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Drug Delivery > Integration > Flashcards

Integration Flashcards

1
Q

What does the GI transit of dosage form depend on? [3]

A
  1. gut motility
  2. type and timing of food ingestion
  3. type of formulation administered (liquid, single-unit, multiple-unit).
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2
Q

Describe gastric motility in the fasted state. [3]

A
  1. Controlled by migrating myoelectric complex (MMC)
  2. Cycle which repeats every 1.5-2 hours.
  3. Housekeeper waves where indigestible solids (large tablets) are removed from the stomach. .
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3
Q

Describe gastric motility in the fed state.

A

Peristaltic contractions mix and mill food and there is controlled passage of chyme to the duodenum. .

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4
Q

What relation is there between calorific content and gastric emptying?

A

Inverse. Low calorie meals are removed faster. .

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5
Q

What does gastric emptying of dosage form depend on? [4]

A
  1. Density, shape and size of dosage form.
  2. Co-admin of other drugs.
  3. biological factors: age, gender, sleep, BMI, disease.
  4. Ingestion and timing of food intake, calorific content. .
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6
Q

What are some expected behaviours of gastric emptying and dosage forms? [5]

A
  1. Liquid formulations = faster emptying.
  2. Larger the dosage form = longer it is retained in the stomach.
  3. Tablets and large units are retained in the stomach until the housekeeper wave.
  4. The higher the calorific content of a meal the longer the gastric emptying time will be.
  5. Administration prior to food can shorten gastric emptying..
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7
Q

Where in the intestine is absorption efficiency the highest?

A

The duodenum then the ileum then the colon. Bacteria can affect drug release and absorption both positively and negatively..

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8
Q

Roughly how long is small intestine transit time?

A

~3-4 hr for all dosage forms but with high inter- and intra-variability..

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9
Q

Why is there high variability with regards to intestinal transport time? [4]

A
  1. Enzymes, pancreatic and bile secretions vary.
  2. Water content and pH varies.
  3. Transporters vary (p-gp etc.)
  4. Mobility can be modified due to disease and drugs..
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10
Q

Where can single and multiple unit dosage forms accumulate in the intestine?

A

Ileo-caecal junction. .

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11
Q

What dosage forms suffer less from inter- and intra-patient variability in terms of GI transit?

A

Multiple unit dosage forms. They also have less risk of dose dumping. .

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12
Q

For which types of drugs is formulation into an extended release product most difficult?

A

Drugs that are poorly absorbed and/or have a small absorption window are difficult to formulate into ER products..

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13
Q

What types of drug may have a very limited/narrow absorption window?

A

Those that are absorbed via transporters. The regional distribution of transporters determines the maximum time available for extended release. (BCS Class III).

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14
Q

What effect does Erythromycin have on gastric and duodenal motility?

A

It increases it. .

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15
Q

For a drug that has optimal/only soluble between pH 5-6, where in the intestine will absorption take place?

A

pH 5-6: Duodenum
pH 7-8: Ileum
pH 5.5-7 Colon

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16
Q

What type of drug has high solubility and high permeability?

A

BCS Class 1

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17
Q

What type of drug has low solubility and high permeability?

A

BSC Class 2

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18
Q

What type of drug has high solubility and low permeability?

A

BSC Class 3

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19
Q

What type of drug has low solubility and low permeability?

A

BSC Class 4.

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20
Q

What are primary PK parameters directly related to?

A

Physiological variables like the volume of distribution (V) and clearance of a drug (Cl).

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21
Q

What do secondary PK parameters such as half-life and elimination rate depend on?

A

The primary ones. Half-life and elimination rate constant depend on Cl and V.

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22
Q

What does the AUC depend on? [3]

A

Cl, F and dose.

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23
Q

What does Css depend on? [4]

A

Cl, F, dose, interval of administration (tau)

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24
Q

What is clearance?

A

The proportionality factor relating elimination rate to drug concentration. Rate of elimination = Cl x Cdrug.

