L30/1 - physiological factors affecting drug absorption after oral administration Flashcards
parameters that effect GI absorption of drugs
- anatomy/histology
- physiology
- pathology
- drug interactions
- food (fed vs fasting)
- GI transit
- metabolism within GI
- first pass effect in liver
- enterohepatic recycling
- active secretion
what is the therapeutic window?
area of concentration you need to be in for efficacy of the drug. most drugs have wide window (e.g 1 paracetamol treats us)
gastric transit & drug absorption
- stomach grinds food and breaks it up by chemical decomposition
- gastric fluid is an acid containing pepsin: which can degrade drugs
- drug absorption across stomach wall does not contribute much to oral absorption of drugs (drugs mostly absorbed in SI)
issue with gastric fluid
- 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)
GI tract motility: gastric emptying
stomach gradually releases its contents into SI
factors affecting gastric emptying and therefore drug absorption
- meal volume: bigger meal = quicker initial emptying rate
- type of meal
- physical state of contents
- chemicals
- drugs
- body position
- disease
- exercise
how does the type of meal affect gastric emptying?
- fatty acid reduces emptying rate (more carbons on chain = more reduce)
- triglycerides reduce emptying rate (occurs in unsaturated more)
- carbs and a.a reduce emptying rate (concentration dependent matter/ osmotic pressure)
how does the physical state of contents affect gastric emptying?
solutions or suspensions of small particles empty quicker than chunks of material
how do chemicals affect gastric emptying?
- acids reduce
- alkalis increase
how do drugs affect gastric emptying?
anticholinergics, narcotics, ethanol reduce emptying rate
how does body position affect gastric emptying?
lying on left side reduces emptying rate
how does disease effect gastric emptying?
ulcers reduce emptying rate
how does excursive affect gastric emptying?
vigorous exercise reduces emptying rate
describe gastric transit and drug absorption when a drug is rapidly released from dosage form into gastric fluid
- drug in solution in stomach
- in fasting subject, the drug leaves stomach rapidly via pylorus
describe gastric transit and drug absorption when there is a gastro resistant dosage form
- 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
intestinal transit and drug absorption
- microvilli of intestinal mucous membrane increase SA
- pH of intestinal fluid is neutral / kinda alkaline
- SI is where most drugs absorbed
what is the rate of absorption in the SI affected by?
- rate of disaggregation and dissolution
- GI transit
- transport across GI memb
class 1 drug
highly soluble, highly permeable: easiest to work with
class 2 drug
poorly soluble, highly permeable: sol can be increased by excipients, changing packet size of drug
class 3 drug
highly soluble, poorly permeable
class 4 drug
poorly soluble, poorly permeable: hardest to work with
how to improve membrane permeability
change drugs structure: pro drugs
what is ampicillin?
- antibiotic with poor oral bioavailability (poor permeability)
- bacampicillin is ester of this
- phyiscochemical properties of bacampicllina low easier passage across intestinal barrier
how does the stomach degrade and metabolise?
- HCL: degrades some drugs, but gastro resistant coatings used to protect drug + delay release
- pepsin: destroys polypeptides (small peptides survive)
how does the duodenum degrade and metabolise?
- Trypsin & elastase (acidic) and chymotrypsin and carboxypeptidase A & B found in lumen
- degrade large proteins to small peptides
- small peptides stable
how does the small intestine degrade + metabolise?
- 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
how does the colon degrade + metabolise?
- metabolic activity decreases from duodenum to colon
- absorption stays good
- gut flora can metabolise + inactive drugs (acidic)
hepatic first pass effect
- 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
what happens if the metabolite produced in the hepatic first pass effect is inactive?
net loss of drug which reach systematic circulation
what does bile do?
helps excretion of endogenous and exogenous compounds and aids digestion of fate and fat soluble vitamins. some drugs excreted through bike/
enterohepatic recycling
- some drugs eliminated in part by biliary secretion
- some drugs elimination in this way into SI
- so can be reabsorbed to reach systemic circulation
what does the amount of drug absorbed depend on?
- its release from dosage form
- stomach, intestinal and hepatic first pass metabolism
- permeation through GI memb
why is the removal rate of drug from inside of cell more efficient than rate of entry sometimes?
- 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)
what is P-glycoprotein (PGP)?
- efflux pump
- responsible for poor bioavailability
- low CNS conc of lots of drugs
what are P-glycoprotein inhibitors?
- 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
role of dosage form?
- allows for accurate dosing
- protects drug during storage + after adminstration
- conceals unpleasant taste/smell
- easy delivery
- optimise delivery + release - fast release or longer release
why may 2 dosage forms have the same rate of absorption, but achieve diff Cmax values at a different Tmax value?
due to significant lag time
4 types of oral dosage forms
- rapid release: solutions + effervescent tablets
- delayed release: enteric coating
- slow release: zero order kinetics
- slow release: first oder kinetics
what is 1st order slow release?
- 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
most drugs have a higher rate of ….. than …..
most drugs have a higher rate of absorption than elimination
what is zero order slow release?
amount released per unit time is constant over period of absorption achieved
affect of food on GI absorption
- 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
what type of simultaneous ingestion should be avoided?
antacids + milk products
what type of dosage forms may be sensitive to presence of food in digestive system?
- delayed or slow release forms
- due to the change in transit time
