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

Question 1

parameters that effect GI absorption of drugs

Answer 1

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

Question 2

what is the therapeutic window?

Answer 2

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

Question 3

gastric transit & drug absorption

Answer 3

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)

Question 4

issue with gastric fluid

Answer 4

• 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)

Question 5

GI tract motility: gastric emptying

Answer 5

stomach gradually releases its contents into SI

Question 6

factors affecting gastric emptying and therefore drug absorption

Answer 6

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

Question 7

how does the type of meal affect gastric emptying?

Answer 7

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)

Question 8

how does the physical state of contents affect gastric emptying?

Answer 8

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

Question 9

how do chemicals affect gastric emptying?

Answer 9

• acids reduce
• alkalis increase

Question 10

how do drugs affect gastric emptying?

Answer 10

anticholinergics, narcotics, ethanol reduce emptying rate

Question 11

how does body position affect gastric emptying?

Answer 11

lying on left side reduces emptying rate

Question 12

how does disease effect gastric emptying?

Answer 12

ulcers reduce emptying rate

Question 13

how does excursive affect gastric emptying?

Answer 13

vigorous exercise reduces emptying rate

Question 14

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

Answer 14

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

Question 15

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

Answer 15

• 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

Question 16

intestinal transit and drug absorption

Answer 16

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

Question 17

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

Answer 17

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

Question 18

class 1 drug

Answer 18

highly soluble, highly permeable: easiest to work with

Question 19

class 2 drug

Answer 19

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

Question 20

class 3 drug

Answer 20

highly soluble, poorly permeable

Question 21

class 4 drug

Answer 21

poorly soluble, poorly permeable: hardest to work with

Question 22

how to improve membrane permeability

Answer 22

change drugs structure: pro drugs

Question 23

what is ampicillin?

Answer 23

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

Question 24

how does the stomach degrade and metabolise?

Answer 24

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

Question 25

how does the duodenum degrade and metabolise?

Answer 25

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

Question 26

how does the small intestine degrade + metabolise?

Answer 26

- 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

Question 27

how does the colon degrade + metabolise?

Answer 27

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

Question 28

hepatic first pass effect

Answer 28

- 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

Question 29

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

Answer 29

net loss of drug which reach systematic circulation

Question 30

what does bile do?

Answer 30

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

Question 31

enterohepatic recycling

Answer 31

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

Question 32

what does the amount of drug absorbed depend on?

Answer 32

- its release from dosage form - stomach, intestinal and hepatic first pass metabolism - permeation through GI memb

Question 33

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

Answer 33

- 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)

Question 34

what is P-glycoprotein (PGP)?

Answer 34

- efflux pump - responsible for poor bioavailability - low CNS conc of lots of drugs

Question 35

what are P-glycoprotein inhibitors?

Answer 35

- 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

Question 36

role of dosage form?

Answer 36

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

Question 37

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

Answer 37

due to significant lag time

Question 38

4 types of oral dosage forms

Answer 38

1. rapid release: solutions + effervescent tablets 2. delayed release: enteric coating 3. slow release: zero order kinetics 5. slow release: first oder kinetics

Question 39

what is 1st order slow release?

Answer 39

- 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

Question 39

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

Answer 39

most drugs have a higher rate of absorption than elimination

Question 40

what is zero order slow release?

Answer 40

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

Question 41

affect of food on GI absorption

Answer 41

- 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

Question 42

what type of simultaneous ingestion should be avoided?

Answer 42

antacids + milk products

Question 43

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

Answer 43

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