What is a general rule of thumb for determining which ionized form of a drug predominates at different pHs?
If the pH is less than the pKa, the protonated form is predominant (HA or BH+), because there are more H+ atoms to be had. If the pH is higher than the pKa, the deprotonated form is predominant (A- or B), because there are fewer H+ to be had. If you need to know precise amounts, use Henderson-Hasselbach (pH = pKa + log [A-]/[HA])
If a lipid barrier separated two aqueous solutions at different pHs, but allowed the non-ionized drug to diffuse freely, the non-ionized form would be present in equal concentrations on both sides at equilibrium. But, a separate equilibrium would exist between the ionized and non-ionized forms in each compartment. Thus the TOTAL CONCENTRATION of the drug would be greater on the side with greater ionization, hence ion-trapping.
What is the physiological consequence of ion-trapping?
A weak acid (pKa 3.4 for example) will be more easily trapped in a more basic environment than in a more acidic environment. The more acidic env (stomach 1.4) favors protonated, non-ionized form that diffuses readily, the more basic env (plasma 7.4) favors the ionized form, resulting in ion-traping in the plasma (for a weak acid).
Clinical applications of ion trapping are rare. What is one significant consideration?
Breast milk is more acidic than plasma (~6.4 vs 7.4), thus, basic drugs/compounds are more likely to accumulate (ion-trapping) in breast milk in greater concentrations than in plasma. Acidic drugs are much less likely to accumulate in the acidic milk.
Is it possible to get GI side effects from an IV drug?
Yes, due to the concentration gradient present between the gut and plasma in areas of close contact between the two. This also leads to ion-trapping in the gut after death, as basic compounds tend to accumulate in the gut and not be reabsorbed.
What is the effect of changes in protein-binding rate of a drug?
Only the free drug can cross membranes. Thus, because most drugs are bound to plasma proteins to become soluble in aqueous env, changes in protein binding after therapy has begun will change therapeutic effects of the drug. These are rare, and usually result from drug-drug interactions.
What effect does protein binding have on therapeutic effect?
It reduces the concentration of active, free drug in the plasma, can limit fetal exposure (given two drugs with differing protein affinity, give pregnant women the one with the higher). It hinders metabolism and excretion of the drug, decreasing the elimination rate and extending half-life, and acts as a drug reservoir that can prolong drug action.
What happens as a result of protein binding dispalcement interactions (drug-drug interactions)?
If the administration of a 2nd drug displaces the 1st drug from binding sites and increases level of free 1st drug, it is subject to increased therapeutic activity and higher metabolism/excretion rates. Rarely of clinical importance unless the displaced drug has: narrow therapeutic window, high doses, Vd is small, or response to drug occurs faster than distribution.
What effect does protein binding in the plasma have on Vd?
Protein binding in the plasma means a small Vd because most of the drug is in the plasma.
How can the excretion of drugs be amplified in a patient?
Modifying the pH of the urine to encourage ion-trapping. Some drugs will lower the urine pH, trapping basic drugs, some will raise the pH, trapping acidic drugs.
What are the general phases of drug metabolism and what characterizes each?
Phase I and Phase II. They are characterized by the reaction types, the enzymes that mediate those reactions, whether they are subject to inducers or inhibitors, and whether they are saturable (Michelis-Menton)
What are the general characteristics of Phase I drug metabolism and where does it occur?
Lipid soluble compounds converted to more water soluble compounds and are thus more readily excretable. The liver is the primary organ of drug metabolism, followed by the lungs, kidneys, intestines, skin, and placenta.
What is the common mechanism of Phase II drug metabolism?
Drug is conjugated with a strongly acidic (ionized) compound and is thus highly water soluble and inactivated.
What are three less common consequences of drug metabolism?
Some drugs (<5%) are not simply inactivated by metabolic pathways, but may actually be activated or toxified. 1) Active drug made more active: Codeine -> Morphine, hydrocondone -> hydromorphone. 2) Inactive prodrug converted to active drug: Valacyclovir -> Acyclovir. 3) Metabolism to toxic metabolyte: acetaminophen -> hepatoxic metabolyte.
What biotransformations typically occur in Phase I metabolism?
Intertion or unmasking of a functional group on a drug (e.g. -OH, -NH2, -SH) Reactions include Oxidation, reduction, hydrolysis (utilizing Oxygen and NADPH cofactors) Drug metabolite can then undergo conjugation in Phase II.
What biotranformations occur in Phase II metabolism?
Conjugations of the Phase I funcitonal group with ionized, bulky substrates. Forms highly polar, water soluble conjugate that is readily excreted in urine. Phase II reactions include glucuronidation, acetylation, glutathione/glycine/sulfate conjugation.
Which phase is more likely to become saturated?
Phase II is more likely to saturate because the cofactors that it uses (glucoronyl, glutathione, acetyl groups) are high energy and present in much lower concetrations than the phase I cofactors (O2, NADPH)
What are the details of metabolism by CYP-450?
More frequently metabolises via oxydation, Substrate must be lipid soluble, Early neo-natal levels are only 50-75% that of adults (thus slower drug metabolism generally, though some drugs are rapidly metabolized in neonates)
What is the nomeclature of cytochromes (CYP450 family) and which individual cytochromes are most important to know?
CYP1A2: CYP (Human cytochrome), 1 (isoform family 1-3), A (subfamily A-E), 2 (individual gene product) CYP3A4 - largest share of metabolism activity, CYP2D6 - codeine metabolism to morphine, CYP2C9 - metabolizes warfarin, CYP2E1 - very small portion of CYP activity but causes toxic acetaminophen metabolite.
How does phase II saturation factor into toxic acetaminophen metabolism?
Acetominophen is normally metabolized directly via Phase II enzymes UGT and GST. Because Phase II is more easily saturated, exceeding the safe (overdosing) dose causes some of the acetaminophen to be metabolized via the Phase I enzyme CYP2E1, resulting in the hepatotoxic metabolite.