What are the genal characteristics of the intestinal epithelium?
1. It is polarized
2. Tight junctions between cells
3. Apical membrane facing the intestinal lumen
4. Basolateral membrane
Which intracellular junctions are tighter proximal or distal?
What kind of molecules can pass through tight junctions?
Very small molecules
What is secreted into the digestive tract to facilitate digestion?
Does digestion of particles change the osmolarity gradient in the intestine?
Yes the digestion of ingested food creates an osmotic gradient that facilitates the movement of water into the lumen.
Is the electrochemical gradient of Na+ into the cell favorable?
How is water reabsorbed by the intestine?
Water moves Paracellularly by passive diffusion as well as having facilitated transport mechanisms through constitutively active and regulated water channels called aquaporins.
Can complex sugars be absorbed into the gut?
No they must be broken down by secreted enzymes or epithelium attached enzymes that can hydrolyze complex sugars to monosaccharides and disaccharides.
How are glucose and galactose transported into the intestine?
Glucose and Galactose utilize a
1. cotransport system SCL5A1 transports one molecule of sugar with with two Na+.
2. Secondary active transport system- Na-K ATPase pumps Na+ out of the epithelial cell and the sugar diffuses down its concentration gradient.
(review) What are some characteristic of facilitated diffusion?
1. Carrier protein involved.
2. Carrier protein is specific for the molecule its transporting
3. ATP is not required
4. Aolutes move from high concentration to low concentration,
5. Carrier Saturation limits flux.
(review) Describe the action of the Na+/K+ ATPase.
Na/K ATPase is an active transport pump that utilizes one molecule of ATP to pump 3 Na out of the cell for every two molecules of K into the cell
Intracellular: 14mM Na / 120mM K
Extracell: 4mM K / 140mM Na
How does the route of venous drainage from the rectum differ from that of the intestines?
Above the pectinate line the venous return from the rectum proceeds to the portal circulation system via the inferior mesenteric vein. This drainage is consistant with the drainage of the stomach spleen small intestine and large intestine
Middle and inferior rectal veins drain into the caval circulation,
fWhat is the advantage of taking drugs rectally versus orally?
When a drug is taken rectally 50% of the drug is absorbed into the portal circulation land 50% into the caval circulation thus making the first pass effect less significant.
What are the advantages and disadvantages of IV administration of a drug?
(+) Suitable for large volumes of potentally toxic drugs or complex mixtures when diluted
(-) Increased risk for adverse effects, must be injected slowly, not suitalbe for oily or poorly soluble substances
What is the disadvantage of of the oral route for drug delivery?
1. low gastric pH can degrade the drug
2. Physical characteristics can preclude absorption
3. Emesis as a result of gastric irritation
4. Patient must cooperate
5. Can be metabolized by enzymes in the
What is Bioavailability and what factors determine this?
Bioavailability is the fraction of unchanged drug reaching the systemic circulation following administration by any route.
When plotted on a graph it is the area under the blood concentration over time curve
**less than 100% for oral drugs due to incomplete absorption (physical and chemical characteristics) and first pass elimination by the liver.
How does molecular weight, hydrophobicity, hydrophilicity affect the absorption rate of a drug?
What is first pass metabolism and where does this take place?
following absorption across the gut wall, the protal blood delivers the drug to the liver prior to entering systemic circulation.
A drug can be metabolized in the gut wall, protal blood, and most commonly by the liver. In addition to metabolism the liver can secrete the drug into bile.
What are some of the variables that impact the rate and extent of absorption?
Oral bioavailability is a complex phenomena that is largly dependent upon the individual drug structure, solubility, stability, membrane permeability, substrate for metabolism or efflux pumps)
The presence of concurrent drugs in the GI tract and functional status of the digestive system play a large role as well.
What gender differences that impact the extent of absorption of an oral drug dose?
Mucosal enzymes show a clear dependence on gender effects.
Differences in gastrointestinal motility, luminal and mucosal features, gastric acid output
GI transit is slower in girls and is subject to hormal alterations.
Gastric output is different
What effect does ionization have on the absorption of a drug?
