Qualitative Pharmacokinetics: ADME Flashcards
What is the primary way in which drugs diffuse throughout the body and what is the driving force?
Passive diffusion - driving force is the concentration gradient.
They must have enough hydrophobic character to pass freely
How do hydrophilic drugs distribute in the body?
Primarily rely on larger aqueous compartments (interstitial space, cytosol), and movement across tight junctions and endothelial lining of blood vessels
What is the significance of special carriers for drug transport?
Many drugs which mimic naturally occurring peptides, amino acids, and sugars can utilize these special carriers for facilitated transport of too large / insoluble particles
What is one additional mechanism which is important in movement of drugs in and out of the cells?
endocytosis / exocytosis
What is the Henderson-Hasselbalch equation?
pH = pKa + log [A-]/[HA]
or
pH = pKa + log [B]/[HB+]
Where does an acid tend to get trapped and why?
Only uncharged substances can move across a membrane. So, acids are easily absorbed in the stomach (low pH), where they are uncharged. They get stuck in the plasma where they are deprotonated and thus negatively charged
Where does a base tend to get trapped and why?
Bases are neutrally charged in basic conditions, so they diffuse well from the plasma or duodenum, and tend to get stuck in low pH environments like the stomach, where they are protonated and thus positively charged
What is the general pH of breast milk, stomach, prostate, and vaginal secretions?
breast milk ~7.0
Stomach ~2.0
Prostate ~7.0
Vaginal ~4.0
What is the definition of bioavailability?
Percent or fraction of the orally administered dose of a drug that actually enters the systemic circulation
-> drugs with very high first pass metabolism will be less bioavailable
What are the bioavailability trends of drugs given IV vs IM, oral, or subcutaneously?
IV: immediately 100% bioavailable
Oral / subcut / IM: delay to peak plasma concentration, generally less than 100% bioavailable
What are the only routes of drug delivery which we worry about first pass metabolism?
Oral and rectal
What is the formula for Vd?
amount of drug administered / (concentration at time 0)
How is the concentration at time 0 of a drug determined? Why do we do this?
Administer the drug, and take blood samples. Extrapolate backwards to 0 from the log-linear portion of the graph (at true time 0, you are in the distribution phase and the drug has not fully distributed to the tissues(includes cells and plasma) to the full “volume of distribution”)
We do this because we know that the only thing controlling drug concentration in the linear portion of the graph is elimination, versus both elimination and distribution
What is the significance of Vd?
Vd is the apparent volume of plasma that would have yielded the extrapolated concentration at t=0 upon administration of the dose
What is the significance of Vd = 5-10, 20-40, 40, and >40 liters?
5-10 = drugs are highly charged or bound to plasma protein i.e. plasma (do not distribute well)
20-40 - moderately lipid soluble
40 - lipid soluble enough to distribute to total body water (for a 70kg person)
>40 liters - highly lipid soluble, sequestered in fat, nervous tissue, and muscle
What drugs will have a high Vd?
Highly lipid soluble ones, whose plasma concentration at t=0 will measure very low (drug has diffused out of plasma)
What are the features of CNS-active drugs? How are they metabolized?
Highly lipid-soluble in order to cross the lipoidal glial cell BBB, and will thus have very large Vd values.
They will be eliminated via hepatic drug metabolsim rather than renal excretion because they are highly lipophilic and cannot be urinated
Why do lipophilic drugs concentrate in the liver?
they gain easy access to liver cells and tend to concentrate in the membranes of the rough ER, where CYP drug metabolism takes place
How are most drugs excreted, and what are some other avenues?
Most are excreted via kidneys, and can be excreted directly if hydrophilic enough
Also excreted via bile, sweat, saliva, exhaled air, or milk
What state must drugs be to be filtered by the renal glomerulus? What drugs cannot be reabsorbed? Give an example drug.
They must be unbound to proteins, and hydrophilic. i.e. digoxin, kanamycin
Drugs which become charged in the urine cannot re-enter the tubules
How can some drugs be transported in the kidney against their concentration gradient, and what drug inhibits this?
Via renal tubular secretion / active transport, even if the drugs are protein-bound (since the complex rapidly dissociates).
This process is competitively inhibited via probenecid, which inhibits the tubular secretion of penicillins
What drugs are most likely to be reabsorbed in the renal tubules? What plays a very important role?
Non-ionized, lipid-soluble drugs.
Thus, pH of the urine plays a very important role -> determines the ionization state of the drug
How does protein binding of drug affect the free drug concentration and metabolism?
Drug action correlates with only free drug concentration. Extensive binding will slow metabolism of the drug (only unbound drug is metabolized), and can act as a depot / reservoir for the drug
What drugs are known to displace drugs with high plasma protein binding?
Warfarin and other anticoagulants
What is given in salicylic acid overdose?
sodium bicarbonate -> causes alkalinization of urine, inhibiting the reabsorption of salicylate in the kidney tubules as it is a weak acid
What is enterohepatic cycling? What drug can inhibit this?
Excretion of drugs in the bile, and reabsorption from the intestine into the body
Drug: cholestyramine, a nonspecific adsorbent
What helps excrete drugs from the CSF into the blood?
choroid plexus
What is the function of Ezetimibe?
Reduces the intestinal absorption of cholesterol via reduction of enterohepatic cycling.
Reduces LDL cholesterol.
