentration?

A

Vd differences among species and ages can dramatically affect PDC

51
Q

What is the general trend in found between Plasma Drug Concentration and Volume of Diffusion=?

A

The PDC (and response to a drug) at a known dose varies inversely with Vd

52
Q

What diseases are likely to increase the volume of distribution, and lower the plasma drug concentration?

A

Diseases associated with fluid retention or obesity are likely to increase the Vd of many drugs (and thus decrease PDC)

53
Q

What diseases are likely to decrease the volume of distribution, and increase the plasma drug concentration?

A

Dehydration or weight loss is likely to decrease Vd and thus increase PDC

54
Q

What is one way which you can determine the compartment to which the drug is distributed to? ***

A

The size of the apparent Vd may indicate the body compartment to which the drug is distributed

55
Q

Finish this sentence:
Any factor that increases Vd will tend to decrease PDC but ____ the elimination ____ ____ and thus _____ the presence of drug in the body

A

Any factor that increases Vd will tend to decrease PDC but prolong the elimination half-life and thus increase the presence of drug in the body

56
Q

What is drug redistribution?

A

The phenomenon of redistribution involves the rapid distribution of drugs to a high-blood-flow organs such as the brain followed by rapid redistribution to lean tissues and then to fatty tissues

Redistribution = Brain -> Muscle/ lean tissue -> Fat

57
Q

What are the characteristics of drugs that show the redistribution effect?

A

They are:
- Highly lipid soluble
- Relevant only for drugs that an immediate effect could be realized ( ex: general anesthetics)

58
Q

What drugs are common to go under redistribution?

A

Thiobarbituates and propofol

59
Q

Why do sighthounds have prolonged recovery from thiobarbituates and propofol?

A

When it comes to the redistribution effect, a bolus of these drugs would first go into the central blood pool, to high flow blood organs like the brain. The drug effect will then rapidly terminate, because the drug is redistributed to the lean tissue (muscle) then to fat ( where these lipid soluble drugs need to go for the patient to recover from anesthesia and be broken down). Since sighthounds have very low body fat percentages (higher ratio of lean muscle mass to total body fat), these drugs will result in prolonged recovery since there is little fat reserves for the drug to go into.

Introduction To Pharmacology I (26 decks)

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