When the salt is named first in the drug name, it is likely ...
an acid
*Weak acids unite with cations like
Na+
*Cation of salt of the acid often named first….i.e. “Sodium pentothal”
When the salt is named last in a drug name, it is likely...
a base
Weak bases unite with anions like Cl-,
sulfate; the Anion is named second…i.e.
Lidocaine hydrochloride & Morphine sulfate
Acid or base drug: local anesthetics
base
Acid or base drug: ketamine
base
Amine structure: RNH2 (lone pair on N can accept a hydrogen ion)
Acid or base drug: benzodiazepines
base
Acid or base drug: etomidate
base
Acid or base drug: opioids
base
Amines are (acid/base)
base
Amine structure: RNH2 (lone pair on N can accept a hydrogen ion)
Is the active form of an acid-drug protonated or non-protonated?
Protonated
HA ↔ H+ + A-
Is the active form of an alkaline (basic) drug protonated or non-protonated?
NONprotonated.
B + H+ ↔ BH+
For an acid drug, if pH < pKa, is the equation shifted to favor the active or inactive form of the drug?
ACTIVE HA ↔ H+ + A- ↓ pH (relative to pKa) = high [H+] = equation shifts to the protonated form. For an acid drug, the protonated form is non-ionized (and can cross the cell membrane = active form).
For a basic (alkaline) drug, if pH < pKa, is the equation shifted to favor the active or inactive form of the drug?
INACTIVE B + H+ ↔ BH+ ↓ pH (relative to pKa) = high [H+] = equation shifts to the protonated form. For a basic drug, the protonated form is ionized (and can NOT cross the cell membrane = inactive form).
What does pKa represent?
the pH (environmental) at which the drug is 50% ionized and 50% nonionized
T/F: The pH of a drug preparation affects its pKa.
No, the pKa is the -log (Ka); this has NO RELATIONSHIP to the pH of the drug preparation. You cannot say that at a pH of 7 a drug is an acid drug, but it is an important factor in determining drug onset.
What is a classic example of ion trapping?
Assume the membrane is the placenta & that there is fetal acidosis. Opioids (basic drug) will cross the placenta and become trapped because free hydrogen ions (from the acid environment) attach to the nonionized drug (B) resulting in ionized opioid (BH+). There will still be a concentration gradient for the nonionized fraction (B) so B continues to cross the membrane, becomes ionized, and is trapped.
Which basic drug will have a faster onset of action: one in which the pKa is < pH, or one in which the pKa is > pH?
the drug with a pKa < pH will have a faster onset of action
For a basic drug, the active form is the nonprotonated nonionized form (remember B + H+ ↔ BH+). So, the onset of action is faster if the equation is driven toward the nonprotonated nonionized side (which occurs when the pH is high, aka less [H+]).
See example from the notes of Alfentanil having a pKa of 6.5 in a physiologic pH of 7.4. Alfentanil had a faster onset of action than Fentanyl, which had a pKa of 8.4.
Which acid drug will have a faster onset of action: one in which the pKa is < pH, or one in which the pKa is > pH?
a drug with a pKa > pH
For an acid drug, the active form is the protonated form (remember HA ↔ H+ + A-). So, the onset of action is faster if the equation is driven toward the protonated nonionized side (which occurs when the pH is low, aka more [H+].
When pH is less than pKa, which form predominates (protonated vs. deprotonated)? What form is this for an acid (ionized/nonionized, active/inactive)? For a base?
protonated form
for an acid, HA = nonionized = active form
for a base, BH+ = ionized = inactive form
if pH is less, it is because [H+] is high, meaning the equation is driven toward the protonated side.
When pH is greater than pKa, which form predominates (protonated vs. deprotonated)? What form is this for an acid (ionized/nonionized, active/inactive)? For a base?
Deprotonated form predominates
For an acid, A- = ionized = inactive
For a base, B = nonionized = active
Is the nonionized form a drug active or inactive?
Active
The nonionized form of a drug is soluble in (lipid vs. water)
lipids
Does the nonionized form of a drug cross the GI tract, the BBB, and the placenta?
Yes, the nonionized drug can cross lipid membranes
Is the nonionized form of a drug subject to hepatic metabolism?
Yes. The role of hepatic metabolism is to convert lipid-soluble drugs into water-soluble drugs so they can be eliminated.
Is the ionized form of a drug active or inactive?
Inactive
The ionized form of a drug is soluble in (lipid vs. water)
water
Does the ionized form of a drug cross the GI tract, the BBB, and the placenta?