The transfer of drug across a biological barrier is proportional to the concentration gradient of the un-ionized form across the membrane.
The ratio of the unionized vs ionized form of terisdpdent of the pKa (ionization constant) of a drug and the pH of the surrounding tissues and fluids.
What is the henderson hasselbalch equation?
For a weak acid
pH= pK + log [A-] / log [HA]
For a weak base
pH = pK + log [B] / [BH+]
When pH = pK 50 % ionization has occured
Drugs with different pK values will diffuse at different rates.
How will treatment for hypergastric acidity affect the absorption of a drug?
Simple antiacids and histamine H2 receptor blockers and proton pump inhibitors raise gastric pH
By making gastric pH more neutral, these drugs can decrease the solubility of some other medications and reduce the rate and extent of absorption. They can also change the extent of ionization shifting the balance of what can and can not be absorbed.
What is the importance of GI motility,
and presence of chelators to the process of oral drug absorption?
If there is the concurrent presence of a GI condition such as siarrhea or constipation this can alter the time the drug is available for absorption.
Perfusion (rate and extent) can be influenced by both the release of local factors (hormones) in the gastrointestinal wall as well as the application of exogenous agents (drugs) that are administered for other purposes.
Chelators- are drugs that will bind up exogenous substrates like bile acids and salts. This will afect bioavailability of drugs in the GI tract.
What do active protein pumps play in the intestinal wall? what are some examples of both drug efflux and uptake mechanisms
Active pumps are involved in drug absorption in certain areas of the gut and will play a role in the transport of drugs against the conc gradient.
**carry materials into the enterocyte. FOR EXAMPLE the organic anion transport protein (OATP)
***NOT to be confused with OTPHJ***
What is a CYP and what effects will it have on drug metabolism?
CYP = Cytochrome p450, and plays a vital role in intermediary metabolism. For example steriodogenesis act to facilitate drug excretion by transforming the drug substrates into more water soluble polar molecules that can be eliminated in urine and bile
** most common
Where in the intestine are the most abundant microflora?
The microbiota are most prevalent in the descending colon.
Intestinal microbiota can have a major impact on drug metabolism and ultimately on bioavailability of oral drugs.
Poor solubility permeability leads to an increased chance that the drug is presented to the lower gut and subsiquently degraded by the microbiota.
The metabolic capacity varies by location in the gut
would you rather do 27 more pharmacology cards or finger-bang the lunch lady?
(you can wear your lab gloves)
..... Tough one, get Rudd to do it for you.
What are the advantages/ disadvantages of subcutaneous deliver of drugs?
(+) Prompt absorption for aqueous solutions. Suitable for some poorly soluble suspensions and for instillation of slow release implants
(-) Not suitable for large volumes, not suitable for large volumes, possible painful necrosis from irritating substances.
What are the pros and cons for intermuscular injections?
(+) Prompt from aqueous solutions. Suitable for large volumes and oily substances. Can be used for self administration and for irritating substances
(-) Precluded during antocoagulant therapy and may interfere with some diagnostic tests.
How are bioequivalence and bioavailability different?
Two drug products are considered to be Pharmecutical equivalents when the rate and extents of bioavailability of the active ingredient in the two products is not significantly different inter suitable test conditions.
Are lipid soluble drugs easily absorbed by the intestional tract?
yes as long as they are not too hydrophobic. As a gneeral rule the more carbon atoms and fewer oxygen atoms a drug has the more lipid soluble a drug is.
Which CYP is most abundant in the wall of the small intestine?
CYP34A- located i the wall of the small intestine CYP34A plays an inportant role and complementary to the efflux pumps in modulating drug access to the hepatic portal circulation.
**CYP34A serves to break down or inactivate drugs before they can have ANY effect on the body. This protein is regulated by gene expression
What are the effects of grapefruit juice on drug absorption?
It will inhibit the absorption of the following drugs via their CYP pumps
Fexofenadine is a nonsedating antihistamine
No but it is a substarte for CYP3A but is a substrate for OATP
Felodipine is a calcium channel blocker that YES is a substrate for CYP3A in the intestinal wall.