Flashcards in Lec 67: Drug Metabolism II Deck (50):
What are the four basic mechanisms of drug passage across membranes?
Passive diffusion, Filtration, Active transport and Endocytosis
What law governs passive diffusion?
Fick's Law. Diffusion down a concentration gradient.
What determines molecular passage in the filtration method of drug passage across biological membranes?
The pore size. Molecules move down a concentration gradient.
What feature distinguishes Active transport most prominently against the other methods of drug transport across membranes?
It requires ATP and can go (and often does) against the concentration gradient.
MDR1 is aka?
Multi Drug Resistance gene 1 and it makes P-glycoprotein. Which is a drug transporter.
The entrance of extracellular substances into the cell by binding a receptor on the cell surface and being pulled into the cell within an individual lipid membrane derived from the cell surface. (Potential vector for virus entrance into cells).
What are 3 key factors that influence diffusional drug passage across the cellular membrane?
Concentration gradient, Lipid Solubility and Ionization
How does concentration gradient affect the diffusional drug passage across the cellular membrane?
Drugs that are able to pass through the membrane will move from an area of lower concentration to an area of higher concentration.
How does lipid solubility affect the diffusional drug passage across the cellular membrane?
The chemical structure of a drug determines the solubility. If it is lipid soluble the drug will pass more easily through the membrane.
How do we measure the lipid solubility of a drug?
With the "Lipid solubility coefficient" - A higher coefficient means that the molecule is more easily able to pass through the lipid membrane.
Two barbituate drugs have lipid solubility coefficients of 3.3 - (thiopental) and 0.002 - (barbital), which passes more easily through lipid membranes?
Thiopental. (Which is why it is used to induce anesthesia, it acts faster because of its higher lipid solubility coefficient).
How does drug ionization affect the ability to diffuse into cells?
Molecules which are charged will have a harder time passing through lipid membranes. Those which are uncharged are free from hydration shells and can often diffuse through the membrane. Hydration shells forming around charged ions block this passage.
If a weak acid (pKa ~ 3.5) is put in an acidic environment (like the stomach pH 1.5) What do can you say about its ionization state and diffusion potential?
It will NOT be ionized and so will be able to diffuse into the stomach.
What are the two drug transporter families we learned in lecture?
ABC (ATP Binding Cassette) and SLC (Solute Linked Carrier) super families.
Name an important example of the ABC super family and describe its mechanism.
MDR1 - Makes P-glycoprotein, an ABC that pumps solutes across cell membranes. (In the brain it often pumps drugs out by ATP hydrolysis, in other organs it can pump in or out depending on what it is used for).
What are two examples of SLC transporters and what do they transport?
SERT - The serotonin transporter. (On which Prozac acts) and DAT - The Dopamine transporter. (On which cocaine and methylphenidate (Ritalin) act).
How do facilitative transporters work?
They use ion coupled secondary active transport to move solutes across the membrane.
What are the four routes of enteral drug administration?
Buccal cavity, stomach, small intestine and rectum.
What are the five routes of parenteral drug administration?
Intravenous (IV), inhalation, intramuscular (IM), subcutaneous (SC) and percutaneous.
What is the advantage of buccal cavity (sublingual) drug administration?
The drug enters the systemic circulation first by being absorbed under the tongue (instead of in the stomach or intestines) which avoids the first pass metabolism of the liver.
What are the advantages/disadvantages of stomach absorption of a drug?
The low pH affects drug stability. Can easily absorb acidic (and weak base) drugs that are not ionized. Drugs are subject to first pass metabolism to the liver and then to the systemic circulation.
What are the advantages/disadvantages of intestinal absorption of drugs?
The pH of the intestines is around 6-7.4. Ease of absorption of most drugs. Subject to first pass metabolism.
What are some advantages/disadvantages of rectal administration of drugs?
There is less irritation than the oral route. You may be able to avoid first pass metabolism depending on location within the rectum. This administration location is less well tolerated than the oral route.
What are some advantages/disadvantages of intravenous drug administration?
Sends the drug directly into the drug stream. 100% absorption and no first pass metabolism.
