When treating your patients, a drug may proceed through up to 4 possible stages, what are they?
What are the 2 types of passive (aka simple) absorption used by drugs?
Utilization of each type is determined by what?
1) Filtration: through pores or channels = paracellular transport
- Determined by osmotic/hydrostatic pressure differential
2) Diffusion: through cells membranes
- Determined by concentration gradient
What type of passive absorption is most commonly utilized by drugs?
- Diffusion: through cell membranes
- Determined by concentration gradient
What are the energy and gradient requirments for passive absorption?
DON'T require energy and CAN'T proceed against gradients
What is the ratio of ionizied to unionized when pKa = pH?
Why is the active absorption/transport process of facilitated diffusion differ from other forms of active transport?
- Does NOT require energy
- Does NOT proceed against gradients
What is the total collective % of a drug in ionized and unionized forms while inside the body?
Always = 100%
How does the ionization status of a drug affects its ability to be absorbed?
- Ionized compounds have lower lipid solubility, and do not easily diffuse across lipid bi-layer of membranes
- Unionized compounds have higher lipid solubility and easily diffuse across lipid bi-layer of membranes
The ionization status of a drug in the body depends on what 2 factors?
1) pKa of the drug
2) pH of membrane-gradient/milieu
Lower the pKa the _____the acid
Which 2 important areas of the body have a lot of pH variance, which commonly impacts ionization status?
1. GI tract
When pKa=pH what is the ratio of ionized:unionized drug?
In a basic enviornment weak acids will have what type of ionization status and how will this affect their absorption?
How about in an acidic enviornment?
- Will be mostly ionized and will not easily pass through membranes
- A weakly acidic drug in an acidic environment will pass through membranes more readily than if it is in an alkaline environment
How does ionization status of a drug affects its reabsorption or elimination in the GI tract and renal tubules?
- Highly ionized drugs DO NOT readily get absorbed in GI tract or re-absorbed from renal tubules, therefore they are eliminated
- Highly unionized drugs DO readily get absorbed in GI tract or re-absorbed from renal tubules back into systemic circulation and are NOT eliminated
What are 3 characteristics of active absorption/transport?
2) Saturable: can experience competitive inhibition by other drugs
3) Movement against gradients
What does the alpha of a drug represent?
- The unbound (free) fraction of a drug
- A small alpha = large % protein bound
*Codeine is only 7% bound so its alpha = 0.93
Are drugs with high alphas more or less affected by drug-drug interaction?
- Less; not as much bound so don't have to compete
- Low protein binding, so there will be low displacement by another drug competing for binding
How do you calculate the net change of a drug-induced, bound-drug displacement?
(New % unbound - old % unbound) / (old % unbound x 100%) = absolute change
What 5 drugs are inhibitors of CYP450?
What 3 drugs are inducer's of CYP450?
What are the 3 main processes of renal elimination?
Each depends on what?
1) Passive glomerular filtration: blood flow dependent
2) Passive tubular diffusion: prox. or distal tubules
- Ionization and concentration status dependent
3) Active tubular secretion: weak acids/bases secreted into prox. tubule
What is the rate of elimination of first-order drugs?
Which value remains constant?
- Proportional to plasma concentration (Cp)
- Amount of drug removed per unit time will vary proportionately with Cp
- The percentage (fraction) of the total amount change in Cp remains constant over time
- If you start with 100 and lose 50% every hour, the amount lost will change, but it will always be a 50% loss every hour
What are the kinetic properties of zero order drugs?
What is the rate of elimination of these drugs like?
- Saturable (Vmax)
- Rate of elimination is NOT proportional to Cp; amount of drug removed per unit time stays the same over time
- The percentage (fraction) of the total amount of change in the Cp is not constant over time
*If you start with 100, and lose 10 every hour, the percent loss is changing every hour, but the amount lost will be fixed at 10
The duration of a drugs actions lies between which 2 values graphically?
Onset of action and Minumum Effective Concentration (MEC)
What is MTC?
Maximum therapeutic concentration
What is Cmin?
Minimum drug concentration
Between what 2 values does the therapeutic range reside?
Maximum therapeutic concentration (MTC) and Minimum Effective Concentration (MEC)
What is the bioavailability (F) for a drug given IV?
- Means it's 100% absorbed
Bioavailability (F) describes what about absorption?
Describes the extent of absorption, does NOT describe the rate
How is bioavailability calculated?
(AUCoral / AUCiv) x 100
What 3 factors determine the amount of drug absorbed?
2) Bioavailability (F)
3) Salt factor (S)
What must be done with Vd before using in an equation?
Must multiply by REFERENCE Vd value by body weight (in kg) to get Vd value used in equation to proper units (L)
What is the formula for IBW in both males and females?
Males: 50 kg + (2.3 kg x (height (in.) - 60 in.))
Females: 45 kg + (2.3 kg x (height (in.) - 60 in.))
How to calculate Adjusted Body Weight for individuals with an ABW of >40% of their IBW?
AdjBW = (0.4 x (ABW - IBW)) + IBW
What is clearance and the units?
Volume of blood per unit of time that is cleared of drug (L/hr)
What is Tau and the units?
- Represents the dosing interval
*q8h would have a Tau = 8*
What is the Tau value for continous infusion administration?
Tau = 1 (q1h)
What is Kel and its units?
- Elimination rate constant; percentage (fraction) of drug removed per unit of time
- Units = xhours
How many half-lives to reach steady state (Cpss)?
After reaching steady state (Cpss) how does changing the dose change the concentration of the drug?
- Double the dose then double the level
- Cut the dose by 50% then drop the level by 50%
How to calculate Creatinine Clearance (eGFR)?
[(140-age) x IBW (in kgs) / (72 x SCr)]
x0.85, if patient is female