Pharmacol Flashcards
What is clinically relevant about the concentration-effect curve?
Effect/ Log of concentration = sigmoid curve, which is essentially linear between approximately 20-80%.
Increasing concentrations above 80% max response (EC80) achieves little therapeutically, but increases the risk of adverse effects (unless there is a large therapeutic index).
In pharmacodynamics, what do “potency” and “efficacy” mean?
Potency = dose at which response occurs
EC50 = concentration at which 50% effect occurs = index of potency
The lower the dose for a given response, the greater the potency.
Ie. Drug B has the greatest potency (pic below)
Efficacy:
Maximal effect (Emax) defines the ultimate achievable response.
Emax can be achieved by a full agonist.
A full agonist has greater efficacy than a partial agonist, independent of potency.
Eg. morphine (full agonist) has greater efficacy than buprenorphine (partial agonist) = better analgesic (eg. with severe pain).
However, buprenorphine is more potent (buprenorphine 0.2mg vs morphine 10mg).
In the log dose-response curve below, Drug C is most potent, but is likely a partial agonist, and is thus less efficacious than A and C. A and C are likely full agonists and have equal efficacy, although C is more potent than A.
In pharmacodynamics, what do “Affinity” and “Intrinsic Activity” mean?
Affinity: Binds strongly to receptor
Intrinsic Activity:
- Explains the difference between magnitude of response between drugs with similar affinity
- A measure of the maximal response produced at high concentrations
eg. Agonist has high affinity and high intrinsic activity
eg. Antagonist has high affinity but no intrinsic activity
If someone is taking Drug C, what effect will co-administration of a COMPETITIVE antagonist have on potency, efficacy, and the log dose-reponse curve (attached below)?
What effect will co-administration of a NON-COMPETITIVE antagonist have?
If a COMPETITIVE antagonist (one that binds to the same Rc site) is added, this will shift the curve to the right (ie. alter the potency but not the efficacy). Ie. (C) –> (A)
If a NON-COMPETITIVE antagonist (one that binds to a different Rc site) is added, the curse will shift “down” (flatten out) – ie. decrease the efficacy.
What is the therapeutic index?
Therapeutic Index
Margin of safety between effective and toxic dose
ratio between minimum effective concentration and maximum tolerated concentration
TI = max non-toxic dose / min effective dose
= TD50/ED50
Note: bigger number always on top
What is the difference between Drug X, which has in anti-clockwise hysteresis loop, and Drug Y, which has a clockwise hysteresis loop?
Give an example of each.
Note: A hysteresis loop relates log of plasma concentration (X axis) to effect (or % of Emax – on Y axis), over time (dictated by arrows).
Drug X has an anti-clockwise hysteresis loop because there is a delay in the distribution of the drug from plasma to its site of action.
Eg. Digoxin has a distribution half-life of 6 hours and has to distribute to its site of action. Therefore it has an anti-clockwise hysteresis loop. Initially there is a low response at a high concentration in the plasma. As the drug distributes through the tissues (to its site of action) the plasma concentration decreases but response increases (to a point, then declines with declining dose).
This is also seen with drugs that have active metabolites, such as codeine. As the drug is converted to active metabolites, its own plasma concentration will fall, but the therapeutic response will increase).
Drug Y has a clockwise hysteresis loop because of TACHYPHYLAXIS.
Eg. GTN is a drug whose effect diminished with repeated / continuous administration. This is known as tachyphylaxis (it can also be called desensitiation and, over a longer period, tolerance). Initially the response increases with increasing dose, but then response declines despite increasing plasma concentration. This is the reason that drug-free intervals are needed with transdermal GTN. There are a variety of mechanisms by which this occurs.
What effect does a drop in plasma binding proteins or drug displacement from binding sites have on free drug concentration?
Basically none: Free drug concentration is dependent on free drug clearance, and does not vary in relation to changes in plasma proteins, or if there is displacement from plasma proteins.
Drug displacement from protein binding sites is almost always clinically unimportant (not a mechanism of drug interactions).
As you produce more free drug (from decreased binding) it gets cleared – so free drug concentration remains relatively stable.
The extent of protein binding is usually expressed at the fraction unbound (Fu).
Fu = unbound (free) drug concentration / total drug concentration.
With decreased binding the total concentration will decrease, the unbound concentration will stay the same, but the unbound fraction will increase in inverse proportion to the total concentration.
Eg. phenytoin binds to albumin. Binding is decreased in renal failure (displacement by organic acids, low albumin) and in the presence of competing drugs such as valproate.
Phenyotin Fu increases roughly 2-fold in renal failure.
This HALVES the therapeutic range, if measuring TOTAL drug (therapeutic range remains constant if measuring UNBOUND level).
However, the LOADING DOSE remains the same, as the unbound drug concentration is not effected.
What the primary plasma binding proteins for acidic drugs? And for basic drugs?
Binding proteins in blood are:
- Albumin (ACIDIC drugs, eg. phenytoin)
- Alpha-1 acid glycoproteins = an acute phase reactant (BASIC drugs eg. lignocaine, verapamil, propranolol)
- Lipoproteins
There is also binding to RBCs, other blood constituents, etc.
Some drugs bind strongly to particular tissue components, eg. amiodarone and chloroquine to melanin-rich tissues.
In most cases drug concentrations at therapeutic doses are well below the capacity of binding proteins.
What is the other name for LINEAR kinetics?
FIRST ORDER KINETICS / Elimination.
This means that the rate of elimination varies with plasma concentration.
- When concentration is high, the rate of elimination is high (slope of Cp/ Time is steep).
- When concentration is low, the rate of elimination is low (slope of Cp/Time is flatter), as the rate of elimination falls as plasma concentration falls.
Zero-order kinetics = constant rate of elimination (does not vary with plasma concentration).
How do you calculate ORAL BIOAVAILABILITY?
What does this mean?
F = Oral Bioavailability = Fraction of administered dose that reaches the systemic circulation.
F = AUCoral / AUCiv
where AUC (area under the curve) on the Cp/Time curve = the total amount of drug in the systemic circulation.
Note: the bioavailability of a parenterally-administered drug is assumed to be 100% (F = 1).
Oral bioavailability represents the EXTENT of absorption, but NOT the RATE.
What is the formula for calculating half life (t1/2)?
t1/2 = (0.693 x Vd) / Cl
Vd = volume of distribution
Cl = clearance (total)
How do you calculate a loading dose from the volume of distribution?
LD = Vd x Cp
LD: loading dose
Vd: volume of distribution
Cp: plasma concentration
Note: can also use to calculate an INCREMENTAL loading dose (ie. what loading dose to give when serum concentration is sub-therapeutic) - DO NOT give a full loading dose in this situation!
What is the formula for volume of distribution?
Vd = Ab / Cp
Vd = volume of distribution
Ab = total amount of drug in the body
Cp = plasma concentration
Vd is not a real volume, it is a parameter that represents the volume into which a drug appears to be distributed with a concentration equal to that in plasma.
Vd is an estimate of the extent to which a drug distributes into extravascular tissues.
What is important about fluoxetine’s effect on P450 enzymes?
Fluoxetine‘s inhibition with CYP2D6 takes weeks due to long half-life and slow generation of a CYP2D6-inhibiting metabolite.
CYP2D6 substrates:
- Tamoxifen (fluoxetine will decrease conversion to active metabolite of tamoxifen so will decrease effect).
- Codeine (decreases effect)
- Beta-blockers
- Haloperidol
- TCAs
- Venlafaxine
