1 - Pharmacokinetics Flashcards
absorption
movement of the drug from site of admin to plasma
distribution
movement of hte drug from plasma to tissues
metabolism
biotransformation of the drug
excretion / elimination
movement of the drug and metabolites out of hte body
Relationship of IAV admin and absorption
IV meds do not require absorption
Other than IV meds, what admin route does not have an absorptive phase?
Any drug delivered directly to target tissues, such as an antifungal topical applied to infected tissue
What are the enteral routes of admin?
oral, sublingual, rectal
What are the parenteral routes of admin?
IV, IM, Sub-Q
Identify the types of membrane crossing
What substances can move directly through the cell membrane?
small lipid solubles
What particles can move through porous gateways in the cell membrane?
Ions or small polarized drugs
What is Fick’s law of simple diffusion?
Flux = (C1 - C2) * [(area * permeability coefficient) / (thickness)]
Fick’s law relates the factors that effect the rate of simple diffusion. Going from high concentration to low concentration, we devide the area by thickness and multiply it by a permeability coefficient.
e.g. if a small amount of medicated paste is on a small part of the skin, the surface is thin and diffusion is quick. If it is on the heel of the foot, it will diffuse slower.
What factors effect absorption?
* diffusion (see Fick’s law)
* dissolution: the rate at which a substance diffuses (e.g. from tablet form into liquid that can contact membranes)
* blood flow [more = better absorption]
* surface area for absorption [more = better absorption]
* contact time [more = better absorption]
* pH and pKa
* expression of P-glycoprotein [less = better absorption]
Most drugs are ___ acids or ____ bases.
Most drugs are weak acids or weak bases.
When are acidic drugs neutral? In what kind of solution is this most likely? If a drug is a weak acid, what are environments when it can cross a biological membrane?
Acidic drugs are in their un-ionized forms they are attached to an H+ ion. This is most likely in an acidic solution.
Acidic drugs are likely to cross the biological membrane …
pK a/b
pKa is the dissocition constant of an acid. It is the pH where:
amount ionized = amount non-ionized.
amount lipid soluble = amount water soluble
amount can move across bio-membrane = amount that can’t
When is an acidic drug with pKa of 2 able to cross the bio-membrane?
Any body area with pH below 2.
Fill
pKa/pKb chart
Is a drug with a pKb of 2 more likely to be absorbed in the stomach or small intestine? Why?
The small intestine, because it is a more basic environment.
What is a P-glycoprotein?
Where in the body is it highly epressed?
Multidrug transmembrane transporter protein that removes drugs from their absorption enviornment and decreases absorption.
It is highly expressed in the Liver, Kidneys, Placenta, Intestine, and Brain Capillaries
Describe first pass metabolism, the role of the portal vein, and consequences for a drug reaching systemic circulation.
Explain which parts of the drug intake process belong to pharmacokinetics and which parts fall under pharmacodynamics.
Which factor affects both?
What is the definition of distribution?
What factors affect distribution?
What is the volume of distribution? How is it calculated? What is it used for?
What % of the body is water? Where in the body is it located and for what portions?
Case Question for volume of distribution
Explain plasma protein binding and free drug level.
What does a drug level tell you?
Why is it significant? What should we be concerned about?
Plasma proteins can bind to drug molecules and effectively de-activate them. Only the drug molecules that are not protein bound (free drug) are able to cross the blood vessel wall and engage with tissue.
A general “drug level” includes both free and protein bound drug. It may be necessary to also test for free drug level.
This is a concern for achieving therapeutic levels and avoiding toxicity. If protein in the blood drops, this can elevate free drug levels. Another drug may compete for protein and actually displace a protein bound drug, adding to the free drug level and possibly creating toxicity.
What is the goal of metabolism? What are the metabolism pathways?
What are the outcomes of metabolism?
The goal of metabolism is to create something easier to eliminate.
What are the results of metabolism?
Explain Phase I and Phase II metabolism.
Phase I:
- Drug is converted to a more polar metabolite
- This may activate, inactivate, or decreate activity
- Phase I is carried out by the Cytochrome P450 enzymes (CYPs)
Why are cytochrome P450 enzymes significant?
Why do they differ between individuals?
What problems can be caused by these differences?
People may be rapid or slow metabolizers of drugs (e.g. opioids) due to differences in CYP enzymes.
There is a fixed number of enzymes/production and they can only accomplish so much work in a given amount of time. Enzyme production can also be activated or inhibited by drugs, effecting metabolism.
What are the red flag drugs that may be CYP enzyme inducers/inhibitors?
Describe phase II metabolism.
- What is a conjugation reaction? What does it enable?
- What is the most common conjugation reaction?
- What is notable about it for neonates?
What is the definition of elimination?
What are the three major routes?
Define clearance.
What are the three points of exit in the kidney?
Explain clearance in bile (enterohepatic recirculation).
What is the role of β-glucuronidase?
What is the involvement of antibioitics?
In the liver, a drug will be glucuronidated, allowing it to move into the intestine for excretion. However, in our intestine are flora that contain β-glucuronidase that removes the polarizing glucuronidate, making the drug non-polar and allowing it to cross the lipid barrier again, re-eintering circulation as active drug.
We rely on this with some drugs, such as estrogen/contraception, allowing us to give a lower total dose. An issue here is if an antibiotic is taken and wipes out normal flora, β-glucorindase levels drop and recirculation/levels decrease.
Explain half-life.
- Is the half-life for a drug, in a particular person, constant or variable
- How many half-lives are needed to eliminate a drug (~97% eliminated)?
4 to 5 half-lifes are the standard amount to eliminate a drug (approx. 97%).
Explain steady-state (Css).
What is the only variable in the time required to reach steady state?
Steady State (Css) is achieved when:
drug in = drug out.
dose = amount eliminated
It is achieved at approximately 4-5 half-lives.
The only variable in time required to reach Css is half-life (t 1/2)
How is the effect of changing frequency of dosing with intermittent dosing?
Does it affect Css?
What is a goal of dosing frequency for antibiotics?
For the same total dose over the same total time, the Css doesn’t change. However, by increasing the frequency and using smaller doses, the fluctuation around Css will be lessened.
With antibioitics it can actually be beneficial to have high peaks and low troughs, as this gives an increased effect of the drug (high peak) but decreased toxicity (low trough).
Key points about pharmacokinetics
Key points about drug dosing
Be familiar with this type of drug summary, may appear on exam.
