Pharmacokinetics Flashcards
ADME
Absorption
Distribution
Metabolism
Excretion/Elimination
bioavailability
fraction of the administered drug enteric systemic circulation
3 types of bypass barriers to bioavailability
physical
chemical
biological
factors affecting bioavailablity
route of administration
formulation of the drug
drug characteristics like lipophilicity, molecular weight and ionization
patient characteristics like GI enzymes, pH, presence of food, hepatic metabolism
Advantages and Disadvantages of enteral administration
Advantages: Simple, self administration, painless, no infection
Disadvantages: Harsh GI environment, first pass metabolism, slow delivery to site
first pass metabolism
drug PO to GI tract
from there through capillary network to hepatic portal vein all of which is called the hepatic portal system
from there to liver that metabolizes drugs and there to general (systemic) circulation
Advantages and Disadvantages of parenteral administration
Advantages: rapid delivery, highest bioavailability, no first pass metabolism or GI environment
Disadvantages: infection, pain, poss need skilled personnel, irreversible
4 types of parenteral administration and their characteristics
SubQ: slower onset, small volumes
IM: oil based drugs
IV: reaches target organ fast, amount of drug not limited
intrathecal: reaches target organ fast, bypass BBB
Advantages and Disadvantages of mucous membrane administration
Advantages: rapid delivery, no first pass or GI environment, painless, low infection chance, direct delivery to affected tissue
disadvantages: few rx can be administered this way
Advantages and Disadvantages of transdermal administration
Advantages: convenient, prolonged continuous admin, no 1st pass or GI
Disadvantages: need highly lipophilic rx, slow delivery to site of pharmacologic action, may be irritating
characteristic of organ and tissue distribution
organs and tissues vary in capacity to take up rx and in proportion of systemic blood flow
volume of distribution definition and equation
fluid volume required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to that in the plasma at steady state
If you have 2 equal potent drugs but one is more highly distributed youll need a higher initial dose to achieve a therapeutic plasma concentration than that is less highly distributed
Vd = Dose/[Drug]plasma
plasma protein binding and how it works with drugs
drugs bind through hydrophobic and electrostatic forces
Can change how much of a drug reaches the target where the drug just stays in circulation and doesnt arrive at destination in the body
Albumin is a marker of protein in blood, if low then less bound and free concentration may be higher which can lead to toxicity if too much free/unbound
Note highly bound protein drugs could compete for binding and push each other off causing a drug interaction which could mean higher free concentration of one of the drugs
biotransformation
the key to metabolism
Drug molecules are transformed into other molecules, some are therapeutic and some are not, some could be toxic
Example: Tylenol usual metabolic pathway could be overwhelmed by alcohol and shifted into a diff pathway that leads to a toxic metabolite
Liver metabolism phase 1
transform drugs into more hydrophilic metabolites
liver metabolism phase 2
modify compounds through attaching hydrophilic groups
examples of the liver metabolism phase 1
- Add or expose polar functional groups
- Cytochrome P450 enzyme oxidations
- P450 independent oxidations
- Alcohol dehydrogenation
- Monoamine oxidase
- Hydrolysis
- Reductions
examples of the liver metabolism phase 2
- Glucuronidation
- Acetylation
- N-Methylation
- O-Methylation
Induction and inhibition in metabolism
CYP 450 enzymes can be induced or inhibited incidentally or deliberately by drugs, environmental pollutants, industrial chemicals
affects many psychotropics
BBB
i. Specialized tight junctions to prevent circ to cerebral
ii. To pass need hydrophobic or use transport proteins
iii. Could do intrathecal drug infusion
Example of plasma protein binding
Ex: valproic acid
For patients with low plasma proteins they could have total serum VPA normal but free concentration could be elevated and lead to toxicity
What contains the most metabolic enzymes of any tissue?
liver
What is the goal of liver in metabolism
to make molecules more lipophilic so they can be eliminated from the body
This is done in phase 1 and 2
p450 refers to
450 nanometer absorption peak characteristics of these heme proteins when they are treated with carbon monoxide
the metabolic pathway described in phase 1 and 2 in the liver is different for every
drug
some are subject to genetic variation or being induced or inhibited by external influences
CYP3A4 inhibitors
-azoles
grapefruit
marijuana
ritonavir
CYP3A4 inducers
carbamazepine
CYP2D6 inhibitors
fluoxetine
paroxetine
sertraline
buproprion
duloxetine
propranolol
CYP2D6 inducers
not inducible but subject to genetic polymorphisms
CYP2C19 inducers
omeprazole/PPIs
fluoxetine
fluconazole
fluvoxamine
CYP2C19 inhibitors
carbamazepine
phenytoin
st johns wort
CYP2C9 inducers
carbamazepine
phenytoin
CYP2C9 inhibitors
fluoxetine
fluconazole
marijuana
gemfibrozil
CYP1A2 inducers
smoking
phenytoin
carbamazepine
CYP1A2 inhibitors
ciprofloxacin
fluvoxamine
acyclovir
CYP 450 enzymes can be induced and inhibited incidentally or deliberately by
drugs
environmental pollutants
industrial chemicals
4 factors that affect metabolism
pharmacogenomics such as polymorphisms (CYP 45o enzymes, cholinesterase, phase 2 acetylation)
Age and sex. Note aging affects CYP 450 enzymes
Diet and environment like grapefruit juice and smoking
Disease of liver, cardiac, thyroid
drug form filtered into the renal tubule
free drug
4 major parts of renal excretion
1) Glomerular filtration
2) Tubular reabsorption
3) Tubular secretion
4) Urine
Biliary excretion is
enterohepatic circulation
drugs secreted into the bile duct enter the GI tract and may be reabsorbed into the small intestine and retained in the systemic circulation
example: oral contraception
clearance =
metabolism + excretion/(drug) plasma
clearance is
It’s the rate of elimination of the drug from the body relative to the concentration of the drug in the plasma expressed in units of volume over time
half life is
Amount of time over which drug concentration in plasma decreases
to one-half its original value
Basically the amount of drug that is metabolized/excreted in a given unit of time is directly proportional to the concentration of the drug
assuming this proportional relationship the half life of a rx is dependent on the volume of distribution and the clearance of the drug
factors that affect half life r/t distribution
aging
obesity
pathologic fluid
factors that affect half life r/t drug clearance
CYP 450 induction/inhibition
hepatic failure
cardiac failure
renal failure
steady state
when rate of drug input and output are equal
point of equilibrium between tissue distribution and plasma concentrations of the drug
affected by bioavailability, clearance and dosing interval
it takes about 4-5 half lives to achieve steady state
loading dose
Distribution causes the initial plasma drug concentration to decrease
Loading doses can be used to compensate for distribution into the tissues
Maintenance doses only need to replace the drug lost to elimination
