Alfred consortium pharmacology Flashcards
What are the cellular transporter proteins and their functions?
- ATP-binding cassette
- Efflux (stops drugs from getting in)
- Solute-linked carrier
- Influx
Found in the proximal tubule, BBB, intestinal lumen
What are substrates of P-gp?
Dabigatran
Digoxin
Verapamil
Amiodarone
Atorvastatin
What are potent inhibitors of P-gp?
Quinidine
Verapamil
Azole
Interaction between probenecid and penicillin
Probenecid is an inibitor of OAT1 so will increase penicillin levels
What is the unit for clearance?
volume/time
(L/hour)
can also be calculated with:
CL = blood flow (volume/time) x extraction ratio (no unit)
What is the unit for dosing rate (DR)
DR = maintainence dose/dosing interval
mg/hour
Is clearance only the active drug or both active and inactive?
Clearance is only the active drug - so includes metabolic conversion but does not include renal removal of inactive metabolite
How to calculate the elimination rate?
Clearance of drug (by organ/body) x plasma drug concentration (mg/hour)
(elimination rate is dependent on the plasma drug concentration where as volume distribution is independent of that)
How to calculate the steady state?
when the maintainence dose rate is the same as the elimination rate
dose rate (at steady state) = clearance x Css (divided by bioavailability if not given IV)
With a constant dose/interval, how long does it take for the Css to be reached?
4-5 half lives
How to calculate clearance using steady state?
Use constant IV infusion until steady stae and formula Cl = DR / Css OR CL = dose / AUC (mg x hour/L)
How to calculate renal clearance?
drug filtered + drug secreted - drug reabsorption
Which phase of metabolism is CYP proteins involved in?
Phase I of 1st pass metabolism in the liver
paracetamol metabolism
Normally undergoes phase II metabolism (95% of the total excreted metabolites) to produce a nontoxic metabolite (glucoronide)
The phase I metabolism pathway (CYP) is only 5% and it can produce a nucleophilic cell macromolecules pathway
In paracetamol toxicity, the normal pathways become saturdated and the toxic metabolite is produced
How does lipid solubility affect volume of distribution?
Lipid soluble drugs will disperse more into the tissues and have a large volume of distribution
If a drug is tightly bound to proteins and not tissues, the volume of distribution is very close to blood volume
What happens when you increase the dose of a drug that has a saturable binding protein
The unbound concentration initially increases linearly with the dose
Less proportionate increase in total concentration
Fraction unbound increases
What is an example of a drug that has saturable binding protein?
Aspirin
How to calculte half life?
0.693 x Vd / CL
How much increase to the duration of action does doubling the dose affect?
Increase of 1 half life (not doubling time of action)
How to calculate oral bioavailability?
fraction absorbed x (1-hepatic extraction ratio)
OR AUC(oral)/AUC(IV)
What is Emax?
maximal effect at high concentrations (When receptors are saturated)
What is the therapeutic index
TD50/ED50
dose to reach 50% toxic effect / dose to reach 50% therapeutic effect
the bigger the better
this is different from the therapeutic window - the affectable dose window without unacceptable adverse effects
What is the difference in pharmacodynamics for competitive inhibitors and non competitive inhibitors
Competitive inhibition reduces potency
Noncompetitive inhibition reduces efficacy
How often to dose a drug?
T1/2 = 8-24hr: dosing = half life
T1/2 <8hr = slow release or if short half life with large therapeutic index can give wider dosing
T1/2 >24hr = daily dosing
What does it mean for a drug to be Cmax:MIC concentration dependent?
And what is an example of that?
That the peak concentration to MIC is the most important factor
e.g. aminoglycosides
What drugs are time>MIC dependent?
beta-lactams
What are examples of drugs which are AUC:MIC concentration dependent?
Vancomycin, fluoroquinolones, macroides, ketolides
Do inducing/inhibiting the liver metabolism enzymes affect drugs that have a high hepatic extraction ratio more or low hepatic extraction ratio?
What direction is the hysteresis graph in
1) delayed distribution?
2) acute tolerance?
1) anticlockwise
2) clockwise (essentially tachyphylaxis is the only cause of clockwise hysteresis curve)
