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GI > Drug Absorption > Flashcards

Drug Absorption Flashcards

1
Q

Epithelium layers

A

Simple epithelium = a single layer

Stratified = multiple cell layers

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2
Q

Trascellular pathway

A

Soluble drug passes through the apical membrane through epithelium, into the basement membrane and blood supply

Trans = across

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3
Q

Paracellular pathway

A

Soluble drug passes through apical membrane through a cell-cell junction, passes between two epithelial cells to reach the basement membrane and blood supply

Para = alongside

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4
Q

Common route of absorption

A

Most common route of absorption is via tight junctions that act as pathways for hydrophilic molecules
Paracellular pathways are minor

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5
Q

Paracellular pathway: tight junctions

A

Neighbouring cell membranes fused by intimate connections between cell surface proteins, forming a band around the entire cell (rate limiting)
Allows passage of small, hydrophilic molecules

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6
Q

Paracellular pathway: adherents junctions

A

Connect actin filaments in the cytoskeletons of neighbouring cells

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7
Q

Paracellular pathway: desmosomes

A

Most common

Fibrous proteins cross the gap between cells and anchor keratin filaments in cytoskeletons together

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8
Q

Paracellular pathway: gap junctions

A

Intracellular, hydrophilic pores
Membranes close together but not fused
Allows small molecules like acids, sugars, nucleotides and vitamins to pass directly between neighbouring cells
Enables direct cell to cell electrical conductivity

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9
Q

Transcellular pathway: passive diffusion

A

Diluted diffuse into cells down a concentration gradient - must partition into the lipid bilayer and out again into cytoplasm
An aqueous pore is a continuous, hydrophilic channel created by transmembrane aquaporin protein, some allow transport of small, neutral solutes like urea and glycerol

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10
Q

Facilitated diffusion

A

Selective
Carrier mediated
Down a concentration gradient

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11
Q

Active transport

A

Selective
Carrier mediated
Against a concentration gradient and requires energy

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12
Q

Minor pathway: endocytosis

A

Internalisation of plasma membrane which engulfs extracellular fluid
Pinocytosis = fluid engulfed
Phagocytosis = monocytes/macrophages engulfed particles
Resulting endosome may fuse with lysosomes and the contents are degraded by lysosomal enzymes
The drug may escape lysosomal degradation and be released through basolateral membrane
Harmful pathogens are taken up by the lung due to endocytosis

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13
Q

Passive diffusion pathway

A

When a system is not in equilibrium so flux occurs

Flux = conc x velocity x area

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14
Q

To improve diffusion

A

Only viscosity and particle radius can be manipulated to improve diffusion

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15
Q

Fick’s law

A

Flux = area x diffusivity x partition coefficient x change in conc gradient
————————————————-
Membrane thickness

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16
Q

Partition coefficient

A 
Usually expressed as log P
P= C oil
     ———
     C water
Oil/water partition coefficient
Lipid soluble drugs= P>1 (logP>0)
Water soluble drugs = P<1 (logP<0)
Equally distributed drugs P=1 (logP=0)

Most drugs have log P between 0 and 5

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17
Q

Log P values and absorption

A

LogP<0 very soluble, poor partitioning
Log P>5 poorly soluble, partitioning too good, sensitive to metabolism

Optimum range for oral delivery is between 0 and 3

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18
Q

Acidic/basic drugs

A

Most drugs are weak acids or bases so exist in solution in equilibrium of un-ionised and ionised forms, depending on the pH of the environment and the pka of the drug

AH + H2O A- + H30+
B + H20 BH+ + OH-

AH and B is unionised drug (lipophilic) and is optimal for transport
A- and BH+ is the ionised form of the drug (hydrophilic) and has reduced transport

The drug accumulated on the side of the membrane where pH favours ionisation (called pH partition hypothesis)

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19
Q

Henderson Hasselbalch equation

A

Acids : pH = pka + log10 [A-]
——
[AH]
Bases : pH = pka + log10 [B]
———
[BH+]

Unionised is absorbable
Ionised is unabsorbable

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20
Q

pH partition hypothesis

A

Does not consider:
Type of epithelium
Surface area of absorption
Ionised drugs absorbed to a small extent
Active transport of drugs
Time of drug at delivery site
Mass transfer of fluids
Charged drugs forming ion pairs with oppositely charged species
Pairing ions increased lipophilicity of drugs - preferably pairing with ions that have fatty acid chains
Any hydrogen bonds have to be broken before the drug can enter the lipophilic plasma membrane
% oral absorption decreases as the number of hydrogen acceptors in a molecule increases

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21
Q

Components of the GI tract

A

Oesophagus
Stomach
Small intestine
Colon

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22
Q

Role of HCl

A

Ingestion of food stimulates secretion of HCl and pepsinogen from mucosal lining
HCl is antiseptic and promotes conversion of pepsinogen to pepsin
Pepsin degrades polypeptides and short peptides pass through the stomach unaffected

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23
Q

Role of duodenum

A

The acid contents of the stomach are neutralised by bicarbonate secretions which enable optimum enzymatic digestion of food
Bile duct delivers secretions from the pancreas here
Majority of absorption occurs in the jejunum while ileum absorbs remaining nutrients (particularly fats)
Villi have lymph and blood system connections

