L30 - Absorption: Physiological factors affecting drug absorption 1 Flashcards
What parameters which determine GI absorption of drugs? (10)
- anatomy/histology
- physiology
- pathology
- drug interactions
- food (fed vs. fasting)
- gastrointestinal transit
- metabolism within the gastro-intestinal tract
- first-pass effect in the liver
- enterohepatic recycling
- active secretion (p-glycoprotein, Pgp)
What is the therapeutic window?
Area of conc for drug to have efficacy
What is the stomach?
Important organ for digestion of food
What is the gastric fluid and what does it contain?
Acid
- active enzyme called pepsin
What are some drugs degraded by?
acidic conditions in the stomach
- so developed dosage forms that don’t release drug in acidic environments
What does drug absorption across the stomach wall not contribute significantly to?
Oral absorption of drugs
Where are drugs principally absorbed?
Small intestine
What are factors that affect the gastric emptying and subsequent drug absorption? (8)
- meal volume
- type of meal
- physical state of contents
- chemicals
- drugs
- body position
- disease
- exercise
How does meal volume affect gastric emptying?
The larger the meal
= the quicker the initial emptying rate
How does the type of meal affect gastric emptying? (3)
- FAs - reduce emptying rate (conc and chain length)
- Triglycerides - reduce emptying rate (unsaturated more than saturated)
- Carbs and a/a - reduce emptying rate (conc dependent manner)
How does physical state of contents affect gastric emptying?
Solutions/suspension of small particles empty quicker
How do chemicals affect gastric emptying? (2)
- acids reduce emptying rate
- alkalis increase emptying rate
How do drugs affect gastric emptying?
Anticholinergics, narcotics and ethanol reduce emptying rate
How does body position affect gastric emptying?
Lying on the left side reduces emptying rate
How does disease affect gastric emptying?
Emptying rate reduced by presence of ulcers and in some diabetics
How does exercise affect gastric emptying?
Vigorous exercise reduces emptying rate
What is an important element with respect to rate of GI absorption?
Passage of frugs through pylorus
How do the intestines offer a very large SA for absorption?
(Micro)villi of the intestinal mucous membrane
What is the pH of intestinal fluid like?
Neutral to slightly alkaline
What is the rate of absorption a composite parameter comprising of? (3)
- rate of disaggregation and dissolution
- GI transit
- transport across GI membrane
How can you improve membrane permeability?
Modifying the drug’s structure - prodrugs
What breaks down nutrients/degrades drugs in the stomach? (2)
- HCl - degrades some drugs
- pepsin - digestive protease - destroys polypeptide drugs
What breaks down nutrients/degrades drugs in the duodenum? (2)
- trypsin, chymotripsin, elastase, carboxypeptidase A & B
- degrade 30-40% of large proteins
What breaks down nutrients/degrades drugs in the SI?
Cytochrom P450, esterases, glycuronosyl transferases
- transfer glucoronic acid to nucleophiic sites on drugs
What breaks down nutrients/degrades drugs in the colon? (2)
- gut flora
- can metabolise and inactivate drugs
What is the first pass effect? And why does it happen?
First pass through the liver greatly reduces bioavailability of the drug
- fraction of amount of drug absorbed is transformed into metabolite (active or inactive)
What happens if the metabolite is inactive after the first pass effect?
Results in net loss of drug which reaches system circulation
What are examples of drugs which metabolites are inactive after the first pass effect? (2)
- haloperidol - so given by IM injection
- isosobide - so given sublingually
What is an example of drugs which metabolite is active after the first pass effect?
Clomipramine
- metabolite similar to parent drug
