L30/1 - physiological factors affecting drug absorption after oral administration Flashcards

1
Q

parameters that effect GI absorption of drugs

A
  • anatomy/histology
  • physiology
  • pathology
  • drug interactions
  • food (fed vs fasting)
  • GI transit
  • metabolism within GI
  • first pass effect in liver
  • enterohepatic recycling
  • active secretion
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2
Q

what is the therapeutic window?

A

area of concentration you need to be in for efficacy of the drug. most drugs have wide window (e.g 1 paracetamol treats us)

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3
Q

gastric transit & drug absorption

A
  1. stomach grinds food and breaks it up by chemical decomposition
  2. gastric fluid is an acid containing pepsin: which can degrade drugs
  3. drug absorption across stomach wall does not contribute much to oral absorption of drugs (drugs mostly absorbed in SI)
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4
Q

issue with gastric fluid

A
  • some drugs are degraded by acidic conditions in stomach
  • so gastro resistant dosage forms that do not release drug in acidic environment have been made
  • polypeptides are completely degraded by pepsin
  • so oral route of administration impossible and alternative found (e.g insulin administered by injection)
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5
Q

GI tract motility: gastric emptying

A

stomach gradually releases its contents into SI

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6
Q

factors affecting gastric emptying and therefore drug absorption

A
  1. meal volume: bigger meal = quicker initial emptying rate
  2. type of meal
  3. physical state of contents
  4. chemicals
  5. drugs
  6. body position
  7. disease
  8. exercise
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7
Q

how does the type of meal affect gastric emptying?

A
  1. fatty acid reduces emptying rate (more carbons on chain = more reduce)
  2. triglycerides reduce emptying rate (occurs in unsaturated more)
  3. carbs and a.a reduce emptying rate (concentration dependent matter/ osmotic pressure)
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8
Q

how does the physical state of contents affect gastric emptying?

A

solutions or suspensions of small particles empty quicker than chunks of material

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9
Q

how do chemicals affect gastric emptying?

A
  • acids reduce
  • alkalis increase
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10
Q

how do drugs affect gastric emptying?

A

anticholinergics, narcotics, ethanol reduce emptying rate

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11
Q

how does body position affect gastric emptying?

A

lying on left side reduces emptying rate

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12
Q

how does disease effect gastric emptying?

A

ulcers reduce emptying rate

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13
Q

how does excursive affect gastric emptying?

A

vigorous exercise reduces emptying rate

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14
Q

describe gastric transit and drug absorption when a drug is rapidly released from dosage form into gastric fluid

A
  • drug in solution in stomach
  • in fasting subject, the drug leaves stomach rapidly via pylorus
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15
Q

describe gastric transit and drug absorption when there is a gastro resistant dosage form

A
  • it cannot pass pylorus
  • only particles of few mm diameter exit
  • need to wait for HOUSE KEEPER WAVE: strong contraction
  • lag time (as nothing has been dissolved) between the moment at which the drug is taken and its arrival at its absorption site
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16
Q

intestinal transit and drug absorption

A
  • microvilli of intestinal mucous membrane increase SA
  • pH of intestinal fluid is neutral / kinda alkaline
  • SI is where most drugs absorbed
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17
Q

what is the rate of absorption in the SI affected by?

A
  1. rate of disaggregation and dissolution
  2. GI transit
  3. transport across GI memb
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18
Q

class 1 drug

A

highly soluble, highly permeable: easiest to work with

19
Q

class 2 drug

A

poorly soluble, highly permeable: sol can be increased by excipients, changing packet size of drug

20
Q

class 3 drug

A

highly soluble, poorly permeable

21
Q

class 4 drug

A

poorly soluble, poorly permeable: hardest to work with

22
Q

how to improve membrane permeability

A

change drugs structure: pro drugs

23
Q

what is ampicillin?

A
  • antibiotic with poor oral bioavailability (poor permeability)
  • bacampicillin is ester of this
  • phyiscochemical properties of bacampicllina low easier passage across intestinal barrier
24
Q

how does the stomach degrade and metabolise?