It is the volume of fluid that is completely cleared of drug per unit time; units = volume/time.

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25
Q

How does the rate in relate to the rate out?

A

Rate in [(F x dose)/time] = rate out (Cl x Css)

26
Q

How does clearance relate to volume of distribution and the elimination rate constant?

A

Cl = V*K

27
Q

How does the elimination rate relate to the clearance and drug concentration?

A

elimination rate = Cl*C

28
Q

What does Cl H measure?

A

Hepatic clearance. The loss of drug across the liver. The volume of blood entering the liver from which all drug is removed per unit time.

29
Q

What is EH?

A

EH = hepatic extraction ratio, the efficiency of hepatic elimination of a drug.

30
Q

If Cl H = 60L/h and QH = 90L/h what is the EH?

A

60L/h of drug is cleared from a total of 90L/h. 60/90 = 2/3 = 0.67.
So the EH = 0.67.

31
Q

What does a EH of 0 represent?

A

No drug elimination takes place via the hepatic route.

32
Q

What does an EH of 1 represent?

A

100% of the drug entering the liver is eliminated.

33
Q

How do Cl H and EH relate?

A

Cl H = QH*EH
Hepatic clearance of drug = rate of drug presentation to liver (blood flow QH) * The efficiency of drug removal by the liver (EH).

34
Q

What is the hepatic clearance of a drug with EH = 0.7, liver blood flow of 1350mL/min and Drug concentration entering the liver of 2mg/L?

A

Cl H = QH * EH.
Cl H = 1.35L/min * 0.7.
Cl H = 0.945L/min
Cl H = 56.7 L/h

35
Q

What is the hepatic elimination rate of a drug with Cl H = 56.7L/h and C = 2mg/L?

A

Elimination rate = Cl H * C.
Elimination rate = 56.7L/h * 2mg/L
Elimination rate = 113.4mg/h.

36
Q

What does the clearance of high extraction ratio depend on?

A

The blood supplying more drug, i,e. perfusion rate-limited.

37
Q

For drugs with high extraction ratio, Cl H is very sensitive to what?

A

Changes in blood flow, particularly to the liver. Relatively insensitive to changes in plasma binding and metabolic activity.

38
Q

For drugs with low extraction ratio, Cl H is very sensitive to what?

A

Changes in plasma binding and metabolic activity but insensitive to changes in blood flow.

39
Q

Hepatic clearance of a drug depends on: [2]

A 
Blood flow QH.
Free fraction (alpha) of drug as only the unbound molecules can diffuse into hepatocytes where metabolism occurs.
40
Q

What does Cl int measure?

A

Cl int = intrinsic ability of liver to eliminate drug.

Depends upon amount of enzyme present and on the affinity of a drug for enzyme.

41
Q

Drug A increases synthesis rate of enzyme involved in metabolism of drug B. Therefore Drug A increases Cl int of drug B. Is this clinically relevant?

A

Depends on if Drug B has a low or a high extraction ratio and upon the route of administration.
The induction of the metabolism of a drug with a high hepatic extraction ratio will have therapeutic implications when the drug is given orally, but not when it is given intravenously.

42
Q

The induction of the metabolism of a drug with a high hepatic extraction ratio will have therapeutic implications only when?

A

Only when it is given orally and is subject to 1st pass. When given IV not.

43
Q

For a high extraction ratio drug how does QH relate to alpha-blood and Cl int?

A

QH

44
Q

For a low extraction ratio drug how does QH relate to alpha-blood and Cl int?

A

QH&raquo_space; (alpha-blood * Cl int).
The hepatic blood flow is greater than the value of the free fraction of drug in blood * the intrinsic ability of the liver to clear this drug.

45
Q

How does FH, the maximum oral bioavailability, relate to: QH, alpha-blood and Cl int for high extraction ratio drugs?

A

When EH ~ 1: QH

46
Q

How does FH, the maximum oral bioavailability, relate to: QH, alpha-blood and Cl int for low extraction ratio drugs?