No. The ionized form can NOT cross lipid barriers.
Is the ionized form of a drug subject to hepatic metabolism?
No (ionized form is water-soluble). The role of hepatic metabolism is to convert lipid-soluble drugs into water-soluble drugs so they can be eliminated.
Which tissue group has the greatest % of body mass?
muscle rich group
50%
Which tissue group receives 75% of the cardiac output?
The vessel rich group.
Surprising, right? NOT
How is the Vd different in the elderly?
Older people have a relative decrease in skeletal muscle mass, and so have a smaller apparent volume of distribution of drugs depending on the drug and what compartments it tends to distribute to.
T/F: If a molecule is small enough, it can cross the lipid bilayer, even if it is water-soluble.
True.
A drug with low MW, lipophilic (hydrophobic) will distribute where?
TBW
Where will a drug that has a low MW & is hydrophilic distribute?
ECF
it goes through slit junctions so capillary → ECF)
What does this graph show?
Rapid drop due to distribution, gradual drop afterward due to biotransformation and elimination.
Why does someone wake up quickly after propofol administration if elimination takes longer?
Distribution...this is why we need to have an inhalational agent!
What is the equation for the Vd?
Vd = D/C
where
C = plasma concentration of drug
D = total amount of drug in body (what was given)
If the tissues are NOT saturated, emergence depends on
distribution
If frequent boluses are given, and the tissues are saturated, emergence depends on
elimination
How does a large Vd affect elimination?
If Vd is large, most of drug is extraplasmic
& unavailable to excretory organs (delivery
to the liver & kidney depends on blood flow & fraction of drug in plasma, any factor that increases Vd, increases half-life and extends duration)
Which organ is responsible for biotransformation?
Liver
Which organ is responsible for elimination after biotransformation?
Kidneys
Your patient has a plasma level of drug X reported to be 10mg/dl after having received a dose of 400mg. What is the Vd?
If the Vd is 4L, what compartment does the drug distribute to?
(plasma, ECF, ICF, or TBW)
plasma
4L is not large enough to be any other compartment
Which protein do most acid drugs bind to?
albumin
Which protein do most basic drugs bind to?
alpha acid glycoprotein
T/F: Protein-bound drugs are more available for excretion since they are restricted to the plasma and exposed to the kidneys/liver.
FALSE. Only unbound drug is available for metabolism/clearance.
T/F: One drug can displace another from albumin increasing the concentration of displaced drug which can cause toxicity
True
Most drugs are (zero or first) order kinetics.
First
In this form of drug metabolism, a constant fraction of available drug is metabolized per unit time
First-order kinetics
Think 1st, like 1, like the fraction 1/1, which is constant...
When the plasma concentration of a drug exceeds the capacity of enzymes, this type of metabolism results
zero-order kinetics
In this form of metabolism, a constant amount of drug is metabolized per unit time.
Zero-order kinetics.
Think "Zero" capacity for distribution, since the tissues are already saturated.
The kidneys can only handle so much. After a certain amount, no more will increase the percent eliminated...so "zero" change in elimination at a certain point.
What do you need to remember about metabolism relating to inactivation?
They are NOT THE SAME
Regardless of the dose of drug in ____-order kinetics, the percent of drug eliminated is the same.
FIRST
Only a certain amount can be eliminated per unit time, regardless of the dose in ____-order kinetics.
zero
Name 3 drugs metabolized by zero-order kinetics.
Alcohol, aspirin, & phenytoin
Hepatic microsomal enzymes (cytochrome P450) are found mostly in the which part of the liver?
Endoplasmic reticulum
These drugs are metabolized via ester hydrolysis:
succinylcholine, esmolol, remifentanyl, ester local anesthetics
Phase II of drug metabolism =
Conjugation
(results in a more polar and water soluble compound, which is usually therapeutically inactive)
In this phase of metabolism (I vs. II), lipophilic molecules are converted into more polar molecules by introducing or unmasking a polar functional group via oxidation, reduction, or hydrolysis.
Phase I
T/F: Infants have an increased drug-metabolizing ability.
False. Infants have a limited drug-metabolizing ability, so they are particulary at risk for toxicity in the first year of life.
How do liver and kidney disease affect steady state concentration?
Increase Css
T/F: a faster rate of infusion decreases the time needed to reach steady state.
False. Only the steady state concentration changes.
T/F: Concentration of steady state and how quickly we achieve it depend on frequency of dosing.
False. Concentration of steady state and how quickly we achieve it are independent of frequency of dosing. Frequency affects the peaks and valleys, but not the mean (or steady state).
