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Medicines design II - solid dosage forms > From Practice Q > Flashcards

From Practice Q Flashcards

0
Q

Pgp increases…

A

As you go down the GI

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1
Q

Bacteria in the…. May degrade drug

A

Colon

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2
Q

Colon or small intestine have larger s a?

A

Small intesting

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3
Q

Stokes einetine equation

A

Diffusivity = Kb T / 6pi viscosity radius

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4
Q

Contents of the colon or small intest are more viscous?

A

Colon (also has smaller s a)

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5
Q

5 ways to improve/target absorption

A
  1. Increasing drug lipohilicity – use of prodrugs.
  2. P-glycoprotein inhibitors.
  3. Cytoadhesion – targeting drugs to specific areas or cells in the GI tract.
  4. Mucoadhesive patches.
  5. New delivery systems (e.g. protective coatings, micro- and nanoparticles
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6
Q

Prodrug example

A

Bacampicillin lipophilic and inactive, easily crosses membrane, cleaved by endogenous esterases to ampicillin (the active)
BA improved from 30-50 up to 80%

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7
Q

Other ways to alter lippohicity to increase absorptions

A

Pro drugs
lipidization (attaching lipids to the drug)
penetration enhancers (essentially partially solubilising the epithelial membrane to increase absorption).

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8
Q

Eg of PGPi

A

topotecan with the P-gp inhibitor elacridar increased oral bioavailabilty in humans from ~40 % to 97 %
(Some also inhibit CYP3A4 to reduce Cl)

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9
Q

Eg mucoadhesives

A

Insulin in mucoadhesive polymer, covered with insoluble coating - protects and directs diffusion to membrane. Improves residence time.

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10
Q

Disadvantages of oral7

A

variable people/pH extremes /motility

Adverse reactions – e.g. gastro-toxicity

High metabolic activity and hepatic first-pass  
Efflux pumps (P-gp)

Impermeability of epithelium(esp large, hydrophobic peptides)

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11
Q

Advantages or oral 4

A

Convenient, accessible, good compliance
Large surface area and rich blood supply
Prolonged retention and potential for zero-order release
Cheap

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12
Q

Situations where rectal is good

A
  • Unconscious patients
  • Children
  • Patients that are nauseous or vomiting
  • Patients with upper GI tract disease
  • Drugs with an objectionable taste
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13
Q

Advantages of rectal

A

Sustained release possible
Highly vascularised end
Possibility of avoiding hepatic first-pass (eg lidocaine)

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14
Q

Disadvantage of rectal

A

Metabolism of some drugs by bacteria
people don’t like it
• Complicated by anastomoses

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15
Q

Absorotion pathways and their prevalence

A

1.Major: transcellular -mainly passive diffusion
(also aqueous pore, endocytosis, facilitated diffusion, active transport)

2.Minor: paracellular

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16
Q

Para cellular is restricted to …. And is minor except…

A 
minor pathway (except transdermal), 
restricted to small, hydrophilic molecules. < 1000 DA
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17
Q

Types of barriers to cross paracellularly? And with is rate limiting

A
  1. Tight junctions - rate lim - fused cells
  2. Adherence - actin joins cytoskeleton
  3. Desmosomes - fibrous + common
  4. Gap juntions - hydrophilic pore
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18
Q

Lipid bilayer is hydrophilic or hydrophobic?

Prevents passage of…?

A

hydrophobic nature

prevents the passage of most polar and charged (i.e. water-soluble) molecules

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19
Q

Compare facilitated and active diffusion

A

Both selective and carrier medicated
Facilitated- down concentration grad
Active - down or against, requires energy (eg l dopa)

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20
Q

Area ups pores allow passage of

A

Made from aquaporin proteins - allow passage of Some Hydrophilic / neutral solute like urea

21
Q

Endocytosis … Define

A

Internalisation of plasma membrane engulfing extracellular fluid to form lysosome - drug may be degraded or escape

22
Q

Two type of endocytotic

And one example

A

Eg polio vaccine
Pinocytosis - drinking
Phagocytosis - only relevant for advance drug delivery

23
Q

Logs p that are good or bad partitioning

A

Log P < 3 = poor partitioning

Log P > 5-6 = Partitioning too good

24
Q

Oh partition hypothesis

A

Drugs accumulate on the side where pH favours ionisation

This is because optimal membrane transport is achieved when unionised.

25
Q

Limitations of pH hypothesis7

A

Type of epithelium
•Surface area of the absorption site
•Ionized drugs will be absorbed to a small extent
•Active transport of drugs
•Residence time of drug at delivery site
•Mass transfer of fluids
•Charged drugs may form ion pairs with oppositely charged species

26
Q

How to count h bond donors and acceptors

A

Number of hydrogen bond acceptors = N + O

Number of hydrogen bond donors = OH + NH

27
Q

Effect of h bonds on absorption

A

Hydrogen bonds must be broken before the drug can enter the lipophilic plasma membrane.