A

When EH is low: (alpha-blood*Cl int)&raquo_space; QH. Then:

FH = (QH/QH) ~1.

47
Q

In patients who develop cirrhosis, what is the effect on low extraction ratio drugs?

A

The clearance will be lower, the half-life will increase but the Oral F is unaffected

48
Q

In patients who develop cirrhosis, what is the effect on high extraction ratio drugs?

A

If IV: no change.

If Oral: large increase in F and hence AUC.

49
Q

In theory, changes in organ blood flow only affects clearance of which drugs?

A

Those with a high extraction ratio that are perfusion-rate limited.

50
Q

If a drug has a low EH what effect do changes in hepatic blood flow have?

A

Little to none on the PK of a poorly cleared drug.

51
Q

If a drug has a high EH what effect do changes in hepatic blood flow have?

A

Decreased blood flow:
Reduced Cl H.
Reduced F.
AUC may increase, decrease or not change.

52
Q

When does a drug undergo restrictive clearance?

A

When its extraction ratio is less than or equal to its unbound fraction in the blood.
E

53
Q

Extraction for a drug that undergoes restrictive clearance is limited by:

A

Protein binding and changes with alpha.

54
Q

When does a drug undergo non-restrictive clearance?

A

When its extraction ratio/efficiency is greater than its unbound fraction in blood:
E > alpha - blood. Binding will not protect the drug from elimination and extraction is not modified by alpha.

55
Q

For a drug which has restrictive clearance and a low hepatic extraction ratio, what occurs with changes to alpha?

A

Changes to alpha will result in modified clearance.

56
Q

Decreased hepatic activity has what effect on the clearance of low EH drugs?

A

Reduces the clearance.

Increase the half-life and AUC.

57
Q

Decreased hepatic activity has what effect on the clearance of high EH drugs?

A

High or low. Increases F.

58
Q

A patient has received simultaneous administration of drug D and drug E, which is known to displace drug D from its plasma protein binding sites. Renal excretion of drug D is 0.97.

What are the expected modifications in the renal and hepatic clearances of drug D? and the total clearance?

A

No effects on Cl-renal.
Increased Cl-hepatic.
As renal clearance represents 97% of total clearance, no significant changes in clearance are expected.

Given as IV so level of Cl-hepatic is not that important anyway?

59
Q

For a drug with a hepatic blood clearance of 1.2 L/min and an
unbound fraction of 0.2. Which of the following is true/false?
A.1. An increase in the unbound fraction will increase hepatic clearance
A.2. An enzyme inducer will significantly increase hepatic clearance
A.3. An enzyme inducer will decrease AUC after an oral dose
A.4. Congestive heart failure may increase the steady-state plasma
concentrations achieved with an intravenous infusion

A

(1.2 / 1.5 L/min (total hepatic blood flow is 90L/h, thats where 1.5L/min comes from) = 0.8) → High EH
so the model predicts: A.1. An increase in the unbound fraction will increase hepatic clearance = False, An enzyme inducer will significantly increase hepatic clearance = False, An enzyme inducer will decrease AUC after an oral dose = True,
Congestive heart failure may increase the steady-state plasma = True.

60
Q

For a drug with a hepatic blood clearance of 60 mL/min and an
unbound fraction of 0.1. Which of the following is true/false?
B.1. An increase in the unbound fraction will decrease AUC
B.2. Enzyme inhibitors will decrease hepatic clearance
B.3. Increased blood flow will decrease AUC from an oral dose
B.4. Enzyme induction will decrease AUC after oral dosing

A

(0.06/1.5L/min = 0.04) –> Low EH, so the model predicts:
B.1. An increase in the unbound fraction will decrease AUC = True
B.2. Enzyme inhibitors will decrease hepatic clearance = True
B.3. Increased blood flow will decrease AUC from an oral dose = False
B.4. Enzyme induction will decrease AUC after oral dosing = True

Drug Delivery (11 decks)

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