24
Q

Role of the colon

A

Reduced surface area and no villi
Contains aerobic and anaerobic bacteria that may metabolise drugs
Some drugs can be absorbed here if they survive bacteria
Absorption slower due to viscous contents

25
Q

Absorption of acids and bases

A

Strongly acidic/basic drugs are poorly absorbed

Basic drugs dissolve easily in the stomach

26
Q

pH of GI tract

A 
Stomach: 1.3-3.5
Duodenum: 5.0-7.0
Jejunum: 6.0-7.0
Ileum: 6.0-7.5
Colon: 5.5-7.0
Rectum: 7.0
27
Q

Peristalsis

A

Muscular movements of GI tract propel food and drink through the intestines
Mix contents of intestines with digestive juices
Preparing unabsorbed material for excretion

28
Q

Optimal drug absorption

A

Sufficient residence time at absorption site
Drug not absorbed if movement too fast
If too slow, no pharmacological effect and drug may be degraded and epithelium becomes irritated

29
Q

Patterns of GI motility: interdigested

Also digested state (fed)

A

Interdigestive (fasted) state
Has alternating cycles of activity called migrating motors complex
Each cycle lasting 90-120 mins and has 3 phases
1. Quiescence (30-60mins and no bike production)
2. Irregular contractions (20-40mins and some bile production)
3. Housekeeper waves (10-20mins with mucus production)

30
Q

Digestive contractions per min

A

4-5
Mix contents and pass them down the tract
Length depends on type of meal

31
Q

Gastric emptying

A

Stomach gradually releases contents into small intestine (zero order)
Larger meals mean quicker emptying rate initially
Fatty acids in food reduce emptying rate (proportional to conc and fatty acid chain length)
Triglycerides, carbohydrates and amino acids reduce emptying rate (conc dependent due to osmotic pressure)

32
Q

Emptying rate

A

Acids reduce emptying rate
Alkalis increase rate at low conc and decrease rate at high conc
Narcotics, AChs and ethanol reduce emptying rate
Laying on left side reduced emptying rate as pyloric sphincter is on the left side so body works against gravity to pump the drug through
Emptying rate reduced by ulcers

33
Q

Enzymes in duodenum

A

Trypsin
Chymotrypsin
Elastase
Charboxypeptidases

34
Q

Enzymes in small intestine

A

CYP expression

Esterases and glucuronosyl transferases

35
Q

Role of bike

A

Facilitated excretion of endogenous compounds

AIDS digestion’s of fat-soluble vitamins

36
Q

Food can potentially alter drugs due to

A 
Delayed gastric emptying
Stimulation of bile secretion (increased solubilisation and absorption of lipophilic drugs)
Increased viscosity of luminal contents
Stimulation of hepatic blood flow
pH changes in GI tract
Physical or chemical interaction
Competition for uptake transporters

Largest effect with e/c tabs and reduced effect with well dispersed dosage forms

37
Q

Efflux pumps

A

Important P-glycoprotein found in apical membrane of small and large intestine (also liver, kidney, pancreas, BBB, cancer cells)

Multi drug resistance protein is also an efflux pump, substrates are mostly lipophilic or cationic
P-gp localised with CYP3A on apical membrane, enhancing metabolism

38
Q

Mucus in GI tract

A

Covers the length of the GI tract
Secreted by submucosal glands and goblet cells
Protective barrier to some drugs

39
Q

Advantages of oral drugs

A 
Convenient
Accessible
Good compliance
Large surface area
Rich blood supply
Prolonged retention
Zero order release
Cheap
40
Q

Oral drug disadvantages

A

Variable
Adverse reactions
High metabolic activity and hepatic first pass effect
pH extremes
Efflux pumps
Intestinal motility
Impermeability of epithelium (esp to large, hydrophilic peptides)

41
Q

Improve oral deliver by

A

Increasing drug lipophilicity (prodrugs)
P-gp inhibitors
Cytoadhesion
Mucoadhesive patches

42
Q

P-gp inhibitor in chemo

A

Prevent chemotherapeutic drugs entering cancerous cells and can prevent oral delivery
Co-administration of chemo and p-gp inhibitors prevents drug efflux from endothelial cells and increased oral bioavailability

43
Q

P-gp inhibitors

A

Also inhibit CYP3A4 which causes reduced drug clearance
Third gen p-gp are specific for the transporter and are clinically effective
Yeah

44
Q

what is the buccal lining

A

inside cheeks

45
Q

what is sub-lingual

A

mucosa under the tongue

46
Q

what is the gingeval

A

mucosa around the gums

47
Q

what is labial

A

lips

48
Q

what is platal

A

roof of mouth

49
Q

what epithelium is the oral mucosa

A

stratified squamous epithelium

50
Q

layers of oral mucosa

A

epithelium, basement membrane, lamina propria (rich in collagen), sub mucosa

51
Q

what are membrane-coating granules

A

lipid deposits between cells

52
Q

non-keratinised oral structures

A

buccal and sublingual

good permeability, so often targeted for drug delivery

53
Q

keratinised oral structures

A

gingeval
palatal
keratin layer protects from mechanical activity in the mouth

54
Q

enzymes in saliva

A

aminopeptidases, carboxypeptidases, esterases, carbohydrases, lysosomes

55
Q

what is residence time

A

the time a dosage form spends at the target site of delivery

sustained residence time gives prolonged drug effect

GI (21 decks)

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