28
Q

Eg of h bonds affecting abosorption

A

Licomycin BA 30%

Clindamycin BA 90% (has Cl instead of oh)

29
Q

What pKas are poorly absorbed

A

Strong acids (pKa < 3) and strong bases (pKa > 10) are poorly absorbed

30
Q

Consequences of residence time

A

If movement through the GI tract is too fast, the drug will pass through the system

without being absorbed.

If movement through the GI tract is too slow, the onset of pharmacological effect

will be retarded, the drug may be degraded or the epithelium may be irritated.

31
Q

Meal volume effecting emptying rate

A

the larger the meal, the quicker the initial emptying rate

32
Q

Content of meal effect emptying rate

A

fatty acids reduce emptying rate, proportional to concentration and chain length (most influence when carbons = 10 or more).
– triglycerides reduce emptying rate; unsaturated more so than saturated
– carbohydrates and amino acids

33
Q

Things that reduce emptying rate

A

Physical state of contents: solutions or suspensions of small particles empty quicker than chunks of material.
Chemicals: acids reduce emptying rate (conc.-dependent) while alkalis increase emptying rate at low (1 %) concentrations and decrease it at higher (5 %) concentrations.
Drugs: anticholinergics, narcotics and ethanol reduce emptying rate.
Body position: lying on the left side reduces emptying rate.
Disease: emptying rate reduced by the presence of ulcers and in some diabetics.
Exercise: vigorous exercise reduces emptying rate

34
Q

How does retention in the stomach vary with large or small forms

A

Solution - exists progressively and rapidly

Solid - must wait for housekeeper waves - lag time

35
Q

What might degrade stuff in the stomach

A

HCL pepsin

36
Q

What might degrade stuff in the duodemum

A

Carboxylpeptidases a and b
Trypsin
Elastase
Chymotrypsin

37
Q

What might degrade stuff in the small I

A

CYP mainly 3A4

Esterases and glucuronosyl transferases

38
Q

What might degrade stuff in the colon

A

Gut flora

39
Q

Four most common liver metabolises and two results

A

oxidation, reduction, hydrolysis and conjugation.

More polar and less active

40
Q

Eg of massive first pass effect

A

Haloperidol 50 % loss

Dose adjust if given by IM

41
Q

Amount of drug reaching circulation depends on three main things

A
  • its release from the dosage form,
  • stomach, intestinal and hepatic 1st-pass effects
  • its absorption across the GI membrane
42
Q

Enterohepatic recycling

A

Drugs eliminated into biliary secretion may be absorbed again into systemic circulation

43
Q

How can food affect absorption

A

–Delayed gastric emptying – damaging to proteins or acid labile drugs
–Stimulation of bile secretion – increased solubilization and absorption of lipophilic drugs e.g. griseofulvin
–Increased viscosity of luminal contents
–Stimulation of hepatic blood flow – effects on first-pass metabolism
–pH changes in the GI tract – decreased pH may aid dissolution of basic drugs
–Changes in luminal metabolism
–Physical or chemical interaction of the drug with food – a drug may bind to components of a meal and form a non-absorbable complex, e.g. tetracyclines interact with divalent cations.
–Competition for uptake transporters, e.g. L-dopa

44
Q

Eg of food effects on a drug

A

Lapatinib – breast cancer drug. Food ↑ bioavailability by 167 % Fatty meal ↑ bioavailability by 325 %

45
Q

Two examples of food metabolism interactions

A

Cruciferous vegetables: Induce the CYP1A enzymes, glutathione-S-transferase & quinone oxidoreductase.
Grapefruit juice: inhibits CYP3A, increasing bioavailability of estradiol, felodipine and cyclosporin. Statins and muscle toxicity

46
Q

Endogenous purpose of efflux pumps

A

Protection mechanism - transports substrates out of cells

Affects drug uptake eg cancer chemo

47
Q

Pgp substrates are usually…

Eg…

A

Substrates are mainly lipophilic or cationic – anthracyclines, cyclosporin, celiprolol.
•Taxol, anti-microtubule drug, was not absorbed orally in pre-clinical trials – flux from basolateral side of the membrane back into the lumen was 4-10 times greater than diffusion into the intestinal epithelium

48
Q

Where is pgp found?

A

170kda found in apical membrane of small intestine - co localised with CYP 3am enhancing metabolism

49
Q

How is mucus a problem

A

Eg warfarin absorption

Predominately neg charge and a barrier to diffusion

50
Q

Eg of physical state affecting absorption

A

Leaky epithelia in infants

Men have higher levels of HCL secretion and CYP enzymes

Medicines design II - solid dosage forms (11 decks)

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