What are some advantages/disadvantages of drug administration by inhalation?
Requires the drug be volatile or gaseous drug, provides rapid absorption for anesthetics or asthma medications.
What are some advantages/disadvantages of intramuscular drug administration?
Enters systemic circulation without first pass metabolism.
What are some advantages/disadvantages of subcutaneous drug administration?
Slower absorption depending on blood flow?
What are some advantages/disadvantages of percutaneous drug administration?
(Example steroid patches) useful for highly potent lipid soluble drugs.
How can you describe the equilibrium between plasma bound drug in the body and free drug?
([Free drug]/[Kd][Free drug])
Plasma protein binding - [total drug] = ?
[Free drug] + [Bound drug]
How might lipophilic drugs interact with albumin?
They may become bound to it.
(Mass of the Drug absorbed)/(plasma volume) = ?
Volume of Distribution
Low volume of distribution indicates?
High plasma concentration
High volume of distribution indicates?
Concentration of the drug in extravascular areas.
Remember that bioavailability affects the amount of drug absorbed.
Also remember the implications for that in IV vs. Oral administration of the drug.
Tissue accumulation of a drug can occur where in the body?
Really anywhere, but key locations are kidney, eye, lung, bone, and fat.
What is the cause of drug accumulation in different organs?
It is caused by binding proteins unique to that organ or just accumulation of lipid soluble drugs in fat deposits.
What happens to resevoirs of drugs (stored in organs) as blood concentration goes down?
The equilibrium will cause the drug to be released into the blood stream.
Three factors affect the ability of drugs to enter the CNS, what are they?
There are relatively few pores in the blood brain barrier to allow entry, highly lipophilic drugs have a better chance of entry, ABC transporters (like MDR-1) pump many drugs that are able to enter, back out.
Three special notes should be made of MDR-1 when it comes to CNS involvement.
Some drugs are especially good substrates for MDR-1 which means they should stay out of the CNS almost entirely.
1) Morphine which only has 10% of the CNS concentration compared to plasma concentration. (This is still enough for a therapeutic effect).
2) HIV proteases are pumped out quickly making the brain a safe haven for HIV
3) Some anti-cancer drugs are pumped out quickly, making using them to treat brain cancers difficult.
What 5 factors influence placental passage of drugs to a growing conceptus?
1) Lipid solubility
2) Size and pH
3) Placental Transporters
4) Protein Binding
5) Placental metabolism of drugs
How is placental passage of drugs affected by Lipid Solubility?
More soluble drugs are able to pass more easily and enter the fetal circulation.
How is placental passage of drugs affected by size and pH of the drug?
Most smaller drugs (250-500) can pass easily depending on their charge and lipophilicity. (500-1000MW) drugs have a harder time and large polar drugs can't pass through it at all (like Heparin).
What should be remembered about fetal blood circulation of drugs? (Specifically blood pH related)
Fetal blood has a pH of about 7.3 making slightly basic drugs more ionized preventing them from leaving fetal circulation and therefore accumulating.
How is placental passage of drugs affected by placental transporters?
P-glycoprotein transporter (MDR-1 gene's product) will affect certain drugs the same way they do for the brain. Namely that they pump them out. This has implications for HIV treatment because the viral protease inhibitors won't be able to remain in fetal circulation and the child will have an increased risk of catching parental HIV.
How is placental passage of drugs affected by protein binding?
Greater protein binding (via albumin usually) leads to lower levels of fetal circulation but may not affect very lipophilic compounds.
How is placental passage of drugs affected by the placental metabolism of drugs?
The placental barrier acts as a block and sometimes a site of metabolism for drugs that are trying to enter fetal circulation. This can have the effect of either increasing or decreasing drug toxicity.
List 4 of the main methods of drug elimination.
Renal clearance, Fecal clearance, Expired clearance (breathing them out), Breast milk clearance (usually very small concentrations).
How does ionization affect the renal clearance of a drug?
Urine pH is about 5.5, and plasma pH is about 7.5. That means that weak bases tend to move from the plasma to the urine in the kidney. (And acids will do the reverse).