A
  1. HCL: degrades some drugs, but gastro resistant coatings used to protect drug + delay release
  2. pepsin: destroys polypeptides (small peptides survive)
25
Q

how does the duodenum degrade and metabolise?

A
  1. Trypsin & elastase (acidic) and chymotrypsin and carboxypeptidase A & B found in lumen
  2. degrade large proteins to small peptides
  3. small peptides stable
26
Q

how does the small intestine degrade + metabolise?

A
  • high expression of cytochrome P450 enzymes (acidic) in intestinal epithelial cells
  • highest conc in villus tips of intestine
  • esterases (alkali) and glucuronosyl transferases (acidic): transfer glucoronic acid to nucleophillic sites on drugs
27
Q

how does the colon degrade + metabolise?

A
  • metabolic activity decreases from duodenum to colon
  • absorption stays good
  • gut flora can metabolise + inactive drugs (acidic)
28
Q

hepatic first pass effect

A
  • after passage across intestinal membrane drug is transported to liver via portal vein
  • during first passage through liver a fraction of drug absorbed is turned into metabolite so drug is lost
  • this can be active or inactive
  • if it is active metabolite there is no loss in bioavailability
29
Q

what happens if the metabolite produced in the hepatic first pass effect is inactive?

A

net loss of drug which reach systematic circulation

30
Q

what does bile do?

A

helps excretion of endogenous and exogenous compounds and aids digestion of fate and fat soluble vitamins. some drugs excreted through bike/

31
Q

enterohepatic recycling

A
  • some drugs eliminated in part by biliary secretion
  • some drugs elimination in this way into SI
  • so can be reabsorbed to reach systemic circulation
32
Q

what does the amount of drug absorbed depend on?

A
  • its release from dosage form
  • stomach, intestinal and hepatic first pass metabolism
  • permeation through GI memb
33
Q

why is the removal rate of drug from inside of cell more efficient than rate of entry sometimes?

A
  • protective mechanism for cells
  • stops toxic molecules accumulating
  • reason why some tumour cells are resistant to anticancer drugs
  • specific transport proteins
  • cellular proteins can stop accumulation by pumping drug back out (efflux pumps)
34
Q

what is P-glycoprotein (PGP)?

A
  • efflux pump
  • responsible for poor bioavailability
  • low CNS conc of lots of drugs
35
Q

what are P-glycoprotein inhibitors?

A
  • co administration of P-gp inhibitor with anti cancer drugs prevents drug efflux from endothelial cells, increasing BA
  • first + second gen P-gp inhibitors specific for the transporter
36
Q

role of dosage form?

A
  • allows for accurate dosing
  • protects drug during storage + after adminstration
  • conceals unpleasant taste/smell
  • easy delivery
  • optimise delivery + release - fast release or longer release
37
Q

why may 2 dosage forms have the same rate of absorption, but achieve diff Cmax values at a different Tmax value?

A

due to significant lag time

38
Q

4 types of oral dosage forms

A
  1. rapid release: solutions + effervescent tablets
  2. delayed release: enteric coating
  3. slow release: zero order kinetics
  4. slow release: first oder kinetics
39
Q

what is 1st order slow release?

A
  • amount released per unit time depends on QUANTITY and the CONC of drug present at absorption site
  • the bigger the amount of drug absorbed the faster the absorption rate
39
Q

most drugs have a higher rate of ….. than …..

A

most drugs have a higher rate of absorption than elimination

40
Q

what is zero order slow release?

A

amount released per unit time is constant over period of absorption achieved

41
Q

affect of food on GI absorption

A
  • some drugs taken under emptying stomach to maximise BA
  • gi absorption decreases when Al, Ca, Mg (found in antacids), Fe present
  • taking sodium fluoride to treat osteoporosis can cause problem if Ca supplement is also prescribed
42
Q

what type of simultaneous ingestion should be avoided?

A

antacids + milk products

43
Q

what type of dosage forms may be sensitive to presence of food in digestive system?

A
  • delayed or slow release forms
  • due to the change in transit time